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American Neurological Association (ANA): Annual Meeting 2017
VIDEO: Salvageable brain tissue can guide decision for stroke thrombectomy
SAN DIEGO – Neurologists have long suspected that some stroke patients could benefit from thrombectomy many hours after they were last seen well. But lingering doubts remained, and physicians weren’t sure which stroke patients were likely to improve.
Now, with the early stoppage of two key clinical trials, the answer is clear, Jeffrey Saver, MD, director of the stroke unit at the University of California, Los Angeles, said in a video interview at the annual meeting of the American Neurological Association.
At the European Stroke Organization Conference in May, Stryker Neurovascular announced the results of its DAWN trial, which tested the company’s mechanical thrombectomy device in patients who’d suffered a stroke within the past 6-24 hours and in whom imaging showed a clinical core mismatch. It was stopped early based on an interim analysis after it met multiple prespecified stopping criteria. At 90 days, 48.6% of patients in the treatment group were functionally independent, compared with 13.1% who received only medical management.
The DEFUSE 3 trial examined endovascular thrombectomy in patients 6-16 hours after a stroke who appeared to have salvageable brain tissue based on target mismatch profile with a less extreme core than in DAWN. It too was halted early because of a high probability of efficacy. Together, the trials suggest neurologists are entering a new era of treating based on tissue and not just time, Dr. Saver said.
SAN DIEGO – Neurologists have long suspected that some stroke patients could benefit from thrombectomy many hours after they were last seen well. But lingering doubts remained, and physicians weren’t sure which stroke patients were likely to improve.
Now, with the early stoppage of two key clinical trials, the answer is clear, Jeffrey Saver, MD, director of the stroke unit at the University of California, Los Angeles, said in a video interview at the annual meeting of the American Neurological Association.
At the European Stroke Organization Conference in May, Stryker Neurovascular announced the results of its DAWN trial, which tested the company’s mechanical thrombectomy device in patients who’d suffered a stroke within the past 6-24 hours and in whom imaging showed a clinical core mismatch. It was stopped early based on an interim analysis after it met multiple prespecified stopping criteria. At 90 days, 48.6% of patients in the treatment group were functionally independent, compared with 13.1% who received only medical management.
The DEFUSE 3 trial examined endovascular thrombectomy in patients 6-16 hours after a stroke who appeared to have salvageable brain tissue based on target mismatch profile with a less extreme core than in DAWN. It too was halted early because of a high probability of efficacy. Together, the trials suggest neurologists are entering a new era of treating based on tissue and not just time, Dr. Saver said.
SAN DIEGO – Neurologists have long suspected that some stroke patients could benefit from thrombectomy many hours after they were last seen well. But lingering doubts remained, and physicians weren’t sure which stroke patients were likely to improve.
Now, with the early stoppage of two key clinical trials, the answer is clear, Jeffrey Saver, MD, director of the stroke unit at the University of California, Los Angeles, said in a video interview at the annual meeting of the American Neurological Association.
At the European Stroke Organization Conference in May, Stryker Neurovascular announced the results of its DAWN trial, which tested the company’s mechanical thrombectomy device in patients who’d suffered a stroke within the past 6-24 hours and in whom imaging showed a clinical core mismatch. It was stopped early based on an interim analysis after it met multiple prespecified stopping criteria. At 90 days, 48.6% of patients in the treatment group were functionally independent, compared with 13.1% who received only medical management.
The DEFUSE 3 trial examined endovascular thrombectomy in patients 6-16 hours after a stroke who appeared to have salvageable brain tissue based on target mismatch profile with a less extreme core than in DAWN. It too was halted early because of a high probability of efficacy. Together, the trials suggest neurologists are entering a new era of treating based on tissue and not just time, Dr. Saver said.
AT ANA 2017
VIDEO: Measuring, treating brain hypoxia looks promising for TBI
SAN DIEGO – It’s been possible for over 15 years for neurointensivists to measure the partial pressure of oxygen in the brain of patients following traumatic brain injury.
But the technology has not been widely adopted because there have been no high-quality data showing that it’s useful. As a result, in most hospitals, TBI treatment is guided mostly by intracranial pressure.
The evidence gap is being filled. In a recent phase 2 trial, there was a trend towards benefit when treatment was guided by both intracranial pressure and the brain oxygenation (Crit Care Med. 2017 Nov;45[11]:1907-14). The study was powered for nonfutility, not clinically meaningful change, but the National Institute of Neurological Disorders and Stroke has recently funded a 45-site, phase 3 trial that will definitively answer whether treatment protocols informed by both pressure and oxygen improve neurologic outcomes, said principal investigator Ramon Diaz-Arrastia, MD, PhD, a professor of neurology at the University of Pennsylvania, Philadelphia.
In an interview at the annual meeting of the American Neurological Association, he explained the work, and exactly how paying attention to brain oxygen levels changed treatment in the phase 2 study. It didn’t take anything unusual to maintain oxygen partial pressure above 20 mm Hg.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – It’s been possible for over 15 years for neurointensivists to measure the partial pressure of oxygen in the brain of patients following traumatic brain injury.
But the technology has not been widely adopted because there have been no high-quality data showing that it’s useful. As a result, in most hospitals, TBI treatment is guided mostly by intracranial pressure.
The evidence gap is being filled. In a recent phase 2 trial, there was a trend towards benefit when treatment was guided by both intracranial pressure and the brain oxygenation (Crit Care Med. 2017 Nov;45[11]:1907-14). The study was powered for nonfutility, not clinically meaningful change, but the National Institute of Neurological Disorders and Stroke has recently funded a 45-site, phase 3 trial that will definitively answer whether treatment protocols informed by both pressure and oxygen improve neurologic outcomes, said principal investigator Ramon Diaz-Arrastia, MD, PhD, a professor of neurology at the University of Pennsylvania, Philadelphia.
In an interview at the annual meeting of the American Neurological Association, he explained the work, and exactly how paying attention to brain oxygen levels changed treatment in the phase 2 study. It didn’t take anything unusual to maintain oxygen partial pressure above 20 mm Hg.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – It’s been possible for over 15 years for neurointensivists to measure the partial pressure of oxygen in the brain of patients following traumatic brain injury.
But the technology has not been widely adopted because there have been no high-quality data showing that it’s useful. As a result, in most hospitals, TBI treatment is guided mostly by intracranial pressure.
The evidence gap is being filled. In a recent phase 2 trial, there was a trend towards benefit when treatment was guided by both intracranial pressure and the brain oxygenation (Crit Care Med. 2017 Nov;45[11]:1907-14). The study was powered for nonfutility, not clinically meaningful change, but the National Institute of Neurological Disorders and Stroke has recently funded a 45-site, phase 3 trial that will definitively answer whether treatment protocols informed by both pressure and oxygen improve neurologic outcomes, said principal investigator Ramon Diaz-Arrastia, MD, PhD, a professor of neurology at the University of Pennsylvania, Philadelphia.
In an interview at the annual meeting of the American Neurological Association, he explained the work, and exactly how paying attention to brain oxygen levels changed treatment in the phase 2 study. It didn’t take anything unusual to maintain oxygen partial pressure above 20 mm Hg.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ANA 2017
VIDEO: Alzheimer’s blood test expected soon
SAN DIEGO – A blood test that could be on the market in as little as 2 years has an accuracy of 89% for detecting amyloid plaques in the brain, according to a report at the annual meeting of the American Neurological Association.
