Neurology

Younger people who experience stroke or intracerebral hemorrhage have about a three- to fivefold increased risk of being diagnosed with cancer in the next few years, new research shows.

In young people, stroke might be the first manifestation of an underlying cancer, according to the investigators, led by Jamie Verhoeven, MD, PhD, with the department of neurology, Radboud University Medical Centre, Nijmegen, the Netherlands.

The new study can be viewed as a “stepping stone for future studies investigating the usefulness of screening for cancer after stroke,” the researchers say.

The study was published online in JAMA Network Open.

Currently, the diagnostic workup for young people with stroke includes searching for rare clotting disorders, although screening for cancer is not regularly performed.

Some research suggests that stroke and cancer are linked, but the literature is limited. In prior studies among people of all ages, cancer incidence after stroke has been variable – from 1% to 5% at 1 year and from 11% to 30% after 10 years.

To the team’s knowledge, only two studies have described the incidence of cancer after stroke among younger patients. One put the risk at 0.5% for people aged 18-50 years in the first year after stroke; the other described a cumulative risk of 17.3% in the 10 years after stroke for patients aged 18-55 years.

Using Dutch data, Dr. Verhoeven and colleagues identified 27,616 young stroke patients (age, 15-49 years; median age, 45 years) and 362,782 older stroke patients (median age, 76 years).

The cumulative incidence of any new cancer at 10 years was 3.7% among the younger stroke patients and 8.5% among the older stroke patients.

The incidence of a new cancer after stroke among younger patients was higher among women than men, while the opposite was true for older stroke patients.

Compared with the general population, younger stroke patients had a more than 2.5-fold greater likelihood of being diagnosed with a new cancer in the first year after ischemic stroke (standardized incidence ratio, 2.6). The risk was highest for lung cancer (SIR, 6.9), followed by hematologic cancers (SIR, 5.2).

Compared with the general population, younger stroke patients had nearly a 5.5-fold greater likelihood of being diagnosed with a new cancer in the first year after intracerebral hemorrhage (SIR, 5.4), and the risk was highest for hematologic cancers (SIR, 14.2).

In younger patients, the cumulative incidence of any cancer decreased over the years but remained significantly higher for 8 years following a stroke.

For patients aged 50 years or older, the 1-year risk for any new cancer after either ischemic stroke or intracerebral hemorrhage was 1.2 times higher, compared with the general population.

“We typically think of occult cancer as being a cause of stroke in an older population, given that the incidence of cancer increases over time [but] what this study shows is that we probably do need to consider occult cancer as an underlying cause of stroke even in a younger population,” said Laura Gioia, MD, stroke neurologist at the University of Montreal, who was not involved in the research.

Dr. Verhoeven and colleagues conclude that their finding supports the hypothesis of a causal link between cancer and stroke. Given the timing between stroke and cancer diagnosis, cancer may have been present when the stroke occurred and possibly played a role in causing it, the authors note. However, conclusions on causal mechanisms cannot be drawn from the current study.

The question of whether young stroke patients should be screened for cancer is a tough one, Dr. Gioia noted. “Cancer represents a small percentage of causes of stroke. That means you would have to screen a lot of people with a benefit that is still uncertain for the moment,” Dr. Gioia said in an interview.

“I think we need to keep cancer in mind as a cause of stroke in our young patients, and that should probably guide our history-taking with the patient and consider imaging when it’s appropriate and when we think that there could be an underlying occult cancer,” Dr. Gioia suggested.

The study was funded in part through unrestricted funding by Stryker, Medtronic, and Cerenovus. Dr. Verhoeven and Dr. Gioia have disclosed no relevant financial relationships.

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

Younger people who experience stroke or intracerebral hemorrhage have about a three- to fivefold increased risk of being diagnosed with cancer in the next few years, new research shows.

In young people, stroke might be the first manifestation of an underlying cancer, according to the investigators, led by Jamie Verhoeven, MD, PhD, with the department of neurology, Radboud University Medical Centre, Nijmegen, the Netherlands.

The new study can be viewed as a “stepping stone for future studies investigating the usefulness of screening for cancer after stroke,” the researchers say.

The study was published online in JAMA Network Open.

Currently, the diagnostic workup for young people with stroke includes searching for rare clotting disorders, although screening for cancer is not regularly performed.

Some research suggests that stroke and cancer are linked, but the literature is limited. In prior studies among people of all ages, cancer incidence after stroke has been variable – from 1% to 5% at 1 year and from 11% to 30% after 10 years.

To the team’s knowledge, only two studies have described the incidence of cancer after stroke among younger patients. One put the risk at 0.5% for people aged 18-50 years in the first year after stroke; the other described a cumulative risk of 17.3% in the 10 years after stroke for patients aged 18-55 years.

Using Dutch data, Dr. Verhoeven and colleagues identified 27,616 young stroke patients (age, 15-49 years; median age, 45 years) and 362,782 older stroke patients (median age, 76 years).

The cumulative incidence of any new cancer at 10 years was 3.7% among the younger stroke patients and 8.5% among the older stroke patients.

The incidence of a new cancer after stroke among younger patients was higher among women than men, while the opposite was true for older stroke patients.

Compared with the general population, younger stroke patients had a more than 2.5-fold greater likelihood of being diagnosed with a new cancer in the first year after ischemic stroke (standardized incidence ratio, 2.6). The risk was highest for lung cancer (SIR, 6.9), followed by hematologic cancers (SIR, 5.2).

Compared with the general population, younger stroke patients had nearly a 5.5-fold greater likelihood of being diagnosed with a new cancer in the first year after intracerebral hemorrhage (SIR, 5.4), and the risk was highest for hematologic cancers (SIR, 14.2).

In younger patients, the cumulative incidence of any cancer decreased over the years but remained significantly higher for 8 years following a stroke.

For patients aged 50 years or older, the 1-year risk for any new cancer after either ischemic stroke or intracerebral hemorrhage was 1.2 times higher, compared with the general population.

“We typically think of occult cancer as being a cause of stroke in an older population, given that the incidence of cancer increases over time [but] what this study shows is that we probably do need to consider occult cancer as an underlying cause of stroke even in a younger population,” said Laura Gioia, MD, stroke neurologist at the University of Montreal, who was not involved in the research.

Dr. Verhoeven and colleagues conclude that their finding supports the hypothesis of a causal link between cancer and stroke. Given the timing between stroke and cancer diagnosis, cancer may have been present when the stroke occurred and possibly played a role in causing it, the authors note. However, conclusions on causal mechanisms cannot be drawn from the current study.

The question of whether young stroke patients should be screened for cancer is a tough one, Dr. Gioia noted. “Cancer represents a small percentage of causes of stroke. That means you would have to screen a lot of people with a benefit that is still uncertain for the moment,” Dr. Gioia said in an interview.

“I think we need to keep cancer in mind as a cause of stroke in our young patients, and that should probably guide our history-taking with the patient and consider imaging when it’s appropriate and when we think that there could be an underlying occult cancer,” Dr. Gioia suggested.

The study was funded in part through unrestricted funding by Stryker, Medtronic, and Cerenovus. Dr. Verhoeven and Dr. Gioia have disclosed no relevant financial relationships.

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

Younger people who experience stroke or intracerebral hemorrhage have about a three- to fivefold increased risk of being diagnosed with cancer in the next few years, new research shows.

In young people, stroke might be the first manifestation of an underlying cancer, according to the investigators, led by Jamie Verhoeven, MD, PhD, with the department of neurology, Radboud University Medical Centre, Nijmegen, the Netherlands.

The new study can be viewed as a “stepping stone for future studies investigating the usefulness of screening for cancer after stroke,” the researchers say.

The study was published online in JAMA Network Open.

Currently, the diagnostic workup for young people with stroke includes searching for rare clotting disorders, although screening for cancer is not regularly performed.

Some research suggests that stroke and cancer are linked, but the literature is limited. In prior studies among people of all ages, cancer incidence after stroke has been variable – from 1% to 5% at 1 year and from 11% to 30% after 10 years.

To the team’s knowledge, only two studies have described the incidence of cancer after stroke among younger patients. One put the risk at 0.5% for people aged 18-50 years in the first year after stroke; the other described a cumulative risk of 17.3% in the 10 years after stroke for patients aged 18-55 years.

Using Dutch data, Dr. Verhoeven and colleagues identified 27,616 young stroke patients (age, 15-49 years; median age, 45 years) and 362,782 older stroke patients (median age, 76 years).

The cumulative incidence of any new cancer at 10 years was 3.7% among the younger stroke patients and 8.5% among the older stroke patients.

The incidence of a new cancer after stroke among younger patients was higher among women than men, while the opposite was true for older stroke patients.

Compared with the general population, younger stroke patients had a more than 2.5-fold greater likelihood of being diagnosed with a new cancer in the first year after ischemic stroke (standardized incidence ratio, 2.6). The risk was highest for lung cancer (SIR, 6.9), followed by hematologic cancers (SIR, 5.2).

Compared with the general population, younger stroke patients had nearly a 5.5-fold greater likelihood of being diagnosed with a new cancer in the first year after intracerebral hemorrhage (SIR, 5.4), and the risk was highest for hematologic cancers (SIR, 14.2).

In younger patients, the cumulative incidence of any cancer decreased over the years but remained significantly higher for 8 years following a stroke.

For patients aged 50 years or older, the 1-year risk for any new cancer after either ischemic stroke or intracerebral hemorrhage was 1.2 times higher, compared with the general population.

“We typically think of occult cancer as being a cause of stroke in an older population, given that the incidence of cancer increases over time [but] what this study shows is that we probably do need to consider occult cancer as an underlying cause of stroke even in a younger population,” said Laura Gioia, MD, stroke neurologist at the University of Montreal, who was not involved in the research.

Dr. Verhoeven and colleagues conclude that their finding supports the hypothesis of a causal link between cancer and stroke. Given the timing between stroke and cancer diagnosis, cancer may have been present when the stroke occurred and possibly played a role in causing it, the authors note. However, conclusions on causal mechanisms cannot be drawn from the current study.

The question of whether young stroke patients should be screened for cancer is a tough one, Dr. Gioia noted. “Cancer represents a small percentage of causes of stroke. That means you would have to screen a lot of people with a benefit that is still uncertain for the moment,” Dr. Gioia said in an interview.

“I think we need to keep cancer in mind as a cause of stroke in our young patients, and that should probably guide our history-taking with the patient and consider imaging when it’s appropriate and when we think that there could be an underlying occult cancer,” Dr. Gioia suggested.

The study was funded in part through unrestricted funding by Stryker, Medtronic, and Cerenovus. Dr. Verhoeven and Dr. Gioia have disclosed no relevant financial relationships.

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

Cluster headache and migraine have strong ties to the circadian system at multiple levels, say new findings that could have significant treatment implications.

A meta-analysis of 16 studies showed a circadian pattern in 71% of cluster headache attacks (3,490 of 4,953), with a clear circadian peak between 9:00 p.m. and 3:00 a.m.

Migraine was also associated with a circadian pattern in 50% of cases (2,698 of 5,385) across eight studies, with a clear circadian trough between 11:00 p.m. and 7:00 a.m.

Seasonal peaks were also evident for cluster headache (spring and autumn) and migraine (April to October).

“In the short term, these findings help us explain the timing to patients – for example, it is possible that a headache at 8 a.m. is due to their internal body clock instead of their pillow, or breakfast food, or morning medications,” lead investigator Mark Burish, MD, PhD, associate professor, department of neurosurgery, at University of Texas Health Houston, told this news organization.

“In the long term, these findings do suggest that medications that target the circadian system could be effective in migraine and headache patients,” Dr. Burish added.

The study was published online in Neurology.


 

Treatment implications?

Across studies, chronotype was “highly variable” for both cluster headache and migraine, the investigators report.

Cluster headache was associated with lower melatonin and higher cortisol levels, compared with non–cluster headache controls.

On a genetic level, cluster headache was associated with two core circadian genes (CLOCK and REV-ERB–alpha), and five of the nine genes that increase the likelihood of having cluster headache are genes with a circadian pattern of expression.

Migraine headache was associated with lower urinary melatonin levels and with the core circadian genes, CK1-delta and ROR-alpha, and 110 of the 168 genes associated with migraine were clock-controlled genes.

“The data suggest that both of these headache disorders are highly circadian at multiple levels, especially cluster headache,” Dr. Burish said in a release.

“This reinforces the importance of the hypothalamus – the area of the brain that houses the primary biological clock – and its role in cluster headache and migraine. It also raises the question of the genetics of triggers such as sleep changes that are known triggers for migraine and are cues for the body’s circadian rhythm,” Dr. Burish said.

“We hope that future research will look into circadian medications as a new treatment option for migraine and cluster headache patients,” Dr. Burish told this news organization.
 

Importance of sleep regulation

The authors of an accompanying editorial note that even though the study doesn’t have immediate clinical implications, it offers a better understanding of the way chronobiologic factors may influence treatment.

“At a minimum, interventions known to regulate and improve sleep (e.g., melatonin, cognitive behavioral therapy), and which are safe and straightforward to introduce, may be useful in some individuals susceptible to circadian misalignment or sleep disorders,” write Heidi Sutherland, PhD, and Lyn Griffiths, PhD, with Queensland University of Technology, Brisbane, Australia.

“Treatment of comorbidities (e.g., insomnia) that result in sleep disturbances may also help headache management. Furthermore, chronobiological aspects of any pharmacological interventions should be considered, as some frequently used headache and migraine drugs can modulate circadian cycles and influence the expression of circadian genes (e.g., verapamil), or have sleep-related side effects,” they add.

A limitation of the study was the lack of information on factors that could influence the circadian cycle, such as medications; other disorders, such as bipolar disorder; or circadian rhythm issues, such as night-shift work.

The study was supported by grants from the Japan Society for the Promotion of Science, the National Institutes of Health, The Welch Foundation, and The Will Erwin Headache Research Foundation. Dr. Burish is an unpaid member of the medical advisory board of Clusterbusters, and a site investigator for a cluster headache clinical trial funded by Lundbeck. Dr. Sutherland has received grant funding from the U.S. Migraine Research Foundation, and received institute support from Queensland University of Technology for genetics research. Dr. Griffiths has received grant funding from the Australian NHMRC, U.S. Department of Defense, and the U.S. Migraine Research Foundation, and consultancy funding from TEVA.

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

Cluster headache and migraine have strong ties to the circadian system at multiple levels, say new findings that could have significant treatment implications.

A meta-analysis of 16 studies showed a circadian pattern in 71% of cluster headache attacks (3,490 of 4,953), with a clear circadian peak between 9:00 p.m. and 3:00 a.m.

Migraine was also associated with a circadian pattern in 50% of cases (2,698 of 5,385) across eight studies, with a clear circadian trough between 11:00 p.m. and 7:00 a.m.

Seasonal peaks were also evident for cluster headache (spring and autumn) and migraine (April to October).

“In the short term, these findings help us explain the timing to patients – for example, it is possible that a headache at 8 a.m. is due to their internal body clock instead of their pillow, or breakfast food, or morning medications,” lead investigator Mark Burish, MD, PhD, associate professor, department of neurosurgery, at University of Texas Health Houston, told this news organization.

