Neurosurgery & Trauma

SAN DIEGO – The practice patterns for endovascular treatment of intracranial aneurysms appear to differ widely between sites inside and outside of North America, "likely reflecting practice variation rather than individual patient differences," according to Dr. Charles J. Prestigiacomo. "This is important to keep in mind when we’re establishing and designing multinational trials."

In terms of clinical outcomes, however, "everybody is doing very good work, no matter where you are in the world. I think that’s a testament to the technology and a testament to the physicians who are taking such good care of these patients," he said at the annual meeting of the Society of Neurointerventional Surgery.

Numerous international studies have shown that aneurysms can be safely and effectively treated via various coil types, "but we’ve had trouble trying to compare the efficacy of one international study with [that of] another, because there are differences in the primary end points of most of these studies," said Dr. Prestigiacomo, who chairs the department of neurological surgery at New Jersey Medical School, Newark. "The very low bleeding or rebleeding rates of treated aneurysms has led most investigators to use angiographic outcomes to compare devices. However, angiographic assessments are operator dependent and can potentially affect trial results."

In an effort to understand the impact of geography on aneurysm treatment, Dr. Prestigiacomo and his associates evaluated data from 626 patients who were enrolled in the MAPS (Matrix and Platinum Science) trial, a prospective, multicenter, multinational trial that compared bare platinum Guglielmi detachable coils and Matrix2 detachable coils, with the primary end point being target aneurysm recurrence. Patients were stratified into two groups: 407 who were treated at 28 North American (NA) sites, which included the United States, Canada, and Mexico, and 219 who were treated at 15 international (INTL) sites, which included South America, Europe, Asia, and the Asia-Pacific region. The researchers analyzed baseline patient demographics, comorbidities, and aneurysm characteristics, and compared procedural complications and clinical and angiographic outcomes between the two groups.

Several patient demographic factors differed significantly between the NA and INTL groups, including the proportion of female patients (76% vs. 60%, respectively), patients with ruptured aneurysms (28% vs. 52%), white patients (86% vs. 72%), and patients with two or more cardiovascular risk factors (31% vs. 15%), all with a P value less than .0001. NA patients were also more likely than their INTL counterparts to have a Hunt and Hess scale grade III or IV aneurysm (33% vs. 21%; P = .0452), to have more posterior-circulation aneurysms treated (16% vs. 8%; P = .0064), to have more aneurysms with a neck size of 4 mm or larger (39% vs. 31%; P = .0353), and to have more patients older than 55 years (54% vs. 40%; P = .0014).

The researchers found that a similar proportion of patients in the NA and INTL groups were alive and living independently at 1 year after the procedure (90% vs. 91% among those with ruptured aneurysms, respectively, and 95% vs. 97% among those with unruptured aneurysms), whereas a higher proportion of NA patients with ruptured aneurysms were discharged within 30 days, compared with their INTL counterparts (89% vs. 72%; P = .007). "I don’t think that is because of a clinical issue with the patients; it’s more of an issue of the health care system within the INTL community vs. the NA community," Dr. Prestigiacomo said.

Immediately post procedure, there was a lower incidence of complete or near complete occlusion in the NA group, compared with the INTL group (56% vs. 73%, respectively; P = .0002). The packing density of more than 25% was similar (43% vs. 39%) and the use of stents was more common in the NA group (45% vs. 19%; P less than .0001).

When the researchers evaluated 1-year angiographic outcomes, they noted no differences between the NA and INTL groups in the incidence of residual aneurysm (37% vs. 29%, respectively; P = .08) and retreatment rates for unruptured aneurysms (11% vs. 7%; P = .2285). But retreatment for ruptured aneurysms occurred significantly more often among those in the NA group than in the INTL group (22% vs. 4%; P = .001).

"When you look at when patients were treated, in North America there seems to be a higher probability of treating recurrent aneurysms within 1 year, and then the lines converge at 2 years," Dr. Prestigiacomo said. "In part, these differences may exist because there is a higher incidence of unruptured aneurysms in the North American population."

Dr. Prestigiacomo disclosed that he is a consultant for Stryker and Aesculap. He is also a member of the scientific advisory board for Thermopeutix and Edge Therapeutics, and is a board member of the International Brain Research Foundation.

SAN DIEGO – The practice patterns for endovascular treatment of intracranial aneurysms appear to differ widely between sites inside and outside of North America, "likely reflecting practice variation rather than individual patient differences," according to Dr. Charles J. Prestigiacomo. "This is important to keep in mind when we’re establishing and designing multinational trials."

In terms of clinical outcomes, however, "everybody is doing very good work, no matter where you are in the world. I think that’s a testament to the technology and a testament to the physicians who are taking such good care of these patients," he said at the annual meeting of the Society of Neurointerventional Surgery.

Numerous international studies have shown that aneurysms can be safely and effectively treated via various coil types, "but we’ve had trouble trying to compare the efficacy of one international study with [that of] another, because there are differences in the primary end points of most of these studies," said Dr. Prestigiacomo, who chairs the department of neurological surgery at New Jersey Medical School, Newark. "The very low bleeding or rebleeding rates of treated aneurysms has led most investigators to use angiographic outcomes to compare devices. However, angiographic assessments are operator dependent and can potentially affect trial results."

In an effort to understand the impact of geography on aneurysm treatment, Dr. Prestigiacomo and his associates evaluated data from 626 patients who were enrolled in the MAPS (Matrix and Platinum Science) trial, a prospective, multicenter, multinational trial that compared bare platinum Guglielmi detachable coils and Matrix2 detachable coils, with the primary end point being target aneurysm recurrence. Patients were stratified into two groups: 407 who were treated at 28 North American (NA) sites, which included the United States, Canada, and Mexico, and 219 who were treated at 15 international (INTL) sites, which included South America, Europe, Asia, and the Asia-Pacific region. The researchers analyzed baseline patient demographics, comorbidities, and aneurysm characteristics, and compared procedural complications and clinical and angiographic outcomes between the two groups.

Several patient demographic factors differed significantly between the NA and INTL groups, including the proportion of female patients (76% vs. 60%, respectively), patients with ruptured aneurysms (28% vs. 52%), white patients (86% vs. 72%), and patients with two or more cardiovascular risk factors (31% vs. 15%), all with a P value less than .0001. NA patients were also more likely than their INTL counterparts to have a Hunt and Hess scale grade III or IV aneurysm (33% vs. 21%; P = .0452), to have more posterior-circulation aneurysms treated (16% vs. 8%; P = .0064), to have more aneurysms with a neck size of 4 mm or larger (39% vs. 31%; P = .0353), and to have more patients older than 55 years (54% vs. 40%; P = .0014).

The researchers found that a similar proportion of patients in the NA and INTL groups were alive and living independently at 1 year after the procedure (90% vs. 91% among those with ruptured aneurysms, respectively, and 95% vs. 97% among those with unruptured aneurysms), whereas a higher proportion of NA patients with ruptured aneurysms were discharged within 30 days, compared with their INTL counterparts (89% vs. 72%; P = .007). "I don’t think that is because of a clinical issue with the patients; it’s more of an issue of the health care system within the INTL community vs. the NA community," Dr. Prestigiacomo said.

Immediately post procedure, there was a lower incidence of complete or near complete occlusion in the NA group, compared with the INTL group (56% vs. 73%, respectively; P = .0002). The packing density of more than 25% was similar (43% vs. 39%) and the use of stents was more common in the NA group (45% vs. 19%; P less than .0001).

When the researchers evaluated 1-year angiographic outcomes, they noted no differences between the NA and INTL groups in the incidence of residual aneurysm (37% vs. 29%, respectively; P = .08) and retreatment rates for unruptured aneurysms (11% vs. 7%; P = .2285). But retreatment for ruptured aneurysms occurred significantly more often among those in the NA group than in the INTL group (22% vs. 4%; P = .001).

"When you look at when patients were treated, in North America there seems to be a higher probability of treating recurrent aneurysms within 1 year, and then the lines converge at 2 years," Dr. Prestigiacomo said. "In part, these differences may exist because there is a higher incidence of unruptured aneurysms in the North American population."

Dr. Prestigiacomo disclosed that he is a consultant for Stryker and Aesculap. He is also a member of the scientific advisory board for Thermopeutix and Edge Therapeutics, and is a board member of the International Brain Research Foundation.

SAN DIEGO – The practice patterns for endovascular treatment of intracranial aneurysms appear to differ widely between sites inside and outside of North America, "likely reflecting practice variation rather than individual patient differences," according to Dr. Charles J. Prestigiacomo. "This is important to keep in mind when we’re establishing and designing multinational trials."

In terms of clinical outcomes, however, "everybody is doing very good work, no matter where you are in the world. I think that’s a testament to the technology and a testament to the physicians who are taking such good care of these patients," he said at the annual meeting of the Society of Neurointerventional Surgery.

Numerous international studies have shown that aneurysms can be safely and effectively treated via various coil types, "but we’ve had trouble trying to compare the efficacy of one international study with [that of] another, because there are differences in the primary end points of most of these studies," said Dr. Prestigiacomo, who chairs the department of neurological surgery at New Jersey Medical School, Newark. "The very low bleeding or rebleeding rates of treated aneurysms has led most investigators to use angiographic outcomes to compare devices. However, angiographic assessments are operator dependent and can potentially affect trial results."

In an effort to understand the impact of geography on aneurysm treatment, Dr. Prestigiacomo and his associates evaluated data from 626 patients who were enrolled in the MAPS (Matrix and Platinum Science) trial, a prospective, multicenter, multinational trial that compared bare platinum Guglielmi detachable coils and Matrix2 detachable coils, with the primary end point being target aneurysm recurrence. Patients were stratified into two groups: 407 who were treated at 28 North American (NA) sites, which included the United States, Canada, and Mexico, and 219 who were treated at 15 international (INTL) sites, which included South America, Europe, Asia, and the Asia-Pacific region. The researchers analyzed baseline patient demographics, comorbidities, and aneurysm characteristics, and compared procedural complications and clinical and angiographic outcomes between the two groups.

Several patient demographic factors differed significantly between the NA and INTL groups, including the proportion of female patients (76% vs. 60%, respectively), patients with ruptured aneurysms (28% vs. 52%), white patients (86% vs. 72%), and patients with two or more cardiovascular risk factors (31% vs. 15%), all with a P value less than .0001. NA patients were also more likely than their INTL counterparts to have a Hunt and Hess scale grade III or IV aneurysm (33% vs. 21%; P = .0452), to have more posterior-circulation aneurysms treated (16% vs. 8%; P = .0064), to have more aneurysms with a neck size of 4 mm or larger (39% vs. 31%; P = .0353), and to have more patients older than 55 years (54% vs. 40%; P = .0014).

The researchers found that a similar proportion of patients in the NA and INTL groups were alive and living independently at 1 year after the procedure (90% vs. 91% among those with ruptured aneurysms, respectively, and 95% vs. 97% among those with unruptured aneurysms), whereas a higher proportion of NA patients with ruptured aneurysms were discharged within 30 days, compared with their INTL counterparts (89% vs. 72%; P = .007). "I don’t think that is because of a clinical issue with the patients; it’s more of an issue of the health care system within the INTL community vs. the NA community," Dr. Prestigiacomo said.