It measures the ratio of amyloid-beta 42 to amyloid-beta 40; the numbers refer to how many amino acids are in the proteins. In healthy individuals, the ratio is “remarkably consistent, but when beta-42 starts to stick to plaques in the brain, it doesn’t get out into the blood, and the ratio drops; that’s what we are detecting.” It’s highly accurate in both “Alzheimer’s patients and people who are completely normal who have amyloid plaques in their brains,” said Randall Bateman, MD, a professor of neurology at Washington University, St. Louis.
The test is being developed by C2N Diagnostics; Dr. Bateman is a cofounder and scientific adviser. The company is working with the Food and Drug Administration and the Centers for Medicare and Medicaid Services to commercialize the test.
If it makes it to market – which seems likely – it could be a game changer, not only for Alzheimer’s research, but also for screening, preclinical detection, and early treatment. At present, CNS amyloidosis is detected largely by positron emission tomography and radioactive tracers.
In an interview at the meeting, Dr. Bateman explained the test, the research behind it, and what it could mean for neurologists and patients. In short, “when effective drugs are found, the blood beta-amyloid test [could] be used to screen millions of people in the general public to identify who is at risk for Alzheimer’s disease” so they can “start treatments even before memory loss and brain damage begin,” he said.
SAN DIEGO – A blood test that could be on the market in as little as 2 years has an accuracy of 89% for detecting amyloid plaques in the brain, according to a report at the annual meeting of the American Neurological Association.
It measures the ratio of amyloid-beta 42 to amyloid-beta 40; the numbers refer to how many amino acids are in the proteins. In healthy individuals, the ratio is “remarkably consistent, but when beta-42 starts to stick to plaques in the brain, it doesn’t get out into the blood, and the ratio drops; that’s what we are detecting.” It’s highly accurate in both “Alzheimer’s patients and people who are completely normal who have amyloid plaques in their brains,” said Randall Bateman, MD, a professor of neurology at Washington University, St. Louis.
The test is being developed by C2N Diagnostics; Dr. Bateman is a cofounder and scientific adviser. The company is working with the Food and Drug Administration and the Centers for Medicare and Medicaid Services to commercialize the test.
If it makes it to market – which seems likely – it could be a game changer, not only for Alzheimer’s research, but also for screening, preclinical detection, and early treatment. At present, CNS amyloidosis is detected largely by positron emission tomography and radioactive tracers.
In an interview at the meeting, Dr. Bateman explained the test, the research behind it, and what it could mean for neurologists and patients. In short, “when effective drugs are found, the blood beta-amyloid test [could] be used to screen millions of people in the general public to identify who is at risk for Alzheimer’s disease” so they can “start treatments even before memory loss and brain damage begin,” he said.
SAN DIEGO – A blood test that could be on the market in as little as 2 years has an accuracy of 89% for detecting amyloid plaques in the brain, according to a report at the annual meeting of the American Neurological Association.
It measures the ratio of amyloid-beta 42 to amyloid-beta 40; the numbers refer to how many amino acids are in the proteins. In healthy individuals, the ratio is “remarkably consistent, but when beta-42 starts to stick to plaques in the brain, it doesn’t get out into the blood, and the ratio drops; that’s what we are detecting.” It’s highly accurate in both “Alzheimer’s patients and people who are completely normal who have amyloid plaques in their brains,” said Randall Bateman, MD, a professor of neurology at Washington University, St. Louis.
The test is being developed by C2N Diagnostics; Dr. Bateman is a cofounder and scientific adviser. The company is working with the Food and Drug Administration and the Centers for Medicare and Medicaid Services to commercialize the test.
If it makes it to market – which seems likely – it could be a game changer, not only for Alzheimer’s research, but also for screening, preclinical detection, and early treatment. At present, CNS amyloidosis is detected largely by positron emission tomography and radioactive tracers.
In an interview at the meeting, Dr. Bateman explained the test, the research behind it, and what it could mean for neurologists and patients. In short, “when effective drugs are found, the blood beta-amyloid test [could] be used to screen millions of people in the general public to identify who is at risk for Alzheimer’s disease” so they can “start treatments even before memory loss and brain damage begin,” he said.
AT ANA 2017
VIDEO: Sildenafil improves cerebrovascular reactivity in chronic TBI
SAN DIEGO – The healthy brain is a master of autoregulation, continuously adjusting blood flow to meet metabolic demand.
But in traumatic brain injury, cerebrovascular reactivity (CVR) breaks down; blood vessels don’t dilate as they should to deliver nutrients and oxygen, leading to progressive neurologic decline.
Sildenafil (Viagra) – a vasodilator in injured blood vessels – might help, according to ongoing research at the University of Pennsylvania, Philadelphia.
Researchers there gave sildenafil to inpatients with persistent symptoms at least 6 months after traumatic brain injury and measured CVR by a novel MRI technique an hour later. “Sildenafil was able to correct the deficit in CVR in many cases. We are hopeful this could be a useful therapy,” said principal investigator Ramon Diaz-Arrastia, MD, a professor of neurology at the university.
He explained the work in an interview at annual meeting of the American Neurological Association. The next step is to see if sildenafil helps CVR in acute traumatic brain injury, and in people who have had multiple, mild brain traumas, including professional athletes.
SAN DIEGO – The healthy brain is a master of autoregulation, continuously adjusting blood flow to meet metabolic demand.
But in traumatic brain injury, cerebrovascular reactivity (CVR) breaks down; blood vessels don’t dilate as they should to deliver nutrients and oxygen, leading to progressive neurologic decline.
Sildenafil (Viagra) – a vasodilator in injured blood vessels – might help, according to ongoing research at the University of Pennsylvania, Philadelphia.
Researchers there gave sildenafil to inpatients with persistent symptoms at least 6 months after traumatic brain injury and measured CVR by a novel MRI technique an hour later. “Sildenafil was able to correct the deficit in CVR in many cases. We are hopeful this could be a useful therapy,” said principal investigator Ramon Diaz-Arrastia, MD, a professor of neurology at the university.
He explained the work in an interview at annual meeting of the American Neurological Association. The next step is to see if sildenafil helps CVR in acute traumatic brain injury, and in people who have had multiple, mild brain traumas, including professional athletes.
SAN DIEGO – The healthy brain is a master of autoregulation, continuously adjusting blood flow to meet metabolic demand.
But in traumatic brain injury, cerebrovascular reactivity (CVR) breaks down; blood vessels don’t dilate as they should to deliver nutrients and oxygen, leading to progressive neurologic decline.
Sildenafil (Viagra) – a vasodilator in injured blood vessels – might help, according to ongoing research at the University of Pennsylvania, Philadelphia.
Researchers there gave sildenafil to inpatients with persistent symptoms at least 6 months after traumatic brain injury and measured CVR by a novel MRI technique an hour later. “Sildenafil was able to correct the deficit in CVR in many cases. We are hopeful this could be a useful therapy,” said principal investigator Ramon Diaz-Arrastia, MD, a professor of neurology at the university.
He explained the work in an interview at annual meeting of the American Neurological Association. The next step is to see if sildenafil helps CVR in acute traumatic brain injury, and in people who have had multiple, mild brain traumas, including professional athletes.
AT ANA 2017
VIDEO: Mobile stroke units aren’t just expensive toys
SAN DIEGO – Mobile stroke units are specially equipped ambulance units designed to respond and deliver treatment to stroke patients as swiftly as possible. They are outfitted with a portable CT scanner, a mobile lab, and specialized personnel, including a telemedicine unit to assist with diagnosis. If a patient is experiencing an ischemic stroke, the unit can deliver thrombolytic therapy on the spot, circumventing travel to an emergency department.