“In the long term, these findings do suggest that medications that target the circadian system could be effective in migraine and headache patients,” Dr. Burish added.

The study was published online in Neurology.


 

Treatment implications?

Across studies, chronotype was “highly variable” for both cluster headache and migraine, the investigators report.

Cluster headache was associated with lower melatonin and higher cortisol levels, compared with non–cluster headache controls.

On a genetic level, cluster headache was associated with two core circadian genes (CLOCK and REV-ERB–alpha), and five of the nine genes that increase the likelihood of having cluster headache are genes with a circadian pattern of expression.

Migraine headache was associated with lower urinary melatonin levels and with the core circadian genes, CK1-delta and ROR-alpha, and 110 of the 168 genes associated with migraine were clock-controlled genes.

“The data suggest that both of these headache disorders are highly circadian at multiple levels, especially cluster headache,” Dr. Burish said in a release.

“This reinforces the importance of the hypothalamus – the area of the brain that houses the primary biological clock – and its role in cluster headache and migraine. It also raises the question of the genetics of triggers such as sleep changes that are known triggers for migraine and are cues for the body’s circadian rhythm,” Dr. Burish said.

“We hope that future research will look into circadian medications as a new treatment option for migraine and cluster headache patients,” Dr. Burish told this news organization.
 

Importance of sleep regulation

The authors of an accompanying editorial note that even though the study doesn’t have immediate clinical implications, it offers a better understanding of the way chronobiologic factors may influence treatment.

“At a minimum, interventions known to regulate and improve sleep (e.g., melatonin, cognitive behavioral therapy), and which are safe and straightforward to introduce, may be useful in some individuals susceptible to circadian misalignment or sleep disorders,” write Heidi Sutherland, PhD, and Lyn Griffiths, PhD, with Queensland University of Technology, Brisbane, Australia.

“Treatment of comorbidities (e.g., insomnia) that result in sleep disturbances may also help headache management. Furthermore, chronobiological aspects of any pharmacological interventions should be considered, as some frequently used headache and migraine drugs can modulate circadian cycles and influence the expression of circadian genes (e.g., verapamil), or have sleep-related side effects,” they add.

A limitation of the study was the lack of information on factors that could influence the circadian cycle, such as medications; other disorders, such as bipolar disorder; or circadian rhythm issues, such as night-shift work.

The study was supported by grants from the Japan Society for the Promotion of Science, the National Institutes of Health, The Welch Foundation, and The Will Erwin Headache Research Foundation. Dr. Burish is an unpaid member of the medical advisory board of Clusterbusters, and a site investigator for a cluster headache clinical trial funded by Lundbeck. Dr. Sutherland has received grant funding from the U.S. Migraine Research Foundation, and received institute support from Queensland University of Technology for genetics research. Dr. Griffiths has received grant funding from the Australian NHMRC, U.S. Department of Defense, and the U.S. Migraine Research Foundation, and consultancy funding from TEVA.

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

Cluster headache and migraine have strong ties to the circadian system at multiple levels, say new findings that could have significant treatment implications.

A meta-analysis of 16 studies showed a circadian pattern in 71% of cluster headache attacks (3,490 of 4,953), with a clear circadian peak between 9:00 p.m. and 3:00 a.m.

Migraine was also associated with a circadian pattern in 50% of cases (2,698 of 5,385) across eight studies, with a clear circadian trough between 11:00 p.m. and 7:00 a.m.

Seasonal peaks were also evident for cluster headache (spring and autumn) and migraine (April to October).

“In the short term, these findings help us explain the timing to patients – for example, it is possible that a headache at 8 a.m. is due to their internal body clock instead of their pillow, or breakfast food, or morning medications,” lead investigator Mark Burish, MD, PhD, associate professor, department of neurosurgery, at University of Texas Health Houston, told this news organization.

“In the long term, these findings do suggest that medications that target the circadian system could be effective in migraine and headache patients,” Dr. Burish added.

The study was published online in Neurology.


 

Treatment implications?

Across studies, chronotype was “highly variable” for both cluster headache and migraine, the investigators report.

Cluster headache was associated with lower melatonin and higher cortisol levels, compared with non–cluster headache controls.

On a genetic level, cluster headache was associated with two core circadian genes (CLOCK and REV-ERB–alpha), and five of the nine genes that increase the likelihood of having cluster headache are genes with a circadian pattern of expression.

Migraine headache was associated with lower urinary melatonin levels and with the core circadian genes, CK1-delta and ROR-alpha, and 110 of the 168 genes associated with migraine were clock-controlled genes.

“The data suggest that both of these headache disorders are highly circadian at multiple levels, especially cluster headache,” Dr. Burish said in a release.

“This reinforces the importance of the hypothalamus – the area of the brain that houses the primary biological clock – and its role in cluster headache and migraine. It also raises the question of the genetics of triggers such as sleep changes that are known triggers for migraine and are cues for the body’s circadian rhythm,” Dr. Burish said.

“We hope that future research will look into circadian medications as a new treatment option for migraine and cluster headache patients,” Dr. Burish told this news organization.
 

Importance of sleep regulation

The authors of an accompanying editorial note that even though the study doesn’t have immediate clinical implications, it offers a better understanding of the way chronobiologic factors may influence treatment.

“At a minimum, interventions known to regulate and improve sleep (e.g., melatonin, cognitive behavioral therapy), and which are safe and straightforward to introduce, may be useful in some individuals susceptible to circadian misalignment or sleep disorders,” write Heidi Sutherland, PhD, and Lyn Griffiths, PhD, with Queensland University of Technology, Brisbane, Australia.

“Treatment of comorbidities (e.g., insomnia) that result in sleep disturbances may also help headache management. Furthermore, chronobiological aspects of any pharmacological interventions should be considered, as some frequently used headache and migraine drugs can modulate circadian cycles and influence the expression of circadian genes (e.g., verapamil), or have sleep-related side effects,” they add.

A limitation of the study was the lack of information on factors that could influence the circadian cycle, such as medications; other disorders, such as bipolar disorder; or circadian rhythm issues, such as night-shift work.

The study was supported by grants from the Japan Society for the Promotion of Science, the National Institutes of Health, The Welch Foundation, and The Will Erwin Headache Research Foundation. Dr. Burish is an unpaid member of the medical advisory board of Clusterbusters, and a site investigator for a cluster headache clinical trial funded by Lundbeck. Dr. Sutherland has received grant funding from the U.S. Migraine Research Foundation, and received institute support from Queensland University of Technology for genetics research. Dr. Griffiths has received grant funding from the Australian NHMRC, U.S. Department of Defense, and the U.S. Migraine Research Foundation, and consultancy funding from TEVA.

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

Ms. A, age 48, is a physician’s assistant with no psychiatric history. She presents to the emergency department (ED) with her partner and daughter due to a 15-minute episode of acute-onset memory loss and concern for stroke. In the ED, Ms. A is confused and repeatedly asks, “Where are we?” “How did we get here?” and “What day is it?” Her partner denies Ms. A has focal neurologic deficits or seizures.

Ms. A had only slept 4 hours the night before she came to the ED because she had just learned that her daughter works in the sex industry. According to her daughter, Ms. A was raped by a soldier many years ago. At that time, her perpetrator told Ms. A that he would kill her entire family if she ever told anyone. As a result, she never pursued any psychological or psychiatric treatment.

During the evaluation, Ms. A shares details regarding her social and medical history; however, she does not recall receiving bad news the night before. She asks the interviewer several times how she got to the hospital, and when a cranial nerve exam is performed, she states, “I am not the patient!”

Ms. A’s vital signs and physical exam are unremarkable. Urinalysis is significant for a ketones level of 20 mmol/L (reference range: negative for ketones), and a urine human chorionic gonadotropin test is negative. A neurologic exam does not identify any focal deficits. No imaging is performed.

Transient global amnesia (TGA) describes an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. On presentation, patients experiencing TGA repeatedly ask, “Where am I?” “What day is it?” and “How did I get here?” However, semantic memory—such as knowledge of the world and autobiographical information—is preserved.¹ The first case of TGA was described in 1956, and its diagnostic criteria were most recently modified in 1990 (Table²).

Though TGA is the most common cause of acute-onset amnesia, it is rare, affecting approximately 3 to 10 individuals per 100,000. The average age of onset is 61 to 63, with most cases occurring after age 50. TGA is generally thought to affect males and females equally, though some studies suggest a female predominance.³ In most cases (approximately 90%), there is a precipitating event such as physical or emotional stress, change in temperature, or sexual intercourse.⁴

In this article, we provide an overview of the classification, presentation, differential diagnosis, workup, and treatment of TGA. While TGA is a neurologic diagnosis, in a subset of patients it can present with psychiatric features resembling conversion disorder. For such patients, we argue that TGA can be considered a neuropsychiatric condition (Box 1^5-12). This classification may empower emergency psychiatry clinicians and psychotherapists to identify and treat the condition, which is not described by the current psychiatric diagnostic system.

Box 1

Continue to: Differential diagnosis and workup

 

 

Differential diagnosis and workup

The differential diagnosis for acute-onset memory loss in the absence of other neurologic or psychiatric features is broad. It includes:

• dissociative amnesia
• ischemic amnesia
• transient epileptic amnesia
• toxic and metabolic amnesia
• posttraumatic amnesia.

Dissociative amnesia (DA), otherwise known as psychogenic amnesia, is “an inability to recall important autobiographical information, usually of a traumatic or stressful nature, that is inconsistent with ordinary forgetting.”¹³ According to this definition, DA features only retro­grade amnesia, as opposed to TGA, which features anterograde amnesia, with possible retrograde amnesia. A subtype of DA—specifically, “continuous amnesia” or “anterograde dissociative amnesia”— is in DSM-5.¹³ However, the diagnostic criteria are unclear, and no cases have been identified in the literature since 1903, before TGA became a diagnostic entity.^5,14 Moreover, patients with DA cannot recall autobiographical information, which is not a feature of TGA. Within DSM-5, TGA is an exclusion criterion for DA.¹³ Thus, an episode of anterograde amnesia with acute onset best meets criteria for TGA, even if there are substantial psychiatric risk factors.

Ischemic amnesia—including stroke and transient ischemic attack (TIA)—is often the primary concern of patients with TGA and their families upon initial presentation, as was the case with Ms. A.^6,15 TIA presenting with isolated, acute-onset amnesia would be highly unusual, because these attacks usually present with focal symptoms including motor deficits, sensory deficits, visual field deficits, and aphasia or dysarthria. A patient with amnesia experiencing a TIA would likely have symptoms lasting from seconds to minutes, which is much shorter than a typical TGA episode.¹⁶

Amnesia secondary to stroke may be transient or permanent.⁷ Amnesia is present in approximately 1% of all strokes and in approximately 19.3% of posterior cerebral artery strokes.^7,17 Unlike TIA and TGA, ischemic amnesia would present with MRI findings detectable at symptom onset. TGA does reveal MRI findings, particularly punctate lesions in the CA1 area of the hippocampus; however, these lesions are typically much smaller than those found in stroke, and are not detectable until 12 to 48 hours after episode onset.^1,17 MRI findings in ischemic amnesia are typically associated with extrahippocampal lesions.¹⁷ Finally, the presence of vascular risk factors such as hyperlipidemia, smoking, diabetes, and hypertension may also favor a diagnosis of stroke or TIA as opposed to TGA, which is not associated with these risk factors.¹⁸ Though ischemic amnesia and TGA usually can be differentiated based on history and presentation, MRI with fluid-attenuated inversion recovery and diffusion-weighted imaging may be performed to definitively distinguish stroke from TGA.⁷

Transient epileptic amnesia (TEA), a focal form of epilepsy within the temporal lobe, should also be considered in patients who present with acute-onset amnesia. Like TGA, TEA may present with simultaneous anterograde and retrograde amnesia accompanied by repetitive questioning.¹⁹ Amnesia can be the sole symptom of TEA in up to 24% of cases. However, several key features distinguish TEA from TGA. TEA most often presents with other clinical signs of seizures, such as oral automatisms and/or olfactory hallucinations.²⁰ There is also a significant difference in episode length; TEA episodes last an average of 30 to 60 minutes and tend to occur upon wakening, whereas TGA episodes last an average of 4 to 6 hours and do not preferentially occur at any particular time.^1,21 In the interictal period—between seizures—patients with TEA may also experience accelerated long-term forgetting, autobiographical amnesia, and topographical amnesia.^19,20 Finally, a diagnosis of TEA also requires recurrent episodes. Recurrence can happen with TGA, but is less frequent.²¹ Generally, history and presentation can distinguish TEA from TGA. Though there is no formal protocol for TEA workup, Lanzone et al²¹ recommend 24-hour EEG or EEG sleep monitoring in patients who present with amnesia as well as other clinical manifestations of epileptic phenomenon.

Continue to: Toxic and metabolic

Toxic and metabolic etiologies of amnesia include opioid and cocaine use, general anesthetics,²² and hypoglycemia.^7,23 Toxic and metabolic causes of amnesia may mirror TGA in their acute onset as well as anterograde nature. However, these patients will likely present with fluctuating consciousness and/or other neuropsychiatric features, such as pressured speech, delusions, and/or distractability.²³ Obtaining a patient’s medical history, including substance use, medication use, and the presence of diabetes,²⁴ is typically sufficient to rule out toxic and metabolic causes.⁷

Posttraumatic amnesia (PTA) describes transient memory loss that occurs after a traumatic brain injury. Anterograde amnesia is most common, though approximately 20% of patients may also experience retro­grade amnesia pertaining to the events near the date of their injury. Unlike TGA, which typically resolves within 24 hours, the recovery time of amnestic symptoms in PTA ranges from minutes to years.⁷ A distinguishing feature of PTA is the presence of confusion, which often resembles a state of delirium.²⁵ The presentation of PTA can vary immensely with regards to agitation, psychotic symptoms, and the time to resolution of the amnesia. Though TGA can be distinguished from PTA based on a lack of clouding of consciousness, a case of anterograde amnesia warrants inquiry into a potential history of head injuries to rule out a traumatic cause.²⁶

Box 2^1,3,23,27-33 outlines current theories of the etiology and pathogenesis of TGA.

Box 2

Transient global ischemia: Psychiatric features

Several studies have demonstrated psychiatric precipitants, features, and comorbidities associated with TGA. Of the TGA cases associated with precipitating events, 29% to 50% are associated with an emotional stressor.^3,4 Examples of emotional stressors include a quarrel,⁴ the announcement of a birth or suicide, and a nightmare.¹⁵ For Ms. A, learning her daughter worked in the sex industry was an emotional stressor.²

During its acute phase, TGA has been shown to present with mood and anxiety symptoms.³⁴ Moreover, during episodes, patients often demonstrate features of panic attacks, such as dizziness, fainting, choking, palpitations, and paresthesia.^3,35

Continue to: Finally, patients with TGA...

