Literature Review

To determine the value of pulse oximetry in detecting seizures, Goldenholz et al evaluated 193 seizures among 45 patients who were being monitored with video EEG, SpO₂, and EKG. Their analysis found that SpO₂ thresholds of 80%-86% were able to detect 63%-73% of generalized convulsions and 20%-28% of focal seizures. While the researchers concluded that continuous SpO₂ monitoring requires a tradeoff between false alarms and accurate detection of seizures, they believe an alarm setting of 86% is likely to be worthwhile in patients who experience fewer false alarms and a setting of 80% would be better for those who have more false alarms.

Goldenholz DM, Kuhn A, Austermuehle A, et al. Long-term monitoring of cardiorespiratory patterns in drug-resistant epilepsy. Epilepsia. 2017;58(1):77-84.

To determine the value of pulse oximetry in detecting seizures, Goldenholz et al evaluated 193 seizures among 45 patients who were being monitored with video EEG, SpO₂, and EKG. Their analysis found that SpO₂ thresholds of 80%-86% were able to detect 63%-73% of generalized convulsions and 20%-28% of focal seizures. While the researchers concluded that continuous SpO₂ monitoring requires a tradeoff between false alarms and accurate detection of seizures, they believe an alarm setting of 86% is likely to be worthwhile in patients who experience fewer false alarms and a setting of 80% would be better for those who have more false alarms.

Goldenholz DM, Kuhn A, Austermuehle A, et al. Long-term monitoring of cardiorespiratory patterns in drug-resistant epilepsy. Epilepsia. 2017;58(1):77-84.

To determine the value of pulse oximetry in detecting seizures, Goldenholz et al evaluated 193 seizures among 45 patients who were being monitored with video EEG, SpO₂, and EKG. Their analysis found that SpO₂ thresholds of 80%-86% were able to detect 63%-73% of generalized convulsions and 20%-28% of focal seizures. While the researchers concluded that continuous SpO₂ monitoring requires a tradeoff between false alarms and accurate detection of seizures, they believe an alarm setting of 86% is likely to be worthwhile in patients who experience fewer false alarms and a setting of 80% would be better for those who have more false alarms.

Goldenholz DM, Kuhn A, Austermuehle A, et al. Long-term monitoring of cardiorespiratory patterns in drug-resistant epilepsy. Epilepsia. 2017;58(1):77-84.

When preparing for epilepsy surgery, neurologists may consider using functional MRI (fMRI) instead of the intracarotid amobarbital procedure (IAP) to map language and memory functions in the brain, according to a practice guideline developed by the American Academy of Neurology (AAN). The current evidence is weak, however, and clinicians should advise patients carefully about the benefits and risks of IAP (also known as the Wada test) and fMRI, according to the guideline, which was published online ahead of print January 11 in Neurology.

IAP, an invasive technique, is the current standard for presurgical evaluation in epilepsy. fMRI is noninvasive and also considered safe. Neither of the two methods has been standardized. “Because fMRI is becoming more widely available, we wanted to see how it compares to the Wada test,” said lead author Jerzy Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham. “While the risks associated with the Wada test are rare, they can be serious, including stroke and injury to the carotid artery.”

The AAN formed an 11-member panel to draft the guidelines. Two panelists independently selected 37 possibly relevant articles. Studies with fewer than 15 cases, case reports, meta-analyses, and editorials were excluded. Two panelists rated each article according to the AAN’s diagnostic and prognostic classification of evidence, and the panel ultimately developed consensus recommendations.

Data Support fMRI for Certain Situations

Class II data indicated that fMRI possibly provides language lateralization information concordant with that of IAP in 87% of people with medial temporal lobe epilepsy and in 81% of patients with extratemporal epilepsy. Current comparative data for temporal tumors or lateral temporal cases are insufficient to draw conclusions. Thus, fMRI may be considered as an option for lateralizing language functions in place of IAP in patients with medial temporal lobe epilepsy (Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C), said the authors. The evidence is unclear for patients with temporal neocortical epilepsy or temporal tumors (Level U).

One Class II study and one Class III study suggested that fMRI is possibly effective in aiding the prediction of postsurgical language deficits in patients undergoing presurgical evaluation for possible temporal lobectomy. The authors recommended that fMRI may be considered for predicting postsurgical language outcomes after anterior temporal lobe resection for the control of temporal lobe epilepsy (Level C).

Class II evidence suggests that in patients with medial temporal lobe epilepsy, fMRI is comparable with IAP in its ability to lateralize memory functions and may be used for this purpose. The authors recommended that fMRI may be considered as an option to lateralize memory functions in place of IAP in patients with medial temporal lobe epilepsy (Level C).

Nine Class II studies with different methods together suggested that fMRI leftward activation asymmetry during encoding of verbal material, regardless of whether measured in the medial temporal lobe or in the language network, probably predicts verbal memory decline after left medial temporal lobe surgery. The authors therefore recommended that presurgical fMRI of verbal memory or of language encoding should be considered as an option to predict verbal memory outcome in patients with epilepsy who are undergoing evaluation for left medial temporal lobe surgery (Level B).

A Class II study indicated that fMRI activation asymmetry during nonverbal (ie, scene and face recognition) memory tasks possibly predicts nonverbal memory decline after medial temporal lobe surgery. The authors recommended that presurgical fMRI using nonverbal memory encoding may be considered as a means to predict visuospatial memory outcomes in patients with epilepsy who are undergoing evaluation for temporal lobe surgery (Level C).

Based on data from one Class II study and one Class III study, the authors recommended that presurgical fMRI may be used instead of the IAP for language lateralization in patients with epilepsy who are undergoing evaluation for brain surgery (Level C). “However, when fMRI is used for this purpose, task design, data analysis methods, and epilepsy type should be considered,” they added.

In addition, based on nine Class II studies, the authors recommended that fMRI of language and verbal memory lateralization may be an alternative to IAP memory testing for prediction of verbal memory outcome in medial temporal lobe epilepsy (Level C). The authors note that fMRI is not yet established as an alternative to the IAP for prediction of global amnesia in patients who have undergone anterior temporal lobe surgery.

More and Larger Studies Are Needed

“The imperfect concordance between fMRI and IAP language lateralization leaves open the question of which test is more accurate in discordant cases,” said the authors. Although the IAP is the reference standard, it is subject to limitations resulting from individual variation in arterial anatomy, variable effects of anesthesia, the rate of amobarbital injection, variability in patient cooperation, and variation in testing methods.

Like the IAP, cognitive fMRI “is a complex diagnostic procedure that requires both advanced technical expertise in imaging and expert interaction with patients to elicit adequate levels of task performance, select a set of activation tasks appropriate to the patient’s ability and the clinical aims of the study, instruct the patient on the tasks, administer the tasks during scanning, and evaluate and provide corrective feedback on task performance during the scanning session,” said the authors.

Global amnesia may result from bilateral medial temporal lobe damage, and some neurologists depend on the IAP to evaluate a patient’s risk for this outcome. “Global amnesia is rare after unilateral temporal lobe surgery, however, and occurs mainly when there is preexisting contralateral medial temporal lobe dysfunction,” said the authors. “One possible approach, therefore, is to reserve use of the IAP memory test for those patients at greatest risk for global amnesia, that is, patients undergoing unilateral anterior temporal lobe resection who have structural or functional evidence of damage to the contralateral medial temporal lobe.”

“Larger studies need to be conducted to increase the quality of available evidence,” Dr. Szaflarski concluded.

—Erik Greb

Suggested Reading

Szaflarski JP, Gloss D, Binder JR, et al. Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy—Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2017 Jan 11 [Epub ahead of print].

When preparing for epilepsy surgery, neurologists may consider using functional MRI (fMRI) instead of the intracarotid amobarbital procedure (IAP) to map language and memory functions in the brain, according to a practice guideline developed by the American Academy of Neurology (AAN). The current evidence is weak, however, and clinicians should advise patients carefully about the benefits and risks of IAP (also known as the Wada test) and fMRI, according to the guideline, which was published online ahead of print January 11 in Neurology.

IAP, an invasive technique, is the current standard for presurgical evaluation in epilepsy. fMRI is noninvasive and also considered safe. Neither of the two methods has been standardized. “Because fMRI is becoming more widely available, we wanted to see how it compares to the Wada test,” said lead author Jerzy Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham. “While the risks associated with the Wada test are rare, they can be serious, including stroke and injury to the carotid artery.”

The AAN formed an 11-member panel to draft the guidelines. Two panelists independently selected 37 possibly relevant articles. Studies with fewer than 15 cases, case reports, meta-analyses, and editorials were excluded. Two panelists rated each article according to the AAN’s diagnostic and prognostic classification of evidence, and the panel ultimately developed consensus recommendations.

Data Support fMRI for Certain Situations

Class II data indicated that fMRI possibly provides language lateralization information concordant with that of IAP in 87% of people with medial temporal lobe epilepsy and in 81% of patients with extratemporal epilepsy. Current comparative data for temporal tumors or lateral temporal cases are insufficient to draw conclusions. Thus, fMRI may be considered as an option for lateralizing language functions in place of IAP in patients with medial temporal lobe epilepsy (Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C), said the authors. The evidence is unclear for patients with temporal neocortical epilepsy or temporal tumors (Level U).

One Class II study and one Class III study suggested that fMRI is possibly effective in aiding the prediction of postsurgical language deficits in patients undergoing presurgical evaluation for possible temporal lobectomy. The authors recommended that fMRI may be considered for predicting postsurgical language outcomes after anterior temporal lobe resection for the control of temporal lobe epilepsy (Level C).

Class II evidence suggests that in patients with medial temporal lobe epilepsy, fMRI is comparable with IAP in its ability to lateralize memory functions and may be used for this purpose. The authors recommended that fMRI may be considered as an option to lateralize memory functions in place of IAP in patients with medial temporal lobe epilepsy (Level C).

Nine Class II studies with different methods together suggested that fMRI leftward activation asymmetry during encoding of verbal material, regardless of whether measured in the medial temporal lobe or in the language network, probably predicts verbal memory decline after left medial temporal lobe surgery. The authors therefore recommended that presurgical fMRI of verbal memory or of language encoding should be considered as an option to predict verbal memory outcome in patients with epilepsy who are undergoing evaluation for left medial temporal lobe surgery (Level B).

A Class II study indicated that fMRI activation asymmetry during nonverbal (ie, scene and face recognition) memory tasks possibly predicts nonverbal memory decline after medial temporal lobe surgery. The authors recommended that presurgical fMRI using nonverbal memory encoding may be considered as a means to predict visuospatial memory outcomes in patients with epilepsy who are undergoing evaluation for temporal lobe surgery (Level C).

Based on data from one Class II study and one Class III study, the authors recommended that presurgical fMRI may be used instead of the IAP for language lateralization in patients with epilepsy who are undergoing evaluation for brain surgery (Level C). “However, when fMRI is used for this purpose, task design, data analysis methods, and epilepsy type should be considered,” they added.

In addition, based on nine Class II studies, the authors recommended that fMRI of language and verbal memory lateralization may be an alternative to IAP memory testing for prediction of verbal memory outcome in medial temporal lobe epilepsy (Level C). The authors note that fMRI is not yet established as an alternative to the IAP for prediction of global amnesia in patients who have undergone anterior temporal lobe surgery.

More and Larger Studies Are Needed

“The imperfect concordance between fMRI and IAP language lateralization leaves open the question of which test is more accurate in discordant cases,” said the authors. Although the IAP is the reference standard, it is subject to limitations resulting from individual variation in arterial anatomy, variable effects of anesthesia, the rate of amobarbital injection, variability in patient cooperation, and variation in testing methods.

Like the IAP, cognitive fMRI “is a complex diagnostic procedure that requires both advanced technical expertise in imaging and expert interaction with patients to elicit adequate levels of task performance, select a set of activation tasks appropriate to the patient’s ability and the clinical aims of the study, instruct the patient on the tasks, administer the tasks during scanning, and evaluate and provide corrective feedback on task performance during the scanning session,” said the authors.

Global amnesia may result from bilateral medial temporal lobe damage, and some neurologists depend on the IAP to evaluate a patient’s risk for this outcome. “Global amnesia is rare after unilateral temporal lobe surgery, however, and occurs mainly when there is preexisting contralateral medial temporal lobe dysfunction,” said the authors. “One possible approach, therefore, is to reserve use of the IAP memory test for those patients at greatest risk for global amnesia, that is, patients undergoing unilateral anterior temporal lobe resection who have structural or functional evidence of damage to the contralateral medial temporal lobe.”

“Larger studies need to be conducted to increase the quality of available evidence,” Dr. Szaflarski concluded.

—Erik Greb

Suggested Reading

Szaflarski JP, Gloss D, Binder JR, et al. Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy—Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2017 Jan 11 [Epub ahead of print].

