Neurology

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.

The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.

The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.

The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.

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

Case

A 60-year-old woman with metastatic breast cancer using morphine extended release 30 mg twice daily and as-needed oxycodone for cancer-related pain presents with fever, dyspnea, and productive cough for 2 days. She also notes several weeks of fatigue, nausea, weight loss, and orthostatic lightheadedness. She is found to have pneumonia and is admitted for intravenous antibiotics. She remains borderline hypotensive after intravenous fluids and the hospitalist suspects opioid-induced adrenal insufficiency (OIAI).

How is OIAI diagnosed and managed?
 

Brief overview of issue

In the United States, 5.4% of the population is currently using long-term opioids.¹ Patients using high doses of opioids for greater than 3 months are 40%-50% more likely to be hospitalized than those on a lower dose or no opioids.² Hospitalists frequently encounter common opioid side effects such as constipation, nausea, and drowsiness, but may be less familiar with their effects on the endocrine system. Chronic, high-dose opioids can suppress the hypothalamic-pituitary-adrenal (HPA) axis and cause secondary, or central, adrenal insufficiency (AI).¹

Recognition of OIAI is critical given the current opioid epidemic and life-threatening consequences of AI in systemically ill patients. While high-dose opioids may acutely suppress the HPA axis,³ OIAI is more commonly associated with long-term opioid use.⁴ The prevalence of OIAI among patients receiving long-term opioids ranges from 8.3% to 29%. This range reflects variations in opioid dose, duration of use, and different methods of assessing the HPA axis.^1,4 When screening for HPA axis suppression in subjects taking chronic opioids, Lamprecht and colleagues found a prevalence of 22.5%.⁵ In comparison, Gibb and colleagues found the prevalence of secondary AI to be 8.3% in patients enrolled in a chronic pain clinic.⁶ Despite the high prevalence on biochemical screening, the clinical significance of OIAI is less clear. Clinical AI and adrenal crisis among patients on opioids are less frequent and mostly limited to case reports.^7,8 In one retrospective cohort, one in 40 patients with OIAI presented with adrenal crisis during a hospitalization for viral gastroenteritis.⁹

With this prevalence, one would expect to diagnose OIAI more commonly in hospitalized patients. A concerning possibility is that this diagnosis is underrecognized because of either a lack of knowledge of the disease or the clinical overlap between the nonspecific symptoms of AI and other diagnoses. In patients reporting symptoms suggestive of OIAI, the diagnosis was delayed by a median of 12 months.⁹ The challenge for the hospitalist is to consider OIAI, even among patients with common infections such as pneumonia, viral gastroenteritis, or endocarditis who present with these nonspecific symptoms, while also avoiding unnecessary testing and treatment with glucocorticoids.
 

Overview of the data

Opiates and opioids exert their physiologic effect through activation of the mu, kappa, and delta receptors. These receptors are located throughout the body, including the hypothalamus and pituitary gland.⁴ Activation of these receptors results in tonic inhibition of the HPA axis and results in central AI.⁴ Central AI is characterized by a low a.m. cortisol, low adrenocorticotropic hormone (ACTH), and low dehydroepiandrosterone sulfate (DHEAS) levels.^1,4 The low ACTH is indicative of central etiology. This effect of opioids is likely dose dependent with patients using more than 60 morphine-equivalent daily dose at greater risk.^1,5

Unexplained or unresolved fatigue, musculoskeletal pain, nausea, vomiting, anorexia, abdominal pain, and orthostatic hypotension in a patient on chronic opioids should prompt consideration of OIAI.⁹ Once suspected, an 8 a.m. cortisol, ACTH level, and DHEAS level should be ordered. Because of the diurnal variation of cortisol levels, 8 a.m. values are best validated for diagnosis.¹⁰ While cutoffs differ, an 8 a.m. cortisol less than 5 mcg/dL combined with ACTH less than 10 pmol/L, and DHEAS less than 50 mcg/dL are highly suggestive of OIAI. Low or indeterminate baseline a.m. cortisol levels warrant confirmatory testing.^4,10 While the insulin tolerance test is considered the gold standard, the high dose (250 mcg) cosyntropin stimulation test (CST) is the more commonly used test to diagnose and confirm AI. A CST peak response greater than 18-20 mcg/dL suggests an intact HPA axis (see Figure 1).¹⁰ This testing will diagnose central AI, but is not specific for OIAI. Other causes of central AI such as exogenous steroid use, pituitary pathology, and head trauma should be considered before attributing AI to opioids (see Table 1).⁴

Dr. Cunningham, Dr. Munoa, and Dr. Indovina.

The abnormal CST in central AI is from chronic ACTH deficiency and lack of adrenal stimulation resulting in adrenal atrophy. Adrenal atrophy leaves the adrenal glands incapable of responding to exogenous ACTH. This process takes several weeks; therefore, those with ACTH suppression caused by recent high-dose opioid use or subacute pituitary injury may have an indeterminate or normal cortisol response to high-dose exogenous ACTH.⁴ Even in the setting of a normal CST, there may remain uncertainty in the diagnosis of OIAI. When evaluating for central AI, the sensitivity and negative likelihood ratio of the CST are only 0.64 and 0.39, respectively.⁴ In the same cohort of 40 patients with OIAI, 11 patients had a normal CST.⁹ The low-dose (1 mcg) CST may increase the sensitivity, but the use of this test is limited because of technical challenges.¹ Endocrinology consultation can assist when the initial diagnostic and clinical presentation is unclear.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina.

To manage a patient on opioid therapy who has laboratory data consistent with central AI, the clinician must weigh the severity of symptoms, probability of opioid weaning, and risks associated with glucocorticoid treatment. Patients presenting with acute adrenal crisis, hypotension, or critical illness should be managed with intravenous steroid replacement per existing guideline recommendations.^10,11

Patients with mild symptoms of nausea, vomiting, or orthostatic symptoms that resolve with treatment of their admitting diagnosis but who have evidence of an abnormal HPA axis should be considered for weaning opioid therapy. Evidence suggests that OIAI is reversible with reduction and cessation of chronic opioid use.^4,9 These patients may not need chronic steroid replacement; however, they should receive education on the symptoms of AI and potentially rescue steroids for home use in the setting of severe illness. Patients with OIAI admitted for surgical procedures should be managed in accordance with existing guidelines for perioperative stress dosing of glucocorticoids for AI.

Those with persisting symptoms of OIAI and an abnormal HPA axis require endocrinology consultation and glucocorticoid replacement. There is limited evidence that suggests low dose steroid replacement in patients with OIAI can improve subjective perception of bodily pain, activity level, and mood in chronic opioid users.⁹ Li and colleagues found that 16 of 23 patients experienced improvement of symptoms on glucocorticoids, and 15 were able to discontinue opioids completely.⁹ The authors speculated that the improvement in fatigue and musculoskeletal pain after steroid replacement is what allowed for successful opioid weaning. Seven of 10 of these patients with available follow-up had recovery of the HPA axis during the follow-up period.⁹ In central AI, doses as low as 10-20 mg/day of hydrocortisone have been used.^10,11 Hospitalists should educate patients on recognizing symptoms of AI, as this low dose may not be sufficient to prevent adrenal crisis.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina

All patients with evidence of abnormalities in the HPA axis should receive a Medic-Alert bracelet to inform other providers of the possibility of adrenal crisis should a major trauma or critical illness render them unconscious.^4,10 Since OIAI is a form of central AI, mineralocorticoid replacement is not generally necessary.¹¹ Endocrinology follow-up can help wean steroids as the HPA axis recovers after weaning opioid therapy. Recognizing and diagnosing OIAI can identify patients with untreated symptoms who are at risk for adrenal crisis, improve communication with patients on benefits of weaning opioids, and provide valuable patient education and safe transition of care.
 

Application of the data to the original case

To make the diagnosis of OIAI, 8 a.m. cortisol, ACTH, and DHEAS should be obtained. Her cortisol was less than 5 mcg/dL, ACTH was 6 pmol/L and DHEAS was 30 mcg/dL. A high dose CST was performed with 30-minute and 60-minute cortisol values of 6 mcg/dL and 9 mcg/dL, respectively. The abnormal CST and low ACTH indicate central AI. She should undergo testing for other etiologies of central AI, such as a brain MRI and pituitary hormone testing, before confirming the diagnosis of OIAI.

The insufficient adrenal response to ACTH in the setting of infection and hypotension should prompt glucocorticoid replacement. Tapering opioids could result in recovery of the HPA axis, though may not be realistic in this patient with chronic cancer-related pain. If the patient is at high risk for adverse effects of glucocorticoids, repeat testing of the HPA axis in the outpatient setting can assess if the patient truly needs steroid replacement daily rather than only during physiologic stress. The patient should be given a Medic-Alert bracelet and instructions on symptoms of AI and stress dosing upon discharge.
 

Bottom line

OIAI is underrecognized because of central adrenal insufficiency. Knowing its clinical characteristics, diagnostic pathways, and treatment options aids in recognition and management.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina are based in the division of hospital medicine at Denver Health and Hospital Authority.

References

1. Donegan D. Opioid induced adrenal insufficiency: What is new? Curr Opin Endocrinol Diabetes Obes. 2019 Jun;26(3):133-8. doi: 10.1097/MED.0000000000000474.

2. Liang Y and Turner BJ. Opioid risk measure for hospitalization. J Hosp Med. 2015 July;10(7):425-31. doi: 10.1002/jhm.2350.

3. Policola C et al. Adrenal insufficiency in acute oral opiate therapy. Endocrinol Diabetes Metab Case Rep. 2014;2014:130071. doi: 10.1530/EDM-13-0071.

4. Donegan D and Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018 July;93(7):937-44. doi: 10.1016/j.mayocp.2018.04.010.

5. Lamprecht A et al. Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain. Eur J Endocrinol. 2018 Dec 1;179(6):353-62. doi: 10.1530/EJE-18-0530.

6. Gibb FW et al. Adrenal insufficiency in patients on long-term opioid analgesia. Clin Endocrinol (Oxf). 2016 June;85(6):831-5. doi:10.1111/cen.13125.

7. Abs R et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000 June;85(6):2215-22. doi: 10.1210/jcem.85.6.6615.

8. Tabet EJ et al. Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia. BMJ Case Rep. 2019 Dec 11;12(12):e230551. doi: 10.1136/bcr-2019-230551.

9. Li T et al. Clinical presentation and outcomes of opioid induced adrenal insufficiency. Endocr Pract. 2020 Nov;26(11):1291-1297. doi: 10.4158/EP-2020-0297.

10. Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. doi: 10.1210/jc.2010-0982.

11. Charmandari E et al. Adrenal insufficiency. Lancet. 2014 June 21;383(9935):2152-67. doi: 10.1016/S0140-6736(13)61684-0.