Immediately post procedure, there was a lower incidence of complete or near complete occlusion in the NA group, compared with the INTL group (56% vs. 73%, respectively; P = .0002). The packing density of more than 25% was similar (43% vs. 39%) and the use of stents was more common in the NA group (45% vs. 19%; P less than .0001).

When the researchers evaluated 1-year angiographic outcomes, they noted no differences between the NA and INTL groups in the incidence of residual aneurysm (37% vs. 29%, respectively; P = .08) and retreatment rates for unruptured aneurysms (11% vs. 7%; P = .2285). But retreatment for ruptured aneurysms occurred significantly more often among those in the NA group than in the INTL group (22% vs. 4%; P = .001).

"When you look at when patients were treated, in North America there seems to be a higher probability of treating recurrent aneurysms within 1 year, and then the lines converge at 2 years," Dr. Prestigiacomo said. "In part, these differences may exist because there is a higher incidence of unruptured aneurysms in the North American population."

Dr. Prestigiacomo disclosed that he is a consultant for Stryker and Aesculap. He is also a member of the scientific advisory board for Thermopeutix and Edge Therapeutics, and is a board member of the International Brain Research Foundation.

HOUSTON – Growth hormone deficiency appears to be common among military veterans with mild traumatic brain injury sustained in combat, according to the first study to look at the issue.

Future studies will attempt to confirm the new finding that GH deficiency in the setting of traumatic brain injury (TBI) appears to be associated with specific neuropsychologic abnormalities, and, further, whether GH replacement therapy in affected veterans enhances TBI rehabilitation efforts, according to Dr. Adriana G. Ioachimescu of Emory University, Atlanta.

At the annual meeting of the Endocrine Society, she presented the results of a pilot study of 20 men (mean age, 34 years) with mild TBI resulting from military combat. The last injury occurred an average of 44 months earlier.

Five subjects, or 25%, were GH deficient on the basis of a peak value of less than 3 ng/mL in response to a glucagon stimulation test. One GH-deficient veteran also had an abnormally low insulin-like growth factor-1 level. But all subjects had normal thyroid status and cortisol function.

Four GH-deficient men and 12 GH-sufficient men were able to put enough effort into their neuropsychologic testing for the results to be valid. The two groups performed similarly on measures of memory, learning, and simple and complex attention.

In contrast, GH deficiency appeared to be associated with executive dysfunction, as manifest in worse performance on measures of inhibitory control and self-monitoring. Depression also was more severe in the GH-deficient men, although they did not experience greater levels of fatigue or posttraumatic stress disorder. The GH-deficient group also scored significantly lower on a validated quality-of-life measure.

This study was supported by Novo Nordisk. The presenter reported having no financial conflicts.

HOUSTON – Growth hormone deficiency appears to be common among military veterans with mild traumatic brain injury sustained in combat, according to the first study to look at the issue.

Future studies will attempt to confirm the new finding that GH deficiency in the setting of traumatic brain injury (TBI) appears to be associated with specific neuropsychologic abnormalities, and, further, whether GH replacement therapy in affected veterans enhances TBI rehabilitation efforts, according to Dr. Adriana G. Ioachimescu of Emory University, Atlanta.

At the annual meeting of the Endocrine Society, she presented the results of a pilot study of 20 men (mean age, 34 years) with mild TBI resulting from military combat. The last injury occurred an average of 44 months earlier.

Five subjects, or 25%, were GH deficient on the basis of a peak value of less than 3 ng/mL in response to a glucagon stimulation test. One GH-deficient veteran also had an abnormally low insulin-like growth factor-1 level. But all subjects had normal thyroid status and cortisol function.

Four GH-deficient men and 12 GH-sufficient men were able to put enough effort into their neuropsychologic testing for the results to be valid. The two groups performed similarly on measures of memory, learning, and simple and complex attention.

In contrast, GH deficiency appeared to be associated with executive dysfunction, as manifest in worse performance on measures of inhibitory control and self-monitoring. Depression also was more severe in the GH-deficient men, although they did not experience greater levels of fatigue or posttraumatic stress disorder. The GH-deficient group also scored significantly lower on a validated quality-of-life measure.

This study was supported by Novo Nordisk. The presenter reported having no financial conflicts.

HOUSTON – Growth hormone deficiency appears to be common among military veterans with mild traumatic brain injury sustained in combat, according to the first study to look at the issue.

Future studies will attempt to confirm the new finding that GH deficiency in the setting of traumatic brain injury (TBI) appears to be associated with specific neuropsychologic abnormalities, and, further, whether GH replacement therapy in affected veterans enhances TBI rehabilitation efforts, according to Dr. Adriana G. Ioachimescu of Emory University, Atlanta.

At the annual meeting of the Endocrine Society, she presented the results of a pilot study of 20 men (mean age, 34 years) with mild TBI resulting from military combat. The last injury occurred an average of 44 months earlier.

Five subjects, or 25%, were GH deficient on the basis of a peak value of less than 3 ng/mL in response to a glucagon stimulation test. One GH-deficient veteran also had an abnormally low insulin-like growth factor-1 level. But all subjects had normal thyroid status and cortisol function.

Four GH-deficient men and 12 GH-sufficient men were able to put enough effort into their neuropsychologic testing for the results to be valid. The two groups performed similarly on measures of memory, learning, and simple and complex attention.

In contrast, GH deficiency appeared to be associated with executive dysfunction, as manifest in worse performance on measures of inhibitory control and self-monitoring. Depression also was more severe in the GH-deficient men, although they did not experience greater levels of fatigue or posttraumatic stress disorder. The GH-deficient group also scored significantly lower on a validated quality-of-life measure.

This study was supported by Novo Nordisk. The presenter reported having no financial conflicts.

SAN DIEGO – Stroke patients who are likely to benefit from endovascular reperfusion can be identified on the basis of their MRI profile, results from a multicenter study demonstrated.

"These results are largely independent of stroke onset time," Dr. Michael P. Marks said at the annual meeting of the Society of Neurointerventional Surgery. "Our belief is that if the right patients are identified, it can be shown that endovascular therapy will be of benefit in the treatment of their acute strokes."

Endovascular treatment is increasingly used in the management of acute stroke, said Dr. Marks, an interventional neuroradiologist at Stanford (Calif.) University. "A randomized trial has shown benefit for intra-arterial thrombolytic agents in this setting," he said (JAMA 1999;282:2003-11). "Single-armed prospective studies have shown that thrombectomy devices improve outcome in patients when reperfusion is successfully attained. Nevertheless, tremendous controversy exists because there is an absence of any study with randomized data and concurrent controls. In addition, many questions remain as to which candidates are best suited for revascularization and whether imaging can help identify those patients," Dr. Marks said.

Against this backdrop, he and his associates at nine clinical sites carried out the DEFUSE-2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study-2) to identify patients who might fit into a randomized controlled trial. DEFUSE-2 is a prospective study of acute stroke patients who underwent endovascular therapy following MRI. The primary hypothesis was that a target mismatch profile (TMM) could be identified where patients had a relatively small area of injured tissue as seen on diffusion-weighted imaging (DWI) relative to a larger volume of ischemic tissue that was still salvageable as identified by perfusion-weighted imaging (PWI); and that patients with a TMM would respond more favorably to endovascular reperfusion therapy than patients without a TMM.

To be eligible for the trial, patients had to have endovascular therapy started within 12 hours of an anterior circulation stroke. They underwent a baseline MRI within 90 minutes of endovascular therapy, a second MRI following reperfusion in the catheter lab, and a third MRI at 5 days to assess infarct volume. This was followed by clinical assessments at day 30 and day 90 using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).

A TMM was defined as PWI volume over the DWI volume of 1.8 or greater, when the PWI volume had a Tmax of more than 6 seconds. PWI reperfusion was defined as a reduction in PWI lesion volume of greater than 50% between baseline and follow-up.

The investigators defined reperfusion as a Thrombolysis in Cerebral Infarction (TICI) score of 2b or 3. In this study, TICI 1 was defined as perfusion past the initial obstruction but little or slow distal perfusion with limited branch filling. TICI 2a was defined as partial perfusion of less than half of the vascular distribution of the occluded artery, TICI 2b was defined as partial perfusion of half or more of the vascular distribution of the occluded artery, and TICI 3 was defined as full perfusion filling of all distal branches.

Dr. Marks reported on outcomes from 78 patients who had a target mismatch and 21 who did not have a target mismatch. The researchers found that reperfusion was associated with a significantly increased odds of a favorable clinical response (odds ratio, 2.8), which was defined as an improvement in NIHSS score between baseline and day 30 of 8 points or more, or an NIHSS score of 0-1 at day 30. This outcome was driven by the target mismatch group, which had significantly greater odds of a favorable response to reperfusion than the no target mismatch group (OR, 5.0 vs. 0.2; P = .004).

A significantly higher percentage of patients in the target mismatch group achieved a 90-day mRS of 0-2 when there was reperfusion, compared with their counterparts in the no target mismatch group (57% vs. 25%), as well as when there was no reperfusion (31% vs. 22%).

The median time to the onset of vascular therapy was 6 hours. "When we divided patients into those started less than 6 hours versus those started greater than 6 hours, the results were very comparable," he said.

Dr. Marks also reported that by day 90, 29% of patients a TICI score of 0-1 achieved an mRS score of 0-2, compared with 25% of patients with a TICI score of 2a, 61% of patients with a score of 2b, and 50% of those with a score of 3. "This was driven by having a target mismatch," he said.

Dr. Marks and his associates are proposing a randomized controlled trial in which the primary hypothesis is that treatment with an approved thrombectomy device within 18-24 hours is more likely to result in a good clinical outcome at 90 days when patients are selected on the basis of a favorable MRI profile.

"The time is right to do this study, because current stentrievers have a high rate of recanalization," Dr. Marks said. "Physiologic imaging can identify patients who will benefit from recanalization in an extended time period."

DEFUSE-2 was funded by the National Institute of Neurological Disorders and Stroke. Dr. Marks said that he had no relevant financial conflicts to disclose.

SAN DIEGO – Stroke patients who are likely to benefit from endovascular reperfusion can be identified on the basis of their MRI profile, results from a multicenter study demonstrated.

"These results are largely independent of stroke onset time," Dr. Michael P. Marks said at the annual meeting of the Society of Neurointerventional Surgery. "Our belief is that if the right patients are identified, it can be shown that endovascular therapy will be of benefit in the treatment of their acute strokes."

Endovascular treatment is increasingly used in the management of acute stroke, said Dr. Marks, an interventional neuroradiologist at Stanford (Calif.) University. "A randomized trial has shown benefit for intra-arterial thrombolytic agents in this setting," he said (JAMA 1999;282:2003-11). "Single-armed prospective studies have shown that thrombectomy devices improve outcome in patients when reperfusion is successfully attained. Nevertheless, tremendous controversy exists because there is an absence of any study with randomized data and concurrent controls. In addition, many questions remain as to which candidates are best suited for revascularization and whether imaging can help identify those patients," Dr. Marks said.

