American Epilepsy Society (AES): Annual Meeting

BALTIMORE – Not all seizure recurrences following epilepsy surgery should be treated in the same way.

Rather, early seizure recurrences may indicate an incomplete resection or inaccurate localization of the epileptic focus, whereas late seizure recurrences are likely due to de novo epileptogenesis. Clinically, this suggests that "patients with early seizure recurrence should be monitored and evaluated for possible reoperation sooner rather than later, while more aggressive medical management may be enough to control seizures in those with late recurrences," Dr. Lara Jehi said at the annual meeting of the American Epilepsy Society.

At 12 years following resective epilepsy surgery of all types, just 45% of patients remain seizure free. For frontal lobectomy in particular, that rate is just 30% (Brain 2007;130:574-84), and for temporal lobectomy the outcome is a little better at 55% (Neurology 2006;66:1938-40). What’s more, that 55% rate has not changed in the past 60 years. "Whether we like it or not, epilepsy surgery is not a magic bullet. ... It doesn’t always work," said Dr. Jehi, a neurologist at the Cleveland Clinic Epilepsy Center, and the head of the Outcomes Research Group there.

But hidden within those statistics is a less-appreciated dichotomy: In the studies just mentioned, the median time of recurrence for all epilepsy surgeries was 4 months. For frontal lobectomy, it was 2 months, and for temporal lobectomy, it was 6.6 months. In all, about half of all failures occurred in the short term, and the rest were spread out over a decade or more, regardless of surgery type. "It’s a common, solid, reproducible observation that reflects two different mechanisms," said Dr. Jehi, who cited an as-yet unpublished study of 1,418 patients that she and her colleagues presented last year at the annual meeting of the American Academy of Neurology.

She noted that a range of factors have been associated with early recurrence in studies of the outcomes of epilepsy surgery. Among 371 patients who underwent anterior temporal lobectomy to treat pharmacoresistant epilepsy, predictors of early recurrence included preoperative seizure frequency, history of generalized tonic-clonic (GTC) seizures, bilateral abnormalities on MRI, use of subdural electrodes, and an epileptiform electroencephalogram at 6 months postoperatively. On the other hand, the only predictor of late recurrence was nonspecific pathology (Neurology 2006;66:1938-40).

In a study of outcomes following failed temporal lobectomy in 68 adult patients, Dr. Jehi and her associates found that there were no early seizure recurrences from foci that were contiguous to the area that had been initially resected, suggesting that early recurrences are likely the result of having "missed the spot," she said (J. Neurosurg. 2010;113:1186-94).

Two other studies by her group also documented a higher rate of early recurrences in "difficult to localize" epilepsies. One examined surgical outcome and prognostic factors of frontal lobe epilepsy surgery in 70 patients (Brain 2007;130:574-84), and the other is a longitudinal study of surgical outcome and its determinants following posterior cortex epilepsy surgery in 57 patients (Epilepsia 2009;50:2040-52).

But in a separate study of 285 patients who were initially seizure free following epilepsy surgery, the presence of preoperative GTC seizures predicted late seizure recurrence among 31 patients with neocortical epilepsy, whereas late age at surgery predicted late recurrence among the remaining 254 with medial temporal lobe epilepsy. Results of MRI and location of surgery were not predictive (Epilepsia 2006;47:567-73).

Dr. Jehi and her group found that there was less risk of intractability with breakthrough seizures that occurred beyond 6 months after temporal lobectomy surgery among 276 patients who had one or more seizures after the immediate postoperative period (Epilepsia 2010;51:994-1003). Her team also determined that late seizure recurrences after frontal lobectomy surgery tended to be milder and less frequent (Brain 2007;130:574-84). These findings suggest a pattern similar to new-onset epilepsy, or "epileptogenesis," she said.

In all, the data suggest that patients with early seizure recurrences need to be investigated as soon as possible for a reoperation via modalities such as video-EEG and repeat brain imaging, and require intense follow-up and management. "In other words, don’t waste much time on switching antiepileptic medications around," Dr. Jehi said in an interview.

On the other hand, patients with late recurrences need more aggressive antiepileptic medication management before another brain surgery is considered. If their seizures subsequently prove to be refractory, brain regions other than the focus of initial resection need to enter into the equation of possible areas in the brain that may be causing seizures, she said.

And, she added, this dichotomy hypothesis "opens the door to investigate antiepileptogenic measures as a tool to improve long-term seizure outcomes after surgery."

Dr. Jehi said that she had no relevant disclosures.

BALTIMORE – Not all seizure recurrences following epilepsy surgery should be treated in the same way.

Rather, early seizure recurrences may indicate an incomplete resection or inaccurate localization of the epileptic focus, whereas late seizure recurrences are likely due to de novo epileptogenesis. Clinically, this suggests that "patients with early seizure recurrence should be monitored and evaluated for possible reoperation sooner rather than later, while more aggressive medical management may be enough to control seizures in those with late recurrences," Dr. Lara Jehi said at the annual meeting of the American Epilepsy Society.

At 12 years following resective epilepsy surgery of all types, just 45% of patients remain seizure free. For frontal lobectomy in particular, that rate is just 30% (Brain 2007;130:574-84), and for temporal lobectomy the outcome is a little better at 55% (Neurology 2006;66:1938-40). What’s more, that 55% rate has not changed in the past 60 years. "Whether we like it or not, epilepsy surgery is not a magic bullet. ... It doesn’t always work," said Dr. Jehi, a neurologist at the Cleveland Clinic Epilepsy Center, and the head of the Outcomes Research Group there.

But hidden within those statistics is a less-appreciated dichotomy: In the studies just mentioned, the median time of recurrence for all epilepsy surgeries was 4 months. For frontal lobectomy, it was 2 months, and for temporal lobectomy, it was 6.6 months. In all, about half of all failures occurred in the short term, and the rest were spread out over a decade or more, regardless of surgery type. "It’s a common, solid, reproducible observation that reflects two different mechanisms," said Dr. Jehi, who cited an as-yet unpublished study of 1,418 patients that she and her colleagues presented last year at the annual meeting of the American Academy of Neurology.

She noted that a range of factors have been associated with early recurrence in studies of the outcomes of epilepsy surgery. Among 371 patients who underwent anterior temporal lobectomy to treat pharmacoresistant epilepsy, predictors of early recurrence included preoperative seizure frequency, history of generalized tonic-clonic (GTC) seizures, bilateral abnormalities on MRI, use of subdural electrodes, and an epileptiform electroencephalogram at 6 months postoperatively. On the other hand, the only predictor of late recurrence was nonspecific pathology (Neurology 2006;66:1938-40).

In a study of outcomes following failed temporal lobectomy in 68 adult patients, Dr. Jehi and her associates found that there were no early seizure recurrences from foci that were contiguous to the area that had been initially resected, suggesting that early recurrences are likely the result of having "missed the spot," she said (J. Neurosurg. 2010;113:1186-94).

Two other studies by her group also documented a higher rate of early recurrences in "difficult to localize" epilepsies. One examined surgical outcome and prognostic factors of frontal lobe epilepsy surgery in 70 patients (Brain 2007;130:574-84), and the other is a longitudinal study of surgical outcome and its determinants following posterior cortex epilepsy surgery in 57 patients (Epilepsia 2009;50:2040-52).

But in a separate study of 285 patients who were initially seizure free following epilepsy surgery, the presence of preoperative GTC seizures predicted late seizure recurrence among 31 patients with neocortical epilepsy, whereas late age at surgery predicted late recurrence among the remaining 254 with medial temporal lobe epilepsy. Results of MRI and location of surgery were not predictive (Epilepsia 2006;47:567-73).

Dr. Jehi and her group found that there was less risk of intractability with breakthrough seizures that occurred beyond 6 months after temporal lobectomy surgery among 276 patients who had one or more seizures after the immediate postoperative period (Epilepsia 2010;51:994-1003). Her team also determined that late seizure recurrences after frontal lobectomy surgery tended to be milder and less frequent (Brain 2007;130:574-84). These findings suggest a pattern similar to new-onset epilepsy, or "epileptogenesis," she said.

In all, the data suggest that patients with early seizure recurrences need to be investigated as soon as possible for a reoperation via modalities such as video-EEG and repeat brain imaging, and require intense follow-up and management. "In other words, don’t waste much time on switching antiepileptic medications around," Dr. Jehi said in an interview.

On the other hand, patients with late recurrences need more aggressive antiepileptic medication management before another brain surgery is considered. If their seizures subsequently prove to be refractory, brain regions other than the focus of initial resection need to enter into the equation of possible areas in the brain that may be causing seizures, she said.

And, she added, this dichotomy hypothesis "opens the door to investigate antiepileptogenic measures as a tool to improve long-term seizure outcomes after surgery."

Dr. Jehi said that she had no relevant disclosures.

BALTIMORE – Not all seizure recurrences following epilepsy surgery should be treated in the same way.

Rather, early seizure recurrences may indicate an incomplete resection or inaccurate localization of the epileptic focus, whereas late seizure recurrences are likely due to de novo epileptogenesis. Clinically, this suggests that "patients with early seizure recurrence should be monitored and evaluated for possible reoperation sooner rather than later, while more aggressive medical management may be enough to control seizures in those with late recurrences," Dr. Lara Jehi said at the annual meeting of the American Epilepsy Society.

At 12 years following resective epilepsy surgery of all types, just 45% of patients remain seizure free. For frontal lobectomy in particular, that rate is just 30% (Brain 2007;130:574-84), and for temporal lobectomy the outcome is a little better at 55% (Neurology 2006;66:1938-40). What’s more, that 55% rate has not changed in the past 60 years. "Whether we like it or not, epilepsy surgery is not a magic bullet. ... It doesn’t always work," said Dr. Jehi, a neurologist at the Cleveland Clinic Epilepsy Center, and the head of the Outcomes Research Group there.

But hidden within those statistics is a less-appreciated dichotomy: In the studies just mentioned, the median time of recurrence for all epilepsy surgeries was 4 months. For frontal lobectomy, it was 2 months, and for temporal lobectomy, it was 6.6 months. In all, about half of all failures occurred in the short term, and the rest were spread out over a decade or more, regardless of surgery type. "It’s a common, solid, reproducible observation that reflects two different mechanisms," said Dr. Jehi, who cited an as-yet unpublished study of 1,418 patients that she and her colleagues presented last year at the annual meeting of the American Academy of Neurology.

She noted that a range of factors have been associated with early recurrence in studies of the outcomes of epilepsy surgery. Among 371 patients who underwent anterior temporal lobectomy to treat pharmacoresistant epilepsy, predictors of early recurrence included preoperative seizure frequency, history of generalized tonic-clonic (GTC) seizures, bilateral abnormalities on MRI, use of subdural electrodes, and an epileptiform electroencephalogram at 6 months postoperatively. On the other hand, the only predictor of late recurrence was nonspecific pathology (Neurology 2006;66:1938-40).

In a study of outcomes following failed temporal lobectomy in 68 adult patients, Dr. Jehi and her associates found that there were no early seizure recurrences from foci that were contiguous to the area that had been initially resected, suggesting that early recurrences are likely the result of having "missed the spot," she said (J. Neurosurg. 2010;113:1186-94).

Two other studies by her group also documented a higher rate of early recurrences in "difficult to localize" epilepsies. One examined surgical outcome and prognostic factors of frontal lobe epilepsy surgery in 70 patients (Brain 2007;130:574-84), and the other is a longitudinal study of surgical outcome and its determinants following posterior cortex epilepsy surgery in 57 patients (Epilepsia 2009;50:2040-52).

But in a separate study of 285 patients who were initially seizure free following epilepsy surgery, the presence of preoperative GTC seizures predicted late seizure recurrence among 31 patients with neocortical epilepsy, whereas late age at surgery predicted late recurrence among the remaining 254 with medial temporal lobe epilepsy. Results of MRI and location of surgery were not predictive (Epilepsia 2006;47:567-73).