Key points

• Opioids can cause central adrenal insufficiency because of tonic suppression of the HPA axis. This effect is likely dose dependent, and reversible upon tapering or withdrawal of opioids.
• The prevalence of biochemical OIAI in chronic opioid users of 8%-29% clinical AI is less frequent but may be underrecognized in hospitalized patients leading to delayed diagnosis.
• Diagnosis of central adrenal insufficiency is based upon low 8 a.m. cortisol and ACTH levels and/or an abnormal CST. OIAI is the likely etiology in patients on chronic opioids for whom other causes of central adrenal insufficiency have been ruled out.
• Management with glucocorticoid replacement is variable depending on clinical presentation, severity of HPA axis suppression, and ability to wean opioid therapy. Patient education regarding symptoms of AI and stress dosing is essential.

Additional reading

Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. doi: 10.1210/jc.2010-0982.

Donegan D and Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018 July;93(7):937-44. doi: 10.1016/j.mayocp.2018.04.010.

Li T et al. Clinical presentation and outcomes of opioid induced adrenal insufficiency. Endocr Pract. 2020 Nov;26(11):1291-7. doi: 10.4158/EP-2020-0297.

Quiz

A 55-year-old man with chronic back pain, for which he takes a total of 90 mg of oral morphine daily, is admitted for pyelonephritis with fever, nausea, vomiting, dysuria, and abdominal pain. He is febrile and tachycardic on presentation, but his vitals quickly normalize after hydration and antibiotics. About 48 hours into his hospitalization his fevers, dysuria, and abdominal pain have resolved, but he has persistent nausea and headaches. On further questioning, he also reports weight loss and fatigue over the past 3 weeks. He is found to have a morning cortisol level less than 5 mcg/dL, as well as low levels of ACTH and DHEAS. OIAI is suspected.

Which of the following is true about management?

A. Glucocorticoid replacement therapy with oral hydrocortisone should be considered to improve his symptoms.

B. Tapering off opioids is unlikely to resolve his adrenal insufficiency.

C. Stress dose steroids should be started immediately with high-dose intravenous hydrocortisone.

D. Given high clinical suspicion for OIAI, further testing for other etiologies of central adrenal insufficiency is not recommended.

Explanation of correct answer

The correct answer is A. This patient’s ongoing nonspecific symptoms that have persisted despite treatment of his acute pyelonephritis are likely caused by adrenal insufficiency. In a symptomatic patient with OIAI, treatment with oral hydrocortisone should be considered to control symptoms and facilitate tapering opioids. Tapering and stopping opioids often leads to recovery of the HPA axis and resolution of the OIAI. Tapering opioids should be considered a mainstay of therapy for OIAI when clinically appropriate, as in this patient with chronic benign pain. Stress dose steroids are not indicated in the absence of critical illness, adrenal crisis, or major surgery. OIAI is a diagnosis of exclusion, and patients should undergo workup for other causes of secondary adrenal insufficiency.

Case

A 60-year-old woman with metastatic breast cancer using morphine extended release 30 mg twice daily and as-needed oxycodone for cancer-related pain presents with fever, dyspnea, and productive cough for 2 days. She also notes several weeks of fatigue, nausea, weight loss, and orthostatic lightheadedness. She is found to have pneumonia and is admitted for intravenous antibiotics. She remains borderline hypotensive after intravenous fluids and the hospitalist suspects opioid-induced adrenal insufficiency (OIAI).

How is OIAI diagnosed and managed?
 

Brief overview of issue

In the United States, 5.4% of the population is currently using long-term opioids.¹ Patients using high doses of opioids for greater than 3 months are 40%-50% more likely to be hospitalized than those on a lower dose or no opioids.² Hospitalists frequently encounter common opioid side effects such as constipation, nausea, and drowsiness, but may be less familiar with their effects on the endocrine system. Chronic, high-dose opioids can suppress the hypothalamic-pituitary-adrenal (HPA) axis and cause secondary, or central, adrenal insufficiency (AI).¹

Recognition of OIAI is critical given the current opioid epidemic and life-threatening consequences of AI in systemically ill patients. While high-dose opioids may acutely suppress the HPA axis,³ OIAI is more commonly associated with long-term opioid use.⁴ The prevalence of OIAI among patients receiving long-term opioids ranges from 8.3% to 29%. This range reflects variations in opioid dose, duration of use, and different methods of assessing the HPA axis.^1,4 When screening for HPA axis suppression in subjects taking chronic opioids, Lamprecht and colleagues found a prevalence of 22.5%.⁵ In comparison, Gibb and colleagues found the prevalence of secondary AI to be 8.3% in patients enrolled in a chronic pain clinic.⁶ Despite the high prevalence on biochemical screening, the clinical significance of OIAI is less clear. Clinical AI and adrenal crisis among patients on opioids are less frequent and mostly limited to case reports.^7,8 In one retrospective cohort, one in 40 patients with OIAI presented with adrenal crisis during a hospitalization for viral gastroenteritis.⁹

With this prevalence, one would expect to diagnose OIAI more commonly in hospitalized patients. A concerning possibility is that this diagnosis is underrecognized because of either a lack of knowledge of the disease or the clinical overlap between the nonspecific symptoms of AI and other diagnoses. In patients reporting symptoms suggestive of OIAI, the diagnosis was delayed by a median of 12 months.⁹ The challenge for the hospitalist is to consider OIAI, even among patients with common infections such as pneumonia, viral gastroenteritis, or endocarditis who present with these nonspecific symptoms, while also avoiding unnecessary testing and treatment with glucocorticoids.
 

Overview of the data

Opiates and opioids exert their physiologic effect through activation of the mu, kappa, and delta receptors. These receptors are located throughout the body, including the hypothalamus and pituitary gland.⁴ Activation of these receptors results in tonic inhibition of the HPA axis and results in central AI.⁴ Central AI is characterized by a low a.m. cortisol, low adrenocorticotropic hormone (ACTH), and low dehydroepiandrosterone sulfate (DHEAS) levels.^1,4 The low ACTH is indicative of central etiology. This effect of opioids is likely dose dependent with patients using more than 60 morphine-equivalent daily dose at greater risk.^1,5

Unexplained or unresolved fatigue, musculoskeletal pain, nausea, vomiting, anorexia, abdominal pain, and orthostatic hypotension in a patient on chronic opioids should prompt consideration of OIAI.⁹ Once suspected, an 8 a.m. cortisol, ACTH level, and DHEAS level should be ordered. Because of the diurnal variation of cortisol levels, 8 a.m. values are best validated for diagnosis.¹⁰ While cutoffs differ, an 8 a.m. cortisol less than 5 mcg/dL combined with ACTH less than 10 pmol/L, and DHEAS less than 50 mcg/dL are highly suggestive of OIAI. Low or indeterminate baseline a.m. cortisol levels warrant confirmatory testing.^4,10 While the insulin tolerance test is considered the gold standard, the high dose (250 mcg) cosyntropin stimulation test (CST) is the more commonly used test to diagnose and confirm AI. A CST peak response greater than 18-20 mcg/dL suggests an intact HPA axis (see Figure 1).¹⁰ This testing will diagnose central AI, but is not specific for OIAI. Other causes of central AI such as exogenous steroid use, pituitary pathology, and head trauma should be considered before attributing AI to opioids (see Table 1).⁴

Dr. Cunningham, Dr. Munoa, and Dr. Indovina.

The abnormal CST in central AI is from chronic ACTH deficiency and lack of adrenal stimulation resulting in adrenal atrophy. Adrenal atrophy leaves the adrenal glands incapable of responding to exogenous ACTH. This process takes several weeks; therefore, those with ACTH suppression caused by recent high-dose opioid use or subacute pituitary injury may have an indeterminate or normal cortisol response to high-dose exogenous ACTH.⁴ Even in the setting of a normal CST, there may remain uncertainty in the diagnosis of OIAI. When evaluating for central AI, the sensitivity and negative likelihood ratio of the CST are only 0.64 and 0.39, respectively.⁴ In the same cohort of 40 patients with OIAI, 11 patients had a normal CST.⁹ The low-dose (1 mcg) CST may increase the sensitivity, but the use of this test is limited because of technical challenges.¹ Endocrinology consultation can assist when the initial diagnostic and clinical presentation is unclear.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina.

To manage a patient on opioid therapy who has laboratory data consistent with central AI, the clinician must weigh the severity of symptoms, probability of opioid weaning, and risks associated with glucocorticoid treatment. Patients presenting with acute adrenal crisis, hypotension, or critical illness should be managed with intravenous steroid replacement per existing guideline recommendations.^10,11

Patients with mild symptoms of nausea, vomiting, or orthostatic symptoms that resolve with treatment of their admitting diagnosis but who have evidence of an abnormal HPA axis should be considered for weaning opioid therapy. Evidence suggests that OIAI is reversible with reduction and cessation of chronic opioid use.^4,9 These patients may not need chronic steroid replacement; however, they should receive education on the symptoms of AI and potentially rescue steroids for home use in the setting of severe illness. Patients with OIAI admitted for surgical procedures should be managed in accordance with existing guidelines for perioperative stress dosing of glucocorticoids for AI.

Those with persisting symptoms of OIAI and an abnormal HPA axis require endocrinology consultation and glucocorticoid replacement. There is limited evidence that suggests low dose steroid replacement in patients with OIAI can improve subjective perception of bodily pain, activity level, and mood in chronic opioid users.⁹ Li and colleagues found that 16 of 23 patients experienced improvement of symptoms on glucocorticoids, and 15 were able to discontinue opioids completely.⁹ The authors speculated that the improvement in fatigue and musculoskeletal pain after steroid replacement is what allowed for successful opioid weaning. Seven of 10 of these patients with available follow-up had recovery of the HPA axis during the follow-up period.⁹ In central AI, doses as low as 10-20 mg/day of hydrocortisone have been used.^10,11 Hospitalists should educate patients on recognizing symptoms of AI, as this low dose may not be sufficient to prevent adrenal crisis.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina

All patients with evidence of abnormalities in the HPA axis should receive a Medic-Alert bracelet to inform other providers of the possibility of adrenal crisis should a major trauma or critical illness render them unconscious.^4,10 Since OIAI is a form of central AI, mineralocorticoid replacement is not generally necessary.¹¹ Endocrinology follow-up can help wean steroids as the HPA axis recovers after weaning opioid therapy. Recognizing and diagnosing OIAI can identify patients with untreated symptoms who are at risk for adrenal crisis, improve communication with patients on benefits of weaning opioids, and provide valuable patient education and safe transition of care.
 

Application of the data to the original case

To make the diagnosis of OIAI, 8 a.m. cortisol, ACTH, and DHEAS should be obtained. Her cortisol was less than 5 mcg/dL, ACTH was 6 pmol/L and DHEAS was 30 mcg/dL. A high dose CST was performed with 30-minute and 60-minute cortisol values of 6 mcg/dL and 9 mcg/dL, respectively. The abnormal CST and low ACTH indicate central AI. She should undergo testing for other etiologies of central AI, such as a brain MRI and pituitary hormone testing, before confirming the diagnosis of OIAI.