When preparing for epilepsy surgery, neurologists may consider using functional MRI (fMRI) instead of the intracarotid amobarbital procedure (IAP) to map language and memory functions in the brain, according to a practice guideline developed by the American Academy of Neurology (AAN). The current evidence is weak, however, and clinicians should advise patients carefully about the benefits and risks of IAP (also known as the Wada test) and fMRI, according to the guideline, which was published online ahead of print January 11 in Neurology.

IAP, an invasive technique, is the current standard for presurgical evaluation in epilepsy. fMRI is noninvasive and also considered safe. Neither of the two methods has been standardized. “Because fMRI is becoming more widely available, we wanted to see how it compares to the Wada test,” said lead author Jerzy Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham. “While the risks associated with the Wada test are rare, they can be serious, including stroke and injury to the carotid artery.”

The AAN formed an 11-member panel to draft the guidelines. Two panelists independently selected 37 possibly relevant articles. Studies with fewer than 15 cases, case reports, meta-analyses, and editorials were excluded. Two panelists rated each article according to the AAN’s diagnostic and prognostic classification of evidence, and the panel ultimately developed consensus recommendations.

Data Support fMRI for Certain Situations

Class II data indicated that fMRI possibly provides language lateralization information concordant with that of IAP in 87% of people with medial temporal lobe epilepsy and in 81% of patients with extratemporal epilepsy. Current comparative data for temporal tumors or lateral temporal cases are insufficient to draw conclusions. Thus, fMRI may be considered as an option for lateralizing language functions in place of IAP in patients with medial temporal lobe epilepsy (Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C), said the authors. The evidence is unclear for patients with temporal neocortical epilepsy or temporal tumors (Level U).

One Class II study and one Class III study suggested that fMRI is possibly effective in aiding the prediction of postsurgical language deficits in patients undergoing presurgical evaluation for possible temporal lobectomy. The authors recommended that fMRI may be considered for predicting postsurgical language outcomes after anterior temporal lobe resection for the control of temporal lobe epilepsy (Level C).

Class II evidence suggests that in patients with medial temporal lobe epilepsy, fMRI is comparable with IAP in its ability to lateralize memory functions and may be used for this purpose. The authors recommended that fMRI may be considered as an option to lateralize memory functions in place of IAP in patients with medial temporal lobe epilepsy (Level C).

Nine Class II studies with different methods together suggested that fMRI leftward activation asymmetry during encoding of verbal material, regardless of whether measured in the medial temporal lobe or in the language network, probably predicts verbal memory decline after left medial temporal lobe surgery. The authors therefore recommended that presurgical fMRI of verbal memory or of language encoding should be considered as an option to predict verbal memory outcome in patients with epilepsy who are undergoing evaluation for left medial temporal lobe surgery (Level B).

A Class II study indicated that fMRI activation asymmetry during nonverbal (ie, scene and face recognition) memory tasks possibly predicts nonverbal memory decline after medial temporal lobe surgery. The authors recommended that presurgical fMRI using nonverbal memory encoding may be considered as a means to predict visuospatial memory outcomes in patients with epilepsy who are undergoing evaluation for temporal lobe surgery (Level C).

Based on data from one Class II study and one Class III study, the authors recommended that presurgical fMRI may be used instead of the IAP for language lateralization in patients with epilepsy who are undergoing evaluation for brain surgery (Level C). “However, when fMRI is used for this purpose, task design, data analysis methods, and epilepsy type should be considered,” they added.

In addition, based on nine Class II studies, the authors recommended that fMRI of language and verbal memory lateralization may be an alternative to IAP memory testing for prediction of verbal memory outcome in medial temporal lobe epilepsy (Level C). The authors note that fMRI is not yet established as an alternative to the IAP for prediction of global amnesia in patients who have undergone anterior temporal lobe surgery.

More and Larger Studies Are Needed

“The imperfect concordance between fMRI and IAP language lateralization leaves open the question of which test is more accurate in discordant cases,” said the authors. Although the IAP is the reference standard, it is subject to limitations resulting from individual variation in arterial anatomy, variable effects of anesthesia, the rate of amobarbital injection, variability in patient cooperation, and variation in testing methods.

Like the IAP, cognitive fMRI “is a complex diagnostic procedure that requires both advanced technical expertise in imaging and expert interaction with patients to elicit adequate levels of task performance, select a set of activation tasks appropriate to the patient’s ability and the clinical aims of the study, instruct the patient on the tasks, administer the tasks during scanning, and evaluate and provide corrective feedback on task performance during the scanning session,” said the authors.

Global amnesia may result from bilateral medial temporal lobe damage, and some neurologists depend on the IAP to evaluate a patient’s risk for this outcome. “Global amnesia is rare after unilateral temporal lobe surgery, however, and occurs mainly when there is preexisting contralateral medial temporal lobe dysfunction,” said the authors. “One possible approach, therefore, is to reserve use of the IAP memory test for those patients at greatest risk for global amnesia, that is, patients undergoing unilateral anterior temporal lobe resection who have structural or functional evidence of damage to the contralateral medial temporal lobe.”

“Larger studies need to be conducted to increase the quality of available evidence,” Dr. Szaflarski concluded.

—Erik Greb

Suggested Reading

Szaflarski JP, Gloss D, Binder JR, et al. Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy—Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2017 Jan 11 [Epub ahead of print].

Two decades of epidemiologic research show that silent cerebrovascular disease is common and associated with an increased risk of stroke and dementia. To summarize evidence for the diagnosis and management of silent cerebrovascular disease to prevent stroke, the Stroke Council of the American Heart Association (AHA) convened a writing committee to evaluate existing evidence, to discuss clinical considerations, and to offer suggestions for future research on stroke prevention. The committee focused on patients with three cardinal manifestations of silent cerebrovascular disease: silent brain infarcts, MRI white matter hyperintensities of presumed vascular origin, and cerebral microbleeds. The committee’s report, which was published as a Scientific Statement from the AHA and the American Stroke Association (ASA), appeared online ahead of print December 15, 2016, in Stroke. The American Academy of Neurology affirmed the value of the AHA/ASA statement as an educational tool for neurologists.

The AHA/ASA writing committee found strong and consistent evidence that silent cerebrovascular disease is a common problem of aging and that silent brain infarcts and white matter hyperintensities are strongly associated with future symptomatic stroke risk, entailing a two- to threefold increase in relative risk, even after controlling for vascular risk factors such as hypertension. Among patients with cerebral microbleeds, evidence suggests that those treated with thrombolysis for acute ischemic stroke have a moderately increased risk of symptomatic intracranial hemorrhage, but little prospective evidence indicates the risk of symptomatic hemorrhage in patients who receive anticoagulation, said lead author and chair of the writing committee, Eric E. Smith, MD, MPH, Associate Professor of Neurology and the Katthy Taylor Chair in Vascular Dementia in the Department of Clinical Neurosciences at the University of Calgary, Alberta, and Hotchkiss Brain Institute. There were no randomized controlled trials targeted specifically to stroke prevention in participants with silent cerebrovascular disease.

According to the AHA/ASA Scientific Statement, primary stroke prevention is indicated in patients with silent brain infarcts, white matter hyperintensities, or microbleeds. The AHA/ASA statement further advises that accurate and reliable radiologic reporting using consensus terms understood by radiologists and nonradiologists alike will be essential to identify patients with silent cerebrovascular disease for appropriate treatment. Adoption of standard terms and definitions for silent cerebrovascular disease, as provided by prior AHA/ASA statements and by a consensus group, may facilitate diagnosis and communication of findings from radiologists to clinicians.

—Glenn S. Williams

Suggested Reading

Smith EE, Saposnik G, Biessels GJ, et al. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016 December 15 [Epub ahead of print].

Two decades of epidemiologic research show that silent cerebrovascular disease is common and associated with an increased risk of stroke and dementia. To summarize evidence for the diagnosis and management of silent cerebrovascular disease to prevent stroke, the Stroke Council of the American Heart Association (AHA) convened a writing committee to evaluate existing evidence, to discuss clinical considerations, and to offer suggestions for future research on stroke prevention. The committee focused on patients with three cardinal manifestations of silent cerebrovascular disease: silent brain infarcts, MRI white matter hyperintensities of presumed vascular origin, and cerebral microbleeds. The committee’s report, which was published as a Scientific Statement from the AHA and the American Stroke Association (ASA), appeared online ahead of print December 15, 2016, in Stroke. The American Academy of Neurology affirmed the value of the AHA/ASA statement as an educational tool for neurologists.

The AHA/ASA writing committee found strong and consistent evidence that silent cerebrovascular disease is a common problem of aging and that silent brain infarcts and white matter hyperintensities are strongly associated with future symptomatic stroke risk, entailing a two- to threefold increase in relative risk, even after controlling for vascular risk factors such as hypertension. Among patients with cerebral microbleeds, evidence suggests that those treated with thrombolysis for acute ischemic stroke have a moderately increased risk of symptomatic intracranial hemorrhage, but little prospective evidence indicates the risk of symptomatic hemorrhage in patients who receive anticoagulation, said lead author and chair of the writing committee, Eric E. Smith, MD, MPH, Associate Professor of Neurology and the Katthy Taylor Chair in Vascular Dementia in the Department of Clinical Neurosciences at the University of Calgary, Alberta, and Hotchkiss Brain Institute. There were no randomized controlled trials targeted specifically to stroke prevention in participants with silent cerebrovascular disease.

According to the AHA/ASA Scientific Statement, primary stroke prevention is indicated in patients with silent brain infarcts, white matter hyperintensities, or microbleeds. The AHA/ASA statement further advises that accurate and reliable radiologic reporting using consensus terms understood by radiologists and nonradiologists alike will be essential to identify patients with silent cerebrovascular disease for appropriate treatment. Adoption of standard terms and definitions for silent cerebrovascular disease, as provided by prior AHA/ASA statements and by a consensus group, may facilitate diagnosis and communication of findings from radiologists to clinicians.

—Glenn S. Williams

Suggested Reading

Smith EE, Saposnik G, Biessels GJ, et al. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016 December 15 [Epub ahead of print].

Two decades of epidemiologic research show that silent cerebrovascular disease is common and associated with an increased risk of stroke and dementia. To summarize evidence for the diagnosis and management of silent cerebrovascular disease to prevent stroke, the Stroke Council of the American Heart Association (AHA) convened a writing committee to evaluate existing evidence, to discuss clinical considerations, and to offer suggestions for future research on stroke prevention. The committee focused on patients with three cardinal manifestations of silent cerebrovascular disease: silent brain infarcts, MRI white matter hyperintensities of presumed vascular origin, and cerebral microbleeds. The committee’s report, which was published as a Scientific Statement from the AHA and the American Stroke Association (ASA), appeared online ahead of print December 15, 2016, in Stroke. The American Academy of Neurology affirmed the value of the AHA/ASA statement as an educational tool for neurologists.

The AHA/ASA writing committee found strong and consistent evidence that silent cerebrovascular disease is a common problem of aging and that silent brain infarcts and white matter hyperintensities are strongly associated with future symptomatic stroke risk, entailing a two- to threefold increase in relative risk, even after controlling for vascular risk factors such as hypertension. Among patients with cerebral microbleeds, evidence suggests that those treated with thrombolysis for acute ischemic stroke have a moderately increased risk of symptomatic intracranial hemorrhage, but little prospective evidence indicates the risk of symptomatic hemorrhage in patients who receive anticoagulation, said lead author and chair of the writing committee, Eric E. Smith, MD, MPH, Associate Professor of Neurology and the Katthy Taylor Chair in Vascular Dementia in the Department of Clinical Neurosciences at the University of Calgary, Alberta, and Hotchkiss Brain Institute. There were no randomized controlled trials targeted specifically to stroke prevention in participants with silent cerebrovascular disease.

According to the AHA/ASA Scientific Statement, primary stroke prevention is indicated in patients with silent brain infarcts, white matter hyperintensities, or microbleeds. The AHA/ASA statement further advises that accurate and reliable radiologic reporting using consensus terms understood by radiologists and nonradiologists alike will be essential to identify patients with silent cerebrovascular disease for appropriate treatment. Adoption of standard terms and definitions for silent cerebrovascular disease, as provided by prior AHA/ASA statements and by a consensus group, may facilitate diagnosis and communication of findings from radiologists to clinicians.

—Glenn S. Williams

Suggested Reading

Smith EE, Saposnik G, Biessels GJ, et al. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016 December 15 [Epub ahead of print].

Among collegiate athletes, elevated plasma tau concentrations within six hours after a sport-related concussion predict a prolonged recovery, according to research published online ahead of print January 6 in Neurology. This finding suggests that tau levels may help to determine when athletes should return to play. Variability of tau concentrations across athletes and the effect of physical exertion on plasma tau may complicate the use of the biomarker for concussion management, however.