Dr. Jehi and her group found that there was less risk of intractability with breakthrough seizures that occurred beyond 6 months after temporal lobectomy surgery among 276 patients who had one or more seizures after the immediate postoperative period (Epilepsia 2010;51:994-1003). Her team also determined that late seizure recurrences after frontal lobectomy surgery tended to be milder and less frequent (Brain 2007;130:574-84). These findings suggest a pattern similar to new-onset epilepsy, or "epileptogenesis," she said.

In all, the data suggest that patients with early seizure recurrences need to be investigated as soon as possible for a reoperation via modalities such as video-EEG and repeat brain imaging, and require intense follow-up and management. "In other words, don’t waste much time on switching antiepileptic medications around," Dr. Jehi said in an interview.

On the other hand, patients with late recurrences need more aggressive antiepileptic medication management before another brain surgery is considered. If their seizures subsequently prove to be refractory, brain regions other than the focus of initial resection need to enter into the equation of possible areas in the brain that may be causing seizures, she said.

And, she added, this dichotomy hypothesis "opens the door to investigate antiepileptogenic measures as a tool to improve long-term seizure outcomes after surgery."

Dr. Jehi said that she had no relevant disclosures.

BALTIMORE – No notable increases in new-onset seizure disorder or exacerbations of a pre-existing seizure disorder were seen following gastric bypass surgery in a retrospective case series of more than 1,500 patients from the Mayo Clinic.

Reports of new-onset or exacerbated seizure disorders following Roux-en-Y surgery are often posted on epilepsy patient-oriented Web sites such as epilepsy.com, along with reports of other neurologic complications such as Wernicke-Korsakoff syndrome, polyradiculoneuropathy, myelopathy, and optic neuropathy. However, few previous studies have examined a potential connection between gastric bypass and epilepsy, Dr. Richard S. Clemmons and Gregory D. Cascino said in a poster at the annual meeting of the American Epilepsy Society.

A diagnosis of epilepsy pre-existed prior to Roux-en-Y surgery in 12 of 1,542 patients who were operated on at the Mayo Clinic between September 1997 and September 2007. Those patients were selected from a larger group of 1,776 patients because they had more than 1 year of follow-up, had undergone surgery for morbid obesity, and were aged 18 years or older. Despite evidence that gastric bypass surgery might result in decreased absorption of drugs with high proximal absorption or low pH (Am. J. Health Syst. Pharm. 2006;63:1852-7), 8 of these 12 patients had no decrease in drug levels, based on patient report or on serum testing before and after surgery. One patient who did have a low drug level was suspected of poor compliance. None of the 12 had exacerbations of their seizures.

"Based on the limited data here, there was not a decrease in serum drug levels for valproic acid, carbamazepine, or levetiracetam. ... Even patients with significant seizure risk factors did not manifest an exacerbation of seizures," noted Dr. Clemmons and Dr. Cascino, both of whom were affiliated with the division of epilepsy in the department of neurology at the Mayo Clinic, Rochester, Minn., at the time of the study. Dr. Clemmons is currently in private practice in Denver.

Only 5 of the 1,542 patients developed new-onset epilepsy following surgery. Of those, only 3 (1.9% of the total cohort) could be considered to have unprovoked epilepsy. One of the other two patients had a history of meningoencephalitis and had just a single seizure 2 years after surgery that was possibly associated with hypoglycemia. The other one had a seizure in the setting of a stroke 3 months after surgery. None of the five developed intractable epilepsy.

About three-fourths of the patients in the study were female. Their charts were examined for evidence of seizure exacerbation post surgery, defined as an increase in seizure frequency above preoperative baseline where another cause was not identified. Patient questionnaires were used to supplement where data were lacking.

"Based on the reviewed data, there is no clear exacerbation of preexisting seizure disorder following gastric bypass ... Most patients with seizure disorder do well following Roux-en-Y," they concluded.

Dr. Clemmons, who presented the poster at the meeting, stated that he had no financial disclosures.

BALTIMORE – No notable increases in new-onset seizure disorder or exacerbations of a pre-existing seizure disorder were seen following gastric bypass surgery in a retrospective case series of more than 1,500 patients from the Mayo Clinic.

Reports of new-onset or exacerbated seizure disorders following Roux-en-Y surgery are often posted on epilepsy patient-oriented Web sites such as epilepsy.com, along with reports of other neurologic complications such as Wernicke-Korsakoff syndrome, polyradiculoneuropathy, myelopathy, and optic neuropathy. However, few previous studies have examined a potential connection between gastric bypass and epilepsy, Dr. Richard S. Clemmons and Gregory D. Cascino said in a poster at the annual meeting of the American Epilepsy Society.

A diagnosis of epilepsy pre-existed prior to Roux-en-Y surgery in 12 of 1,542 patients who were operated on at the Mayo Clinic between September 1997 and September 2007. Those patients were selected from a larger group of 1,776 patients because they had more than 1 year of follow-up, had undergone surgery for morbid obesity, and were aged 18 years or older. Despite evidence that gastric bypass surgery might result in decreased absorption of drugs with high proximal absorption or low pH (Am. J. Health Syst. Pharm. 2006;63:1852-7), 8 of these 12 patients had no decrease in drug levels, based on patient report or on serum testing before and after surgery. One patient who did have a low drug level was suspected of poor compliance. None of the 12 had exacerbations of their seizures.

"Based on the limited data here, there was not a decrease in serum drug levels for valproic acid, carbamazepine, or levetiracetam. ... Even patients with significant seizure risk factors did not manifest an exacerbation of seizures," noted Dr. Clemmons and Dr. Cascino, both of whom were affiliated with the division of epilepsy in the department of neurology at the Mayo Clinic, Rochester, Minn., at the time of the study. Dr. Clemmons is currently in private practice in Denver.

Only 5 of the 1,542 patients developed new-onset epilepsy following surgery. Of those, only 3 (1.9% of the total cohort) could be considered to have unprovoked epilepsy. One of the other two patients had a history of meningoencephalitis and had just a single seizure 2 years after surgery that was possibly associated with hypoglycemia. The other one had a seizure in the setting of a stroke 3 months after surgery. None of the five developed intractable epilepsy.

About three-fourths of the patients in the study were female. Their charts were examined for evidence of seizure exacerbation post surgery, defined as an increase in seizure frequency above preoperative baseline where another cause was not identified. Patient questionnaires were used to supplement where data were lacking.

"Based on the reviewed data, there is no clear exacerbation of preexisting seizure disorder following gastric bypass ... Most patients with seizure disorder do well following Roux-en-Y," they concluded.

Dr. Clemmons, who presented the poster at the meeting, stated that he had no financial disclosures.

BALTIMORE – No notable increases in new-onset seizure disorder or exacerbations of a pre-existing seizure disorder were seen following gastric bypass surgery in a retrospective case series of more than 1,500 patients from the Mayo Clinic.

Reports of new-onset or exacerbated seizure disorders following Roux-en-Y surgery are often posted on epilepsy patient-oriented Web sites such as epilepsy.com, along with reports of other neurologic complications such as Wernicke-Korsakoff syndrome, polyradiculoneuropathy, myelopathy, and optic neuropathy. However, few previous studies have examined a potential connection between gastric bypass and epilepsy, Dr. Richard S. Clemmons and Gregory D. Cascino said in a poster at the annual meeting of the American Epilepsy Society.

A diagnosis of epilepsy pre-existed prior to Roux-en-Y surgery in 12 of 1,542 patients who were operated on at the Mayo Clinic between September 1997 and September 2007. Those patients were selected from a larger group of 1,776 patients because they had more than 1 year of follow-up, had undergone surgery for morbid obesity, and were aged 18 years or older. Despite evidence that gastric bypass surgery might result in decreased absorption of drugs with high proximal absorption or low pH (Am. J. Health Syst. Pharm. 2006;63:1852-7), 8 of these 12 patients had no decrease in drug levels, based on patient report or on serum testing before and after surgery. One patient who did have a low drug level was suspected of poor compliance. None of the 12 had exacerbations of their seizures.

"Based on the limited data here, there was not a decrease in serum drug levels for valproic acid, carbamazepine, or levetiracetam. ... Even patients with significant seizure risk factors did not manifest an exacerbation of seizures," noted Dr. Clemmons and Dr. Cascino, both of whom were affiliated with the division of epilepsy in the department of neurology at the Mayo Clinic, Rochester, Minn., at the time of the study. Dr. Clemmons is currently in private practice in Denver.

Only 5 of the 1,542 patients developed new-onset epilepsy following surgery. Of those, only 3 (1.9% of the total cohort) could be considered to have unprovoked epilepsy. One of the other two patients had a history of meningoencephalitis and had just a single seizure 2 years after surgery that was possibly associated with hypoglycemia. The other one had a seizure in the setting of a stroke 3 months after surgery. None of the five developed intractable epilepsy.

About three-fourths of the patients in the study were female. Their charts were examined for evidence of seizure exacerbation post surgery, defined as an increase in seizure frequency above preoperative baseline where another cause was not identified. Patient questionnaires were used to supplement where data were lacking.

"Based on the reviewed data, there is no clear exacerbation of preexisting seizure disorder following gastric bypass ... Most patients with seizure disorder do well following Roux-en-Y," they concluded.

Dr. Clemmons, who presented the poster at the meeting, stated that he had no financial disclosures.

BALTIMORE – Levetiracetam had effects on bone mineral density and markers of bone turnover that were similar to those seen with the older antiepileptic drugs carbamazepine and sodium valproate in a 12-month, randomized, controlled trial of 84 patients with partial epilepsy.

The finding was counter to the expectation that levetiracetam (Keppra) would have neutral or more benign effects on bone health because of its "cleaner pharmacokinetics – no effect on vitamin D metabolism – and a different mechanism of action," study investigator Dr. Terence J. O’Brien said in an interview. "Most [experts] thought it would be better for bone health. However, there is a previous study in rats that did show effect on bone. ... The clinical message is that neurologists need to monitor bone heath on all their patients chronically treated with AEDs."

Chronic antiepileptic drug use has been associated with increased risk of both bone disease and fracture, as well as weight gain and insulin resistance. It has been hoped that newer antiepileptic drugs with different mechanisms of action would minimize or eliminate these effects. One of these newer agents, levetiracetam, has a novel mechanism of action, binding to the SV2A receptors that interfere with synaptic vesicle exocytosis. It is not hepatically metabolized, so it does not affect hormonal levels.

"The clinical message is that neurologists need to monitor bone heath on all their patients chronically treated with antiepileptic drugs."

"There are plenty of reasons to believe it would have fewer bone and metabolic effects, but this had never been tested before in a randomized, controlled trial," said Dr. O’Brien, a professor of medicine at the University of Melbourne and head of the department of medicine at the Royal Melbourne Hospital.

Of 84 patients randomized to open-label substitution monotherapy with either levetiracetam or carbamazepine or valproate in the KONQUEST trial, 40 levetiracetam patients and 30 carbamazepine/valproate patients completed an assessment at 15 months. Dosing in the trial was flexible, and was increased or decreased by the treating neurologist according to tolerability and seizure control.

Dual energy X-ray absorptiometry (DXA) measurements of areal bone mineral density (aBMD) in the forearm was significantly lower at 15 months in both the levetiracetam and carbamazepine/valproate groups, compared with measurements taken at 3 months, but more so for levetiracetam, with reductions of 1.4% (P less than .001) and 0.96% (P = .015), respectively. Peripheral quantitative CT measurement of trabecular BMD in the radius was also reduced in both groups, by 2.25% (P = .005) with levetiracetam and by 2.9% (P = .001) for the older AEDs. There were no differences from 3-month assessments in aBMD of the lumbar spine or hip in either treatment group.

Markers of bone formation and resorption were among the secondary end points. The bone resorption marker beta C-terminal telopeptide of type 1 collagen was reduced in both treatment groups, by 12.8% (P = .021) with levetiracetam and by 15.6% (P = .028) with carbamazepine/valproate. However, the bone formation marker procollagen type 1 N-terminal propeptide was reduced only with the older AEDs, by 20.9% (P = .008). There were no differences in vitamin D or other markers of calcium homeostasis, Dr. O’Brien said.