The insufficient adrenal response to ACTH in the setting of infection and hypotension should prompt glucocorticoid replacement. Tapering opioids could result in recovery of the HPA axis, though may not be realistic in this patient with chronic cancer-related pain. If the patient is at high risk for adverse effects of glucocorticoids, repeat testing of the HPA axis in the outpatient setting can assess if the patient truly needs steroid replacement daily rather than only during physiologic stress. The patient should be given a Medic-Alert bracelet and instructions on symptoms of AI and stress dosing upon discharge.
 

Bottom line

OIAI is underrecognized because of central adrenal insufficiency. Knowing its clinical characteristics, diagnostic pathways, and treatment options aids in recognition and management.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina are based in the division of hospital medicine at Denver Health and Hospital Authority.

References

1. Donegan D. Opioid induced adrenal insufficiency: What is new? Curr Opin Endocrinol Diabetes Obes. 2019 Jun;26(3):133-8. doi: 10.1097/MED.0000000000000474.

2. Liang Y and Turner BJ. Opioid risk measure for hospitalization. J Hosp Med. 2015 July;10(7):425-31. doi: 10.1002/jhm.2350.

3. Policola C et al. Adrenal insufficiency in acute oral opiate therapy. Endocrinol Diabetes Metab Case Rep. 2014;2014:130071. doi: 10.1530/EDM-13-0071.

4. Donegan D and Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018 July;93(7):937-44. doi: 10.1016/j.mayocp.2018.04.010.

5. Lamprecht A et al. Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain. Eur J Endocrinol. 2018 Dec 1;179(6):353-62. doi: 10.1530/EJE-18-0530.

6. Gibb FW et al. Adrenal insufficiency in patients on long-term opioid analgesia. Clin Endocrinol (Oxf). 2016 June;85(6):831-5. doi:10.1111/cen.13125.

7. Abs R et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000 June;85(6):2215-22. doi: 10.1210/jcem.85.6.6615.

8. Tabet EJ et al. Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia. BMJ Case Rep. 2019 Dec 11;12(12):e230551. doi: 10.1136/bcr-2019-230551.

9. Li T et al. Clinical presentation and outcomes of opioid induced adrenal insufficiency. Endocr Pract. 2020 Nov;26(11):1291-1297. doi: 10.4158/EP-2020-0297.

10. Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. doi: 10.1210/jc.2010-0982.

11. Charmandari E et al. Adrenal insufficiency. Lancet. 2014 June 21;383(9935):2152-67. doi: 10.1016/S0140-6736(13)61684-0.

Key points

• Opioids can cause central adrenal insufficiency because of tonic suppression of the HPA axis. This effect is likely dose dependent, and reversible upon tapering or withdrawal of opioids.
• The prevalence of biochemical OIAI in chronic opioid users of 8%-29% clinical AI is less frequent but may be underrecognized in hospitalized patients leading to delayed diagnosis.
• Diagnosis of central adrenal insufficiency is based upon low 8 a.m. cortisol and ACTH levels and/or an abnormal CST. OIAI is the likely etiology in patients on chronic opioids for whom other causes of central adrenal insufficiency have been ruled out.
• Management with glucocorticoid replacement is variable depending on clinical presentation, severity of HPA axis suppression, and ability to wean opioid therapy. Patient education regarding symptoms of AI and stress dosing is essential.

Additional reading

Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. doi: 10.1210/jc.2010-0982.

Donegan D and Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018 July;93(7):937-44. doi: 10.1016/j.mayocp.2018.04.010.

Li T et al. Clinical presentation and outcomes of opioid induced adrenal insufficiency. Endocr Pract. 2020 Nov;26(11):1291-7. doi: 10.4158/EP-2020-0297.

Quiz

A 55-year-old man with chronic back pain, for which he takes a total of 90 mg of oral morphine daily, is admitted for pyelonephritis with fever, nausea, vomiting, dysuria, and abdominal pain. He is febrile and tachycardic on presentation, but his vitals quickly normalize after hydration and antibiotics. About 48 hours into his hospitalization his fevers, dysuria, and abdominal pain have resolved, but he has persistent nausea and headaches. On further questioning, he also reports weight loss and fatigue over the past 3 weeks. He is found to have a morning cortisol level less than 5 mcg/dL, as well as low levels of ACTH and DHEAS. OIAI is suspected.

Which of the following is true about management?

A. Glucocorticoid replacement therapy with oral hydrocortisone should be considered to improve his symptoms.

B. Tapering off opioids is unlikely to resolve his adrenal insufficiency.

C. Stress dose steroids should be started immediately with high-dose intravenous hydrocortisone.

D. Given high clinical suspicion for OIAI, further testing for other etiologies of central adrenal insufficiency is not recommended.

Explanation of correct answer

The correct answer is A. This patient’s ongoing nonspecific symptoms that have persisted despite treatment of his acute pyelonephritis are likely caused by adrenal insufficiency. In a symptomatic patient with OIAI, treatment with oral hydrocortisone should be considered to control symptoms and facilitate tapering opioids. Tapering and stopping opioids often leads to recovery of the HPA axis and resolution of the OIAI. Tapering opioids should be considered a mainstay of therapy for OIAI when clinically appropriate, as in this patient with chronic benign pain. Stress dose steroids are not indicated in the absence of critical illness, adrenal crisis, or major surgery. OIAI is a diagnosis of exclusion, and patients should undergo workup for other causes of secondary adrenal insufficiency.

Case

A 60-year-old woman with metastatic breast cancer using morphine extended release 30 mg twice daily and as-needed oxycodone for cancer-related pain presents with fever, dyspnea, and productive cough for 2 days. She also notes several weeks of fatigue, nausea, weight loss, and orthostatic lightheadedness. She is found to have pneumonia and is admitted for intravenous antibiotics. She remains borderline hypotensive after intravenous fluids and the hospitalist suspects opioid-induced adrenal insufficiency (OIAI).

How is OIAI diagnosed and managed?
 

Brief overview of issue

In the United States, 5.4% of the population is currently using long-term opioids.¹ Patients using high doses of opioids for greater than 3 months are 40%-50% more likely to be hospitalized than those on a lower dose or no opioids.² Hospitalists frequently encounter common opioid side effects such as constipation, nausea, and drowsiness, but may be less familiar with their effects on the endocrine system. Chronic, high-dose opioids can suppress the hypothalamic-pituitary-adrenal (HPA) axis and cause secondary, or central, adrenal insufficiency (AI).¹

Recognition of OIAI is critical given the current opioid epidemic and life-threatening consequences of AI in systemically ill patients. While high-dose opioids may acutely suppress the HPA axis,³ OIAI is more commonly associated with long-term opioid use.⁴ The prevalence of OIAI among patients receiving long-term opioids ranges from 8.3% to 29%. This range reflects variations in opioid dose, duration of use, and different methods of assessing the HPA axis.^1,4 When screening for HPA axis suppression in subjects taking chronic opioids, Lamprecht and colleagues found a prevalence of 22.5%.⁵ In comparison, Gibb and colleagues found the prevalence of secondary AI to be 8.3% in patients enrolled in a chronic pain clinic.⁶ Despite the high prevalence on biochemical screening, the clinical significance of OIAI is less clear. Clinical AI and adrenal crisis among patients on opioids are less frequent and mostly limited to case reports.^7,8 In one retrospective cohort, one in 40 patients with OIAI presented with adrenal crisis during a hospitalization for viral gastroenteritis.⁹

With this prevalence, one would expect to diagnose OIAI more commonly in hospitalized patients. A concerning possibility is that this diagnosis is underrecognized because of either a lack of knowledge of the disease or the clinical overlap between the nonspecific symptoms of AI and other diagnoses. In patients reporting symptoms suggestive of OIAI, the diagnosis was delayed by a median of 12 months.⁹ The challenge for the hospitalist is to consider OIAI, even among patients with common infections such as pneumonia, viral gastroenteritis, or endocarditis who present with these nonspecific symptoms, while also avoiding unnecessary testing and treatment with glucocorticoids.
 

Overview of the data

Opiates and opioids exert their physiologic effect through activation of the mu, kappa, and delta receptors. These receptors are located throughout the body, including the hypothalamus and pituitary gland.⁴ Activation of these receptors results in tonic inhibition of the HPA axis and results in central AI.⁴ Central AI is characterized by a low a.m. cortisol, low adrenocorticotropic hormone (ACTH), and low dehydroepiandrosterone sulfate (DHEAS) levels.^1,4 The low ACTH is indicative of central etiology. This effect of opioids is likely dose dependent with patients using more than 60 morphine-equivalent daily dose at greater risk.^1,5

Unexplained or unresolved fatigue, musculoskeletal pain, nausea, vomiting, anorexia, abdominal pain, and orthostatic hypotension in a patient on chronic opioids should prompt consideration of OIAI.⁹ Once suspected, an 8 a.m. cortisol, ACTH level, and DHEAS level should be ordered. Because of the diurnal variation of cortisol levels, 8 a.m. values are best validated for diagnosis.¹⁰ While cutoffs differ, an 8 a.m. cortisol less than 5 mcg/dL combined with ACTH less than 10 pmol/L, and DHEAS less than 50 mcg/dL are highly suggestive of OIAI. Low or indeterminate baseline a.m. cortisol levels warrant confirmatory testing.^4,10 While the insulin tolerance test is considered the gold standard, the high dose (250 mcg) cosyntropin stimulation test (CST) is the more commonly used test to diagnose and confirm AI. A CST peak response greater than 18-20 mcg/dL suggests an intact HPA axis (see Figure 1).¹⁰ This testing will diagnose central AI, but is not specific for OIAI. Other causes of central AI such as exogenous steroid use, pituitary pathology, and head trauma should be considered before attributing AI to opioids (see Table 1).⁴

Dr. Cunningham, Dr. Munoa, and Dr. Indovina.

The abnormal CST in central AI is from chronic ACTH deficiency and lack of adrenal stimulation resulting in adrenal atrophy. Adrenal atrophy leaves the adrenal glands incapable of responding to exogenous ACTH. This process takes several weeks; therefore, those with ACTH suppression caused by recent high-dose opioid use or subacute pituitary injury may have an indeterminate or normal cortisol response to high-dose exogenous ACTH.⁴ Even in the setting of a normal CST, there may remain uncertainty in the diagnosis of OIAI. When evaluating for central AI, the sensitivity and negative likelihood ratio of the CST are only 0.64 and 0.39, respectively.⁴ In the same cohort of 40 patients with OIAI, 11 patients had a normal CST.⁹ The low-dose (1 mcg) CST may increase the sensitivity, but the use of this test is limited because of technical challenges.¹ Endocrinology consultation can assist when the initial diagnostic and clinical presentation is unclear.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina.

