Neurology

MILWAUKEE – More than 40% of white physician trainees demonstrated racial bias in medical decision making about treatment of low back pain, as did 31% of nonwhite trainees. However, just 6% of white residents and fellows, and 10% of the nonwhite residents and fellows, reported that patient race had factored into their treatment decisions in a virtual patient task.

The 444 medical residents and fellows who participated viewed video vignettes presenting 12 virtual patients who presented with low back pain, wrote Alexis Grant of Indiana University–Purdue University Indianapolis and her colleagues. In a poster presentation at the scientific meeting of the American Pain Society, Ms. Grant, a doctoral student in clinical psychology, and her collaborators explained that participants agreed to view a series of 12 videos of virtual patients.

The videos presented male and female virtual patients who were black or white and who had jobs associated with low or high socioeconomic status (SES). Information in text vignettes accompanying the videos included occupation, pain etiology, physical exam findings, and pain intensity by self-report.

After viewing the videos and reading the vignettes, participating clinicians were asked to use a 0-100 visual analog scale to report their likelihood of referring patients to a pain specialist or to physical therapy and of recommending opioid or nonopioid analgesia.

“Next, they rated the degree to which they considered different sources of patient information when making treatment decision,” Ms. Grant and her coauthors wrote. Statistical analysis “examined the extent to which providers demonstrated statistically reliable treatment differences across patient race and SES.” These findings were compared with how clinicians reported they used patient race and SES in decision making.

Demonstrated race-based decision making occurred for 41% of white and 31% of nonwhite clinicians. About two-thirds of providers (67.3%) were white, and of the remainder, 26.3% were Asian, 4.4% were classified as “other,” and 2.1% were black. The respondents were aged a mean 29.7 years, and were 42.3% female.

In addition, Ms. Grant and her coauthors estimated provider SES by asking about parental SES, dividing respondents into low (less than $38,000), medium ($38,000-$75,000), and high (greater than $75,000) SES categories.

Demonstrated bias based on socioeconomic status was common, and similar across levels of provider SES, at 41%, 43%, and 38% for low, medium, and high SES residents and fellows, respectively. However, the disconnect between reported and demonstrated bias that was seen with race was not seen with SES bias, with 43%-48% of providers in each SES group reporting that they had factored patient SES into their treatment decision making.

“These results suggest that providers have low awareness of making different pain treatment decisions” for black patients, compared with decision making for white patients, Ms. Grant and her colleagues wrote. “Decision-making awareness did not substantially differ across provider race or SES.” She and her collaborators called for more research into whether raising awareness about demonstrated racial bias in decision making can improve both racial and socioeconomic gaps in pain care.

The authors reported funding from the National Institutes of Health. They reported no conflicts of interest.

koakes@mdedge.com

MILWAUKEE – More than 40% of white physician trainees demonstrated racial bias in medical decision making about treatment of low back pain, as did 31% of nonwhite trainees. However, just 6% of white residents and fellows, and 10% of the nonwhite residents and fellows, reported that patient race had factored into their treatment decisions in a virtual patient task.

The 444 medical residents and fellows who participated viewed video vignettes presenting 12 virtual patients who presented with low back pain, wrote Alexis Grant of Indiana University–Purdue University Indianapolis and her colleagues. In a poster presentation at the scientific meeting of the American Pain Society, Ms. Grant, a doctoral student in clinical psychology, and her collaborators explained that participants agreed to view a series of 12 videos of virtual patients.

The videos presented male and female virtual patients who were black or white and who had jobs associated with low or high socioeconomic status (SES). Information in text vignettes accompanying the videos included occupation, pain etiology, physical exam findings, and pain intensity by self-report.

After viewing the videos and reading the vignettes, participating clinicians were asked to use a 0-100 visual analog scale to report their likelihood of referring patients to a pain specialist or to physical therapy and of recommending opioid or nonopioid analgesia.

“Next, they rated the degree to which they considered different sources of patient information when making treatment decision,” Ms. Grant and her coauthors wrote. Statistical analysis “examined the extent to which providers demonstrated statistically reliable treatment differences across patient race and SES.” These findings were compared with how clinicians reported they used patient race and SES in decision making.

Demonstrated race-based decision making occurred for 41% of white and 31% of nonwhite clinicians. About two-thirds of providers (67.3%) were white, and of the remainder, 26.3% were Asian, 4.4% were classified as “other,” and 2.1% were black. The respondents were aged a mean 29.7 years, and were 42.3% female.

In addition, Ms. Grant and her coauthors estimated provider SES by asking about parental SES, dividing respondents into low (less than $38,000), medium ($38,000-$75,000), and high (greater than $75,000) SES categories.

Demonstrated bias based on socioeconomic status was common, and similar across levels of provider SES, at 41%, 43%, and 38% for low, medium, and high SES residents and fellows, respectively. However, the disconnect between reported and demonstrated bias that was seen with race was not seen with SES bias, with 43%-48% of providers in each SES group reporting that they had factored patient SES into their treatment decision making.

“These results suggest that providers have low awareness of making different pain treatment decisions” for black patients, compared with decision making for white patients, Ms. Grant and her colleagues wrote. “Decision-making awareness did not substantially differ across provider race or SES.” She and her collaborators called for more research into whether raising awareness about demonstrated racial bias in decision making can improve both racial and socioeconomic gaps in pain care.

The authors reported funding from the National Institutes of Health. They reported no conflicts of interest.

koakes@mdedge.com

MILWAUKEE – More than 40% of white physician trainees demonstrated racial bias in medical decision making about treatment of low back pain, as did 31% of nonwhite trainees. However, just 6% of white residents and fellows, and 10% of the nonwhite residents and fellows, reported that patient race had factored into their treatment decisions in a virtual patient task.

The 444 medical residents and fellows who participated viewed video vignettes presenting 12 virtual patients who presented with low back pain, wrote Alexis Grant of Indiana University–Purdue University Indianapolis and her colleagues. In a poster presentation at the scientific meeting of the American Pain Society, Ms. Grant, a doctoral student in clinical psychology, and her collaborators explained that participants agreed to view a series of 12 videos of virtual patients.

The videos presented male and female virtual patients who were black or white and who had jobs associated with low or high socioeconomic status (SES). Information in text vignettes accompanying the videos included occupation, pain etiology, physical exam findings, and pain intensity by self-report.

After viewing the videos and reading the vignettes, participating clinicians were asked to use a 0-100 visual analog scale to report their likelihood of referring patients to a pain specialist or to physical therapy and of recommending opioid or nonopioid analgesia.

“Next, they rated the degree to which they considered different sources of patient information when making treatment decision,” Ms. Grant and her coauthors wrote. Statistical analysis “examined the extent to which providers demonstrated statistically reliable treatment differences across patient race and SES.” These findings were compared with how clinicians reported they used patient race and SES in decision making.

Demonstrated race-based decision making occurred for 41% of white and 31% of nonwhite clinicians. About two-thirds of providers (67.3%) were white, and of the remainder, 26.3% were Asian, 4.4% were classified as “other,” and 2.1% were black. The respondents were aged a mean 29.7 years, and were 42.3% female.

In addition, Ms. Grant and her coauthors estimated provider SES by asking about parental SES, dividing respondents into low (less than $38,000), medium ($38,000-$75,000), and high (greater than $75,000) SES categories.

Demonstrated bias based on socioeconomic status was common, and similar across levels of provider SES, at 41%, 43%, and 38% for low, medium, and high SES residents and fellows, respectively. However, the disconnect between reported and demonstrated bias that was seen with race was not seen with SES bias, with 43%-48% of providers in each SES group reporting that they had factored patient SES into their treatment decision making.

“These results suggest that providers have low awareness of making different pain treatment decisions” for black patients, compared with decision making for white patients, Ms. Grant and her colleagues wrote. “Decision-making awareness did not substantially differ across provider race or SES.” She and her collaborators called for more research into whether raising awareness about demonstrated racial bias in decision making can improve both racial and socioeconomic gaps in pain care.

The authors reported funding from the National Institutes of Health. They reported no conflicts of interest.

koakes@mdedge.com

Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.

HISTORY & PHYSICAL EXAM

Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.

Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.

CLINICAL IMPRESSION

Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:

Obesity: Examination reveals an overweight female with a BMI of 31.1.

Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.

Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.

Continue to: Ambulation difficulty

Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.

Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.

Smoking: Sharon smokes 1 pack of cigarettes daily.

Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.

The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.

Continue to: DISCUSSION

 

 

DISCUSSION

Sharon has relapsing MS treated with ­disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.¹

The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as “Your therapy works as long as you take it on a regular basis” empowers the patient to sustain adherence and take control of her disease.

The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.