Reduction in serum markers of bone turnover suggests reduced bone remodeling with AEDs, "an atypical mechanism for bone loss which warrants further study," he said.

In the interview, he added that the lack of effect on markers of bone formation for levetiracetam may indicate some differences in the mechanism of its effect, or may just have been a lack of power.

The exploratory end points of femoral neck aBMD, total bone area (trabecular), trabecular bone mineral content, and total bone area (cortical) were all significantly reduced in both groups. However, the anthropometric exploratory end points of weight and body mass index were increased only with the older AEDs, by 2.0% (P = .039) and 2.15% (P = .044), respectively.

There are no clear guidelines for bone health monitoring in patients on AEDs. "What we recommend is when you start the drug, [get] a baseline, and then [monitor] every 3-5 years. Vitamin D levels should also be checked and supplemented if deficient," he said in the interview.

A UCB Pharma spokeswoman declined to comment on the findings of KONQUEST. The study was partially funded by the company, but it had no role in its design, data collection, analysis, or interpretation. Dr. O’Brien said that he had no additional disclosures.

BALTIMORE – Levetiracetam had effects on bone mineral density and markers of bone turnover that were similar to those seen with the older antiepileptic drugs carbamazepine and sodium valproate in a 12-month, randomized, controlled trial of 84 patients with partial epilepsy.

The finding was counter to the expectation that levetiracetam (Keppra) would have neutral or more benign effects on bone health because of its "cleaner pharmacokinetics – no effect on vitamin D metabolism – and a different mechanism of action," study investigator Dr. Terence J. O’Brien said in an interview. "Most [experts] thought it would be better for bone health. However, there is a previous study in rats that did show effect on bone. ... The clinical message is that neurologists need to monitor bone heath on all their patients chronically treated with AEDs."

Chronic antiepileptic drug use has been associated with increased risk of both bone disease and fracture, as well as weight gain and insulin resistance. It has been hoped that newer antiepileptic drugs with different mechanisms of action would minimize or eliminate these effects. One of these newer agents, levetiracetam, has a novel mechanism of action, binding to the SV2A receptors that interfere with synaptic vesicle exocytosis. It is not hepatically metabolized, so it does not affect hormonal levels.

"The clinical message is that neurologists need to monitor bone heath on all their patients chronically treated with antiepileptic drugs."

"There are plenty of reasons to believe it would have fewer bone and metabolic effects, but this had never been tested before in a randomized, controlled trial," said Dr. O’Brien, a professor of medicine at the University of Melbourne and head of the department of medicine at the Royal Melbourne Hospital.

Of 84 patients randomized to open-label substitution monotherapy with either levetiracetam or carbamazepine or valproate in the KONQUEST trial, 40 levetiracetam patients and 30 carbamazepine/valproate patients completed an assessment at 15 months. Dosing in the trial was flexible, and was increased or decreased by the treating neurologist according to tolerability and seizure control.

Dual energy X-ray absorptiometry (DXA) measurements of areal bone mineral density (aBMD) in the forearm was significantly lower at 15 months in both the levetiracetam and carbamazepine/valproate groups, compared with measurements taken at 3 months, but more so for levetiracetam, with reductions of 1.4% (P less than .001) and 0.96% (P = .015), respectively. Peripheral quantitative CT measurement of trabecular BMD in the radius was also reduced in both groups, by 2.25% (P = .005) with levetiracetam and by 2.9% (P = .001) for the older AEDs. There were no differences from 3-month assessments in aBMD of the lumbar spine or hip in either treatment group.

Markers of bone formation and resorption were among the secondary end points. The bone resorption marker beta C-terminal telopeptide of type 1 collagen was reduced in both treatment groups, by 12.8% (P = .021) with levetiracetam and by 15.6% (P = .028) with carbamazepine/valproate. However, the bone formation marker procollagen type 1 N-terminal propeptide was reduced only with the older AEDs, by 20.9% (P = .008). There were no differences in vitamin D or other markers of calcium homeostasis, Dr. O’Brien said.

Reduction in serum markers of bone turnover suggests reduced bone remodeling with AEDs, "an atypical mechanism for bone loss which warrants further study," he said.

In the interview, he added that the lack of effect on markers of bone formation for levetiracetam may indicate some differences in the mechanism of its effect, or may just have been a lack of power.

The exploratory end points of femoral neck aBMD, total bone area (trabecular), trabecular bone mineral content, and total bone area (cortical) were all significantly reduced in both groups. However, the anthropometric exploratory end points of weight and body mass index were increased only with the older AEDs, by 2.0% (P = .039) and 2.15% (P = .044), respectively.

There are no clear guidelines for bone health monitoring in patients on AEDs. "What we recommend is when you start the drug, [get] a baseline, and then [monitor] every 3-5 years. Vitamin D levels should also be checked and supplemented if deficient," he said in the interview.

A UCB Pharma spokeswoman declined to comment on the findings of KONQUEST. The study was partially funded by the company, but it had no role in its design, data collection, analysis, or interpretation. Dr. O’Brien said that he had no additional disclosures.

BALTIMORE – Levetiracetam had effects on bone mineral density and markers of bone turnover that were similar to those seen with the older antiepileptic drugs carbamazepine and sodium valproate in a 12-month, randomized, controlled trial of 84 patients with partial epilepsy.

The finding was counter to the expectation that levetiracetam (Keppra) would have neutral or more benign effects on bone health because of its "cleaner pharmacokinetics – no effect on vitamin D metabolism – and a different mechanism of action," study investigator Dr. Terence J. O’Brien said in an interview. "Most [experts] thought it would be better for bone health. However, there is a previous study in rats that did show effect on bone. ... The clinical message is that neurologists need to monitor bone heath on all their patients chronically treated with AEDs."

Chronic antiepileptic drug use has been associated with increased risk of both bone disease and fracture, as well as weight gain and insulin resistance. It has been hoped that newer antiepileptic drugs with different mechanisms of action would minimize or eliminate these effects. One of these newer agents, levetiracetam, has a novel mechanism of action, binding to the SV2A receptors that interfere with synaptic vesicle exocytosis. It is not hepatically metabolized, so it does not affect hormonal levels.

"The clinical message is that neurologists need to monitor bone heath on all their patients chronically treated with antiepileptic drugs."

"There are plenty of reasons to believe it would have fewer bone and metabolic effects, but this had never been tested before in a randomized, controlled trial," said Dr. O’Brien, a professor of medicine at the University of Melbourne and head of the department of medicine at the Royal Melbourne Hospital.

Of 84 patients randomized to open-label substitution monotherapy with either levetiracetam or carbamazepine or valproate in the KONQUEST trial, 40 levetiracetam patients and 30 carbamazepine/valproate patients completed an assessment at 15 months. Dosing in the trial was flexible, and was increased or decreased by the treating neurologist according to tolerability and seizure control.

Dual energy X-ray absorptiometry (DXA) measurements of areal bone mineral density (aBMD) in the forearm was significantly lower at 15 months in both the levetiracetam and carbamazepine/valproate groups, compared with measurements taken at 3 months, but more so for levetiracetam, with reductions of 1.4% (P less than .001) and 0.96% (P = .015), respectively. Peripheral quantitative CT measurement of trabecular BMD in the radius was also reduced in both groups, by 2.25% (P = .005) with levetiracetam and by 2.9% (P = .001) for the older AEDs. There were no differences from 3-month assessments in aBMD of the lumbar spine or hip in either treatment group.

Markers of bone formation and resorption were among the secondary end points. The bone resorption marker beta C-terminal telopeptide of type 1 collagen was reduced in both treatment groups, by 12.8% (P = .021) with levetiracetam and by 15.6% (P = .028) with carbamazepine/valproate. However, the bone formation marker procollagen type 1 N-terminal propeptide was reduced only with the older AEDs, by 20.9% (P = .008). There were no differences in vitamin D or other markers of calcium homeostasis, Dr. O’Brien said.

Reduction in serum markers of bone turnover suggests reduced bone remodeling with AEDs, "an atypical mechanism for bone loss which warrants further study," he said.

In the interview, he added that the lack of effect on markers of bone formation for levetiracetam may indicate some differences in the mechanism of its effect, or may just have been a lack of power.

The exploratory end points of femoral neck aBMD, total bone area (trabecular), trabecular bone mineral content, and total bone area (cortical) were all significantly reduced in both groups. However, the anthropometric exploratory end points of weight and body mass index were increased only with the older AEDs, by 2.0% (P = .039) and 2.15% (P = .044), respectively.

There are no clear guidelines for bone health monitoring in patients on AEDs. "What we recommend is when you start the drug, [get] a baseline, and then [monitor] every 3-5 years. Vitamin D levels should also be checked and supplemented if deficient," he said in the interview.

A UCB Pharma spokeswoman declined to comment on the findings of KONQUEST. The study was partially funded by the company, but it had no role in its design, data collection, analysis, or interpretation. Dr. O’Brien said that he had no additional disclosures.

BALTIMORE – A seizure was initially the only presenting symptom in 1% of patients diagnosed with pulmonary embolism during a 5-year retrospective study of cases seen at an emergency department.

Although it is an unusual presentation, pulmonary embolism–related seizure does occur – and when it does, it’s a life-threatening emergency, Dr. Kimitoshi Kimura reported in a poster at the annual meeting of the American Epilepsy Society.

"With a seizure, clinical evaluation may be compromised by the postictal confusional state. Hypoxia, tachypnea, and tachycardia, which are important signs of PE, may be attributed to the seizure. This results in delayed diagnosis," said Dr. Kimura of the department of neurology at Kurashiki (Japan) Central Hospital.

He reported a retrospective study of 319 pulmonary embolism (PE) cases seen at the hospital over a 5-year period. The vast majority of these (282) did not involve any seizure activity. Most (165) had classic PE symptoms of chest pain, hypoxia, and impaired consciousness. In 75 cases, the only early symptom was swelling or tenderness in the leg, leading to a PE diagnosis. Another 42 cases were asymptomatic and were detected incidentally. No diagnostic details were available for 34 cases.

Only 1% (3 cases) initially presented as a seizure; none of these patients had a history of any seizure or cardiopulmonary disorders.

The first case was a 78-year-old man who "suddenly raised his hands over his head and stared at a fixed point for a substantial period of time," Dr. Kimura wrote. "On the next evening, he complained of increasing dyspnea and was taken to our hospital."

When he arrived, the patient was already in cardiopulmonary arrest. The embolism was diagnosed soon after, but the patient died the next day.

The second case was an 87-year-old woman who complained of chest discomfort while at home. The next morning, she experienced generalized tonic seizures with conjugated deviation; the seizures occurred intermittently for 4 hours. She was admitted to the hospital and received four 5-mg doses of diazepam. When the seizures stopped, the patient had persistent hypoxia and an elevated d-dimer of more than 10 mcg/mL (normal is less than 1.0 mcg/mL). Mild right ventricular overload and PE were detected.

"In this case, she was treated successfully with anticoagulation therapy," Dr. Kimura wrote.

The third patient was a 78-year-old woman admitted because of a 5-minute generalized tonic-clonic seizure and drowsiness. After the seizure, she also remained hypoxic and had a d-dimer value of 2.3 mcg/mL.

"At first, we suspected the cause of the seizure was a cerebral infarction because a small subacute infarction was detected, but intermittent oxygen desaturation persisted," Dr. Kimura noted. The embolism was diagnosed 2 days later. This patient was successfully treated with heparin.

Neither of the surviving patients required any antiepileptic drugs after discharge, he added.

Dr. Kimura reported that he had no financial conflicts.

BALTIMORE – A seizure was initially the only presenting symptom in 1% of patients diagnosed with pulmonary embolism during a 5-year retrospective study of cases seen at an emergency department.

Although it is an unusual presentation, pulmonary embolism–related seizure does occur – and when it does, it’s a life-threatening emergency, Dr. Kimitoshi Kimura reported in a poster at the annual meeting of the American Epilepsy Society.

