Breast Cancer ICYMI

PHOENIX – Despite clear guidance on lack of benefit and potential harms, many patients with early-stage breast cancers at low metastasis risk have undergone imaging tests for staging, recent retrospective studies have shown.

Nearly one-third of early-stage breast cancer patients received the unnecessary and potentially harmful interventions in one of the two studies presented at a symposium on quality care sponsored by the American Society of Clinical Oncology (ASCO).

Low-risk patients in that study were more likely to undergo imaging if they were younger or had triple-negative disease, among other factors, said researcher Brett Barlow, of the University of Alabama at Birmingham.

Physicians should be further educated about the low-risk nature of early-stage breast cancer, even in subgroups that are perceived to be higher risk, Mr. Barlow said in an interview.

“I think we can reassure physicians that these patients will do well and that these guidelines are based on good data,” he said “There could potentially be an element of distrust in these guidelines in these higher-risk patients, and that may be what’s driving some of these extra tests.”

According to Mr. Barlow, imaging low-risk patients is inconsistent with guidance from Choosing Wisely, an initiative designed to promote discussions between clinicians and patients about medical tests or procedures that are unnecessary.

As part of that initiative, ASCO recommended that PET, CT, and radionuclide bone scans should not be performed for staging of early-stage breast cancer at low risk for metastasis.

There is a lack of evidence that demonstrates a benefit for those imaging modalities in patients with newly identified ductal carcinoma in situ (DCIS) or clinical stage I or II disease, the society said at the time.

Unnecessary imaging can result in unnecessary invasive procedures, overtreatment, radiation exposure, and misdiagnosis, the society said in the guidance, which was published in 2012.

Despite the guidance, 262 out of 872 patients with stage 0-II breast cancer (30%) seen during 2013-2015 underwent imaging, according to results of the single-center retrospective cohort study Mr. Barlow and his coauthors described in a poster presentation.

The median age of the patients who underwent unnecessary imaging was 55 years versus 60 years for patients who did not, according to the researchers.

Risk of inappropriate imaging was increased in younger patients, those with triple-negative disease versus those with any hormone receptor–positive disease, those with higher-stage breast cancer, and those without Medicare insurance, investigators found.

Although it’s unclear whether there were any formal, institution-level efforts to promote the ASCO recommendations during the 2013-2015 period, it was “definitely a topic of debate at the time,” Mr. Barlow said.

“Something we hope to evaluate further is whether we have improved,” he said. “It’s important to set a baseline and see how we did in this area. We look forward to reevaluating that in a few years to see.”

In a separate study, investigators reviewed records from Mount Sinai Health System in New York and found that unnecessary scans were performed in 19% of patients diagnosed with stage I-II breast cancer during 2014-2015.

No cases of metastatic disease were found in 733 patients included in the study, and 43% had false-positive findings, according to Ana I. Velazquez Manana, MD, MS, of Mount Sinai Beth Israel Foundation, New York, and her coinvestigators.

Imaging increased costs by $4,480 per patient, according to the investigators, who found in multivariate analysis that the unnecessary scans were associated with young age, presence of T2 tumor, positive lymph nodes, and triple-negative disease.

“Further educational efforts are needed to avoid unnecessary scans in patients with early-stage breast cancer,” the researchers wrote in an abstract describing the results.

Mr. Barlow reported no disclosures, while one coauthor reported disclosures related to Carevive Systems, Genentech/Roche, Medscape, Pack Health, and Pfizer. Dr. Velazquez Manana and her coauthors had no relationships to disclose, and their study was funded by the Medical Student Rotation for Underrepresented Populations.

SOURCE: Barlow B et al. Quality Care Symposium, Abstract 51. Velazquez Manana AI et al. Quality Care Symposium, Abstract 52.

PHOENIX – Despite clear guidance on lack of benefit and potential harms, many patients with early-stage breast cancers at low metastasis risk have undergone imaging tests for staging, recent retrospective studies have shown.

Nearly one-third of early-stage breast cancer patients received the unnecessary and potentially harmful interventions in one of the two studies presented at a symposium on quality care sponsored by the American Society of Clinical Oncology (ASCO).

Low-risk patients in that study were more likely to undergo imaging if they were younger or had triple-negative disease, among other factors, said researcher Brett Barlow, of the University of Alabama at Birmingham.

Physicians should be further educated about the low-risk nature of early-stage breast cancer, even in subgroups that are perceived to be higher risk, Mr. Barlow said in an interview.

“I think we can reassure physicians that these patients will do well and that these guidelines are based on good data,” he said “There could potentially be an element of distrust in these guidelines in these higher-risk patients, and that may be what’s driving some of these extra tests.”

According to Mr. Barlow, imaging low-risk patients is inconsistent with guidance from Choosing Wisely, an initiative designed to promote discussions between clinicians and patients about medical tests or procedures that are unnecessary.

As part of that initiative, ASCO recommended that PET, CT, and radionuclide bone scans should not be performed for staging of early-stage breast cancer at low risk for metastasis.

There is a lack of evidence that demonstrates a benefit for those imaging modalities in patients with newly identified ductal carcinoma in situ (DCIS) or clinical stage I or II disease, the society said at the time.

Unnecessary imaging can result in unnecessary invasive procedures, overtreatment, radiation exposure, and misdiagnosis, the society said in the guidance, which was published in 2012.

Despite the guidance, 262 out of 872 patients with stage 0-II breast cancer (30%) seen during 2013-2015 underwent imaging, according to results of the single-center retrospective cohort study Mr. Barlow and his coauthors described in a poster presentation.

The median age of the patients who underwent unnecessary imaging was 55 years versus 60 years for patients who did not, according to the researchers.

Risk of inappropriate imaging was increased in younger patients, those with triple-negative disease versus those with any hormone receptor–positive disease, those with higher-stage breast cancer, and those without Medicare insurance, investigators found.

Although it’s unclear whether there were any formal, institution-level efforts to promote the ASCO recommendations during the 2013-2015 period, it was “definitely a topic of debate at the time,” Mr. Barlow said.

“Something we hope to evaluate further is whether we have improved,” he said. “It’s important to set a baseline and see how we did in this area. We look forward to reevaluating that in a few years to see.”

In a separate study, investigators reviewed records from Mount Sinai Health System in New York and found that unnecessary scans were performed in 19% of patients diagnosed with stage I-II breast cancer during 2014-2015.

No cases of metastatic disease were found in 733 patients included in the study, and 43% had false-positive findings, according to Ana I. Velazquez Manana, MD, MS, of Mount Sinai Beth Israel Foundation, New York, and her coinvestigators.

Imaging increased costs by $4,480 per patient, according to the investigators, who found in multivariate analysis that the unnecessary scans were associated with young age, presence of T2 tumor, positive lymph nodes, and triple-negative disease.

“Further educational efforts are needed to avoid unnecessary scans in patients with early-stage breast cancer,” the researchers wrote in an abstract describing the results.

Mr. Barlow reported no disclosures, while one coauthor reported disclosures related to Carevive Systems, Genentech/Roche, Medscape, Pack Health, and Pfizer. Dr. Velazquez Manana and her coauthors had no relationships to disclose, and their study was funded by the Medical Student Rotation for Underrepresented Populations.

SOURCE: Barlow B et al. Quality Care Symposium, Abstract 51. Velazquez Manana AI et al. Quality Care Symposium, Abstract 52.

PHOENIX – Despite clear guidance on lack of benefit and potential harms, many patients with early-stage breast cancers at low metastasis risk have undergone imaging tests for staging, recent retrospective studies have shown.

Nearly one-third of early-stage breast cancer patients received the unnecessary and potentially harmful interventions in one of the two studies presented at a symposium on quality care sponsored by the American Society of Clinical Oncology (ASCO).