To manage a patient on opioid therapy who has laboratory data consistent with central AI, the clinician must weigh the severity of symptoms, probability of opioid weaning, and risks associated with glucocorticoid treatment. Patients presenting with acute adrenal crisis, hypotension, or critical illness should be managed with intravenous steroid replacement per existing guideline recommendations.^10,11

Patients with mild symptoms of nausea, vomiting, or orthostatic symptoms that resolve with treatment of their admitting diagnosis but who have evidence of an abnormal HPA axis should be considered for weaning opioid therapy. Evidence suggests that OIAI is reversible with reduction and cessation of chronic opioid use.^4,9 These patients may not need chronic steroid replacement; however, they should receive education on the symptoms of AI and potentially rescue steroids for home use in the setting of severe illness. Patients with OIAI admitted for surgical procedures should be managed in accordance with existing guidelines for perioperative stress dosing of glucocorticoids for AI.

Those with persisting symptoms of OIAI and an abnormal HPA axis require endocrinology consultation and glucocorticoid replacement. There is limited evidence that suggests low dose steroid replacement in patients with OIAI can improve subjective perception of bodily pain, activity level, and mood in chronic opioid users.⁹ Li and colleagues found that 16 of 23 patients experienced improvement of symptoms on glucocorticoids, and 15 were able to discontinue opioids completely.⁹ The authors speculated that the improvement in fatigue and musculoskeletal pain after steroid replacement is what allowed for successful opioid weaning. Seven of 10 of these patients with available follow-up had recovery of the HPA axis during the follow-up period.⁹ In central AI, doses as low as 10-20 mg/day of hydrocortisone have been used.^10,11 Hospitalists should educate patients on recognizing symptoms of AI, as this low dose may not be sufficient to prevent adrenal crisis.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina

All patients with evidence of abnormalities in the HPA axis should receive a Medic-Alert bracelet to inform other providers of the possibility of adrenal crisis should a major trauma or critical illness render them unconscious.^4,10 Since OIAI is a form of central AI, mineralocorticoid replacement is not generally necessary.¹¹ Endocrinology follow-up can help wean steroids as the HPA axis recovers after weaning opioid therapy. Recognizing and diagnosing OIAI can identify patients with untreated symptoms who are at risk for adrenal crisis, improve communication with patients on benefits of weaning opioids, and provide valuable patient education and safe transition of care.
 

Application of the data to the original case

To make the diagnosis of OIAI, 8 a.m. cortisol, ACTH, and DHEAS should be obtained. Her cortisol was less than 5 mcg/dL, ACTH was 6 pmol/L and DHEAS was 30 mcg/dL. A high dose CST was performed with 30-minute and 60-minute cortisol values of 6 mcg/dL and 9 mcg/dL, respectively. The abnormal CST and low ACTH indicate central AI. She should undergo testing for other etiologies of central AI, such as a brain MRI and pituitary hormone testing, before confirming the diagnosis of OIAI.

The insufficient adrenal response to ACTH in the setting of infection and hypotension should prompt glucocorticoid replacement. Tapering opioids could result in recovery of the HPA axis, though may not be realistic in this patient with chronic cancer-related pain. If the patient is at high risk for adverse effects of glucocorticoids, repeat testing of the HPA axis in the outpatient setting can assess if the patient truly needs steroid replacement daily rather than only during physiologic stress. The patient should be given a Medic-Alert bracelet and instructions on symptoms of AI and stress dosing upon discharge.
 

Bottom line

OIAI is underrecognized because of central adrenal insufficiency. Knowing its clinical characteristics, diagnostic pathways, and treatment options aids in recognition and management.

Dr. Cunningham, Dr. Munoa, and Dr. Indovina are based in the division of hospital medicine at Denver Health and Hospital Authority.

References

1. Donegan D. Opioid induced adrenal insufficiency: What is new? Curr Opin Endocrinol Diabetes Obes. 2019 Jun;26(3):133-8. doi: 10.1097/MED.0000000000000474.

2. Liang Y and Turner BJ. Opioid risk measure for hospitalization. J Hosp Med. 2015 July;10(7):425-31. doi: 10.1002/jhm.2350.

3. Policola C et al. Adrenal insufficiency in acute oral opiate therapy. Endocrinol Diabetes Metab Case Rep. 2014;2014:130071. doi: 10.1530/EDM-13-0071.

4. Donegan D and Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018 July;93(7):937-44. doi: 10.1016/j.mayocp.2018.04.010.

5. Lamprecht A et al. Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain. Eur J Endocrinol. 2018 Dec 1;179(6):353-62. doi: 10.1530/EJE-18-0530.

6. Gibb FW et al. Adrenal insufficiency in patients on long-term opioid analgesia. Clin Endocrinol (Oxf). 2016 June;85(6):831-5. doi:10.1111/cen.13125.

7. Abs R et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000 June;85(6):2215-22. doi: 10.1210/jcem.85.6.6615.

8. Tabet EJ et al. Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia. BMJ Case Rep. 2019 Dec 11;12(12):e230551. doi: 10.1136/bcr-2019-230551.

9. Li T et al. Clinical presentation and outcomes of opioid induced adrenal insufficiency. Endocr Pract. 2020 Nov;26(11):1291-1297. doi: 10.4158/EP-2020-0297.

10. Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. doi: 10.1210/jc.2010-0982.

11. Charmandari E et al. Adrenal insufficiency. Lancet. 2014 June 21;383(9935):2152-67. doi: 10.1016/S0140-6736(13)61684-0.

Key points

• Opioids can cause central adrenal insufficiency because of tonic suppression of the HPA axis. This effect is likely dose dependent, and reversible upon tapering or withdrawal of opioids.
• The prevalence of biochemical OIAI in chronic opioid users of 8%-29% clinical AI is less frequent but may be underrecognized in hospitalized patients leading to delayed diagnosis.
• Diagnosis of central adrenal insufficiency is based upon low 8 a.m. cortisol and ACTH levels and/or an abnormal CST. OIAI is the likely etiology in patients on chronic opioids for whom other causes of central adrenal insufficiency have been ruled out.
• Management with glucocorticoid replacement is variable depending on clinical presentation, severity of HPA axis suppression, and ability to wean opioid therapy. Patient education regarding symptoms of AI and stress dosing is essential.

Additional reading

Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. doi: 10.1210/jc.2010-0982.

Donegan D and Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018 July;93(7):937-44. doi: 10.1016/j.mayocp.2018.04.010.

Li T et al. Clinical presentation and outcomes of opioid induced adrenal insufficiency. Endocr Pract. 2020 Nov;26(11):1291-7. doi: 10.4158/EP-2020-0297.

Quiz

A 55-year-old man with chronic back pain, for which he takes a total of 90 mg of oral morphine daily, is admitted for pyelonephritis with fever, nausea, vomiting, dysuria, and abdominal pain. He is febrile and tachycardic on presentation, but his vitals quickly normalize after hydration and antibiotics. About 48 hours into his hospitalization his fevers, dysuria, and abdominal pain have resolved, but he has persistent nausea and headaches. On further questioning, he also reports weight loss and fatigue over the past 3 weeks. He is found to have a morning cortisol level less than 5 mcg/dL, as well as low levels of ACTH and DHEAS. OIAI is suspected.

Which of the following is true about management?

A. Glucocorticoid replacement therapy with oral hydrocortisone should be considered to improve his symptoms.

B. Tapering off opioids is unlikely to resolve his adrenal insufficiency.

C. Stress dose steroids should be started immediately with high-dose intravenous hydrocortisone.

D. Given high clinical suspicion for OIAI, further testing for other etiologies of central adrenal insufficiency is not recommended.

Explanation of correct answer

The correct answer is A. This patient’s ongoing nonspecific symptoms that have persisted despite treatment of his acute pyelonephritis are likely caused by adrenal insufficiency. In a symptomatic patient with OIAI, treatment with oral hydrocortisone should be considered to control symptoms and facilitate tapering opioids. Tapering and stopping opioids often leads to recovery of the HPA axis and resolution of the OIAI. Tapering opioids should be considered a mainstay of therapy for OIAI when clinically appropriate, as in this patient with chronic benign pain. Stress dose steroids are not indicated in the absence of critical illness, adrenal crisis, or major surgery. OIAI is a diagnosis of exclusion, and patients should undergo workup for other causes of secondary adrenal insufficiency.

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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

Updated European guidelines on the treatment of patients with multiple sclerosis (MS) have been announced and include a recommendation for siponimod (Mayzent) in progressive MS, as well as a general emphasis toward earlier and more aggressive treatment.

The updated guidelines were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and are the result of a collaboration between ECTRIMS and the European Academy of Neurology (EAN).

Maria Pia Amato, MD, ECTRIMS president and co-chair of the guidelines steering committee, noted that the European MS treatment guidelines were last published in 2018. “Since then more trials have been published, and we felt this was a good time to incorporate the new evidence into updated guidelines,” she said.

“As before, the updated guidelines contain a number of core questions that address the efficacy of disease-modifying therapies, early treatment decisions, disease/treatment response monitoring and treatment modifications, treatment suspension and disease reactivation, and pregnancy and breastfeeding,” Dr. Amato said.
 

New recommendations

New features of the updated guidelines include a recommendation for siponimod for secondary progressive MS with evidence of disease inflammatory activity; in addition, there is more emphasis on starting treatment early, with greater consideration of higher efficacy drugs, depending on the characteristics of the disease and the patient, Dr. Amato commented.

“We also provided more detailed information on disease-modifying therapy use in pregnancy and breastfeeding and also for women with high disease activity who desire to become pregnant,” she added.

Other new features include the introduction of clinical questions dealing with treatment safety and monitoring (for example, for natalizumab) and also considering the current COVID-19 pandemic scenario; switching strategies with more detailed practical indications on timing; and long lasting effects of drugs such as alemtuzumab and cladribine, Dr. Amato said.

The updated guidelines include the following recommendations:

• The entire spectrum of disease-modifying drugs should be prescribed by a neurologist with expertise in MS and ready access to adequate infrastructure to provide proper monitoring of patents, comprehensive assessment, early detection of side effects, and the capacity to address those side effects promptly.
• Offer interferon or glatiramer acetate to patients with clinically isolated syndrome (CIS) highly suggestive of MS and an abnormal MRI with lesions suggestive of MS who do not fulfill criteria for MS.
• For patients with relapsing-remitting MS, the choice between a wide range of available drugs (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, ozanimod, ponesimod, natalizumab, alemtuzumab, ocrelizumab, rituximab, or ofatumumab), from modestly to highly effective, will depend on factors including: underlying disability progression, disease severity/clinical or radiological activity, patient characteristics and morbidity, drug safety profile, family planning, and patient preferences.

Progressive MS

• For patients with secondary progressive MS with evidence of inflammatory activity (relapses and/or MRI activity), offer treatment with siponimod. Treatment with other therapies used for relapsing remitting MS may also be considered.
• For secondary progressive MS without evidence of inflammatory activity, particularly in young patients and those in whom progression has started recently, consider treatment with siponimod or anti-CD20 monoclonal antibodies, taking into account that there is scarce evidence to support their use in this setting.  
• For patients with active secondary progressive MS when there is no other therapy available, consider treatment with mitoxantrone, taking into account the safety concerns and tolerability issues of this agent. 
• Consider ocrelizumab for patients with primary progressive MS, particularly early and active (clinically and/or radiologically) disease.