"With a seizure, clinical evaluation may be compromised by the postictal confusional state. Hypoxia, tachypnea, and tachycardia, which are important signs of PE, may be attributed to the seizure. This results in delayed diagnosis," said Dr. Kimura of the department of neurology at Kurashiki (Japan) Central Hospital.

He reported a retrospective study of 319 pulmonary embolism (PE) cases seen at the hospital over a 5-year period. The vast majority of these (282) did not involve any seizure activity. Most (165) had classic PE symptoms of chest pain, hypoxia, and impaired consciousness. In 75 cases, the only early symptom was swelling or tenderness in the leg, leading to a PE diagnosis. Another 42 cases were asymptomatic and were detected incidentally. No diagnostic details were available for 34 cases.

Only 1% (3 cases) initially presented as a seizure; none of these patients had a history of any seizure or cardiopulmonary disorders.

The first case was a 78-year-old man who "suddenly raised his hands over his head and stared at a fixed point for a substantial period of time," Dr. Kimura wrote. "On the next evening, he complained of increasing dyspnea and was taken to our hospital."

When he arrived, the patient was already in cardiopulmonary arrest. The embolism was diagnosed soon after, but the patient died the next day.

The second case was an 87-year-old woman who complained of chest discomfort while at home. The next morning, she experienced generalized tonic seizures with conjugated deviation; the seizures occurred intermittently for 4 hours. She was admitted to the hospital and received four 5-mg doses of diazepam. When the seizures stopped, the patient had persistent hypoxia and an elevated d-dimer of more than 10 mcg/mL (normal is less than 1.0 mcg/mL). Mild right ventricular overload and PE were detected.

"In this case, she was treated successfully with anticoagulation therapy," Dr. Kimura wrote.

The third patient was a 78-year-old woman admitted because of a 5-minute generalized tonic-clonic seizure and drowsiness. After the seizure, she also remained hypoxic and had a d-dimer value of 2.3 mcg/mL.

"At first, we suspected the cause of the seizure was a cerebral infarction because a small subacute infarction was detected, but intermittent oxygen desaturation persisted," Dr. Kimura noted. The embolism was diagnosed 2 days later. This patient was successfully treated with heparin.

Neither of the surviving patients required any antiepileptic drugs after discharge, he added.

Dr. Kimura reported that he had no financial conflicts.

BALTIMORE – A seizure was initially the only presenting symptom in 1% of patients diagnosed with pulmonary embolism during a 5-year retrospective study of cases seen at an emergency department.

Although it is an unusual presentation, pulmonary embolism–related seizure does occur – and when it does, it’s a life-threatening emergency, Dr. Kimitoshi Kimura reported in a poster at the annual meeting of the American Epilepsy Society.

"With a seizure, clinical evaluation may be compromised by the postictal confusional state. Hypoxia, tachypnea, and tachycardia, which are important signs of PE, may be attributed to the seizure. This results in delayed diagnosis," said Dr. Kimura of the department of neurology at Kurashiki (Japan) Central Hospital.

He reported a retrospective study of 319 pulmonary embolism (PE) cases seen at the hospital over a 5-year period. The vast majority of these (282) did not involve any seizure activity. Most (165) had classic PE symptoms of chest pain, hypoxia, and impaired consciousness. In 75 cases, the only early symptom was swelling or tenderness in the leg, leading to a PE diagnosis. Another 42 cases were asymptomatic and were detected incidentally. No diagnostic details were available for 34 cases.

Only 1% (3 cases) initially presented as a seizure; none of these patients had a history of any seizure or cardiopulmonary disorders.

The first case was a 78-year-old man who "suddenly raised his hands over his head and stared at a fixed point for a substantial period of time," Dr. Kimura wrote. "On the next evening, he complained of increasing dyspnea and was taken to our hospital."

When he arrived, the patient was already in cardiopulmonary arrest. The embolism was diagnosed soon after, but the patient died the next day.

The second case was an 87-year-old woman who complained of chest discomfort while at home. The next morning, she experienced generalized tonic seizures with conjugated deviation; the seizures occurred intermittently for 4 hours. She was admitted to the hospital and received four 5-mg doses of diazepam. When the seizures stopped, the patient had persistent hypoxia and an elevated d-dimer of more than 10 mcg/mL (normal is less than 1.0 mcg/mL). Mild right ventricular overload and PE were detected.

"In this case, she was treated successfully with anticoagulation therapy," Dr. Kimura wrote.

The third patient was a 78-year-old woman admitted because of a 5-minute generalized tonic-clonic seizure and drowsiness. After the seizure, she also remained hypoxic and had a d-dimer value of 2.3 mcg/mL.

"At first, we suspected the cause of the seizure was a cerebral infarction because a small subacute infarction was detected, but intermittent oxygen desaturation persisted," Dr. Kimura noted. The embolism was diagnosed 2 days later. This patient was successfully treated with heparin.

Neither of the surviving patients required any antiepileptic drugs after discharge, he added.

Dr. Kimura reported that he had no financial conflicts.

BALTIMORE – A new study hints that mapping the functional connectivity of the brain may allow surgeons to pinpoint previously unidentified epileptogenic networks more precisely, leading to more effective epilepsy surgery.

Functional connectivity mapping could not only identify epileptogenic networks, but also could predict successful and failed epilepsy surgeries, Dr. Hyang Woon Lee reported in a study of the resting state functional MRI (fMRI) scans of 29 patients who underwent surgery for intractable partial epilepsy.

Photos courtesy Dr. Hyang Woon Lee and Dr. R. Todd Constable

"I was quite thrilled to find that intrinsic functional connectivity changes stand out in the epileptogenic zones," Dr. Lee said in an interview at the annual meeting of the American Epilepsy Society. She is in the departments of neurology at Yale University, New Haven, Conn., and at Ewha Womans University in Seoul, South Korea.

The research is based on a relatively new method of identifying brain regions that are structurally separate but functionally connected by previously unidentifiable neural networks. Dr. Lee’s colleague at Yale, R. Todd Constable, Ph.D., developed the technique of using a mathematical algorithm called intrinsic connectivity contrast (ICC) to identify interrelationships between the blood oxygenation level dependent signal of voxels measured with fMRI. A high degree of ICC for a particular voxel means that it has a strong connection to other brain areas. The resulting image shows the degree of these connections, and "provides a measure as to how well-connected any given tissue element is," Dr. Lee wrote in her poster.

The analysis can be done ipsilaterally, where connections to each voxel are compared with all others in the same hemisphere, and contralaterally, where connections to voxels in the other hemisphere are measured. The resulting maps identify functionally connected networks, Dr. Lee said. In the case of patients with focal epilepsy, they sometimes show that epileptogenic areas identified by intracranial EEG have additional connections, or are even part of a nodal network of abnormally functioning tissue.

Each of the 29 patients underwent presurgical fMRI and intracranial EEG to localize the seizure foci. Dr. Lee, Dr. Constable, and their coauthors analyzed the fMRI images with the ICC algorithm, both ipsilaterally and contralaterally. Dr. Lee then compared the ICC results to the intracranial EEG data that guided the epilepsy surgery. The ICC maps were a good match for the seizure onset and propagation zones detected by intracranial EEG, she said.

"Intracranial EEG seizure onset zones might have decreased ICCs, since the epileptogenic foci are likely to be abnormal brain tissue, often due to neuronal damage," she said.

Overall, 15 patients had good surgical outcomes, defined as an Engels class I, meaning they were free of disabling seizures. The other 14 patients had poor surgical outcomes: Engels classes II (rare disabling seizures), III (worthwhile improvement), and IV (no worthwhile improvement).

The determination of the seizure onset zones with ICC was concordant with presurgical intracranial EEG testing in 13 of the 15 patients with good surgical outcomes and in 7 of the 14 patients with poor outcomes.

The concordance between ICC and intracranial EEG also varied by the type of epilepsy. The techniques were 100% concordant among patients with extratemporal lobe epilepsy who had good outcomes. These patients often have ictal onset zones that are diffuse and sometimes difficult to determine.

The measurement of functional connectivity with fMRI has the potential to become a noninvasive presurgical diagnostic tool in epilepsy surgery based on its strong ability to identify the nodes of an epileptogenic network, Dr. Lee said.

"It might also help in the diagnosis of other neuropsychiatric disorders, such as Alzheimer’s disease, stroke, and schizophrenia by elucidating altered functional connectivity in the neural network. Although it’s still in the early stages of development, I believe this approach can be widely used for both clinical and scientific purposes with further validation."

Dr. Lee said that she had no financial disclosures.

BALTIMORE – A new study hints that mapping the functional connectivity of the brain may allow surgeons to pinpoint previously unidentified epileptogenic networks more precisely, leading to more effective epilepsy surgery.

Functional connectivity mapping could not only identify epileptogenic networks, but also could predict successful and failed epilepsy surgeries, Dr. Hyang Woon Lee reported in a study of the resting state functional MRI (fMRI) scans of 29 patients who underwent surgery for intractable partial epilepsy.

Photos courtesy Dr. Hyang Woon Lee and Dr. R. Todd Constable

"I was quite thrilled to find that intrinsic functional connectivity changes stand out in the epileptogenic zones," Dr. Lee said in an interview at the annual meeting of the American Epilepsy Society. She is in the departments of neurology at Yale University, New Haven, Conn., and at Ewha Womans University in Seoul, South Korea.

The research is based on a relatively new method of identifying brain regions that are structurally separate but functionally connected by previously unidentifiable neural networks. Dr. Lee’s colleague at Yale, R. Todd Constable, Ph.D., developed the technique of using a mathematical algorithm called intrinsic connectivity contrast (ICC) to identify interrelationships between the blood oxygenation level dependent signal of voxels measured with fMRI. A high degree of ICC for a particular voxel means that it has a strong connection to other brain areas. The resulting image shows the degree of these connections, and "provides a measure as to how well-connected any given tissue element is," Dr. Lee wrote in her poster.

The analysis can be done ipsilaterally, where connections to each voxel are compared with all others in the same hemisphere, and contralaterally, where connections to voxels in the other hemisphere are measured. The resulting maps identify functionally connected networks, Dr. Lee said. In the case of patients with focal epilepsy, they sometimes show that epileptogenic areas identified by intracranial EEG have additional connections, or are even part of a nodal network of abnormally functioning tissue.

Each of the 29 patients underwent presurgical fMRI and intracranial EEG to localize the seizure foci. Dr. Lee, Dr. Constable, and their coauthors analyzed the fMRI images with the ICC algorithm, both ipsilaterally and contralaterally. Dr. Lee then compared the ICC results to the intracranial EEG data that guided the epilepsy surgery. The ICC maps were a good match for the seizure onset and propagation zones detected by intracranial EEG, she said.

"Intracranial EEG seizure onset zones might have decreased ICCs, since the epileptogenic foci are likely to be abnormal brain tissue, often due to neuronal damage," she said.

Overall, 15 patients had good surgical outcomes, defined as an Engels class I, meaning they were free of disabling seizures. The other 14 patients had poor surgical outcomes: Engels classes II (rare disabling seizures), III (worthwhile improvement), and IV (no worthwhile improvement).

The determination of the seizure onset zones with ICC was concordant with presurgical intracranial EEG testing in 13 of the 15 patients with good surgical outcomes and in 7 of the 14 patients with poor outcomes.

The concordance between ICC and intracranial EEG also varied by the type of epilepsy. The techniques were 100% concordant among patients with extratemporal lobe epilepsy who had good outcomes. These patients often have ictal onset zones that are diffuse and sometimes difficult to determine.

The measurement of functional connectivity with fMRI has the potential to become a noninvasive presurgical diagnostic tool in epilepsy surgery based on its strong ability to identify the nodes of an epileptogenic network, Dr. Lee said.