But are they cost effective? There are 13 active units in the United States, and they’re not cheap. They cost about $3.5 million to build and operate over 5 years, according to James Grotta, MD, a neurologist with the Memorial Hermann Medical Group and director of stroke research at Memorial Hermann–Texas Medical Center, both in Houston.
In a video interview at the annual meeting of the American Neurological Association, Dr. Grotta described how his group is studying the impact of mobile stroke units on time to treatment and the long-term costs and cost savings associated with them in an ongoing clinical trial that is comparing outcomes in patients eligible for tissue plasminogen activator when treated by a mobile stroke unit versus standard prehospital triage and transport by emergency medical services. The study is comparing outcomes when the mobile stroke unit and emergency medical services are the primary responders on alternating weeks. Primary outcomes include cost-effectiveness, the change in Rankin scale score from baseline to 90 days, and the diagnostic agreement between a vascular neurologist in the mobile stroke unit and a telemedicine vascular neurologist consulted from the unit.
Mobile stroke units can even supplement existing health care in case of an emergency. Dr. Grotta also recounted how one unit assisted during the aftermath of Hurricane Harvey.
SAN DIEGO – Mobile stroke units are specially equipped ambulance units designed to respond and deliver treatment to stroke patients as swiftly as possible. They are outfitted with a portable CT scanner, a mobile lab, and specialized personnel, including a telemedicine unit to assist with diagnosis. If a patient is experiencing an ischemic stroke, the unit can deliver thrombolytic therapy on the spot, circumventing travel to an emergency department.
But are they cost effective? There are 13 active units in the United States, and they’re not cheap. They cost about $3.5 million to build and operate over 5 years, according to James Grotta, MD, a neurologist with the Memorial Hermann Medical Group and director of stroke research at Memorial Hermann–Texas Medical Center, both in Houston.
In a video interview at the annual meeting of the American Neurological Association, Dr. Grotta described how his group is studying the impact of mobile stroke units on time to treatment and the long-term costs and cost savings associated with them in an ongoing clinical trial that is comparing outcomes in patients eligible for tissue plasminogen activator when treated by a mobile stroke unit versus standard prehospital triage and transport by emergency medical services. The study is comparing outcomes when the mobile stroke unit and emergency medical services are the primary responders on alternating weeks. Primary outcomes include cost-effectiveness, the change in Rankin scale score from baseline to 90 days, and the diagnostic agreement between a vascular neurologist in the mobile stroke unit and a telemedicine vascular neurologist consulted from the unit.
Mobile stroke units can even supplement existing health care in case of an emergency. Dr. Grotta also recounted how one unit assisted during the aftermath of Hurricane Harvey.
SAN DIEGO – Mobile stroke units are specially equipped ambulance units designed to respond and deliver treatment to stroke patients as swiftly as possible. They are outfitted with a portable CT scanner, a mobile lab, and specialized personnel, including a telemedicine unit to assist with diagnosis. If a patient is experiencing an ischemic stroke, the unit can deliver thrombolytic therapy on the spot, circumventing travel to an emergency department.
But are they cost effective? There are 13 active units in the United States, and they’re not cheap. They cost about $3.5 million to build and operate over 5 years, according to James Grotta, MD, a neurologist with the Memorial Hermann Medical Group and director of stroke research at Memorial Hermann–Texas Medical Center, both in Houston.
In a video interview at the annual meeting of the American Neurological Association, Dr. Grotta described how his group is studying the impact of mobile stroke units on time to treatment and the long-term costs and cost savings associated with them in an ongoing clinical trial that is comparing outcomes in patients eligible for tissue plasminogen activator when treated by a mobile stroke unit versus standard prehospital triage and transport by emergency medical services. The study is comparing outcomes when the mobile stroke unit and emergency medical services are the primary responders on alternating weeks. Primary outcomes include cost-effectiveness, the change in Rankin scale score from baseline to 90 days, and the diagnostic agreement between a vascular neurologist in the mobile stroke unit and a telemedicine vascular neurologist consulted from the unit.
Mobile stroke units can even supplement existing health care in case of an emergency. Dr. Grotta also recounted how one unit assisted during the aftermath of Hurricane Harvey.
AT ANA 2017
MRI brainstem volume loss predicts SUDEP
SAN DIEGO – Brainstem volume loss is extensive in sudden unexplained death in epilepsy, suggesting that loss of brainstem volume on MRI might predict who is at risk, according to investigators from the Center for SUDEP Research, a multicenter research collaborative.
The “MRI can detect potentially life threatening brainstem damage before SUDEP [sudden unexplained death in epilepsy] onset and ought to be further studied as a clinically useful biomarker to identify patients at risk for SUDEP,” said lead investigator Alica Goldman, MD, PhD, associate professor of neurology and neurophysiology at Baylor College of Medicine, Houston, and an investigator for the research collaborative.
It’s possible SUDEP is due to autonomic failure secondary to damage to areas of the brainstem that control autonomic functions such as breathing and heartbeat. Cardiorespiratory failure has been reported in cases of witnessed SUDEP, and the team previously reported structural mesencephalic and lower brainstem abnormalities in two SUDEP cases with temporal lobe epilepsy (Neuroimage Clin. 2014 Jul 9;5:208-16).
“It was a logical transition to have a larger study,” Dr. Goldman said at the annual meeting of the American Neurological Association.
The team compared findings from standardized 3T MRI exams in 18 patients with focal-onset epilepsy, 27 SUDEP cases that had focal-onset epilepsy and one or more MRIs within 10 years of death, and 11 controls without epilepsy.
They also looked at heart rate variability based on ECG readings, a proxy of autonomic control. Abnormal variability is a risk factor for arrhythmias and sudden cardiac death, and has been shown previously to correlate with epilepsy duration and frequency. It also seems worse at night, when SUDEP risk is highest.
In the living epilepsy patients, the team found structural volume loss in the dorsal mesencephalon and other brainstem areas, and the loss correlated with abnormal heart rate variability (P less than .001).
In the SUDEP cases, “we found that patients who died from SUDEP had widespread brainstem volume loss in their last MRI before death, and the extent of volume loss in the brainstem correlated with shorter survival time” from the final MRI (P = .03).
The SUDEP cases were a mean of 23 years old at their last MRI; the majority of the cases were men.
The National Institutes of Health and the Epilepsy Foundation supported the work. Dr. Goldman had no relevant disclosures.
SAN DIEGO – Brainstem volume loss is extensive in sudden unexplained death in epilepsy, suggesting that loss of brainstem volume on MRI might predict who is at risk, according to investigators from the Center for SUDEP Research, a multicenter research collaborative.
The “MRI can detect potentially life threatening brainstem damage before SUDEP [sudden unexplained death in epilepsy] onset and ought to be further studied as a clinically useful biomarker to identify patients at risk for SUDEP,” said lead investigator Alica Goldman, MD, PhD, associate professor of neurology and neurophysiology at Baylor College of Medicine, Houston, and an investigator for the research collaborative.
It’s possible SUDEP is due to autonomic failure secondary to damage to areas of the brainstem that control autonomic functions such as breathing and heartbeat. Cardiorespiratory failure has been reported in cases of witnessed SUDEP, and the team previously reported structural mesencephalic and lower brainstem abnormalities in two SUDEP cases with temporal lobe epilepsy (Neuroimage Clin. 2014 Jul 9;5:208-16).
“It was a logical transition to have a larger study,” Dr. Goldman said at the annual meeting of the American Neurological Association.