Emphasis toward higher-efficacy drugs

• Consider choosing a higher-efficacy disease-modifying drug early on, according to disease activity (either clinically or on MRI).
• Offer a more efficacious drug to patients who show evidence of disease activity with their current treatment.
• When treatment with a high-efficacy drug is stopped, whether because of inefficacy or risk of adverse effects, consider starting another high-efficacy drug, taking into account clinical and MRI disease activity before and during treatment, pharmacokinetics and biological activity of the previous drug, and the potential for resumed disease activity or even rebound syndrome (particularly with natalizumab and S1P modulators).
• In the stable patient (clinically and on MRI) who shows no safety or tolerability issues, consider continuing treatment with disease-modifying therapy, taking into account patient characteristics and comorbidities, drug safety profile, family planning, and patient preferences.

Recommendations for pregnancy and breastfeeding

Recommendations for pregnant women and mothers who choose to breastfeed include:

• Advise women who wish to become pregnant to plan their pregnancy beforehand.
• Advise women of childbearing potential that MS disease-modifying therapies are not licensed during pregnancy, with the exception of interferons and glatiramer acetate.
• For women planning a pregnancy, offer interferons and glatiramer acetate and consider continuing these agents during pregnancy after assessment of risk and benefits. Consider using dimethyl fumarate until pregnancy is confirmed and stopping during pregnancy after assessment of the risks and benefits. 
• For women with highly active disease who wish to become pregnant, there are a number of therapeutic options:

1)  treatment with long lasting effects such as alemtuzumab or cladribine provided that at least 4 or 6 months respectively have elapsed between the last dose and conception2)  treatment with anti-CD20 drugs before pregnancy with advice to wait for 2-6 months after the last infusion before becoming pregnant and to avoid further infusions during pregnancy, or3) for patients treated with natalizumab, consider continuing treatment during pregnancy using a 6-week extended dosage regimen until the end of the second trimester or up until week 34 and resuming after delivery (in newborns exposed to natalizumab, check for hematological abnormalities and liver function)

• Only interferons and ofatumumab are currently approved during breastfeeding.   
•  

Treatment safety/monitoring

• When treating patients with natalizumab and after a period of stability, consider switching to a 6-week interval regimen in order to minimize the risk of progressive multifocal leukoencephalopathy (PML).
• Consider treatment with high-efficacy drugs including natalizumab in patients with high disease activity, in whom a quick therapeutic effect is required, taking into account the risk of PML in John Cunningham virus (JCV)-positive patients, as well as the therapeutic lag of the different disease-modifying drugs.
• Ideally, prioritize vaccination against COVID-19 before starting immunosuppressive disease-modifying treatments to achieve the highest protection rate possible.
•  

Long-lasting treatments

• When using long-lasting treatments (alemtuzumab or cladribine) in patients who experience disease activity before the treatment is completed (between the first and second cycles), consider waiting until completion of the therapeutic regimen before switching to other drugs.
• Consider offering additional courses of alemtuzumab after the first two cycles at least 1 year apart from each other when disease activity has not remitted completely or reappears after a period of stability, taking into account the balance between the potential benefits and side effects.

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

Updated European guidelines on the treatment of patients with multiple sclerosis (MS) have been announced and include a recommendation for siponimod (Mayzent) in progressive MS, as well as a general emphasis toward earlier and more aggressive treatment.

The updated guidelines were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and are the result of a collaboration between ECTRIMS and the European Academy of Neurology (EAN).

Maria Pia Amato, MD, ECTRIMS president and co-chair of the guidelines steering committee, noted that the European MS treatment guidelines were last published in 2018. “Since then more trials have been published, and we felt this was a good time to incorporate the new evidence into updated guidelines,” she said.

“As before, the updated guidelines contain a number of core questions that address the efficacy of disease-modifying therapies, early treatment decisions, disease/treatment response monitoring and treatment modifications, treatment suspension and disease reactivation, and pregnancy and breastfeeding,” Dr. Amato said.
 

New recommendations

New features of the updated guidelines include a recommendation for siponimod for secondary progressive MS with evidence of disease inflammatory activity; in addition, there is more emphasis on starting treatment early, with greater consideration of higher efficacy drugs, depending on the characteristics of the disease and the patient, Dr. Amato commented.

“We also provided more detailed information on disease-modifying therapy use in pregnancy and breastfeeding and also for women with high disease activity who desire to become pregnant,” she added.

Other new features include the introduction of clinical questions dealing with treatment safety and monitoring (for example, for natalizumab) and also considering the current COVID-19 pandemic scenario; switching strategies with more detailed practical indications on timing; and long lasting effects of drugs such as alemtuzumab and cladribine, Dr. Amato said.

The updated guidelines include the following recommendations:

• The entire spectrum of disease-modifying drugs should be prescribed by a neurologist with expertise in MS and ready access to adequate infrastructure to provide proper monitoring of patents, comprehensive assessment, early detection of side effects, and the capacity to address those side effects promptly.
• Offer interferon or glatiramer acetate to patients with clinically isolated syndrome (CIS) highly suggestive of MS and an abnormal MRI with lesions suggestive of MS who do not fulfill criteria for MS.
• For patients with relapsing-remitting MS, the choice between a wide range of available drugs (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, ozanimod, ponesimod, natalizumab, alemtuzumab, ocrelizumab, rituximab, or ofatumumab), from modestly to highly effective, will depend on factors including: underlying disability progression, disease severity/clinical or radiological activity, patient characteristics and morbidity, drug safety profile, family planning, and patient preferences.

Progressive MS

• For patients with secondary progressive MS with evidence of inflammatory activity (relapses and/or MRI activity), offer treatment with siponimod. Treatment with other therapies used for relapsing remitting MS may also be considered.
• For secondary progressive MS without evidence of inflammatory activity, particularly in young patients and those in whom progression has started recently, consider treatment with siponimod or anti-CD20 monoclonal antibodies, taking into account that there is scarce evidence to support their use in this setting.  
• For patients with active secondary progressive MS when there is no other therapy available, consider treatment with mitoxantrone, taking into account the safety concerns and tolerability issues of this agent. 
• Consider ocrelizumab for patients with primary progressive MS, particularly early and active (clinically and/or radiologically) disease.

Emphasis toward higher-efficacy drugs

• Consider choosing a higher-efficacy disease-modifying drug early on, according to disease activity (either clinically or on MRI).
• Offer a more efficacious drug to patients who show evidence of disease activity with their current treatment.
• When treatment with a high-efficacy drug is stopped, whether because of inefficacy or risk of adverse effects, consider starting another high-efficacy drug, taking into account clinical and MRI disease activity before and during treatment, pharmacokinetics and biological activity of the previous drug, and the potential for resumed disease activity or even rebound syndrome (particularly with natalizumab and S1P modulators).
• In the stable patient (clinically and on MRI) who shows no safety or tolerability issues, consider continuing treatment with disease-modifying therapy, taking into account patient characteristics and comorbidities, drug safety profile, family planning, and patient preferences.

Recommendations for pregnancy and breastfeeding

Recommendations for pregnant women and mothers who choose to breastfeed include:

• Advise women who wish to become pregnant to plan their pregnancy beforehand.
• Advise women of childbearing potential that MS disease-modifying therapies are not licensed during pregnancy, with the exception of interferons and glatiramer acetate.
• For women planning a pregnancy, offer interferons and glatiramer acetate and consider continuing these agents during pregnancy after assessment of risk and benefits. Consider using dimethyl fumarate until pregnancy is confirmed and stopping during pregnancy after assessment of the risks and benefits. 
• For women with highly active disease who wish to become pregnant, there are a number of therapeutic options:

1)  treatment with long lasting effects such as alemtuzumab or cladribine provided that at least 4 or 6 months respectively have elapsed between the last dose and conception2)  treatment with anti-CD20 drugs before pregnancy with advice to wait for 2-6 months after the last infusion before becoming pregnant and to avoid further infusions during pregnancy, or3) for patients treated with natalizumab, consider continuing treatment during pregnancy using a 6-week extended dosage regimen until the end of the second trimester or up until week 34 and resuming after delivery (in newborns exposed to natalizumab, check for hematological abnormalities and liver function)

• Only interferons and ofatumumab are currently approved during breastfeeding.   
•  

Treatment safety/monitoring

• When treating patients with natalizumab and after a period of stability, consider switching to a 6-week interval regimen in order to minimize the risk of progressive multifocal leukoencephalopathy (PML).
• Consider treatment with high-efficacy drugs including natalizumab in patients with high disease activity, in whom a quick therapeutic effect is required, taking into account the risk of PML in John Cunningham virus (JCV)-positive patients, as well as the therapeutic lag of the different disease-modifying drugs.
• Ideally, prioritize vaccination against COVID-19 before starting immunosuppressive disease-modifying treatments to achieve the highest protection rate possible.
•  

Long-lasting treatments

• When using long-lasting treatments (alemtuzumab or cladribine) in patients who experience disease activity before the treatment is completed (between the first and second cycles), consider waiting until completion of the therapeutic regimen before switching to other drugs.
• Consider offering additional courses of alemtuzumab after the first two cycles at least 1 year apart from each other when disease activity has not remitted completely or reappears after a period of stability, taking into account the balance between the potential benefits and side effects.

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

Updated European guidelines on the treatment of patients with multiple sclerosis (MS) have been announced and include a recommendation for siponimod (Mayzent) in progressive MS, as well as a general emphasis toward earlier and more aggressive treatment.

The updated guidelines were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and are the result of a collaboration between ECTRIMS and the European Academy of Neurology (EAN).

Maria Pia Amato, MD, ECTRIMS president and co-chair of the guidelines steering committee, noted that the European MS treatment guidelines were last published in 2018. “Since then more trials have been published, and we felt this was a good time to incorporate the new evidence into updated guidelines,” she said.

“As before, the updated guidelines contain a number of core questions that address the efficacy of disease-modifying therapies, early treatment decisions, disease/treatment response monitoring and treatment modifications, treatment suspension and disease reactivation, and pregnancy and breastfeeding,” Dr. Amato said.
 

New recommendations

New features of the updated guidelines include a recommendation for siponimod for secondary progressive MS with evidence of disease inflammatory activity; in addition, there is more emphasis on starting treatment early, with greater consideration of higher efficacy drugs, depending on the characteristics of the disease and the patient, Dr. Amato commented.

“We also provided more detailed information on disease-modifying therapy use in pregnancy and breastfeeding and also for women with high disease activity who desire to become pregnant,” she added.

Other new features include the introduction of clinical questions dealing with treatment safety and monitoring (for example, for natalizumab) and also considering the current COVID-19 pandemic scenario; switching strategies with more detailed practical indications on timing; and long lasting effects of drugs such as alemtuzumab and cladribine, Dr. Amato said.