"It might also help in the diagnosis of other neuropsychiatric disorders, such as Alzheimer’s disease, stroke, and schizophrenia by elucidating altered functional connectivity in the neural network. Although it’s still in the early stages of development, I believe this approach can be widely used for both clinical and scientific purposes with further validation."

Dr. Lee said that she had no financial disclosures.

BALTIMORE – A new study hints that mapping the functional connectivity of the brain may allow surgeons to pinpoint previously unidentified epileptogenic networks more precisely, leading to more effective epilepsy surgery.

Functional connectivity mapping could not only identify epileptogenic networks, but also could predict successful and failed epilepsy surgeries, Dr. Hyang Woon Lee reported in a study of the resting state functional MRI (fMRI) scans of 29 patients who underwent surgery for intractable partial epilepsy.

Photos courtesy Dr. Hyang Woon Lee and Dr. R. Todd Constable

"I was quite thrilled to find that intrinsic functional connectivity changes stand out in the epileptogenic zones," Dr. Lee said in an interview at the annual meeting of the American Epilepsy Society. She is in the departments of neurology at Yale University, New Haven, Conn., and at Ewha Womans University in Seoul, South Korea.

The research is based on a relatively new method of identifying brain regions that are structurally separate but functionally connected by previously unidentifiable neural networks. Dr. Lee’s colleague at Yale, R. Todd Constable, Ph.D., developed the technique of using a mathematical algorithm called intrinsic connectivity contrast (ICC) to identify interrelationships between the blood oxygenation level dependent signal of voxels measured with fMRI. A high degree of ICC for a particular voxel means that it has a strong connection to other brain areas. The resulting image shows the degree of these connections, and "provides a measure as to how well-connected any given tissue element is," Dr. Lee wrote in her poster.

The analysis can be done ipsilaterally, where connections to each voxel are compared with all others in the same hemisphere, and contralaterally, where connections to voxels in the other hemisphere are measured. The resulting maps identify functionally connected networks, Dr. Lee said. In the case of patients with focal epilepsy, they sometimes show that epileptogenic areas identified by intracranial EEG have additional connections, or are even part of a nodal network of abnormally functioning tissue.

Each of the 29 patients underwent presurgical fMRI and intracranial EEG to localize the seizure foci. Dr. Lee, Dr. Constable, and their coauthors analyzed the fMRI images with the ICC algorithm, both ipsilaterally and contralaterally. Dr. Lee then compared the ICC results to the intracranial EEG data that guided the epilepsy surgery. The ICC maps were a good match for the seizure onset and propagation zones detected by intracranial EEG, she said.

"Intracranial EEG seizure onset zones might have decreased ICCs, since the epileptogenic foci are likely to be abnormal brain tissue, often due to neuronal damage," she said.

Overall, 15 patients had good surgical outcomes, defined as an Engels class I, meaning they were free of disabling seizures. The other 14 patients had poor surgical outcomes: Engels classes II (rare disabling seizures), III (worthwhile improvement), and IV (no worthwhile improvement).

The determination of the seizure onset zones with ICC was concordant with presurgical intracranial EEG testing in 13 of the 15 patients with good surgical outcomes and in 7 of the 14 patients with poor outcomes.

The concordance between ICC and intracranial EEG also varied by the type of epilepsy. The techniques were 100% concordant among patients with extratemporal lobe epilepsy who had good outcomes. These patients often have ictal onset zones that are diffuse and sometimes difficult to determine.

The measurement of functional connectivity with fMRI has the potential to become a noninvasive presurgical diagnostic tool in epilepsy surgery based on its strong ability to identify the nodes of an epileptogenic network, Dr. Lee said.

"It might also help in the diagnosis of other neuropsychiatric disorders, such as Alzheimer’s disease, stroke, and schizophrenia by elucidating altered functional connectivity in the neural network. Although it’s still in the early stages of development, I believe this approach can be widely used for both clinical and scientific purposes with further validation."

Dr. Lee said that she had no financial disclosures.

BALTIMORE – Patients who acquired a nosocomial infection during their hospital stay for status epilepticus had five times greater odds of dying than did noninfected patients in a single-center, observational cohort study.

The infections, most of which involved the respiratory tract, also were associated with having treatment-refractory status epilepticus, a longer ICU stay, and a worse overall outcome, Dr. Raoul Sutter said at the annual meeting of the American Epilepsy Society.

"Our findings underscore the importance of close observation of these patents and rigorous adherence to the prevention guidelines for hospital-acquired infections, as well as the urgent need for early diagnosis and treatment of status epilepticus and infection-related complications, especially in the first 3 days," said Dr. Sutter, who conducted the research while he was a member of the departments of neurology and intensive care medicine at University Hospital Basel (Switzerland). He is now a research fellow in the neurosciences critical care unit at Johns Hopkins University, Baltimore.

Dr. Sutter and his coinvestigators could not identify a reliable one-time marker for indicating the presence of infection at the onset of status.

He and his colleagues studied a cohort of 160 patients hospitalized for status epilepticus at University Hospital Basel (Switzerland) during a 5-year period. Their median age was 65 years (range 17-91 years) and more than half (55%) required mechanical ventilation.

About 22% of the cohort developed an infection during the first 3 days of hospital stay. Patients with an infection had a significantly longer ICU stay (mean of 11 days vs. 6 days) and five times greater odds of dying than did patients without infections, according to the study’s findings, which Dr. Sutter presented in two posters at the meeting.

Most of the infections involved the respiratory tract, with half being ventilator-associated pneumonias. Compared with patients without infections, patients with respiratory tract infections had a significantly longer duration of status (mean 7 vs. 2 days) and a longer ICU stay (mean 11 vs. 7 days). These infections also were associated with a significant increase in the odds of developing refractory status (odds ratio, 5.4) and dying (OR, 4). A majority (59%) with refractory status and an infection died (59%).

"Time of onset of infectious complications during status epilepticus was a critical element in outcome," Dr. Sutter said in an interview. "Patients who had a confirmed infection before admission had no significant increase in the risk of refractory status or death."

Early detection and treatment of infectious complications may mitigate their deleterious effects on these critically ill patients. Because early detection in this setting can be challenging, biomarkers could be useful for their diagnosis, he said.

In a search for a biomarker to indicate the presence of infection at the onset of status, the investigators found that serum procalcitonin, C-reactive protein (CRP), or white blood cell count did not accurately predict an oncoming hospital-acquired infection. However, a serial increase in CRP and white blood cell count over 3 days after status onset was significantly associated with infection.

Low levels tended to rule out infections. The negative predictive value of a low CRP over 3 days was 97%, but specificity remained low and did not improve despite using several cut-off values.

"Right now, we have identified the problem and deleterious impact of infections in status epilepticus, but we don’t really have an ideal solution to it," Dr. Sutter said.

The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America have issued practice recommendations to reduce the risk of ventilator-associated pneumonia. In addition to minimizing mechanical ventilation, the recommendations suggest measures to reduce colonization of the aerodigestive tract and prevent aspiration.

Selective digestive tract decontamination and selective oropharyngeal decontamination have recently been reported to reduce the mortality rate of critical ill patients by an estimated 3.5% and 2.9%, respectively, Dr. Sutter said.

"Despite the potential benefits described, selective decontamination of the digestive tract has not been largely adopted, most likely because of major concerns about promoting the growth of resistant bacteria," he said. "However, in light of the association of respiratory tract infections and worse outcomes that we observed, the benefit may outweigh this risk by far."

Dr. Sutter reported having no financial disclosures.

BALTIMORE – Patients who acquired a nosocomial infection during their hospital stay for status epilepticus had five times greater odds of dying than did noninfected patients in a single-center, observational cohort study.

The infections, most of which involved the respiratory tract, also were associated with having treatment-refractory status epilepticus, a longer ICU stay, and a worse overall outcome, Dr. Raoul Sutter said at the annual meeting of the American Epilepsy Society.

"Our findings underscore the importance of close observation of these patents and rigorous adherence to the prevention guidelines for hospital-acquired infections, as well as the urgent need for early diagnosis and treatment of status epilepticus and infection-related complications, especially in the first 3 days," said Dr. Sutter, who conducted the research while he was a member of the departments of neurology and intensive care medicine at University Hospital Basel (Switzerland). He is now a research fellow in the neurosciences critical care unit at Johns Hopkins University, Baltimore.

Dr. Sutter and his coinvestigators could not identify a reliable one-time marker for indicating the presence of infection at the onset of status.

He and his colleagues studied a cohort of 160 patients hospitalized for status epilepticus at University Hospital Basel (Switzerland) during a 5-year period. Their median age was 65 years (range 17-91 years) and more than half (55%) required mechanical ventilation.

About 22% of the cohort developed an infection during the first 3 days of hospital stay. Patients with an infection had a significantly longer ICU stay (mean of 11 days vs. 6 days) and five times greater odds of dying than did patients without infections, according to the study’s findings, which Dr. Sutter presented in two posters at the meeting.

Most of the infections involved the respiratory tract, with half being ventilator-associated pneumonias. Compared with patients without infections, patients with respiratory tract infections had a significantly longer duration of status (mean 7 vs. 2 days) and a longer ICU stay (mean 11 vs. 7 days). These infections also were associated with a significant increase in the odds of developing refractory status (odds ratio, 5.4) and dying (OR, 4). A majority (59%) with refractory status and an infection died (59%).

"Time of onset of infectious complications during status epilepticus was a critical element in outcome," Dr. Sutter said in an interview. "Patients who had a confirmed infection before admission had no significant increase in the risk of refractory status or death."

Early detection and treatment of infectious complications may mitigate their deleterious effects on these critically ill patients. Because early detection in this setting can be challenging, biomarkers could be useful for their diagnosis, he said.

In a search for a biomarker to indicate the presence of infection at the onset of status, the investigators found that serum procalcitonin, C-reactive protein (CRP), or white blood cell count did not accurately predict an oncoming hospital-acquired infection. However, a serial increase in CRP and white blood cell count over 3 days after status onset was significantly associated with infection.

Low levels tended to rule out infections. The negative predictive value of a low CRP over 3 days was 97%, but specificity remained low and did not improve despite using several cut-off values.

"Right now, we have identified the problem and deleterious impact of infections in status epilepticus, but we don’t really have an ideal solution to it," Dr. Sutter said.

The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America have issued practice recommendations to reduce the risk of ventilator-associated pneumonia. In addition to minimizing mechanical ventilation, the recommendations suggest measures to reduce colonization of the aerodigestive tract and prevent aspiration.

Selective digestive tract decontamination and selective oropharyngeal decontamination have recently been reported to reduce the mortality rate of critical ill patients by an estimated 3.5% and 2.9%, respectively, Dr. Sutter said.

"Despite the potential benefits described, selective decontamination of the digestive tract has not been largely adopted, most likely because of major concerns about promoting the growth of resistant bacteria," he said. "However, in light of the association of respiratory tract infections and worse outcomes that we observed, the benefit may outweigh this risk by far."

Dr. Sutter reported having no financial disclosures.

BALTIMORE – Patients who acquired a nosocomial infection during their hospital stay for status epilepticus had five times greater odds of dying than did noninfected patients in a single-center, observational cohort study.

The infections, most of which involved the respiratory tract, also were associated with having treatment-refractory status epilepticus, a longer ICU stay, and a worse overall outcome, Dr. Raoul Sutter said at the annual meeting of the American Epilepsy Society.

"Our findings underscore the importance of close observation of these patents and rigorous adherence to the prevention guidelines for hospital-acquired infections, as well as the urgent need for early diagnosis and treatment of status epilepticus and infection-related complications, especially in the first 3 days," said Dr. Sutter, who conducted the research while he was a member of the departments of neurology and intensive care medicine at University Hospital Basel (Switzerland). He is now a research fellow in the neurosciences critical care unit at Johns Hopkins University, Baltimore.

Dr. Sutter and his coinvestigators could not identify a reliable one-time marker for indicating the presence of infection at the onset of status.

He and his colleagues studied a cohort of 160 patients hospitalized for status epilepticus at University Hospital Basel (Switzerland) during a 5-year period. Their median age was 65 years (range 17-91 years) and more than half (55%) required mechanical ventilation.