Approximately 3.8 million sport-related concussions occur each year in the United States, but no biomarkers are known to predict recovery and an athlete’s readiness to return to play. Postconcussive symptoms typically resolve within 10 days in about half of collegiate athletes, but symptoms are chronic in a subset of patients. Shahim et al found that plasma tau elevations predicted a return to play of more than 10 days in professional ice hockey players in Sweden.

Diagnosing Sport-Related Concussion

Jessica Gill, RN, PhD, an investigator with the National Institute of Nursing Research at the NIH, and colleagues conducted a study to determine whether changes in plasma tau after sport-related concussion relate to return to play in men and women collegiate athletes. The researchers included students with concussion, as well as athlete and nonathlete controls. The athletes participated in various National Collegiate Athletic Association (NCAA) division I and III contact sports (ie, football, soccer, basketball, hockey, and lacrosse).

Between 2009 and 2014, 632 athletes underwent plasma sampling and cognitive testing prior to the sports seasons and were followed prospectively for a diagnosis of sport-related concussion. Sport-related concussions were witnessed by an on-field certified athletic trainer and met the Sport Concussion Assessment Tool 2 definition of concussion.Investigators collected blood samples from athletes with concussion and athlete controls at six hours, 24 hours, 72 hours, and seven days after a concussion. Nonathlete controls had blood draws at an unrelated time point. Investigators measured total tau using an ultrasensitive immunoassay.

Return to play for each athlete was determined by athletic trainers or team physicians. They followed NCAA guidelines, which recommend that athletes be asymptomatic at rest and as they progressively resume activity before returning to play.

A total of 46 athletes were diagnosed with a sport-related concussion. Concussions occurred between 19 days and 218 days after baseline assessments (mean, 92.3 days). Thirty-seven athletes without concussion served as athlete controls. Athletes with and without concussion did not differ significantly in sport played, history of sport-related concussion, or other demographic features. A control group of 21 healthy nonathletes was demographically similar to the athlete groups.Return to play information was available for 41 of the athletes with concussion. Athletes who took more than 10 days to recover were considered to have a long return to play (23 athletes). Those who recovered in less than 10 days had a short return to play (18 athletes). The mean return to play duration was 21.68 days (range, two days to 263 days). Five athletes had a return to play duration of 30 days or more. Approximately 39% returned to play in less than 10 days. There were no significant differences in sport played or history of concussion among those with long return to play versus short return to play. Women made up 61% of the long return to play group and 28% of the short return to play group.

Tau Measurements

Compared with nonathletes, athletes had significantly higher mean tau concentrations at baseline and all other time points. The longitudinal pattern of tau differed significantly between athletes with and without concussion. Athletes with concussion had significantly lower mean total tau at 24 hours (6.06 pg/mL vs 7.89 pg/mL) and 72 hours (5.19 pg/mL vs 6.94 pg/mL), compared with athlete controls.

Athletes with a long return to play had higher tau concentrations overall, after controlling for sex, than those with a short return to play. The differences were statistically significant at six hours (10.98 pg/mL vs 7.02 pg/mL), 24 hours (7.19 pg/mL vs 4.08 pg/mL), and 72 hours (6.29 pg/mL vs 3.94 pg/mL).

Mean change in tau from baseline also significantly differed between the return to play groups. Athletes with long return to play had a mean increase of 2.26 pg/mL at six hours postconcussion, compared with a mean reduction of 1.19 pg/mL in the short return to play group, after controlling for sex. Area under the curve (AUC) analyses revealed that higher total tau six hours post concussion and change in tau from baseline to six hours post concussion predicted long return to play (AUC of 0.81 and 0.80, respectively). Higher total tau at 72 hours postconcussion also was a significant predictor of long return to play (AUC, 0.82).

“These findings suggest that changes in total tau within six hours of a sport-related concussion may provide vital information about return to play decisions, and may serve to mitigate the negative consequences of returning to play prematurely,” Dr. Gill and colleagues said. Preclinical models link insufficient recovery time from a mild traumatic brain injury (mTBI) to greater neuropathology following a subsequent mTBI, including pathology that overlaps with that of chronic traumatic encephalopathy.

Lower levels of tau in athletes with concussion, compared with athletes without concussion, at 24 hours and 72 hours “may be due to the effects of physical exertion on tau,” the researchers said. Limitations of the study include the relatively small sample size within subanalyses of long and short return to play.

More Research Is Needed

“While normally measured in CSF, tau measured in blood could provide the opportunity to assess neurologic injury shortly after concussion, as well as facilitate monitoring of recovery over time,” said Barbara B. Bendlin, PhD, Associate Professor of Medicine and Public Health at the University of Wisconsin–Madison, and Michael Makdissi, MBBS, PhD, research fellow at the Florey Institute of Neuroscience and Mental Health and Adjunct Associate Professor of Rehabilitation, Nutrition, and Sport at the La Trobe Sport and Exercise Medicine Research Centre in Australia, in an accompanying editorial.

However, differences in plasma tau levels between athletes and nonathletes; lower plasma tau levels at 24 hours and 72 hours post concussion in athletes with concussion, compared with nonconcussed teammates; variability across players; and fluctuations in plasma tau levels over time in general may complicate the use of the biomarker in concussion management. In addition, tau in plasma may reflect CNS and peripheral nervous system origins.

“This study and others conducted in the sports setting open the door for further evaluation and possible future implementation of blood-based biomarkers for evaluation of concussion,” they said. “Nevertheless, more work is needed before blood-based biomarkers can be used for management of sport-related concussion.”

—Jake Remaly

Suggested Reading

Bendlin BB, Makdissi M. Blood-based biomarkers for evaluating sport-related concussion: Back in the game. Neurology. 2017 Jan 6 [Epub ahead of print].

Gill J, Merchant-Borna K, Jeromin A, et al. Acute plasma tau relates to prolonged return to play after concussion. Neurology. 2017 Jan 6 [Epub ahead of print].

Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol. 2014;71(6):684-692.

Among collegiate athletes, elevated plasma tau concentrations within six hours after a sport-related concussion predict a prolonged recovery, according to research published online ahead of print January 6 in Neurology. This finding suggests that tau levels may help to determine when athletes should return to play. Variability of tau concentrations across athletes and the effect of physical exertion on plasma tau may complicate the use of the biomarker for concussion management, however.

Approximately 3.8 million sport-related concussions occur each year in the United States, but no biomarkers are known to predict recovery and an athlete’s readiness to return to play. Postconcussive symptoms typically resolve within 10 days in about half of collegiate athletes, but symptoms are chronic in a subset of patients. Shahim et al found that plasma tau elevations predicted a return to play of more than 10 days in professional ice hockey players in Sweden.

Diagnosing Sport-Related Concussion

Jessica Gill, RN, PhD, an investigator with the National Institute of Nursing Research at the NIH, and colleagues conducted a study to determine whether changes in plasma tau after sport-related concussion relate to return to play in men and women collegiate athletes. The researchers included students with concussion, as well as athlete and nonathlete controls. The athletes participated in various National Collegiate Athletic Association (NCAA) division I and III contact sports (ie, football, soccer, basketball, hockey, and lacrosse).

Between 2009 and 2014, 632 athletes underwent plasma sampling and cognitive testing prior to the sports seasons and were followed prospectively for a diagnosis of sport-related concussion. Sport-related concussions were witnessed by an on-field certified athletic trainer and met the Sport Concussion Assessment Tool 2 definition of concussion.Investigators collected blood samples from athletes with concussion and athlete controls at six hours, 24 hours, 72 hours, and seven days after a concussion. Nonathlete controls had blood draws at an unrelated time point. Investigators measured total tau using an ultrasensitive immunoassay.

Return to play for each athlete was determined by athletic trainers or team physicians. They followed NCAA guidelines, which recommend that athletes be asymptomatic at rest and as they progressively resume activity before returning to play.

A total of 46 athletes were diagnosed with a sport-related concussion. Concussions occurred between 19 days and 218 days after baseline assessments (mean, 92.3 days). Thirty-seven athletes without concussion served as athlete controls. Athletes with and without concussion did not differ significantly in sport played, history of sport-related concussion, or other demographic features. A control group of 21 healthy nonathletes was demographically similar to the athlete groups.Return to play information was available for 41 of the athletes with concussion. Athletes who took more than 10 days to recover were considered to have a long return to play (23 athletes). Those who recovered in less than 10 days had a short return to play (18 athletes). The mean return to play duration was 21.68 days (range, two days to 263 days). Five athletes had a return to play duration of 30 days or more. Approximately 39% returned to play in less than 10 days. There were no significant differences in sport played or history of concussion among those with long return to play versus short return to play. Women made up 61% of the long return to play group and 28% of the short return to play group.

Tau Measurements

Compared with nonathletes, athletes had significantly higher mean tau concentrations at baseline and all other time points. The longitudinal pattern of tau differed significantly between athletes with and without concussion. Athletes with concussion had significantly lower mean total tau at 24 hours (6.06 pg/mL vs 7.89 pg/mL) and 72 hours (5.19 pg/mL vs 6.94 pg/mL), compared with athlete controls.

Athletes with a long return to play had higher tau concentrations overall, after controlling for sex, than those with a short return to play. The differences were statistically significant at six hours (10.98 pg/mL vs 7.02 pg/mL), 24 hours (7.19 pg/mL vs 4.08 pg/mL), and 72 hours (6.29 pg/mL vs 3.94 pg/mL).

Mean change in tau from baseline also significantly differed between the return to play groups. Athletes with long return to play had a mean increase of 2.26 pg/mL at six hours postconcussion, compared with a mean reduction of 1.19 pg/mL in the short return to play group, after controlling for sex. Area under the curve (AUC) analyses revealed that higher total tau six hours post concussion and change in tau from baseline to six hours post concussion predicted long return to play (AUC of 0.81 and 0.80, respectively). Higher total tau at 72 hours postconcussion also was a significant predictor of long return to play (AUC, 0.82).

“These findings suggest that changes in total tau within six hours of a sport-related concussion may provide vital information about return to play decisions, and may serve to mitigate the negative consequences of returning to play prematurely,” Dr. Gill and colleagues said. Preclinical models link insufficient recovery time from a mild traumatic brain injury (mTBI) to greater neuropathology following a subsequent mTBI, including pathology that overlaps with that of chronic traumatic encephalopathy.

Lower levels of tau in athletes with concussion, compared with athletes without concussion, at 24 hours and 72 hours “may be due to the effects of physical exertion on tau,” the researchers said. Limitations of the study include the relatively small sample size within subanalyses of long and short return to play.

More Research Is Needed

“While normally measured in CSF, tau measured in blood could provide the opportunity to assess neurologic injury shortly after concussion, as well as facilitate monitoring of recovery over time,” said Barbara B. Bendlin, PhD, Associate Professor of Medicine and Public Health at the University of Wisconsin–Madison, and Michael Makdissi, MBBS, PhD, research fellow at the Florey Institute of Neuroscience and Mental Health and Adjunct Associate Professor of Rehabilitation, Nutrition, and Sport at the La Trobe Sport and Exercise Medicine Research Centre in Australia, in an accompanying editorial.

However, differences in plasma tau levels between athletes and nonathletes; lower plasma tau levels at 24 hours and 72 hours post concussion in athletes with concussion, compared with nonconcussed teammates; variability across players; and fluctuations in plasma tau levels over time in general may complicate the use of the biomarker in concussion management. In addition, tau in plasma may reflect CNS and peripheral nervous system origins.

“This study and others conducted in the sports setting open the door for further evaluation and possible future implementation of blood-based biomarkers for evaluation of concussion,” they said. “Nevertheless, more work is needed before blood-based biomarkers can be used for management of sport-related concussion.”

—Jake Remaly

Suggested Reading

Bendlin BB, Makdissi M. Blood-based biomarkers for evaluating sport-related concussion: Back in the game. Neurology. 2017 Jan 6 [Epub ahead of print].

Gill J, Merchant-Borna K, Jeromin A, et al. Acute plasma tau relates to prolonged return to play after concussion. Neurology. 2017 Jan 6 [Epub ahead of print].

Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol. 2014;71(6):684-692.

Among collegiate athletes, elevated plasma tau concentrations within six hours after a sport-related concussion predict a prolonged recovery, according to research published online ahead of print January 6 in Neurology. This finding suggests that tau levels may help to determine when athletes should return to play. Variability of tau concentrations across athletes and the effect of physical exertion on plasma tau may complicate the use of the biomarker for concussion management, however.

Approximately 3.8 million sport-related concussions occur each year in the United States, but no biomarkers are known to predict recovery and an athlete’s readiness to return to play. Postconcussive symptoms typically resolve within 10 days in about half of collegiate athletes, but symptoms are chronic in a subset of patients. Shahim et al found that plasma tau elevations predicted a return to play of more than 10 days in professional ice hockey players in Sweden.