The updated guidelines include the following recommendations:

• The entire spectrum of disease-modifying drugs should be prescribed by a neurologist with expertise in MS and ready access to adequate infrastructure to provide proper monitoring of patents, comprehensive assessment, early detection of side effects, and the capacity to address those side effects promptly.
• Offer interferon or glatiramer acetate to patients with clinically isolated syndrome (CIS) highly suggestive of MS and an abnormal MRI with lesions suggestive of MS who do not fulfill criteria for MS.
• For patients with relapsing-remitting MS, the choice between a wide range of available drugs (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, ozanimod, ponesimod, natalizumab, alemtuzumab, ocrelizumab, rituximab, or ofatumumab), from modestly to highly effective, will depend on factors including: underlying disability progression, disease severity/clinical or radiological activity, patient characteristics and morbidity, drug safety profile, family planning, and patient preferences.

Progressive MS

• For patients with secondary progressive MS with evidence of inflammatory activity (relapses and/or MRI activity), offer treatment with siponimod. Treatment with other therapies used for relapsing remitting MS may also be considered.
• For secondary progressive MS without evidence of inflammatory activity, particularly in young patients and those in whom progression has started recently, consider treatment with siponimod or anti-CD20 monoclonal antibodies, taking into account that there is scarce evidence to support their use in this setting.  
• For patients with active secondary progressive MS when there is no other therapy available, consider treatment with mitoxantrone, taking into account the safety concerns and tolerability issues of this agent. 
• Consider ocrelizumab for patients with primary progressive MS, particularly early and active (clinically and/or radiologically) disease.

Emphasis toward higher-efficacy drugs

• Consider choosing a higher-efficacy disease-modifying drug early on, according to disease activity (either clinically or on MRI).
• Offer a more efficacious drug to patients who show evidence of disease activity with their current treatment.
• When treatment with a high-efficacy drug is stopped, whether because of inefficacy or risk of adverse effects, consider starting another high-efficacy drug, taking into account clinical and MRI disease activity before and during treatment, pharmacokinetics and biological activity of the previous drug, and the potential for resumed disease activity or even rebound syndrome (particularly with natalizumab and S1P modulators).
• In the stable patient (clinically and on MRI) who shows no safety or tolerability issues, consider continuing treatment with disease-modifying therapy, taking into account patient characteristics and comorbidities, drug safety profile, family planning, and patient preferences.

Recommendations for pregnancy and breastfeeding

Recommendations for pregnant women and mothers who choose to breastfeed include:

• Advise women who wish to become pregnant to plan their pregnancy beforehand.
• Advise women of childbearing potential that MS disease-modifying therapies are not licensed during pregnancy, with the exception of interferons and glatiramer acetate.
• For women planning a pregnancy, offer interferons and glatiramer acetate and consider continuing these agents during pregnancy after assessment of risk and benefits. Consider using dimethyl fumarate until pregnancy is confirmed and stopping during pregnancy after assessment of the risks and benefits. 
• For women with highly active disease who wish to become pregnant, there are a number of therapeutic options:

1)  treatment with long lasting effects such as alemtuzumab or cladribine provided that at least 4 or 6 months respectively have elapsed between the last dose and conception2)  treatment with anti-CD20 drugs before pregnancy with advice to wait for 2-6 months after the last infusion before becoming pregnant and to avoid further infusions during pregnancy, or3) for patients treated with natalizumab, consider continuing treatment during pregnancy using a 6-week extended dosage regimen until the end of the second trimester or up until week 34 and resuming after delivery (in newborns exposed to natalizumab, check for hematological abnormalities and liver function)

• Only interferons and ofatumumab are currently approved during breastfeeding.   
•  

Treatment safety/monitoring

• When treating patients with natalizumab and after a period of stability, consider switching to a 6-week interval regimen in order to minimize the risk of progressive multifocal leukoencephalopathy (PML).
• Consider treatment with high-efficacy drugs including natalizumab in patients with high disease activity, in whom a quick therapeutic effect is required, taking into account the risk of PML in John Cunningham virus (JCV)-positive patients, as well as the therapeutic lag of the different disease-modifying drugs.
• Ideally, prioritize vaccination against COVID-19 before starting immunosuppressive disease-modifying treatments to achieve the highest protection rate possible.
•  

Long-lasting treatments

• When using long-lasting treatments (alemtuzumab or cladribine) in patients who experience disease activity before the treatment is completed (between the first and second cycles), consider waiting until completion of the therapeutic regimen before switching to other drugs.
• Consider offering additional courses of alemtuzumab after the first two cycles at least 1 year apart from each other when disease activity has not remitted completely or reappears after a period of stability, taking into account the balance between the potential benefits and side effects.

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

Among pediatric patients with multiple sclerosis (MS), some specific clinical characteristics, as well as treatment with disease-modifying therapies (DMTs), are linked to less future disability.

An estimated 3%-10% of MS patients are diagnosed during childhood. These patients experience a higher relapse rate and have higher magnetic resonance imaging (MRI) activity than do adult-onset patients. They have a slower rate of progression, but they reach irreversible disability milestones at an early age, with more than 50% having secondary progressive disease by age 30.

Studies in adults suggest that use of high-efficacy DMTs is most effective when initiated during the early active phase of MS, but little is known about children. “Early recognition of predictors of faster disability in children is crucial for clinicians to make the treatment decisions at the earliest possible time,” Sifat Sharmin, PhD, said during her presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Sharmin is a statistician and research fellow at the University of Melbourne.
 

‘Reassuring’ data

“I think the most important observation that was made here is the protective factor of use of high efficacy disease modifying therapies,” said Bruce Cree, MD, PhD, who was asked to comment on the study.

That result wasn’t unexpected, but it should provide reassurance. “For parents of children who are hesitant about use of high efficacy therapies, this study provides supporting evidence for use of these high efficacy therapies early on, to try and prevent irreversible disability from occurring,” said Dr. Cree, professor of clinical neurology and the George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California at San Francisco UCSF Weill Institute for Neurosciences.

The study provides real-world data to back up findings from a phase 3 clinical trial that showed fewer relapses and fewer new lesions in pediatric patients with MS who were taking fingolimod versus interferon beta-1a.

“Given a large randomized, controlled trial, and now with this additional real-world data set showing the same thing, the only conclusion to reach is that if you’ve got a kid with MS, they should be treated with fingolimod,” said Dr. Cree. He noted that other DMTs such as natalizumab may also benefit pediatric patients, but fingolimod is the only drug that has been studied in randomized, controlled trials in children.

Real-world data

The researchers analyzed data from 672 patients drawn from the international MSBase Neuroimmunology Registry, who had undergone neurological assessment within 1 year of symptom onset and had at least two annual visits where the Expanded Disability Status Scale (EDSS) was recorded. They sought to identify predictors of Multiple Sclerosis Severity Score (MSSS). A secondary analysis looked at predictors of EDSS sustained worsening at 6 months, defined as an increase of 1.5 if EDSS baseline was 0, 1.0 or more if baseline EDSS was 1.0-5.5, or 0.5 if baseline EDSS was over 5.5.

The researchers also conducted a sensitivity analysis that looked at relapse phenotypes and relapse frequency in the first year, as well as a subgroup analysis of patients with available MRI data from the first year. The researchers adjusted for time on high-efficacy DMTs at each visit.

Among the study participants, 70% were female. The median age of onset was 16 years. The median EDSS score was 1.5 at inclusion, and the median score was 1.0 at follow-up of 3 years. At 6 months, 82 worsening events occurred in 57 patients.

A total of 76% of the patients were treated with DMTs. The most commonly prescribed DMTs were interferon beta (40.63%), natalizumab (8.48%), and fingolimod (6.40%). Seventy-eight percent of those who received DMTs started treatment before age 18. Twenty-seven percent received high-efficacy DMTs.

The analysis showed associations between disability and older age at onset [exp(beta), 1.09; 95% confidence interval, 1.03-1.16], maximum EDSS score during the first year of disease [exp(beta), 1.25; 95% CI, 1.13-1.36], or first-year pyramidal symptoms [exp(beta), 1.34; 95% CI, 1.13-1.58], visual symptoms [exp(beta), 1.28; 95% CI, 1.10-1.48], or cerebellum symptoms [exp(beta), 1.17; 95% CI, 1.00-1.39]. A greater amount of time on high-efficacy DMTs was associated with a lower probability of disability [exp(beta), 0.96; 95% CI, 0.93-0.99].

A complete recovery from the first relapse was associated with a lower probability of relapse, though this association did not reach statistical significance [exp(beta), 0.83; 95% CI, 0.68-1.03].

The secondary analyses found that the only predictor of 6-month EDSS worsening [exp(beta), 1.32; 95% CI, 1.21-1.45] was having a maximum EDSS score in the first year. Sensitivity analyses of complete and incomplete recovery from relapses found that a higher MSSS was associated incomplete recovery [exp(beta), 1.16; 95% CI, 1.02-1.32], and confirmed the primary finding that recovery from first relapse was associated with a lower probability of disability [exp(beta), 0.78; 95% CI, 0.63-0.96].

Among patients with MRI data, a new MRI lesion in year 1 was associated with a lower future MSSS score [exp(beta), 0.81; 95% CI, 0.66-0.99].

The study was funded by the National Health and Medical Research Council of Australia. The study authors disclosed ties with a wide range of pharmaceutical companies, including Biogen and Novartis. Dr. Cree has consulted for Biogen, Novartis, and other pharmaceutical companies.

Among pediatric patients with multiple sclerosis (MS), some specific clinical characteristics, as well as treatment with disease-modifying therapies (DMTs), are linked to less future disability.

An estimated 3%-10% of MS patients are diagnosed during childhood. These patients experience a higher relapse rate and have higher magnetic resonance imaging (MRI) activity than do adult-onset patients. They have a slower rate of progression, but they reach irreversible disability milestones at an early age, with more than 50% having secondary progressive disease by age 30.

Studies in adults suggest that use of high-efficacy DMTs is most effective when initiated during the early active phase of MS, but little is known about children. “Early recognition of predictors of faster disability in children is crucial for clinicians to make the treatment decisions at the earliest possible time,” Sifat Sharmin, PhD, said during her presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Sharmin is a statistician and research fellow at the University of Melbourne.
 

‘Reassuring’ data

“I think the most important observation that was made here is the protective factor of use of high efficacy disease modifying therapies,” said Bruce Cree, MD, PhD, who was asked to comment on the study.

That result wasn’t unexpected, but it should provide reassurance. “For parents of children who are hesitant about use of high efficacy therapies, this study provides supporting evidence for use of these high efficacy therapies early on, to try and prevent irreversible disability from occurring,” said Dr. Cree, professor of clinical neurology and the George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California at San Francisco UCSF Weill Institute for Neurosciences.

The study provides real-world data to back up findings from a phase 3 clinical trial that showed fewer relapses and fewer new lesions in pediatric patients with MS who were taking fingolimod versus interferon beta-1a.