Against this backdrop, he and his associates at nine clinical sites carried out the DEFUSE-2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study-2) to identify patients who might fit into a randomized controlled trial. DEFUSE-2 is a prospective study of acute stroke patients who underwent endovascular therapy following MRI. The primary hypothesis was that a target mismatch profile (TMM) could be identified where patients had a relatively small area of injured tissue as seen on diffusion-weighted imaging (DWI) relative to a larger volume of ischemic tissue that was still salvageable as identified by perfusion-weighted imaging (PWI); and that patients with a TMM would respond more favorably to endovascular reperfusion therapy than patients without a TMM.

To be eligible for the trial, patients had to have endovascular therapy started within 12 hours of an anterior circulation stroke. They underwent a baseline MRI within 90 minutes of endovascular therapy, a second MRI following reperfusion in the catheter lab, and a third MRI at 5 days to assess infarct volume. This was followed by clinical assessments at day 30 and day 90 using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).

A TMM was defined as PWI volume over the DWI volume of 1.8 or greater, when the PWI volume had a Tmax of more than 6 seconds. PWI reperfusion was defined as a reduction in PWI lesion volume of greater than 50% between baseline and follow-up.

The investigators defined reperfusion as a Thrombolysis in Cerebral Infarction (TICI) score of 2b or 3. In this study, TICI 1 was defined as perfusion past the initial obstruction but little or slow distal perfusion with limited branch filling. TICI 2a was defined as partial perfusion of less than half of the vascular distribution of the occluded artery, TICI 2b was defined as partial perfusion of half or more of the vascular distribution of the occluded artery, and TICI 3 was defined as full perfusion filling of all distal branches.

Dr. Marks reported on outcomes from 78 patients who had a target mismatch and 21 who did not have a target mismatch. The researchers found that reperfusion was associated with a significantly increased odds of a favorable clinical response (odds ratio, 2.8), which was defined as an improvement in NIHSS score between baseline and day 30 of 8 points or more, or an NIHSS score of 0-1 at day 30. This outcome was driven by the target mismatch group, which had significantly greater odds of a favorable response to reperfusion than the no target mismatch group (OR, 5.0 vs. 0.2; P = .004).

A significantly higher percentage of patients in the target mismatch group achieved a 90-day mRS of 0-2 when there was reperfusion, compared with their counterparts in the no target mismatch group (57% vs. 25%), as well as when there was no reperfusion (31% vs. 22%).

The median time to the onset of vascular therapy was 6 hours. "When we divided patients into those started less than 6 hours versus those started greater than 6 hours, the results were very comparable," he said.

Dr. Marks also reported that by day 90, 29% of patients a TICI score of 0-1 achieved an mRS score of 0-2, compared with 25% of patients with a TICI score of 2a, 61% of patients with a score of 2b, and 50% of those with a score of 3. "This was driven by having a target mismatch," he said.

Dr. Marks and his associates are proposing a randomized controlled trial in which the primary hypothesis is that treatment with an approved thrombectomy device within 18-24 hours is more likely to result in a good clinical outcome at 90 days when patients are selected on the basis of a favorable MRI profile.

"The time is right to do this study, because current stentrievers have a high rate of recanalization," Dr. Marks said. "Physiologic imaging can identify patients who will benefit from recanalization in an extended time period."

DEFUSE-2 was funded by the National Institute of Neurological Disorders and Stroke. Dr. Marks said that he had no relevant financial conflicts to disclose.

SAN DIEGO – Stroke patients who are likely to benefit from endovascular reperfusion can be identified on the basis of their MRI profile, results from a multicenter study demonstrated.

"These results are largely independent of stroke onset time," Dr. Michael P. Marks said at the annual meeting of the Society of Neurointerventional Surgery. "Our belief is that if the right patients are identified, it can be shown that endovascular therapy will be of benefit in the treatment of their acute strokes."

Endovascular treatment is increasingly used in the management of acute stroke, said Dr. Marks, an interventional neuroradiologist at Stanford (Calif.) University. "A randomized trial has shown benefit for intra-arterial thrombolytic agents in this setting," he said (JAMA 1999;282:2003-11). "Single-armed prospective studies have shown that thrombectomy devices improve outcome in patients when reperfusion is successfully attained. Nevertheless, tremendous controversy exists because there is an absence of any study with randomized data and concurrent controls. In addition, many questions remain as to which candidates are best suited for revascularization and whether imaging can help identify those patients," Dr. Marks said.

Against this backdrop, he and his associates at nine clinical sites carried out the DEFUSE-2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study-2) to identify patients who might fit into a randomized controlled trial. DEFUSE-2 is a prospective study of acute stroke patients who underwent endovascular therapy following MRI. The primary hypothesis was that a target mismatch profile (TMM) could be identified where patients had a relatively small area of injured tissue as seen on diffusion-weighted imaging (DWI) relative to a larger volume of ischemic tissue that was still salvageable as identified by perfusion-weighted imaging (PWI); and that patients with a TMM would respond more favorably to endovascular reperfusion therapy than patients without a TMM.

To be eligible for the trial, patients had to have endovascular therapy started within 12 hours of an anterior circulation stroke. They underwent a baseline MRI within 90 minutes of endovascular therapy, a second MRI following reperfusion in the catheter lab, and a third MRI at 5 days to assess infarct volume. This was followed by clinical assessments at day 30 and day 90 using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).

A TMM was defined as PWI volume over the DWI volume of 1.8 or greater, when the PWI volume had a Tmax of more than 6 seconds. PWI reperfusion was defined as a reduction in PWI lesion volume of greater than 50% between baseline and follow-up.

The investigators defined reperfusion as a Thrombolysis in Cerebral Infarction (TICI) score of 2b or 3. In this study, TICI 1 was defined as perfusion past the initial obstruction but little or slow distal perfusion with limited branch filling. TICI 2a was defined as partial perfusion of less than half of the vascular distribution of the occluded artery, TICI 2b was defined as partial perfusion of half or more of the vascular distribution of the occluded artery, and TICI 3 was defined as full perfusion filling of all distal branches.

Dr. Marks reported on outcomes from 78 patients who had a target mismatch and 21 who did not have a target mismatch. The researchers found that reperfusion was associated with a significantly increased odds of a favorable clinical response (odds ratio, 2.8), which was defined as an improvement in NIHSS score between baseline and day 30 of 8 points or more, or an NIHSS score of 0-1 at day 30. This outcome was driven by the target mismatch group, which had significantly greater odds of a favorable response to reperfusion than the no target mismatch group (OR, 5.0 vs. 0.2; P = .004).

A significantly higher percentage of patients in the target mismatch group achieved a 90-day mRS of 0-2 when there was reperfusion, compared with their counterparts in the no target mismatch group (57% vs. 25%), as well as when there was no reperfusion (31% vs. 22%).

The median time to the onset of vascular therapy was 6 hours. "When we divided patients into those started less than 6 hours versus those started greater than 6 hours, the results were very comparable," he said.

Dr. Marks also reported that by day 90, 29% of patients a TICI score of 0-1 achieved an mRS score of 0-2, compared with 25% of patients with a TICI score of 2a, 61% of patients with a score of 2b, and 50% of those with a score of 3. "This was driven by having a target mismatch," he said.

Dr. Marks and his associates are proposing a randomized controlled trial in which the primary hypothesis is that treatment with an approved thrombectomy device within 18-24 hours is more likely to result in a good clinical outcome at 90 days when patients are selected on the basis of a favorable MRI profile.

"The time is right to do this study, because current stentrievers have a high rate of recanalization," Dr. Marks said. "Physiologic imaging can identify patients who will benefit from recanalization in an extended time period."

DEFUSE-2 was funded by the National Institute of Neurological Disorders and Stroke. Dr. Marks said that he had no relevant financial conflicts to disclose.

New labeling changes approved by the Food and Drug Administration limit the patients eligible for treatment with the Stryker Wingspan Stent System, according to a statement and safety communication issued by the agency on Aug. 8.

The changes specify the patients most likely to benefit from treatment with the stent system. Data from studies conducted since the system’s approval in 2005 suggest that the risks, including stroke and death, may outweigh the benefits for some patients, according to the press release.

"After careful consideration of available safety information, the FDA believes this device should remain available for this specific subgroup of patients who have exhausted other options," Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said in the statement.

Under the new label, the Wingspan system is approved only for patients aged 22-80 years who meet four specific criteria: two or more strokes despite aggressive medical management; a most recent stroke more than 7 days prior to planned treatment with the Wingspan system; 70%-99% stenosis (due to atherosclerosis of the intracranial artery related to the recurrent strokes); and good recovery from previous strokes, defined in part by a modified Rankin score of 3 or less before treatment with the Wingspan system.

According to the safety communication, the Wingspan system should not be used for "the treatment of stroke with an onset of symptoms within 7 days or less of treatment; or for the treatment of transient ischemic attacks (TIAs)."

The FDA approved the changes after reviewing data from the original clinical study, postapproval studies, and the SAMMPRIS (Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) study.

The safety communication states that "a patient may be treated with Wingspan only if its use has been approved in advance by the treating physician’s Institutional Review Board (IRB)," and that the physician is responsible for obtaining IRB approval before treating a patient with the Wingspan system.

Clinicians can report adverse events associated with the Wingspan system to the FDA via the MedWatch program. The safety communication can be viewed here.

New labeling changes approved by the Food and Drug Administration limit the patients eligible for treatment with the Stryker Wingspan Stent System, according to a statement and safety communication issued by the agency on Aug. 8.

The changes specify the patients most likely to benefit from treatment with the stent system. Data from studies conducted since the system’s approval in 2005 suggest that the risks, including stroke and death, may outweigh the benefits for some patients, according to the press release.

"After careful consideration of available safety information, the FDA believes this device should remain available for this specific subgroup of patients who have exhausted other options," Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said in the statement.

Under the new label, the Wingspan system is approved only for patients aged 22-80 years who meet four specific criteria: two or more strokes despite aggressive medical management; a most recent stroke more than 7 days prior to planned treatment with the Wingspan system; 70%-99% stenosis (due to atherosclerosis of the intracranial artery related to the recurrent strokes); and good recovery from previous strokes, defined in part by a modified Rankin score of 3 or less before treatment with the Wingspan system.

According to the safety communication, the Wingspan system should not be used for "the treatment of stroke with an onset of symptoms within 7 days or less of treatment; or for the treatment of transient ischemic attacks (TIAs)."

The FDA approved the changes after reviewing data from the original clinical study, postapproval studies, and the SAMMPRIS (Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) study.

The safety communication states that "a patient may be treated with Wingspan only if its use has been approved in advance by the treating physician’s Institutional Review Board (IRB)," and that the physician is responsible for obtaining IRB approval before treating a patient with the Wingspan system.

Clinicians can report adverse events associated with the Wingspan system to the FDA via the MedWatch program. The safety communication can be viewed here.

New labeling changes approved by the Food and Drug Administration limit the patients eligible for treatment with the Stryker Wingspan Stent System, according to a statement and safety communication issued by the agency on Aug. 8.