By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes

• Dietary modifications to improve nutrition and promote healthy weight loss
• A program of daily walking to improve stamina and support the patient’s weight loss program²
• Smoking cessation, including participation in a local support group of former smokers.³

Continue to: In Sharon's case...

In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.

Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.

HISTORY & PHYSICAL EXAM

Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.

Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.

CLINICAL IMPRESSION

Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:

Obesity: Examination reveals an overweight female with a BMI of 31.1.

Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.

Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.

Continue to: Ambulation difficulty

Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.

Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.

Smoking: Sharon smokes 1 pack of cigarettes daily.

Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.

The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.

Continue to: DISCUSSION

 

 

DISCUSSION

Sharon has relapsing MS treated with ­disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.¹

The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as “Your therapy works as long as you take it on a regular basis” empowers the patient to sustain adherence and take control of her disease.

The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.

By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes

• Dietary modifications to improve nutrition and promote healthy weight loss
• A program of daily walking to improve stamina and support the patient’s weight loss program²
• Smoking cessation, including participation in a local support group of former smokers.³

Continue to: In Sharon's case...

In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.

Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.

HISTORY & PHYSICAL EXAM

Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.

Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.

CLINICAL IMPRESSION

Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:

Obesity: Examination reveals an overweight female with a BMI of 31.1.

Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.

Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.

Continue to: Ambulation difficulty

Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.

Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.

Smoking: Sharon smokes 1 pack of cigarettes daily.

Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.

The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.

Continue to: DISCUSSION

 

 

DISCUSSION

Sharon has relapsing MS treated with ­disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.¹

The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as “Your therapy works as long as you take it on a regular basis” empowers the patient to sustain adherence and take control of her disease.

The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.

By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes

• Dietary modifications to improve nutrition and promote healthy weight loss
• A program of daily walking to improve stamina and support the patient’s weight loss program²
• Smoking cessation, including participation in a local support group of former smokers.³

Continue to: In Sharon's case...

In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.

The severity of traumatic brain injury (TBI) is typically defined at the time of the initial injury, but a diagnosis may not come for months or even years later. Given the complexities of diagnosing what might be a slowly revealed condition, with signs and symptoms that may manifest over time; the need for self-report of symptoms; and the time that might have elapsed since the original injury, a diagnostician needs not only to have experience with TBI but to stay abreast of the state of the science.

As of now, only health care professionals in 4 specialties—neurologist, neurosurgeon, physiatrist, or psychiatrist—are allowed to diagnose TBI in the VA’s disability compensation process. A new congressionally mandated report by the National Academies of Sciences, Engineering, and Medicine, though, is advising that it’s training and experience that count, not necessarily the specialty.

In Evaluation of the Disability Determination Process for Traumatic Brain Injury in Veterans, a committee of experts in emergency medicine, neurology, neurosurgery, psychiatry, psychology, physical medicine and rehabilitation, and epidemiology and biostatistics review the process and current literature on TBI. The committee advises that any health care professional with “pertinent and ongoing brain injury training and experience” and up-to-date knowledge about TBI should be included in the diagnostic process.

The disability compensation is a tax-free benefit paid to veterans with disabilities resulting from disease or injury incurred or aggravated during active military service. The amount is determined in a 6-step process beginning when the veteran (or a proxy) files a claim. An approved clinician typically must diagnose and evaluate the degree of impairment, functional limitation, and disability.

Between 2000 and 2018, an estimated 384,000 incidents of TBI occurred in the military. That increasing prevalence means more medical specialties now include TBI training in their curriculum. The committee notes that at least 18 brain injury programs are accredited by the Accreditation Council for Graduate Medical Education to train physicians in many specialties to diagnose, treat, and rehabilitate patients with brain injury. 

Among other recommendations, the committee advised that the VA take specific actions to increase transparency at both individual and systemwide levels, such as providing veterans full access to the details of their examinations, allowing veterans to rate the quality of their evaluations, and providing public access to detailed systemwide data on the outcomes of evaluations and outcome quality. Those changes will represent a “fundamental enhancement” in the quality of disability evaluations, the committee says, which added that shifting from a focus on the consistency of the process and practitioner qualifications to a focus on the accuracy of the outcome of the evaluation will help identify steps or components in the process that warrant improvement.

It also suggested regularly updating the Veteran Affairs Schedule for Rating Disabilities and the Disability Benefits Questionnaires (DBQs) for residuals of TBI to “better reflect the current state of medical knowledge.” The committee found that 3 important residuals of TBI are not adequately covered by any of the existing DBQs: insomnia, vestibular dysfunction, and near-vision dysfunction. Although 4 DBQs (mental disorder, chronic fatigue syndrome, PTSD, and sleep apnea) contain isolated questions related to insomnia and sleep disruption, no single DBQ, the committee says, combines them all “in a way that captures the full extent of disability associated with post-TBI sleep disruption.” Similarly, no single DBQ captures the full extent of disability associated with post-TBI vestibular dysfunction or the disability associated with near-vision dysfunction.

The committee sums up: “[B]y adopting an explicit learning structure in which the reliability and validity of disability determinations are directly assessed, the VA will be able to devote its resources to those modifications and enhancements … that will have the greatest impact in improving the service provided to injured veterans.”

The severity of traumatic brain injury (TBI) is typically defined at the time of the initial injury, but a diagnosis may not come for months or even years later. Given the complexities of diagnosing what might be a slowly revealed condition, with signs and symptoms that may manifest over time; the need for self-report of symptoms; and the time that might have elapsed since the original injury, a diagnostician needs not only to have experience with TBI but to stay abreast of the state of the science.

As of now, only health care professionals in 4 specialties—neurologist, neurosurgeon, physiatrist, or psychiatrist—are allowed to diagnose TBI in the VA’s disability compensation process. A new congressionally mandated report by the National Academies of Sciences, Engineering, and Medicine, though, is advising that it’s training and experience that count, not necessarily the specialty.

In Evaluation of the Disability Determination Process for Traumatic Brain Injury in Veterans, a committee of experts in emergency medicine, neurology, neurosurgery, psychiatry, psychology, physical medicine and rehabilitation, and epidemiology and biostatistics review the process and current literature on TBI. The committee advises that any health care professional with “pertinent and ongoing brain injury training and experience” and up-to-date knowledge about TBI should be included in the diagnostic process.

The disability compensation is a tax-free benefit paid to veterans with disabilities resulting from disease or injury incurred or aggravated during active military service. The amount is determined in a 6-step process beginning when the veteran (or a proxy) files a claim. An approved clinician typically must diagnose and evaluate the degree of impairment, functional limitation, and disability.

Between 2000 and 2018, an estimated 384,000 incidents of TBI occurred in the military. That increasing prevalence means more medical specialties now include TBI training in their curriculum. The committee notes that at least 18 brain injury programs are accredited by the Accreditation Council for Graduate Medical Education to train physicians in many specialties to diagnose, treat, and rehabilitate patients with brain injury. 

Among other recommendations, the committee advised that the VA take specific actions to increase transparency at both individual and systemwide levels, such as providing veterans full access to the details of their examinations, allowing veterans to rate the quality of their evaluations, and providing public access to detailed systemwide data on the outcomes of evaluations and outcome quality. Those changes will represent a “fundamental enhancement” in the quality of disability evaluations, the committee says, which added that shifting from a focus on the consistency of the process and practitioner qualifications to a focus on the accuracy of the outcome of the evaluation will help identify steps or components in the process that warrant improvement.

It also suggested regularly updating the Veteran Affairs Schedule for Rating Disabilities and the Disability Benefits Questionnaires (DBQs) for residuals of TBI to “better reflect the current state of medical knowledge.” The committee found that 3 important residuals of TBI are not adequately covered by any of the existing DBQs: insomnia, vestibular dysfunction, and near-vision dysfunction. Although 4 DBQs (mental disorder, chronic fatigue syndrome, PTSD, and sleep apnea) contain isolated questions related to insomnia and sleep disruption, no single DBQ, the committee says, combines them all “in a way that captures the full extent of disability associated with post-TBI sleep disruption.” Similarly, no single DBQ captures the full extent of disability associated with post-TBI vestibular dysfunction or the disability associated with near-vision dysfunction.

The committee sums up: “[B]y adopting an explicit learning structure in which the reliability and validity of disability determinations are directly assessed, the VA will be able to devote its resources to those modifications and enhancements … that will have the greatest impact in improving the service provided to injured veterans.”

The severity of traumatic brain injury (TBI) is typically defined at the time of the initial injury, but a diagnosis may not come for months or even years later. Given the complexities of diagnosing what might be a slowly revealed condition, with signs and symptoms that may manifest over time; the need for self-report of symptoms; and the time that might have elapsed since the original injury, a diagnostician needs not only to have experience with TBI but to stay abreast of the state of the science.