The team compared findings from standardized 3T MRI exams in 18 patients with focal-onset epilepsy, 27 SUDEP cases that had focal-onset epilepsy and one or more MRIs within 10 years of death, and 11 controls without epilepsy.
They also looked at heart rate variability based on ECG readings, a proxy of autonomic control. Abnormal variability is a risk factor for arrhythmias and sudden cardiac death, and has been shown previously to correlate with epilepsy duration and frequency. It also seems worse at night, when SUDEP risk is highest.
In the living epilepsy patients, the team found structural volume loss in the dorsal mesencephalon and other brainstem areas, and the loss correlated with abnormal heart rate variability (P less than .001).
In the SUDEP cases, “we found that patients who died from SUDEP had widespread brainstem volume loss in their last MRI before death, and the extent of volume loss in the brainstem correlated with shorter survival time” from the final MRI (P = .03).
The SUDEP cases were a mean of 23 years old at their last MRI; the majority of the cases were men.
The National Institutes of Health and the Epilepsy Foundation supported the work. Dr. Goldman had no relevant disclosures.
SAN DIEGO – Brainstem volume loss is extensive in sudden unexplained death in epilepsy, suggesting that loss of brainstem volume on MRI might predict who is at risk, according to investigators from the Center for SUDEP Research, a multicenter research collaborative.
The “MRI can detect potentially life threatening brainstem damage before SUDEP [sudden unexplained death in epilepsy] onset and ought to be further studied as a clinically useful biomarker to identify patients at risk for SUDEP,” said lead investigator Alica Goldman, MD, PhD, associate professor of neurology and neurophysiology at Baylor College of Medicine, Houston, and an investigator for the research collaborative.
It’s possible SUDEP is due to autonomic failure secondary to damage to areas of the brainstem that control autonomic functions such as breathing and heartbeat. Cardiorespiratory failure has been reported in cases of witnessed SUDEP, and the team previously reported structural mesencephalic and lower brainstem abnormalities in two SUDEP cases with temporal lobe epilepsy (Neuroimage Clin. 2014 Jul 9;5:208-16).
“It was a logical transition to have a larger study,” Dr. Goldman said at the annual meeting of the American Neurological Association.
The team compared findings from standardized 3T MRI exams in 18 patients with focal-onset epilepsy, 27 SUDEP cases that had focal-onset epilepsy and one or more MRIs within 10 years of death, and 11 controls without epilepsy.
They also looked at heart rate variability based on ECG readings, a proxy of autonomic control. Abnormal variability is a risk factor for arrhythmias and sudden cardiac death, and has been shown previously to correlate with epilepsy duration and frequency. It also seems worse at night, when SUDEP risk is highest.
In the living epilepsy patients, the team found structural volume loss in the dorsal mesencephalon and other brainstem areas, and the loss correlated with abnormal heart rate variability (P less than .001).
In the SUDEP cases, “we found that patients who died from SUDEP had widespread brainstem volume loss in their last MRI before death, and the extent of volume loss in the brainstem correlated with shorter survival time” from the final MRI (P = .03).
The SUDEP cases were a mean of 23 years old at their last MRI; the majority of the cases were men.
The National Institutes of Health and the Epilepsy Foundation supported the work. Dr. Goldman had no relevant disclosures.
AT ANA 2017
Key clinical point:
Major finding: Patients who died from SUDEP had widespread brainstem volume loss in their last MRI before death (P = .03).
Data source: Imaging review of 27 SUDEP cases, 18 patients with focal epilepsy, and 11 controls.
Disclosures: The National Institutes of Health and the Epilepsy Foundation supported the work. The lead investigator had no relevant disclosures.
Eye movement, not CT or MRI, rules out posterior stroke
SAN DIEGO – When a patient with vertigo and dizziness presents to the emergency department, the first order of business is to figure out if they’re due to benign inner ear problems or a posterior fossa stroke.
Emergency department physicians usually use noncontrast CT (NCCT) to rule out stroke, while neurologists turn to MRI with diffusion-weighted imaging (MRI-DWI) to make the call.
Neither are good enough. The sensitivity of NCCT for acute posterior fossa strokes is just 30.8%. The sensitivity of MRI-DWI is better at 76.4%, but “false negatives [occur] in roughly one [of] four brainstem strokes in the first 48 hours,” according to a meta-analysis from Johns Hopkins University, Baltimore. The study, presented at the annual meeting of the American Neurological Association, involved more than 800 patients in the 14 strongest studies to look into the issue since 1990.
“Anterior circulation strokes are obvious, but posterior circulation strokes are subtle. We’ve surveyed ED physicians, and there’s a certain rate in the population who just don’t understand how bad CTs are for detecting acute stroke.” Meanwhile, “neurologists know” they can’t rely on CTs, “but they think MRIs are good enough. That turns out not to be true either,” he said.
Dr. Newman-Toker’s comments were sparked by a discussion about the meta-analysis, but he spoke from years of work trying to improve the situation. He was clear about what’s at stake: The early recognition of posterior fossa strokes, treatment with thrombolytics and surgical decompression (when warranted), and prevention of a second, larger stroke, can mean the difference between walking out of the hospital and dying or being wheelchair bound for life.
He and his colleagues have developed a way to detect posterior fossa strokes using eye movement abnormalities. They call it HINTS, which stands for “head impulse, nystagmus, and test of skew. “It turns out that the eye movements of inner ear disease look slightly different than the eye movements of brain disease; the subtle differences are enough to distinguish between the two.” When the technique is mastered, “our best estimate is that the sensitivity for posterior circulation stroke is around 99%,” Dr. Newman-Toker said. He is working to get the message out and train people; a video of the technique is online (Semin Neurol. 2015 Oct;35[5]:506-21).
As for the meta-analysis, “none of us were terribly surprised that CT wasn’t much good, and I knew that MRI wasn’t going to be perfect, but it was worse than I expected when we crunched all the numbers,” he said.
It’s no surprise that eye movement trumps imaging. “Physiology beats anatomy in the acute phase. It’s takes a little while for anatomy to change” on imaging, but eye movements change immediately “when patients become symptomatic with dizziness and vertigo,” he said.
Meanwhile, “if you don’t know how to evaluate peoples’ eye movements, I think MRIs are the next best thing,” he said.
There was no industry funding for the work. Johns Hopkins is working with a company called Natus to develop HINTS training. Dr. Newman-Toker might earn royalties, but so far “I haven’t made any money off it, and there’s no document saying I’m ever going to make any money from it,” he said.
SAN DIEGO – When a patient with vertigo and dizziness presents to the emergency department, the first order of business is to figure out if they’re due to benign inner ear problems or a posterior fossa stroke.
Emergency department physicians usually use noncontrast CT (NCCT) to rule out stroke, while neurologists turn to MRI with diffusion-weighted imaging (MRI-DWI) to make the call.
Neither are good enough. The sensitivity of NCCT for acute posterior fossa strokes is just 30.8%. The sensitivity of MRI-DWI is better at 76.4%, but “false negatives [occur] in roughly one [of] four brainstem strokes in the first 48 hours,” according to a meta-analysis from Johns Hopkins University, Baltimore. The study, presented at the annual meeting of the American Neurological Association, involved more than 800 patients in the 14 strongest studies to look into the issue since 1990.
“Anterior circulation strokes are obvious, but posterior circulation strokes are subtle. We’ve surveyed ED physicians, and there’s a certain rate in the population who just don’t understand how bad CTs are for detecting acute stroke.” Meanwhile, “neurologists know” they can’t rely on CTs, “but they think MRIs are good enough. That turns out not to be true either,” he said.