The changes specify the patients most likely to benefit from treatment with the stent system. Data from studies conducted since the system’s approval in 2005 suggest that the risks, including stroke and death, may outweigh the benefits for some patients, according to the press release.

"After careful consideration of available safety information, the FDA believes this device should remain available for this specific subgroup of patients who have exhausted other options," Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said in the statement.

Under the new label, the Wingspan system is approved only for patients aged 22-80 years who meet four specific criteria: two or more strokes despite aggressive medical management; a most recent stroke more than 7 days prior to planned treatment with the Wingspan system; 70%-99% stenosis (due to atherosclerosis of the intracranial artery related to the recurrent strokes); and good recovery from previous strokes, defined in part by a modified Rankin score of 3 or less before treatment with the Wingspan system.

According to the safety communication, the Wingspan system should not be used for "the treatment of stroke with an onset of symptoms within 7 days or less of treatment; or for the treatment of transient ischemic attacks (TIAs)."

The FDA approved the changes after reviewing data from the original clinical study, postapproval studies, and the SAMMPRIS (Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) study.

The safety communication states that "a patient may be treated with Wingspan only if its use has been approved in advance by the treating physician’s Institutional Review Board (IRB)," and that the physician is responsible for obtaining IRB approval before treating a patient with the Wingspan system.

Clinicians can report adverse events associated with the Wingspan system to the FDA via the MedWatch program. The safety communication can be viewed here.

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.

A mathematical model that estimates intracranial pressure using measurements of arterial blood pressure and middle cerebral artery blood flow velocity provided accurate readings in a retrospective, proof-of-concept study of patients with severe traumatic brain injury.

This model-based approach for noninvasive intracranial pressure (ICP) monitoring, which allows near-real-time estimation, does not require patient-specific calibration or training on a reference population. These features make it an improvement over previously tested methods for noninvasively measuring ICP, such as sensing tympanic membrane displacement, measuring the diameter of the optic nerve sheath, or applying external pressure to the eyeball while monitoring ophthalmic artery flow.

Thomas Heldt, Ph.D., and Faisal M. Kashif, Ph.D., of the Massachusetts Institute of Technology, Cambridge, worked with colleagues at the University of Cambridge (England) and at Beth Israel Deaconess Medical Center, Boston, to obtain and analyze a data set of 35 hours of simultaneous recordings of arterial blood pressure from radial artery catheterization (used as a surrogate for arterial blood pressure in the brain), cerebral blood flow velocity from transcranial Doppler ultrasound, and ICP measurements from an indwelling parenchymal probe in 37 comatose patients with severe closed head injury (Sci. Transl. Med. 2012;4:129ra44). None of the patients had a significant stenosis in the vasculature between the radial artery and the middle cerebral artery, which would affect arterial blood pressure measurements. Within each time window of 60 heartbeats that the investigators used to estimate ICP, they ignored the production of cerebrospinal fluid, but they accounted for it when providing longer estimates of ICP across nonoverlapping time windows.

In an estimate of the ICP over 10 consecutive 60-beat windows of data for each patient, there was an error of 1.6 mm Hg and a standard deviation error of 6.9 mm Hg. In 30 patients who had bilateral, rather than just unilateral, cerebral blood flow velocity recordings, the results improved to an error of 1.5 mm Hg and a standard deviation error of 4.9 mm Hg. The individual ICP estimates for each of the patient records, rather than just the data windows, gave results of 0.9 mm Hg and 6.5 mm Hg, respectively. The estimates performed well with pressures up to 100 mm Hg.

The model could identify ICP greater than 20 mm Hg – a commonly used threshold for treatment in traumatic brain injury – with 83% sensitivity and 70% specificity for all data sets combined. On a patient-record basis, a threshold of greater than 20 mm Hg gave 90% sensitivity and 80% specificity.

"The feedback that we’ve gotten from our clinical colleagues is that they are very encouraged by the statistics and accuracy that our method shows, that we’re getting within range of what is clinically acceptable, but we’re not there yet," Dr. Heldt said in an interview.

The technique for estimating ICP makes it possible to perform spot assessments or intermittent monitoring, or obtain "accurate estimation of the trend in ICP" over a period of hours, Dr. Heldt said.

Dr. Stephan A. Mayer, head of the division of critical care neurology at the Neurological Institute of New York at Columbia University Medical Center, agreed, noting that "noninvasive ICP monitoring doesn’t even have to be that precise," particularly if it is accurate enough to screen patients for elevated ICP who may need invasive monitoring.

But the many attempts to develop a noninvasive approach to ICP monitoring over the past 20 years have suffered from problems of reproducibility of results in different settings, said Dr. Mayer, who was not involved in the study. "The real trick is going to be who can make it simple and work in the hands of anybody with minimal expertise," he said in an interview.

Dr. Heldt and his colleagues are planning to work with colleagues at Beth Israel Deaconess Medical Center to validate their model further in subarachnoid hemorrhage patients. Future work would also try to examine other injuries to the brain to see if there are particular pathologies or patient profiles where the model breaks down. If the method is validated in those studies, Dr. Heldt said the researchers plan to try it in conditions where ICP data are not already available for comparison, such as in chronic migraine, headaches, or certain kinds of visual disorders.

"We currently do not have a way of assessing ICP in these kinds of conditions, and don’t really know if ICP is a contributing factor or might even be a causative factor," Dr. Heldt said.

The study was supported by grants from the National Institutes of Health and the Center for Integration of Medicine and Innovative Technology. Massachusetts Institute of Technology has filed patent applications for the algorithms involved, listing several authors as coinventors. One of the authors has a financial interest in a software package for multimodal neurointensive care monitoring, which has a commercially available noninvasive ICP plug-in. Dr. Mayer said that he is on the scientific advisory board for Orsan Medical Technologies, an Israeli start-up company that is developing noninvasive ICP technology. He also receives research support from Noninvasive ICP Technologies.

This column, "Neuroscience Today, Neurology Tomorrow," appears regularly in Clinical Neurology News, a publication of Elsevier.

A mathematical model that estimates intracranial pressure using measurements of arterial blood pressure and middle cerebral artery blood flow velocity provided accurate readings in a retrospective, proof-of-concept study of patients with severe traumatic brain injury.

This model-based approach for noninvasive intracranial pressure (ICP) monitoring, which allows near-real-time estimation, does not require patient-specific calibration or training on a reference population. These features make it an improvement over previously tested methods for noninvasively measuring ICP, such as sensing tympanic membrane displacement, measuring the diameter of the optic nerve sheath, or applying external pressure to the eyeball while monitoring ophthalmic artery flow.

Thomas Heldt, Ph.D., and Faisal M. Kashif, Ph.D., of the Massachusetts Institute of Technology, Cambridge, worked with colleagues at the University of Cambridge (England) and at Beth Israel Deaconess Medical Center, Boston, to obtain and analyze a data set of 35 hours of simultaneous recordings of arterial blood pressure from radial artery catheterization (used as a surrogate for arterial blood pressure in the brain), cerebral blood flow velocity from transcranial Doppler ultrasound, and ICP measurements from an indwelling parenchymal probe in 37 comatose patients with severe closed head injury (Sci. Transl. Med. 2012;4:129ra44). None of the patients had a significant stenosis in the vasculature between the radial artery and the middle cerebral artery, which would affect arterial blood pressure measurements. Within each time window of 60 heartbeats that the investigators used to estimate ICP, they ignored the production of cerebrospinal fluid, but they accounted for it when providing longer estimates of ICP across nonoverlapping time windows.

In an estimate of the ICP over 10 consecutive 60-beat windows of data for each patient, there was an error of 1.6 mm Hg and a standard deviation error of 6.9 mm Hg. In 30 patients who had bilateral, rather than just unilateral, cerebral blood flow velocity recordings, the results improved to an error of 1.5 mm Hg and a standard deviation error of 4.9 mm Hg. The individual ICP estimates for each of the patient records, rather than just the data windows, gave results of 0.9 mm Hg and 6.5 mm Hg, respectively. The estimates performed well with pressures up to 100 mm Hg.

The model could identify ICP greater than 20 mm Hg – a commonly used threshold for treatment in traumatic brain injury – with 83% sensitivity and 70% specificity for all data sets combined. On a patient-record basis, a threshold of greater than 20 mm Hg gave 90% sensitivity and 80% specificity.

"The feedback that we’ve gotten from our clinical colleagues is that they are very encouraged by the statistics and accuracy that our method shows, that we’re getting within range of what is clinically acceptable, but we’re not there yet," Dr. Heldt said in an interview.

The technique for estimating ICP makes it possible to perform spot assessments or intermittent monitoring, or obtain "accurate estimation of the trend in ICP" over a period of hours, Dr. Heldt said.

Dr. Stephan A. Mayer, head of the division of critical care neurology at the Neurological Institute of New York at Columbia University Medical Center, agreed, noting that "noninvasive ICP monitoring doesn’t even have to be that precise," particularly if it is accurate enough to screen patients for elevated ICP who may need invasive monitoring.

But the many attempts to develop a noninvasive approach to ICP monitoring over the past 20 years have suffered from problems of reproducibility of results in different settings, said Dr. Mayer, who was not involved in the study. "The real trick is going to be who can make it simple and work in the hands of anybody with minimal expertise," he said in an interview.

Dr. Heldt and his colleagues are planning to work with colleagues at Beth Israel Deaconess Medical Center to validate their model further in subarachnoid hemorrhage patients. Future work would also try to examine other injuries to the brain to see if there are particular pathologies or patient profiles where the model breaks down. If the method is validated in those studies, Dr. Heldt said the researchers plan to try it in conditions where ICP data are not already available for comparison, such as in chronic migraine, headaches, or certain kinds of visual disorders.

"We currently do not have a way of assessing ICP in these kinds of conditions, and don’t really know if ICP is a contributing factor or might even be a causative factor," Dr. Heldt said.

The study was supported by grants from the National Institutes of Health and the Center for Integration of Medicine and Innovative Technology. Massachusetts Institute of Technology has filed patent applications for the algorithms involved, listing several authors as coinventors. One of the authors has a financial interest in a software package for multimodal neurointensive care monitoring, which has a commercially available noninvasive ICP plug-in. Dr. Mayer said that he is on the scientific advisory board for Orsan Medical Technologies, an Israeli start-up company that is developing noninvasive ICP technology. He also receives research support from Noninvasive ICP Technologies.

This column, "Neuroscience Today, Neurology Tomorrow," appears regularly in Clinical Neurology News, a publication of Elsevier.

A mathematical model that estimates intracranial pressure using measurements of arterial blood pressure and middle cerebral artery blood flow velocity provided accurate readings in a retrospective, proof-of-concept study of patients with severe traumatic brain injury.

This model-based approach for noninvasive intracranial pressure (ICP) monitoring, which allows near-real-time estimation, does not require patient-specific calibration or training on a reference population. These features make it an improvement over previously tested methods for noninvasively measuring ICP, such as sensing tympanic membrane displacement, measuring the diameter of the optic nerve sheath, or applying external pressure to the eyeball while monitoring ophthalmic artery flow.