As of now, only health care professionals in 4 specialties—neurologist, neurosurgeon, physiatrist, or psychiatrist—are allowed to diagnose TBI in the VA’s disability compensation process. A new congressionally mandated report by the National Academies of Sciences, Engineering, and Medicine, though, is advising that it’s training and experience that count, not necessarily the specialty.

In Evaluation of the Disability Determination Process for Traumatic Brain Injury in Veterans, a committee of experts in emergency medicine, neurology, neurosurgery, psychiatry, psychology, physical medicine and rehabilitation, and epidemiology and biostatistics review the process and current literature on TBI. The committee advises that any health care professional with “pertinent and ongoing brain injury training and experience” and up-to-date knowledge about TBI should be included in the diagnostic process.

The disability compensation is a tax-free benefit paid to veterans with disabilities resulting from disease or injury incurred or aggravated during active military service. The amount is determined in a 6-step process beginning when the veteran (or a proxy) files a claim. An approved clinician typically must diagnose and evaluate the degree of impairment, functional limitation, and disability.

Between 2000 and 2018, an estimated 384,000 incidents of TBI occurred in the military. That increasing prevalence means more medical specialties now include TBI training in their curriculum. The committee notes that at least 18 brain injury programs are accredited by the Accreditation Council for Graduate Medical Education to train physicians in many specialties to diagnose, treat, and rehabilitate patients with brain injury. 

Among other recommendations, the committee advised that the VA take specific actions to increase transparency at both individual and systemwide levels, such as providing veterans full access to the details of their examinations, allowing veterans to rate the quality of their evaluations, and providing public access to detailed systemwide data on the outcomes of evaluations and outcome quality. Those changes will represent a “fundamental enhancement” in the quality of disability evaluations, the committee says, which added that shifting from a focus on the consistency of the process and practitioner qualifications to a focus on the accuracy of the outcome of the evaluation will help identify steps or components in the process that warrant improvement.

It also suggested regularly updating the Veteran Affairs Schedule for Rating Disabilities and the Disability Benefits Questionnaires (DBQs) for residuals of TBI to “better reflect the current state of medical knowledge.” The committee found that 3 important residuals of TBI are not adequately covered by any of the existing DBQs: insomnia, vestibular dysfunction, and near-vision dysfunction. Although 4 DBQs (mental disorder, chronic fatigue syndrome, PTSD, and sleep apnea) contain isolated questions related to insomnia and sleep disruption, no single DBQ, the committee says, combines them all “in a way that captures the full extent of disability associated with post-TBI sleep disruption.” Similarly, no single DBQ captures the full extent of disability associated with post-TBI vestibular dysfunction or the disability associated with near-vision dysfunction.

The committee sums up: “[B]y adopting an explicit learning structure in which the reliability and validity of disability determinations are directly assessed, the VA will be able to devote its resources to those modifications and enhancements … that will have the greatest impact in improving the service provided to injured veterans.”

Fingolimod, a sphingosine-1-phosphate receptor modulator, has been used to treat > 55,000 patients in the US, according to the manufacturer (Gilenya/Novartis). It is believed to work by keeping lymphocytes from migrating into the CNS, sequestering them in the lymph nodes.

Although it has been found effective in randomized controlled trials, fingolimod is also known to have a wide range of adverse effects (AEs), including some that are serious and even life-threatening, such as bradycardia and atrioventricular block. The drug is contraindicated for patients who have had myocardial infarction, unstable angina, or heart failure, among other conditions. Ventricular tachycardia has been reported only once, but clinicians from Hurley Medical Center in Flint, Michigan, suggest that it may actually be an underrecognized cause of sudden death.

They describe the case of their patient, a 63-year-old woman with relapsing-remitting multiple sclerosis and hypertension who was about to start fingolomod. She underwent a basal ECG to be cleared before starting treatment. She received her first dose of fingolimod at the cardiology office, was monitored for 6 hours, and went home with a surface-mounted Holter monitor.

Two weeks later, she was in the emergency department because the monitor had captured ventricular tachycardia, and she was reporting palpitations.

Lab work was normal; the echocardiogram was normal. Cardiac monitoring showed no other evidence of cardiac arrhythmias. Her only other medication was amlodipine. The fingolimod was held back. She was observed for4 days then discharged in a stable condition. Her clinicians followed her for 2 months but the arrhythmia did not return.

Although this patient had no further arrhythmias, the authors warn that serious outcomes are possible. They urge health care practitioners to let patients know of this potential AE and advise them to report symptoms such as palpitations immediately.

Fingolimod, a sphingosine-1-phosphate receptor modulator, has been used to treat > 55,000 patients in the US, according to the manufacturer (Gilenya/Novartis). It is believed to work by keeping lymphocytes from migrating into the CNS, sequestering them in the lymph nodes.

Although it has been found effective in randomized controlled trials, fingolimod is also known to have a wide range of adverse effects (AEs), including some that are serious and even life-threatening, such as bradycardia and atrioventricular block. The drug is contraindicated for patients who have had myocardial infarction, unstable angina, or heart failure, among other conditions. Ventricular tachycardia has been reported only once, but clinicians from Hurley Medical Center in Flint, Michigan, suggest that it may actually be an underrecognized cause of sudden death.

They describe the case of their patient, a 63-year-old woman with relapsing-remitting multiple sclerosis and hypertension who was about to start fingolomod. She underwent a basal ECG to be cleared before starting treatment. She received her first dose of fingolimod at the cardiology office, was monitored for 6 hours, and went home with a surface-mounted Holter monitor.

Two weeks later, she was in the emergency department because the monitor had captured ventricular tachycardia, and she was reporting palpitations.

Lab work was normal; the echocardiogram was normal. Cardiac monitoring showed no other evidence of cardiac arrhythmias. Her only other medication was amlodipine. The fingolimod was held back. She was observed for4 days then discharged in a stable condition. Her clinicians followed her for 2 months but the arrhythmia did not return.

Although this patient had no further arrhythmias, the authors warn that serious outcomes are possible. They urge health care practitioners to let patients know of this potential AE and advise them to report symptoms such as palpitations immediately.

Fingolimod, a sphingosine-1-phosphate receptor modulator, has been used to treat > 55,000 patients in the US, according to the manufacturer (Gilenya/Novartis). It is believed to work by keeping lymphocytes from migrating into the CNS, sequestering them in the lymph nodes.

Although it has been found effective in randomized controlled trials, fingolimod is also known to have a wide range of adverse effects (AEs), including some that are serious and even life-threatening, such as bradycardia and atrioventricular block. The drug is contraindicated for patients who have had myocardial infarction, unstable angina, or heart failure, among other conditions. Ventricular tachycardia has been reported only once, but clinicians from Hurley Medical Center in Flint, Michigan, suggest that it may actually be an underrecognized cause of sudden death.

They describe the case of their patient, a 63-year-old woman with relapsing-remitting multiple sclerosis and hypertension who was about to start fingolomod. She underwent a basal ECG to be cleared before starting treatment. She received her first dose of fingolimod at the cardiology office, was monitored for 6 hours, and went home with a surface-mounted Holter monitor.

Two weeks later, she was in the emergency department because the monitor had captured ventricular tachycardia, and she was reporting palpitations.

Lab work was normal; the echocardiogram was normal. Cardiac monitoring showed no other evidence of cardiac arrhythmias. Her only other medication was amlodipine. The fingolimod was held back. She was observed for4 days then discharged in a stable condition. Her clinicians followed her for 2 months but the arrhythmia did not return.

Although this patient had no further arrhythmias, the authors warn that serious outcomes are possible. They urge health care practitioners to let patients know of this potential AE and advise them to report symptoms such as palpitations immediately.

The Food and Drug Administration on April 19 approved the first generic naloxone hydrochloride nasal spray (Narcan) as treatment for stopping or reversing an opioid overdose.

“In the wake of the opioid crisis, a number of efforts are underway to make this emergency overdose reversal treatment more readily available and more accessible,” said Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, in a press release. “In addition to this approval of the first generic naloxone nasal spray, moving forward, we will prioritize our review of generic drug applications for naloxone.”

The agency said the naloxone nasal spray does not need assembly and can be used by anyone, regardless of medical training. The drug is administered by spraying naloxone into one nostril while a patient is lying on his or her back and can be repeated. If the spray is administered quickly after the overdose begins, the effect of the opioid will be countered, often within minutes. However, patients should still seek immediate medical attention.

The FDA cautioned that, when used on a patient with an opioid dependence, naloxone can cause severe opioid withdrawal, characterized by symptoms such as body aches, diarrhea, tachycardia, fever, runny nose, sneezing, goose bumps, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration on April 19 approved the first generic naloxone hydrochloride nasal spray (Narcan) as treatment for stopping or reversing an opioid overdose.