Dr. Newman-Toker’s comments were sparked by a discussion about the meta-analysis, but he spoke from years of work trying to improve the situation. He was clear about what’s at stake: The early recognition of posterior fossa strokes, treatment with thrombolytics and surgical decompression (when warranted), and prevention of a second, larger stroke, can mean the difference between walking out of the hospital and dying or being wheelchair bound for life.
He and his colleagues have developed a way to detect posterior fossa strokes using eye movement abnormalities. They call it HINTS, which stands for “head impulse, nystagmus, and test of skew. “It turns out that the eye movements of inner ear disease look slightly different than the eye movements of brain disease; the subtle differences are enough to distinguish between the two.” When the technique is mastered, “our best estimate is that the sensitivity for posterior circulation stroke is around 99%,” Dr. Newman-Toker said. He is working to get the message out and train people; a video of the technique is online (Semin Neurol. 2015 Oct;35[5]:506-21).
As for the meta-analysis, “none of us were terribly surprised that CT wasn’t much good, and I knew that MRI wasn’t going to be perfect, but it was worse than I expected when we crunched all the numbers,” he said.
It’s no surprise that eye movement trumps imaging. “Physiology beats anatomy in the acute phase. It’s takes a little while for anatomy to change” on imaging, but eye movements change immediately “when patients become symptomatic with dizziness and vertigo,” he said.
Meanwhile, “if you don’t know how to evaluate peoples’ eye movements, I think MRIs are the next best thing,” he said.
There was no industry funding for the work. Johns Hopkins is working with a company called Natus to develop HINTS training. Dr. Newman-Toker might earn royalties, but so far “I haven’t made any money off it, and there’s no document saying I’m ever going to make any money from it,” he said.
SAN DIEGO – When a patient with vertigo and dizziness presents to the emergency department, the first order of business is to figure out if they’re due to benign inner ear problems or a posterior fossa stroke.
Emergency department physicians usually use noncontrast CT (NCCT) to rule out stroke, while neurologists turn to MRI with diffusion-weighted imaging (MRI-DWI) to make the call.
Neither are good enough. The sensitivity of NCCT for acute posterior fossa strokes is just 30.8%. The sensitivity of MRI-DWI is better at 76.4%, but “false negatives [occur] in roughly one [of] four brainstem strokes in the first 48 hours,” according to a meta-analysis from Johns Hopkins University, Baltimore. The study, presented at the annual meeting of the American Neurological Association, involved more than 800 patients in the 14 strongest studies to look into the issue since 1990.
“Anterior circulation strokes are obvious, but posterior circulation strokes are subtle. We’ve surveyed ED physicians, and there’s a certain rate in the population who just don’t understand how bad CTs are for detecting acute stroke.” Meanwhile, “neurologists know” they can’t rely on CTs, “but they think MRIs are good enough. That turns out not to be true either,” he said.
Dr. Newman-Toker’s comments were sparked by a discussion about the meta-analysis, but he spoke from years of work trying to improve the situation. He was clear about what’s at stake: The early recognition of posterior fossa strokes, treatment with thrombolytics and surgical decompression (when warranted), and prevention of a second, larger stroke, can mean the difference between walking out of the hospital and dying or being wheelchair bound for life.
He and his colleagues have developed a way to detect posterior fossa strokes using eye movement abnormalities. They call it HINTS, which stands for “head impulse, nystagmus, and test of skew. “It turns out that the eye movements of inner ear disease look slightly different than the eye movements of brain disease; the subtle differences are enough to distinguish between the two.” When the technique is mastered, “our best estimate is that the sensitivity for posterior circulation stroke is around 99%,” Dr. Newman-Toker said. He is working to get the message out and train people; a video of the technique is online (Semin Neurol. 2015 Oct;35[5]:506-21).
As for the meta-analysis, “none of us were terribly surprised that CT wasn’t much good, and I knew that MRI wasn’t going to be perfect, but it was worse than I expected when we crunched all the numbers,” he said.
It’s no surprise that eye movement trumps imaging. “Physiology beats anatomy in the acute phase. It’s takes a little while for anatomy to change” on imaging, but eye movements change immediately “when patients become symptomatic with dizziness and vertigo,” he said.
Meanwhile, “if you don’t know how to evaluate peoples’ eye movements, I think MRIs are the next best thing,” he said.
There was no industry funding for the work. Johns Hopkins is working with a company called Natus to develop HINTS training. Dr. Newman-Toker might earn royalties, but so far “I haven’t made any money off it, and there’s no document saying I’m ever going to make any money from it,” he said.
AT ANA 2017
Key clinical point:
Major finding: The sensitivity of CT for acute posterior strokes was just 30.8%. The sensitivity of MRI was better at 76.4%, but it still missed one in four.
Data source: Meta-analysis of more than 800 patients
Disclosures: There was no industry funding for the work. The senior investigator might profit from commercialization of HINTS training.
Young adult stroke survivors have distinct risk profile
SAN DIEGO – Young adults who have suffered a stroke are at greater risk of a second stroke than other cardiovascular events, at least in the first year. That’s the conclusion drawn from a new analysis of 2013 data drawn from the Nationwide Readmissions Database.
The results suggest that younger adults who have a first-time stroke have a different risk profile than older adults and could require different management to improve long-term outcomes. The incidence of stroke has increased in recent years to the point that this population now accounts for about 10% of all strokes.
The analysis looked at all admissions for ischemic stroke in patients aged 18-45. The researchers found a cumulative risk of rehospitalization of 5.5% at 300 days, compared with 3.6% for cardiovascular disease.
The study can’t explain the association, nor can it prove causation. “Our thought was that the effects of hypertension might take longer to manifest in terms of cardiovascular outcomes as compared to hypercholesterolemia and diabetes,” said Dr. Jin, who is chief resident in the department of neurology at Icahn School of Medicine at Mount Sinai, New York. He presented the research at the annual meeting of the American Neurological Association.
The result sends a clear message for physicians caring for young adults who have experienced a first-time stroke. “They should be rigorously worked up and managed for any disorders in blood sugar and lipid disorders,” Dr. Jin said. Their care is vital because these younger adults have more time to accumulate second, third, or fourth strokes that could dramatically increase the burden of disease. “It’s just a matter of time. Optimizing their secondary prevention is crucial,” Dr. Jin said.
The study included data from 12,392 young adults in the Nationwide Readmissions Database who had suffered a first-time stroke. The researchers identified a higher readmission rate for stroke than cardiovascular events at 90 days (2,913.3 vs. 1,132.4 per 100,000 index hospitalizations). This pattern held when the analysis was restricted to patients who had no cardiovascular risk factors prior to the index hospitalization (2,534.9 vs. 676 per 100,000 index hospitalizations).
At 100 days, the cumulative risks were 3.2% for stroke and 2.5% for cardiovascular events. The risks were 4.3% and 3.2% at 200 days, and 5.5% and 3.6% at 300 days.
A multivariate analysis showed that patients with baseline diabetes were at a heightened risk of cardiovascular events (hazard ratio, 1.49; 95% confidence interval, 1.17-1.88), as were patients with hypercholesterolemia (HR, 1.43; 95% CI, 1.15-1.79) and those with atrial fibrillation or flutter (HR, 3.86; 95% CI, 2.74-5.43). Only diabetes was significantly associated with increased risk for hospitalization for recurrent stroke (HR, 1.5; 95% CI, 1.22-1.84).
Dr. Jin is eager to see if future research might establish a causative link between these risk factors and outcomes. The current work grew out of an administrative data set, but registry data or a prospective study could be more robust.