Finally, patients with TGA are more likely to have psychiatric comorbidities than those without the condition. In a study of 25 patients who experienced TGA triggered by a precipitant, Inzitari et al⁴ found a strong association of TGA with phobic personality traits, including agoraphobia and simple phobic attitudes (ie, fear of traveling far from home or the sight of blood). Pantoni et al³⁵ replicated these results in 2005 and found that in comparison to patients with TIA, patients with TGA are more likely to have personal and family histories of psychiatric disease. A 2014 study by Dohring et al³⁶ found that compared to healthy controls, patients with TGA are more likely to have maladaptive coping strategies and stress responses. Patients with TGA tended to exhibit increased feelings of guilt, take more medication, and exhibit more anxiety compared to healthy controls.³⁶

Treatment: Benzodiazepines

There are no published treatment guidelines for TGA. However, in case reports, benzodiazepines (specifically lorazepam³⁷) have been shown to have utility in diagnosing and treating DA. The success of benzodiazepines is attributed to its gamma-aminobutyric acid mechanism, which involves inhibiting activity of the N-methyl-D-aspartate (NMDA) receptor, thereby reversing amnesia.³⁷ The NMDA receptor is also implicated in the stress theory of TGA. Though TGA typically resolves on its own within 24 hours, given the distressing nature of this disorder, benzodiazepines may be a suitable option to hasten memory improvement, particularly in patients with psychiatric risk factors.

However, the benzodiazepine midazolam has been identified as a precipitant of TGA. In a case report, Rinehart et al²² identified flumazenil—a benzodiazepine antagonist used primarily to treat retrograde postoperative amnesia—as an antidote. The potentially paradoxical role of benzodiazepines in both the precipitation and treatment of TGA may relate back to the heterogeneity of the etiologies of TGA. Further research comparing the treatment of TGA in patients with stress-induced TGA vs postoperative TGA is needed to better understand the neurochemical basis of TGA and work toward establishing optimal treatment options for different patient demographics.

A generally favorable prognosis

TGA carries a low risk of recurrence. In studies with 3- to 7-year follow-up periods, the recurrence rates ranged from 1.4% to 23.8%.^23,35,38

Memory impairments may be present for 5 to 6 months following a TGA episode. The severity of these impairments may range from clinically unnoticeable to the patient meeting the criteria for mild cognitive impairment.^23,39 The risk is higher in patients who have had recurrent TGA compared to those patients who have experienced only a single episode.²³

Continue to: TGA does not increase...

TGA does not increase the risk of cerebrovascular events. There is controversy regarding a potentially increased risk for dementia as well as epilepsy, though there is insufficient evidence to support these findings.^23,40

CASE CONTINUED

Five hours after the onset of Ms. A’s symptoms, the treatment team initiates oral lorazepam 1 mg. One hour after taking lorazepam, Ms. A’s anterograde and retrograde amnesia improve. She cannot recall why she was brought to the hospital but does remember the date and location, which she was not able to do on initial presentation. She feels safe, states a clear plan for self-care, and is discharged in the care of her partner. Though Ms. A’s memory improved soon after she received lorazepam, this improvement also could be attributed to the natural course of time, as TGA tends to resolve on its own within 24 hours.

Bottom Line

Transient global amnesia (TGA) is an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. It represents an interesting diagnosis at the intersection of psychiatry and neurology. TGA has many established psychiatric risk factors and features—some of which may resemble conversion disorder—but these may only apply to a particular subset of patients, which reflects the heterogeneity of the condition.

Related Resources

• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part I: pathophysiology and etiology. J Clin Med. 2022;11(12): 3373. doi:10.3390/jcm1112337
• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part II: a clinical road map. J Clin Med. 2022;11(14):3940. doi:10.3390/ jcm11143940

Drug Brand Names

Flumazenil • Romazicon
Lorazepam • Ativan
Midazolam • Versed

Ms. A, age 48, is a physician’s assistant with no psychiatric history. She presents to the emergency department (ED) with her partner and daughter due to a 15-minute episode of acute-onset memory loss and concern for stroke. In the ED, Ms. A is confused and repeatedly asks, “Where are we?” “How did we get here?” and “What day is it?” Her partner denies Ms. A has focal neurologic deficits or seizures.

Ms. A had only slept 4 hours the night before she came to the ED because she had just learned that her daughter works in the sex industry. According to her daughter, Ms. A was raped by a soldier many years ago. At that time, her perpetrator told Ms. A that he would kill her entire family if she ever told anyone. As a result, she never pursued any psychological or psychiatric treatment.

During the evaluation, Ms. A shares details regarding her social and medical history; however, she does not recall receiving bad news the night before. She asks the interviewer several times how she got to the hospital, and when a cranial nerve exam is performed, she states, “I am not the patient!”

Ms. A’s vital signs and physical exam are unremarkable. Urinalysis is significant for a ketones level of 20 mmol/L (reference range: negative for ketones), and a urine human chorionic gonadotropin test is negative. A neurologic exam does not identify any focal deficits. No imaging is performed.

Transient global amnesia (TGA) describes an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. On presentation, patients experiencing TGA repeatedly ask, “Where am I?” “What day is it?” and “How did I get here?” However, semantic memory—such as knowledge of the world and autobiographical information—is preserved.¹ The first case of TGA was described in 1956, and its diagnostic criteria were most recently modified in 1990 (Table²).

Though TGA is the most common cause of acute-onset amnesia, it is rare, affecting approximately 3 to 10 individuals per 100,000. The average age of onset is 61 to 63, with most cases occurring after age 50. TGA is generally thought to affect males and females equally, though some studies suggest a female predominance.³ In most cases (approximately 90%), there is a precipitating event such as physical or emotional stress, change in temperature, or sexual intercourse.⁴

In this article, we provide an overview of the classification, presentation, differential diagnosis, workup, and treatment of TGA. While TGA is a neurologic diagnosis, in a subset of patients it can present with psychiatric features resembling conversion disorder. For such patients, we argue that TGA can be considered a neuropsychiatric condition (Box 1^5-12). This classification may empower emergency psychiatry clinicians and psychotherapists to identify and treat the condition, which is not described by the current psychiatric diagnostic system.

Box 1

Continue to: Differential diagnosis and workup

 

 

Differential diagnosis and workup

The differential diagnosis for acute-onset memory loss in the absence of other neurologic or psychiatric features is broad. It includes:

• dissociative amnesia
• ischemic amnesia
• transient epileptic amnesia
• toxic and metabolic amnesia
• posttraumatic amnesia.

Dissociative amnesia (DA), otherwise known as psychogenic amnesia, is “an inability to recall important autobiographical information, usually of a traumatic or stressful nature, that is inconsistent with ordinary forgetting.”¹³ According to this definition, DA features only retro­grade amnesia, as opposed to TGA, which features anterograde amnesia, with possible retrograde amnesia. A subtype of DA—specifically, “continuous amnesia” or “anterograde dissociative amnesia”— is in DSM-5.¹³ However, the diagnostic criteria are unclear, and no cases have been identified in the literature since 1903, before TGA became a diagnostic entity.^5,14 Moreover, patients with DA cannot recall autobiographical information, which is not a feature of TGA. Within DSM-5, TGA is an exclusion criterion for DA.¹³ Thus, an episode of anterograde amnesia with acute onset best meets criteria for TGA, even if there are substantial psychiatric risk factors.

Ischemic amnesia—including stroke and transient ischemic attack (TIA)—is often the primary concern of patients with TGA and their families upon initial presentation, as was the case with Ms. A.^6,15 TIA presenting with isolated, acute-onset amnesia would be highly unusual, because these attacks usually present with focal symptoms including motor deficits, sensory deficits, visual field deficits, and aphasia or dysarthria. A patient with amnesia experiencing a TIA would likely have symptoms lasting from seconds to minutes, which is much shorter than a typical TGA episode.¹⁶

Amnesia secondary to stroke may be transient or permanent.⁷ Amnesia is present in approximately 1% of all strokes and in approximately 19.3% of posterior cerebral artery strokes.^7,17 Unlike TIA and TGA, ischemic amnesia would present with MRI findings detectable at symptom onset. TGA does reveal MRI findings, particularly punctate lesions in the CA1 area of the hippocampus; however, these lesions are typically much smaller than those found in stroke, and are not detectable until 12 to 48 hours after episode onset.^1,17 MRI findings in ischemic amnesia are typically associated with extrahippocampal lesions.¹⁷ Finally, the presence of vascular risk factors such as hyperlipidemia, smoking, diabetes, and hypertension may also favor a diagnosis of stroke or TIA as opposed to TGA, which is not associated with these risk factors.¹⁸ Though ischemic amnesia and TGA usually can be differentiated based on history and presentation, MRI with fluid-attenuated inversion recovery and diffusion-weighted imaging may be performed to definitively distinguish stroke from TGA.⁷

Transient epileptic amnesia (TEA), a focal form of epilepsy within the temporal lobe, should also be considered in patients who present with acute-onset amnesia. Like TGA, TEA may present with simultaneous anterograde and retrograde amnesia accompanied by repetitive questioning.¹⁹ Amnesia can be the sole symptom of TEA in up to 24% of cases. However, several key features distinguish TEA from TGA. TEA most often presents with other clinical signs of seizures, such as oral automatisms and/or olfactory hallucinations.²⁰ There is also a significant difference in episode length; TEA episodes last an average of 30 to 60 minutes and tend to occur upon wakening, whereas TGA episodes last an average of 4 to 6 hours and do not preferentially occur at any particular time.^1,21 In the interictal period—between seizures—patients with TEA may also experience accelerated long-term forgetting, autobiographical amnesia, and topographical amnesia.^19,20 Finally, a diagnosis of TEA also requires recurrent episodes. Recurrence can happen with TGA, but is less frequent.²¹ Generally, history and presentation can distinguish TEA from TGA. Though there is no formal protocol for TEA workup, Lanzone et al²¹ recommend 24-hour EEG or EEG sleep monitoring in patients who present with amnesia as well as other clinical manifestations of epileptic phenomenon.

Continue to: Toxic and metabolic

Toxic and metabolic etiologies of amnesia include opioid and cocaine use, general anesthetics,²² and hypoglycemia.^7,23 Toxic and metabolic causes of amnesia may mirror TGA in their acute onset as well as anterograde nature. However, these patients will likely present with fluctuating consciousness and/or other neuropsychiatric features, such as pressured speech, delusions, and/or distractability.²³ Obtaining a patient’s medical history, including substance use, medication use, and the presence of diabetes,²⁴ is typically sufficient to rule out toxic and metabolic causes.⁷

Posttraumatic amnesia (PTA) describes transient memory loss that occurs after a traumatic brain injury. Anterograde amnesia is most common, though approximately 20% of patients may also experience retro­grade amnesia pertaining to the events near the date of their injury. Unlike TGA, which typically resolves within 24 hours, the recovery time of amnestic symptoms in PTA ranges from minutes to years.⁷ A distinguishing feature of PTA is the presence of confusion, which often resembles a state of delirium.²⁵ The presentation of PTA can vary immensely with regards to agitation, psychotic symptoms, and the time to resolution of the amnesia. Though TGA can be distinguished from PTA based on a lack of clouding of consciousness, a case of anterograde amnesia warrants inquiry into a potential history of head injuries to rule out a traumatic cause.²⁶

Box 2^1,3,23,27-33 outlines current theories of the etiology and pathogenesis of TGA.

Box 2

Transient global ischemia: Psychiatric features

Several studies have demonstrated psychiatric precipitants, features, and comorbidities associated with TGA. Of the TGA cases associated with precipitating events, 29% to 50% are associated with an emotional stressor.^3,4 Examples of emotional stressors include a quarrel,⁴ the announcement of a birth or suicide, and a nightmare.¹⁵ For Ms. A, learning her daughter worked in the sex industry was an emotional stressor.²

During its acute phase, TGA has been shown to present with mood and anxiety symptoms.³⁴ Moreover, during episodes, patients often demonstrate features of panic attacks, such as dizziness, fainting, choking, palpitations, and paresthesia.^3,35

Continue to: Finally, patients with TGA...

Finally, patients with TGA are more likely to have psychiatric comorbidities than those without the condition. In a study of 25 patients who experienced TGA triggered by a precipitant, Inzitari et al⁴ found a strong association of TGA with phobic personality traits, including agoraphobia and simple phobic attitudes (ie, fear of traveling far from home or the sight of blood). Pantoni et al³⁵ replicated these results in 2005 and found that in comparison to patients with TIA, patients with TGA are more likely to have personal and family histories of psychiatric disease. A 2014 study by Dohring et al³⁶ found that compared to healthy controls, patients with TGA are more likely to have maladaptive coping strategies and stress responses. Patients with TGA tended to exhibit increased feelings of guilt, take more medication, and exhibit more anxiety compared to healthy controls.³⁶

Treatment: Benzodiazepines

There are no published treatment guidelines for TGA. However, in case reports, benzodiazepines (specifically lorazepam³⁷) have been shown to have utility in diagnosing and treating DA. The success of benzodiazepines is attributed to its gamma-aminobutyric acid mechanism, which involves inhibiting activity of the N-methyl-D-aspartate (NMDA) receptor, thereby reversing amnesia.³⁷ The NMDA receptor is also implicated in the stress theory of TGA. Though TGA typically resolves on its own within 24 hours, given the distressing nature of this disorder, benzodiazepines may be a suitable option to hasten memory improvement, particularly in patients with psychiatric risk factors.

However, the benzodiazepine midazolam has been identified as a precipitant of TGA. In a case report, Rinehart et al²² identified flumazenil—a benzodiazepine antagonist used primarily to treat retrograde postoperative amnesia—as an antidote. The potentially paradoxical role of benzodiazepines in both the precipitation and treatment of TGA may relate back to the heterogeneity of the etiologies of TGA. Further research comparing the treatment of TGA in patients with stress-induced TGA vs postoperative TGA is needed to better understand the neurochemical basis of TGA and work toward establishing optimal treatment options for different patient demographics.

A generally favorable prognosis

TGA carries a low risk of recurrence. In studies with 3- to 7-year follow-up periods, the recurrence rates ranged from 1.4% to 23.8%.^23,35,38

Memory impairments may be present for 5 to 6 months following a TGA episode. The severity of these impairments may range from clinically unnoticeable to the patient meeting the criteria for mild cognitive impairment.^23,39 The risk is higher in patients who have had recurrent TGA compared to those patients who have experienced only a single episode.²³

Continue to: TGA does not increase...

TGA does not increase the risk of cerebrovascular events. There is controversy regarding a potentially increased risk for dementia as well as epilepsy, though there is insufficient evidence to support these findings.^23,40

CASE CONTINUED

Five hours after the onset of Ms. A’s symptoms, the treatment team initiates oral lorazepam 1 mg. One hour after taking lorazepam, Ms. A’s anterograde and retrograde amnesia improve. She cannot recall why she was brought to the hospital but does remember the date and location, which she was not able to do on initial presentation. She feels safe, states a clear plan for self-care, and is discharged in the care of her partner. Though Ms. A’s memory improved soon after she received lorazepam, this improvement also could be attributed to the natural course of time, as TGA tends to resolve on its own within 24 hours.

Bottom Line

Transient global amnesia (TGA) is an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. It represents an interesting diagnosis at the intersection of psychiatry and neurology. TGA has many established psychiatric risk factors and features—some of which may resemble conversion disorder—but these may only apply to a particular subset of patients, which reflects the heterogeneity of the condition.