Diagnosing Sport-Related Concussion

Jessica Gill, RN, PhD, an investigator with the National Institute of Nursing Research at the NIH, and colleagues conducted a study to determine whether changes in plasma tau after sport-related concussion relate to return to play in men and women collegiate athletes. The researchers included students with concussion, as well as athlete and nonathlete controls. The athletes participated in various National Collegiate Athletic Association (NCAA) division I and III contact sports (ie, football, soccer, basketball, hockey, and lacrosse).

Between 2009 and 2014, 632 athletes underwent plasma sampling and cognitive testing prior to the sports seasons and were followed prospectively for a diagnosis of sport-related concussion. Sport-related concussions were witnessed by an on-field certified athletic trainer and met the Sport Concussion Assessment Tool 2 definition of concussion.Investigators collected blood samples from athletes with concussion and athlete controls at six hours, 24 hours, 72 hours, and seven days after a concussion. Nonathlete controls had blood draws at an unrelated time point. Investigators measured total tau using an ultrasensitive immunoassay.

Return to play for each athlete was determined by athletic trainers or team physicians. They followed NCAA guidelines, which recommend that athletes be asymptomatic at rest and as they progressively resume activity before returning to play.

A total of 46 athletes were diagnosed with a sport-related concussion. Concussions occurred between 19 days and 218 days after baseline assessments (mean, 92.3 days). Thirty-seven athletes without concussion served as athlete controls. Athletes with and without concussion did not differ significantly in sport played, history of sport-related concussion, or other demographic features. A control group of 21 healthy nonathletes was demographically similar to the athlete groups.Return to play information was available for 41 of the athletes with concussion. Athletes who took more than 10 days to recover were considered to have a long return to play (23 athletes). Those who recovered in less than 10 days had a short return to play (18 athletes). The mean return to play duration was 21.68 days (range, two days to 263 days). Five athletes had a return to play duration of 30 days or more. Approximately 39% returned to play in less than 10 days. There were no significant differences in sport played or history of concussion among those with long return to play versus short return to play. Women made up 61% of the long return to play group and 28% of the short return to play group.

Tau Measurements

Compared with nonathletes, athletes had significantly higher mean tau concentrations at baseline and all other time points. The longitudinal pattern of tau differed significantly between athletes with and without concussion. Athletes with concussion had significantly lower mean total tau at 24 hours (6.06 pg/mL vs 7.89 pg/mL) and 72 hours (5.19 pg/mL vs 6.94 pg/mL), compared with athlete controls.

Athletes with a long return to play had higher tau concentrations overall, after controlling for sex, than those with a short return to play. The differences were statistically significant at six hours (10.98 pg/mL vs 7.02 pg/mL), 24 hours (7.19 pg/mL vs 4.08 pg/mL), and 72 hours (6.29 pg/mL vs 3.94 pg/mL).

Mean change in tau from baseline also significantly differed between the return to play groups. Athletes with long return to play had a mean increase of 2.26 pg/mL at six hours postconcussion, compared with a mean reduction of 1.19 pg/mL in the short return to play group, after controlling for sex. Area under the curve (AUC) analyses revealed that higher total tau six hours post concussion and change in tau from baseline to six hours post concussion predicted long return to play (AUC of 0.81 and 0.80, respectively). Higher total tau at 72 hours postconcussion also was a significant predictor of long return to play (AUC, 0.82).

“These findings suggest that changes in total tau within six hours of a sport-related concussion may provide vital information about return to play decisions, and may serve to mitigate the negative consequences of returning to play prematurely,” Dr. Gill and colleagues said. Preclinical models link insufficient recovery time from a mild traumatic brain injury (mTBI) to greater neuropathology following a subsequent mTBI, including pathology that overlaps with that of chronic traumatic encephalopathy.

Lower levels of tau in athletes with concussion, compared with athletes without concussion, at 24 hours and 72 hours “may be due to the effects of physical exertion on tau,” the researchers said. Limitations of the study include the relatively small sample size within subanalyses of long and short return to play.

More Research Is Needed

“While normally measured in CSF, tau measured in blood could provide the opportunity to assess neurologic injury shortly after concussion, as well as facilitate monitoring of recovery over time,” said Barbara B. Bendlin, PhD, Associate Professor of Medicine and Public Health at the University of Wisconsin–Madison, and Michael Makdissi, MBBS, PhD, research fellow at the Florey Institute of Neuroscience and Mental Health and Adjunct Associate Professor of Rehabilitation, Nutrition, and Sport at the La Trobe Sport and Exercise Medicine Research Centre in Australia, in an accompanying editorial.

However, differences in plasma tau levels between athletes and nonathletes; lower plasma tau levels at 24 hours and 72 hours post concussion in athletes with concussion, compared with nonconcussed teammates; variability across players; and fluctuations in plasma tau levels over time in general may complicate the use of the biomarker in concussion management. In addition, tau in plasma may reflect CNS and peripheral nervous system origins.

“This study and others conducted in the sports setting open the door for further evaluation and possible future implementation of blood-based biomarkers for evaluation of concussion,” they said. “Nevertheless, more work is needed before blood-based biomarkers can be used for management of sport-related concussion.”

—Jake Remaly

Suggested Reading

Bendlin BB, Makdissi M. Blood-based biomarkers for evaluating sport-related concussion: Back in the game. Neurology. 2017 Jan 6 [Epub ahead of print].

Gill J, Merchant-Borna K, Jeromin A, et al. Acute plasma tau relates to prolonged return to play after concussion. Neurology. 2017 Jan 6 [Epub ahead of print].

Shahim P, Tegner Y, Wilson DH, et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol. 2014;71(6):684-692.

Several genes previously implicated only in rare, severe forms of pediatric epilepsy may also contribute to common forms of the disorder, according to a report published online ahead of print January 13 in Lancet Neurology. “Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise genetic cause of disease, may also extend to a proportion of common epilepsy syndromes,” said study leader David B. Goldstein, PhD, Director of the Institute for Genomic Medicine and Professor in the Departments of Genetics and Development and Neurology at Columbia University Medical Center in New York City.

In recent years, researchers have identified dozens of genes that, alone or in combination with other factors, cause rare pediatric epilepsies. These discoveries have led to the use of targeted therapies for some seizure disorders, such as the ketogenic diet for patients with Dravet syndrome or GLUT-1 deficiency syndrome. Other therapies such as quinidine, a medication to treat heart arrhythmias, and memantine, an Alzheimer’s disease treatment, have been tried in children with certain gene mutations. These attempts have not proved universally effective for all patients with these mutations, but suggest the potential to repurpose existing medicines to treat rare genetic forms of epilepsy.

“Unlike very rare types of epilepsies, previous studies had shed little light on the genetic underpinnings of common epilepsies, which suggested that this precision medicine paradigm may have a very narrow application,” said Dr. Goldstein.

To learn more about the genetics of epilepsy, Dr. Goldstein and his colleagues conducted a study to identify the genetic contributions to more common forms of epilepsy. Analyses were conducted at Columbia University Medical Center’s Institute for Genomic Medicine, in collaboration with NewYork-Presbyterian, as part of Epi4K, an international consortium of epilepsy clinicians and researchers. Most of the patients were recruited through the Epilepsy Phenome/Genome Project.

The researchers separately compared the sequence data from 640 individuals with familial genetic generalized epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3,877 controls. The researchers found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalized epilepsy, odd ratio 2.3; familial non-acquired focal epilepsy, odds ratio 3.6). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals.

Five Genes Implicated

For the individuals with familial non-acquired focal epilepsy, the researchers found that five known epilepsy genes—DEPDC5, LG11, PCDH19, SCN1A, and GRIN2A—ranked as the top five genes enriched for ultra-rare deleterious variation. “After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy,” said Erin Heinzen Cox, PhD, Assistant Professor in the Department of Pathology and Cell Biology and Deputy Director of the Institute for Genomic Medicine at Columbia University Medical Center.

Treatment Targeted to Epilepsy Subtype

The findings have important implications for clinical practice and for research. “At present, all common epilepsies are treated the same way, with the same group of medications,” said Dr. Goldstein. “But as we identify more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought, we can begin to try targeted therapies across these patient populations. As this genetically driven treatment paradigm becomes more established, our field, which is accustomed to undertaking large clinical trials in broad patient populations, will need to take a new approach to clinical research, focusing on patients based on their genetic subtype.”

“This is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures … or generalized seizures,” said James J. Riviello, MD, the Sergievsky Family Professor of Neurology and Pediatrics and Chief of Child Neurology at NewYork-Presbyterian Morgan Stanley Children’s Hospital in New York City. “Genetic testing for epilepsy may allow us to identify the specific anticonvulsant medication that potentially works best for an individual patient. We have already identified children in whom knowing the underlying genetic basis of the epilepsy has guided our treatment choices.”

Additional studies, which will analyze 10,000 to 12,000 samples, are planned for the coming year. “With a larger analysis, we expect to find additional genetic variations that contribute to common epilepsies,” said Dr. Goldstein.

Suggested Reading

Epi4K consortium, Epilepsy Phenome/Genome Project. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol. 2017;16(2):135-143.

Several genes previously implicated only in rare, severe forms of pediatric epilepsy may also contribute to common forms of the disorder, according to a report published online ahead of print January 13 in Lancet Neurology. “Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise genetic cause of disease, may also extend to a proportion of common epilepsy syndromes,” said study leader David B. Goldstein, PhD, Director of the Institute for Genomic Medicine and Professor in the Departments of Genetics and Development and Neurology at Columbia University Medical Center in New York City.

In recent years, researchers have identified dozens of genes that, alone or in combination with other factors, cause rare pediatric epilepsies. These discoveries have led to the use of targeted therapies for some seizure disorders, such as the ketogenic diet for patients with Dravet syndrome or GLUT-1 deficiency syndrome. Other therapies such as quinidine, a medication to treat heart arrhythmias, and memantine, an Alzheimer’s disease treatment, have been tried in children with certain gene mutations. These attempts have not proved universally effective for all patients with these mutations, but suggest the potential to repurpose existing medicines to treat rare genetic forms of epilepsy.

“Unlike very rare types of epilepsies, previous studies had shed little light on the genetic underpinnings of common epilepsies, which suggested that this precision medicine paradigm may have a very narrow application,” said Dr. Goldstein.

To learn more about the genetics of epilepsy, Dr. Goldstein and his colleagues conducted a study to identify the genetic contributions to more common forms of epilepsy. Analyses were conducted at Columbia University Medical Center’s Institute for Genomic Medicine, in collaboration with NewYork-Presbyterian, as part of Epi4K, an international consortium of epilepsy clinicians and researchers. Most of the patients were recruited through the Epilepsy Phenome/Genome Project.

The researchers separately compared the sequence data from 640 individuals with familial genetic generalized epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3,877 controls. The researchers found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalized epilepsy, odd ratio 2.3; familial non-acquired focal epilepsy, odds ratio 3.6). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals.

Five Genes Implicated

For the individuals with familial non-acquired focal epilepsy, the researchers found that five known epilepsy genes—DEPDC5, LG11, PCDH19, SCN1A, and GRIN2A—ranked as the top five genes enriched for ultra-rare deleterious variation. “After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy,” said Erin Heinzen Cox, PhD, Assistant Professor in the Department of Pathology and Cell Biology and Deputy Director of the Institute for Genomic Medicine at Columbia University Medical Center.

Treatment Targeted to Epilepsy Subtype

The findings have important implications for clinical practice and for research. “At present, all common epilepsies are treated the same way, with the same group of medications,” said Dr. Goldstein. “But as we identify more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought, we can begin to try targeted therapies across these patient populations. As this genetically driven treatment paradigm becomes more established, our field, which is accustomed to undertaking large clinical trials in broad patient populations, will need to take a new approach to clinical research, focusing on patients based on their genetic subtype.”

“This is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures … or generalized seizures,” said James J. Riviello, MD, the Sergievsky Family Professor of Neurology and Pediatrics and Chief of Child Neurology at NewYork-Presbyterian Morgan Stanley Children’s Hospital in New York City. “Genetic testing for epilepsy may allow us to identify the specific anticonvulsant medication that potentially works best for an individual patient. We have already identified children in whom knowing the underlying genetic basis of the epilepsy has guided our treatment choices.”

Additional studies, which will analyze 10,000 to 12,000 samples, are planned for the coming year. “With a larger analysis, we expect to find additional genetic variations that contribute to common epilepsies,” said Dr. Goldstein.

Suggested Reading

Epi4K consortium, Epilepsy Phenome/Genome Project. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol. 2017;16(2):135-143.

Several genes previously implicated only in rare, severe forms of pediatric epilepsy may also contribute to common forms of the disorder, according to a report published online ahead of print January 13 in Lancet Neurology. “Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise genetic cause of disease, may also extend to a proportion of common epilepsy syndromes,” said study leader David B. Goldstein, PhD, Director of the Institute for Genomic Medicine and Professor in the Departments of Genetics and Development and Neurology at Columbia University Medical Center in New York City.