The study received no external funding. Dr. Jin reported having no financial disclosures.
SAN DIEGO – Young adults who have suffered a stroke are at greater risk of a second stroke than other cardiovascular events, at least in the first year. That’s the conclusion drawn from a new analysis of 2013 data drawn from the Nationwide Readmissions Database.
The results suggest that younger adults who have a first-time stroke have a different risk profile than older adults and could require different management to improve long-term outcomes. The incidence of stroke has increased in recent years to the point that this population now accounts for about 10% of all strokes.
The analysis looked at all admissions for ischemic stroke in patients aged 18-45. The researchers found a cumulative risk of rehospitalization of 5.5% at 300 days, compared with 3.6% for cardiovascular disease.
The study can’t explain the association, nor can it prove causation. “Our thought was that the effects of hypertension might take longer to manifest in terms of cardiovascular outcomes as compared to hypercholesterolemia and diabetes,” said Dr. Jin, who is chief resident in the department of neurology at Icahn School of Medicine at Mount Sinai, New York. He presented the research at the annual meeting of the American Neurological Association.
The result sends a clear message for physicians caring for young adults who have experienced a first-time stroke. “They should be rigorously worked up and managed for any disorders in blood sugar and lipid disorders,” Dr. Jin said. Their care is vital because these younger adults have more time to accumulate second, third, or fourth strokes that could dramatically increase the burden of disease. “It’s just a matter of time. Optimizing their secondary prevention is crucial,” Dr. Jin said.
The study included data from 12,392 young adults in the Nationwide Readmissions Database who had suffered a first-time stroke. The researchers identified a higher readmission rate for stroke than cardiovascular events at 90 days (2,913.3 vs. 1,132.4 per 100,000 index hospitalizations). This pattern held when the analysis was restricted to patients who had no cardiovascular risk factors prior to the index hospitalization (2,534.9 vs. 676 per 100,000 index hospitalizations).
At 100 days, the cumulative risks were 3.2% for stroke and 2.5% for cardiovascular events. The risks were 4.3% and 3.2% at 200 days, and 5.5% and 3.6% at 300 days.
A multivariate analysis showed that patients with baseline diabetes were at a heightened risk of cardiovascular events (hazard ratio, 1.49; 95% confidence interval, 1.17-1.88), as were patients with hypercholesterolemia (HR, 1.43; 95% CI, 1.15-1.79) and those with atrial fibrillation or flutter (HR, 3.86; 95% CI, 2.74-5.43). Only diabetes was significantly associated with increased risk for hospitalization for recurrent stroke (HR, 1.5; 95% CI, 1.22-1.84).
Dr. Jin is eager to see if future research might establish a causative link between these risk factors and outcomes. The current work grew out of an administrative data set, but registry data or a prospective study could be more robust.
The study received no external funding. Dr. Jin reported having no financial disclosures.
SAN DIEGO – Young adults who have suffered a stroke are at greater risk of a second stroke than other cardiovascular events, at least in the first year. That’s the conclusion drawn from a new analysis of 2013 data drawn from the Nationwide Readmissions Database.
The results suggest that younger adults who have a first-time stroke have a different risk profile than older adults and could require different management to improve long-term outcomes. The incidence of stroke has increased in recent years to the point that this population now accounts for about 10% of all strokes.
The analysis looked at all admissions for ischemic stroke in patients aged 18-45. The researchers found a cumulative risk of rehospitalization of 5.5% at 300 days, compared with 3.6% for cardiovascular disease.
The study can’t explain the association, nor can it prove causation. “Our thought was that the effects of hypertension might take longer to manifest in terms of cardiovascular outcomes as compared to hypercholesterolemia and diabetes,” said Dr. Jin, who is chief resident in the department of neurology at Icahn School of Medicine at Mount Sinai, New York. He presented the research at the annual meeting of the American Neurological Association.
The result sends a clear message for physicians caring for young adults who have experienced a first-time stroke. “They should be rigorously worked up and managed for any disorders in blood sugar and lipid disorders,” Dr. Jin said. Their care is vital because these younger adults have more time to accumulate second, third, or fourth strokes that could dramatically increase the burden of disease. “It’s just a matter of time. Optimizing their secondary prevention is crucial,” Dr. Jin said.
The study included data from 12,392 young adults in the Nationwide Readmissions Database who had suffered a first-time stroke. The researchers identified a higher readmission rate for stroke than cardiovascular events at 90 days (2,913.3 vs. 1,132.4 per 100,000 index hospitalizations). This pattern held when the analysis was restricted to patients who had no cardiovascular risk factors prior to the index hospitalization (2,534.9 vs. 676 per 100,000 index hospitalizations).
At 100 days, the cumulative risks were 3.2% for stroke and 2.5% for cardiovascular events. The risks were 4.3% and 3.2% at 200 days, and 5.5% and 3.6% at 300 days.
A multivariate analysis showed that patients with baseline diabetes were at a heightened risk of cardiovascular events (hazard ratio, 1.49; 95% confidence interval, 1.17-1.88), as were patients with hypercholesterolemia (HR, 1.43; 95% CI, 1.15-1.79) and those with atrial fibrillation or flutter (HR, 3.86; 95% CI, 2.74-5.43). Only diabetes was significantly associated with increased risk for hospitalization for recurrent stroke (HR, 1.5; 95% CI, 1.22-1.84).
Dr. Jin is eager to see if future research might establish a causative link between these risk factors and outcomes. The current work grew out of an administrative data set, but registry data or a prospective study could be more robust.
The study received no external funding. Dr. Jin reported having no financial disclosures.
AT ANA 2017
Key clinical point:
Major finding: Hospitalization for cardiovascular disease was associated with baseline diabetes (HR, 1.49) and hypercholesterolemia (HR, 1.43).
Data source: A retrospective analysis of data from the Nationwide Readmissions Database (n = 12,392).
Disclosures: The study received no external funding. Dr. Jin reported having no financial disclosures.
VIDEO: Rethinking deep brain stimulation for depression
SAN DIEGO – Earlier this month, an article in Lancet Psychiatry reported the results of a prospective, randomized, sham-controlled trial that tested deep brain stimulation of the Brodmann area 25 within the subcallosal cingulate white matter in 90 patients with treatment-resistant depression. Unfortunately, the study showed no significant benefit at 6 months.
The approach had shown promise in some previous open-label studies, which prompted the multicenter trial (Lancet Psychiatry. 2017 Oct 4. doi: 10.1016/S2215-0366(17)30371-1).
Although the 6-month results were disappointing, the open-label phase of the study told a different story. At 2 years, 48% of patients in the stimulation group achieved an antidepressant response, higher than what would be expected from treatment as usual in this difficult population.
In this video interview at the annual meeting of the American Neurological Association, Helen Mayberg, MD, one of the study authors and professor of psychiatry, neurology, and radiology at Emory University, Atlanta, discusses these long-term results and their implications, as well as lessons learned and how they might inform future research.
SAN DIEGO – Earlier this month, an article in Lancet Psychiatry reported the results of a prospective, randomized, sham-controlled trial that tested deep brain stimulation of the Brodmann area 25 within the subcallosal cingulate white matter in 90 patients with treatment-resistant depression. Unfortunately, the study showed no significant benefit at 6 months.
The approach had shown promise in some previous open-label studies, which prompted the multicenter trial (Lancet Psychiatry. 2017 Oct 4. doi: 10.1016/S2215-0366(17)30371-1).
Although the 6-month results were disappointing, the open-label phase of the study told a different story. At 2 years, 48% of patients in the stimulation group achieved an antidepressant response, higher than what would be expected from treatment as usual in this difficult population.
