Diana Mahoney

Identifying the cause of fever should be the top priority when evaluating infants or young children after a simple febrile seizure, and the differential diagnosis should always include meningitis, according to a new clinical practice guideline published by the American Academy of Pediatrics.

In most situations, however, "a simple febrile seizure does not usually require further evaluation, specifically electroencephalography, blood studies, or neuroimaging," the AAP Subcommittee on Febrile Seizures wrote in the February 2011 issue of Pediatrics.

The new guideline replaces the 1996 AAP practice parameter for the neurodiagnostic evaluation of healthy infants and children 6-60 months of age who have had a simple febrile seizure and who present for evaluation within 12 hours of the event (Pediatrics 1996;97:769-72).

The new document is based on a comprehensive review of the evidence-based literature published from 1996 to February 2009, with an emphasis on research that differentiated simple febrile seizures from other seizure types. The final recommendations, presented as action statements relating to the use of lumbar puncture, electroencephalography, laboratory testing, and neuroimaging, were developed based on the quality of supporting evidence and the balance of benefit and harm if the given policy is carried out, said lead author Dr. Patricia K. Duffner, professor of neurology and pediatrics at the State University of New York at Buffalo, and associates (Pediatrics 2011 Jan. 31 [doi: 10.1542/peds.2010-3318]).

According to the document:

• Lumbar puncture. It is strongly recommended for children who present with febrile seizure and have meningeal signs and symptoms, including neck stiffness, Kernig signs, or Brudzinski signs, or those whose history or exam suggests possible meningitis or intracranial infection. The procedure is optional for infants between 6 and 12 months who have not received scheduled Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae immunizations or when immunization status is unknown, and for children with febrile seizure who have been pretreated with antibiotics, which could potentially mask the signs and symptoms of meningitis.

Since the previous practice parameter was published, there has been widespread immunization in the United States for two of the most common causes of bacterial meningitis in this age range: Hib and S. pneumoniae. Compliance with all recommended immunizations does not completely eliminate the possibility of bacterial meningitis from the differential diagnosis, but "current data no longer support routine lumbar puncture in well-appearing, fully immunized children who present with a simple febrile seizure. Moreover, although approximately 25% of young children with meningitis have seizures as the presenting sign of the disease, some are either obtunded or comatose when evaluated by a physician for the seizure, and the remainder most often have obvious clinical signs of meningitis (focal seizures, recurrent seizures, petechial rash, or nuchal rigidity)," the guideline says.

• Electroencephalography (EEG). It should not be used routinely in the evaluation of simple febrile seizures in otherwise neurologically healthy children. "There is no evidence that EEG readings performed either at the time of presentation after a simple febrile seizure or within the following month are predictive of either recurrence of febrile seizures or the development of afebrile seizures/epilepsy within the next 2 years," the authors wrote.

• Measurement of serum electrolytes, calcium, phosphorus, magnesium, blood glucose, or complete blood cell count. Such measurements should not be performed routinely for the sole purpose of identifying the cause of a simple febrile seizure. "When fever is present, the decision regarding the need for laboratory testing should be directed toward identifying the source of the fever rather than as part of the routine evaluation of the seizure itself," Dr. Duffner and her associates concluded.

• Neuroimaging. It is not recommended for the routine evaluation of children who present with simple febrile seizures. "The literature does not support the use of skull films in evaluation of the child with a febrile seizure," they explained, nor have data been published that support or negate the need for CT or MRI in this population.

Data do show that "CT scanning is associated with radiation exposure that may escalate future cancer risk. MRI is associated with risks from required sedation and high cost," Dr. Duffner and her associates said. Additionally, extrapolation of data from CT studies in neurologically healthy children with generalized epilepsy "has shown that clinically important intracranial structural abnormalities in this patient population are uncommon," they noted.

All of the authors filed conflict of interest statements with the AAP, and any conflicts have been resolved through a process approved by the Board of Directors. The AAP reported having neither solicited nor accepted any commercial involvement in the development of the revised guideline.