In recent years, researchers have identified dozens of genes that, alone or in combination with other factors, cause rare pediatric epilepsies. These discoveries have led to the use of targeted therapies for some seizure disorders, such as the ketogenic diet for patients with Dravet syndrome or GLUT-1 deficiency syndrome. Other therapies such as quinidine, a medication to treat heart arrhythmias, and memantine, an Alzheimer’s disease treatment, have been tried in children with certain gene mutations. These attempts have not proved universally effective for all patients with these mutations, but suggest the potential to repurpose existing medicines to treat rare genetic forms of epilepsy.

“Unlike very rare types of epilepsies, previous studies had shed little light on the genetic underpinnings of common epilepsies, which suggested that this precision medicine paradigm may have a very narrow application,” said Dr. Goldstein.

To learn more about the genetics of epilepsy, Dr. Goldstein and his colleagues conducted a study to identify the genetic contributions to more common forms of epilepsy. Analyses were conducted at Columbia University Medical Center’s Institute for Genomic Medicine, in collaboration with NewYork-Presbyterian, as part of Epi4K, an international consortium of epilepsy clinicians and researchers. Most of the patients were recruited through the Epilepsy Phenome/Genome Project.

The researchers separately compared the sequence data from 640 individuals with familial genetic generalized epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3,877 controls. The researchers found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalized epilepsy, odd ratio 2.3; familial non-acquired focal epilepsy, odds ratio 3.6). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals.

Five Genes Implicated

For the individuals with familial non-acquired focal epilepsy, the researchers found that five known epilepsy genes—DEPDC5, LG11, PCDH19, SCN1A, and GRIN2A—ranked as the top five genes enriched for ultra-rare deleterious variation. “After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy,” said Erin Heinzen Cox, PhD, Assistant Professor in the Department of Pathology and Cell Biology and Deputy Director of the Institute for Genomic Medicine at Columbia University Medical Center.

Treatment Targeted to Epilepsy Subtype

The findings have important implications for clinical practice and for research. “At present, all common epilepsies are treated the same way, with the same group of medications,” said Dr. Goldstein. “But as we identify more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought, we can begin to try targeted therapies across these patient populations. As this genetically driven treatment paradigm becomes more established, our field, which is accustomed to undertaking large clinical trials in broad patient populations, will need to take a new approach to clinical research, focusing on patients based on their genetic subtype.”

“This is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures … or generalized seizures,” said James J. Riviello, MD, the Sergievsky Family Professor of Neurology and Pediatrics and Chief of Child Neurology at NewYork-Presbyterian Morgan Stanley Children’s Hospital in New York City. “Genetic testing for epilepsy may allow us to identify the specific anticonvulsant medication that potentially works best for an individual patient. We have already identified children in whom knowing the underlying genetic basis of the epilepsy has guided our treatment choices.”

Additional studies, which will analyze 10,000 to 12,000 samples, are planned for the coming year. “With a larger analysis, we expect to find additional genetic variations that contribute to common epilepsies,” said Dr. Goldstein.

Suggested Reading

Epi4K consortium, Epilepsy Phenome/Genome Project. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol. 2017;16(2):135-143.

Ocrelizumab is associated with lower rates of disease activity and progression in patients with relapsing-remitting multiple sclerosis (MS), compared with interferon beta-1a, according to research published in the New England Journal of Medicine. A separate study published in the same journal indicates that ocrelizumab is associated with lower rates of clinical and MRI progression in patients with primary progressive MS, compared with placebo. Ocrelizumab selectively depletes CD20+ B cells, and both studies provide evidence that B cells contribute to the pathogenesis of MS.

“This is the first drug to show a significant effect in slowing disability progression in a phase III trial in primary progressive MS, and therefore the trial represents a landmark study in the field,” said Peter A. Calabresi, MD, Professor of Neurology at Johns Hopkins University School of Medicine in Baltimore, in an accompanying editorial. The articles and editorial were published online ahead of print December 21, 2016.

Ocrelizumab in Relapsing-Remitting MS

Stephen L. Hauser, MD, Chair of Neurology at the University of California, San Francisco School of Medicine, and colleagues conducted OPERA I and OPERA II, two phase III studies to investigate the safety and efficacy of ocrelizumab, compared with interferon beta-1a, in patients with relapsing-remitting MS. The trials had identical protocols, but were conducted at separate trial sites. Eligible participants were between ages 18 and 55, had an Expanded Disability Status Scale (EDSS) score no greater than 5.5 at screening, a history of relapses, and MRI abnormalities consistent with MS. Patients who previously had received a B-cell-targeted therapy or other immunosuppressive medication were excluded.

A total of 821 patients in OPERA I and 835 patients in OPERA II were randomized to 600 mg of IV ocrelizumab every 24 weeks or to 44 µg of subcutaneous interferon beta-1a three times weekly. The treatment period was 96 weeks. Each trial site had separate treating and examining investigators, all of whom were unaware of participants’ treatment assignments. The primary end point was the annualized relapse rate by 96 weeks. Secondary end points included the proportion of patients with disability progression confirmed at 12 weeks, the mean number of gadolinium-enhancing lesions identified on T1-weighted MRI, and the proportion of patients with disability improvement confirmed at 12 weeks.

The annualized relapse rate at 96 weeks in OPERA I was 0.16 in the ocrelizumab group, compared with 0.29 in the interferon beta-1a group. In OPERA II, the annualized relapse rate was 0.16 in the ocrelizumab group, compared with 0.29 in the interferon beta-1a group. These data suggest a 46% lower annualized relapse rate with ocrelizumab in OPERA I and a 47% lower rate with ocrelizumab in OPERA II.

The mean numbers of gadolinium-enhancing lesions in OPERA I were 0.02 with ocrelizumab versus 0.29 with interferon beta-1a. The numbers in OPERA II were 0.02 with ocrelizumab versus 0.42 with interferon beta-1a. The mean numbers of new or newly enlarged T2 hyperintense lesions in OPERA I were 0.32 with ocrelizumab and 1.41 with interferon beta-1a (ie, 77% fewer lesions with ocrelizumab). The values in OPERA II were 0.33 with ocrelizumab versus 1.90 with interferon beta-1a.

In a pooled analysis, 9.1% of patients in the ocrelizumab group had disability progression confirmed at 12 weeks, compared with 13.6% of patients in the interferon beta-1a group. The percentage of patients with disability improvement confirmed at 12 weeks was 20.7% in the ocrelizumab group, compared with 15.6% in the interferon beta-1a group (ie, a 33% higher rate of improvement with ocrelizumab). The effect of ocrelizumab on the rate of confirmed disability improvement was significant in OPERA I, but nonsignificant in OPERA II.

“Additional and extended studies will be required to determine whether the outcomes observed in these 96-week trials, including a near-complete cessation of new plaque formation, as assessed by MRI of the brain, translate into enhanced protection against accrual of disability over the long term,” said Dr. Hauser.

Ocrelizumab in Progressive MS

To examine the safety and efficacy of ocrelizumab in primary progressive MS, Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the MS Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona, and colleagues conducted the phase III ORATORIO trial. Eligible patients were between ages 18 and 55 and had an EDSS score between 3.0 and 6.5 at screening. Patients with a history of relapsing-remitting MS, secondary progressive MS, or progressive relapsing MS were excluded, as were patients who had had previous treatment with B-cell-targeted therapies and other immunosuppressive medications.

Patients were randomized in a 2:1 ratio to receive 600 mg of IV ocrelizumab or matching placebo every 24 weeks. Double-blinded treatment was administered for at least 120 weeks. As in the OPERA trials, each trial site had separate treating and examining investigators. Patients who completed the blinded treatment phase were eligible to enter an open-label extension phase.

The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. Secondary end points included the percentage of patients with disability progression confirmed at 24 weeks, change in performance on the timed 25-foot walk from baseline to week 120, change in the total volume of brain lesions on T2-weighted MRI from baseline to week 120, change in brain volume from week 24 to week 120, and change in the Physical Component Summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), version 2, from baseline to week 120.

In all, 488 patients received ocrelizumab, and 244 received placebo. A total of 402 patients in the ocrelizumab arm and 174 controls completed the 120-week treatment period. The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo. The data suggest a 24% reduction in the risk of this outcome with ocrelizumab.

The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab and 35.7% with placebo (ie, a relative risk reduction of 25% with ocrelizumab). The mean change from baseline to week 120 in performance on the timed 25-foot walk was 38.9% with ocrelizumab versus 55.1% with placebo (ie, a relative reduction of 29.3% with ocrelizumab). The researchers found no significant between-group difference in the change in the SF-36 Physical Component Summary score from baseline to week 120.

In addition, the total volume of hyperintense lesions on T2-weighted images from baseline to week 120 decreased with ocrelizumab and increased with placebo (mean percent change, −3.4% vs 7.4%). The adjusted mean percent change in brain volume from week 24 to week 120 was lower with ocrelizumab than with placebo (–0.90% vs –1.09%).

Infusion-related reactions were more common in the ocrelizumab group than among controls. Neoplasms were reported in 11 of 486 patients (2.3%) in the ocrelizumab group and in two of 239 patients (0.8%) in the placebo group. “Safety will continue to be assessed throughout the open-label extension phase,” said Dr. Montalban.

Unknown Mechanism of Action

The mechanism by which B-cell depletion slows disability progression is not fully understood. It “may be multifunctional, because B cells have important roles in antibody secretion, antigen presentation, and the release of effector cytokines,” said Dr. Calabresi. By virtue of their number, B cells may be more important than other antigen-presenting cells in MS.

One potential reason that ocrelizumab showed positive effects in ORATORIO is that the patient population was relatively young (mean age, 45) and had active MRI scans (more than 25% of the population had gadolinium-enhancing lesions). These factors enabled the demonstration of a measurable anti-inflammatory effect of ocrelizumab in patients with inflammation at an early, reversible stage of the disease. “Another possible explanation is that B cells may mediate pathologic processes by secretion of cytokines or by deposition of immunoglobulins after they enter the CNS,” said Dr. Calabresi. “B cells and plasma cells secrete antibodies that may target CNS antigens such as myelin, neurons, and glia, which could accelerate neurodegeneration or inhibit myelin repair. The continued separation of disability progression curves in the ORATORIO trial beyond 52 weeks, when anti-inflammatory effects have been maximized, and success in the relatively noninflammatory disorder of primary progressive MS suggest that additional mechanisms of action may be operational, and further study is warranted.”

Because ocrelizumab appears to entail a higher risk of herpes reactivation and of neoplasms, “clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early,” Dr. Calabresi concluded.

—Erik Greb

Suggested Reading

Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Calabresi PA. B-cell depletion - a frontier in monoclonal antibodies for multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Ocrelizumab is associated with lower rates of disease activity and progression in patients with relapsing-remitting multiple sclerosis (MS), compared with interferon beta-1a, according to research published in the New England Journal of Medicine. A separate study published in the same journal indicates that ocrelizumab is associated with lower rates of clinical and MRI progression in patients with primary progressive MS, compared with placebo. Ocrelizumab selectively depletes CD20+ B cells, and both studies provide evidence that B cells contribute to the pathogenesis of MS.

“This is the first drug to show a significant effect in slowing disability progression in a phase III trial in primary progressive MS, and therefore the trial represents a landmark study in the field,” said Peter A. Calabresi, MD, Professor of Neurology at Johns Hopkins University School of Medicine in Baltimore, in an accompanying editorial. The articles and editorial were published online ahead of print December 21, 2016.

Ocrelizumab in Relapsing-Remitting MS

Stephen L. Hauser, MD, Chair of Neurology at the University of California, San Francisco School of Medicine, and colleagues conducted OPERA I and OPERA II, two phase III studies to investigate the safety and efficacy of ocrelizumab, compared with interferon beta-1a, in patients with relapsing-remitting MS. The trials had identical protocols, but were conducted at separate trial sites. Eligible participants were between ages 18 and 55, had an Expanded Disability Status Scale (EDSS) score no greater than 5.5 at screening, a history of relapses, and MRI abnormalities consistent with MS. Patients who previously had received a B-cell-targeted therapy or other immunosuppressive medication were excluded.

A total of 821 patients in OPERA I and 835 patients in OPERA II were randomized to 600 mg of IV ocrelizumab every 24 weeks or to 44 µg of subcutaneous interferon beta-1a three times weekly. The treatment period was 96 weeks. Each trial site had separate treating and examining investigators, all of whom were unaware of participants’ treatment assignments. The primary end point was the annualized relapse rate by 96 weeks. Secondary end points included the proportion of patients with disability progression confirmed at 12 weeks, the mean number of gadolinium-enhancing lesions identified on T1-weighted MRI, and the proportion of patients with disability improvement confirmed at 12 weeks.