Low-risk patients in that study were more likely to undergo imaging if they were younger or had triple-negative disease, among other factors, said researcher Brett Barlow, of the University of Alabama at Birmingham.

Physicians should be further educated about the low-risk nature of early-stage breast cancer, even in subgroups that are perceived to be higher risk, Mr. Barlow said in an interview.

“I think we can reassure physicians that these patients will do well and that these guidelines are based on good data,” he said “There could potentially be an element of distrust in these guidelines in these higher-risk patients, and that may be what’s driving some of these extra tests.”

According to Mr. Barlow, imaging low-risk patients is inconsistent with guidance from Choosing Wisely, an initiative designed to promote discussions between clinicians and patients about medical tests or procedures that are unnecessary.

As part of that initiative, ASCO recommended that PET, CT, and radionuclide bone scans should not be performed for staging of early-stage breast cancer at low risk for metastasis.

There is a lack of evidence that demonstrates a benefit for those imaging modalities in patients with newly identified ductal carcinoma in situ (DCIS) or clinical stage I or II disease, the society said at the time.

Unnecessary imaging can result in unnecessary invasive procedures, overtreatment, radiation exposure, and misdiagnosis, the society said in the guidance, which was published in 2012.

Despite the guidance, 262 out of 872 patients with stage 0-II breast cancer (30%) seen during 2013-2015 underwent imaging, according to results of the single-center retrospective cohort study Mr. Barlow and his coauthors described in a poster presentation.

The median age of the patients who underwent unnecessary imaging was 55 years versus 60 years for patients who did not, according to the researchers.

Risk of inappropriate imaging was increased in younger patients, those with triple-negative disease versus those with any hormone receptor–positive disease, those with higher-stage breast cancer, and those without Medicare insurance, investigators found.

Although it’s unclear whether there were any formal, institution-level efforts to promote the ASCO recommendations during the 2013-2015 period, it was “definitely a topic of debate at the time,” Mr. Barlow said.

“Something we hope to evaluate further is whether we have improved,” he said. “It’s important to set a baseline and see how we did in this area. We look forward to reevaluating that in a few years to see.”

In a separate study, investigators reviewed records from Mount Sinai Health System in New York and found that unnecessary scans were performed in 19% of patients diagnosed with stage I-II breast cancer during 2014-2015.

No cases of metastatic disease were found in 733 patients included in the study, and 43% had false-positive findings, according to Ana I. Velazquez Manana, MD, MS, of Mount Sinai Beth Israel Foundation, New York, and her coinvestigators.

Imaging increased costs by $4,480 per patient, according to the investigators, who found in multivariate analysis that the unnecessary scans were associated with young age, presence of T2 tumor, positive lymph nodes, and triple-negative disease.

“Further educational efforts are needed to avoid unnecessary scans in patients with early-stage breast cancer,” the researchers wrote in an abstract describing the results.

Mr. Barlow reported no disclosures, while one coauthor reported disclosures related to Carevive Systems, Genentech/Roche, Medscape, Pack Health, and Pfizer. Dr. Velazquez Manana and her coauthors had no relationships to disclose, and their study was funded by the Medical Student Rotation for Underrepresented Populations.

SOURCE: Barlow B et al. Quality Care Symposium, Abstract 51. Velazquez Manana AI et al. Quality Care Symposium, Abstract 52.

The CDC has developed a guideline for the diagnosis and management of mild traumatic brain injury (mTBI) in children. The guideline was published online ahead of print September 4 in JAMA Pediatrics. To support the “multifaceted approach” that the authors recommend for implementing the guideline, the CDC has created materials such as a screening tool, online training, fact sheets, patient discharge instructions, and symptom-based recovery tips.

The number of emergency department visits for mTBI has increased significantly during the past decade, said the authors, yet no evidence-based clinical guidelines had been drafted in the United States to guide the diagnosis, prognosis, and management of this condition. To fill this gap, the CDC established the Pediatric mTBI Guideline Workgroup, which drafted recommendations based on a systematic review of research published from January 1990 through July 2015.

Diagnosis

The first section of the guideline offers recommendations for diagnosis. Health care professionals should not routinely obtain head CT in children with suspected mTBI, say the authors. They should, however, use validated clinical decision rules to identify children with mTBI at low risk for intracranial injury in whom CT is not indicated, as well as children at higher risk for intracranial injury for whom CT may be warranted. The authors cite the Pediatric Emergency Care Applied Research Network (PECARN) decision rules as an example.

Furthermore, health care professionals should not routinely use brain MRI to evaluate suspected or diagnosed mTBI in children, according to the guideline. No study examining whether this imaging technique is appropriate met the workgroup’s inclusion criteria.

An age-appropriate, validated symptom rating scale should be one component of the diagnostic evaluation, say the authors. The Standardized Assessment of Concussion, however, “should not be exclusively used to diagnose mTBI in children aged 6 to 18,” they add. Finally, the guideline discourages the use of biomarkers (ie, serum markers) for diagnosis outside of a research setting.

Prognosis

The second section of the document provides guidance on developing a prognosis. Clinicians should advise patients and their families that most children with mTBI do not have significant difficulties that last for more than one to three months after injury, say the authors. They also should state that even though certain factors predict a child’s risk for prolonged symptoms, “each child’s recovery from mTBI is unique and will follow its own trajectory.”

Health care professionals should evaluate a child’s premorbid history as soon as possible to help determine the prognosis, say the authors. Children and families should be advised that factors such as history of mTBI, lower cognitive ability, and neurologic disorder can delay recovery from mTBI. Clinicians should screen for known risk factors for persistent symptoms and use a combination of tools (eg, validated symptom scales, cognitive testing, and balance testing) to assess recovery, according to the guideline.

Children with mTBI at high risk for persistent symptoms should be monitored closely. “For children with mTBI whose symptoms do not resolve as expected with standard care (ie, within four to six weeks), health care professionals should provide or refer for appropriate assessments and interventions,” say the authors.

Management and Treatment

The guideline’s section devoted to management and treatment begins with recommendations for returning to normal activities. Clinicians should recommend restricting physical and cognitive activity during the first several days after pediatric mTBI, according to the authors. After that point, doctors should advise patients and families “to resume a gradual schedule of activity that does not exacerbate symptoms, with close monitoring of symptom expression.” If the patient completes this step successfully, the clinician should offer an active rehabilitation program that progressively reintroduces noncontact aerobic activity that does not worsen symptoms. The number and severity of symptoms should be monitored closely throughout the patient’s recovery. A patient should resume full activity when his or her performance returns to its premorbid level, provided that he or she has no symptoms at rest or with increasing levels of exertion, according to the guideline.

“To assist children returning to school after mTBI, medical and school-based teams should counsel the student and family regarding the process of gradually increasing the duration and intensity of academic activities as tolerated, with the goal of increasing participation without significantly exacerbating symptoms,” say the authors. Return-to-school protocols should be adapted to the severity of the child’s postconcussion symptoms. School personnel should assess the need for additional educational support in students with prolonged symptoms that harm their academic performance, according to the guideline.

If a child with mTBI develops severe headache, especially if the headache is associated with other risk factors or has worsened after mTBI, emergency department professionals should observe him or her and consider obtaining a head CT to evaluate for intracranial injury, say the authors. Health care professionals should explain proper sleep hygiene to all patients with mTBI and their families to facilitate recovery.

If a child with mTBI has cognitive dysfunction, clinicians should attempt to determine its etiology within the context of other mTBI symptoms, say the authors. Treatment for cognitive dysfunction should reflect its presumed etiology, they conclude.