“In the wake of the opioid crisis, a number of efforts are underway to make this emergency overdose reversal treatment more readily available and more accessible,” said Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, in a press release. “In addition to this approval of the first generic naloxone nasal spray, moving forward, we will prioritize our review of generic drug applications for naloxone.”

The agency said the naloxone nasal spray does not need assembly and can be used by anyone, regardless of medical training. The drug is administered by spraying naloxone into one nostril while a patient is lying on his or her back and can be repeated. If the spray is administered quickly after the overdose begins, the effect of the opioid will be countered, often within minutes. However, patients should still seek immediate medical attention.

The FDA cautioned that, when used on a patient with an opioid dependence, naloxone can cause severe opioid withdrawal, characterized by symptoms such as body aches, diarrhea, tachycardia, fever, runny nose, sneezing, goose bumps, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration on April 19 approved the first generic naloxone hydrochloride nasal spray (Narcan) as treatment for stopping or reversing an opioid overdose.

“In the wake of the opioid crisis, a number of efforts are underway to make this emergency overdose reversal treatment more readily available and more accessible,” said Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, in a press release. “In addition to this approval of the first generic naloxone nasal spray, moving forward, we will prioritize our review of generic drug applications for naloxone.”

The agency said the naloxone nasal spray does not need assembly and can be used by anyone, regardless of medical training. The drug is administered by spraying naloxone into one nostril while a patient is lying on his or her back and can be repeated. If the spray is administered quickly after the overdose begins, the effect of the opioid will be countered, often within minutes. However, patients should still seek immediate medical attention.

The FDA cautioned that, when used on a patient with an opioid dependence, naloxone can cause severe opioid withdrawal, characterized by symptoms such as body aches, diarrhea, tachycardia, fever, runny nose, sneezing, goose bumps, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.

Find the full press release on the FDA website.

lfranki@mdedge.com

The severity and duration of vaccine-proximate febrile seizures (VP-FSs) are no worse than non–vaccine proximate febrile seizures (NVP-FSs), according to a study in Pediatrics.

KatarzynaBialasiewicz/Thinkstock

Lucy Deng, MBBS, of the University of Sydney and her colleagues investigated 1,022 index febrile seizures in children aged 6 years or less, of which 6% (n = 67) were VP-FSs and 94% (n = 955) were NVP-FSs. Both univariate and multivariate analyses showed no increased risk of severe seizure associated with VP-FSs, compared with NVP-FS. Most of the febrile seizures of either type were brief (15 minutes or less) and had a length of stay of 1 day or less; there also were no differences in 24-hour recurrence. The most common symptom was respiratory, and the rates were similar in each group (62.7% with VP-FS vs. 62.8% with NVP-FS). In keeping with a known 100% increased risk associated with measles vaccination, 84% of VP-FSs were associated with measles-containing vaccines. The majority of the remaining VP-FSs occurred after combination vaccines.

One limitation is that, because these cases were documented in sentinel tertiary pediatric hospitals, the case ascertainment may not be representative. Also, the small proportion of VP-FSs and limited cohort size means the study may not have been powered to detect true differences in prolonged seizures between the groups, Dr. Deng and her colleagues wrote.

“This study confirms that VP-FSs are clinically not any different from NVP-FSs and should be managed the same way,” the researchers concluded.

The authors reported no relevant financial disclosures, although Dr. Deng is supported by the University of Sydney Training Program scholarship, and two other study authors are supported by Australian National Health and Medical Research Council Career Development Fellowships. The study was funded by a grant from the Australian Government Department of Health and the National Health and Medical Research Council.

cpalmer@mdedge.com

SOURCE: Deng L et al. Pediatrics. 2019 Apr 19. doi: 10.1542/peds.2018-2120.

The severity and duration of vaccine-proximate febrile seizures (VP-FSs) are no worse than non–vaccine proximate febrile seizures (NVP-FSs), according to a study in Pediatrics.

KatarzynaBialasiewicz/Thinkstock

Lucy Deng, MBBS, of the University of Sydney and her colleagues investigated 1,022 index febrile seizures in children aged 6 years or less, of which 6% (n = 67) were VP-FSs and 94% (n = 955) were NVP-FSs. Both univariate and multivariate analyses showed no increased risk of severe seizure associated with VP-FSs, compared with NVP-FS. Most of the febrile seizures of either type were brief (15 minutes or less) and had a length of stay of 1 day or less; there also were no differences in 24-hour recurrence. The most common symptom was respiratory, and the rates were similar in each group (62.7% with VP-FS vs. 62.8% with NVP-FS). In keeping with a known 100% increased risk associated with measles vaccination, 84% of VP-FSs were associated with measles-containing vaccines. The majority of the remaining VP-FSs occurred after combination vaccines.

One limitation is that, because these cases were documented in sentinel tertiary pediatric hospitals, the case ascertainment may not be representative. Also, the small proportion of VP-FSs and limited cohort size means the study may not have been powered to detect true differences in prolonged seizures between the groups, Dr. Deng and her colleagues wrote.

“This study confirms that VP-FSs are clinically not any different from NVP-FSs and should be managed the same way,” the researchers concluded.

The authors reported no relevant financial disclosures, although Dr. Deng is supported by the University of Sydney Training Program scholarship, and two other study authors are supported by Australian National Health and Medical Research Council Career Development Fellowships. The study was funded by a grant from the Australian Government Department of Health and the National Health and Medical Research Council.

cpalmer@mdedge.com

SOURCE: Deng L et al. Pediatrics. 2019 Apr 19. doi: 10.1542/peds.2018-2120.

The severity and duration of vaccine-proximate febrile seizures (VP-FSs) are no worse than non–vaccine proximate febrile seizures (NVP-FSs), according to a study in Pediatrics.

KatarzynaBialasiewicz/Thinkstock

Lucy Deng, MBBS, of the University of Sydney and her colleagues investigated 1,022 index febrile seizures in children aged 6 years or less, of which 6% (n = 67) were VP-FSs and 94% (n = 955) were NVP-FSs. Both univariate and multivariate analyses showed no increased risk of severe seizure associated with VP-FSs, compared with NVP-FS. Most of the febrile seizures of either type were brief (15 minutes or less) and had a length of stay of 1 day or less; there also were no differences in 24-hour recurrence. The most common symptom was respiratory, and the rates were similar in each group (62.7% with VP-FS vs. 62.8% with NVP-FS). In keeping with a known 100% increased risk associated with measles vaccination, 84% of VP-FSs were associated with measles-containing vaccines. The majority of the remaining VP-FSs occurred after combination vaccines.

One limitation is that, because these cases were documented in sentinel tertiary pediatric hospitals, the case ascertainment may not be representative. Also, the small proportion of VP-FSs and limited cohort size means the study may not have been powered to detect true differences in prolonged seizures between the groups, Dr. Deng and her colleagues wrote.

“This study confirms that VP-FSs are clinically not any different from NVP-FSs and should be managed the same way,” the researchers concluded.

The authors reported no relevant financial disclosures, although Dr. Deng is supported by the University of Sydney Training Program scholarship, and two other study authors are supported by Australian National Health and Medical Research Council Career Development Fellowships. The study was funded by a grant from the Australian Government Department of Health and the National Health and Medical Research Council.

cpalmer@mdedge.com

SOURCE: Deng L et al. Pediatrics. 2019 Apr 19. doi: 10.1542/peds.2018-2120.

Treatment with pembrolizumab or nivolumab may benefit patients with progressive multifocal leukoencephalopathy (PML), investigators reported in the New England Journal of Medicine.

Three research teams described 10 cases in which patients with PML received pembrolizumab or nivolumab.

In one study, researchers administered pembrolizumab to eight adults with PML. Five patients had clinical improvement or stabilization, whereas 3 patients did not. Among the patients with clinical improvement, treatment led to reduced JC viral load in cerebrospinal fluid (CSF) and increased CD4+ and CD8+ anti–JC virus activity in vitro. Among patients without clinical improvement, treatment did not meaningfully change viral load or antiviral cellular immune response.

In a separate letter, researchers in Germany described an additional patient with PML who had clinical stabilization and no disease progression on MRI after treatment with pembrolizumab.

In another letter, researchers in France described a patient with PML whose condition improved after treatment with nivolumab.

“Do pembrolizumab and nivolumab fit the bill for treatment of PML? The current reports are encouraging but suggest that the presence of JC virus–specific T cells in the blood is a prerequisite for their use,” said Igor J. Koralnik, MD, of the department of neurological sciences at Rush University Medical Center in Chicago, in an accompanying editorial. “A controlled trial may be needed to determine whether immune checkpoint inhibitors are indeed able to keep JC virus in check in patients with PML.”