About 22% of the cohort developed an infection during the first 3 days of hospital stay. Patients with an infection had a significantly longer ICU stay (mean of 11 days vs. 6 days) and five times greater odds of dying than did patients without infections, according to the study’s findings, which Dr. Sutter presented in two posters at the meeting.

Most of the infections involved the respiratory tract, with half being ventilator-associated pneumonias. Compared with patients without infections, patients with respiratory tract infections had a significantly longer duration of status (mean 7 vs. 2 days) and a longer ICU stay (mean 11 vs. 7 days). These infections also were associated with a significant increase in the odds of developing refractory status (odds ratio, 5.4) and dying (OR, 4). A majority (59%) with refractory status and an infection died (59%).

"Time of onset of infectious complications during status epilepticus was a critical element in outcome," Dr. Sutter said in an interview. "Patients who had a confirmed infection before admission had no significant increase in the risk of refractory status or death."

Early detection and treatment of infectious complications may mitigate their deleterious effects on these critically ill patients. Because early detection in this setting can be challenging, biomarkers could be useful for their diagnosis, he said.

In a search for a biomarker to indicate the presence of infection at the onset of status, the investigators found that serum procalcitonin, C-reactive protein (CRP), or white blood cell count did not accurately predict an oncoming hospital-acquired infection. However, a serial increase in CRP and white blood cell count over 3 days after status onset was significantly associated with infection.

Low levels tended to rule out infections. The negative predictive value of a low CRP over 3 days was 97%, but specificity remained low and did not improve despite using several cut-off values.

"Right now, we have identified the problem and deleterious impact of infections in status epilepticus, but we don’t really have an ideal solution to it," Dr. Sutter said.

The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America have issued practice recommendations to reduce the risk of ventilator-associated pneumonia. In addition to minimizing mechanical ventilation, the recommendations suggest measures to reduce colonization of the aerodigestive tract and prevent aspiration.

Selective digestive tract decontamination and selective oropharyngeal decontamination have recently been reported to reduce the mortality rate of critical ill patients by an estimated 3.5% and 2.9%, respectively, Dr. Sutter said.

"Despite the potential benefits described, selective decontamination of the digestive tract has not been largely adopted, most likely because of major concerns about promoting the growth of resistant bacteria," he said. "However, in light of the association of respiratory tract infections and worse outcomes that we observed, the benefit may outweigh this risk by far."

Dr. Sutter reported having no financial disclosures.

BALTIMORE – Comorbid attention-deficit/hyperactivity disorder persistently affected the cognitive development of children with epilepsy up to 5 or 6 years after the onset of seizures in a prospective case-control study.

In a previous study of the same group of children, Connie Sung and her colleagues found that children with new-onset epilepsy and comorbid ADHD (with or without academic problems) had poorer cognitive performance at baseline and abnormal cognitive development after 2 years, compared with healthy control children and children with new-onset epilepsy but without ADHD.

In the current study, Ms. Sung, a doctoral student in the department of rehabilitation psychology and special education at the University of Wisconsin, Madison, and her colleagues conducted cognitive assessments of 75 children with epilepsy and 62 of their healthy first-degree cousins who served as controls. They gave the children a comprehensive battery of neurologic tests to assess academic achievement, intelligence, language, memory, executive function, and motor function at baseline and at 2 years’ and 5-6 years’ follow-up. The children’s average age at last follow-up was 13 years.

At baseline, ADHD and academic performance were significantly associated with neuropsychological impairment across all cognitive domains. However, children with epilepsy who did not have either ADHD or academic performance problems had "entirely normal" cognition, compared with controls, Ms. Sung reported in a poster at the annual meeting of the American Epilepsy Society.

"This effect at baseline suggests an antecedent neurobiological effect," Ms. Sung wrote.

These trends persisted after 2 years and 5-6 years. Full-scale raw IQ scores after 2 years were approximately 88 for healthy controls and for children with epilepsy without comorbidities, compared with 76 in children with epilepsy and academic performance problems and 68 in children with epilepsy and comorbid ADHD.

At 5-6 years after onset, children with epilepsy and either ADHD or academic problems had significantly worse cognitive trajectories than did controls, but children with epilepsy who did not have these comorbidities had normal cognitive trajectories.

The researchers said that their findings were limited by the study’s relatively small sample size, but the results suggest that specific neurobehavioral comorbidities at the time of the onset of epilepsy appear to be markers for abnormal cognitive development before and after epilepsy.

"These effects are strong and consistent [and] affect all cognitive domains," Ms. Sung wrote.

The researchers are now studying the effects of the presence or absence of ADHD and learning disorders on real-life outcomes such as employment, education, and income, as their study population ages. "These comorbidities may represent early risk factors for later life span complications [in children with epilepsy], opening the possibility for early intervention," Ms. Sung reported.

The study was supported in part by a grant from the National Institute of Neurological Disorders and Stroke. The researchers said they had no relevant financial disclosures.

BALTIMORE – Comorbid attention-deficit/hyperactivity disorder persistently affected the cognitive development of children with epilepsy up to 5 or 6 years after the onset of seizures in a prospective case-control study.

In a previous study of the same group of children, Connie Sung and her colleagues found that children with new-onset epilepsy and comorbid ADHD (with or without academic problems) had poorer cognitive performance at baseline and abnormal cognitive development after 2 years, compared with healthy control children and children with new-onset epilepsy but without ADHD.

In the current study, Ms. Sung, a doctoral student in the department of rehabilitation psychology and special education at the University of Wisconsin, Madison, and her colleagues conducted cognitive assessments of 75 children with epilepsy and 62 of their healthy first-degree cousins who served as controls. They gave the children a comprehensive battery of neurologic tests to assess academic achievement, intelligence, language, memory, executive function, and motor function at baseline and at 2 years’ and 5-6 years’ follow-up. The children’s average age at last follow-up was 13 years.

At baseline, ADHD and academic performance were significantly associated with neuropsychological impairment across all cognitive domains. However, children with epilepsy who did not have either ADHD or academic performance problems had "entirely normal" cognition, compared with controls, Ms. Sung reported in a poster at the annual meeting of the American Epilepsy Society.

"This effect at baseline suggests an antecedent neurobiological effect," Ms. Sung wrote.

These trends persisted after 2 years and 5-6 years. Full-scale raw IQ scores after 2 years were approximately 88 for healthy controls and for children with epilepsy without comorbidities, compared with 76 in children with epilepsy and academic performance problems and 68 in children with epilepsy and comorbid ADHD.

At 5-6 years after onset, children with epilepsy and either ADHD or academic problems had significantly worse cognitive trajectories than did controls, but children with epilepsy who did not have these comorbidities had normal cognitive trajectories.

The researchers said that their findings were limited by the study’s relatively small sample size, but the results suggest that specific neurobehavioral comorbidities at the time of the onset of epilepsy appear to be markers for abnormal cognitive development before and after epilepsy.

"These effects are strong and consistent [and] affect all cognitive domains," Ms. Sung wrote.

The researchers are now studying the effects of the presence or absence of ADHD and learning disorders on real-life outcomes such as employment, education, and income, as their study population ages. "These comorbidities may represent early risk factors for later life span complications [in children with epilepsy], opening the possibility for early intervention," Ms. Sung reported.

The study was supported in part by a grant from the National Institute of Neurological Disorders and Stroke. The researchers said they had no relevant financial disclosures.

BALTIMORE – Comorbid attention-deficit/hyperactivity disorder persistently affected the cognitive development of children with epilepsy up to 5 or 6 years after the onset of seizures in a prospective case-control study.

In a previous study of the same group of children, Connie Sung and her colleagues found that children with new-onset epilepsy and comorbid ADHD (with or without academic problems) had poorer cognitive performance at baseline and abnormal cognitive development after 2 years, compared with healthy control children and children with new-onset epilepsy but without ADHD.

In the current study, Ms. Sung, a doctoral student in the department of rehabilitation psychology and special education at the University of Wisconsin, Madison, and her colleagues conducted cognitive assessments of 75 children with epilepsy and 62 of their healthy first-degree cousins who served as controls. They gave the children a comprehensive battery of neurologic tests to assess academic achievement, intelligence, language, memory, executive function, and motor function at baseline and at 2 years’ and 5-6 years’ follow-up. The children’s average age at last follow-up was 13 years.

At baseline, ADHD and academic performance were significantly associated with neuropsychological impairment across all cognitive domains. However, children with epilepsy who did not have either ADHD or academic performance problems had "entirely normal" cognition, compared with controls, Ms. Sung reported in a poster at the annual meeting of the American Epilepsy Society.

"This effect at baseline suggests an antecedent neurobiological effect," Ms. Sung wrote.

These trends persisted after 2 years and 5-6 years. Full-scale raw IQ scores after 2 years were approximately 88 for healthy controls and for children with epilepsy without comorbidities, compared with 76 in children with epilepsy and academic performance problems and 68 in children with epilepsy and comorbid ADHD.

At 5-6 years after onset, children with epilepsy and either ADHD or academic problems had significantly worse cognitive trajectories than did controls, but children with epilepsy who did not have these comorbidities had normal cognitive trajectories.

The researchers said that their findings were limited by the study’s relatively small sample size, but the results suggest that specific neurobehavioral comorbidities at the time of the onset of epilepsy appear to be markers for abnormal cognitive development before and after epilepsy.

"These effects are strong and consistent [and] affect all cognitive domains," Ms. Sung wrote.

The researchers are now studying the effects of the presence or absence of ADHD and learning disorders on real-life outcomes such as employment, education, and income, as their study population ages. "These comorbidities may represent early risk factors for later life span complications [in children with epilepsy], opening the possibility for early intervention," Ms. Sung reported.

The study was supported in part by a grant from the National Institute of Neurological Disorders and Stroke. The researchers said they had no relevant financial disclosures.

BALTIMORE – The risk for children with febrile seizures to develop epilepsy decreased with time in an analysis of the prospective U.K. National General Practice Study of Epilepsy.

Short-term studies have shown that 1%-3% of children with febrile seizures develop afebrile seizures later in life, said Dr. Gail S. Bell of University College London Institute of Neurology.

Dr. Bell and her colleagues sought to determine if the risk of newly developing epilepsy in children with febrile seizures would decrease over time despite a continual increase in the cumulative incidence of epilepsy over time. They presented their findings in a poster at the annual meeting of the American Epilepsy Society.

They reviewed data from a cohort of 220 individuals with febrile seizures (aside from neonatal seizures) who were enrolled in the study in 1984-1987.

Overall, 68% of the children had no further seizures after their initial seizure. Of 181 individuals who were followed through 2009-2010, 175 had been free of seizures for the past 5 years, including 171 who were not taking antiepileptic drugs, the researchers noted.

However, the risk of recurrent seizures was slightly higher among children for whom the index seizure was not the first febrile seizure (hazard ratio, 1.76).

A total of 14 patients (6%) developed epilepsy and 17 (8%) developed afebrile seizures, the researchers said. Overall, "the probability of developing epilepsy by 20 years after the index seizure was 6.7%," they noted. The standardized incidence ratio for developing epilepsy was 9.7; this was highest among children aged 0-10 years with up to 10 years of follow-up, and it decreased with age until it was no longer significant in individuals aged 15-20 years with 10-20 years of follow-up.

The findings were limited by the relatively small study population, but the results suggest that epilepsy risk decreases with time in most cases, the researchers said. "Larger studies, ideally stratified by ethnic group, are required to establish whether the risk of developing epilepsy decreases to the population rate."

The study was funded by the U.K. Brain Research Trust and the U.K. Epilepsy Society. The researchers had no financial conflicts to disclose.

BALTIMORE – The risk for children with febrile seizures to develop epilepsy decreased with time in an analysis of the prospective U.K. National General Practice Study of Epilepsy.

Short-term studies have shown that 1%-3% of children with febrile seizures develop afebrile seizures later in life, said Dr. Gail S. Bell of University College London Institute of Neurology.