—Erik Greb

Suggested Reading

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Centers for Disease Control and Prevention guideline on the diagnosis and management of mild traumatic brain injury among children. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Diagnosis and management of mild traumatic brain injury in children: a systematic review. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

McCrea M, Manley G. State of the science on pediatric mild traumatic brain injury: progress toward clinical translation. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

The CDC has developed a guideline for the diagnosis and management of mild traumatic brain injury (mTBI) in children. The guideline was published online ahead of print September 4 in JAMA Pediatrics. To support the “multifaceted approach” that the authors recommend for implementing the guideline, the CDC has created materials such as a screening tool, online training, fact sheets, patient discharge instructions, and symptom-based recovery tips.

The number of emergency department visits for mTBI has increased significantly during the past decade, said the authors, yet no evidence-based clinical guidelines had been drafted in the United States to guide the diagnosis, prognosis, and management of this condition. To fill this gap, the CDC established the Pediatric mTBI Guideline Workgroup, which drafted recommendations based on a systematic review of research published from January 1990 through July 2015.

Diagnosis

The first section of the guideline offers recommendations for diagnosis. Health care professionals should not routinely obtain head CT in children with suspected mTBI, say the authors. They should, however, use validated clinical decision rules to identify children with mTBI at low risk for intracranial injury in whom CT is not indicated, as well as children at higher risk for intracranial injury for whom CT may be warranted. The authors cite the Pediatric Emergency Care Applied Research Network (PECARN) decision rules as an example.

Furthermore, health care professionals should not routinely use brain MRI to evaluate suspected or diagnosed mTBI in children, according to the guideline. No study examining whether this imaging technique is appropriate met the workgroup’s inclusion criteria.

An age-appropriate, validated symptom rating scale should be one component of the diagnostic evaluation, say the authors. The Standardized Assessment of Concussion, however, “should not be exclusively used to diagnose mTBI in children aged 6 to 18,” they add. Finally, the guideline discourages the use of biomarkers (ie, serum markers) for diagnosis outside of a research setting.

Prognosis

The second section of the document provides guidance on developing a prognosis. Clinicians should advise patients and their families that most children with mTBI do not have significant difficulties that last for more than one to three months after injury, say the authors. They also should state that even though certain factors predict a child’s risk for prolonged symptoms, “each child’s recovery from mTBI is unique and will follow its own trajectory.”

Health care professionals should evaluate a child’s premorbid history as soon as possible to help determine the prognosis, say the authors. Children and families should be advised that factors such as history of mTBI, lower cognitive ability, and neurologic disorder can delay recovery from mTBI. Clinicians should screen for known risk factors for persistent symptoms and use a combination of tools (eg, validated symptom scales, cognitive testing, and balance testing) to assess recovery, according to the guideline.

Children with mTBI at high risk for persistent symptoms should be monitored closely. “For children with mTBI whose symptoms do not resolve as expected with standard care (ie, within four to six weeks), health care professionals should provide or refer for appropriate assessments and interventions,” say the authors.

Management and Treatment

The guideline’s section devoted to management and treatment begins with recommendations for returning to normal activities. Clinicians should recommend restricting physical and cognitive activity during the first several days after pediatric mTBI, according to the authors. After that point, doctors should advise patients and families “to resume a gradual schedule of activity that does not exacerbate symptoms, with close monitoring of symptom expression.” If the patient completes this step successfully, the clinician should offer an active rehabilitation program that progressively reintroduces noncontact aerobic activity that does not worsen symptoms. The number and severity of symptoms should be monitored closely throughout the patient’s recovery. A patient should resume full activity when his or her performance returns to its premorbid level, provided that he or she has no symptoms at rest or with increasing levels of exertion, according to the guideline.

“To assist children returning to school after mTBI, medical and school-based teams should counsel the student and family regarding the process of gradually increasing the duration and intensity of academic activities as tolerated, with the goal of increasing participation without significantly exacerbating symptoms,” say the authors. Return-to-school protocols should be adapted to the severity of the child’s postconcussion symptoms. School personnel should assess the need for additional educational support in students with prolonged symptoms that harm their academic performance, according to the guideline.

If a child with mTBI develops severe headache, especially if the headache is associated with other risk factors or has worsened after mTBI, emergency department professionals should observe him or her and consider obtaining a head CT to evaluate for intracranial injury, say the authors. Health care professionals should explain proper sleep hygiene to all patients with mTBI and their families to facilitate recovery.

If a child with mTBI has cognitive dysfunction, clinicians should attempt to determine its etiology within the context of other mTBI symptoms, say the authors. Treatment for cognitive dysfunction should reflect its presumed etiology, they conclude.

—Erik Greb

Suggested Reading

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Centers for Disease Control and Prevention guideline on the diagnosis and management of mild traumatic brain injury among children. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Diagnosis and management of mild traumatic brain injury in children: a systematic review. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

McCrea M, Manley G. State of the science on pediatric mild traumatic brain injury: progress toward clinical translation. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

The CDC has developed a guideline for the diagnosis and management of mild traumatic brain injury (mTBI) in children. The guideline was published online ahead of print September 4 in JAMA Pediatrics. To support the “multifaceted approach” that the authors recommend for implementing the guideline, the CDC has created materials such as a screening tool, online training, fact sheets, patient discharge instructions, and symptom-based recovery tips.

The number of emergency department visits for mTBI has increased significantly during the past decade, said the authors, yet no evidence-based clinical guidelines had been drafted in the United States to guide the diagnosis, prognosis, and management of this condition. To fill this gap, the CDC established the Pediatric mTBI Guideline Workgroup, which drafted recommendations based on a systematic review of research published from January 1990 through July 2015.

Diagnosis

The first section of the guideline offers recommendations for diagnosis. Health care professionals should not routinely obtain head CT in children with suspected mTBI, say the authors. They should, however, use validated clinical decision rules to identify children with mTBI at low risk for intracranial injury in whom CT is not indicated, as well as children at higher risk for intracranial injury for whom CT may be warranted. The authors cite the Pediatric Emergency Care Applied Research Network (PECARN) decision rules as an example.

Furthermore, health care professionals should not routinely use brain MRI to evaluate suspected or diagnosed mTBI in children, according to the guideline. No study examining whether this imaging technique is appropriate met the workgroup’s inclusion criteria.

An age-appropriate, validated symptom rating scale should be one component of the diagnostic evaluation, say the authors. The Standardized Assessment of Concussion, however, “should not be exclusively used to diagnose mTBI in children aged 6 to 18,” they add. Finally, the guideline discourages the use of biomarkers (ie, serum markers) for diagnosis outside of a research setting.

Prognosis

The second section of the document provides guidance on developing a prognosis. Clinicians should advise patients and their families that most children with mTBI do not have significant difficulties that last for more than one to three months after injury, say the authors. They also should state that even though certain factors predict a child’s risk for prolonged symptoms, “each child’s recovery from mTBI is unique and will follow its own trajectory.”

Health care professionals should evaluate a child’s premorbid history as soon as possible to help determine the prognosis, say the authors. Children and families should be advised that factors such as history of mTBI, lower cognitive ability, and neurologic disorder can delay recovery from mTBI. Clinicians should screen for known risk factors for persistent symptoms and use a combination of tools (eg, validated symptom scales, cognitive testing, and balance testing) to assess recovery, according to the guideline.

Children with mTBI at high risk for persistent symptoms should be monitored closely. “For children with mTBI whose symptoms do not resolve as expected with standard care (ie, within four to six weeks), health care professionals should provide or refer for appropriate assessments and interventions,” say the authors.