 

Reinvigorating T cells

Both monoclonal antibodies target programmed cell death protein 1 (PD-1), which inhibits T-cell proliferation and cytokine production when it binds its associated ligand, Dr. Koralnik said. Pembrolizumab and nivolumab block this inhibition and have been used to spur T-cell activity against tumors in patients with cancer.

PML, an often fatal brain infection caused by the JC virus in patients with immunosuppression, has no specific treatment. Management hinges on “recovery of the immune system, either by treating the underlying cause of immunosuppression or by discontinuing the use of immunosuppressive medications,” said Dr. Koralnik.
 

Pembrolizumab

Prior studies have found that PD-1 expression is elevated on T lymphocytes of patients with PML. To determine whether PD-1 blockade with pembrolizumab reinvigorates anti–JC virus immune activity in patients with PML, Irene Cortese, MD, of the National Institutes of Health’s Neuroimmunology Clinic and her research colleagues administered pembrolizumab at a dose of 2 mg/kg of body weight every 4-6 weeks to eight adults with PML. The patients received 1-3 doses, and each patient had a different underlying condition.

In all patients, treatment induced down-regulation of PD-1 expression on lymphocytes in CSF and peripheral blood, and five of the eight patients had clinical stabilization or improvement. Of the other three patients who did not improve, one had stabilized prior to treatment and remained stable. The other two patients died from PML.
 

Additional reports

Separately, Sebastian Rauer, MD, of Albert Ludwigs University in Freiburg, Germany, and his colleagues reported that a patient with PML whose symptoms culminated in mutism in February 2018 began speaking again after receiving five infusions of pembrolizumab over 10 weeks. “In addition, the size and number of lesions on MRI decreased, and JCV was no longer detectable in CSF,” Dr. Rauer and his colleagues wrote. “The patient has remained stable as of the end of March 2019, with persistent but abating psychomotor slowing, aphasia, and disorientation.”

Finally, Ondine Walter, of Toulouse (France) University Hospital and colleagues described the case of a 60-year-old woman with PML who received nivolumab on a compassionate-use basis. Two weeks after treatment, JC viral load in CSF and blood had decreased. “Starting 8 weeks after the initiation of nivolumab therapy, the patient’s neurologic symptoms and signs stabilized, and subsequently she showed improved alertness, and the ptosis and hemiplegia abated.”
 

Reason for caution

Prior studies, however, give reasons for caution when considering the potential use of immune checkpoint inhibitors to treat PML, Dr. Koralnik noted. In one case, a patient developed an inflammatory form of PML known as immune reconstitution inflammatory syndrome after receiving nivolumab (J Neurovirol. 2019 March 12. doi: 10.1007/s13365-019-00738-x). In addition, researchers have reported a case of PML that occurred after 1 year of nivolumab treatment, and four cases of PML related to nivolumab have been reported in pharmacovigilance databases (Emerg Infect Dis. 2018;24:1594-6). The cost and safety profiles of the medications also may be considerations, Dr. Koralnik said.

The study by Dr. Cortese and colleagues was funded by the National Institutes of Health, and the authors had no relevant disclosures. Some of the research letter authors disclosed grants and personal fees from pharmaceutical companies.

jremaly@mdedge.com

SOURCES: Cortese I et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1815039; Rauer S et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1817193; Walter O et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1816198; Koralnik IJ. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMe1904140.

Treatment with pembrolizumab or nivolumab may benefit patients with progressive multifocal leukoencephalopathy (PML), investigators reported in the New England Journal of Medicine.

Three research teams described 10 cases in which patients with PML received pembrolizumab or nivolumab.

In one study, researchers administered pembrolizumab to eight adults with PML. Five patients had clinical improvement or stabilization, whereas 3 patients did not. Among the patients with clinical improvement, treatment led to reduced JC viral load in cerebrospinal fluid (CSF) and increased CD4+ and CD8+ anti–JC virus activity in vitro. Among patients without clinical improvement, treatment did not meaningfully change viral load or antiviral cellular immune response.

In a separate letter, researchers in Germany described an additional patient with PML who had clinical stabilization and no disease progression on MRI after treatment with pembrolizumab.

In another letter, researchers in France described a patient with PML whose condition improved after treatment with nivolumab.

“Do pembrolizumab and nivolumab fit the bill for treatment of PML? The current reports are encouraging but suggest that the presence of JC virus–specific T cells in the blood is a prerequisite for their use,” said Igor J. Koralnik, MD, of the department of neurological sciences at Rush University Medical Center in Chicago, in an accompanying editorial. “A controlled trial may be needed to determine whether immune checkpoint inhibitors are indeed able to keep JC virus in check in patients with PML.”


 

Reinvigorating T cells

Both monoclonal antibodies target programmed cell death protein 1 (PD-1), which inhibits T-cell proliferation and cytokine production when it binds its associated ligand, Dr. Koralnik said. Pembrolizumab and nivolumab block this inhibition and have been used to spur T-cell activity against tumors in patients with cancer.

PML, an often fatal brain infection caused by the JC virus in patients with immunosuppression, has no specific treatment. Management hinges on “recovery of the immune system, either by treating the underlying cause of immunosuppression or by discontinuing the use of immunosuppressive medications,” said Dr. Koralnik.
 

Pembrolizumab

Prior studies have found that PD-1 expression is elevated on T lymphocytes of patients with PML. To determine whether PD-1 blockade with pembrolizumab reinvigorates anti–JC virus immune activity in patients with PML, Irene Cortese, MD, of the National Institutes of Health’s Neuroimmunology Clinic and her research colleagues administered pembrolizumab at a dose of 2 mg/kg of body weight every 4-6 weeks to eight adults with PML. The patients received 1-3 doses, and each patient had a different underlying condition.

In all patients, treatment induced down-regulation of PD-1 expression on lymphocytes in CSF and peripheral blood, and five of the eight patients had clinical stabilization or improvement. Of the other three patients who did not improve, one had stabilized prior to treatment and remained stable. The other two patients died from PML.
 

Additional reports

Separately, Sebastian Rauer, MD, of Albert Ludwigs University in Freiburg, Germany, and his colleagues reported that a patient with PML whose symptoms culminated in mutism in February 2018 began speaking again after receiving five infusions of pembrolizumab over 10 weeks. “In addition, the size and number of lesions on MRI decreased, and JCV was no longer detectable in CSF,” Dr. Rauer and his colleagues wrote. “The patient has remained stable as of the end of March 2019, with persistent but abating psychomotor slowing, aphasia, and disorientation.”

Finally, Ondine Walter, of Toulouse (France) University Hospital and colleagues described the case of a 60-year-old woman with PML who received nivolumab on a compassionate-use basis. Two weeks after treatment, JC viral load in CSF and blood had decreased. “Starting 8 weeks after the initiation of nivolumab therapy, the patient’s neurologic symptoms and signs stabilized, and subsequently she showed improved alertness, and the ptosis and hemiplegia abated.”
 

Reason for caution

Prior studies, however, give reasons for caution when considering the potential use of immune checkpoint inhibitors to treat PML, Dr. Koralnik noted. In one case, a patient developed an inflammatory form of PML known as immune reconstitution inflammatory syndrome after receiving nivolumab (J Neurovirol. 2019 March 12. doi: 10.1007/s13365-019-00738-x). In addition, researchers have reported a case of PML that occurred after 1 year of nivolumab treatment, and four cases of PML related to nivolumab have been reported in pharmacovigilance databases (Emerg Infect Dis. 2018;24:1594-6). The cost and safety profiles of the medications also may be considerations, Dr. Koralnik said.

The study by Dr. Cortese and colleagues was funded by the National Institutes of Health, and the authors had no relevant disclosures. Some of the research letter authors disclosed grants and personal fees from pharmaceutical companies.

jremaly@mdedge.com

SOURCES: Cortese I et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1815039; Rauer S et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1817193; Walter O et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1816198; Koralnik IJ. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMe1904140.

Treatment with pembrolizumab or nivolumab may benefit patients with progressive multifocal leukoencephalopathy (PML), investigators reported in the New England Journal of Medicine.

Three research teams described 10 cases in which patients with PML received pembrolizumab or nivolumab.

In one study, researchers administered pembrolizumab to eight adults with PML. Five patients had clinical improvement or stabilization, whereas 3 patients did not. Among the patients with clinical improvement, treatment led to reduced JC viral load in cerebrospinal fluid (CSF) and increased CD4+ and CD8+ anti–JC virus activity in vitro. Among patients without clinical improvement, treatment did not meaningfully change viral load or antiviral cellular immune response.

In a separate letter, researchers in Germany described an additional patient with PML who had clinical stabilization and no disease progression on MRI after treatment with pembrolizumab.