Related Resources

• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part I: pathophysiology and etiology. J Clin Med. 2022;11(12): 3373. doi:10.3390/jcm1112337
• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part II: a clinical road map. J Clin Med. 2022;11(14):3940. doi:10.3390/ jcm11143940

Drug Brand Names

Flumazenil • Romazicon
Lorazepam • Ativan
Midazolam • Versed

Ms. A, age 48, is a physician’s assistant with no psychiatric history. She presents to the emergency department (ED) with her partner and daughter due to a 15-minute episode of acute-onset memory loss and concern for stroke. In the ED, Ms. A is confused and repeatedly asks, “Where are we?” “How did we get here?” and “What day is it?” Her partner denies Ms. A has focal neurologic deficits or seizures.

Ms. A had only slept 4 hours the night before she came to the ED because she had just learned that her daughter works in the sex industry. According to her daughter, Ms. A was raped by a soldier many years ago. At that time, her perpetrator told Ms. A that he would kill her entire family if she ever told anyone. As a result, she never pursued any psychological or psychiatric treatment.

During the evaluation, Ms. A shares details regarding her social and medical history; however, she does not recall receiving bad news the night before. She asks the interviewer several times how she got to the hospital, and when a cranial nerve exam is performed, she states, “I am not the patient!”

Ms. A’s vital signs and physical exam are unremarkable. Urinalysis is significant for a ketones level of 20 mmol/L (reference range: negative for ketones), and a urine human chorionic gonadotropin test is negative. A neurologic exam does not identify any focal deficits. No imaging is performed.

Transient global amnesia (TGA) describes an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. On presentation, patients experiencing TGA repeatedly ask, “Where am I?” “What day is it?” and “How did I get here?” However, semantic memory—such as knowledge of the world and autobiographical information—is preserved.¹ The first case of TGA was described in 1956, and its diagnostic criteria were most recently modified in 1990 (Table²).

Though TGA is the most common cause of acute-onset amnesia, it is rare, affecting approximately 3 to 10 individuals per 100,000. The average age of onset is 61 to 63, with most cases occurring after age 50. TGA is generally thought to affect males and females equally, though some studies suggest a female predominance.³ In most cases (approximately 90%), there is a precipitating event such as physical or emotional stress, change in temperature, or sexual intercourse.⁴

In this article, we provide an overview of the classification, presentation, differential diagnosis, workup, and treatment of TGA. While TGA is a neurologic diagnosis, in a subset of patients it can present with psychiatric features resembling conversion disorder. For such patients, we argue that TGA can be considered a neuropsychiatric condition (Box 1^5-12). This classification may empower emergency psychiatry clinicians and psychotherapists to identify and treat the condition, which is not described by the current psychiatric diagnostic system.

Box 1

Continue to: Differential diagnosis and workup

 

 

Differential diagnosis and workup

The differential diagnosis for acute-onset memory loss in the absence of other neurologic or psychiatric features is broad. It includes:

• dissociative amnesia
• ischemic amnesia
• transient epileptic amnesia
• toxic and metabolic amnesia
• posttraumatic amnesia.

Dissociative amnesia (DA), otherwise known as psychogenic amnesia, is “an inability to recall important autobiographical information, usually of a traumatic or stressful nature, that is inconsistent with ordinary forgetting.”¹³ According to this definition, DA features only retro­grade amnesia, as opposed to TGA, which features anterograde amnesia, with possible retrograde amnesia. A subtype of DA—specifically, “continuous amnesia” or “anterograde dissociative amnesia”— is in DSM-5.¹³ However, the diagnostic criteria are unclear, and no cases have been identified in the literature since 1903, before TGA became a diagnostic entity.^5,14 Moreover, patients with DA cannot recall autobiographical information, which is not a feature of TGA. Within DSM-5, TGA is an exclusion criterion for DA.¹³ Thus, an episode of anterograde amnesia with acute onset best meets criteria for TGA, even if there are substantial psychiatric risk factors.

Ischemic amnesia—including stroke and transient ischemic attack (TIA)—is often the primary concern of patients with TGA and their families upon initial presentation, as was the case with Ms. A.^6,15 TIA presenting with isolated, acute-onset amnesia would be highly unusual, because these attacks usually present with focal symptoms including motor deficits, sensory deficits, visual field deficits, and aphasia or dysarthria. A patient with amnesia experiencing a TIA would likely have symptoms lasting from seconds to minutes, which is much shorter than a typical TGA episode.¹⁶

Amnesia secondary to stroke may be transient or permanent.⁷ Amnesia is present in approximately 1% of all strokes and in approximately 19.3% of posterior cerebral artery strokes.^7,17 Unlike TIA and TGA, ischemic amnesia would present with MRI findings detectable at symptom onset. TGA does reveal MRI findings, particularly punctate lesions in the CA1 area of the hippocampus; however, these lesions are typically much smaller than those found in stroke, and are not detectable until 12 to 48 hours after episode onset.^1,17 MRI findings in ischemic amnesia are typically associated with extrahippocampal lesions.¹⁷ Finally, the presence of vascular risk factors such as hyperlipidemia, smoking, diabetes, and hypertension may also favor a diagnosis of stroke or TIA as opposed to TGA, which is not associated with these risk factors.¹⁸ Though ischemic amnesia and TGA usually can be differentiated based on history and presentation, MRI with fluid-attenuated inversion recovery and diffusion-weighted imaging may be performed to definitively distinguish stroke from TGA.⁷

Transient epileptic amnesia (TEA), a focal form of epilepsy within the temporal lobe, should also be considered in patients who present with acute-onset amnesia. Like TGA, TEA may present with simultaneous anterograde and retrograde amnesia accompanied by repetitive questioning.¹⁹ Amnesia can be the sole symptom of TEA in up to 24% of cases. However, several key features distinguish TEA from TGA. TEA most often presents with other clinical signs of seizures, such as oral automatisms and/or olfactory hallucinations.²⁰ There is also a significant difference in episode length; TEA episodes last an average of 30 to 60 minutes and tend to occur upon wakening, whereas TGA episodes last an average of 4 to 6 hours and do not preferentially occur at any particular time.^1,21 In the interictal period—between seizures—patients with TEA may also experience accelerated long-term forgetting, autobiographical amnesia, and topographical amnesia.^19,20 Finally, a diagnosis of TEA also requires recurrent episodes. Recurrence can happen with TGA, but is less frequent.²¹ Generally, history and presentation can distinguish TEA from TGA. Though there is no formal protocol for TEA workup, Lanzone et al²¹ recommend 24-hour EEG or EEG sleep monitoring in patients who present with amnesia as well as other clinical manifestations of epileptic phenomenon.

Continue to: Toxic and metabolic

Toxic and metabolic etiologies of amnesia include opioid and cocaine use, general anesthetics,²² and hypoglycemia.^7,23 Toxic and metabolic causes of amnesia may mirror TGA in their acute onset as well as anterograde nature. However, these patients will likely present with fluctuating consciousness and/or other neuropsychiatric features, such as pressured speech, delusions, and/or distractability.²³ Obtaining a patient’s medical history, including substance use, medication use, and the presence of diabetes,²⁴ is typically sufficient to rule out toxic and metabolic causes.⁷

Posttraumatic amnesia (PTA) describes transient memory loss that occurs after a traumatic brain injury. Anterograde amnesia is most common, though approximately 20% of patients may also experience retro­grade amnesia pertaining to the events near the date of their injury. Unlike TGA, which typically resolves within 24 hours, the recovery time of amnestic symptoms in PTA ranges from minutes to years.⁷ A distinguishing feature of PTA is the presence of confusion, which often resembles a state of delirium.²⁵ The presentation of PTA can vary immensely with regards to agitation, psychotic symptoms, and the time to resolution of the amnesia. Though TGA can be distinguished from PTA based on a lack of clouding of consciousness, a case of anterograde amnesia warrants inquiry into a potential history of head injuries to rule out a traumatic cause.²⁶

Box 2^1,3,23,27-33 outlines current theories of the etiology and pathogenesis of TGA.

Box 2

Transient global ischemia: Psychiatric features

Several studies have demonstrated psychiatric precipitants, features, and comorbidities associated with TGA. Of the TGA cases associated with precipitating events, 29% to 50% are associated with an emotional stressor.^3,4 Examples of emotional stressors include a quarrel,⁴ the announcement of a birth or suicide, and a nightmare.¹⁵ For Ms. A, learning her daughter worked in the sex industry was an emotional stressor.²

During its acute phase, TGA has been shown to present with mood and anxiety symptoms.³⁴ Moreover, during episodes, patients often demonstrate features of panic attacks, such as dizziness, fainting, choking, palpitations, and paresthesia.^3,35

Continue to: Finally, patients with TGA...

Finally, patients with TGA are more likely to have psychiatric comorbidities than those without the condition. In a study of 25 patients who experienced TGA triggered by a precipitant, Inzitari et al⁴ found a strong association of TGA with phobic personality traits, including agoraphobia and simple phobic attitudes (ie, fear of traveling far from home or the sight of blood). Pantoni et al³⁵ replicated these results in 2005 and found that in comparison to patients with TIA, patients with TGA are more likely to have personal and family histories of psychiatric disease. A 2014 study by Dohring et al³⁶ found that compared to healthy controls, patients with TGA are more likely to have maladaptive coping strategies and stress responses. Patients with TGA tended to exhibit increased feelings of guilt, take more medication, and exhibit more anxiety compared to healthy controls.³⁶

Treatment: Benzodiazepines

There are no published treatment guidelines for TGA. However, in case reports, benzodiazepines (specifically lorazepam³⁷) have been shown to have utility in diagnosing and treating DA. The success of benzodiazepines is attributed to its gamma-aminobutyric acid mechanism, which involves inhibiting activity of the N-methyl-D-aspartate (NMDA) receptor, thereby reversing amnesia.³⁷ The NMDA receptor is also implicated in the stress theory of TGA. Though TGA typically resolves on its own within 24 hours, given the distressing nature of this disorder, benzodiazepines may be a suitable option to hasten memory improvement, particularly in patients with psychiatric risk factors.

However, the benzodiazepine midazolam has been identified as a precipitant of TGA. In a case report, Rinehart et al²² identified flumazenil—a benzodiazepine antagonist used primarily to treat retrograde postoperative amnesia—as an antidote. The potentially paradoxical role of benzodiazepines in both the precipitation and treatment of TGA may relate back to the heterogeneity of the etiologies of TGA. Further research comparing the treatment of TGA in patients with stress-induced TGA vs postoperative TGA is needed to better understand the neurochemical basis of TGA and work toward establishing optimal treatment options for different patient demographics.

A generally favorable prognosis

TGA carries a low risk of recurrence. In studies with 3- to 7-year follow-up periods, the recurrence rates ranged from 1.4% to 23.8%.^23,35,38

Memory impairments may be present for 5 to 6 months following a TGA episode. The severity of these impairments may range from clinically unnoticeable to the patient meeting the criteria for mild cognitive impairment.^23,39 The risk is higher in patients who have had recurrent TGA compared to those patients who have experienced only a single episode.²³

Continue to: TGA does not increase...

TGA does not increase the risk of cerebrovascular events. There is controversy regarding a potentially increased risk for dementia as well as epilepsy, though there is insufficient evidence to support these findings.^23,40

CASE CONTINUED

Five hours after the onset of Ms. A’s symptoms, the treatment team initiates oral lorazepam 1 mg. One hour after taking lorazepam, Ms. A’s anterograde and retrograde amnesia improve. She cannot recall why she was brought to the hospital but does remember the date and location, which she was not able to do on initial presentation. She feels safe, states a clear plan for self-care, and is discharged in the care of her partner. Though Ms. A’s memory improved soon after she received lorazepam, this improvement also could be attributed to the natural course of time, as TGA tends to resolve on its own within 24 hours.

Bottom Line

Transient global amnesia (TGA) is an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. It represents an interesting diagnosis at the intersection of psychiatry and neurology. TGA has many established psychiatric risk factors and features—some of which may resemble conversion disorder—but these may only apply to a particular subset of patients, which reflects the heterogeneity of the condition.

Related Resources

• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part I: pathophysiology and etiology. J Clin Med. 2022;11(12): 3373. doi:10.3390/jcm1112337
• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part II: a clinical road map. J Clin Med. 2022;11(14):3940. doi:10.3390/ jcm11143940

Drug Brand Names

Flumazenil • Romazicon
Lorazepam • Ativan
Midazolam • Versed

Increasing intake of folate and vitamin B6 beyond recommended daily levels offers no protective benefit against Parkinson’s disease (PD), a new study shows.

Though there was some evidence that vitamin B12 early in life was associated with decreased PD risk, the findings were inconsistent and were observed only in people whose daily intake was 10 times the recommended level.

“The results of this large prospective study do not support the hypothesis that increasing folate or vitamin B6 intakes above the current levels would reduce PD risk in this population of mostly White U.S. health professionals,” lead investigator Mario H. Flores-Torres, MD, PhD, a research scientist in the department of nutrition at the Harvard T.H. Chan School of Public Health, Boston, said in an interview.

However, he added, the study “leaves open the possibility that in some individuals the intake of vitamin B12 contributes to PD risk – a finding that warrants further research.”

The findings were published online  in Movement Disorders.
 

Mixed findings

Previous studies have suggested B vitamins – including folate, B6 and B12 – might affect PD risk, but results have been mixed.

The new study included 80,965 women from the Nurses’ Health Study (1984-2016) and 48,837 men from the Health Professionals Follow-up Study (1986-2016). The average age at baseline was 50 years in women and 54 years in men, and participants were followed for about 30 years.

Participants completed questionnaires about diet at the beginning of the study and again every 4 years.

To account for the possibility of reverse causation due to the long prodromal phase of PD, investigators conducted lagged analyses at 8, 12, 16, and 20 years.

During the follow-up period, 1,426 incident cases of PD were diagnosed (687 in women and 739 in men).

Researchers found no link between reduced PD risk and intake of vitamin B6 or folate.

Though the total cumulative average intake of vitamin B12 was not associated with PD risk, investigators noted a modest decrease in risk between those with highest baseline of B12 and participants with the lowest baseline levels (hazard ratio, 0.80; P = .01).

Individuals in the highest quintile of B12 intake at baseline had an average intake of 21-22 mcg/d, close to 10 times the recommended daily intake of 2.4 mcg/d.

“Although some of our results suggest that a higher intake of vitamin B12 may decrease the risk of PD in a population of U.S. health professionals, the associations we observed were modest and not entirely consistent,” Dr. Flores-Torres said.

“Additional studies need to confirm our findings to better understand whether people who take higher amounts of B12 younger in life may have a protective benefit against PD,” he added.
 

The whole picture?

Commenting on the findings for this article, Rebecca Gilbert, MD, PhD, chief scientific officer of the American Parkinson Disease Association, New York, noted that checking B vitamin levels is a fairly standard practice for most clinicians. In that regard, this study highlights why this is important.

“Neurologists will often test B12 levels and recommend a supplement if your level is below the normal range,” she said. “No one is questioning the value of B12 for nerves and recommend that B12 is in the normal to high normal range.”