The annualized relapse rate at 96 weeks in OPERA I was 0.16 in the ocrelizumab group, compared with 0.29 in the interferon beta-1a group. In OPERA II, the annualized relapse rate was 0.16 in the ocrelizumab group, compared with 0.29 in the interferon beta-1a group. These data suggest a 46% lower annualized relapse rate with ocrelizumab in OPERA I and a 47% lower rate with ocrelizumab in OPERA II.

The mean numbers of gadolinium-enhancing lesions in OPERA I were 0.02 with ocrelizumab versus 0.29 with interferon beta-1a. The numbers in OPERA II were 0.02 with ocrelizumab versus 0.42 with interferon beta-1a. The mean numbers of new or newly enlarged T2 hyperintense lesions in OPERA I were 0.32 with ocrelizumab and 1.41 with interferon beta-1a (ie, 77% fewer lesions with ocrelizumab). The values in OPERA II were 0.33 with ocrelizumab versus 1.90 with interferon beta-1a.

In a pooled analysis, 9.1% of patients in the ocrelizumab group had disability progression confirmed at 12 weeks, compared with 13.6% of patients in the interferon beta-1a group. The percentage of patients with disability improvement confirmed at 12 weeks was 20.7% in the ocrelizumab group, compared with 15.6% in the interferon beta-1a group (ie, a 33% higher rate of improvement with ocrelizumab). The effect of ocrelizumab on the rate of confirmed disability improvement was significant in OPERA I, but nonsignificant in OPERA II.

“Additional and extended studies will be required to determine whether the outcomes observed in these 96-week trials, including a near-complete cessation of new plaque formation, as assessed by MRI of the brain, translate into enhanced protection against accrual of disability over the long term,” said Dr. Hauser.

Ocrelizumab in Progressive MS

To examine the safety and efficacy of ocrelizumab in primary progressive MS, Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the MS Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona, and colleagues conducted the phase III ORATORIO trial. Eligible patients were between ages 18 and 55 and had an EDSS score between 3.0 and 6.5 at screening. Patients with a history of relapsing-remitting MS, secondary progressive MS, or progressive relapsing MS were excluded, as were patients who had had previous treatment with B-cell-targeted therapies and other immunosuppressive medications.

Patients were randomized in a 2:1 ratio to receive 600 mg of IV ocrelizumab or matching placebo every 24 weeks. Double-blinded treatment was administered for at least 120 weeks. As in the OPERA trials, each trial site had separate treating and examining investigators. Patients who completed the blinded treatment phase were eligible to enter an open-label extension phase.

The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. Secondary end points included the percentage of patients with disability progression confirmed at 24 weeks, change in performance on the timed 25-foot walk from baseline to week 120, change in the total volume of brain lesions on T2-weighted MRI from baseline to week 120, change in brain volume from week 24 to week 120, and change in the Physical Component Summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), version 2, from baseline to week 120.

In all, 488 patients received ocrelizumab, and 244 received placebo. A total of 402 patients in the ocrelizumab arm and 174 controls completed the 120-week treatment period. The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo. The data suggest a 24% reduction in the risk of this outcome with ocrelizumab.

The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab and 35.7% with placebo (ie, a relative risk reduction of 25% with ocrelizumab). The mean change from baseline to week 120 in performance on the timed 25-foot walk was 38.9% with ocrelizumab versus 55.1% with placebo (ie, a relative reduction of 29.3% with ocrelizumab). The researchers found no significant between-group difference in the change in the SF-36 Physical Component Summary score from baseline to week 120.

In addition, the total volume of hyperintense lesions on T2-weighted images from baseline to week 120 decreased with ocrelizumab and increased with placebo (mean percent change, −3.4% vs 7.4%). The adjusted mean percent change in brain volume from week 24 to week 120 was lower with ocrelizumab than with placebo (–0.90% vs –1.09%).

Infusion-related reactions were more common in the ocrelizumab group than among controls. Neoplasms were reported in 11 of 486 patients (2.3%) in the ocrelizumab group and in two of 239 patients (0.8%) in the placebo group. “Safety will continue to be assessed throughout the open-label extension phase,” said Dr. Montalban.

Unknown Mechanism of Action

The mechanism by which B-cell depletion slows disability progression is not fully understood. It “may be multifunctional, because B cells have important roles in antibody secretion, antigen presentation, and the release of effector cytokines,” said Dr. Calabresi. By virtue of their number, B cells may be more important than other antigen-presenting cells in MS.

One potential reason that ocrelizumab showed positive effects in ORATORIO is that the patient population was relatively young (mean age, 45) and had active MRI scans (more than 25% of the population had gadolinium-enhancing lesions). These factors enabled the demonstration of a measurable anti-inflammatory effect of ocrelizumab in patients with inflammation at an early, reversible stage of the disease. “Another possible explanation is that B cells may mediate pathologic processes by secretion of cytokines or by deposition of immunoglobulins after they enter the CNS,” said Dr. Calabresi. “B cells and plasma cells secrete antibodies that may target CNS antigens such as myelin, neurons, and glia, which could accelerate neurodegeneration or inhibit myelin repair. The continued separation of disability progression curves in the ORATORIO trial beyond 52 weeks, when anti-inflammatory effects have been maximized, and success in the relatively noninflammatory disorder of primary progressive MS suggest that additional mechanisms of action may be operational, and further study is warranted.”

Because ocrelizumab appears to entail a higher risk of herpes reactivation and of neoplasms, “clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early,” Dr. Calabresi concluded.

—Erik Greb

Suggested Reading

Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Calabresi PA. B-cell depletion - a frontier in monoclonal antibodies for multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Ocrelizumab is associated with lower rates of disease activity and progression in patients with relapsing-remitting multiple sclerosis (MS), compared with interferon beta-1a, according to research published in the New England Journal of Medicine. A separate study published in the same journal indicates that ocrelizumab is associated with lower rates of clinical and MRI progression in patients with primary progressive MS, compared with placebo. Ocrelizumab selectively depletes CD20+ B cells, and both studies provide evidence that B cells contribute to the pathogenesis of MS.

“This is the first drug to show a significant effect in slowing disability progression in a phase III trial in primary progressive MS, and therefore the trial represents a landmark study in the field,” said Peter A. Calabresi, MD, Professor of Neurology at Johns Hopkins University School of Medicine in Baltimore, in an accompanying editorial. The articles and editorial were published online ahead of print December 21, 2016.

Ocrelizumab in Relapsing-Remitting MS

Stephen L. Hauser, MD, Chair of Neurology at the University of California, San Francisco School of Medicine, and colleagues conducted OPERA I and OPERA II, two phase III studies to investigate the safety and efficacy of ocrelizumab, compared with interferon beta-1a, in patients with relapsing-remitting MS. The trials had identical protocols, but were conducted at separate trial sites. Eligible participants were between ages 18 and 55, had an Expanded Disability Status Scale (EDSS) score no greater than 5.5 at screening, a history of relapses, and MRI abnormalities consistent with MS. Patients who previously had received a B-cell-targeted therapy or other immunosuppressive medication were excluded.

A total of 821 patients in OPERA I and 835 patients in OPERA II were randomized to 600 mg of IV ocrelizumab every 24 weeks or to 44 µg of subcutaneous interferon beta-1a three times weekly. The treatment period was 96 weeks. Each trial site had separate treating and examining investigators, all of whom were unaware of participants’ treatment assignments. The primary end point was the annualized relapse rate by 96 weeks. Secondary end points included the proportion of patients with disability progression confirmed at 12 weeks, the mean number of gadolinium-enhancing lesions identified on T1-weighted MRI, and the proportion of patients with disability improvement confirmed at 12 weeks.

The annualized relapse rate at 96 weeks in OPERA I was 0.16 in the ocrelizumab group, compared with 0.29 in the interferon beta-1a group. In OPERA II, the annualized relapse rate was 0.16 in the ocrelizumab group, compared with 0.29 in the interferon beta-1a group. These data suggest a 46% lower annualized relapse rate with ocrelizumab in OPERA I and a 47% lower rate with ocrelizumab in OPERA II.

The mean numbers of gadolinium-enhancing lesions in OPERA I were 0.02 with ocrelizumab versus 0.29 with interferon beta-1a. The numbers in OPERA II were 0.02 with ocrelizumab versus 0.42 with interferon beta-1a. The mean numbers of new or newly enlarged T2 hyperintense lesions in OPERA I were 0.32 with ocrelizumab and 1.41 with interferon beta-1a (ie, 77% fewer lesions with ocrelizumab). The values in OPERA II were 0.33 with ocrelizumab versus 1.90 with interferon beta-1a.

In a pooled analysis, 9.1% of patients in the ocrelizumab group had disability progression confirmed at 12 weeks, compared with 13.6% of patients in the interferon beta-1a group. The percentage of patients with disability improvement confirmed at 12 weeks was 20.7% in the ocrelizumab group, compared with 15.6% in the interferon beta-1a group (ie, a 33% higher rate of improvement with ocrelizumab). The effect of ocrelizumab on the rate of confirmed disability improvement was significant in OPERA I, but nonsignificant in OPERA II.

“Additional and extended studies will be required to determine whether the outcomes observed in these 96-week trials, including a near-complete cessation of new plaque formation, as assessed by MRI of the brain, translate into enhanced protection against accrual of disability over the long term,” said Dr. Hauser.

Ocrelizumab in Progressive MS

To examine the safety and efficacy of ocrelizumab in primary progressive MS, Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the MS Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona, and colleagues conducted the phase III ORATORIO trial. Eligible patients were between ages 18 and 55 and had an EDSS score between 3.0 and 6.5 at screening. Patients with a history of relapsing-remitting MS, secondary progressive MS, or progressive relapsing MS were excluded, as were patients who had had previous treatment with B-cell-targeted therapies and other immunosuppressive medications.

Patients were randomized in a 2:1 ratio to receive 600 mg of IV ocrelizumab or matching placebo every 24 weeks. Double-blinded treatment was administered for at least 120 weeks. As in the OPERA trials, each trial site had separate treating and examining investigators. Patients who completed the blinded treatment phase were eligible to enter an open-label extension phase.

The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. Secondary end points included the percentage of patients with disability progression confirmed at 24 weeks, change in performance on the timed 25-foot walk from baseline to week 120, change in the total volume of brain lesions on T2-weighted MRI from baseline to week 120, change in brain volume from week 24 to week 120, and change in the Physical Component Summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), version 2, from baseline to week 120.

In all, 488 patients received ocrelizumab, and 244 received placebo. A total of 402 patients in the ocrelizumab arm and 174 controls completed the 120-week treatment period. The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo. The data suggest a 24% reduction in the risk of this outcome with ocrelizumab.

The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab and 35.7% with placebo (ie, a relative risk reduction of 25% with ocrelizumab). The mean change from baseline to week 120 in performance on the timed 25-foot walk was 38.9% with ocrelizumab versus 55.1% with placebo (ie, a relative reduction of 29.3% with ocrelizumab). The researchers found no significant between-group difference in the change in the SF-36 Physical Component Summary score from baseline to week 120.

In addition, the total volume of hyperintense lesions on T2-weighted images from baseline to week 120 decreased with ocrelizumab and increased with placebo (mean percent change, −3.4% vs 7.4%). The adjusted mean percent change in brain volume from week 24 to week 120 was lower with ocrelizumab than with placebo (–0.90% vs –1.09%).

Infusion-related reactions were more common in the ocrelizumab group than among controls. Neoplasms were reported in 11 of 486 patients (2.3%) in the ocrelizumab group and in two of 239 patients (0.8%) in the placebo group. “Safety will continue to be assessed throughout the open-label extension phase,” said Dr. Montalban.

Unknown Mechanism of Action

The mechanism by which B-cell depletion slows disability progression is not fully understood. It “may be multifunctional, because B cells have important roles in antibody secretion, antigen presentation, and the release of effector cytokines,” said Dr. Calabresi. By virtue of their number, B cells may be more important than other antigen-presenting cells in MS.

One potential reason that ocrelizumab showed positive effects in ORATORIO is that the patient population was relatively young (mean age, 45) and had active MRI scans (more than 25% of the population had gadolinium-enhancing lesions). These factors enabled the demonstration of a measurable anti-inflammatory effect of ocrelizumab in patients with inflammation at an early, reversible stage of the disease. “Another possible explanation is that B cells may mediate pathologic processes by secretion of cytokines or by deposition of immunoglobulins after they enter the CNS,” said Dr. Calabresi. “B cells and plasma cells secrete antibodies that may target CNS antigens such as myelin, neurons, and glia, which could accelerate neurodegeneration or inhibit myelin repair. The continued separation of disability progression curves in the ORATORIO trial beyond 52 weeks, when anti-inflammatory effects have been maximized, and success in the relatively noninflammatory disorder of primary progressive MS suggest that additional mechanisms of action may be operational, and further study is warranted.”