Thomas Heldt, Ph.D., and Faisal M. Kashif, Ph.D., of the Massachusetts Institute of Technology, Cambridge, worked with colleagues at the University of Cambridge (England) and at Beth Israel Deaconess Medical Center, Boston, to obtain and analyze a data set of 35 hours of simultaneous recordings of arterial blood pressure from radial artery catheterization (used as a surrogate for arterial blood pressure in the brain), cerebral blood flow velocity from transcranial Doppler ultrasound, and ICP measurements from an indwelling parenchymal probe in 37 comatose patients with severe closed head injury (Sci. Transl. Med. 2012;4:129ra44). None of the patients had a significant stenosis in the vasculature between the radial artery and the middle cerebral artery, which would affect arterial blood pressure measurements. Within each time window of 60 heartbeats that the investigators used to estimate ICP, they ignored the production of cerebrospinal fluid, but they accounted for it when providing longer estimates of ICP across nonoverlapping time windows.

In an estimate of the ICP over 10 consecutive 60-beat windows of data for each patient, there was an error of 1.6 mm Hg and a standard deviation error of 6.9 mm Hg. In 30 patients who had bilateral, rather than just unilateral, cerebral blood flow velocity recordings, the results improved to an error of 1.5 mm Hg and a standard deviation error of 4.9 mm Hg. The individual ICP estimates for each of the patient records, rather than just the data windows, gave results of 0.9 mm Hg and 6.5 mm Hg, respectively. The estimates performed well with pressures up to 100 mm Hg.

The model could identify ICP greater than 20 mm Hg – a commonly used threshold for treatment in traumatic brain injury – with 83% sensitivity and 70% specificity for all data sets combined. On a patient-record basis, a threshold of greater than 20 mm Hg gave 90% sensitivity and 80% specificity.

"The feedback that we’ve gotten from our clinical colleagues is that they are very encouraged by the statistics and accuracy that our method shows, that we’re getting within range of what is clinically acceptable, but we’re not there yet," Dr. Heldt said in an interview.

The technique for estimating ICP makes it possible to perform spot assessments or intermittent monitoring, or obtain "accurate estimation of the trend in ICP" over a period of hours, Dr. Heldt said.

Dr. Stephan A. Mayer, head of the division of critical care neurology at the Neurological Institute of New York at Columbia University Medical Center, agreed, noting that "noninvasive ICP monitoring doesn’t even have to be that precise," particularly if it is accurate enough to screen patients for elevated ICP who may need invasive monitoring.

But the many attempts to develop a noninvasive approach to ICP monitoring over the past 20 years have suffered from problems of reproducibility of results in different settings, said Dr. Mayer, who was not involved in the study. "The real trick is going to be who can make it simple and work in the hands of anybody with minimal expertise," he said in an interview.

Dr. Heldt and his colleagues are planning to work with colleagues at Beth Israel Deaconess Medical Center to validate their model further in subarachnoid hemorrhage patients. Future work would also try to examine other injuries to the brain to see if there are particular pathologies or patient profiles where the model breaks down. If the method is validated in those studies, Dr. Heldt said the researchers plan to try it in conditions where ICP data are not already available for comparison, such as in chronic migraine, headaches, or certain kinds of visual disorders.

"We currently do not have a way of assessing ICP in these kinds of conditions, and don’t really know if ICP is a contributing factor or might even be a causative factor," Dr. Heldt said.

The study was supported by grants from the National Institutes of Health and the Center for Integration of Medicine and Innovative Technology. Massachusetts Institute of Technology has filed patent applications for the algorithms involved, listing several authors as coinventors. One of the authors has a financial interest in a software package for multimodal neurointensive care monitoring, which has a commercially available noninvasive ICP plug-in. Dr. Mayer said that he is on the scientific advisory board for Orsan Medical Technologies, an Israeli start-up company that is developing noninvasive ICP technology. He also receives research support from Noninvasive ICP Technologies.

This column, "Neuroscience Today, Neurology Tomorrow," appears regularly in Clinical Neurology News, a publication of Elsevier.

NEW ORLEANS – An investigative, minimally invasive surgery for reducing intracranial clot volume following an intracerebral hemorrhage showed promise in results from a phase II study.

In the controlled study, 54 patients who underwent clot removal by minimally-invasive surgery (MIS) had a 10% increased rate of achieving a modified Rankin Scale (mRS) score of 1-3 at 180 days, compared with 39 patients managed by conventional, medical therapy, Dr. Daniel F. Hanley said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

"These data may establish a surgical goal for MIS of reducing clot burden to 15 mL or less by 3-4 days" after the intracerebral hemorrhage (ICH), said Dr. Hanley, a professor of neurology and neurosurgery at Johns Hopkins University in Baltimore. The study enrolled patients within a day of their ICH with a clot volume of at least 20 mL; the average volume for the 93 patients was 40 mL.

The next step will be a pivotal, controlled study planned to enroll 500 patients at 35-50 centers, with an expected study duration of 5 years. Dr. Hanley and his associates are seeking funding for the phase III trial from the National Institutes of Health.

The MISTIE (Minimally Invasive [Stereotactic] Surgery and rTPA for ICH Extraction) study used a combination of intracerebrally infused recombinant tissue plasminogen activator (rTPA) and placement of a cannula into a patient’s skull to remove thrombolysed clot, a method that "has been around" for several years, but never before underwent assessment as a standardized procedure and in a prospective, controlled study, Dr. Hanley said in an interview. "MIS is widely available, and could be practical to use on ICH patients" once it is clearly shown to be safe and effective.

The study enrolled patients at 35 international sites who were 18-75 years old and had a spontaneous, supratentorial ICH with a stable clot. They also had received rTPA within 54 hours of their first diagnostic CT examination. The mean age of the enrolled patients was 61 years, two-thirds were men, and the patients randomized to MIS received their initial rTPA treatment an average of 48 hours after the ICH began. During an initial phase of the study patients received 0.3 mg of rTPA, but during the later phase the dose increased to 1.0 mg, the amount that most of the MIS patients received.

Safety data showed that patients treated with MIS had a 7-day mortality rate of 2 and a 30-day mortality of 15%, compared with a rate of 8% at 30 days in the medically-treated control patients. Symptomatic bleeds occurred in two of the MIS patients and one of the controls, and a brain infection occurred in none of the MIS patients and in one control patient. During follow-up out to 180 days, mortality rates were virtually identical, about 20%, in both arms of the study, and dropouts also reached similar levels in both arms, about 45%.

During their first 4 days in the study, MIS patients had an average 65% reduction in their intracerebral clot volume, compared with no change in the control patients. The two-thirds reduction with MIS corresponded to an average 28 mL drop in volume. Twenty-four surgeons participated in the study, and the analysis showed very little surgeon-to-surgeon variation in their ability to achieve clot-volume reductions. Roughly two-thirds of the surgeons had never previously performed the procedure, but each surgeon treated a run-in patient before the study formally began.

The study’s primary outcome was mRS at 180 days, with data available for 50 MIS patients and 33 controls. No patients in either group had an mRS of 0. An mRS of 1 occurred in two MIS patients and none of the controls. An mRS of 1-3 occurred in about 35% of the MIS patients and about 25% of the controls.

An analysis of all patients showed a strong link between clot volume after 4 days in the study and 180-day outcomes. The prespecified goal of MIS was removal of at least 15 mL of clot, and surgeons achieved this in about a third of the MIS patients. When patients attained that level of clot reduction, they had a statistically significant, 3.7-fold increased rate of having an mRS of 1-3 at 180 days, compared with patients who did not reach this goal.

The impact of MIS on outcome was even stronger in patients who entered the study with larger clots. Among the subgroup with a clot burden of at least 50 mL, MIS led to a 17% increased rate of patients achieving an mRS of 1-3, compared with the controls, Dr. Hanley said. Among patients treated medically, those with a clot burden on entry of about 20 mL often had an mRS of 1-3 at 180 days, but among those who began with a clot of at least 30 mL, only three patients reached an mRS of 1-3.

The MIS tested in the study used a frameless stereotactic technique that relied on an electromagnetic wave or infrared light system to guide surgical navigation. Several commercial forms of these systems exist; surgeons could use whichever they preferred, Dr. Hanley said.

The National Institute of Neurological Disorders and Stroke funded the trial. Dr. Hanley said that Johns Hopkins Medical Institutions holds a patent on intracerebral treatment with rTPA. He had no other disclosures.

NEW ORLEANS – An investigative, minimally invasive surgery for reducing intracranial clot volume following an intracerebral hemorrhage showed promise in results from a phase II study.

In the controlled study, 54 patients who underwent clot removal by minimally-invasive surgery (MIS) had a 10% increased rate of achieving a modified Rankin Scale (mRS) score of 1-3 at 180 days, compared with 39 patients managed by conventional, medical therapy, Dr. Daniel F. Hanley said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

"These data may establish a surgical goal for MIS of reducing clot burden to 15 mL or less by 3-4 days" after the intracerebral hemorrhage (ICH), said Dr. Hanley, a professor of neurology and neurosurgery at Johns Hopkins University in Baltimore. The study enrolled patients within a day of their ICH with a clot volume of at least 20 mL; the average volume for the 93 patients was 40 mL.

The next step will be a pivotal, controlled study planned to enroll 500 patients at 35-50 centers, with an expected study duration of 5 years. Dr. Hanley and his associates are seeking funding for the phase III trial from the National Institutes of Health.

The MISTIE (Minimally Invasive [Stereotactic] Surgery and rTPA for ICH Extraction) study used a combination of intracerebrally infused recombinant tissue plasminogen activator (rTPA) and placement of a cannula into a patient’s skull to remove thrombolysed clot, a method that "has been around" for several years, but never before underwent assessment as a standardized procedure and in a prospective, controlled study, Dr. Hanley said in an interview. "MIS is widely available, and could be practical to use on ICH patients" once it is clearly shown to be safe and effective.

The study enrolled patients at 35 international sites who were 18-75 years old and had a spontaneous, supratentorial ICH with a stable clot. They also had received rTPA within 54 hours of their first diagnostic CT examination. The mean age of the enrolled patients was 61 years, two-thirds were men, and the patients randomized to MIS received their initial rTPA treatment an average of 48 hours after the ICH began. During an initial phase of the study patients received 0.3 mg of rTPA, but during the later phase the dose increased to 1.0 mg, the amount that most of the MIS patients received.

Safety data showed that patients treated with MIS had a 7-day mortality rate of 2 and a 30-day mortality of 15%, compared with a rate of 8% at 30 days in the medically-treated control patients. Symptomatic bleeds occurred in two of the MIS patients and one of the controls, and a brain infection occurred in none of the MIS patients and in one control patient. During follow-up out to 180 days, mortality rates were virtually identical, about 20%, in both arms of the study, and dropouts also reached similar levels in both arms, about 45%.

During their first 4 days in the study, MIS patients had an average 65% reduction in their intracerebral clot volume, compared with no change in the control patients. The two-thirds reduction with MIS corresponded to an average 28 mL drop in volume. Twenty-four surgeons participated in the study, and the analysis showed very little surgeon-to-surgeon variation in their ability to achieve clot-volume reductions. Roughly two-thirds of the surgeons had never previously performed the procedure, but each surgeon treated a run-in patient before the study formally began.