Management and Treatment

The guideline’s section devoted to management and treatment begins with recommendations for returning to normal activities. Clinicians should recommend restricting physical and cognitive activity during the first several days after pediatric mTBI, according to the authors. After that point, doctors should advise patients and families “to resume a gradual schedule of activity that does not exacerbate symptoms, with close monitoring of symptom expression.” If the patient completes this step successfully, the clinician should offer an active rehabilitation program that progressively reintroduces noncontact aerobic activity that does not worsen symptoms. The number and severity of symptoms should be monitored closely throughout the patient’s recovery. A patient should resume full activity when his or her performance returns to its premorbid level, provided that he or she has no symptoms at rest or with increasing levels of exertion, according to the guideline.

“To assist children returning to school after mTBI, medical and school-based teams should counsel the student and family regarding the process of gradually increasing the duration and intensity of academic activities as tolerated, with the goal of increasing participation without significantly exacerbating symptoms,” say the authors. Return-to-school protocols should be adapted to the severity of the child’s postconcussion symptoms. School personnel should assess the need for additional educational support in students with prolonged symptoms that harm their academic performance, according to the guideline.

If a child with mTBI develops severe headache, especially if the headache is associated with other risk factors or has worsened after mTBI, emergency department professionals should observe him or her and consider obtaining a head CT to evaluate for intracranial injury, say the authors. Health care professionals should explain proper sleep hygiene to all patients with mTBI and their families to facilitate recovery.

If a child with mTBI has cognitive dysfunction, clinicians should attempt to determine its etiology within the context of other mTBI symptoms, say the authors. Treatment for cognitive dysfunction should reflect its presumed etiology, they conclude.

—Erik Greb

Suggested Reading

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Centers for Disease Control and Prevention guideline on the diagnosis and management of mild traumatic brain injury among children. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

Lumba-Brown A, Yeates KO, Sarmiento K, et al. Diagnosis and management of mild traumatic brain injury in children: a systematic review. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

McCrea M, Manley G. State of the science on pediatric mild traumatic brain injury: progress toward clinical translation. JAMA Pediatr. 2018 Sep 4 [Epub ahead of print].

Among people with Parkinson’s disease, REM sleep behavior disorder (RBD) is associated with more rapid motor progression in patients with high levels of synuclein and dopaminergic pathology, according to research published online ahead of print August 8 in Neurology. RBD also indicates an increased risk of cognitive decline in patients with high degrees of synuclein and amyloid pathology.

“Our study is the first to link the predictive value of RBD symptoms to the presence of amyloid and synuclein pathology,” said Marios Politis, MD, PhD, Lily Safra Professor of Neurology and Neuroimaging, Consultant Neurologist, and the Director of the Neurodegeneration Imaging Group at King’s College London, and colleagues. “Measuring dopaminergic dysfunction and amyloid and synuclein burden in the screening of patients with RBD at an early stage of Parkinson’s disease, possibly even at the premotor phase of disease, could potentially identify the ones more likely to progress and develop dementia.”

—Erik Greb

Suggested Reading

Pagano G, De Micco R, Yousaf T, et al. REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease. Neurology. 2018 Aug 8 [Epub ahead of print].

Among people with Parkinson’s disease, REM sleep behavior disorder (RBD) is associated with more rapid motor progression in patients with high levels of synuclein and dopaminergic pathology, according to research published online ahead of print August 8 in Neurology. RBD also indicates an increased risk of cognitive decline in patients with high degrees of synuclein and amyloid pathology.

“Our study is the first to link the predictive value of RBD symptoms to the presence of amyloid and synuclein pathology,” said Marios Politis, MD, PhD, Lily Safra Professor of Neurology and Neuroimaging, Consultant Neurologist, and the Director of the Neurodegeneration Imaging Group at King’s College London, and colleagues. “Measuring dopaminergic dysfunction and amyloid and synuclein burden in the screening of patients with RBD at an early stage of Parkinson’s disease, possibly even at the premotor phase of disease, could potentially identify the ones more likely to progress and develop dementia.”

—Erik Greb

Suggested Reading

Pagano G, De Micco R, Yousaf T, et al. REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease. Neurology. 2018 Aug 8 [Epub ahead of print].

Among people with Parkinson’s disease, REM sleep behavior disorder (RBD) is associated with more rapid motor progression in patients with high levels of synuclein and dopaminergic pathology, according to research published online ahead of print August 8 in Neurology. RBD also indicates an increased risk of cognitive decline in patients with high degrees of synuclein and amyloid pathology.

“Our study is the first to link the predictive value of RBD symptoms to the presence of amyloid and synuclein pathology,” said Marios Politis, MD, PhD, Lily Safra Professor of Neurology and Neuroimaging, Consultant Neurologist, and the Director of the Neurodegeneration Imaging Group at King’s College London, and colleagues. “Measuring dopaminergic dysfunction and amyloid and synuclein burden in the screening of patients with RBD at an early stage of Parkinson’s disease, possibly even at the premotor phase of disease, could potentially identify the ones more likely to progress and develop dementia.”

—Erik Greb

Suggested Reading

Pagano G, De Micco R, Yousaf T, et al. REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease. Neurology. 2018 Aug 8 [Epub ahead of print].

Multiday epileptic seizure cycles may occur in many individuals with epilepsy, according to a retrospective cohort study published online ahead of print September 12 in Lancet Neurology.

About 80% of patients in the study showed circadian modulation of their seizure rates, and more than 20% had strong circaseptan (ie, seven-day) rhythms, said Mark J. Cook, MD, a neurologist at St. Vincent’s Hospital in Melbourne, and colleagues.

—Andrew D. Bowser

Suggested Reading

Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018 Sep 12 [Epub ahead of print].

Multiday epileptic seizure cycles may occur in many individuals with epilepsy, according to a retrospective cohort study published online ahead of print September 12 in Lancet Neurology.

About 80% of patients in the study showed circadian modulation of their seizure rates, and more than 20% had strong circaseptan (ie, seven-day) rhythms, said Mark J. Cook, MD, a neurologist at St. Vincent’s Hospital in Melbourne, and colleagues.

—Andrew D. Bowser

Suggested Reading

Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018 Sep 12 [Epub ahead of print].

Multiday epileptic seizure cycles may occur in many individuals with epilepsy, according to a retrospective cohort study published online ahead of print September 12 in Lancet Neurology.

About 80% of patients in the study showed circadian modulation of their seizure rates, and more than 20% had strong circaseptan (ie, seven-day) rhythms, said Mark J. Cook, MD, a neurologist at St. Vincent’s Hospital in Melbourne, and colleagues.

—Andrew D. Bowser

Suggested Reading

Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018 Sep 12 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

Subcutaneous apomorphine infusion significantly reduces off time in patients with Parkinson’s disease and inadequately controlled motor fluctuations, according to data published in the September issue of Lancet Neurology. The data result from the first randomized controlled trial of apomorphine in this population.

In 1988, an open-label study indicated that apomorphine had antiparkinsonian efficacy equivalent to that of levodopa. Several uncontrolled studies have indicated that it effectively reduces off time, improves dyskinesias, and allows doses of oral levodopa to be decreased.

A Multicenter European Study

Regina Katzenschlager, MD, a neurologist at Danube Hospital in Vienna, and colleagues investigated the safety and efficacy of apomorphine infusion in a randomized, placebo-controlled, double-blind trial. They enrolled patients at 23 European hospitals who had received a diagnosis of Parkinson’s disease more than three years previously and had motor fluctuations that were inadequately controlled. Patients were randomized in equal groups to 3–8-mg/h infusions of apomorphine or saline for approximately 16 h/day. The treatment period lasted for 12 weeks. During the first four weeks, investigators adjusted the dose according to efficacy and tolerability, and the remaining eight weeks were a maintenance period.