Dr. Bell and her colleagues sought to determine if the risk of newly developing epilepsy in children with febrile seizures would decrease over time despite a continual increase in the cumulative incidence of epilepsy over time. They presented their findings in a poster at the annual meeting of the American Epilepsy Society.

They reviewed data from a cohort of 220 individuals with febrile seizures (aside from neonatal seizures) who were enrolled in the study in 1984-1987.

Overall, 68% of the children had no further seizures after their initial seizure. Of 181 individuals who were followed through 2009-2010, 175 had been free of seizures for the past 5 years, including 171 who were not taking antiepileptic drugs, the researchers noted.

However, the risk of recurrent seizures was slightly higher among children for whom the index seizure was not the first febrile seizure (hazard ratio, 1.76).

A total of 14 patients (6%) developed epilepsy and 17 (8%) developed afebrile seizures, the researchers said. Overall, "the probability of developing epilepsy by 20 years after the index seizure was 6.7%," they noted. The standardized incidence ratio for developing epilepsy was 9.7; this was highest among children aged 0-10 years with up to 10 years of follow-up, and it decreased with age until it was no longer significant in individuals aged 15-20 years with 10-20 years of follow-up.

The findings were limited by the relatively small study population, but the results suggest that epilepsy risk decreases with time in most cases, the researchers said. "Larger studies, ideally stratified by ethnic group, are required to establish whether the risk of developing epilepsy decreases to the population rate."

The study was funded by the U.K. Brain Research Trust and the U.K. Epilepsy Society. The researchers had no financial conflicts to disclose.

BALTIMORE – The risk for children with febrile seizures to develop epilepsy decreased with time in an analysis of the prospective U.K. National General Practice Study of Epilepsy.

Short-term studies have shown that 1%-3% of children with febrile seizures develop afebrile seizures later in life, said Dr. Gail S. Bell of University College London Institute of Neurology.

Dr. Bell and her colleagues sought to determine if the risk of newly developing epilepsy in children with febrile seizures would decrease over time despite a continual increase in the cumulative incidence of epilepsy over time. They presented their findings in a poster at the annual meeting of the American Epilepsy Society.

They reviewed data from a cohort of 220 individuals with febrile seizures (aside from neonatal seizures) who were enrolled in the study in 1984-1987.

Overall, 68% of the children had no further seizures after their initial seizure. Of 181 individuals who were followed through 2009-2010, 175 had been free of seizures for the past 5 years, including 171 who were not taking antiepileptic drugs, the researchers noted.

However, the risk of recurrent seizures was slightly higher among children for whom the index seizure was not the first febrile seizure (hazard ratio, 1.76).

A total of 14 patients (6%) developed epilepsy and 17 (8%) developed afebrile seizures, the researchers said. Overall, "the probability of developing epilepsy by 20 years after the index seizure was 6.7%," they noted. The standardized incidence ratio for developing epilepsy was 9.7; this was highest among children aged 0-10 years with up to 10 years of follow-up, and it decreased with age until it was no longer significant in individuals aged 15-20 years with 10-20 years of follow-up.

The findings were limited by the relatively small study population, but the results suggest that epilepsy risk decreases with time in most cases, the researchers said. "Larger studies, ideally stratified by ethnic group, are required to establish whether the risk of developing epilepsy decreases to the population rate."

The study was funded by the U.K. Brain Research Trust and the U.K. Epilepsy Society. The researchers had no financial conflicts to disclose.

BALTIMORE – The safety profile for retigabine is generally consistent with that of other antiepileptic drugs, but data from studies in its evaluation process show that it also carries a novel, small increased risk of urinary voiding dysfunction.

At the annual meeting of the American Epilepsy Society Dr. Neil Brickel of GlaxoSmithKline’s clinical safety and pharmacovigilance group in Middlesex, England, reported on the safety of the novel drug in three phase III, randomized, double-blind, placebo-controlled trials, four phase II studies, and six long-term open-label extension studies, totalling 1,365 patients.

Retigabine is the international nonproprietary name of the drug, but it was approved in the United States in June 2011 under the adopted name ezogabine as an adjunctive therapy in adults with partial-onset seizures. It is a first-in-class potassium channel opener manufactured by GlaxoSmithKline and Valeant Pharmaceuticals International, and sold under the brand name Trobalt in Europe and Potiga in the United States.

In all of the studies that Dr. Brickel analyzed, retigabine was evaluated as a second, add-on agent. As of Oct. 2, 2009, 1,217 of the 1,365 patients had been on treatment at least 1 month, 801 for at least 6 months, and 586 for 1 year or longer.

As expected with any antiepileptic drug (AED), the most frequent adverse events involved the central nervous system. The most common in the three pivotal controlled trials were dizziness (23% of retigabine-treated patients vs. 9% of placebo-treated patients) and somnolence (reported by 22% vs. 12%, respectively). The only CNS adverse events that were not dose related were headache (reported by 15% of the retigabine group vs. 16% of the placebo group) and fatigue (by 15% and 6%, respectively). Other adverse events occurring in more than 10% of subjects were confusional state, tremor, and abnormal coordination. For the most part, patients reported these adverse events early on, during the titration phases of the trials, Dr. Brickel said.

Adverse events led to discontinuation in 437 patients (32%) of the total phase II/III study population. Again, these were primarily CNS and dose related. Discontinuations for any event occurred in 11% of the placebo group. Among those taking retigabine, discontinuations occurred in 17% of those assigned to 600 mg, 25% of those assigned to 900 mg, and 31% of those assigned to 1,200 mg. The most common reason for discontinuation was dizziness.

"Two-thirds of patients were able to continue in the study, even with the fixed titration regimen and at the 1,200-mg dose," Dr. Brickel noted.

Serious adverse events (SAEs) were infrequent, and also typically CNS related. In the three pivotal controlled trials, SAEs occurred in 6% of the placebo group and 9% of the retigabine patients. Six of the patients taking retigabine developed a psychotic disorder (five with 1,200 mg, one with 900 mg), compared with none of the placebo patients. Convulsions occurred in 1.2% of the placebo group and in 1.5% of the retigabine patients, across all doses. This finding was not unexpected, considering the underlying epilepsy, he said.

No other SAE was reported in more than two patients in any group. Deaths occurred in three placebo patients and two patients in the retigabine group. One in each group was a sudden death.

In the three pivotal trials, urinary and renal-related adverse events occurred in 17% of retigabine patients, compared with 13% of the placebo-treated patients. In the entire phase II/III study population, 26% of the 1,365 patients reported a urinary adverse event.

However, events related to urinary voiding dysfunction, which have a plausible biological relation to retigabine’s pharmacology, occurred in less than 4% of retigabine-treated patients in the phase III trials alone and in all phase II and III trial populations combined. Urinary hesitation was the most common of these in the entire phase II and III study group, occurring in 3.1%, followed by urinary retention in 1.9%. Catheterization was required in four patients taking retigabine and in one patient on placebo.

"These all occurred in a smaller number of patients and provide a better guide as to how many patents are potentially at risk. It is also important to note that these events were for the most part ‘mild’ in intensity and the patients were able to continue treatment," Dr. Brickel said in an interview.

Dr. Brickel also said that GSK is "communicating these risks to potential prescribers and encouraging them to advise patients of the symptoms relating to difficulty in passing urine that could range from discomfort on bladder emptying, hesitancy, poor flow through to a complete inability to void (acute urinary retention). GSK is keen to proactively manage this."

The study was funded by GSK and Valeant Pharmaceuticals International, and all of the investigators are employees of either company.

BALTIMORE – The safety profile for retigabine is generally consistent with that of other antiepileptic drugs, but data from studies in its evaluation process show that it also carries a novel, small increased risk of urinary voiding dysfunction.

At the annual meeting of the American Epilepsy Society Dr. Neil Brickel of GlaxoSmithKline’s clinical safety and pharmacovigilance group in Middlesex, England, reported on the safety of the novel drug in three phase III, randomized, double-blind, placebo-controlled trials, four phase II studies, and six long-term open-label extension studies, totalling 1,365 patients.

Retigabine is the international nonproprietary name of the drug, but it was approved in the United States in June 2011 under the adopted name ezogabine as an adjunctive therapy in adults with partial-onset seizures. It is a first-in-class potassium channel opener manufactured by GlaxoSmithKline and Valeant Pharmaceuticals International, and sold under the brand name Trobalt in Europe and Potiga in the United States.

In all of the studies that Dr. Brickel analyzed, retigabine was evaluated as a second, add-on agent. As of Oct. 2, 2009, 1,217 of the 1,365 patients had been on treatment at least 1 month, 801 for at least 6 months, and 586 for 1 year or longer.

As expected with any antiepileptic drug (AED), the most frequent adverse events involved the central nervous system. The most common in the three pivotal controlled trials were dizziness (23% of retigabine-treated patients vs. 9% of placebo-treated patients) and somnolence (reported by 22% vs. 12%, respectively). The only CNS adverse events that were not dose related were headache (reported by 15% of the retigabine group vs. 16% of the placebo group) and fatigue (by 15% and 6%, respectively). Other adverse events occurring in more than 10% of subjects were confusional state, tremor, and abnormal coordination. For the most part, patients reported these adverse events early on, during the titration phases of the trials, Dr. Brickel said.

Adverse events led to discontinuation in 437 patients (32%) of the total phase II/III study population. Again, these were primarily CNS and dose related. Discontinuations for any event occurred in 11% of the placebo group. Among those taking retigabine, discontinuations occurred in 17% of those assigned to 600 mg, 25% of those assigned to 900 mg, and 31% of those assigned to 1,200 mg. The most common reason for discontinuation was dizziness.

"Two-thirds of patients were able to continue in the study, even with the fixed titration regimen and at the 1,200-mg dose," Dr. Brickel noted.

Serious adverse events (SAEs) were infrequent, and also typically CNS related. In the three pivotal controlled trials, SAEs occurred in 6% of the placebo group and 9% of the retigabine patients. Six of the patients taking retigabine developed a psychotic disorder (five with 1,200 mg, one with 900 mg), compared with none of the placebo patients. Convulsions occurred in 1.2% of the placebo group and in 1.5% of the retigabine patients, across all doses. This finding was not unexpected, considering the underlying epilepsy, he said.

No other SAE was reported in more than two patients in any group. Deaths occurred in three placebo patients and two patients in the retigabine group. One in each group was a sudden death.

In the three pivotal trials, urinary and renal-related adverse events occurred in 17% of retigabine patients, compared with 13% of the placebo-treated patients. In the entire phase II/III study population, 26% of the 1,365 patients reported a urinary adverse event.

However, events related to urinary voiding dysfunction, which have a plausible biological relation to retigabine’s pharmacology, occurred in less than 4% of retigabine-treated patients in the phase III trials alone and in all phase II and III trial populations combined. Urinary hesitation was the most common of these in the entire phase II and III study group, occurring in 3.1%, followed by urinary retention in 1.9%. Catheterization was required in four patients taking retigabine and in one patient on placebo.

"These all occurred in a smaller number of patients and provide a better guide as to how many patents are potentially at risk. It is also important to note that these events were for the most part ‘mild’ in intensity and the patients were able to continue treatment," Dr. Brickel said in an interview.

Dr. Brickel also said that GSK is "communicating these risks to potential prescribers and encouraging them to advise patients of the symptoms relating to difficulty in passing urine that could range from discomfort on bladder emptying, hesitancy, poor flow through to a complete inability to void (acute urinary retention). GSK is keen to proactively manage this."

The study was funded by GSK and Valeant Pharmaceuticals International, and all of the investigators are employees of either company.

BALTIMORE – The safety profile for retigabine is generally consistent with that of other antiepileptic drugs, but data from studies in its evaluation process show that it also carries a novel, small increased risk of urinary voiding dysfunction.

At the annual meeting of the American Epilepsy Society Dr. Neil Brickel of GlaxoSmithKline’s clinical safety and pharmacovigilance group in Middlesex, England, reported on the safety of the novel drug in three phase III, randomized, double-blind, placebo-controlled trials, four phase II studies, and six long-term open-label extension studies, totalling 1,365 patients.