But understanding how B vitamins may or may not affect PD risk might require a different kind of study.

“This analysis, much like many others, is trying so hard to figure out what is it in diets that affects Parkinson’s disease risk,” Dr. Gilbert said. “But we have yet to say these are the nutrients that prevent Parkinson’s or increase the risk.”

One reason for the conflicting results in studies such as this could be that the explanation for the link between diet and PD risk may not be in specific minerals consumed but rather in the diet as a whole.

“Focusing on specific elements of a diet may not give us the answer,” Dr. Gilbert said. “We should be analyzing diet as a complete holistic picture because it’s not just the elements but how everything in what we eat works together.”

The study was funded by the National Institutes of Health and the Parkinson’s Foundation. Dr. Flores-Torres and Dr. Gilbert report no relevant conflicts.
 

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

Increasing intake of folate and vitamin B6 beyond recommended daily levels offers no protective benefit against Parkinson’s disease (PD), a new study shows.

Though there was some evidence that vitamin B12 early in life was associated with decreased PD risk, the findings were inconsistent and were observed only in people whose daily intake was 10 times the recommended level.

“The results of this large prospective study do not support the hypothesis that increasing folate or vitamin B6 intakes above the current levels would reduce PD risk in this population of mostly White U.S. health professionals,” lead investigator Mario H. Flores-Torres, MD, PhD, a research scientist in the department of nutrition at the Harvard T.H. Chan School of Public Health, Boston, said in an interview.

However, he added, the study “leaves open the possibility that in some individuals the intake of vitamin B12 contributes to PD risk – a finding that warrants further research.”

The findings were published online  in Movement Disorders.
 

Mixed findings

Previous studies have suggested B vitamins – including folate, B6 and B12 – might affect PD risk, but results have been mixed.

The new study included 80,965 women from the Nurses’ Health Study (1984-2016) and 48,837 men from the Health Professionals Follow-up Study (1986-2016). The average age at baseline was 50 years in women and 54 years in men, and participants were followed for about 30 years.

Participants completed questionnaires about diet at the beginning of the study and again every 4 years.

To account for the possibility of reverse causation due to the long prodromal phase of PD, investigators conducted lagged analyses at 8, 12, 16, and 20 years.

During the follow-up period, 1,426 incident cases of PD were diagnosed (687 in women and 739 in men).

Researchers found no link between reduced PD risk and intake of vitamin B6 or folate.

Though the total cumulative average intake of vitamin B12 was not associated with PD risk, investigators noted a modest decrease in risk between those with highest baseline of B12 and participants with the lowest baseline levels (hazard ratio, 0.80; P = .01).

Individuals in the highest quintile of B12 intake at baseline had an average intake of 21-22 mcg/d, close to 10 times the recommended daily intake of 2.4 mcg/d.

“Although some of our results suggest that a higher intake of vitamin B12 may decrease the risk of PD in a population of U.S. health professionals, the associations we observed were modest and not entirely consistent,” Dr. Flores-Torres said.

“Additional studies need to confirm our findings to better understand whether people who take higher amounts of B12 younger in life may have a protective benefit against PD,” he added.
 

The whole picture?

Commenting on the findings for this article, Rebecca Gilbert, MD, PhD, chief scientific officer of the American Parkinson Disease Association, New York, noted that checking B vitamin levels is a fairly standard practice for most clinicians. In that regard, this study highlights why this is important.

“Neurologists will often test B12 levels and recommend a supplement if your level is below the normal range,” she said. “No one is questioning the value of B12 for nerves and recommend that B12 is in the normal to high normal range.”

But understanding how B vitamins may or may not affect PD risk might require a different kind of study.

“This analysis, much like many others, is trying so hard to figure out what is it in diets that affects Parkinson’s disease risk,” Dr. Gilbert said. “But we have yet to say these are the nutrients that prevent Parkinson’s or increase the risk.”

One reason for the conflicting results in studies such as this could be that the explanation for the link between diet and PD risk may not be in specific minerals consumed but rather in the diet as a whole.

“Focusing on specific elements of a diet may not give us the answer,” Dr. Gilbert said. “We should be analyzing diet as a complete holistic picture because it’s not just the elements but how everything in what we eat works together.”

The study was funded by the National Institutes of Health and the Parkinson’s Foundation. Dr. Flores-Torres and Dr. Gilbert report no relevant conflicts.
 

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

Increasing intake of folate and vitamin B6 beyond recommended daily levels offers no protective benefit against Parkinson’s disease (PD), a new study shows.

Though there was some evidence that vitamin B12 early in life was associated with decreased PD risk, the findings were inconsistent and were observed only in people whose daily intake was 10 times the recommended level.

“The results of this large prospective study do not support the hypothesis that increasing folate or vitamin B6 intakes above the current levels would reduce PD risk in this population of mostly White U.S. health professionals,” lead investigator Mario H. Flores-Torres, MD, PhD, a research scientist in the department of nutrition at the Harvard T.H. Chan School of Public Health, Boston, said in an interview.

However, he added, the study “leaves open the possibility that in some individuals the intake of vitamin B12 contributes to PD risk – a finding that warrants further research.”

The findings were published online  in Movement Disorders.
 

Mixed findings

Previous studies have suggested B vitamins – including folate, B6 and B12 – might affect PD risk, but results have been mixed.

The new study included 80,965 women from the Nurses’ Health Study (1984-2016) and 48,837 men from the Health Professionals Follow-up Study (1986-2016). The average age at baseline was 50 years in women and 54 years in men, and participants were followed for about 30 years.

Participants completed questionnaires about diet at the beginning of the study and again every 4 years.

To account for the possibility of reverse causation due to the long prodromal phase of PD, investigators conducted lagged analyses at 8, 12, 16, and 20 years.

During the follow-up period, 1,426 incident cases of PD were diagnosed (687 in women and 739 in men).

Researchers found no link between reduced PD risk and intake of vitamin B6 or folate.

Though the total cumulative average intake of vitamin B12 was not associated with PD risk, investigators noted a modest decrease in risk between those with highest baseline of B12 and participants with the lowest baseline levels (hazard ratio, 0.80; P = .01).

Individuals in the highest quintile of B12 intake at baseline had an average intake of 21-22 mcg/d, close to 10 times the recommended daily intake of 2.4 mcg/d.

“Although some of our results suggest that a higher intake of vitamin B12 may decrease the risk of PD in a population of U.S. health professionals, the associations we observed were modest and not entirely consistent,” Dr. Flores-Torres said.

“Additional studies need to confirm our findings to better understand whether people who take higher amounts of B12 younger in life may have a protective benefit against PD,” he added.
 

The whole picture?

Commenting on the findings for this article, Rebecca Gilbert, MD, PhD, chief scientific officer of the American Parkinson Disease Association, New York, noted that checking B vitamin levels is a fairly standard practice for most clinicians. In that regard, this study highlights why this is important.

“Neurologists will often test B12 levels and recommend a supplement if your level is below the normal range,” she said. “No one is questioning the value of B12 for nerves and recommend that B12 is in the normal to high normal range.”

But understanding how B vitamins may or may not affect PD risk might require a different kind of study.

“This analysis, much like many others, is trying so hard to figure out what is it in diets that affects Parkinson’s disease risk,” Dr. Gilbert said. “But we have yet to say these are the nutrients that prevent Parkinson’s or increase the risk.”

One reason for the conflicting results in studies such as this could be that the explanation for the link between diet and PD risk may not be in specific minerals consumed but rather in the diet as a whole.

“Focusing on specific elements of a diet may not give us the answer,” Dr. Gilbert said. “We should be analyzing diet as a complete holistic picture because it’s not just the elements but how everything in what we eat works together.”

The study was funded by the National Institutes of Health and the Parkinson’s Foundation. Dr. Flores-Torres and Dr. Gilbert report no relevant conflicts.
 

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

Imaging tests may miss early signs of multiple sclerosis (MS) in children who have no symptoms of the disease, according to a recent study that points to the need for a change in diagnostic criteria for the neuromuscular condition.

The findings suggest that children, unlike adults, may not need to meet the current clinical standard criteria to be considered at risk for MS.

“This is an important study confirming that some children who have no symptoms of demyelinating disease may nonetheless have MRI findings suggestive of demyelination detected on brain imaging,” said Naila Makhani, MD, associate professor of pediatrics and of neurology at Yale University and director of the Yale Pediatric Neuroimmunology Program, New Haven, Conn. Dr. Makhani was not affiliated with the study.

Researchers reviewed the MRI scans of 38 children aged 7-17 years who had radiologically isolated syndrome (RIS), a possible precursor to MS.

Like MS, RIS is characterized by destruction of the myelin. However, RIS is generally asymptomatic.

While RIS has been linked to MS, a diagnosis of RIS does not mean someone will be diagnosed with MS. Previous studies have shown that at least 3% of MS cases begin before age 16.

The children in the study likely received an MRI because of complaints of headaches or after having been diagnosed with a concussion, according to the researchers. The participants also did not show physical symptoms for MS, nor did they meet the McDonald or Barkohf criteria, which are clinical standards used to diagnose the condition in adults and children.

Within an average of 3 years following the imaging and RIS diagnosis, almost 36% of the children experienced a clinical attack, which led to an MS diagnosis. Almost three-fourths of the children developed additional brain and spinal cord lesions in the myelin that were evident on MRI.

MS often is diagnosed after a patient has had a clinical attack, such as vision impairment, loss of balance, inflammation, or severe fatigue. Identifying the potential for the disease earlier may allow clinicians to treat sooner, according to Leslie Benson, MD, assistant director of pediatric neuroimmunology at Massachusetts General Hospital, Boston, and one of the study authors.

“The field is leaning toward [the question of], ‘Should we treat presymptomatic MS?’ ” said Dr. Benson. “If we have the opportunity to prevent disability and improve long-term outcomes with safe medications, then we would like to do so.”

The findings were published in the journal Multiple Sclerosis and Related Disorders.

According to Dr. Benson and her colleagues, adjustments to the McDonald or Barkohf criteria for children may help in the detection of RIS and may allow earlier identification of MS.

“We don’t really know when MS first starts,” Dr. Benson said. “Unless you happen to have an MRI or symptoms, there’s no way to know how long the lesions have been evolving and how long the disease progression that led to those lesions has been there.”

MRI images showing lesions in the brain stem and spinal cord of children appeared to be different from those typically seen in adults, according to Tanuja Chitnis, MD, director of the Mass General Brigham Pediatric MS Center in Boston, who is one of the study’s coauthors.

“The concern of many practitioners is whether we should be treating at the first sign of MS,” Dr. Chitnis said. “We need to understand it better in children, and in teenagers especially, when these probably start biologically.”

Dr. Benson said current criteria for diagnosing MS in children require meeting a high threshold, which may limit diagnoses to those whose condition has progressed.

“This may miss patients at risk for MS,” Dr. Benson said. “That idea of who do you diagnose RIS and what criteria work to accurately diagnose RIS is really important.”

For now, the challenge remains of investigating characteristics of patients with RIS who will later have a clinical attack.

“We need a better understanding of what criteria do need to be met and how we can best risk-stratify our patients,” Dr. Benson said. “If it is recommended to treat presymptomatic cases, that we can best stratify those at risk and not overtreat those not at risk.”

Dr. Makhani receives funding from the National Institutes of Health, the Charles H. Hood Foundation, and the Multiple Sclerosis Society.

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

Imaging tests may miss early signs of multiple sclerosis (MS) in children who have no symptoms of the disease, according to a recent study that points to the need for a change in diagnostic criteria for the neuromuscular condition.

The findings suggest that children, unlike adults, may not need to meet the current clinical standard criteria to be considered at risk for MS.

“This is an important study confirming that some children who have no symptoms of demyelinating disease may nonetheless have MRI findings suggestive of demyelination detected on brain imaging,” said Naila Makhani, MD, associate professor of pediatrics and of neurology at Yale University and director of the Yale Pediatric Neuroimmunology Program, New Haven, Conn. Dr. Makhani was not affiliated with the study.

Researchers reviewed the MRI scans of 38 children aged 7-17 years who had radiologically isolated syndrome (RIS), a possible precursor to MS.

Like MS, RIS is characterized by destruction of the myelin. However, RIS is generally asymptomatic.

While RIS has been linked to MS, a diagnosis of RIS does not mean someone will be diagnosed with MS. Previous studies have shown that at least 3% of MS cases begin before age 16.

The children in the study likely received an MRI because of complaints of headaches or after having been diagnosed with a concussion, according to the researchers. The participants also did not show physical symptoms for MS, nor did they meet the McDonald or Barkohf criteria, which are clinical standards used to diagnose the condition in adults and children.

Within an average of 3 years following the imaging and RIS diagnosis, almost 36% of the children experienced a clinical attack, which led to an MS diagnosis. Almost three-fourths of the children developed additional brain and spinal cord lesions in the myelin that were evident on MRI.

MS often is diagnosed after a patient has had a clinical attack, such as vision impairment, loss of balance, inflammation, or severe fatigue. Identifying the potential for the disease earlier may allow clinicians to treat sooner, according to Leslie Benson, MD, assistant director of pediatric neuroimmunology at Massachusetts General Hospital, Boston, and one of the study authors.

“The field is leaning toward [the question of], ‘Should we treat presymptomatic MS?’ ” said Dr. Benson. “If we have the opportunity to prevent disability and improve long-term outcomes with safe medications, then we would like to do so.”

The findings were published in the journal Multiple Sclerosis and Related Disorders.

According to Dr. Benson and her colleagues, adjustments to the McDonald or Barkohf criteria for children may help in the detection of RIS and may allow earlier identification of MS.

“We don’t really know when MS first starts,” Dr. Benson said. “Unless you happen to have an MRI or symptoms, there’s no way to know how long the lesions have been evolving and how long the disease progression that led to those lesions has been there.”

MRI images showing lesions in the brain stem and spinal cord of children appeared to be different from those typically seen in adults, according to Tanuja Chitnis, MD, director of the Mass General Brigham Pediatric MS Center in Boston, who is one of the study’s coauthors.

“The concern of many practitioners is whether we should be treating at the first sign of MS,” Dr. Chitnis said. “We need to understand it better in children, and in teenagers especially, when these probably start biologically.”

Dr. Benson said current criteria for diagnosing MS in children require meeting a high threshold, which may limit diagnoses to those whose condition has progressed.

“This may miss patients at risk for MS,” Dr. Benson said. “That idea of who do you diagnose RIS and what criteria work to accurately diagnose RIS is really important.”

For now, the challenge remains of investigating characteristics of patients with RIS who will later have a clinical attack.

“We need a better understanding of what criteria do need to be met and how we can best risk-stratify our patients,” Dr. Benson said. “If it is recommended to treat presymptomatic cases, that we can best stratify those at risk and not overtreat those not at risk.”

Dr. Makhani receives funding from the National Institutes of Health, the Charles H. Hood Foundation, and the Multiple Sclerosis Society.

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

Imaging tests may miss early signs of multiple sclerosis (MS) in children who have no symptoms of the disease, according to a recent study that points to the need for a change in diagnostic criteria for the neuromuscular condition.