Patients completed home diary assessments of motor status and visited the hospital for regular evaluations. The study’s primary end point was the absolute change in off time from baseline to 12 weeks, based on diary assessments. Secondary end points included response to therapy (ie, a reduction in off time of at least two hours from baseline), absolute change in on time without troublesome dyskinesia, Patient Global Impression of Change (PGIC) score, change in levodopa dose, change in motor score, and change in quality of life.

Results Were Consistent in Prespecified Subgroups

A total of 53 patients were randomized to apomorphine, and 54 patients were randomized to placebo. The mean final dose of study drug was 4.68 mg/h in the apomorphine group and 5.76 mg/h in the placebo group.

Mean reduction in off time was significantly greater at week 12 in the apomorphine group (−2.47 h/day) than among controls (−0.58 h/day). The results were consistent in sensitivity analyses. Approximately 62% of patients in the apomorphine group responded to therapy, compared with 29% of controls.

Mean on time without troublesome dyskinesia was significantly increased in the apomorphine group (2.77 h/day), compared with the placebo group (0.80 h/day). Apomorphine also improved PGIC scores significantly at 12 weeks, compared with placebo. Mean reduction in oral levodopa dose was greater in the apomorphine group, but the difference between groups was not statistically significant. Changes in motor score and quality of life were not significantly different between groups at 12 weeks.

The treatment was well tolerated, and the researchers found no unexpected safety signals. The rate of treatment-emergent adverse events was 93% in the apomorphine group and 57% among controls. The most common adverse events were skin reactions, nausea, and somnolence. Six patients had an adverse event that prompted study withdrawal; all were in the apomorphine group. Five patients in the apomorphine group had serious adverse events, including severe hypotension, myocardial infarction, and persistently abnormal hematology test results indicating mild leukopenia and moderate anemia.

“From a practical viewpoint, our study shows that some patients tolerate and receive benefit from doses exceeding the common range of hourly flow rates currently used in practice,” said the authors. “Many centers use higher flow rates than the mean dose in our study, and it is possible that the full potential of apomorphine has not been investigated here.”

How Effective Would Apomorphine Monotherapy Be?

The findings of Dr. Katzenschlager and colleagues “should help guide clinicians in making decisions about management of patients with advanced Parkinson’s disease, particularly when considering use of deep brain stimulation or intestinal infusion of levodopa–carbidopa gel,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan, in an accompanying editorial. “In view of its efficacy and safety profile, apomorphine infusion should be considered before embarking on other invasive therapies.”

On average, apomorphine infusion decreased off time by approximately one-third from patients’ baseline levels. “One might ask why the study did not achieve better results,” said Dr. LeWitt. A potential explanation is that impaired brain circuitry in patients with advanced Parkinson’s disease loses its long-term response to levodopa and is associated with dyskinesias and freezing of gait, he added. It also is possible that participants’ medical treatment had not been optimized at baseline.

“Despite a heavy load of levodopa and adjunctive medications (most participants in the study also received dopaminergic agonists, and inhibitors of catechol-O-methyltransferase and monoamine oxidase type B were used liberally), many patients continue to be burdened by substantial daily off time fluctuations,” said Dr. LeWitt. “A final question unanswered by this study is the effectiveness of apomorphine monotherapy, which has been previously tested in only a few studies. Future studies might investigate this question and what benefit, if any, is offered by concomitant levodopa treatment.”

—Erik Greb

Suggested Reading

Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759.

LeWitt PA. At last, a randomised controlled trial of apomorphine infusion. Lancet Neurol. 2018;17(9):732-733.

Subcutaneous apomorphine infusion significantly reduces off time in patients with Parkinson’s disease and inadequately controlled motor fluctuations, according to data published in the September issue of Lancet Neurology. The data result from the first randomized controlled trial of apomorphine in this population.

In 1988, an open-label study indicated that apomorphine had antiparkinsonian efficacy equivalent to that of levodopa. Several uncontrolled studies have indicated that it effectively reduces off time, improves dyskinesias, and allows doses of oral levodopa to be decreased.

A Multicenter European Study

Regina Katzenschlager, MD, a neurologist at Danube Hospital in Vienna, and colleagues investigated the safety and efficacy of apomorphine infusion in a randomized, placebo-controlled, double-blind trial. They enrolled patients at 23 European hospitals who had received a diagnosis of Parkinson’s disease more than three years previously and had motor fluctuations that were inadequately controlled. Patients were randomized in equal groups to 3–8-mg/h infusions of apomorphine or saline for approximately 16 h/day. The treatment period lasted for 12 weeks. During the first four weeks, investigators adjusted the dose according to efficacy and tolerability, and the remaining eight weeks were a maintenance period.

Patients completed home diary assessments of motor status and visited the hospital for regular evaluations. The study’s primary end point was the absolute change in off time from baseline to 12 weeks, based on diary assessments. Secondary end points included response to therapy (ie, a reduction in off time of at least two hours from baseline), absolute change in on time without troublesome dyskinesia, Patient Global Impression of Change (PGIC) score, change in levodopa dose, change in motor score, and change in quality of life.

Results Were Consistent in Prespecified Subgroups

A total of 53 patients were randomized to apomorphine, and 54 patients were randomized to placebo. The mean final dose of study drug was 4.68 mg/h in the apomorphine group and 5.76 mg/h in the placebo group.

Mean reduction in off time was significantly greater at week 12 in the apomorphine group (−2.47 h/day) than among controls (−0.58 h/day). The results were consistent in sensitivity analyses. Approximately 62% of patients in the apomorphine group responded to therapy, compared with 29% of controls.

Mean on time without troublesome dyskinesia was significantly increased in the apomorphine group (2.77 h/day), compared with the placebo group (0.80 h/day). Apomorphine also improved PGIC scores significantly at 12 weeks, compared with placebo. Mean reduction in oral levodopa dose was greater in the apomorphine group, but the difference between groups was not statistically significant. Changes in motor score and quality of life were not significantly different between groups at 12 weeks.

The treatment was well tolerated, and the researchers found no unexpected safety signals. The rate of treatment-emergent adverse events was 93% in the apomorphine group and 57% among controls. The most common adverse events were skin reactions, nausea, and somnolence. Six patients had an adverse event that prompted study withdrawal; all were in the apomorphine group. Five patients in the apomorphine group had serious adverse events, including severe hypotension, myocardial infarction, and persistently abnormal hematology test results indicating mild leukopenia and moderate anemia.

“From a practical viewpoint, our study shows that some patients tolerate and receive benefit from doses exceeding the common range of hourly flow rates currently used in practice,” said the authors. “Many centers use higher flow rates than the mean dose in our study, and it is possible that the full potential of apomorphine has not been investigated here.”

How Effective Would Apomorphine Monotherapy Be?

The findings of Dr. Katzenschlager and colleagues “should help guide clinicians in making decisions about management of patients with advanced Parkinson’s disease, particularly when considering use of deep brain stimulation or intestinal infusion of levodopa–carbidopa gel,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan, in an accompanying editorial. “In view of its efficacy and safety profile, apomorphine infusion should be considered before embarking on other invasive therapies.”

On average, apomorphine infusion decreased off time by approximately one-third from patients’ baseline levels. “One might ask why the study did not achieve better results,” said Dr. LeWitt. A potential explanation is that impaired brain circuitry in patients with advanced Parkinson’s disease loses its long-term response to levodopa and is associated with dyskinesias and freezing of gait, he added. It also is possible that participants’ medical treatment had not been optimized at baseline.