Retigabine is the international nonproprietary name of the drug, but it was approved in the United States in June 2011 under the adopted name ezogabine as an adjunctive therapy in adults with partial-onset seizures. It is a first-in-class potassium channel opener manufactured by GlaxoSmithKline and Valeant Pharmaceuticals International, and sold under the brand name Trobalt in Europe and Potiga in the United States.

In all of the studies that Dr. Brickel analyzed, retigabine was evaluated as a second, add-on agent. As of Oct. 2, 2009, 1,217 of the 1,365 patients had been on treatment at least 1 month, 801 for at least 6 months, and 586 for 1 year or longer.

As expected with any antiepileptic drug (AED), the most frequent adverse events involved the central nervous system. The most common in the three pivotal controlled trials were dizziness (23% of retigabine-treated patients vs. 9% of placebo-treated patients) and somnolence (reported by 22% vs. 12%, respectively). The only CNS adverse events that were not dose related were headache (reported by 15% of the retigabine group vs. 16% of the placebo group) and fatigue (by 15% and 6%, respectively). Other adverse events occurring in more than 10% of subjects were confusional state, tremor, and abnormal coordination. For the most part, patients reported these adverse events early on, during the titration phases of the trials, Dr. Brickel said.

Adverse events led to discontinuation in 437 patients (32%) of the total phase II/III study population. Again, these were primarily CNS and dose related. Discontinuations for any event occurred in 11% of the placebo group. Among those taking retigabine, discontinuations occurred in 17% of those assigned to 600 mg, 25% of those assigned to 900 mg, and 31% of those assigned to 1,200 mg. The most common reason for discontinuation was dizziness.

"Two-thirds of patients were able to continue in the study, even with the fixed titration regimen and at the 1,200-mg dose," Dr. Brickel noted.

Serious adverse events (SAEs) were infrequent, and also typically CNS related. In the three pivotal controlled trials, SAEs occurred in 6% of the placebo group and 9% of the retigabine patients. Six of the patients taking retigabine developed a psychotic disorder (five with 1,200 mg, one with 900 mg), compared with none of the placebo patients. Convulsions occurred in 1.2% of the placebo group and in 1.5% of the retigabine patients, across all doses. This finding was not unexpected, considering the underlying epilepsy, he said.

No other SAE was reported in more than two patients in any group. Deaths occurred in three placebo patients and two patients in the retigabine group. One in each group was a sudden death.

In the three pivotal trials, urinary and renal-related adverse events occurred in 17% of retigabine patients, compared with 13% of the placebo-treated patients. In the entire phase II/III study population, 26% of the 1,365 patients reported a urinary adverse event.

However, events related to urinary voiding dysfunction, which have a plausible biological relation to retigabine’s pharmacology, occurred in less than 4% of retigabine-treated patients in the phase III trials alone and in all phase II and III trial populations combined. Urinary hesitation was the most common of these in the entire phase II and III study group, occurring in 3.1%, followed by urinary retention in 1.9%. Catheterization was required in four patients taking retigabine and in one patient on placebo.

"These all occurred in a smaller number of patients and provide a better guide as to how many patents are potentially at risk. It is also important to note that these events were for the most part ‘mild’ in intensity and the patients were able to continue treatment," Dr. Brickel said in an interview.

Dr. Brickel also said that GSK is "communicating these risks to potential prescribers and encouraging them to advise patients of the symptoms relating to difficulty in passing urine that could range from discomfort on bladder emptying, hesitancy, poor flow through to a complete inability to void (acute urinary retention). GSK is keen to proactively manage this."

The study was funded by GSK and Valeant Pharmaceuticals International, and all of the investigators are employees of either company.

BALTIMORE – "Pay now, save later" could be the motto in the case of vagus nerve stimulation surgery for young Medicaid patients who have intractable epilepsy.

In a study of 30-month outcomes in 445 children, vagus nerve stimulation (VNS) surgery had nearly paid for itself within a year, and began to save taxpayers money soon afterward, Dr. Sandra Helmers reported at the annual meeting of the American Epilepsy Society.

"When we looked at the annual costs of emergency department and hospitalization before and after VNS surgery, we found that the overall cost savings began in the fifth or sixth quarter after surgery," and continued to increase in succeeding quarters, said Dr. Helmers, a neurologist at Emory University Hospital and Clinic, Atlanta. "This is the way we need to look at these treatments, in terms of real-world outcomes in both health and finances."

She and her colleagues divided the group of children by age: patients aged 1-11 years (238) and patients aged 12-17 years (207). All were Medicaid recipients.

Among the younger group, the mean age at the time of surgery was 7 years. All had still been having seizures despite medical therapy. They had tried a mean of four antiepileptic drugs before surgery, and 63% were on polytherapy.

The mean age at the time of surgery in the older group was 15 years. They had tried a mean of four antiepileptic drugs before surgery, and 64% were on polytherapy.

The cost of the surgery ranged from about $20,000 to $30,000, which is "fairly high relative to the preimplant costs," Dr. Helmers said.

But it didn’t take long before the savings began to show, in terms of decreased hospital and ED visits, she said. In the first 6 months after the surgery, the younger patients were 27% less likely to have an ED visit and 26% less likely to have a hospital admission than they were in the prior 6 months. The surgery resulted in savings, but the overall costs were not quite statistically significant ($17,831 vs. $18,220 quarterly [P = .052]) in the 6 months before and after surgery.

During their 6-month postsurgery period, older patients were 57% less likely to go to the ED and 56% less likely to have a hospital admission. Average total health care costs were significantly lower in the 6 months after surgery than the 6 months before ($14,068 vs. $19,047 quarterly [P = .002]).

Although VNS surgery did positively affect hospitalizations, it did not significantly change the number of antiepileptic drugs the children took, Dr. Helmers noted. "We can’t really say anything about adding new medications, because these were refractory patients and for them, another trial of medicine typically does not give much benefit."

The findings are encouraging, because they show that the short-term expense of stabilizing children’s intractable epilepsy brings long-term savings.

"It is difficult for these children to get this intervention. Health insurance is the major barrier to good care for epilepsy. And if you don’t have insurance, you are unlikely to get this."

Policy makers need to know this kind of information, she said. "This pays off [in the United States] just as it has been shown to in other parts of the world. In our country we don’t use data like these to dictate policy – but that is coming. How that will play out in the future is something we still don’t know."

Dr. Helmers had no financial disclosures.

BALTIMORE – "Pay now, save later" could be the motto in the case of vagus nerve stimulation surgery for young Medicaid patients who have intractable epilepsy.

In a study of 30-month outcomes in 445 children, vagus nerve stimulation (VNS) surgery had nearly paid for itself within a year, and began to save taxpayers money soon afterward, Dr. Sandra Helmers reported at the annual meeting of the American Epilepsy Society.

"When we looked at the annual costs of emergency department and hospitalization before and after VNS surgery, we found that the overall cost savings began in the fifth or sixth quarter after surgery," and continued to increase in succeeding quarters, said Dr. Helmers, a neurologist at Emory University Hospital and Clinic, Atlanta. "This is the way we need to look at these treatments, in terms of real-world outcomes in both health and finances."

She and her colleagues divided the group of children by age: patients aged 1-11 years (238) and patients aged 12-17 years (207). All were Medicaid recipients.

Among the younger group, the mean age at the time of surgery was 7 years. All had still been having seizures despite medical therapy. They had tried a mean of four antiepileptic drugs before surgery, and 63% were on polytherapy.

The mean age at the time of surgery in the older group was 15 years. They had tried a mean of four antiepileptic drugs before surgery, and 64% were on polytherapy.

The cost of the surgery ranged from about $20,000 to $30,000, which is "fairly high relative to the preimplant costs," Dr. Helmers said.

But it didn’t take long before the savings began to show, in terms of decreased hospital and ED visits, she said. In the first 6 months after the surgery, the younger patients were 27% less likely to have an ED visit and 26% less likely to have a hospital admission than they were in the prior 6 months. The surgery resulted in savings, but the overall costs were not quite statistically significant ($17,831 vs. $18,220 quarterly [P = .052]) in the 6 months before and after surgery.

During their 6-month postsurgery period, older patients were 57% less likely to go to the ED and 56% less likely to have a hospital admission. Average total health care costs were significantly lower in the 6 months after surgery than the 6 months before ($14,068 vs. $19,047 quarterly [P = .002]).

Although VNS surgery did positively affect hospitalizations, it did not significantly change the number of antiepileptic drugs the children took, Dr. Helmers noted. "We can’t really say anything about adding new medications, because these were refractory patients and for them, another trial of medicine typically does not give much benefit."

The findings are encouraging, because they show that the short-term expense of stabilizing children’s intractable epilepsy brings long-term savings.

"It is difficult for these children to get this intervention. Health insurance is the major barrier to good care for epilepsy. And if you don’t have insurance, you are unlikely to get this."

Policy makers need to know this kind of information, she said. "This pays off [in the United States] just as it has been shown to in other parts of the world. In our country we don’t use data like these to dictate policy – but that is coming. How that will play out in the future is something we still don’t know."

Dr. Helmers had no financial disclosures.

BALTIMORE – "Pay now, save later" could be the motto in the case of vagus nerve stimulation surgery for young Medicaid patients who have intractable epilepsy.

In a study of 30-month outcomes in 445 children, vagus nerve stimulation (VNS) surgery had nearly paid for itself within a year, and began to save taxpayers money soon afterward, Dr. Sandra Helmers reported at the annual meeting of the American Epilepsy Society.

"When we looked at the annual costs of emergency department and hospitalization before and after VNS surgery, we found that the overall cost savings began in the fifth or sixth quarter after surgery," and continued to increase in succeeding quarters, said Dr. Helmers, a neurologist at Emory University Hospital and Clinic, Atlanta. "This is the way we need to look at these treatments, in terms of real-world outcomes in both health and finances."

She and her colleagues divided the group of children by age: patients aged 1-11 years (238) and patients aged 12-17 years (207). All were Medicaid recipients.

Among the younger group, the mean age at the time of surgery was 7 years. All had still been having seizures despite medical therapy. They had tried a mean of four antiepileptic drugs before surgery, and 63% were on polytherapy.

The mean age at the time of surgery in the older group was 15 years. They had tried a mean of four antiepileptic drugs before surgery, and 64% were on polytherapy.

The cost of the surgery ranged from about $20,000 to $30,000, which is "fairly high relative to the preimplant costs," Dr. Helmers said.

But it didn’t take long before the savings began to show, in terms of decreased hospital and ED visits, she said. In the first 6 months after the surgery, the younger patients were 27% less likely to have an ED visit and 26% less likely to have a hospital admission than they were in the prior 6 months. The surgery resulted in savings, but the overall costs were not quite statistically significant ($17,831 vs. $18,220 quarterly [P = .052]) in the 6 months before and after surgery.

During their 6-month postsurgery period, older patients were 57% less likely to go to the ED and 56% less likely to have a hospital admission. Average total health care costs were significantly lower in the 6 months after surgery than the 6 months before ($14,068 vs. $19,047 quarterly [P = .002]).

Although VNS surgery did positively affect hospitalizations, it did not significantly change the number of antiepileptic drugs the children took, Dr. Helmers noted. "We can’t really say anything about adding new medications, because these were refractory patients and for them, another trial of medicine typically does not give much benefit."

The findings are encouraging, because they show that the short-term expense of stabilizing children’s intractable epilepsy brings long-term savings.

"It is difficult for these children to get this intervention. Health insurance is the major barrier to good care for epilepsy. And if you don’t have insurance, you are unlikely to get this."

Policy makers need to know this kind of information, she said. "This pays off [in the United States] just as it has been shown to in other parts of the world. In our country we don’t use data like these to dictate policy – but that is coming. How that will play out in the future is something we still don’t know."

Dr. Helmers had no financial disclosures.