In this video interview at the annual meeting of the American Neurological Association, Helen Mayberg, MD, one of the study authors and professor of psychiatry, neurology, and radiology at Emory University, Atlanta, discusses these long-term results and their implications, as well as lessons learned and how they might inform future research.
SAN DIEGO – Earlier this month, an article in Lancet Psychiatry reported the results of a prospective, randomized, sham-controlled trial that tested deep brain stimulation of the Brodmann area 25 within the subcallosal cingulate white matter in 90 patients with treatment-resistant depression. Unfortunately, the study showed no significant benefit at 6 months.
The approach had shown promise in some previous open-label studies, which prompted the multicenter trial (Lancet Psychiatry. 2017 Oct 4. doi: 10.1016/S2215-0366(17)30371-1).
Although the 6-month results were disappointing, the open-label phase of the study told a different story. At 2 years, 48% of patients in the stimulation group achieved an antidepressant response, higher than what would be expected from treatment as usual in this difficult population.
In this video interview at the annual meeting of the American Neurological Association, Helen Mayberg, MD, one of the study authors and professor of psychiatry, neurology, and radiology at Emory University, Atlanta, discusses these long-term results and their implications, as well as lessons learned and how they might inform future research.
AT ANA 2017
Everolimus has long-term efficacy in tuberous sclerosis complex
SAN DIEGO – Everolimus reduces the frequency of epileptic seizures in patients with tuberous sclerosis complex (TSC), and its effect appears to gain strength over time. By the end of an extension study, half of patients had at least a 31.7% reduction in seizure frequency at 18 weeks, and that percentage rose to 56.9% at 2 years.
The drug was chosen because it inhibits mammalian target of rapamycin (mTOR), which plays a central role in protein synthesis, cell division, and other vital processes. In patients with TSC, the kinase is overactive, and this leads to abnormalities in brain development. Overall, 85% of TSC patients experience seizures, and 60% are refractory to antiepileptic drugs.
The success of everolimus (Afinitor) is encouraging, and it’s the first epilepsy drug to be chosen for its mechanism of action, David Neal Franz, MD, said in an interview. “It has been used off label, but this study really shows that it has a statistically significant benefit that improves over time. A lot of things are used off label, but most don’t have this kind of class II evidence to support being used,” said Dr. Franz, who presented the study at the annual meeting of the American Neurological Association.
The drug was particularly effective in children, who experienced a greater reduction in seizure frequency over time. That suggests that earlier treatment with everolimus could counter some of the damage in these patients before it becomes entrenched. “We’re planning to do studies to evaluate that. Because if you can avoid intractable epilepsy and its effects on development, there’s the potential to have a very significant benefit for children,” said Dr. Franz, who is a professor of pediatrics and neurology and founding director of the Tuberous Sclerosis Clinic at the University of Cincinnati. He noted that some previous studies showed that early treatment of infantile spasms is associated with lower risk of intellectual disability and autism.
The study enrolled 361 TSC patients with epilepsy across a wide age range (2-65 years). Their epilepsy had remained uncontrolled following treatment with at least six previous drugs. The core phase of the trial lasted 18 weeks, followed by an extension phase in which patients in the placebo group were switched to everolimus with a target dose of 3-15 ng/mL.
The primary efficacy outcome was the change in weekly seizure frequency. The researchers defined a response as a 50% or higher reduction.
In the original pivotal trial (EXIST-3), 15.1% of patients on placebo responded (95% confidence interval, 9.2%-22.8%) at week 18, compared with 28.2% of patients receiving a 3-7 ng/mL dose of everolimus (95% CI, 20.3%-37.3%; P = .0077) and 40% of patients receiving a 9-15 ng/mL dose of everolimus (95% CI, 31.5%-49%; P less than .0001).
The response rate at 18 weeks of treatment when combining both the original everolimus-treated patients and also the group switching over to everolimus in the extension phase was 31% (95% CI, 26.2%-36.1%). By 1 year, 46.6% had responded (95% CI, 40.9%-52.5%), and 57.7% had responded at 2 years (95% CI, 49.7%-65.4%).
The median percentage reduction in seizure frequency rose from 31.7% at week 18 (95% CI, 28.5%-36.1%) to 46.7% at 1 year (95% CI, 40.2%-54.0%) and 56.9% at 2 years (95% CI, 50%-68.4%).
Younger patients experienced greater improvements over time. At 2 years, 76% of 101 patients aged 0-6 years had responded (95% CI, 58.8%-88.2%), compared with 58.5% of patients aged 6-12 years (95% CI, 44.1%-71.9%), 51.1% of patients aged 12-18 years (95% CI, 35.8%-66.3%), and 43% of patients 18 years and older (95% CI, 24.5%-62.8%).
A sensitivity analysis of patients who discontinued the drug and were categorized as nonresponders showed the drug was still associated with a risk reduction of 30.2% at week 18 (95% CI, 25.5%-35.2%), 38.8% at 1 year (95% CI, 33.7%-44.1%), and 41% at 2 years (95% CI, 34.6%-47.7%).
Adverse events declined over time from 76.1% during the first 6 months of treatment to 46.8% at 1 year and 45.2% at 2 years. A total of 40.2% of patients experienced grade III/IV adverse events, and 13% of patients discontinued medication as a result. Another 1.7% experienced pneumonia, and 1.4% experienced stomatitis.
The most concerning side effects noted were tied to infection risk, which was not surprising given that everolimus is an immunosuppressive agent that is also used to prevent organ rejection. “The good thing is that you can hold everolimus when patients get sick or have a fever, and it doesn’t immediately lose efficacy. It binds avidly to mTOR, and so you can often go several weeks off the drug before you see loss of seizure control,” Dr. Franz said.
The study was funded by Novartis. Dr. Franz has received travel funding and honoraria from Novartis.
SAN DIEGO – Everolimus reduces the frequency of epileptic seizures in patients with tuberous sclerosis complex (TSC), and its effect appears to gain strength over time. By the end of an extension study, half of patients had at least a 31.7% reduction in seizure frequency at 18 weeks, and that percentage rose to 56.9% at 2 years.
The drug was chosen because it inhibits mammalian target of rapamycin (mTOR), which plays a central role in protein synthesis, cell division, and other vital processes. In patients with TSC, the kinase is overactive, and this leads to abnormalities in brain development. Overall, 85% of TSC patients experience seizures, and 60% are refractory to antiepileptic drugs.
The success of everolimus (Afinitor) is encouraging, and it’s the first epilepsy drug to be chosen for its mechanism of action, David Neal Franz, MD, said in an interview. “It has been used off label, but this study really shows that it has a statistically significant benefit that improves over time. A lot of things are used off label, but most don’t have this kind of class II evidence to support being used,” said Dr. Franz, who presented the study at the annual meeting of the American Neurological Association.
The drug was particularly effective in children, who experienced a greater reduction in seizure frequency over time. That suggests that earlier treatment with everolimus could counter some of the damage in these patients before it becomes entrenched. “We’re planning to do studies to evaluate that. Because if you can avoid intractable epilepsy and its effects on development, there’s the potential to have a very significant benefit for children,” said Dr. Franz, who is a professor of pediatrics and neurology and founding director of the Tuberous Sclerosis Clinic at the University of Cincinnati. He noted that some previous studies showed that early treatment of infantile spasms is associated with lower risk of intellectual disability and autism.