“Despite a heavy load of levodopa and adjunctive medications (most participants in the study also received dopaminergic agonists, and inhibitors of catechol-O-methyltransferase and monoamine oxidase type B were used liberally), many patients continue to be burdened by substantial daily off time fluctuations,” said Dr. LeWitt. “A final question unanswered by this study is the effectiveness of apomorphine monotherapy, which has been previously tested in only a few studies. Future studies might investigate this question and what benefit, if any, is offered by concomitant levodopa treatment.”

—Erik Greb

Suggested Reading

Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759.

LeWitt PA. At last, a randomised controlled trial of apomorphine infusion. Lancet Neurol. 2018;17(9):732-733.

Subcutaneous apomorphine infusion significantly reduces off time in patients with Parkinson’s disease and inadequately controlled motor fluctuations, according to data published in the September issue of Lancet Neurology. The data result from the first randomized controlled trial of apomorphine in this population.

In 1988, an open-label study indicated that apomorphine had antiparkinsonian efficacy equivalent to that of levodopa. Several uncontrolled studies have indicated that it effectively reduces off time, improves dyskinesias, and allows doses of oral levodopa to be decreased.

A Multicenter European Study

Regina Katzenschlager, MD, a neurologist at Danube Hospital in Vienna, and colleagues investigated the safety and efficacy of apomorphine infusion in a randomized, placebo-controlled, double-blind trial. They enrolled patients at 23 European hospitals who had received a diagnosis of Parkinson’s disease more than three years previously and had motor fluctuations that were inadequately controlled. Patients were randomized in equal groups to 3–8-mg/h infusions of apomorphine or saline for approximately 16 h/day. The treatment period lasted for 12 weeks. During the first four weeks, investigators adjusted the dose according to efficacy and tolerability, and the remaining eight weeks were a maintenance period.

Patients completed home diary assessments of motor status and visited the hospital for regular evaluations. The study’s primary end point was the absolute change in off time from baseline to 12 weeks, based on diary assessments. Secondary end points included response to therapy (ie, a reduction in off time of at least two hours from baseline), absolute change in on time without troublesome dyskinesia, Patient Global Impression of Change (PGIC) score, change in levodopa dose, change in motor score, and change in quality of life.

Results Were Consistent in Prespecified Subgroups

A total of 53 patients were randomized to apomorphine, and 54 patients were randomized to placebo. The mean final dose of study drug was 4.68 mg/h in the apomorphine group and 5.76 mg/h in the placebo group.

Mean reduction in off time was significantly greater at week 12 in the apomorphine group (−2.47 h/day) than among controls (−0.58 h/day). The results were consistent in sensitivity analyses. Approximately 62% of patients in the apomorphine group responded to therapy, compared with 29% of controls.

Mean on time without troublesome dyskinesia was significantly increased in the apomorphine group (2.77 h/day), compared with the placebo group (0.80 h/day). Apomorphine also improved PGIC scores significantly at 12 weeks, compared with placebo. Mean reduction in oral levodopa dose was greater in the apomorphine group, but the difference between groups was not statistically significant. Changes in motor score and quality of life were not significantly different between groups at 12 weeks.

The treatment was well tolerated, and the researchers found no unexpected safety signals. The rate of treatment-emergent adverse events was 93% in the apomorphine group and 57% among controls. The most common adverse events were skin reactions, nausea, and somnolence. Six patients had an adverse event that prompted study withdrawal; all were in the apomorphine group. Five patients in the apomorphine group had serious adverse events, including severe hypotension, myocardial infarction, and persistently abnormal hematology test results indicating mild leukopenia and moderate anemia.

“From a practical viewpoint, our study shows that some patients tolerate and receive benefit from doses exceeding the common range of hourly flow rates currently used in practice,” said the authors. “Many centers use higher flow rates than the mean dose in our study, and it is possible that the full potential of apomorphine has not been investigated here.”

How Effective Would Apomorphine Monotherapy Be?

The findings of Dr. Katzenschlager and colleagues “should help guide clinicians in making decisions about management of patients with advanced Parkinson’s disease, particularly when considering use of deep brain stimulation or intestinal infusion of levodopa–carbidopa gel,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan, in an accompanying editorial. “In view of its efficacy and safety profile, apomorphine infusion should be considered before embarking on other invasive therapies.”

On average, apomorphine infusion decreased off time by approximately one-third from patients’ baseline levels. “One might ask why the study did not achieve better results,” said Dr. LeWitt. A potential explanation is that impaired brain circuitry in patients with advanced Parkinson’s disease loses its long-term response to levodopa and is associated with dyskinesias and freezing of gait, he added. It also is possible that participants’ medical treatment had not been optimized at baseline.

“Despite a heavy load of levodopa and adjunctive medications (most participants in the study also received dopaminergic agonists, and inhibitors of catechol-O-methyltransferase and monoamine oxidase type B were used liberally), many patients continue to be burdened by substantial daily off time fluctuations,” said Dr. LeWitt. “A final question unanswered by this study is the effectiveness of apomorphine monotherapy, which has been previously tested in only a few studies. Future studies might investigate this question and what benefit, if any, is offered by concomitant levodopa treatment.”

—Erik Greb

Suggested Reading

Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759.

LeWitt PA. At last, a randomised controlled trial of apomorphine infusion. Lancet Neurol. 2018;17(9):732-733.

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].

In patients with multiple sclerosis (MS), levels of light-chain neurofilament (NfL) in CSF at diagnosis seem to predict long-term clinical outcome and conversion from the relapsing-remitting phase of the disease to the secondary progressive phase, according to a study published in the September issue of Multiple Sclerosis Journal. “NfL is thought to reflect ongoing axonal degeneration, which dominates early in the disease phase, and our results support that increased early disease activity, as identified by increased levels of CSF-NfL, has a prognostic effect several years later,” said lead author Alok Bhan, MD, and colleagues. Dr. Bhan works in the Department of Neurology at Stavanger University Hospital in Norway.

Searching for Prognostic Markers

To test whether CSF-NfL levels in patients with MS could predict clinical outcome, Dr. Bhan and colleagues conducted standardized clinical assessments of patients with newly diagnosed MS at baseline and at five- and 10-year follow-up. Expanded Disability Status Scale (EDSS) progression between assessments was defined as an increase of 1 point or more for scores less than 6 and of 0.5 points or more for scores of 6 or greater. CSF obtained at baseline was analyzed for levels of NfL using enzyme-linked immunosorbent assay technology.

The study cohort included 44 patients, of whom 35 (80%) had relapsing-remitting MS, seven (16%) had secondary progressive MS, and two (4%) had primary progressive MS at baseline. Patients who progressed on EDSS tended to have higher median baseline CSF-NfL levels than patients who did not progress after five years (947 ng/L vs 246 ng/L, respectively) and those who did not progress after 10 years (708 ng/L vs 265 ng/L, respectively), although the latter difference was not statistically significant. Patients who converted from relapsing-remitting MS to secondary progressive MS at five years had a significantly higher median CSF level of NfL (2,122 ng/L), compared with those who did not convert (246 ng/L).

“We found a statistically significant correlation between NfL levels at baseline and EDSS progression and conversion from relapsing-remitting MS to secondary progressive MS at the five-year follow-up, but a weaker correlation at the 10-year follow-up,” the researchers said. “This [finding] may be due to the increasing number of patients on disease-modifying therapy throughout the study period, as only 16% received therapy at baseline, but 54% [did] at 10-year follow-up.”

The Predictive Value of NfL

“This is now another important report underscoring the predictive value of NfL levels for the evolution of future disability in MS, but the … study clearly suffers from the relatively low number of patients investigated,” said Michael Khalil, MD, PhD, in an accompanying editorial. Dr. Khalil is an Associate Professor of General Neurology at the Medical University of Graz in Austria. “Nevertheless, neurofilaments are currently the most promising markers to indicate neuro-axonal damage in MS and other neurologic diseases. The availability of a highly sensitive blood assay now facilitates its use for further research and in clinical practice.”