In another letter, researchers in France described a patient with PML whose condition improved after treatment with nivolumab.

“Do pembrolizumab and nivolumab fit the bill for treatment of PML? The current reports are encouraging but suggest that the presence of JC virus–specific T cells in the blood is a prerequisite for their use,” said Igor J. Koralnik, MD, of the department of neurological sciences at Rush University Medical Center in Chicago, in an accompanying editorial. “A controlled trial may be needed to determine whether immune checkpoint inhibitors are indeed able to keep JC virus in check in patients with PML.”


 

Reinvigorating T cells

Both monoclonal antibodies target programmed cell death protein 1 (PD-1), which inhibits T-cell proliferation and cytokine production when it binds its associated ligand, Dr. Koralnik said. Pembrolizumab and nivolumab block this inhibition and have been used to spur T-cell activity against tumors in patients with cancer.

PML, an often fatal brain infection caused by the JC virus in patients with immunosuppression, has no specific treatment. Management hinges on “recovery of the immune system, either by treating the underlying cause of immunosuppression or by discontinuing the use of immunosuppressive medications,” said Dr. Koralnik.
 

Pembrolizumab

Prior studies have found that PD-1 expression is elevated on T lymphocytes of patients with PML. To determine whether PD-1 blockade with pembrolizumab reinvigorates anti–JC virus immune activity in patients with PML, Irene Cortese, MD, of the National Institutes of Health’s Neuroimmunology Clinic and her research colleagues administered pembrolizumab at a dose of 2 mg/kg of body weight every 4-6 weeks to eight adults with PML. The patients received 1-3 doses, and each patient had a different underlying condition.

In all patients, treatment induced down-regulation of PD-1 expression on lymphocytes in CSF and peripheral blood, and five of the eight patients had clinical stabilization or improvement. Of the other three patients who did not improve, one had stabilized prior to treatment and remained stable. The other two patients died from PML.
 

Additional reports

Separately, Sebastian Rauer, MD, of Albert Ludwigs University in Freiburg, Germany, and his colleagues reported that a patient with PML whose symptoms culminated in mutism in February 2018 began speaking again after receiving five infusions of pembrolizumab over 10 weeks. “In addition, the size and number of lesions on MRI decreased, and JCV was no longer detectable in CSF,” Dr. Rauer and his colleagues wrote. “The patient has remained stable as of the end of March 2019, with persistent but abating psychomotor slowing, aphasia, and disorientation.”

Finally, Ondine Walter, of Toulouse (France) University Hospital and colleagues described the case of a 60-year-old woman with PML who received nivolumab on a compassionate-use basis. Two weeks after treatment, JC viral load in CSF and blood had decreased. “Starting 8 weeks after the initiation of nivolumab therapy, the patient’s neurologic symptoms and signs stabilized, and subsequently she showed improved alertness, and the ptosis and hemiplegia abated.”
 

Reason for caution

Prior studies, however, give reasons for caution when considering the potential use of immune checkpoint inhibitors to treat PML, Dr. Koralnik noted. In one case, a patient developed an inflammatory form of PML known as immune reconstitution inflammatory syndrome after receiving nivolumab (J Neurovirol. 2019 March 12. doi: 10.1007/s13365-019-00738-x). In addition, researchers have reported a case of PML that occurred after 1 year of nivolumab treatment, and four cases of PML related to nivolumab have been reported in pharmacovigilance databases (Emerg Infect Dis. 2018;24:1594-6). The cost and safety profiles of the medications also may be considerations, Dr. Koralnik said.

The study by Dr. Cortese and colleagues was funded by the National Institutes of Health, and the authors had no relevant disclosures. Some of the research letter authors disclosed grants and personal fees from pharmaceutical companies.

jremaly@mdedge.com

SOURCES: Cortese I et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1815039; Rauer S et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1817193; Walter O et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1816198; Koralnik IJ. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMe1904140.

Spinal cord injuries (SCI) are common in veteran populations.¹ Veterans with spinal cord injuries and disorders (SCI/D) also may have concurrent sleep disturbances. Spinal cord injury typically causes spasticity.^2,3 Hypersensitivity of the flexor reflex pathways is believed to cause painful muscle spasms in patients with SCI.⁴ Neuropathic pain at or below the level of the lesion also is common.

Restless legs syndrome (RLS) is a common sleep disorder that affects sleep quality and can occur concomitantly with spinal cord lesions.⁵ In about 80% of RLS cases, involuntary movements of legs across hip, knee, and ankle joints during sleep, known as periodic limb movement during sleep (PLMS), occurs.⁶ Several studies showed increased prevalence of PLMS in patients with SCI, and some case reports suggest an increased prevalence of RLS in this population.^7,8 One small study showed that 100% of patients with SCI had symptoms of RLS.⁶ Another study found that SCI could trigger PLMS.⁸

The pathophysiology of RLS and PLMS in patients with SCI is not fully understood, but case reports describing PLM in SCI patients points to a possible role of central pattern generators and the flexor reflex afferents in the pathophysiology of PLMS.^9,10 Changes of the tissue microstructure in the midbrain and upper cervical spinal cord have been described in patients with RLS.¹¹The objective of this study was to assess the prevalence of RLS in a veteran population with SCI/D and to determine possible neuroanatomical patterns involved in RLS and SCI/D.

Methods

The institutional review and ethical approval boards of the Minneapolis VA Health Care System approved the study. Within the VA system, 666 patients with SCI/D were identified using a national database. Of the 666 people, 316 were excluded, 199 were included, and 151 were deceased.

Patients aged between 18 and 65 years were included in the study. Charts of patients who had been discharged with the diagnosis of SCI from 2002 to 2008 were studied. All patients met the inclusion criteria of the International Restless Legs Syndrome Study Group diagnosis.

Exclusion criteria were as follows: Patients with evidence of brain pathology (eg, stroke), concurrent neurologic condition associated with RLS (Parkinson disease, spinocerebellar ataxia, peripheral neuropathy), concurrent psychiatric condition within the setting of treatment with dopamine antagonists, secondary causes of RLS (renal failure/uremia, iron deficiency, rheumatoid arthritis, and pregnancy) and a recent history of alcohol or drug misuse or current evidence of substance use of < 1 year.

A patient list was compiled that included the etiology of the SCI (vascular injury, multiple sclerosis [MS], trauma, unknown, and other), the level(s) and completeness of the SCI per radiology report, RLS pharmacotherapies, and pertinent medical history.

Axial T2-weighted images on magnetic resonance imaging (MRI) scans were retrospectively reviewed. Sagittal T1/T2-weighted and axial T2-weighted sequences were performed routinely on all patients with spinal cord lesions. The analysis included the extension of the lesion on both sagittal and axial distributions. The anatomic location of the cord lesion was categorized by the following: (1) pure gray matter (central cord); (2) white matter (dorsal [D], dorsolateral [DL], ventral [V], ventrolateral areas [VL]).

A questionnaire using standard diagnostic criteria for RLS was mailed to the 199 patients who met the inclusion criteria (Appendix A).

All analyses were carried out using StataCorp STATA 13 (College Station, TX). Descriptive statistics were used. The analyses were carried out using chi-square and Fisher exact tests. Differences between the groups were considered statistically significant at P < .05. The data were analyzed to obtain point prevalence among patients with SCI, and comparisons were made among the different subgroups.

Results

Of the 162 patients who chose to participate in the study, the sleep specialists confirmed 31 (19%) to have RLS, 112 (69%) were confirmed negative for RLS, and an additional 19 (12%) screened positive for RLS but were not confirmed to have RLS by the sleep specialists (Figure 1).

The etiology of SCI was subdivided into 4 groups: MS, trauma, vascular, and other/unknown. Within each group (– RLS vs + RLS), MS and trauma were the most common etiologies with 55% MS and 36% trauma in the + RLS group.

When comparing RLS among the spinal cord levels (cervical, thoracic, lumbar and cervical + thoracic), only the cervical + thoracic subgroup (18% + RLS vs 5% – RLS) showed a significant difference (Figure 2).

There was no significant difference found with the prevalence of RLS in the axial plane of the spinal cord lesions (ventral/ventro-lateral/central cord vs dorsal/dorsolateral) or by the completeness of spinal cord lesions, P = .76. There was a higher prevalence of incomplete cord injury, however, within each subgroup of RLS.

The Mann-Whitney test was used to analyze the burden of disease in both groups (+ RLS vs – RLS). Moderate level of burden was most frequently reported with a higher prevalence within the + RLS group. Of those receiving treatment for RLS, 71% were + RLS vs 46% – RLS with a P value of .01. Symptoms of RLS after cord injury were 89% + RLS vs 55% – RLS with a P value of .03.