“Given a large randomized, controlled trial, and now with this additional real-world data set showing the same thing, the only conclusion to reach is that if you’ve got a kid with MS, they should be treated with fingolimod,” said Dr. Cree. He noted that other DMTs such as natalizumab may also benefit pediatric patients, but fingolimod is the only drug that has been studied in randomized, controlled trials in children.

Real-world data

The researchers analyzed data from 672 patients drawn from the international MSBase Neuroimmunology Registry, who had undergone neurological assessment within 1 year of symptom onset and had at least two annual visits where the Expanded Disability Status Scale (EDSS) was recorded. They sought to identify predictors of Multiple Sclerosis Severity Score (MSSS). A secondary analysis looked at predictors of EDSS sustained worsening at 6 months, defined as an increase of 1.5 if EDSS baseline was 0, 1.0 or more if baseline EDSS was 1.0-5.5, or 0.5 if baseline EDSS was over 5.5.

The researchers also conducted a sensitivity analysis that looked at relapse phenotypes and relapse frequency in the first year, as well as a subgroup analysis of patients with available MRI data from the first year. The researchers adjusted for time on high-efficacy DMTs at each visit.

Among the study participants, 70% were female. The median age of onset was 16 years. The median EDSS score was 1.5 at inclusion, and the median score was 1.0 at follow-up of 3 years. At 6 months, 82 worsening events occurred in 57 patients.

A total of 76% of the patients were treated with DMTs. The most commonly prescribed DMTs were interferon beta (40.63%), natalizumab (8.48%), and fingolimod (6.40%). Seventy-eight percent of those who received DMTs started treatment before age 18. Twenty-seven percent received high-efficacy DMTs.

The analysis showed associations between disability and older age at onset [exp(beta), 1.09; 95% confidence interval, 1.03-1.16], maximum EDSS score during the first year of disease [exp(beta), 1.25; 95% CI, 1.13-1.36], or first-year pyramidal symptoms [exp(beta), 1.34; 95% CI, 1.13-1.58], visual symptoms [exp(beta), 1.28; 95% CI, 1.10-1.48], or cerebellum symptoms [exp(beta), 1.17; 95% CI, 1.00-1.39]. A greater amount of time on high-efficacy DMTs was associated with a lower probability of disability [exp(beta), 0.96; 95% CI, 0.93-0.99].

A complete recovery from the first relapse was associated with a lower probability of relapse, though this association did not reach statistical significance [exp(beta), 0.83; 95% CI, 0.68-1.03].

The secondary analyses found that the only predictor of 6-month EDSS worsening [exp(beta), 1.32; 95% CI, 1.21-1.45] was having a maximum EDSS score in the first year. Sensitivity analyses of complete and incomplete recovery from relapses found that a higher MSSS was associated incomplete recovery [exp(beta), 1.16; 95% CI, 1.02-1.32], and confirmed the primary finding that recovery from first relapse was associated with a lower probability of disability [exp(beta), 0.78; 95% CI, 0.63-0.96].

Among patients with MRI data, a new MRI lesion in year 1 was associated with a lower future MSSS score [exp(beta), 0.81; 95% CI, 0.66-0.99].

The study was funded by the National Health and Medical Research Council of Australia. The study authors disclosed ties with a wide range of pharmaceutical companies, including Biogen and Novartis. Dr. Cree has consulted for Biogen, Novartis, and other pharmaceutical companies.

Among pediatric patients with multiple sclerosis (MS), some specific clinical characteristics, as well as treatment with disease-modifying therapies (DMTs), are linked to less future disability.

An estimated 3%-10% of MS patients are diagnosed during childhood. These patients experience a higher relapse rate and have higher magnetic resonance imaging (MRI) activity than do adult-onset patients. They have a slower rate of progression, but they reach irreversible disability milestones at an early age, with more than 50% having secondary progressive disease by age 30.

Studies in adults suggest that use of high-efficacy DMTs is most effective when initiated during the early active phase of MS, but little is known about children. “Early recognition of predictors of faster disability in children is crucial for clinicians to make the treatment decisions at the earliest possible time,” Sifat Sharmin, PhD, said during her presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Sharmin is a statistician and research fellow at the University of Melbourne.
 

‘Reassuring’ data

“I think the most important observation that was made here is the protective factor of use of high efficacy disease modifying therapies,” said Bruce Cree, MD, PhD, who was asked to comment on the study.

That result wasn’t unexpected, but it should provide reassurance. “For parents of children who are hesitant about use of high efficacy therapies, this study provides supporting evidence for use of these high efficacy therapies early on, to try and prevent irreversible disability from occurring,” said Dr. Cree, professor of clinical neurology and the George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California at San Francisco UCSF Weill Institute for Neurosciences.

The study provides real-world data to back up findings from a phase 3 clinical trial that showed fewer relapses and fewer new lesions in pediatric patients with MS who were taking fingolimod versus interferon beta-1a.

“Given a large randomized, controlled trial, and now with this additional real-world data set showing the same thing, the only conclusion to reach is that if you’ve got a kid with MS, they should be treated with fingolimod,” said Dr. Cree. He noted that other DMTs such as natalizumab may also benefit pediatric patients, but fingolimod is the only drug that has been studied in randomized, controlled trials in children.

Real-world data

The researchers analyzed data from 672 patients drawn from the international MSBase Neuroimmunology Registry, who had undergone neurological assessment within 1 year of symptom onset and had at least two annual visits where the Expanded Disability Status Scale (EDSS) was recorded. They sought to identify predictors of Multiple Sclerosis Severity Score (MSSS). A secondary analysis looked at predictors of EDSS sustained worsening at 6 months, defined as an increase of 1.5 if EDSS baseline was 0, 1.0 or more if baseline EDSS was 1.0-5.5, or 0.5 if baseline EDSS was over 5.5.

The researchers also conducted a sensitivity analysis that looked at relapse phenotypes and relapse frequency in the first year, as well as a subgroup analysis of patients with available MRI data from the first year. The researchers adjusted for time on high-efficacy DMTs at each visit.

Among the study participants, 70% were female. The median age of onset was 16 years. The median EDSS score was 1.5 at inclusion, and the median score was 1.0 at follow-up of 3 years. At 6 months, 82 worsening events occurred in 57 patients.

A total of 76% of the patients were treated with DMTs. The most commonly prescribed DMTs were interferon beta (40.63%), natalizumab (8.48%), and fingolimod (6.40%). Seventy-eight percent of those who received DMTs started treatment before age 18. Twenty-seven percent received high-efficacy DMTs.

The analysis showed associations between disability and older age at onset [exp(beta), 1.09; 95% confidence interval, 1.03-1.16], maximum EDSS score during the first year of disease [exp(beta), 1.25; 95% CI, 1.13-1.36], or first-year pyramidal symptoms [exp(beta), 1.34; 95% CI, 1.13-1.58], visual symptoms [exp(beta), 1.28; 95% CI, 1.10-1.48], or cerebellum symptoms [exp(beta), 1.17; 95% CI, 1.00-1.39]. A greater amount of time on high-efficacy DMTs was associated with a lower probability of disability [exp(beta), 0.96; 95% CI, 0.93-0.99].

A complete recovery from the first relapse was associated with a lower probability of relapse, though this association did not reach statistical significance [exp(beta), 0.83; 95% CI, 0.68-1.03].

The secondary analyses found that the only predictor of 6-month EDSS worsening [exp(beta), 1.32; 95% CI, 1.21-1.45] was having a maximum EDSS score in the first year. Sensitivity analyses of complete and incomplete recovery from relapses found that a higher MSSS was associated incomplete recovery [exp(beta), 1.16; 95% CI, 1.02-1.32], and confirmed the primary finding that recovery from first relapse was associated with a lower probability of disability [exp(beta), 0.78; 95% CI, 0.63-0.96].

Among patients with MRI data, a new MRI lesion in year 1 was associated with a lower future MSSS score [exp(beta), 0.81; 95% CI, 0.66-0.99].

The study was funded by the National Health and Medical Research Council of Australia. The study authors disclosed ties with a wide range of pharmaceutical companies, including Biogen and Novartis. Dr. Cree has consulted for Biogen, Novartis, and other pharmaceutical companies.

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

The U.S. Food and Drug Administration has given marketing clearance to CognICA, an artificial intelligence–powered integrated cognitive assessment for the early detection of dementia.

Developed by Cognetivity Neurosciences, CognICA is a 5-minute, computerized cognitive assessment that is completed using an iPad. The test offers several advantages over traditional pen-and-paper–based cognitive tests, the company said in a news release.

“These include its high sensitivity to early-stage cognitive impairment, avoidance of cultural or educational bias, and absence of learning effect upon repeat testing,” the company notes.

Because the test runs on a computer, it can support remote, self-administered testing at scale and is geared toward seamless integration with existing electronic health record systems, they add.

According to the latest Alzheimer’s Disease Facts and Figures, published by the Alzheimer’s Association, more than 6 million Americans are now living with Alzheimer’s disease. That number is projected to increase to 12.7 million by 2050.

“We’re excited about the opportunity to revolutionize the way cognitive impairment is assessed and managed in the U.S. and make a positive impact on the health and wellbeing of millions of Americans,” Sina Habibi, PhD, cofounder and CEO of Cognetivity, said in the news release.

The test has already received European regulatory approval as a CE-marked medical device and has been deployed in both primary and specialist clinical care in the U.K.’s National Health Service.

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

The U.S. Food and Drug Administration has given marketing clearance to CognICA, an artificial intelligence–powered integrated cognitive assessment for the early detection of dementia.

Developed by Cognetivity Neurosciences, CognICA is a 5-minute, computerized cognitive assessment that is completed using an iPad. The test offers several advantages over traditional pen-and-paper–based cognitive tests, the company said in a news release.

“These include its high sensitivity to early-stage cognitive impairment, avoidance of cultural or educational bias, and absence of learning effect upon repeat testing,” the company notes.

Because the test runs on a computer, it can support remote, self-administered testing at scale and is geared toward seamless integration with existing electronic health record systems, they add.

According to the latest Alzheimer’s Disease Facts and Figures, published by the Alzheimer’s Association, more than 6 million Americans are now living with Alzheimer’s disease. That number is projected to increase to 12.7 million by 2050.

“We’re excited about the opportunity to revolutionize the way cognitive impairment is assessed and managed in the U.S. and make a positive impact on the health and wellbeing of millions of Americans,” Sina Habibi, PhD, cofounder and CEO of Cognetivity, said in the news release.

The test has already received European regulatory approval as a CE-marked medical device and has been deployed in both primary and specialist clinical care in the U.K.’s National Health Service.

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

The U.S. Food and Drug Administration has given marketing clearance to CognICA, an artificial intelligence–powered integrated cognitive assessment for the early detection of dementia.