The study’s primary outcome was mRS at 180 days, with data available for 50 MIS patients and 33 controls. No patients in either group had an mRS of 0. An mRS of 1 occurred in two MIS patients and none of the controls. An mRS of 1-3 occurred in about 35% of the MIS patients and about 25% of the controls.

An analysis of all patients showed a strong link between clot volume after 4 days in the study and 180-day outcomes. The prespecified goal of MIS was removal of at least 15 mL of clot, and surgeons achieved this in about a third of the MIS patients. When patients attained that level of clot reduction, they had a statistically significant, 3.7-fold increased rate of having an mRS of 1-3 at 180 days, compared with patients who did not reach this goal.

The impact of MIS on outcome was even stronger in patients who entered the study with larger clots. Among the subgroup with a clot burden of at least 50 mL, MIS led to a 17% increased rate of patients achieving an mRS of 1-3, compared with the controls, Dr. Hanley said. Among patients treated medically, those with a clot burden on entry of about 20 mL often had an mRS of 1-3 at 180 days, but among those who began with a clot of at least 30 mL, only three patients reached an mRS of 1-3.

The MIS tested in the study used a frameless stereotactic technique that relied on an electromagnetic wave or infrared light system to guide surgical navigation. Several commercial forms of these systems exist; surgeons could use whichever they preferred, Dr. Hanley said.

The National Institute of Neurological Disorders and Stroke funded the trial. Dr. Hanley said that Johns Hopkins Medical Institutions holds a patent on intracerebral treatment with rTPA. He had no other disclosures.

NEW ORLEANS – An investigative, minimally invasive surgery for reducing intracranial clot volume following an intracerebral hemorrhage showed promise in results from a phase II study.

In the controlled study, 54 patients who underwent clot removal by minimally-invasive surgery (MIS) had a 10% increased rate of achieving a modified Rankin Scale (mRS) score of 1-3 at 180 days, compared with 39 patients managed by conventional, medical therapy, Dr. Daniel F. Hanley said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

"These data may establish a surgical goal for MIS of reducing clot burden to 15 mL or less by 3-4 days" after the intracerebral hemorrhage (ICH), said Dr. Hanley, a professor of neurology and neurosurgery at Johns Hopkins University in Baltimore. The study enrolled patients within a day of their ICH with a clot volume of at least 20 mL; the average volume for the 93 patients was 40 mL.

The next step will be a pivotal, controlled study planned to enroll 500 patients at 35-50 centers, with an expected study duration of 5 years. Dr. Hanley and his associates are seeking funding for the phase III trial from the National Institutes of Health.

The MISTIE (Minimally Invasive [Stereotactic] Surgery and rTPA for ICH Extraction) study used a combination of intracerebrally infused recombinant tissue plasminogen activator (rTPA) and placement of a cannula into a patient’s skull to remove thrombolysed clot, a method that "has been around" for several years, but never before underwent assessment as a standardized procedure and in a prospective, controlled study, Dr. Hanley said in an interview. "MIS is widely available, and could be practical to use on ICH patients" once it is clearly shown to be safe and effective.

The study enrolled patients at 35 international sites who were 18-75 years old and had a spontaneous, supratentorial ICH with a stable clot. They also had received rTPA within 54 hours of their first diagnostic CT examination. The mean age of the enrolled patients was 61 years, two-thirds were men, and the patients randomized to MIS received their initial rTPA treatment an average of 48 hours after the ICH began. During an initial phase of the study patients received 0.3 mg of rTPA, but during the later phase the dose increased to 1.0 mg, the amount that most of the MIS patients received.

Safety data showed that patients treated with MIS had a 7-day mortality rate of 2 and a 30-day mortality of 15%, compared with a rate of 8% at 30 days in the medically-treated control patients. Symptomatic bleeds occurred in two of the MIS patients and one of the controls, and a brain infection occurred in none of the MIS patients and in one control patient. During follow-up out to 180 days, mortality rates were virtually identical, about 20%, in both arms of the study, and dropouts also reached similar levels in both arms, about 45%.

During their first 4 days in the study, MIS patients had an average 65% reduction in their intracerebral clot volume, compared with no change in the control patients. The two-thirds reduction with MIS corresponded to an average 28 mL drop in volume. Twenty-four surgeons participated in the study, and the analysis showed very little surgeon-to-surgeon variation in their ability to achieve clot-volume reductions. Roughly two-thirds of the surgeons had never previously performed the procedure, but each surgeon treated a run-in patient before the study formally began.

The study’s primary outcome was mRS at 180 days, with data available for 50 MIS patients and 33 controls. No patients in either group had an mRS of 0. An mRS of 1 occurred in two MIS patients and none of the controls. An mRS of 1-3 occurred in about 35% of the MIS patients and about 25% of the controls.

An analysis of all patients showed a strong link between clot volume after 4 days in the study and 180-day outcomes. The prespecified goal of MIS was removal of at least 15 mL of clot, and surgeons achieved this in about a third of the MIS patients. When patients attained that level of clot reduction, they had a statistically significant, 3.7-fold increased rate of having an mRS of 1-3 at 180 days, compared with patients who did not reach this goal.

The impact of MIS on outcome was even stronger in patients who entered the study with larger clots. Among the subgroup with a clot burden of at least 50 mL, MIS led to a 17% increased rate of patients achieving an mRS of 1-3, compared with the controls, Dr. Hanley said. Among patients treated medically, those with a clot burden on entry of about 20 mL often had an mRS of 1-3 at 180 days, but among those who began with a clot of at least 30 mL, only three patients reached an mRS of 1-3.

The MIS tested in the study used a frameless stereotactic technique that relied on an electromagnetic wave or infrared light system to guide surgical navigation. Several commercial forms of these systems exist; surgeons could use whichever they preferred, Dr. Hanley said.

The National Institute of Neurological Disorders and Stroke funded the trial. Dr. Hanley said that Johns Hopkins Medical Institutions holds a patent on intracerebral treatment with rTPA. He had no other disclosures.

Surgery was clearly superior to pharmacotherapy at relieving seizures in a study of patients with intractable mesial temporal lobe epilepsy who were no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs.

Though the study sample was small, with only 38 subjects, surgery also proved to be better at improving quality of life, allowing patients to drive vehicles, and increasing their socialization, according Dr. Jerome Engel Jr. of the University of California, Los Angeles, and his associates, whose report was published March 7 in JAMA.

"We found that the benefit of surgery in newly intractable epilepsy is very large (allowing it to be demonstrated in a small randomized trial)," and that patients who avoid surgery are very unlikely to improve with further pharmacotherapy. This probably raises their risk of death and of adverse psychological and social consequences, the investigators noted.

Surgery for epilepsy is often delayed for years or avoided altogether, in part because many consider it a last resort. "There is concern that surgery early in the course of mesial temporal lobe epilepsy could produce cognitive deficits in otherwise cognitively intact patients," Dr. Engel and his colleagues wrote.

In fact, this trial was terminated early solely because so few patients were being referred to the participating epilepsy centers for possible surgery that subject accrual was deemed inadequate.

But earlier surgery could prevent significant morbidity and even premature death. The American Academy of Neurology has recommended surgery as the treatment of choice for medically intractable epilepsy since 2003, but the excess lag time before surgical referral hasn’t decreased since then and still remains at more than 10 years.

The Early Randomized Surgical Epilepsy Trial (ERSET) was designed to compare the outcomes of surgery with those of continued pharmacotherapy, focusing on patients no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs. This interval was considered "a time when adverse psychological and social consequences of disabling seizures might be minimal, and seizures might conceivably still respond to further trials of AEDs [antiepileptic drugs]," the researchers wrote.

In all, 38 patients aged 12 years and older (mean age 34 years) with intractable, disabling seizures were referred from 16 medical centers and randomly assigned to continue pharmacotherapy (23 subjects) or to undergo en bloc resection of the anterior 3.5-4 cm of the lateral temporal lobe, sparing the superior temporal gyrus, followed by removal of the mesial structures (15 subjects). The patients were followed every 3 months for 2 years.

Despite efforts to include adolescent patients in this trial, only two were ultimately recruited, and both were randomly assigned to the pharmacotherapy group. Therefore it remains unknown whether the study results apply to adolescent patients.

Eleven (73%) of the 15 patients who underwent surgery were free from disabling seizures during the second year of follow-up (the primary outcome of the trial), but none of the patients taking only AEDs reached that end point (JAMA 2012;307:922-30).

Moreover, "the 2 participants in the surgical group who continued to have seizures in year 2 experienced substantial improvement in seizure frequency," the investigators noted.

Patients who became seizure free also reported that they no longer experienced auras.

The mean number of AEDs used by patients in each group did not change appreciably in either group from baseline to 2 years.

The surgical group had significantly greater increases in health-related quality of life than did the pharmacotherapy group at all time points during follow-up. Twelve (80%) were able to drive vehicles at 2 years, compared with 5 (22%) in the pharmacotherapy group. And the surgery group reported a median increase of 7 days per month in socializing with friends, compared with a median decrease of 1 day per month with pharmacotherapy.

There were no differences between the study groups in employment status, hours worked per week, sick days, or days socializing with family.

Thirteen serious adverse events occurred, seven in the medical group and six in the surgical group. Events in the medical group were related to continuing seizures, including three cases of status epilepticus. Events in the surgical group included postoperative vomiting that required a gastrostomy, bleeding into the subarachnoid space that required placement of a shunt, and a mild cerebral infarction that fully resolved during follow-up.

Patients in the surgery group had substantially lower performances than did those in the medical group on immediate and delayed recall, but not on any nonmemory measures. "Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe of participants with normal presurgical memory," the investigators wrote.

Nevertheless, the sample size in this study "was too small to permit a definitive conclusion that early surgery does not present a greater risk for cognitive disturbances than continued pharmacotherapy," they added.

Overall, the ERSET results "reinforce the view that surgery soon after failure of two antiepileptic drug trials offers the best chance of preventing a lifetime of disability," Dr. Engel and his colleagues said.

The findings also remind clinicians that "all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 antiepileptic drugs fail, and surgery should be performed," they added.

The ERSET study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Several of the authors reported receiving consultancy fees, lecture or speakers bureau fees, or travel expense fees from manufacturers of devices and drugs to treat epilepsy.

Surgery was clearly superior to pharmacotherapy at relieving seizures in a study of patients with intractable mesial temporal lobe epilepsy who were no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs.

Though the study sample was small, with only 38 subjects, surgery also proved to be better at improving quality of life, allowing patients to drive vehicles, and increasing their socialization, according Dr. Jerome Engel Jr. of the University of California, Los Angeles, and his associates, whose report was published March 7 in JAMA.

"We found that the benefit of surgery in newly intractable epilepsy is very large (allowing it to be demonstrated in a small randomized trial)," and that patients who avoid surgery are very unlikely to improve with further pharmacotherapy. This probably raises their risk of death and of adverse psychological and social consequences, the investigators noted.