The findings suggest that children, unlike adults, may not need to meet the current clinical standard criteria to be considered at risk for MS.

“This is an important study confirming that some children who have no symptoms of demyelinating disease may nonetheless have MRI findings suggestive of demyelination detected on brain imaging,” said Naila Makhani, MD, associate professor of pediatrics and of neurology at Yale University and director of the Yale Pediatric Neuroimmunology Program, New Haven, Conn. Dr. Makhani was not affiliated with the study.

Researchers reviewed the MRI scans of 38 children aged 7-17 years who had radiologically isolated syndrome (RIS), a possible precursor to MS.

Like MS, RIS is characterized by destruction of the myelin. However, RIS is generally asymptomatic.

While RIS has been linked to MS, a diagnosis of RIS does not mean someone will be diagnosed with MS. Previous studies have shown that at least 3% of MS cases begin before age 16.

The children in the study likely received an MRI because of complaints of headaches or after having been diagnosed with a concussion, according to the researchers. The participants also did not show physical symptoms for MS, nor did they meet the McDonald or Barkohf criteria, which are clinical standards used to diagnose the condition in adults and children.

Within an average of 3 years following the imaging and RIS diagnosis, almost 36% of the children experienced a clinical attack, which led to an MS diagnosis. Almost three-fourths of the children developed additional brain and spinal cord lesions in the myelin that were evident on MRI.

MS often is diagnosed after a patient has had a clinical attack, such as vision impairment, loss of balance, inflammation, or severe fatigue. Identifying the potential for the disease earlier may allow clinicians to treat sooner, according to Leslie Benson, MD, assistant director of pediatric neuroimmunology at Massachusetts General Hospital, Boston, and one of the study authors.

“The field is leaning toward [the question of], ‘Should we treat presymptomatic MS?’ ” said Dr. Benson. “If we have the opportunity to prevent disability and improve long-term outcomes with safe medications, then we would like to do so.”

The findings were published in the journal Multiple Sclerosis and Related Disorders.

According to Dr. Benson and her colleagues, adjustments to the McDonald or Barkohf criteria for children may help in the detection of RIS and may allow earlier identification of MS.

“We don’t really know when MS first starts,” Dr. Benson said. “Unless you happen to have an MRI or symptoms, there’s no way to know how long the lesions have been evolving and how long the disease progression that led to those lesions has been there.”

MRI images showing lesions in the brain stem and spinal cord of children appeared to be different from those typically seen in adults, according to Tanuja Chitnis, MD, director of the Mass General Brigham Pediatric MS Center in Boston, who is one of the study’s coauthors.

“The concern of many practitioners is whether we should be treating at the first sign of MS,” Dr. Chitnis said. “We need to understand it better in children, and in teenagers especially, when these probably start biologically.”

Dr. Benson said current criteria for diagnosing MS in children require meeting a high threshold, which may limit diagnoses to those whose condition has progressed.

“This may miss patients at risk for MS,” Dr. Benson said. “That idea of who do you diagnose RIS and what criteria work to accurately diagnose RIS is really important.”

For now, the challenge remains of investigating characteristics of patients with RIS who will later have a clinical attack.

“We need a better understanding of what criteria do need to be met and how we can best risk-stratify our patients,” Dr. Benson said. “If it is recommended to treat presymptomatic cases, that we can best stratify those at risk and not overtreat those not at risk.”

Dr. Makhani receives funding from the National Institutes of Health, the Charles H. Hood Foundation, and the Multiple Sclerosis Society.

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

Physical exercise may improve the motor symptoms and quality of life for patients with Parkinson’s disease, new research shows. A systematic review of 156 clinical trials involving 8,000 patients with Parkinson’s disease showed dancing and aquatic exercise, in particular, were most likely to improve motor symptoms, while swimming, endurance training, and mind-body training were most likely to benefit quality of life.

“For most types of exercise we studied, we observed positive effects on both the severity of motor signs and quality of life. These results highlight the importance of exercise in general, as they suggest people with Parkinson’s disease can benefit from a variety of exercises,” said study investigator Moritz Ernst, MSc, deputy head of the working group on evidence-based medicine at the University Hospital Cologne (Germany).

University Hospital Cologne

“Clinicians and people with Parkinson’s disease may have several options of exercise programs to choose from when establishing an individual training routine,” he added, emphasizing that overall those with Parkinson’s disease should seek professional advice, including assessment of motor and nonmotor symptoms, to develop a training agenda based on their individual needs.

The study was published online in the Cochrane Database of Systematic Reviews.
 

May I have this dance?

The investigators analyzed data from randomized, controlled trials comparing different types of exercise and no exercise and the subsequent effect on Parkinson’s disease symptoms. Exercise included dance, strength-resistance training, mind-body training such as tai chi and yoga, water-based training, resistance training, gait/balance/functional training, and endurance training.

The average age of study participants ranged from 60 to 74 years, and most of the studies included patients with mild to moderate Parkinson’s disease. The mean length of the various interventions was 12 weeks.

When the researchers examined the effect of exercise on motor symptoms, they found that dance (P = .88), aqua-based training (P = .69), and gait/balance/functional training (P = .67) were most likely to reduce symptom severity.

Aqua-based training (P = .95), endurance training (P = .77), and mind-body training (P = .75) were most were most likely to benefit quality of life, although the investigators caution that these findings were at risk of bias because quality of life was self-reported.

The investigators noted other study limitations including the fact that most of the studies included in the review had small sample sizes and their study only included patients with mild to moderate versus severe Parkinson’s disease.

The authors said that future research should include larger samples, report intent-to-treat analyses, and involve participants with more advanced forms of Parkinson’s disease who may also have cognitive difficulties.
 

Prescribe exercise

“We should be giving our patients, no matter where they are in their disease stage, a ‘prescription’ to exercise,” said Mitra Afshari, MD, MPH. Dr. Afshari was not involved in the study but leads her own research on Parkinson’s disease and exercise as the site principal investigator on the National Institutes of Health–funded SPARX3 Study in Parkinson’s Disease and Exercise at Rush University in Chicago. She said that, based on her experience caring for patients with Parkinson’s disease at all disease stages, “patients who have been physically active their whole lives and can maintain that activity despite their diagnosis fare the best.”

However, she added, those who initiate physical exercise after diagnosis can also do very well and reap benefits, including improved motor symptoms.

The study was funded by University Hospital of Cologne, Faculty of Medicine and University Hospital, University of Cologne, and the German Ministry of Education and Research. The authors have disclosed no relevant financial relationships.

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

Physical exercise may improve the motor symptoms and quality of life for patients with Parkinson’s disease, new research shows. A systematic review of 156 clinical trials involving 8,000 patients with Parkinson’s disease showed dancing and aquatic exercise, in particular, were most likely to improve motor symptoms, while swimming, endurance training, and mind-body training were most likely to benefit quality of life.

“For most types of exercise we studied, we observed positive effects on both the severity of motor signs and quality of life. These results highlight the importance of exercise in general, as they suggest people with Parkinson’s disease can benefit from a variety of exercises,” said study investigator Moritz Ernst, MSc, deputy head of the working group on evidence-based medicine at the University Hospital Cologne (Germany).

University Hospital Cologne

“Clinicians and people with Parkinson’s disease may have several options of exercise programs to choose from when establishing an individual training routine,” he added, emphasizing that overall those with Parkinson’s disease should seek professional advice, including assessment of motor and nonmotor symptoms, to develop a training agenda based on their individual needs.

The study was published online in the Cochrane Database of Systematic Reviews.
 

May I have this dance?

The investigators analyzed data from randomized, controlled trials comparing different types of exercise and no exercise and the subsequent effect on Parkinson’s disease symptoms. Exercise included dance, strength-resistance training, mind-body training such as tai chi and yoga, water-based training, resistance training, gait/balance/functional training, and endurance training.

The average age of study participants ranged from 60 to 74 years, and most of the studies included patients with mild to moderate Parkinson’s disease. The mean length of the various interventions was 12 weeks.

When the researchers examined the effect of exercise on motor symptoms, they found that dance (P = .88), aqua-based training (P = .69), and gait/balance/functional training (P = .67) were most likely to reduce symptom severity.

Aqua-based training (P = .95), endurance training (P = .77), and mind-body training (P = .75) were most were most likely to benefit quality of life, although the investigators caution that these findings were at risk of bias because quality of life was self-reported.

The investigators noted other study limitations including the fact that most of the studies included in the review had small sample sizes and their study only included patients with mild to moderate versus severe Parkinson’s disease.

The authors said that future research should include larger samples, report intent-to-treat analyses, and involve participants with more advanced forms of Parkinson’s disease who may also have cognitive difficulties.
 

Prescribe exercise

“We should be giving our patients, no matter where they are in their disease stage, a ‘prescription’ to exercise,” said Mitra Afshari, MD, MPH. Dr. Afshari was not involved in the study but leads her own research on Parkinson’s disease and exercise as the site principal investigator on the National Institutes of Health–funded SPARX3 Study in Parkinson’s Disease and Exercise at Rush University in Chicago. She said that, based on her experience caring for patients with Parkinson’s disease at all disease stages, “patients who have been physically active their whole lives and can maintain that activity despite their diagnosis fare the best.”

However, she added, those who initiate physical exercise after diagnosis can also do very well and reap benefits, including improved motor symptoms.

The study was funded by University Hospital of Cologne, Faculty of Medicine and University Hospital, University of Cologne, and the German Ministry of Education and Research. The authors have disclosed no relevant financial relationships.

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

Physical exercise may improve the motor symptoms and quality of life for patients with Parkinson’s disease, new research shows. A systematic review of 156 clinical trials involving 8,000 patients with Parkinson’s disease showed dancing and aquatic exercise, in particular, were most likely to improve motor symptoms, while swimming, endurance training, and mind-body training were most likely to benefit quality of life.

“For most types of exercise we studied, we observed positive effects on both the severity of motor signs and quality of life. These results highlight the importance of exercise in general, as they suggest people with Parkinson’s disease can benefit from a variety of exercises,” said study investigator Moritz Ernst, MSc, deputy head of the working group on evidence-based medicine at the University Hospital Cologne (Germany).

University Hospital Cologne

“Clinicians and people with Parkinson’s disease may have several options of exercise programs to choose from when establishing an individual training routine,” he added, emphasizing that overall those with Parkinson’s disease should seek professional advice, including assessment of motor and nonmotor symptoms, to develop a training agenda based on their individual needs.

The study was published online in the Cochrane Database of Systematic Reviews.
 

May I have this dance?

The investigators analyzed data from randomized, controlled trials comparing different types of exercise and no exercise and the subsequent effect on Parkinson’s disease symptoms. Exercise included dance, strength-resistance training, mind-body training such as tai chi and yoga, water-based training, resistance training, gait/balance/functional training, and endurance training.

The average age of study participants ranged from 60 to 74 years, and most of the studies included patients with mild to moderate Parkinson’s disease. The mean length of the various interventions was 12 weeks.

When the researchers examined the effect of exercise on motor symptoms, they found that dance (P = .88), aqua-based training (P = .69), and gait/balance/functional training (P = .67) were most likely to reduce symptom severity.

Aqua-based training (P = .95), endurance training (P = .77), and mind-body training (P = .75) were most were most likely to benefit quality of life, although the investigators caution that these findings were at risk of bias because quality of life was self-reported.

The investigators noted other study limitations including the fact that most of the studies included in the review had small sample sizes and their study only included patients with mild to moderate versus severe Parkinson’s disease.

The authors said that future research should include larger samples, report intent-to-treat analyses, and involve participants with more advanced forms of Parkinson’s disease who may also have cognitive difficulties.
 

Prescribe exercise

“We should be giving our patients, no matter where they are in their disease stage, a ‘prescription’ to exercise,” said Mitra Afshari, MD, MPH. Dr. Afshari was not involved in the study but leads her own research on Parkinson’s disease and exercise as the site principal investigator on the National Institutes of Health–funded SPARX3 Study in Parkinson’s Disease and Exercise at Rush University in Chicago. She said that, based on her experience caring for patients with Parkinson’s disease at all disease stages, “patients who have been physically active their whole lives and can maintain that activity despite their diagnosis fare the best.”

However, she added, those who initiate physical exercise after diagnosis can also do very well and reap benefits, including improved motor symptoms.

The study was funded by University Hospital of Cologne, Faculty of Medicine and University Hospital, University of Cologne, and the German Ministry of Education and Research. The authors have disclosed no relevant financial relationships.

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

Childhood autism rates have ticked up once again, according to the latest data from Centers for Disease Control and Prevention.

According to the CDC, 1 in 36 (2.8%) 8-year-old children have been identified with autism spectrum disorder (ASD) – up from the previous 2018 estimate of 1 in 44 (2.3%).

The updated data come from 11 communities in the Autism and Developmental Disabilities Monitoring (ADDM) network and were published online in Morbidity and Mortality Weekly Report.

A separate report in the MMWR on 4-year-old children in the same 11 communities highlights the impact of COVID-19, showing disruptions in progress in early autism detection.

In the early months of the pandemic, 4-year-old children were less likely to have an evaluation or be identified with ASD than 8-year-old children when they were the same age. This coincides with interruptions in childcare and health care services during the COVID-19 pandemic.

“Disruptions due to the pandemic in the timely evaluation of children and delays in connecting children to the services and support they need could have long-lasting effects,” Karen Remley, MD, director of CDC’s National Center on Birth Defects and Developmental Disabilities, said in a statement.

“The data in this report can help communities better understand how the pandemic impacted early identification of autism in young children and anticipate future needs as these children get older,” Dr. Remley noted.
 

Shifting demographics

The latest data also show that ASD prevalence among Asian, Black, and Hispanic children was at least 30% higher in 2020 than in 2018, and ASD prevalence among White children was 14.6% higher than in 2018.

For the first time, according to the CDC, the percentage of 8-year-old Asian/Pacific Islander (3.3%), Hispanic (3.2%) and Black (2.9%) children identified with autism was higher than the percentage of 8-year-old White children (2.4%).

This is the opposite of racial and ethnic differences seen in previous ADDM reports for 8-year-olds. These shifts may reflect improved screening, awareness, and access to services among historically underserved groups, the CDC said.

Disparities for co-occurring intellectual disability have also persisted, with a higher percentage of Black children with autism identified with intellectual disability compared with White, Hispanic, or Asian/Pacific Islander children with autism. These differences could relate in part to access to services that diagnose and support children with autism, the CDC noted.

Overall, autism prevalence within the 11 ADDM communities was nearly four times higher for boys than girls. However, it’s the first time that the prevalence of autism among 8-year-old girls has topped 1%.
 

Community differences

Autism prevalence in the 11 ADDM communities ranged from 1 in 43 (2.3%) children in Maryland to 1 in 22 (4.5%) in California – variations that could be due to how communities identify children with autism.

This variability affords an opportunity to compare local policies and models for delivering diagnostic and interventional services that could enhance autism identification and provide more comprehensive support to people with autism, the CDC said.
 

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

Childhood autism rates have ticked up once again, according to the latest data from Centers for Disease Control and Prevention.