Developed by Cognetivity Neurosciences, CognICA is a 5-minute, computerized cognitive assessment that is completed using an iPad. The test offers several advantages over traditional pen-and-paper–based cognitive tests, the company said in a news release.

“These include its high sensitivity to early-stage cognitive impairment, avoidance of cultural or educational bias, and absence of learning effect upon repeat testing,” the company notes.

Because the test runs on a computer, it can support remote, self-administered testing at scale and is geared toward seamless integration with existing electronic health record systems, they add.

According to the latest Alzheimer’s Disease Facts and Figures, published by the Alzheimer’s Association, more than 6 million Americans are now living with Alzheimer’s disease. That number is projected to increase to 12.7 million by 2050.

“We’re excited about the opportunity to revolutionize the way cognitive impairment is assessed and managed in the U.S. and make a positive impact on the health and wellbeing of millions of Americans,” Sina Habibi, PhD, cofounder and CEO of Cognetivity, said in the news release.

The test has already received European regulatory approval as a CE-marked medical device and has been deployed in both primary and specialist clinical care in the U.K.’s National Health Service.

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

Dementia remains a major cause of disability in older adults. In addition, it places a strain on family members and other caregivers taking care of these patients.

It is estimated that by the year 2060, 13.9 million Americans over the age of 65 will be diagnosed with dementia. Few good treatments are currently available.

Earlier this year, the American Psychological Association (APA) Task Force issued clinical guidelines “for the Evaluation of Dementia and Age-Related Cognitive Change.” While these 16 guidelines are aimed at psychologists, primary care doctors are often the first ones to evaluate a patient who may have dementia. As a family physician, I find having these guidelines especially helpful.
 

Neuropsychiatric testing and defining severity and type

This new guidance places emphasis on neuropsychiatric testing and defining the severity and type of dementia present.

Over the past 2 decades, diagnoses of mild neurocognitive disorders have increased, and this, in part, is due to diagnosing these problems earlier and with greater precision. It is also important to know that biomarkers are being increasingly researched, and it is imperative that we stay current with this research.

Cognitive decline may also occur with the coexistence of other mental health disorders, such as depression, so it is important that we screen for these as well. This is often difficult given the behavioral changes that can arise in dementia, but, as primary care doctors, we must differentiate these to treat our patients appropriately.
 

Informed consent

Informed consent can become an issue with patients with dementia. It must be assessed whether the patient has the capacity to make an informed decision and can competently communicate that decision.

The diagnosis of dementia alone does not preclude a patient from giving informed consent. A patient’s mental capacity must be determined, and if they are not capable of making an informed decision, the person legally responsible for giving informed consent on behalf of the patient must be identified.

Patients with dementia often have other medical comorbidities and take several medications. It is imperative to keep accurate medical records and medication lists. Sometimes, patients with dementia cannot provide this information. If that is the case, every attempt should be made to obtain records from every possible source.
 

Cultural competence

The guidelines also stress that there may be cultural differences when applying neuropsychiatric tests. It is our duty to maintain cultural competence and understand these differences. We all need to work to ensure we control our biases, and it is suggested that we review relevant evidence-based literature.

While ageism is common in our society, it shouldn’t be in our practices. For these reasons, outreach in at-risk populations is very important.
 

Pertinent data

The guidelines also suggest obtaining all possible information in our evaluation, especially when the patient is unable to give it to us.

Often, as primary care physicians, we refer these patients to other providers, and we should be providing all pertinent data to those we are referring these patients to. If all information is not available at the time of evaluation, follow-up visits should be scheduled.

If possible, family members should be present at the time of visit. They often provide valuable information regarding the extent and progression of the decline. Also, they know how the patient is functioning in the home setting and how much assistance they need with activities of daily living.
 

Caretaker support

Another important factor to consider is caretaker burnout. Caretakers are often under a lot of stress and have high rates of depression. It is important to provide them with education and support, as well as resources that may be available to them. For some, accepting the diagnosis that their loved one has dementia may be a struggle.

As doctors treating dementia patients, we need to know the resources that are available to assist dementia patients and their families. There are many local organizations that can help.

Also, research into dementia is ongoing and we need to stay current. The diagnosis of dementia should be made as early as possible using appropriate screening tools. The sooner the diagnosis is made, the quicker interventions can be started and the family members, as well as the patient, can come to accept the diagnosis.

As the population ages, we can expect the demands of dementia to rise as well. Primary care doctors are in a unique position to diagnose dementia once it starts to appear.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Dementia remains a major cause of disability in older adults. In addition, it places a strain on family members and other caregivers taking care of these patients.

It is estimated that by the year 2060, 13.9 million Americans over the age of 65 will be diagnosed with dementia. Few good treatments are currently available.

Earlier this year, the American Psychological Association (APA) Task Force issued clinical guidelines “for the Evaluation of Dementia and Age-Related Cognitive Change.” While these 16 guidelines are aimed at psychologists, primary care doctors are often the first ones to evaluate a patient who may have dementia. As a family physician, I find having these guidelines especially helpful.
 

Neuropsychiatric testing and defining severity and type

This new guidance places emphasis on neuropsychiatric testing and defining the severity and type of dementia present.

Over the past 2 decades, diagnoses of mild neurocognitive disorders have increased, and this, in part, is due to diagnosing these problems earlier and with greater precision. It is also important to know that biomarkers are being increasingly researched, and it is imperative that we stay current with this research.

Cognitive decline may also occur with the coexistence of other mental health disorders, such as depression, so it is important that we screen for these as well. This is often difficult given the behavioral changes that can arise in dementia, but, as primary care doctors, we must differentiate these to treat our patients appropriately.
 

Informed consent

Informed consent can become an issue with patients with dementia. It must be assessed whether the patient has the capacity to make an informed decision and can competently communicate that decision.

The diagnosis of dementia alone does not preclude a patient from giving informed consent. A patient’s mental capacity must be determined, and if they are not capable of making an informed decision, the person legally responsible for giving informed consent on behalf of the patient must be identified.

Patients with dementia often have other medical comorbidities and take several medications. It is imperative to keep accurate medical records and medication lists. Sometimes, patients with dementia cannot provide this information. If that is the case, every attempt should be made to obtain records from every possible source.
 

Cultural competence

The guidelines also stress that there may be cultural differences when applying neuropsychiatric tests. It is our duty to maintain cultural competence and understand these differences. We all need to work to ensure we control our biases, and it is suggested that we review relevant evidence-based literature.

While ageism is common in our society, it shouldn’t be in our practices. For these reasons, outreach in at-risk populations is very important.
 

Pertinent data

The guidelines also suggest obtaining all possible information in our evaluation, especially when the patient is unable to give it to us.

Often, as primary care physicians, we refer these patients to other providers, and we should be providing all pertinent data to those we are referring these patients to. If all information is not available at the time of evaluation, follow-up visits should be scheduled.

If possible, family members should be present at the time of visit. They often provide valuable information regarding the extent and progression of the decline. Also, they know how the patient is functioning in the home setting and how much assistance they need with activities of daily living.
 

Caretaker support

Another important factor to consider is caretaker burnout. Caretakers are often under a lot of stress and have high rates of depression. It is important to provide them with education and support, as well as resources that may be available to them. For some, accepting the diagnosis that their loved one has dementia may be a struggle.

As doctors treating dementia patients, we need to know the resources that are available to assist dementia patients and their families. There are many local organizations that can help.

Also, research into dementia is ongoing and we need to stay current. The diagnosis of dementia should be made as early as possible using appropriate screening tools. The sooner the diagnosis is made, the quicker interventions can be started and the family members, as well as the patient, can come to accept the diagnosis.

As the population ages, we can expect the demands of dementia to rise as well. Primary care doctors are in a unique position to diagnose dementia once it starts to appear.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Dementia remains a major cause of disability in older adults. In addition, it places a strain on family members and other caregivers taking care of these patients.

It is estimated that by the year 2060, 13.9 million Americans over the age of 65 will be diagnosed with dementia. Few good treatments are currently available.

Earlier this year, the American Psychological Association (APA) Task Force issued clinical guidelines “for the Evaluation of Dementia and Age-Related Cognitive Change.” While these 16 guidelines are aimed at psychologists, primary care doctors are often the first ones to evaluate a patient who may have dementia. As a family physician, I find having these guidelines especially helpful.
 

Neuropsychiatric testing and defining severity and type

This new guidance places emphasis on neuropsychiatric testing and defining the severity and type of dementia present.

Over the past 2 decades, diagnoses of mild neurocognitive disorders have increased, and this, in part, is due to diagnosing these problems earlier and with greater precision. It is also important to know that biomarkers are being increasingly researched, and it is imperative that we stay current with this research.

Cognitive decline may also occur with the coexistence of other mental health disorders, such as depression, so it is important that we screen for these as well. This is often difficult given the behavioral changes that can arise in dementia, but, as primary care doctors, we must differentiate these to treat our patients appropriately.
 

Informed consent

Informed consent can become an issue with patients with dementia. It must be assessed whether the patient has the capacity to make an informed decision and can competently communicate that decision.

The diagnosis of dementia alone does not preclude a patient from giving informed consent. A patient’s mental capacity must be determined, and if they are not capable of making an informed decision, the person legally responsible for giving informed consent on behalf of the patient must be identified.

Patients with dementia often have other medical comorbidities and take several medications. It is imperative to keep accurate medical records and medication lists. Sometimes, patients with dementia cannot provide this information. If that is the case, every attempt should be made to obtain records from every possible source.
 

Cultural competence

The guidelines also stress that there may be cultural differences when applying neuropsychiatric tests. It is our duty to maintain cultural competence and understand these differences. We all need to work to ensure we control our biases, and it is suggested that we review relevant evidence-based literature.

While ageism is common in our society, it shouldn’t be in our practices. For these reasons, outreach in at-risk populations is very important.
 

Pertinent data

The guidelines also suggest obtaining all possible information in our evaluation, especially when the patient is unable to give it to us.

Often, as primary care physicians, we refer these patients to other providers, and we should be providing all pertinent data to those we are referring these patients to. If all information is not available at the time of evaluation, follow-up visits should be scheduled.

If possible, family members should be present at the time of visit. They often provide valuable information regarding the extent and progression of the decline. Also, they know how the patient is functioning in the home setting and how much assistance they need with activities of daily living.
 

Caretaker support

Another important factor to consider is caretaker burnout. Caretakers are often under a lot of stress and have high rates of depression. It is important to provide them with education and support, as well as resources that may be available to them. For some, accepting the diagnosis that their loved one has dementia may be a struggle.

As doctors treating dementia patients, we need to know the resources that are available to assist dementia patients and their families. There are many local organizations that can help.

Also, research into dementia is ongoing and we need to stay current. The diagnosis of dementia should be made as early as possible using appropriate screening tools. The sooner the diagnosis is made, the quicker interventions can be started and the family members, as well as the patient, can come to accept the diagnosis.

As the population ages, we can expect the demands of dementia to rise as well. Primary care doctors are in a unique position to diagnose dementia once it starts to appear.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.