Surgery for epilepsy is often delayed for years or avoided altogether, in part because many consider it a last resort. "There is concern that surgery early in the course of mesial temporal lobe epilepsy could produce cognitive deficits in otherwise cognitively intact patients," Dr. Engel and his colleagues wrote.

In fact, this trial was terminated early solely because so few patients were being referred to the participating epilepsy centers for possible surgery that subject accrual was deemed inadequate.

But earlier surgery could prevent significant morbidity and even premature death. The American Academy of Neurology has recommended surgery as the treatment of choice for medically intractable epilepsy since 2003, but the excess lag time before surgical referral hasn’t decreased since then and still remains at more than 10 years.

The Early Randomized Surgical Epilepsy Trial (ERSET) was designed to compare the outcomes of surgery with those of continued pharmacotherapy, focusing on patients no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs. This interval was considered "a time when adverse psychological and social consequences of disabling seizures might be minimal, and seizures might conceivably still respond to further trials of AEDs [antiepileptic drugs]," the researchers wrote.

In all, 38 patients aged 12 years and older (mean age 34 years) with intractable, disabling seizures were referred from 16 medical centers and randomly assigned to continue pharmacotherapy (23 subjects) or to undergo en bloc resection of the anterior 3.5-4 cm of the lateral temporal lobe, sparing the superior temporal gyrus, followed by removal of the mesial structures (15 subjects). The patients were followed every 3 months for 2 years.

Despite efforts to include adolescent patients in this trial, only two were ultimately recruited, and both were randomly assigned to the pharmacotherapy group. Therefore it remains unknown whether the study results apply to adolescent patients.

Eleven (73%) of the 15 patients who underwent surgery were free from disabling seizures during the second year of follow-up (the primary outcome of the trial), but none of the patients taking only AEDs reached that end point (JAMA 2012;307:922-30).

Moreover, "the 2 participants in the surgical group who continued to have seizures in year 2 experienced substantial improvement in seizure frequency," the investigators noted.

Patients who became seizure free also reported that they no longer experienced auras.

The mean number of AEDs used by patients in each group did not change appreciably in either group from baseline to 2 years.

The surgical group had significantly greater increases in health-related quality of life than did the pharmacotherapy group at all time points during follow-up. Twelve (80%) were able to drive vehicles at 2 years, compared with 5 (22%) in the pharmacotherapy group. And the surgery group reported a median increase of 7 days per month in socializing with friends, compared with a median decrease of 1 day per month with pharmacotherapy.

There were no differences between the study groups in employment status, hours worked per week, sick days, or days socializing with family.

Thirteen serious adverse events occurred, seven in the medical group and six in the surgical group. Events in the medical group were related to continuing seizures, including three cases of status epilepticus. Events in the surgical group included postoperative vomiting that required a gastrostomy, bleeding into the subarachnoid space that required placement of a shunt, and a mild cerebral infarction that fully resolved during follow-up.

Patients in the surgery group had substantially lower performances than did those in the medical group on immediate and delayed recall, but not on any nonmemory measures. "Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe of participants with normal presurgical memory," the investigators wrote.

Nevertheless, the sample size in this study "was too small to permit a definitive conclusion that early surgery does not present a greater risk for cognitive disturbances than continued pharmacotherapy," they added.

Overall, the ERSET results "reinforce the view that surgery soon after failure of two antiepileptic drug trials offers the best chance of preventing a lifetime of disability," Dr. Engel and his colleagues said.

The findings also remind clinicians that "all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 antiepileptic drugs fail, and surgery should be performed," they added.

The ERSET study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Several of the authors reported receiving consultancy fees, lecture or speakers bureau fees, or travel expense fees from manufacturers of devices and drugs to treat epilepsy.

Surgery was clearly superior to pharmacotherapy at relieving seizures in a study of patients with intractable mesial temporal lobe epilepsy who were no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs.

Though the study sample was small, with only 38 subjects, surgery also proved to be better at improving quality of life, allowing patients to drive vehicles, and increasing their socialization, according Dr. Jerome Engel Jr. of the University of California, Los Angeles, and his associates, whose report was published March 7 in JAMA.

"We found that the benefit of surgery in newly intractable epilepsy is very large (allowing it to be demonstrated in a small randomized trial)," and that patients who avoid surgery are very unlikely to improve with further pharmacotherapy. This probably raises their risk of death and of adverse psychological and social consequences, the investigators noted.

Surgery for epilepsy is often delayed for years or avoided altogether, in part because many consider it a last resort. "There is concern that surgery early in the course of mesial temporal lobe epilepsy could produce cognitive deficits in otherwise cognitively intact patients," Dr. Engel and his colleagues wrote.

In fact, this trial was terminated early solely because so few patients were being referred to the participating epilepsy centers for possible surgery that subject accrual was deemed inadequate.

But earlier surgery could prevent significant morbidity and even premature death. The American Academy of Neurology has recommended surgery as the treatment of choice for medically intractable epilepsy since 2003, but the excess lag time before surgical referral hasn’t decreased since then and still remains at more than 10 years.

The Early Randomized Surgical Epilepsy Trial (ERSET) was designed to compare the outcomes of surgery with those of continued pharmacotherapy, focusing on patients no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs. This interval was considered "a time when adverse psychological and social consequences of disabling seizures might be minimal, and seizures might conceivably still respond to further trials of AEDs [antiepileptic drugs]," the researchers wrote.

In all, 38 patients aged 12 years and older (mean age 34 years) with intractable, disabling seizures were referred from 16 medical centers and randomly assigned to continue pharmacotherapy (23 subjects) or to undergo en bloc resection of the anterior 3.5-4 cm of the lateral temporal lobe, sparing the superior temporal gyrus, followed by removal of the mesial structures (15 subjects). The patients were followed every 3 months for 2 years.

Despite efforts to include adolescent patients in this trial, only two were ultimately recruited, and both were randomly assigned to the pharmacotherapy group. Therefore it remains unknown whether the study results apply to adolescent patients.

Eleven (73%) of the 15 patients who underwent surgery were free from disabling seizures during the second year of follow-up (the primary outcome of the trial), but none of the patients taking only AEDs reached that end point (JAMA 2012;307:922-30).

Moreover, "the 2 participants in the surgical group who continued to have seizures in year 2 experienced substantial improvement in seizure frequency," the investigators noted.

Patients who became seizure free also reported that they no longer experienced auras.

The mean number of AEDs used by patients in each group did not change appreciably in either group from baseline to 2 years.

The surgical group had significantly greater increases in health-related quality of life than did the pharmacotherapy group at all time points during follow-up. Twelve (80%) were able to drive vehicles at 2 years, compared with 5 (22%) in the pharmacotherapy group. And the surgery group reported a median increase of 7 days per month in socializing with friends, compared with a median decrease of 1 day per month with pharmacotherapy.

There were no differences between the study groups in employment status, hours worked per week, sick days, or days socializing with family.

Thirteen serious adverse events occurred, seven in the medical group and six in the surgical group. Events in the medical group were related to continuing seizures, including three cases of status epilepticus. Events in the surgical group included postoperative vomiting that required a gastrostomy, bleeding into the subarachnoid space that required placement of a shunt, and a mild cerebral infarction that fully resolved during follow-up.

Patients in the surgery group had substantially lower performances than did those in the medical group on immediate and delayed recall, but not on any nonmemory measures. "Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe of participants with normal presurgical memory," the investigators wrote.

Nevertheless, the sample size in this study "was too small to permit a definitive conclusion that early surgery does not present a greater risk for cognitive disturbances than continued pharmacotherapy," they added.

Overall, the ERSET results "reinforce the view that surgery soon after failure of two antiepileptic drug trials offers the best chance of preventing a lifetime of disability," Dr. Engel and his colleagues said.

The findings also remind clinicians that "all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 antiepileptic drugs fail, and surgery should be performed," they added.

The ERSET study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Several of the authors reported receiving consultancy fees, lecture or speakers bureau fees, or travel expense fees from manufacturers of devices and drugs to treat epilepsy.

A 4-week course of amantadine sped the rate of functional recovery in an international, randomized, double-blind, placebo-controlled trial of patients who had disorders of consciousness following traumatic brain injury.

Both patients given amantadine and those given placebo improved, but the rate of recovery was more rapid with the active drug. It affected "functionally meaningful behaviors such as consistent responses to commands, intelligible speech, reliable yes-or-no communication, and functional-object use," Joseph T. Giacino, Ph.D., of the JFK Johnson Rehabilitation Institute, Edison, N.J., and his associates reported in the March 1 issue of the New England Journal of Medicine.

The rate of recovery attenuated when treatment stopped, and scores on the Disability Rating Scale (DRS) were virtually indistinguishable between the treatment group and the control group 6 weeks later, indicating that the response was drug dependent.

"Practical and ethical constraints required the use of a brief treatment interval and a short-term assessment of the outcome [in this study], because we anticipated that caregivers would withdraw patients who were not making gains in order to try other treatments. Thus, our findings do not address the effects of prolonged treatment on long-term outcomes," the investigators noted.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown."

The researchers conducted the trial after a pilot study indicated that amantadine improved functional outcomes after traumatic brain injury. They enrolled 184 patients aged 16-65 years who had sustained a nonpenetrating TBI 4-16 weeks previously and who were receiving usual inpatient rehabilitation at 11 medical centers in three countries.

Patients were diagnosed as being in a vegetative state, in which there was wakefulness without behavioral evidence of conscious awareness, or in a minimally conscious state, in which there was at least one clearly discernible behavioral sign of consciousness. All had scores above 11 on the DRS, which ranges from 0 (best) to 29 (worst); none were able to follow commands consistently or to engage in functional communication as assessed using the Coma Recovery Scale-Revised (CRS-R).

A total of 87 patients were randomly assigned to receive amantadine and 97 to receive a visually identical placebo for 4 weeks. They began at a dose of 100 mg twice daily, with escalations to 150 mg twice daily at week 3 and to 200 mg twice daily at week 4 if the DRS score had not improved by at least 2 points from baseline. Then the drug or placebo was tapered, and patients were assessed for another 6 weeks, according to Dr. Giacino and his associates. Dr. Giacino is also director of rehabilitation neuropsychology at the Spaulding Rehabilitation Hospital and is an associate professor in the department of physical medicine and rehabilitation at Harvard Medical School, both in Boston.

The primary outcome measure was the rate of improvement in the DRS score during treatment. DRS scores were assessed weekly by an interdisciplinary treatment team that was blinded to treatment assignment. Study personnel assessed clinically relevant behavioral benchmarks using the CRS-R.

Both study groups had significantly improved DRS scores at the end of the 4 weeks of treatment, but the amantadine group showed significantly faster improvement (–0.24 points/week more). In addition, at the final follow-up assessment, more patients in the amantadine group showed favorable outcomes on the DRS, fewer remained in a vegetative state, and more showed recovery of key behavioral benchmarks, Dr. Giacino and his colleagues said (N. Engl. J. Med. 2012;366:819-26). These benefits were consistent across all subgroups of patients. They were seen both in subjects in a minimally conscious state and in those in a vegetative state. And they were noted regardless of how long after the TBI injury the patients began treatment.