Because ocrelizumab appears to entail a higher risk of herpes reactivation and of neoplasms, “clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early,” Dr. Calabresi concluded.

—Erik Greb

Suggested Reading

Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Calabresi PA. B-cell depletion - a frontier in monoclonal antibodies for multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].

Patients who undergo surgery have an increased risk of perioperative ischemic stroke if they have a history of migraine, according to a prospective study published January 10 in the BMJ. Surgical patients with a history of migraine also have an increased 30-day hospital readmission rate, compared with patients without migraine.

“Understanding this risk period offers unique opportunities to study ischemic stroke in migraine and might result in treatment considerations for patients at risk who are not undergoing surgical intervention,” said Matthias Eikermann, MD, PhD, Associate Professor of Anesthesia at Harvard Medical School in Boston, and colleagues. “An individual perioperative risk assessment for perioperative ischemic stroke in patients with migraine undergoing surgery may be crucial.”

Dr. Eikermann and colleagues conducted a prospective hospital registry study that encompassed 124,558 patients who underwent surgery at Massachusetts General Hospital and two community hospitals in Massachusetts between January 2007 and August 2014. The researchers determined participants’ history of migraine and migraine aura status using ICD-9 diagnosis codes. The primary outcome was perioperative ischemic stroke within 30 days after surgery. The secondary outcome was hospital readmission within 30 days of discharge.

The mean age of participants was 52.6. Approximately 55% of patients were women. The investigators identified 10,179 (8.2%) patients with migraine, of whom 1,278 (12.6%) had migraine with aura. Compared with participants without migraine, migraineurs were more often female, were younger, and had an overall lower frequency of vascular risk factors.

Among the 124,558 patients who underwent surgery, the investigators observed 771 (0.6%) perioperative ischemic strokes. Of all patients with perioperative ischemic stroke, 89 (11.5%) had migraine. Among migraineurs, 18 (2.3%) had migraine with aura, and 71 (9.2%) had migraine without aura. Patients with migraine had an increased risk for perioperative ischemic stroke, compared with patients without migraine (adjusted odds ratio, 1.75). The risk of ischemic stroke was higher for patients with migraine with aura (adjusted odds ratio, 2.61), but also was apparent for migraine without aura (adjusted odds ratio, 1.62), compared with surgical patients without migraine.

Dr. Eikermann and colleagues predicted that 2.4 ischemic strokes would occur for every 1,000 surgical patients. This risk increased to 4.3 strokes for every 1,000 patients with migraine. Stratified by migraine with aura status, these numbers are 3.9 strokes for migraine without aura and 6.3 strokes for migraine with aura.

A total of 10,088 participants were readmitted to the hospital within 30 days. The 30-day hospital readmission rate was higher for patients with migraine than for those with no migraine (adjusted odds ratio, 1.31). Migraine with aura (adjusted odds ratio, 1.59) and migraine without aura (adjusted odds ratio, 1.27) were associated with a higher risk of 30-day hospital readmission, compared with patients without migraine.

“The use of high-dose vasopressors during surgery, as well a history of a possible right-to-left shunt, may represent modifiable risk factors for perioperative ischemic stroke in patients with migraine with aura,” said Dr. Eikermann. “Early detection of symptoms of stroke through close postoperative monitoring of patients at high risk should be crucial to optimize the value of perioperative care in patients with migraine.”

—Erik Greb

Suggested Reading

Timm FP, Houle TT, Grabitz SD, et al. Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study. BMJ. 2017 Jan 10;356:i6635.

Patients who undergo surgery have an increased risk of perioperative ischemic stroke if they have a history of migraine, according to a prospective study published January 10 in the BMJ. Surgical patients with a history of migraine also have an increased 30-day hospital readmission rate, compared with patients without migraine.

“Understanding this risk period offers unique opportunities to study ischemic stroke in migraine and might result in treatment considerations for patients at risk who are not undergoing surgical intervention,” said Matthias Eikermann, MD, PhD, Associate Professor of Anesthesia at Harvard Medical School in Boston, and colleagues. “An individual perioperative risk assessment for perioperative ischemic stroke in patients with migraine undergoing surgery may be crucial.”

Dr. Eikermann and colleagues conducted a prospective hospital registry study that encompassed 124,558 patients who underwent surgery at Massachusetts General Hospital and two community hospitals in Massachusetts between January 2007 and August 2014. The researchers determined participants’ history of migraine and migraine aura status using ICD-9 diagnosis codes. The primary outcome was perioperative ischemic stroke within 30 days after surgery. The secondary outcome was hospital readmission within 30 days of discharge.

The mean age of participants was 52.6. Approximately 55% of patients were women. The investigators identified 10,179 (8.2%) patients with migraine, of whom 1,278 (12.6%) had migraine with aura. Compared with participants without migraine, migraineurs were more often female, were younger, and had an overall lower frequency of vascular risk factors.

Among the 124,558 patients who underwent surgery, the investigators observed 771 (0.6%) perioperative ischemic strokes. Of all patients with perioperative ischemic stroke, 89 (11.5%) had migraine. Among migraineurs, 18 (2.3%) had migraine with aura, and 71 (9.2%) had migraine without aura. Patients with migraine had an increased risk for perioperative ischemic stroke, compared with patients without migraine (adjusted odds ratio, 1.75). The risk of ischemic stroke was higher for patients with migraine with aura (adjusted odds ratio, 2.61), but also was apparent for migraine without aura (adjusted odds ratio, 1.62), compared with surgical patients without migraine.

Dr. Eikermann and colleagues predicted that 2.4 ischemic strokes would occur for every 1,000 surgical patients. This risk increased to 4.3 strokes for every 1,000 patients with migraine. Stratified by migraine with aura status, these numbers are 3.9 strokes for migraine without aura and 6.3 strokes for migraine with aura.

A total of 10,088 participants were readmitted to the hospital within 30 days. The 30-day hospital readmission rate was higher for patients with migraine than for those with no migraine (adjusted odds ratio, 1.31). Migraine with aura (adjusted odds ratio, 1.59) and migraine without aura (adjusted odds ratio, 1.27) were associated with a higher risk of 30-day hospital readmission, compared with patients without migraine.

“The use of high-dose vasopressors during surgery, as well a history of a possible right-to-left shunt, may represent modifiable risk factors for perioperative ischemic stroke in patients with migraine with aura,” said Dr. Eikermann. “Early detection of symptoms of stroke through close postoperative monitoring of patients at high risk should be crucial to optimize the value of perioperative care in patients with migraine.”

—Erik Greb

Suggested Reading

Timm FP, Houle TT, Grabitz SD, et al. Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study. BMJ. 2017 Jan 10;356:i6635.

Patients who undergo surgery have an increased risk of perioperative ischemic stroke if they have a history of migraine, according to a prospective study published January 10 in the BMJ. Surgical patients with a history of migraine also have an increased 30-day hospital readmission rate, compared with patients without migraine.

“Understanding this risk period offers unique opportunities to study ischemic stroke in migraine and might result in treatment considerations for patients at risk who are not undergoing surgical intervention,” said Matthias Eikermann, MD, PhD, Associate Professor of Anesthesia at Harvard Medical School in Boston, and colleagues. “An individual perioperative risk assessment for perioperative ischemic stroke in patients with migraine undergoing surgery may be crucial.”

Dr. Eikermann and colleagues conducted a prospective hospital registry study that encompassed 124,558 patients who underwent surgery at Massachusetts General Hospital and two community hospitals in Massachusetts between January 2007 and August 2014. The researchers determined participants’ history of migraine and migraine aura status using ICD-9 diagnosis codes. The primary outcome was perioperative ischemic stroke within 30 days after surgery. The secondary outcome was hospital readmission within 30 days of discharge.

The mean age of participants was 52.6. Approximately 55% of patients were women. The investigators identified 10,179 (8.2%) patients with migraine, of whom 1,278 (12.6%) had migraine with aura. Compared with participants without migraine, migraineurs were more often female, were younger, and had an overall lower frequency of vascular risk factors.

Among the 124,558 patients who underwent surgery, the investigators observed 771 (0.6%) perioperative ischemic strokes. Of all patients with perioperative ischemic stroke, 89 (11.5%) had migraine. Among migraineurs, 18 (2.3%) had migraine with aura, and 71 (9.2%) had migraine without aura. Patients with migraine had an increased risk for perioperative ischemic stroke, compared with patients without migraine (adjusted odds ratio, 1.75). The risk of ischemic stroke was higher for patients with migraine with aura (adjusted odds ratio, 2.61), but also was apparent for migraine without aura (adjusted odds ratio, 1.62), compared with surgical patients without migraine.

Dr. Eikermann and colleagues predicted that 2.4 ischemic strokes would occur for every 1,000 surgical patients. This risk increased to 4.3 strokes for every 1,000 patients with migraine. Stratified by migraine with aura status, these numbers are 3.9 strokes for migraine without aura and 6.3 strokes for migraine with aura.

A total of 10,088 participants were readmitted to the hospital within 30 days. The 30-day hospital readmission rate was higher for patients with migraine than for those with no migraine (adjusted odds ratio, 1.31). Migraine with aura (adjusted odds ratio, 1.59) and migraine without aura (adjusted odds ratio, 1.27) were associated with a higher risk of 30-day hospital readmission, compared with patients without migraine.

“The use of high-dose vasopressors during surgery, as well a history of a possible right-to-left shunt, may represent modifiable risk factors for perioperative ischemic stroke in patients with migraine with aura,” said Dr. Eikermann. “Early detection of symptoms of stroke through close postoperative monitoring of patients at high risk should be crucial to optimize the value of perioperative care in patients with migraine.”

—Erik Greb

Suggested Reading

Timm FP, Houle TT, Grabitz SD, et al. Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study. BMJ. 2017 Jan 10;356:i6635.

Compared with the natural history of the disease, disease-modifying treatments for multiple sclerosis (MS) significantly reduce the risks of long-term disability worsening and evolution to secondary progressive MS (SPMS), according to research published in the October issue of Annals of Neurology. The data also suggest that patients who have no evidence of disease activity (NEDA) for two years are no more likely to have long-term stability than patients who do not reach this end point.

“These observations challenge the concept that NEDA represents remission. Although NEDA may be a useful measure for assessing relative therapeutic efficacy, many patients who meet NEDA criteria over two years go on to develop clinically significant disability,” said Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco School of Medicine. “Worsening in patients who meet the two-year NEDA end point could result from active spinal cord disease not captured with brain MRI, progressive axonal or neuronal degeneration, or an escape from a true but transient remission state.

Researchers had anticipated that between 36% and 50% of patients with relapsing MS (RMS) would develop SPMS, but 11.3% of the cohort transitioned to SPMS during the course of the study. Evolution of sustained disability was also slower than expected, said Dr. Cree.

Examining Long-Term Effects of Treatment

Natural history studies from the pretreatment era suggest that between one-third and one-half of patients with MS experience substantial worsening of neurologic disability approximately 15 years after disease onset. Disease-modifying therapies in MS have been studied during the past two decades and are associated with improvement in the short term. Their effect on long-term outcomes is unknown, however. Furthermore, little is known about the relationship between short-term MRI measurements and long-term disability in MS.

As a result, Dr. Cree and colleagues conducted a prospective study to characterize the accrual of long-term disability in a cohort of actively treated patients with MS. Additionally, they sought to assess whether clinical and MRI data used in clinical trials have long-term prognostic value.

Eligible participants had all clinical subtypes of MS and were first evaluated at the MS Center at the University of California, San Francisco between July 2004 and September 2005. Patients were excluded if they were unable to tolerate MRI scans, had poor venous access, or if they had other significant medical illnesses that might interfere with goals of the study. Investigators followed participants annually for five years. In addition, patients underwent re-evaluation at extended time points for as long as 10 years after baseline.

Researchers defined disability progression as a clinically significant worsening in the Expanded Disability Status Scale (EDSS), the timed 25-foot walk, the nine-hole peg test, and the paced serial auditory addition test.

Two Tiers of Therapy

Participants were treated with FDA-approved therapies or off-label therapies. Researchers defined two treatment tiers and categorized therapies based on their relative perceived effectiveness using data from clinical trials.

The first tier of treatment, platform therapy, included interferon (IFN) beta, glatiramer acetate, and off-label therapies such as glucocorticoids, azathioprine, and mycophenolate mofetil. The second tier of treatment, high-potency therapy, included natalizumab, rituximab, mitoxantrone, and cyclophosphamide.