—Glenn S. Williams

Suggested Reading

Bhan A, Jacobsen C, Myhr KM, et al. Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler. 2018; 24(10):1301-1307.

Khalil M. Are neurofilaments valuable biomarkers for long-term disease prognostication in MS? Mult Scler. 2018; 24(10):1270-1271.

In patients with multiple sclerosis (MS), levels of light-chain neurofilament (NfL) in CSF at diagnosis seem to predict long-term clinical outcome and conversion from the relapsing-remitting phase of the disease to the secondary progressive phase, according to a study published in the September issue of Multiple Sclerosis Journal. “NfL is thought to reflect ongoing axonal degeneration, which dominates early in the disease phase, and our results support that increased early disease activity, as identified by increased levels of CSF-NfL, has a prognostic effect several years later,” said lead author Alok Bhan, MD, and colleagues. Dr. Bhan works in the Department of Neurology at Stavanger University Hospital in Norway.

Searching for Prognostic Markers

To test whether CSF-NfL levels in patients with MS could predict clinical outcome, Dr. Bhan and colleagues conducted standardized clinical assessments of patients with newly diagnosed MS at baseline and at five- and 10-year follow-up. Expanded Disability Status Scale (EDSS) progression between assessments was defined as an increase of 1 point or more for scores less than 6 and of 0.5 points or more for scores of 6 or greater. CSF obtained at baseline was analyzed for levels of NfL using enzyme-linked immunosorbent assay technology.

The study cohort included 44 patients, of whom 35 (80%) had relapsing-remitting MS, seven (16%) had secondary progressive MS, and two (4%) had primary progressive MS at baseline. Patients who progressed on EDSS tended to have higher median baseline CSF-NfL levels than patients who did not progress after five years (947 ng/L vs 246 ng/L, respectively) and those who did not progress after 10 years (708 ng/L vs 265 ng/L, respectively), although the latter difference was not statistically significant. Patients who converted from relapsing-remitting MS to secondary progressive MS at five years had a significantly higher median CSF level of NfL (2,122 ng/L), compared with those who did not convert (246 ng/L).

“We found a statistically significant correlation between NfL levels at baseline and EDSS progression and conversion from relapsing-remitting MS to secondary progressive MS at the five-year follow-up, but a weaker correlation at the 10-year follow-up,” the researchers said. “This [finding] may be due to the increasing number of patients on disease-modifying therapy throughout the study period, as only 16% received therapy at baseline, but 54% [did] at 10-year follow-up.”

The Predictive Value of NfL

“This is now another important report underscoring the predictive value of NfL levels for the evolution of future disability in MS, but the … study clearly suffers from the relatively low number of patients investigated,” said Michael Khalil, MD, PhD, in an accompanying editorial. Dr. Khalil is an Associate Professor of General Neurology at the Medical University of Graz in Austria. “Nevertheless, neurofilaments are currently the most promising markers to indicate neuro-axonal damage in MS and other neurologic diseases. The availability of a highly sensitive blood assay now facilitates its use for further research and in clinical practice.”

—Glenn S. Williams

Suggested Reading

Bhan A, Jacobsen C, Myhr KM, et al. Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler. 2018; 24(10):1301-1307.

Khalil M. Are neurofilaments valuable biomarkers for long-term disease prognostication in MS? Mult Scler. 2018; 24(10):1270-1271.

In patients with multiple sclerosis (MS), levels of light-chain neurofilament (NfL) in CSF at diagnosis seem to predict long-term clinical outcome and conversion from the relapsing-remitting phase of the disease to the secondary progressive phase, according to a study published in the September issue of Multiple Sclerosis Journal. “NfL is thought to reflect ongoing axonal degeneration, which dominates early in the disease phase, and our results support that increased early disease activity, as identified by increased levels of CSF-NfL, has a prognostic effect several years later,” said lead author Alok Bhan, MD, and colleagues. Dr. Bhan works in the Department of Neurology at Stavanger University Hospital in Norway.

Searching for Prognostic Markers

To test whether CSF-NfL levels in patients with MS could predict clinical outcome, Dr. Bhan and colleagues conducted standardized clinical assessments of patients with newly diagnosed MS at baseline and at five- and 10-year follow-up. Expanded Disability Status Scale (EDSS) progression between assessments was defined as an increase of 1 point or more for scores less than 6 and of 0.5 points or more for scores of 6 or greater. CSF obtained at baseline was analyzed for levels of NfL using enzyme-linked immunosorbent assay technology.

The study cohort included 44 patients, of whom 35 (80%) had relapsing-remitting MS, seven (16%) had secondary progressive MS, and two (4%) had primary progressive MS at baseline. Patients who progressed on EDSS tended to have higher median baseline CSF-NfL levels than patients who did not progress after five years (947 ng/L vs 246 ng/L, respectively) and those who did not progress after 10 years (708 ng/L vs 265 ng/L, respectively), although the latter difference was not statistically significant. Patients who converted from relapsing-remitting MS to secondary progressive MS at five years had a significantly higher median CSF level of NfL (2,122 ng/L), compared with those who did not convert (246 ng/L).

“We found a statistically significant correlation between NfL levels at baseline and EDSS progression and conversion from relapsing-remitting MS to secondary progressive MS at the five-year follow-up, but a weaker correlation at the 10-year follow-up,” the researchers said. “This [finding] may be due to the increasing number of patients on disease-modifying therapy throughout the study period, as only 16% received therapy at baseline, but 54% [did] at 10-year follow-up.”

The Predictive Value of NfL

“This is now another important report underscoring the predictive value of NfL levels for the evolution of future disability in MS, but the … study clearly suffers from the relatively low number of patients investigated,” said Michael Khalil, MD, PhD, in an accompanying editorial. Dr. Khalil is an Associate Professor of General Neurology at the Medical University of Graz in Austria. “Nevertheless, neurofilaments are currently the most promising markers to indicate neuro-axonal damage in MS and other neurologic diseases. The availability of a highly sensitive blood assay now facilitates its use for further research and in clinical practice.”

—Glenn S. Williams

Suggested Reading

Bhan A, Jacobsen C, Myhr KM, et al. Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler. 2018; 24(10):1301-1307.

Khalil M. Are neurofilaments valuable biomarkers for long-term disease prognostication in MS? Mult Scler. 2018; 24(10):1270-1271.

Pooled data from an expanded-access program provide further evidence that adjunctive cannabidiol (CBD) provides meaningful reductions in seizure frequency in patients with treatment-resistant epilepsies. The data were published in the August issue of Epilepsia.

Studies have recently indicated that adjunctive CBD effectively reduces seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. An expanded-access program was created in January 2014 to offer CBD to patients with treatment-resistant epilepsies. Data on safety, tolerability, and efficacy during the first year of the study have been reported. Jerzy P. Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham, and colleagues examined results for safety outcomes at 144 weeks and efficacy outcomes at 96 weeks.

An Expanded-Access Program

All participants in the program had treatment-resistant epilepsy and were receiving stable doses of antiepileptic drugs (AEDs) for at least four weeks before enrollment. During a four-week baseline period, parents and caregivers kept diaries of all countable seizure types. Participants subsequently received a plant-based oral pharmaceutical formulation of CBD (100 mg/mL). Treatment was initiated at a dose of 2–10 mg/kg/day and was titrated to a maximum dose of 25–50 mg/kg/day.

Patients were examined every two to four weeks until the 16th week, and every two to 12 weeks after that point. The efficacy outcomes included the percentage change from baseline in median monthly convulsive seizure frequency and total seizure frequency, and the percentages of patients with at least 50%, at least 75%, and 100% reductions in seizures, compared with baseline. Investigators documented adverse events at each visit.