However, the treatment effect declined when drug therapy stopped, until there were no significant differences at the final follow-up assessment between patients who received the active drug and those who received placebo.

In particular, the proportion of patients who were able to engage in each of six clinically relevant behaviors was higher with amantadine during the month of therapy, but the difference between the two study groups was negligible at the final follow-up. These six behaviors were consistent command-following, object recognition, functional use of objects, intelligible verbalization, reliable yes-or-no communication, and sustained attention.

Amantadine "did not increase the risk of adverse medical, neurologic, or behavioral events, including those of greatest concern in this population (e.g., seizure)," the researchers noted.

The drug’s mechanism of action in these patients is uncertain. Amantadine is thought to promote dopaminergic activity "by facilitating presynaptic release and blocking reuptake postsynaptically." It may also enhance neurotransmission "in the dopamine-dependent nigrostriatal, mesolimbic, and frontostriatal circuits that are responsible for mediating arousal, drive, and attentional functions," they added.

"We conclude that amantadine is effective in accelerating the pace of recovery during acute rehabilitation in patients with prolonged post-traumatic disturbances in consciousness. Exposure to amantadine is associated with more rapid emergence of cognitively mediated behaviors that serve as the foundation for functional independence," Dr. Giacino and his associates wrote.

The study was supported by the U.S. National Institute on Disability and Rehabilitation Research. Dr. Giacino reported no relevant financial conflicts of interest, but a coauthor reported ties to Allergan, Merz, Ipsen, and Medtronic. Several other coauthors disclosed providing expert testimony on patients with TBI and disorders of consciousness.

A 4-week course of amantadine sped the rate of functional recovery in an international, randomized, double-blind, placebo-controlled trial of patients who had disorders of consciousness following traumatic brain injury.

Both patients given amantadine and those given placebo improved, but the rate of recovery was more rapid with the active drug. It affected "functionally meaningful behaviors such as consistent responses to commands, intelligible speech, reliable yes-or-no communication, and functional-object use," Joseph T. Giacino, Ph.D., of the JFK Johnson Rehabilitation Institute, Edison, N.J., and his associates reported in the March 1 issue of the New England Journal of Medicine.

The rate of recovery attenuated when treatment stopped, and scores on the Disability Rating Scale (DRS) were virtually indistinguishable between the treatment group and the control group 6 weeks later, indicating that the response was drug dependent.

"Practical and ethical constraints required the use of a brief treatment interval and a short-term assessment of the outcome [in this study], because we anticipated that caregivers would withdraw patients who were not making gains in order to try other treatments. Thus, our findings do not address the effects of prolonged treatment on long-term outcomes," the investigators noted.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown."

The researchers conducted the trial after a pilot study indicated that amantadine improved functional outcomes after traumatic brain injury. They enrolled 184 patients aged 16-65 years who had sustained a nonpenetrating TBI 4-16 weeks previously and who were receiving usual inpatient rehabilitation at 11 medical centers in three countries.

Patients were diagnosed as being in a vegetative state, in which there was wakefulness without behavioral evidence of conscious awareness, or in a minimally conscious state, in which there was at least one clearly discernible behavioral sign of consciousness. All had scores above 11 on the DRS, which ranges from 0 (best) to 29 (worst); none were able to follow commands consistently or to engage in functional communication as assessed using the Coma Recovery Scale-Revised (CRS-R).

A total of 87 patients were randomly assigned to receive amantadine and 97 to receive a visually identical placebo for 4 weeks. They began at a dose of 100 mg twice daily, with escalations to 150 mg twice daily at week 3 and to 200 mg twice daily at week 4 if the DRS score had not improved by at least 2 points from baseline. Then the drug or placebo was tapered, and patients were assessed for another 6 weeks, according to Dr. Giacino and his associates. Dr. Giacino is also director of rehabilitation neuropsychology at the Spaulding Rehabilitation Hospital and is an associate professor in the department of physical medicine and rehabilitation at Harvard Medical School, both in Boston.

The primary outcome measure was the rate of improvement in the DRS score during treatment. DRS scores were assessed weekly by an interdisciplinary treatment team that was blinded to treatment assignment. Study personnel assessed clinically relevant behavioral benchmarks using the CRS-R.

Both study groups had significantly improved DRS scores at the end of the 4 weeks of treatment, but the amantadine group showed significantly faster improvement (–0.24 points/week more). In addition, at the final follow-up assessment, more patients in the amantadine group showed favorable outcomes on the DRS, fewer remained in a vegetative state, and more showed recovery of key behavioral benchmarks, Dr. Giacino and his colleagues said (N. Engl. J. Med. 2012;366:819-26). These benefits were consistent across all subgroups of patients. They were seen both in subjects in a minimally conscious state and in those in a vegetative state. And they were noted regardless of how long after the TBI injury the patients began treatment.

However, the treatment effect declined when drug therapy stopped, until there were no significant differences at the final follow-up assessment between patients who received the active drug and those who received placebo.

In particular, the proportion of patients who were able to engage in each of six clinically relevant behaviors was higher with amantadine during the month of therapy, but the difference between the two study groups was negligible at the final follow-up. These six behaviors were consistent command-following, object recognition, functional use of objects, intelligible verbalization, reliable yes-or-no communication, and sustained attention.

Amantadine "did not increase the risk of adverse medical, neurologic, or behavioral events, including those of greatest concern in this population (e.g., seizure)," the researchers noted.

The drug’s mechanism of action in these patients is uncertain. Amantadine is thought to promote dopaminergic activity "by facilitating presynaptic release and blocking reuptake postsynaptically." It may also enhance neurotransmission "in the dopamine-dependent nigrostriatal, mesolimbic, and frontostriatal circuits that are responsible for mediating arousal, drive, and attentional functions," they added.

"We conclude that amantadine is effective in accelerating the pace of recovery during acute rehabilitation in patients with prolonged post-traumatic disturbances in consciousness. Exposure to amantadine is associated with more rapid emergence of cognitively mediated behaviors that serve as the foundation for functional independence," Dr. Giacino and his associates wrote.

The study was supported by the U.S. National Institute on Disability and Rehabilitation Research. Dr. Giacino reported no relevant financial conflicts of interest, but a coauthor reported ties to Allergan, Merz, Ipsen, and Medtronic. Several other coauthors disclosed providing expert testimony on patients with TBI and disorders of consciousness.

A 4-week course of amantadine sped the rate of functional recovery in an international, randomized, double-blind, placebo-controlled trial of patients who had disorders of consciousness following traumatic brain injury.

Both patients given amantadine and those given placebo improved, but the rate of recovery was more rapid with the active drug. It affected "functionally meaningful behaviors such as consistent responses to commands, intelligible speech, reliable yes-or-no communication, and functional-object use," Joseph T. Giacino, Ph.D., of the JFK Johnson Rehabilitation Institute, Edison, N.J., and his associates reported in the March 1 issue of the New England Journal of Medicine.

The rate of recovery attenuated when treatment stopped, and scores on the Disability Rating Scale (DRS) were virtually indistinguishable between the treatment group and the control group 6 weeks later, indicating that the response was drug dependent.

"Practical and ethical constraints required the use of a brief treatment interval and a short-term assessment of the outcome [in this study], because we anticipated that caregivers would withdraw patients who were not making gains in order to try other treatments. Thus, our findings do not address the effects of prolonged treatment on long-term outcomes," the investigators noted.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown."

The researchers conducted the trial after a pilot study indicated that amantadine improved functional outcomes after traumatic brain injury. They enrolled 184 patients aged 16-65 years who had sustained a nonpenetrating TBI 4-16 weeks previously and who were receiving usual inpatient rehabilitation at 11 medical centers in three countries.

Patients were diagnosed as being in a vegetative state, in which there was wakefulness without behavioral evidence of conscious awareness, or in a minimally conscious state, in which there was at least one clearly discernible behavioral sign of consciousness. All had scores above 11 on the DRS, which ranges from 0 (best) to 29 (worst); none were able to follow commands consistently or to engage in functional communication as assessed using the Coma Recovery Scale-Revised (CRS-R).

A total of 87 patients were randomly assigned to receive amantadine and 97 to receive a visually identical placebo for 4 weeks. They began at a dose of 100 mg twice daily, with escalations to 150 mg twice daily at week 3 and to 200 mg twice daily at week 4 if the DRS score had not improved by at least 2 points from baseline. Then the drug or placebo was tapered, and patients were assessed for another 6 weeks, according to Dr. Giacino and his associates. Dr. Giacino is also director of rehabilitation neuropsychology at the Spaulding Rehabilitation Hospital and is an associate professor in the department of physical medicine and rehabilitation at Harvard Medical School, both in Boston.

The primary outcome measure was the rate of improvement in the DRS score during treatment. DRS scores were assessed weekly by an interdisciplinary treatment team that was blinded to treatment assignment. Study personnel assessed clinically relevant behavioral benchmarks using the CRS-R.

Both study groups had significantly improved DRS scores at the end of the 4 weeks of treatment, but the amantadine group showed significantly faster improvement (–0.24 points/week more). In addition, at the final follow-up assessment, more patients in the amantadine group showed favorable outcomes on the DRS, fewer remained in a vegetative state, and more showed recovery of key behavioral benchmarks, Dr. Giacino and his colleagues said (N. Engl. J. Med. 2012;366:819-26). These benefits were consistent across all subgroups of patients. They were seen both in subjects in a minimally conscious state and in those in a vegetative state. And they were noted regardless of how long after the TBI injury the patients began treatment.

However, the treatment effect declined when drug therapy stopped, until there were no significant differences at the final follow-up assessment between patients who received the active drug and those who received placebo.

In particular, the proportion of patients who were able to engage in each of six clinically relevant behaviors was higher with amantadine during the month of therapy, but the difference between the two study groups was negligible at the final follow-up. These six behaviors were consistent command-following, object recognition, functional use of objects, intelligible verbalization, reliable yes-or-no communication, and sustained attention.

Amantadine "did not increase the risk of adverse medical, neurologic, or behavioral events, including those of greatest concern in this population (e.g., seizure)," the researchers noted.

The drug’s mechanism of action in these patients is uncertain. Amantadine is thought to promote dopaminergic activity "by facilitating presynaptic release and blocking reuptake postsynaptically." It may also enhance neurotransmission "in the dopamine-dependent nigrostriatal, mesolimbic, and frontostriatal circuits that are responsible for mediating arousal, drive, and attentional functions," they added.

"We conclude that amantadine is effective in accelerating the pace of recovery during acute rehabilitation in patients with prolonged post-traumatic disturbances in consciousness. Exposure to amantadine is associated with more rapid emergence of cognitively mediated behaviors that serve as the foundation for functional independence," Dr. Giacino and his associates wrote.

The study was supported by the U.S. National Institute on Disability and Rehabilitation Research. Dr. Giacino reported no relevant financial conflicts of interest, but a coauthor reported ties to Allergan, Merz, Ipsen, and Medtronic. Several other coauthors disclosed providing expert testimony on patients with TBI and disorders of consciousness.