According to the CDC, 1 in 36 (2.8%) 8-year-old children have been identified with autism spectrum disorder (ASD) – up from the previous 2018 estimate of 1 in 44 (2.3%).

The updated data come from 11 communities in the Autism and Developmental Disabilities Monitoring (ADDM) network and were published online in Morbidity and Mortality Weekly Report.

A separate report in the MMWR on 4-year-old children in the same 11 communities highlights the impact of COVID-19, showing disruptions in progress in early autism detection.

In the early months of the pandemic, 4-year-old children were less likely to have an evaluation or be identified with ASD than 8-year-old children when they were the same age. This coincides with interruptions in childcare and health care services during the COVID-19 pandemic.

“Disruptions due to the pandemic in the timely evaluation of children and delays in connecting children to the services and support they need could have long-lasting effects,” Karen Remley, MD, director of CDC’s National Center on Birth Defects and Developmental Disabilities, said in a statement.

“The data in this report can help communities better understand how the pandemic impacted early identification of autism in young children and anticipate future needs as these children get older,” Dr. Remley noted.
 

Shifting demographics

The latest data also show that ASD prevalence among Asian, Black, and Hispanic children was at least 30% higher in 2020 than in 2018, and ASD prevalence among White children was 14.6% higher than in 2018.

For the first time, according to the CDC, the percentage of 8-year-old Asian/Pacific Islander (3.3%), Hispanic (3.2%) and Black (2.9%) children identified with autism was higher than the percentage of 8-year-old White children (2.4%).

This is the opposite of racial and ethnic differences seen in previous ADDM reports for 8-year-olds. These shifts may reflect improved screening, awareness, and access to services among historically underserved groups, the CDC said.

Disparities for co-occurring intellectual disability have also persisted, with a higher percentage of Black children with autism identified with intellectual disability compared with White, Hispanic, or Asian/Pacific Islander children with autism. These differences could relate in part to access to services that diagnose and support children with autism, the CDC noted.

Overall, autism prevalence within the 11 ADDM communities was nearly four times higher for boys than girls. However, it’s the first time that the prevalence of autism among 8-year-old girls has topped 1%.
 

Community differences

Autism prevalence in the 11 ADDM communities ranged from 1 in 43 (2.3%) children in Maryland to 1 in 22 (4.5%) in California – variations that could be due to how communities identify children with autism.

This variability affords an opportunity to compare local policies and models for delivering diagnostic and interventional services that could enhance autism identification and provide more comprehensive support to people with autism, the CDC said.
 

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

Childhood autism rates have ticked up once again, according to the latest data from Centers for Disease Control and Prevention.

According to the CDC, 1 in 36 (2.8%) 8-year-old children have been identified with autism spectrum disorder (ASD) – up from the previous 2018 estimate of 1 in 44 (2.3%).

The updated data come from 11 communities in the Autism and Developmental Disabilities Monitoring (ADDM) network and were published online in Morbidity and Mortality Weekly Report.

A separate report in the MMWR on 4-year-old children in the same 11 communities highlights the impact of COVID-19, showing disruptions in progress in early autism detection.

In the early months of the pandemic, 4-year-old children were less likely to have an evaluation or be identified with ASD than 8-year-old children when they were the same age. This coincides with interruptions in childcare and health care services during the COVID-19 pandemic.

“Disruptions due to the pandemic in the timely evaluation of children and delays in connecting children to the services and support they need could have long-lasting effects,” Karen Remley, MD, director of CDC’s National Center on Birth Defects and Developmental Disabilities, said in a statement.

“The data in this report can help communities better understand how the pandemic impacted early identification of autism in young children and anticipate future needs as these children get older,” Dr. Remley noted.
 

Shifting demographics

The latest data also show that ASD prevalence among Asian, Black, and Hispanic children was at least 30% higher in 2020 than in 2018, and ASD prevalence among White children was 14.6% higher than in 2018.

For the first time, according to the CDC, the percentage of 8-year-old Asian/Pacific Islander (3.3%), Hispanic (3.2%) and Black (2.9%) children identified with autism was higher than the percentage of 8-year-old White children (2.4%).

This is the opposite of racial and ethnic differences seen in previous ADDM reports for 8-year-olds. These shifts may reflect improved screening, awareness, and access to services among historically underserved groups, the CDC said.

Disparities for co-occurring intellectual disability have also persisted, with a higher percentage of Black children with autism identified with intellectual disability compared with White, Hispanic, or Asian/Pacific Islander children with autism. These differences could relate in part to access to services that diagnose and support children with autism, the CDC noted.

Overall, autism prevalence within the 11 ADDM communities was nearly four times higher for boys than girls. However, it’s the first time that the prevalence of autism among 8-year-old girls has topped 1%.
 

Community differences

Autism prevalence in the 11 ADDM communities ranged from 1 in 43 (2.3%) children in Maryland to 1 in 22 (4.5%) in California – variations that could be due to how communities identify children with autism.

This variability affords an opportunity to compare local policies and models for delivering diagnostic and interventional services that could enhance autism identification and provide more comprehensive support to people with autism, the CDC said.
 

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

The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.

However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant.  

Rasi Bhadramani/iStock/Getty Images

Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
 

A new pathway for heart transplantation

The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.

As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.  

However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.

In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death. 

Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed. 

The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.

For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.

Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.

In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.

It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.  

Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.  

Two different approaches to DCD heart transplantation have been developed.
 

The direct procurement approach

The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.

The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.

Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”

Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
 

Normothermic regional perfusion (NRP)  

The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).

Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.

“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”

Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.” 

The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.

He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts. 

DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.

The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
 

Ethical concerns about NRP

Restarting the circulation during the NRP process has raised ethical concerns.

When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).

Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.

There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule. 

“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.

“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”

The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.

“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.

With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”

The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
 

The argument for NRP

Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.

“People are confusing many issues to produce an argument against NRP,” he said.

“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”

Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.

“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”

On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”

He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.” 

On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”

But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”

Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD?  We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.

“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”

Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?

Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”

He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”

But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.

“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.

“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.  

“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
 

Cautious nod

In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.

The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”

The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”

However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.

“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.

“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”

Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
 

Variations in practice around the world 

This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.

In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t. 

David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.

“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.

Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.

“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.

Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.

“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”

Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants. 

“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”

He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”

Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.

“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said. 

“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”  

But he acknowledged that the whole concept of DCD is somewhat controversial.  

“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.

“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”

Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”

A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.

In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.

Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.

However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.

But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”

The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.

If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
 

Definition of death  

The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.  

DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”

Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.

“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function. 

“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”

Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier. 

In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.

“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.” 

Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
 

Collaborative decision

Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.

Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”

Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”

He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.” 

Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”

He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.

“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”

These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.

The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.

Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”

If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”  

Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”

He is hopeful that some of these issues will be resolved this year.

Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
 

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

The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.

However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant.  

Rasi Bhadramani/iStock/Getty Images

Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
 

A new pathway for heart transplantation

The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.

As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.  

However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.

In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death. 

Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed. 

The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.

For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.

Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.

In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.

It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.  

Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.  

Two different approaches to DCD heart transplantation have been developed.
 

The direct procurement approach

The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.

The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.

Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”

Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
 

Normothermic regional perfusion (NRP)  

The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).

Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.

“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”

Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.” 

The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.

He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts. 

DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.

The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
 

Ethical concerns about NRP

Restarting the circulation during the NRP process has raised ethical concerns.

When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).

Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.

There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule. 

“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.

“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”

The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.

“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.

With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”

The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
 

The argument for NRP

Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.

“People are confusing many issues to produce an argument against NRP,” he said.

“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”

Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.

“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”

On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”

He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.” 

On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”

But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”

Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD?  We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.

“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”

Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?

Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”

He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”

But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.

“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.

“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.  

“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
 

Cautious nod

In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.

The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”

The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”

However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.

“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.

“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”

Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
 

Variations in practice around the world 

This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.

In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t. 

David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.

“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.

Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.

“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.

Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.

“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”

Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants. 

“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”

He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”

Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.

“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said. 

“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”  

But he acknowledged that the whole concept of DCD is somewhat controversial.  

“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.

“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”

Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”

A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.

In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.

Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.

However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.

But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”

The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.

If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
 

Definition of death  

The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.  

DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”

Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.

“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function. 

“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”

Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier. 

In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.

“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.” 

Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
 

Collaborative decision

Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.

Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”

Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”

He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.” 

Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”

He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.

“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”

These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.

The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.

Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”

If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”  

Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”

He is hopeful that some of these issues will be resolved this year.

Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
 

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

The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.

However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant.  

Rasi Bhadramani/iStock/Getty Images

Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
 

A new pathway for heart transplantation

The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.

As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.  

However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.

In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death. 

Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed. 

The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.

For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.

Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.

In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.

It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.  

Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.  

Two different approaches to DCD heart transplantation have been developed.
 

The direct procurement approach

The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.

The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.

Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”

Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
 

Normothermic regional perfusion (NRP)  

The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).

Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.

“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”

Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.” 

The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.

He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts. 

DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.

The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
 

Ethical concerns about NRP

Restarting the circulation during the NRP process has raised ethical concerns.

When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).

Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.

There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule. 

“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.

“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”

The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.

“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.

With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”

The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
 

The argument for NRP

Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.

“People are confusing many issues to produce an argument against NRP,” he said.

“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”

Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.

“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”

On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”

He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.” 

On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”

But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”

Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD?  We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.

“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”

Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?

Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”

He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”

But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.

“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.

“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.  

“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
 

Cautious nod

In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.

The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”

The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”

However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.

“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.

“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”

Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
 

Variations in practice around the world 

This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.

In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t. 

David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.

“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.

Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.

“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.

Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.

“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”

Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants. 

“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”

He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”

Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.

“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said. 

“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”  

But he acknowledged that the whole concept of DCD is somewhat controversial.  

“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.

“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”

Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”

A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.

In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.

Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.

However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.

But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”

The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.

If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
 

Definition of death  

The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.  

DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”

Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.

“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function. 

“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”

Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier. 

In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.

“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.” 

Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
 

Collaborative decision

Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.

Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”

Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”

He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.” 

Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”

He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.

“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”

These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.

The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.

Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”

If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”  

Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”

He is hopeful that some of these issues will be resolved this year.

Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
 

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

Low bone mineral density (BMD), particularly at the femoral neck, emerged as a “robust” risk factor for dementia in older adults in the long-running Rotterdam Study. After adjusting for relevant factors, adults with the lowest versus highest BMD at the femoral neck were 42% more likely to develop dementia over roughly 10 years.

“Our research has found a link between bone loss and dementia, but further studies are needed to better understand this connection between bone density and memory loss,” study investigator Mohammad Arfan Ikram, MD, PhD, with Erasmus University Medical Center in Rotterdam, the Netherlands, said in a statement.

“It’s possible that bone loss may occur already in the earliest phases of dementia, years before any clinical symptoms manifest themselves. If that were the case, bone loss could be an indicator of risk for dementia and people with bone loss could be targeted for screening and improved care,” Dr. Ikram added.

The study was published online in Neurology.


 

Common bedfellows

Low BMD and dementia commonly co-occur in the older population, with bone loss accelerating in dementia patients because of physical inactivity and poor nutrition. However, the extent to which bone loss already exists prior to the onset of dementia remains unclear.

The new findings are based on 3,651 adults (mean age 72 years, 58% women) in the Rotterdam Study who were free of dementia between 2002 and 2005. At that time, BMD at the femoral neck, lumbar spine, and total body were obtained using dual-energy radiography absorptiometry (DXA) and the trabecular bone score, which offers further details such as bone microarchitecture, was calculated. Participants were followed up until Jan. 1, 2020.

Analyses were adjusted for age, sex, education, physical activity, smoking status, body mass index, blood pressure, cholesterol, history of comorbidities (stroke and diabetes), and apolipoprotein E genotype.

During follow-up, 688 (19%) participants developed dementia, mostly Alzheimer’s disease (77%).

Throughout the entire follow-up period, lower BMD at the femoral neck (per standard deviation), but not at other bone sites, correlated with a higher risk for all-cause dementia (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) and Alzheimer’s disease (HR, 1.14; 95% CI, 1.02-1.28).

Within the first 10 years after baseline, the risk for dementia was greatest in individuals with the lowest BMD at the femoral neck (HR, 2.03; 95% CI, 1.39-2.96) and total body (HR, 1.42; 95% CI, 1.01-2.02) and lowest trabecular bone score (HR, 1.59; 95% CI, 1.11-2.28).

Only BMD at the femoral neck was related to incident all-cause dementia in the first 5 years of follow-up (HR, 2.13; 95% CI, 1.28-3.57).

These findings add “extra knowledge to previous findings that associations change with time, with the strength of the effect decreasing with increasing follow-up time,” the investigators noted.

They suggest that total BMD and trabecular bone score might occur as “prodromal features instead of causes of dementia and related toxic protein accumulation in the brain. In other words, persons with subclinical, incipient dementia may have poor bone health due to the dementia process instead of vice versa.”

The investigators noted that further research focusing on the predictive ability of BMD for dementia is necessary. “As an indicator of dementia risk, intervening in BMD may improve clinical care of these persons, especially considering the multicomorbidities and polypharmacy that are highly preventive in this group,” they concluded.
 

Little known bone-brain axis to blame?

In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, noted that “bone health is increasingly becoming front of mind in older adults. This study confirms an association between poor bone health – low bone mineral density and bone scores – and poor brain health.”

However, it’s unclear whether the link is causal – that is, whether poor bone health actually leads to poor brain health, and whether that can be staved off by directly supporting bone density,” Dr. Lakhan said.

“The link may very well be the little known ‘brain-bone axis’ – where our bones actually regulate our brain,” he added.

“Take for example the bone-generated hormone osteocalcin that crosses the blood-brain barrier and regulates brain functions like memory and cognition. Mice who don’t express the osteocalcin gene or are injected with antibodies that block osteocalcin actually have poor memory and worse anxiety,” Dr. Lakhan said.

“In any event, good bone health begins with healthy habits: a diet with plenty of calcium, vitamin D, and protein; a regimen of not just cardio, but also weight-bearing exercises; and staying clear of smoking and heavy alcohol intake,” he concluded.

The study was funded by Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission, and the Municipality of Rotterdam. Dr. Ikram and Dr. Lakhan report no relevant disclosures.

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

Low bone mineral density (BMD), particularly at the femoral neck, emerged as a “robust” risk factor for dementia in older adults in the long-running Rotterdam Study. After adjusting for relevant factors, adults with the lowest versus highest BMD at the femoral neck were 42% more likely to develop dementia over roughly 10 years.

“Our research has found a link between bone loss and dementia, but further studies are needed to better understand this connection between bone density and memory loss,” study investigator Mohammad Arfan Ikram, MD, PhD, with Erasmus University Medical Center in Rotterdam, the Netherlands, said in a statement.

“It’s possible that bone loss may occur already in the earliest phases of dementia, years before any clinical symptoms manifest themselves. If that were the case, bone loss could be an indicator of risk for dementia and people with bone loss could be targeted for screening and improved care,” Dr. Ikram added.

The study was published online in Neurology.


 

Common bedfellows

Low BMD and dementia commonly co-occur in the older population, with bone loss accelerating in dementia patients because of physical inactivity and poor nutrition. However, the extent to which bone loss already exists prior to the onset of dementia remains unclear.