NEDA and Long-Term Disability

Of 517 actively managed patients with MS enrolled in the study, 366 had RMS, 48 had SPMS, 21 had primary progressive MS (PPMS), and 82 had clinically isolated syndrome (CIS). After 10 years of follow-up, neurologic disability was stable or improved, compared with baseline, in 41% of patients. Serum vitamin D levels were inversely associated with short-term MS disease activity, but were not associated with long-term disability. At a median time of 16.8 years after disease onset, 10.7% of patients reached an EDSS score of greater than or equal to 6, and 18.1% of patients evolved from RMS to SPMS.

The investigators concluded that evolution to SPMS in this study was significantly lower than expected, based on natural history studies. They also noted that short-term increases in EDSS did not necessarily predict future accumulation of long-term disability in patients with RMS. In addition, subjects with NEDA by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole.

“Treating to target with two-year NEDA as the goal may not result in protection against long-term disability,” said Dr. Cree. “Long-term studies are urgently needed to determine if high-intensity therapy, initiated at the time of diagnosis or used in patients with seemingly inactive disease, is superior to the escalation approach employed in this cohort.”

—Erica Tricarico

Suggested Reading

University of California, San Francisco MS-EPIC Team, Cree BA, Gourraud PA, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499-510.

Compared with the natural history of the disease, disease-modifying treatments for multiple sclerosis (MS) significantly reduce the risks of long-term disability worsening and evolution to secondary progressive MS (SPMS), according to research published in the October issue of Annals of Neurology. The data also suggest that patients who have no evidence of disease activity (NEDA) for two years are no more likely to have long-term stability than patients who do not reach this end point.

“These observations challenge the concept that NEDA represents remission. Although NEDA may be a useful measure for assessing relative therapeutic efficacy, many patients who meet NEDA criteria over two years go on to develop clinically significant disability,” said Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco School of Medicine. “Worsening in patients who meet the two-year NEDA end point could result from active spinal cord disease not captured with brain MRI, progressive axonal or neuronal degeneration, or an escape from a true but transient remission state.

Researchers had anticipated that between 36% and 50% of patients with relapsing MS (RMS) would develop SPMS, but 11.3% of the cohort transitioned to SPMS during the course of the study. Evolution of sustained disability was also slower than expected, said Dr. Cree.

Examining Long-Term Effects of Treatment

Natural history studies from the pretreatment era suggest that between one-third and one-half of patients with MS experience substantial worsening of neurologic disability approximately 15 years after disease onset. Disease-modifying therapies in MS have been studied during the past two decades and are associated with improvement in the short term. Their effect on long-term outcomes is unknown, however. Furthermore, little is known about the relationship between short-term MRI measurements and long-term disability in MS.

As a result, Dr. Cree and colleagues conducted a prospective study to characterize the accrual of long-term disability in a cohort of actively treated patients with MS. Additionally, they sought to assess whether clinical and MRI data used in clinical trials have long-term prognostic value.

Eligible participants had all clinical subtypes of MS and were first evaluated at the MS Center at the University of California, San Francisco between July 2004 and September 2005. Patients were excluded if they were unable to tolerate MRI scans, had poor venous access, or if they had other significant medical illnesses that might interfere with goals of the study. Investigators followed participants annually for five years. In addition, patients underwent re-evaluation at extended time points for as long as 10 years after baseline.

Researchers defined disability progression as a clinically significant worsening in the Expanded Disability Status Scale (EDSS), the timed 25-foot walk, the nine-hole peg test, and the paced serial auditory addition test.

Two Tiers of Therapy

Participants were treated with FDA-approved therapies or off-label therapies. Researchers defined two treatment tiers and categorized therapies based on their relative perceived effectiveness using data from clinical trials.

The first tier of treatment, platform therapy, included interferon (IFN) beta, glatiramer acetate, and off-label therapies such as glucocorticoids, azathioprine, and mycophenolate mofetil. The second tier of treatment, high-potency therapy, included natalizumab, rituximab, mitoxantrone, and cyclophosphamide.

NEDA and Long-Term Disability

Of 517 actively managed patients with MS enrolled in the study, 366 had RMS, 48 had SPMS, 21 had primary progressive MS (PPMS), and 82 had clinically isolated syndrome (CIS). After 10 years of follow-up, neurologic disability was stable or improved, compared with baseline, in 41% of patients. Serum vitamin D levels were inversely associated with short-term MS disease activity, but were not associated with long-term disability. At a median time of 16.8 years after disease onset, 10.7% of patients reached an EDSS score of greater than or equal to 6, and 18.1% of patients evolved from RMS to SPMS.

The investigators concluded that evolution to SPMS in this study was significantly lower than expected, based on natural history studies. They also noted that short-term increases in EDSS did not necessarily predict future accumulation of long-term disability in patients with RMS. In addition, subjects with NEDA by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole.

“Treating to target with two-year NEDA as the goal may not result in protection against long-term disability,” said Dr. Cree. “Long-term studies are urgently needed to determine if high-intensity therapy, initiated at the time of diagnosis or used in patients with seemingly inactive disease, is superior to the escalation approach employed in this cohort.”

—Erica Tricarico

Suggested Reading

University of California, San Francisco MS-EPIC Team, Cree BA, Gourraud PA, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499-510.

Compared with the natural history of the disease, disease-modifying treatments for multiple sclerosis (MS) significantly reduce the risks of long-term disability worsening and evolution to secondary progressive MS (SPMS), according to research published in the October issue of Annals of Neurology. The data also suggest that patients who have no evidence of disease activity (NEDA) for two years are no more likely to have long-term stability than patients who do not reach this end point.

“These observations challenge the concept that NEDA represents remission. Although NEDA may be a useful measure for assessing relative therapeutic efficacy, many patients who meet NEDA criteria over two years go on to develop clinically significant disability,” said Bruce A. C. Cree, MD, PhD, Associate Professor of Neurology at the University of California, San Francisco School of Medicine. “Worsening in patients who meet the two-year NEDA end point could result from active spinal cord disease not captured with brain MRI, progressive axonal or neuronal degeneration, or an escape from a true but transient remission state.

Researchers had anticipated that between 36% and 50% of patients with relapsing MS (RMS) would develop SPMS, but 11.3% of the cohort transitioned to SPMS during the course of the study. Evolution of sustained disability was also slower than expected, said Dr. Cree.

Examining Long-Term Effects of Treatment

Natural history studies from the pretreatment era suggest that between one-third and one-half of patients with MS experience substantial worsening of neurologic disability approximately 15 years after disease onset. Disease-modifying therapies in MS have been studied during the past two decades and are associated with improvement in the short term. Their effect on long-term outcomes is unknown, however. Furthermore, little is known about the relationship between short-term MRI measurements and long-term disability in MS.

As a result, Dr. Cree and colleagues conducted a prospective study to characterize the accrual of long-term disability in a cohort of actively treated patients with MS. Additionally, they sought to assess whether clinical and MRI data used in clinical trials have long-term prognostic value.

Eligible participants had all clinical subtypes of MS and were first evaluated at the MS Center at the University of California, San Francisco between July 2004 and September 2005. Patients were excluded if they were unable to tolerate MRI scans, had poor venous access, or if they had other significant medical illnesses that might interfere with goals of the study. Investigators followed participants annually for five years. In addition, patients underwent re-evaluation at extended time points for as long as 10 years after baseline.

Researchers defined disability progression as a clinically significant worsening in the Expanded Disability Status Scale (EDSS), the timed 25-foot walk, the nine-hole peg test, and the paced serial auditory addition test.

Two Tiers of Therapy

Participants were treated with FDA-approved therapies or off-label therapies. Researchers defined two treatment tiers and categorized therapies based on their relative perceived effectiveness using data from clinical trials.

The first tier of treatment, platform therapy, included interferon (IFN) beta, glatiramer acetate, and off-label therapies such as glucocorticoids, azathioprine, and mycophenolate mofetil. The second tier of treatment, high-potency therapy, included natalizumab, rituximab, mitoxantrone, and cyclophosphamide.

NEDA and Long-Term Disability

Of 517 actively managed patients with MS enrolled in the study, 366 had RMS, 48 had SPMS, 21 had primary progressive MS (PPMS), and 82 had clinically isolated syndrome (CIS). After 10 years of follow-up, neurologic disability was stable or improved, compared with baseline, in 41% of patients. Serum vitamin D levels were inversely associated with short-term MS disease activity, but were not associated with long-term disability. At a median time of 16.8 years after disease onset, 10.7% of patients reached an EDSS score of greater than or equal to 6, and 18.1% of patients evolved from RMS to SPMS.

The investigators concluded that evolution to SPMS in this study was significantly lower than expected, based on natural history studies. They also noted that short-term increases in EDSS did not necessarily predict future accumulation of long-term disability in patients with RMS. In addition, subjects with NEDA by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole.

“Treating to target with two-year NEDA as the goal may not result in protection against long-term disability,” said Dr. Cree. “Long-term studies are urgently needed to determine if high-intensity therapy, initiated at the time of diagnosis or used in patients with seemingly inactive disease, is superior to the escalation approach employed in this cohort.”

—Erica Tricarico

Suggested Reading

University of California, San Francisco MS-EPIC Team, Cree BA, Gourraud PA, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499-510.

Patients with epilepsy who do not respond to drug therapy and who are not candidates for surgery sometimes respond to vagus nerve stimulation (VNS). Research suggests that VNS reduces the frequency of seizures, but a recent study now suggests it may also improve patients’ quality of life. Englot et al found that the therapy improves alertness, post-ictal state, cluster seizures, mood, verbal communication, school and professional achievements, and memory. Several factors predicted patients’ improvement, including a shorter time to implant, female gender, generalized seizure type, and being Caucasian.

Englot DJ, Hassnain KH, Rolston JD, et al. Quality-of-life metrics with vagus nerve stimulation for epilepsy from provider survey data. Epilepsy Behav. 2017;66:4-9.

Patients with epilepsy who do not respond to drug therapy and who are not candidates for surgery sometimes respond to vagus nerve stimulation (VNS). Research suggests that VNS reduces the frequency of seizures, but a recent study now suggests it may also improve patients’ quality of life. Englot et al found that the therapy improves alertness, post-ictal state, cluster seizures, mood, verbal communication, school and professional achievements, and memory. Several factors predicted patients’ improvement, including a shorter time to implant, female gender, generalized seizure type, and being Caucasian.

Englot DJ, Hassnain KH, Rolston JD, et al. Quality-of-life metrics with vagus nerve stimulation for epilepsy from provider survey data. Epilepsy Behav. 2017;66:4-9.

Patients with epilepsy who do not respond to drug therapy and who are not candidates for surgery sometimes respond to vagus nerve stimulation (VNS). Research suggests that VNS reduces the frequency of seizures, but a recent study now suggests it may also improve patients’ quality of life. Englot et al found that the therapy improves alertness, post-ictal state, cluster seizures, mood, verbal communication, school and professional achievements, and memory. Several factors predicted patients’ improvement, including a shorter time to implant, female gender, generalized seizure type, and being Caucasian.

Englot DJ, Hassnain KH, Rolston JD, et al. Quality-of-life metrics with vagus nerve stimulation for epilepsy from provider survey data. Epilepsy Behav. 2017;66:4-9.

Patients with temporal lobe epilepsy are more likely to fare poorly after surgery if they experience auditory auras. When Ali A. Asadi-Pooya and associates performed a retrospective analysis of 1186 drug-resistant patients who had had a temporal resection, they found that those with auditory auras were more likely to relapse after surgery, when compared to those who did not experience the auras (P=.03). The side of the head in which the procedure was performed did not affect postoperative prognosis.

Asadi-Pooya AA, Wyeth D, Nei M, et al. Postsurgical outcome in patients with auditory auras and drug-resistant epilepsy. Epilepsy Behav. 2017;66:49-52.

Patients with temporal lobe epilepsy are more likely to fare poorly after surgery if they experience auditory auras. When Ali A. Asadi-Pooya and associates performed a retrospective analysis of 1186 drug-resistant patients who had had a temporal resection, they found that those with auditory auras were more likely to relapse after surgery, when compared to those who did not experience the auras (P=.03). The side of the head in which the procedure was performed did not affect postoperative prognosis.

Asadi-Pooya AA, Wyeth D, Nei M, et al. Postsurgical outcome in patients with auditory auras and drug-resistant epilepsy. Epilepsy Behav. 2017;66:49-52.

Patients with temporal lobe epilepsy are more likely to fare poorly after surgery if they experience auditory auras. When Ali A. Asadi-Pooya and associates performed a retrospective analysis of 1186 drug-resistant patients who had had a temporal resection, they found that those with auditory auras were more likely to relapse after surgery, when compared to those who did not experience the auras (P=.03). The side of the head in which the procedure was performed did not affect postoperative prognosis.

Asadi-Pooya AA, Wyeth D, Nei M, et al. Postsurgical outcome in patients with auditory auras and drug-resistant epilepsy. Epilepsy Behav. 2017;66:49-52.