Discussion

This study represents one of the first studies to determine the prevalence of RLS in veterans with spinal cord disease. Research in this area is important to raise awareness of RLS among the veteran population with and without SCI and disorders. Restless legs syndrome often escapes diagnosis because of difficulty understanding the patient’s descriptions of their sensations. In addition, RLS may cause debilitating symptoms of sleep deprivation, daytime sleepiness, discomfort, and fatigue, which often results in decreased quality of life (QOL). Proper screening and treatment may improve QOL.

A study by Kumru and colleagues showed a similar rate of RLS in patients with SCI and RLS symptoms presented in the first year after SCI as did this study (18% vs 19%, respectively).⁴ In that study, RLS was more common in patients with lesions in lumbosacral area. Kumru and colleagues also showed that a dopaminergic medication improved symptoms of RLS in this population, whereas this study did not explore treatment outcomes.⁴

The pathogenesis of RLS is not fully known, but hereditary factors, iron metabolism, and the brain dopaminergic system are thought to be involved.¹¹ It is hypothesized that spinal cord lesions allow the appearance of RLS symptoms and spinal leg movement generator by blocking descending inhibitory spinal pathways.¹² One hypothesis is that damage to A11 nuclei (the main source of dopamine in the spinal cord or its diencephalospinal tract in animals) causes hyperexcitability of the spinal cord and leads to PLM and RLS symptoms.¹³ As the axons of A11 nuclei are present along the whole span of the spinal cord, SCI/D in patients with RLS might interrupt this dopaminergic tract and produce the RLS symptoms.

Limitations

This study included only veterans, so the prevalence may not apply to the nonveteran SCI population. Also, the population mainly was male, and there was no accurate information on race. Ferritin levels of the patients were not checked and is a major factor in RLS. The reported onset of RLS after the SCI could be due to recall bias.

Conclusion

The prevalence of RLS in veterans with SCI is above that reported in the general population (19% vs 10%, respectively). Furthermore, those with RLS have symptoms that often started after the SCI (suggesting causality) and required therapy due to their level of RLS symptom burden. A spectrum of severity of symptoms is present among those with RLS, with 83% having moderate-to-severe RLS affecting their QOL.

Although there was not a statistically significant relationship between RLS and spinal cord lesion level, there was a slightly higher prevalence of RLS at the cervical and thoracic levels, which may be relevant for future studies. There was no difference found between the RLS subgroups with respect to the location of the lesion within the spinal cord; however, a larger sample size may be needed to determine whether this would reach statistical significance. Prompt search for symptoms of RLS in veterans with SCI is warranted to provide adequate treatment to improve sleep health and QOL in this population.

Spinal cord injuries (SCI) are common in veteran populations.¹ Veterans with spinal cord injuries and disorders (SCI/D) also may have concurrent sleep disturbances. Spinal cord injury typically causes spasticity.^2,3 Hypersensitivity of the flexor reflex pathways is believed to cause painful muscle spasms in patients with SCI.⁴ Neuropathic pain at or below the level of the lesion also is common.

Restless legs syndrome (RLS) is a common sleep disorder that affects sleep quality and can occur concomitantly with spinal cord lesions.⁵ In about 80% of RLS cases, involuntary movements of legs across hip, knee, and ankle joints during sleep, known as periodic limb movement during sleep (PLMS), occurs.⁶ Several studies showed increased prevalence of PLMS in patients with SCI, and some case reports suggest an increased prevalence of RLS in this population.^7,8 One small study showed that 100% of patients with SCI had symptoms of RLS.⁶ Another study found that SCI could trigger PLMS.⁸

The pathophysiology of RLS and PLMS in patients with SCI is not fully understood, but case reports describing PLM in SCI patients points to a possible role of central pattern generators and the flexor reflex afferents in the pathophysiology of PLMS.^9,10 Changes of the tissue microstructure in the midbrain and upper cervical spinal cord have been described in patients with RLS.¹¹The objective of this study was to assess the prevalence of RLS in a veteran population with SCI/D and to determine possible neuroanatomical patterns involved in RLS and SCI/D.

Methods

The institutional review and ethical approval boards of the Minneapolis VA Health Care System approved the study. Within the VA system, 666 patients with SCI/D were identified using a national database. Of the 666 people, 316 were excluded, 199 were included, and 151 were deceased.

Patients aged between 18 and 65 years were included in the study. Charts of patients who had been discharged with the diagnosis of SCI from 2002 to 2008 were studied. All patients met the inclusion criteria of the International Restless Legs Syndrome Study Group diagnosis.

Exclusion criteria were as follows: Patients with evidence of brain pathology (eg, stroke), concurrent neurologic condition associated with RLS (Parkinson disease, spinocerebellar ataxia, peripheral neuropathy), concurrent psychiatric condition within the setting of treatment with dopamine antagonists, secondary causes of RLS (renal failure/uremia, iron deficiency, rheumatoid arthritis, and pregnancy) and a recent history of alcohol or drug misuse or current evidence of substance use of < 1 year.

A patient list was compiled that included the etiology of the SCI (vascular injury, multiple sclerosis [MS], trauma, unknown, and other), the level(s) and completeness of the SCI per radiology report, RLS pharmacotherapies, and pertinent medical history.

Axial T2-weighted images on magnetic resonance imaging (MRI) scans were retrospectively reviewed. Sagittal T1/T2-weighted and axial T2-weighted sequences were performed routinely on all patients with spinal cord lesions. The analysis included the extension of the lesion on both sagittal and axial distributions. The anatomic location of the cord lesion was categorized by the following: (1) pure gray matter (central cord); (2) white matter (dorsal [D], dorsolateral [DL], ventral [V], ventrolateral areas [VL]).

A questionnaire using standard diagnostic criteria for RLS was mailed to the 199 patients who met the inclusion criteria (Appendix A).

All analyses were carried out using StataCorp STATA 13 (College Station, TX). Descriptive statistics were used. The analyses were carried out using chi-square and Fisher exact tests. Differences between the groups were considered statistically significant at P < .05. The data were analyzed to obtain point prevalence among patients with SCI, and comparisons were made among the different subgroups.

Results

Of the 162 patients who chose to participate in the study, the sleep specialists confirmed 31 (19%) to have RLS, 112 (69%) were confirmed negative for RLS, and an additional 19 (12%) screened positive for RLS but were not confirmed to have RLS by the sleep specialists (Figure 1).

The etiology of SCI was subdivided into 4 groups: MS, trauma, vascular, and other/unknown. Within each group (– RLS vs + RLS), MS and trauma were the most common etiologies with 55% MS and 36% trauma in the + RLS group.

When comparing RLS among the spinal cord levels (cervical, thoracic, lumbar and cervical + thoracic), only the cervical + thoracic subgroup (18% + RLS vs 5% – RLS) showed a significant difference (Figure 2).

There was no significant difference found with the prevalence of RLS in the axial plane of the spinal cord lesions (ventral/ventro-lateral/central cord vs dorsal/dorsolateral) or by the completeness of spinal cord lesions, P = .76. There was a higher prevalence of incomplete cord injury, however, within each subgroup of RLS.

The Mann-Whitney test was used to analyze the burden of disease in both groups (+ RLS vs – RLS). Moderate level of burden was most frequently reported with a higher prevalence within the + RLS group. Of those receiving treatment for RLS, 71% were + RLS vs 46% – RLS with a P value of .01. Symptoms of RLS after cord injury were 89% + RLS vs 55% – RLS with a P value of .03.

Discussion

This study represents one of the first studies to determine the prevalence of RLS in veterans with spinal cord disease. Research in this area is important to raise awareness of RLS among the veteran population with and without SCI and disorders. Restless legs syndrome often escapes diagnosis because of difficulty understanding the patient’s descriptions of their sensations. In addition, RLS may cause debilitating symptoms of sleep deprivation, daytime sleepiness, discomfort, and fatigue, which often results in decreased quality of life (QOL). Proper screening and treatment may improve QOL.

A study by Kumru and colleagues showed a similar rate of RLS in patients with SCI and RLS symptoms presented in the first year after SCI as did this study (18% vs 19%, respectively).⁴ In that study, RLS was more common in patients with lesions in lumbosacral area. Kumru and colleagues also showed that a dopaminergic medication improved symptoms of RLS in this population, whereas this study did not explore treatment outcomes.⁴

The pathogenesis of RLS is not fully known, but hereditary factors, iron metabolism, and the brain dopaminergic system are thought to be involved.¹¹ It is hypothesized that spinal cord lesions allow the appearance of RLS symptoms and spinal leg movement generator by blocking descending inhibitory spinal pathways.¹² One hypothesis is that damage to A11 nuclei (the main source of dopamine in the spinal cord or its diencephalospinal tract in animals) causes hyperexcitability of the spinal cord and leads to PLM and RLS symptoms.¹³ As the axons of A11 nuclei are present along the whole span of the spinal cord, SCI/D in patients with RLS might interrupt this dopaminergic tract and produce the RLS symptoms.