The study enrolled 361 TSC patients with epilepsy across a wide age range (2-65 years). Their epilepsy had remained uncontrolled following treatment with at least six previous drugs. The core phase of the trial lasted 18 weeks, followed by an extension phase in which patients in the placebo group were switched to everolimus with a target dose of 3-15 ng/mL.
The primary efficacy outcome was the change in weekly seizure frequency. The researchers defined a response as a 50% or higher reduction.
In the original pivotal trial (EXIST-3), 15.1% of patients on placebo responded (95% confidence interval, 9.2%-22.8%) at week 18, compared with 28.2% of patients receiving a 3-7 ng/mL dose of everolimus (95% CI, 20.3%-37.3%; P = .0077) and 40% of patients receiving a 9-15 ng/mL dose of everolimus (95% CI, 31.5%-49%; P less than .0001).
The response rate at 18 weeks of treatment when combining both the original everolimus-treated patients and also the group switching over to everolimus in the extension phase was 31% (95% CI, 26.2%-36.1%). By 1 year, 46.6% had responded (95% CI, 40.9%-52.5%), and 57.7% had responded at 2 years (95% CI, 49.7%-65.4%).
The median percentage reduction in seizure frequency rose from 31.7% at week 18 (95% CI, 28.5%-36.1%) to 46.7% at 1 year (95% CI, 40.2%-54.0%) and 56.9% at 2 years (95% CI, 50%-68.4%).
Younger patients experienced greater improvements over time. At 2 years, 76% of 101 patients aged 0-6 years had responded (95% CI, 58.8%-88.2%), compared with 58.5% of patients aged 6-12 years (95% CI, 44.1%-71.9%), 51.1% of patients aged 12-18 years (95% CI, 35.8%-66.3%), and 43% of patients 18 years and older (95% CI, 24.5%-62.8%).
A sensitivity analysis of patients who discontinued the drug and were categorized as nonresponders showed the drug was still associated with a risk reduction of 30.2% at week 18 (95% CI, 25.5%-35.2%), 38.8% at 1 year (95% CI, 33.7%-44.1%), and 41% at 2 years (95% CI, 34.6%-47.7%).
Adverse events declined over time from 76.1% during the first 6 months of treatment to 46.8% at 1 year and 45.2% at 2 years. A total of 40.2% of patients experienced grade III/IV adverse events, and 13% of patients discontinued medication as a result. Another 1.7% experienced pneumonia, and 1.4% experienced stomatitis.
The most concerning side effects noted were tied to infection risk, which was not surprising given that everolimus is an immunosuppressive agent that is also used to prevent organ rejection. “The good thing is that you can hold everolimus when patients get sick or have a fever, and it doesn’t immediately lose efficacy. It binds avidly to mTOR, and so you can often go several weeks off the drug before you see loss of seizure control,” Dr. Franz said.
The study was funded by Novartis. Dr. Franz has received travel funding and honoraria from Novartis.
SAN DIEGO – Everolimus reduces the frequency of epileptic seizures in patients with tuberous sclerosis complex (TSC), and its effect appears to gain strength over time. By the end of an extension study, half of patients had at least a 31.7% reduction in seizure frequency at 18 weeks, and that percentage rose to 56.9% at 2 years.
The drug was chosen because it inhibits mammalian target of rapamycin (mTOR), which plays a central role in protein synthesis, cell division, and other vital processes. In patients with TSC, the kinase is overactive, and this leads to abnormalities in brain development. Overall, 85% of TSC patients experience seizures, and 60% are refractory to antiepileptic drugs.
The success of everolimus (Afinitor) is encouraging, and it’s the first epilepsy drug to be chosen for its mechanism of action, David Neal Franz, MD, said in an interview. “It has been used off label, but this study really shows that it has a statistically significant benefit that improves over time. A lot of things are used off label, but most don’t have this kind of class II evidence to support being used,” said Dr. Franz, who presented the study at the annual meeting of the American Neurological Association.
The drug was particularly effective in children, who experienced a greater reduction in seizure frequency over time. That suggests that earlier treatment with everolimus could counter some of the damage in these patients before it becomes entrenched. “We’re planning to do studies to evaluate that. Because if you can avoid intractable epilepsy and its effects on development, there’s the potential to have a very significant benefit for children,” said Dr. Franz, who is a professor of pediatrics and neurology and founding director of the Tuberous Sclerosis Clinic at the University of Cincinnati. He noted that some previous studies showed that early treatment of infantile spasms is associated with lower risk of intellectual disability and autism.
The study enrolled 361 TSC patients with epilepsy across a wide age range (2-65 years). Their epilepsy had remained uncontrolled following treatment with at least six previous drugs. The core phase of the trial lasted 18 weeks, followed by an extension phase in which patients in the placebo group were switched to everolimus with a target dose of 3-15 ng/mL.
The primary efficacy outcome was the change in weekly seizure frequency. The researchers defined a response as a 50% or higher reduction.
In the original pivotal trial (EXIST-3), 15.1% of patients on placebo responded (95% confidence interval, 9.2%-22.8%) at week 18, compared with 28.2% of patients receiving a 3-7 ng/mL dose of everolimus (95% CI, 20.3%-37.3%; P = .0077) and 40% of patients receiving a 9-15 ng/mL dose of everolimus (95% CI, 31.5%-49%; P less than .0001).
The response rate at 18 weeks of treatment when combining both the original everolimus-treated patients and also the group switching over to everolimus in the extension phase was 31% (95% CI, 26.2%-36.1%). By 1 year, 46.6% had responded (95% CI, 40.9%-52.5%), and 57.7% had responded at 2 years (95% CI, 49.7%-65.4%).
The median percentage reduction in seizure frequency rose from 31.7% at week 18 (95% CI, 28.5%-36.1%) to 46.7% at 1 year (95% CI, 40.2%-54.0%) and 56.9% at 2 years (95% CI, 50%-68.4%).
Younger patients experienced greater improvements over time. At 2 years, 76% of 101 patients aged 0-6 years had responded (95% CI, 58.8%-88.2%), compared with 58.5% of patients aged 6-12 years (95% CI, 44.1%-71.9%), 51.1% of patients aged 12-18 years (95% CI, 35.8%-66.3%), and 43% of patients 18 years and older (95% CI, 24.5%-62.8%).
A sensitivity analysis of patients who discontinued the drug and were categorized as nonresponders showed the drug was still associated with a risk reduction of 30.2% at week 18 (95% CI, 25.5%-35.2%), 38.8% at 1 year (95% CI, 33.7%-44.1%), and 41% at 2 years (95% CI, 34.6%-47.7%).
Adverse events declined over time from 76.1% during the first 6 months of treatment to 46.8% at 1 year and 45.2% at 2 years. A total of 40.2% of patients experienced grade III/IV adverse events, and 13% of patients discontinued medication as a result. Another 1.7% experienced pneumonia, and 1.4% experienced stomatitis.
The most concerning side effects noted were tied to infection risk, which was not surprising given that everolimus is an immunosuppressive agent that is also used to prevent organ rejection. “The good thing is that you can hold everolimus when patients get sick or have a fever, and it doesn’t immediately lose efficacy. It binds avidly to mTOR, and so you can often go several weeks off the drug before you see loss of seizure control,” Dr. Franz said.
The study was funded by Novartis. Dr. Franz has received travel funding and honoraria from Novartis.
AT ANA 2017
Key clinical point:
Major finding: The response rate rose from 31% at week 18 to 57.7% at 2 years.
Data source: An extension study of a double-blind, randomized, placebo-controlled trial (n = 361).
Disclosures: The study was funded by Novartis. Dr. Franz has received travel funding and honoraria from Novartis.