The new findings are based on 3,651 adults (mean age 72 years, 58% women) in the Rotterdam Study who were free of dementia between 2002 and 2005. At that time, BMD at the femoral neck, lumbar spine, and total body were obtained using dual-energy radiography absorptiometry (DXA) and the trabecular bone score, which offers further details such as bone microarchitecture, was calculated. Participants were followed up until Jan. 1, 2020.

Analyses were adjusted for age, sex, education, physical activity, smoking status, body mass index, blood pressure, cholesterol, history of comorbidities (stroke and diabetes), and apolipoprotein E genotype.

During follow-up, 688 (19%) participants developed dementia, mostly Alzheimer’s disease (77%).

Throughout the entire follow-up period, lower BMD at the femoral neck (per standard deviation), but not at other bone sites, correlated with a higher risk for all-cause dementia (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) and Alzheimer’s disease (HR, 1.14; 95% CI, 1.02-1.28).

Within the first 10 years after baseline, the risk for dementia was greatest in individuals with the lowest BMD at the femoral neck (HR, 2.03; 95% CI, 1.39-2.96) and total body (HR, 1.42; 95% CI, 1.01-2.02) and lowest trabecular bone score (HR, 1.59; 95% CI, 1.11-2.28).

Only BMD at the femoral neck was related to incident all-cause dementia in the first 5 years of follow-up (HR, 2.13; 95% CI, 1.28-3.57).

These findings add “extra knowledge to previous findings that associations change with time, with the strength of the effect decreasing with increasing follow-up time,” the investigators noted.

They suggest that total BMD and trabecular bone score might occur as “prodromal features instead of causes of dementia and related toxic protein accumulation in the brain. In other words, persons with subclinical, incipient dementia may have poor bone health due to the dementia process instead of vice versa.”

The investigators noted that further research focusing on the predictive ability of BMD for dementia is necessary. “As an indicator of dementia risk, intervening in BMD may improve clinical care of these persons, especially considering the multicomorbidities and polypharmacy that are highly preventive in this group,” they concluded.
 

Little known bone-brain axis to blame?

In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, noted that “bone health is increasingly becoming front of mind in older adults. This study confirms an association between poor bone health – low bone mineral density and bone scores – and poor brain health.”

However, it’s unclear whether the link is causal – that is, whether poor bone health actually leads to poor brain health, and whether that can be staved off by directly supporting bone density,” Dr. Lakhan said.

“The link may very well be the little known ‘brain-bone axis’ – where our bones actually regulate our brain,” he added.

“Take for example the bone-generated hormone osteocalcin that crosses the blood-brain barrier and regulates brain functions like memory and cognition. Mice who don’t express the osteocalcin gene or are injected with antibodies that block osteocalcin actually have poor memory and worse anxiety,” Dr. Lakhan said.

“In any event, good bone health begins with healthy habits: a diet with plenty of calcium, vitamin D, and protein; a regimen of not just cardio, but also weight-bearing exercises; and staying clear of smoking and heavy alcohol intake,” he concluded.

The study was funded by Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission, and the Municipality of Rotterdam. Dr. Ikram and Dr. Lakhan report no relevant disclosures.

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

Low bone mineral density (BMD), particularly at the femoral neck, emerged as a “robust” risk factor for dementia in older adults in the long-running Rotterdam Study. After adjusting for relevant factors, adults with the lowest versus highest BMD at the femoral neck were 42% more likely to develop dementia over roughly 10 years.

“Our research has found a link between bone loss and dementia, but further studies are needed to better understand this connection between bone density and memory loss,” study investigator Mohammad Arfan Ikram, MD, PhD, with Erasmus University Medical Center in Rotterdam, the Netherlands, said in a statement.

“It’s possible that bone loss may occur already in the earliest phases of dementia, years before any clinical symptoms manifest themselves. If that were the case, bone loss could be an indicator of risk for dementia and people with bone loss could be targeted for screening and improved care,” Dr. Ikram added.

The study was published online in Neurology.


 

Common bedfellows

Low BMD and dementia commonly co-occur in the older population, with bone loss accelerating in dementia patients because of physical inactivity and poor nutrition. However, the extent to which bone loss already exists prior to the onset of dementia remains unclear.

The new findings are based on 3,651 adults (mean age 72 years, 58% women) in the Rotterdam Study who were free of dementia between 2002 and 2005. At that time, BMD at the femoral neck, lumbar spine, and total body were obtained using dual-energy radiography absorptiometry (DXA) and the trabecular bone score, which offers further details such as bone microarchitecture, was calculated. Participants were followed up until Jan. 1, 2020.

Analyses were adjusted for age, sex, education, physical activity, smoking status, body mass index, blood pressure, cholesterol, history of comorbidities (stroke and diabetes), and apolipoprotein E genotype.

During follow-up, 688 (19%) participants developed dementia, mostly Alzheimer’s disease (77%).

Throughout the entire follow-up period, lower BMD at the femoral neck (per standard deviation), but not at other bone sites, correlated with a higher risk for all-cause dementia (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) and Alzheimer’s disease (HR, 1.14; 95% CI, 1.02-1.28).

Within the first 10 years after baseline, the risk for dementia was greatest in individuals with the lowest BMD at the femoral neck (HR, 2.03; 95% CI, 1.39-2.96) and total body (HR, 1.42; 95% CI, 1.01-2.02) and lowest trabecular bone score (HR, 1.59; 95% CI, 1.11-2.28).

Only BMD at the femoral neck was related to incident all-cause dementia in the first 5 years of follow-up (HR, 2.13; 95% CI, 1.28-3.57).

These findings add “extra knowledge to previous findings that associations change with time, with the strength of the effect decreasing with increasing follow-up time,” the investigators noted.

They suggest that total BMD and trabecular bone score might occur as “prodromal features instead of causes of dementia and related toxic protein accumulation in the brain. In other words, persons with subclinical, incipient dementia may have poor bone health due to the dementia process instead of vice versa.”

The investigators noted that further research focusing on the predictive ability of BMD for dementia is necessary. “As an indicator of dementia risk, intervening in BMD may improve clinical care of these persons, especially considering the multicomorbidities and polypharmacy that are highly preventive in this group,” they concluded.
 

Little known bone-brain axis to blame?

In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, noted that “bone health is increasingly becoming front of mind in older adults. This study confirms an association between poor bone health – low bone mineral density and bone scores – and poor brain health.”

However, it’s unclear whether the link is causal – that is, whether poor bone health actually leads to poor brain health, and whether that can be staved off by directly supporting bone density,” Dr. Lakhan said.

“The link may very well be the little known ‘brain-bone axis’ – where our bones actually regulate our brain,” he added.

“Take for example the bone-generated hormone osteocalcin that crosses the blood-brain barrier and regulates brain functions like memory and cognition. Mice who don’t express the osteocalcin gene or are injected with antibodies that block osteocalcin actually have poor memory and worse anxiety,” Dr. Lakhan said.

“In any event, good bone health begins with healthy habits: a diet with plenty of calcium, vitamin D, and protein; a regimen of not just cardio, but also weight-bearing exercises; and staying clear of smoking and heavy alcohol intake,” he concluded.

The study was funded by Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission, and the Municipality of Rotterdam. Dr. Ikram and Dr. Lakhan report no relevant disclosures.

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

Telomere shortening – a sign of cellular aging – is associated with multiple changes in the brain associated with dementia, whereas longer telomeres associate with better brain health and lower risk for dementia, new research suggests.

“This is the largest and most systematic investigation of telomere length and brain structure and function,” said Anya Topiwala, of the University of Oxford (England). “We found that longer telomeres associated with protection against dementia. The links with brain structure, we think, offer a possible mechanism for this protection. The hope is, by understanding the mechanism, new treatment targets could be uncovered,” Dr. Topiwala said.

The study was published online in PLOS ONE.
 

UK Biobank cohort

Telomeres form protective caps at the ends of chromosomes, and they progressively shorten with age, which may increase susceptibility to age-related diseases including Alzheimer’s disease. The mechanism underlying this risk is unclear and may involve changes in brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized.

Dr. Topiwala and colleagues compared telomere length in white blood cells to brain MRI and health record data in 31,661 middle-aged and older adults in UK Biobank. They found that longer leucocyte telomere length (LTL) was associated with a larger volume of global and subcortical grey matter and a larger hippocampus – both of which shrink in patients with Alzheimer’s disease. Longer telomeres were also associated with a thicker cerebral cortex, which thins as Alzheimer’s disease progresses.

Longer LTL was also associated with reduced incidence of dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.91-0.96).

Dr. Topiwala noted that many of the factors related to telomere shortening, such as age, genetics, and sex, can’t be changed. However, in a previous study, her team found that drinking alcohol may shorten telomere length. “So by this logic, reducing your alcohol intake could curb the shortening,” Dr. Topiwala said.

She said that a limitation of the study is that telomere length was measured in blood rather than brain and that it’s not clear at present how closely the two relate. Also, UK Biobank participants are generally more healthy than is the general population. Also, though telomere length and brain measures were associated, “we cannot from this study prove one is causing the other,” she added.
 

Need for more research

Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said that it’s been “known for some time that shortened telomeres – the caps at the end of DNA – are associated with increased aging.”

This new study is “interesting,” said Dr. Percy, in that it shows an association between longer telomere length in white blood cells and healthier brain structures in the areas associated with Alzheimer’s disease. The longer telomeres were also associated with lower incidence of all-cause dementia.

But echoing Dr. Topiwala, “association does not mean causation,” Dr. Griffin said. “More research is needed to understand how diverse mechanisms contributing to Alzheimer’s and other dementia can be targeted.”

“The Alzheimer’s Association is accelerating the discovery of novel therapies through its Part the Cloud funding program, which has invested more than $65 million to accelerate the development of 65 drug development programs,” Dr. Griffin said.

The study had no specific funding. Dr. Topiwala and Dr. Griffin report no relevant disclosures.

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

Telomere shortening – a sign of cellular aging – is associated with multiple changes in the brain associated with dementia, whereas longer telomeres associate with better brain health and lower risk for dementia, new research suggests.

“This is the largest and most systematic investigation of telomere length and brain structure and function,” said Anya Topiwala, of the University of Oxford (England). “We found that longer telomeres associated with protection against dementia. The links with brain structure, we think, offer a possible mechanism for this protection. The hope is, by understanding the mechanism, new treatment targets could be uncovered,” Dr. Topiwala said.

The study was published online in PLOS ONE.
 

UK Biobank cohort

Telomeres form protective caps at the ends of chromosomes, and they progressively shorten with age, which may increase susceptibility to age-related diseases including Alzheimer’s disease. The mechanism underlying this risk is unclear and may involve changes in brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized.

Dr. Topiwala and colleagues compared telomere length in white blood cells to brain MRI and health record data in 31,661 middle-aged and older adults in UK Biobank. They found that longer leucocyte telomere length (LTL) was associated with a larger volume of global and subcortical grey matter and a larger hippocampus – both of which shrink in patients with Alzheimer’s disease. Longer telomeres were also associated with a thicker cerebral cortex, which thins as Alzheimer’s disease progresses.

Longer LTL was also associated with reduced incidence of dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.91-0.96).

Dr. Topiwala noted that many of the factors related to telomere shortening, such as age, genetics, and sex, can’t be changed. However, in a previous study, her team found that drinking alcohol may shorten telomere length. “So by this logic, reducing your alcohol intake could curb the shortening,” Dr. Topiwala said.

She said that a limitation of the study is that telomere length was measured in blood rather than brain and that it’s not clear at present how closely the two relate. Also, UK Biobank participants are generally more healthy than is the general population. Also, though telomere length and brain measures were associated, “we cannot from this study prove one is causing the other,” she added.
 

Need for more research

Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said that it’s been “known for some time that shortened telomeres – the caps at the end of DNA – are associated with increased aging.”

This new study is “interesting,” said Dr. Percy, in that it shows an association between longer telomere length in white blood cells and healthier brain structures in the areas associated with Alzheimer’s disease. The longer telomeres were also associated with lower incidence of all-cause dementia.

But echoing Dr. Topiwala, “association does not mean causation,” Dr. Griffin said. “More research is needed to understand how diverse mechanisms contributing to Alzheimer’s and other dementia can be targeted.”

“The Alzheimer’s Association is accelerating the discovery of novel therapies through its Part the Cloud funding program, which has invested more than $65 million to accelerate the development of 65 drug development programs,” Dr. Griffin said.

The study had no specific funding. Dr. Topiwala and Dr. Griffin report no relevant disclosures.

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

Telomere shortening – a sign of cellular aging – is associated with multiple changes in the brain associated with dementia, whereas longer telomeres associate with better brain health and lower risk for dementia, new research suggests.

“This is the largest and most systematic investigation of telomere length and brain structure and function,” said Anya Topiwala, of the University of Oxford (England). “We found that longer telomeres associated with protection against dementia. The links with brain structure, we think, offer a possible mechanism for this protection. The hope is, by understanding the mechanism, new treatment targets could be uncovered,” Dr. Topiwala said.

The study was published online in PLOS ONE.
 

UK Biobank cohort

Telomeres form protective caps at the ends of chromosomes, and they progressively shorten with age, which may increase susceptibility to age-related diseases including Alzheimer’s disease. The mechanism underlying this risk is unclear and may involve changes in brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized.

Dr. Topiwala and colleagues compared telomere length in white blood cells to brain MRI and health record data in 31,661 middle-aged and older adults in UK Biobank. They found that longer leucocyte telomere length (LTL) was associated with a larger volume of global and subcortical grey matter and a larger hippocampus – both of which shrink in patients with Alzheimer’s disease. Longer telomeres were also associated with a thicker cerebral cortex, which thins as Alzheimer’s disease progresses.

Longer LTL was also associated with reduced incidence of dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.91-0.96).

Dr. Topiwala noted that many of the factors related to telomere shortening, such as age, genetics, and sex, can’t be changed. However, in a previous study, her team found that drinking alcohol may shorten telomere length. “So by this logic, reducing your alcohol intake could curb the shortening,” Dr. Topiwala said.

She said that a limitation of the study is that telomere length was measured in blood rather than brain and that it’s not clear at present how closely the two relate. Also, UK Biobank participants are generally more healthy than is the general population. Also, though telomere length and brain measures were associated, “we cannot from this study prove one is causing the other,” she added.
 

Need for more research

Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said that it’s been “known for some time that shortened telomeres – the caps at the end of DNA – are associated with increased aging.”

This new study is “interesting,” said Dr. Percy, in that it shows an association between longer telomere length in white blood cells and healthier brain structures in the areas associated with Alzheimer’s disease. The longer telomeres were also associated with lower incidence of all-cause dementia.

But echoing Dr. Topiwala, “association does not mean causation,” Dr. Griffin said. “More research is needed to understand how diverse mechanisms contributing to Alzheimer’s and other dementia can be targeted.”

“The Alzheimer’s Association is accelerating the discovery of novel therapies through its Part the Cloud funding program, which has invested more than $65 million to accelerate the development of 65 drug development programs,” Dr. Griffin said.

The study had no specific funding. Dr. Topiwala and Dr. Griffin report no relevant disclosures.

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