Limitations

This study included only veterans, so the prevalence may not apply to the nonveteran SCI population. Also, the population mainly was male, and there was no accurate information on race. Ferritin levels of the patients were not checked and is a major factor in RLS. The reported onset of RLS after the SCI could be due to recall bias.

Conclusion

The prevalence of RLS in veterans with SCI is above that reported in the general population (19% vs 10%, respectively). Furthermore, those with RLS have symptoms that often started after the SCI (suggesting causality) and required therapy due to their level of RLS symptom burden. A spectrum of severity of symptoms is present among those with RLS, with 83% having moderate-to-severe RLS affecting their QOL.

Although there was not a statistically significant relationship between RLS and spinal cord lesion level, there was a slightly higher prevalence of RLS at the cervical and thoracic levels, which may be relevant for future studies. There was no difference found between the RLS subgroups with respect to the location of the lesion within the spinal cord; however, a larger sample size may be needed to determine whether this would reach statistical significance. Prompt search for symptoms of RLS in veterans with SCI is warranted to provide adequate treatment to improve sleep health and QOL in this population.

Spinal cord injuries (SCI) are common in veteran populations.¹ Veterans with spinal cord injuries and disorders (SCI/D) also may have concurrent sleep disturbances. Spinal cord injury typically causes spasticity.^2,3 Hypersensitivity of the flexor reflex pathways is believed to cause painful muscle spasms in patients with SCI.⁴ Neuropathic pain at or below the level of the lesion also is common.

Restless legs syndrome (RLS) is a common sleep disorder that affects sleep quality and can occur concomitantly with spinal cord lesions.⁵ In about 80% of RLS cases, involuntary movements of legs across hip, knee, and ankle joints during sleep, known as periodic limb movement during sleep (PLMS), occurs.⁶ Several studies showed increased prevalence of PLMS in patients with SCI, and some case reports suggest an increased prevalence of RLS in this population.^7,8 One small study showed that 100% of patients with SCI had symptoms of RLS.⁶ Another study found that SCI could trigger PLMS.⁸

The pathophysiology of RLS and PLMS in patients with SCI is not fully understood, but case reports describing PLM in SCI patients points to a possible role of central pattern generators and the flexor reflex afferents in the pathophysiology of PLMS.^9,10 Changes of the tissue microstructure in the midbrain and upper cervical spinal cord have been described in patients with RLS.¹¹The objective of this study was to assess the prevalence of RLS in a veteran population with SCI/D and to determine possible neuroanatomical patterns involved in RLS and SCI/D.

Methods

The institutional review and ethical approval boards of the Minneapolis VA Health Care System approved the study. Within the VA system, 666 patients with SCI/D were identified using a national database. Of the 666 people, 316 were excluded, 199 were included, and 151 were deceased.

Patients aged between 18 and 65 years were included in the study. Charts of patients who had been discharged with the diagnosis of SCI from 2002 to 2008 were studied. All patients met the inclusion criteria of the International Restless Legs Syndrome Study Group diagnosis.

Exclusion criteria were as follows: Patients with evidence of brain pathology (eg, stroke), concurrent neurologic condition associated with RLS (Parkinson disease, spinocerebellar ataxia, peripheral neuropathy), concurrent psychiatric condition within the setting of treatment with dopamine antagonists, secondary causes of RLS (renal failure/uremia, iron deficiency, rheumatoid arthritis, and pregnancy) and a recent history of alcohol or drug misuse or current evidence of substance use of < 1 year.

A patient list was compiled that included the etiology of the SCI (vascular injury, multiple sclerosis [MS], trauma, unknown, and other), the level(s) and completeness of the SCI per radiology report, RLS pharmacotherapies, and pertinent medical history.

Axial T2-weighted images on magnetic resonance imaging (MRI) scans were retrospectively reviewed. Sagittal T1/T2-weighted and axial T2-weighted sequences were performed routinely on all patients with spinal cord lesions. The analysis included the extension of the lesion on both sagittal and axial distributions. The anatomic location of the cord lesion was categorized by the following: (1) pure gray matter (central cord); (2) white matter (dorsal [D], dorsolateral [DL], ventral [V], ventrolateral areas [VL]).

A questionnaire using standard diagnostic criteria for RLS was mailed to the 199 patients who met the inclusion criteria (Appendix A).

All analyses were carried out using StataCorp STATA 13 (College Station, TX). Descriptive statistics were used. The analyses were carried out using chi-square and Fisher exact tests. Differences between the groups were considered statistically significant at P < .05. The data were analyzed to obtain point prevalence among patients with SCI, and comparisons were made among the different subgroups.

Results

Of the 162 patients who chose to participate in the study, the sleep specialists confirmed 31 (19%) to have RLS, 112 (69%) were confirmed negative for RLS, and an additional 19 (12%) screened positive for RLS but were not confirmed to have RLS by the sleep specialists (Figure 1).

The etiology of SCI was subdivided into 4 groups: MS, trauma, vascular, and other/unknown. Within each group (– RLS vs + RLS), MS and trauma were the most common etiologies with 55% MS and 36% trauma in the + RLS group.

When comparing RLS among the spinal cord levels (cervical, thoracic, lumbar and cervical + thoracic), only the cervical + thoracic subgroup (18% + RLS vs 5% – RLS) showed a significant difference (Figure 2).

There was no significant difference found with the prevalence of RLS in the axial plane of the spinal cord lesions (ventral/ventro-lateral/central cord vs dorsal/dorsolateral) or by the completeness of spinal cord lesions, P = .76. There was a higher prevalence of incomplete cord injury, however, within each subgroup of RLS.

The Mann-Whitney test was used to analyze the burden of disease in both groups (+ RLS vs – RLS). Moderate level of burden was most frequently reported with a higher prevalence within the + RLS group. Of those receiving treatment for RLS, 71% were + RLS vs 46% – RLS with a P value of .01. Symptoms of RLS after cord injury were 89% + RLS vs 55% – RLS with a P value of .03.

Discussion

This study represents one of the first studies to determine the prevalence of RLS in veterans with spinal cord disease. Research in this area is important to raise awareness of RLS among the veteran population with and without SCI and disorders. Restless legs syndrome often escapes diagnosis because of difficulty understanding the patient’s descriptions of their sensations. In addition, RLS may cause debilitating symptoms of sleep deprivation, daytime sleepiness, discomfort, and fatigue, which often results in decreased quality of life (QOL). Proper screening and treatment may improve QOL.

A study by Kumru and colleagues showed a similar rate of RLS in patients with SCI and RLS symptoms presented in the first year after SCI as did this study (18% vs 19%, respectively).⁴ In that study, RLS was more common in patients with lesions in lumbosacral area. Kumru and colleagues also showed that a dopaminergic medication improved symptoms of RLS in this population, whereas this study did not explore treatment outcomes.⁴

The pathogenesis of RLS is not fully known, but hereditary factors, iron metabolism, and the brain dopaminergic system are thought to be involved.¹¹ It is hypothesized that spinal cord lesions allow the appearance of RLS symptoms and spinal leg movement generator by blocking descending inhibitory spinal pathways.¹² One hypothesis is that damage to A11 nuclei (the main source of dopamine in the spinal cord or its diencephalospinal tract in animals) causes hyperexcitability of the spinal cord and leads to PLM and RLS symptoms.¹³ As the axons of A11 nuclei are present along the whole span of the spinal cord, SCI/D in patients with RLS might interrupt this dopaminergic tract and produce the RLS symptoms.

Limitations

This study included only veterans, so the prevalence may not apply to the nonveteran SCI population. Also, the population mainly was male, and there was no accurate information on race. Ferritin levels of the patients were not checked and is a major factor in RLS. The reported onset of RLS after the SCI could be due to recall bias.

Conclusion

The prevalence of RLS in veterans with SCI is above that reported in the general population (19% vs 10%, respectively). Furthermore, those with RLS have symptoms that often started after the SCI (suggesting causality) and required therapy due to their level of RLS symptom burden. A spectrum of severity of symptoms is present among those with RLS, with 83% having moderate-to-severe RLS affecting their QOL.

Although there was not a statistically significant relationship between RLS and spinal cord lesion level, there was a slightly higher prevalence of RLS at the cervical and thoracic levels, which may be relevant for future studies. There was no difference found between the RLS subgroups with respect to the location of the lesion within the spinal cord; however, a larger sample size may be needed to determine whether this would reach statistical significance. Prompt search for symptoms of RLS in veterans with SCI is warranted to provide adequate treatment to improve sleep health and QOL in this population.

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.