CBD Was Well Tolerated

The safety analysis included 607 patients, and the efficacy analysis included 580 patients. Among patients included in the safety analysis, 24% withdrew from the study. The most common reasons for withdrawal were lack of efficacy (15%) and adverse events (5%). Participants’ mean age was 13, and 52% of patients were male. The median number of concomitant AEDs was three, the median dose of CBD was 25 mg/kg/day, and the median treatment duration was 48 weeks.

At 12 weeks, adjunctive CBD was associated with a 51% reduction in median monthly convulsive seizures and a 48% reduction in total seizures. Reductions in these seizure types were similar through 96 weeks. At 12 weeks, 52% of patients had a reduction in convulsive seizures of at least 50%, 31% had a reduction of at least 75%, and 11% had a 100% reduction. These response rates were similar through 96 weeks of treatment.

CBD was generally well tolerated. The most common adverse events were diarrhea (29%) and somnolence (22%). About 10% of patients had abnormal liver adverse events, and 75% of them were taking valproate. Among patients taking concomitant clobazam, 38% had somnolence, compared with 14% of patients not taking concomitant clobazam.

The expanded-access program is not placebo-controlled, and neither patients nor investigators are blinded. Furthermore, reporting methods varied between study sites. Despite these limitations, the data indicate that adjunctive CBD significantly reduces seizure frequency, according to the authors.

The data support the results of double-blind, placebo-controlled trials that found that add-on CBD reduces seizure frequency, compared with placebo. The FDA in June approved Epidiolex, the formulation of CBD used in the expanded-access program, for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

—Erik Greb

Suggested Reading

Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540-1548.

Pooled data from an expanded-access program provide further evidence that adjunctive cannabidiol (CBD) provides meaningful reductions in seizure frequency in patients with treatment-resistant epilepsies. The data were published in the August issue of Epilepsia.

Studies have recently indicated that adjunctive CBD effectively reduces seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. An expanded-access program was created in January 2014 to offer CBD to patients with treatment-resistant epilepsies. Data on safety, tolerability, and efficacy during the first year of the study have been reported. Jerzy P. Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham, and colleagues examined results for safety outcomes at 144 weeks and efficacy outcomes at 96 weeks.

An Expanded-Access Program

All participants in the program had treatment-resistant epilepsy and were receiving stable doses of antiepileptic drugs (AEDs) for at least four weeks before enrollment. During a four-week baseline period, parents and caregivers kept diaries of all countable seizure types. Participants subsequently received a plant-based oral pharmaceutical formulation of CBD (100 mg/mL). Treatment was initiated at a dose of 2–10 mg/kg/day and was titrated to a maximum dose of 25–50 mg/kg/day.

Patients were examined every two to four weeks until the 16th week, and every two to 12 weeks after that point. The efficacy outcomes included the percentage change from baseline in median monthly convulsive seizure frequency and total seizure frequency, and the percentages of patients with at least 50%, at least 75%, and 100% reductions in seizures, compared with baseline. Investigators documented adverse events at each visit.

CBD Was Well Tolerated

The safety analysis included 607 patients, and the efficacy analysis included 580 patients. Among patients included in the safety analysis, 24% withdrew from the study. The most common reasons for withdrawal were lack of efficacy (15%) and adverse events (5%). Participants’ mean age was 13, and 52% of patients were male. The median number of concomitant AEDs was three, the median dose of CBD was 25 mg/kg/day, and the median treatment duration was 48 weeks.

At 12 weeks, adjunctive CBD was associated with a 51% reduction in median monthly convulsive seizures and a 48% reduction in total seizures. Reductions in these seizure types were similar through 96 weeks. At 12 weeks, 52% of patients had a reduction in convulsive seizures of at least 50%, 31% had a reduction of at least 75%, and 11% had a 100% reduction. These response rates were similar through 96 weeks of treatment.

CBD was generally well tolerated. The most common adverse events were diarrhea (29%) and somnolence (22%). About 10% of patients had abnormal liver adverse events, and 75% of them were taking valproate. Among patients taking concomitant clobazam, 38% had somnolence, compared with 14% of patients not taking concomitant clobazam.

The expanded-access program is not placebo-controlled, and neither patients nor investigators are blinded. Furthermore, reporting methods varied between study sites. Despite these limitations, the data indicate that adjunctive CBD significantly reduces seizure frequency, according to the authors.

The data support the results of double-blind, placebo-controlled trials that found that add-on CBD reduces seizure frequency, compared with placebo. The FDA in June approved Epidiolex, the formulation of CBD used in the expanded-access program, for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

—Erik Greb

Suggested Reading

Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540-1548.

Pooled data from an expanded-access program provide further evidence that adjunctive cannabidiol (CBD) provides meaningful reductions in seizure frequency in patients with treatment-resistant epilepsies. The data were published in the August issue of Epilepsia.

Studies have recently indicated that adjunctive CBD effectively reduces seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. An expanded-access program was created in January 2014 to offer CBD to patients with treatment-resistant epilepsies. Data on safety, tolerability, and efficacy during the first year of the study have been reported. Jerzy P. Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham, and colleagues examined results for safety outcomes at 144 weeks and efficacy outcomes at 96 weeks.

An Expanded-Access Program

All participants in the program had treatment-resistant epilepsy and were receiving stable doses of antiepileptic drugs (AEDs) for at least four weeks before enrollment. During a four-week baseline period, parents and caregivers kept diaries of all countable seizure types. Participants subsequently received a plant-based oral pharmaceutical formulation of CBD (100 mg/mL). Treatment was initiated at a dose of 2–10 mg/kg/day and was titrated to a maximum dose of 25–50 mg/kg/day.

Patients were examined every two to four weeks until the 16th week, and every two to 12 weeks after that point. The efficacy outcomes included the percentage change from baseline in median monthly convulsive seizure frequency and total seizure frequency, and the percentages of patients with at least 50%, at least 75%, and 100% reductions in seizures, compared with baseline. Investigators documented adverse events at each visit.

CBD Was Well Tolerated

The safety analysis included 607 patients, and the efficacy analysis included 580 patients. Among patients included in the safety analysis, 24% withdrew from the study. The most common reasons for withdrawal were lack of efficacy (15%) and adverse events (5%). Participants’ mean age was 13, and 52% of patients were male. The median number of concomitant AEDs was three, the median dose of CBD was 25 mg/kg/day, and the median treatment duration was 48 weeks.

At 12 weeks, adjunctive CBD was associated with a 51% reduction in median monthly convulsive seizures and a 48% reduction in total seizures. Reductions in these seizure types were similar through 96 weeks. At 12 weeks, 52% of patients had a reduction in convulsive seizures of at least 50%, 31% had a reduction of at least 75%, and 11% had a 100% reduction. These response rates were similar through 96 weeks of treatment.

CBD was generally well tolerated. The most common adverse events were diarrhea (29%) and somnolence (22%). About 10% of patients had abnormal liver adverse events, and 75% of them were taking valproate. Among patients taking concomitant clobazam, 38% had somnolence, compared with 14% of patients not taking concomitant clobazam.

The expanded-access program is not placebo-controlled, and neither patients nor investigators are blinded. Furthermore, reporting methods varied between study sites. Despite these limitations, the data indicate that adjunctive CBD significantly reduces seizure frequency, according to the authors.

The data support the results of double-blind, placebo-controlled trials that found that add-on CBD reduces seizure frequency, compared with placebo. The FDA in June approved Epidiolex, the formulation of CBD used in the expanded-access program, for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

—Erik Greb

Suggested Reading

Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540-1548.