Identifying the cause of fever should be the top priority when evaluating infants or young children after a simple febrile seizure, and the differential diagnosis should always include meningitis, according to a new clinical practice guideline published by the American Academy of Pediatrics.

In most situations, however, "a simple febrile seizure does not usually require further evaluation, specifically electroencephalography, blood studies, or neuroimaging," the AAP Subcommittee on Febrile Seizures wrote in the February 2011 issue of Pediatrics.

The new guideline replaces the 1996 AAP practice parameter for the neurodiagnostic evaluation of healthy infants and children 6-60 months of age who have had a simple febrile seizure and who present for evaluation within 12 hours of the event (Pediatrics 1996;97:769-72).

The new document is based on a comprehensive review of the evidence-based literature published from 1996 to February 2009, with an emphasis on research that differentiated simple febrile seizures from other seizure types. The final recommendations, presented as action statements relating to the use of lumbar puncture, electroencephalography, laboratory testing, and neuroimaging, were developed based on the quality of supporting evidence and the balance of benefit and harm if the given policy is carried out, said lead author Dr. Patricia K. Duffner, professor of neurology and pediatrics at the State University of New York at Buffalo, and associates (Pediatrics 2011 Jan. 31 [doi: 10.1542/peds.2010-3318]).

According to the document:

• Lumbar puncture. It is strongly recommended for children who present with febrile seizure and have meningeal signs and symptoms, including neck stiffness, Kernig signs, or Brudzinski signs, or those whose history or exam suggests possible meningitis or intracranial infection. The procedure is optional for infants between 6 and 12 months who have not received scheduled Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae immunizations or when immunization status is unknown, and for children with febrile seizure who have been pretreated with antibiotics, which could potentially mask the signs and symptoms of meningitis.

Since the previous practice parameter was published, there has been widespread immunization in the United States for two of the most common causes of bacterial meningitis in this age range: Hib and S. pneumoniae. Compliance with all recommended immunizations does not completely eliminate the possibility of bacterial meningitis from the differential diagnosis, but "current data no longer support routine lumbar puncture in well-appearing, fully immunized children who present with a simple febrile seizure. Moreover, although approximately 25% of young children with meningitis have seizures as the presenting sign of the disease, some are either obtunded or comatose when evaluated by a physician for the seizure, and the remainder most often have obvious clinical signs of meningitis (focal seizures, recurrent seizures, petechial rash, or nuchal rigidity)," the guideline says.

• Electroencephalography (EEG). It should not be used routinely in the evaluation of simple febrile seizures in otherwise neurologically healthy children. "There is no evidence that EEG readings performed either at the time of presentation after a simple febrile seizure or within the following month are predictive of either recurrence of febrile seizures or the development of afebrile seizures/epilepsy within the next 2 years," the authors wrote.

• Measurement of serum electrolytes, calcium, phosphorus, magnesium, blood glucose, or complete blood cell count. Such measurements should not be performed routinely for the sole purpose of identifying the cause of a simple febrile seizure. "When fever is present, the decision regarding the need for laboratory testing should be directed toward identifying the source of the fever rather than as part of the routine evaluation of the seizure itself," Dr. Duffner and her associates concluded.

• Neuroimaging. It is not recommended for the routine evaluation of children who present with simple febrile seizures. "The literature does not support the use of skull films in evaluation of the child with a febrile seizure," they explained, nor have data been published that support or negate the need for CT or MRI in this population.

Data do show that "CT scanning is associated with radiation exposure that may escalate future cancer risk. MRI is associated with risks from required sedation and high cost," Dr. Duffner and her associates said. Additionally, extrapolation of data from CT studies in neurologically healthy children with generalized epilepsy "has shown that clinically important intracranial structural abnormalities in this patient population are uncommon," they noted.

All of the authors filed conflict of interest statements with the AAP, and any conflicts have been resolved through a process approved by the Board of Directors. The AAP reported having neither solicited nor accepted any commercial involvement in the development of the revised guideline.

Identifying the cause of fever should be the top priority when evaluating infants or young children after a simple febrile seizure, and the differential diagnosis should always include meningitis, according to a new clinical practice guideline published by the American Academy of Pediatrics.

In most situations, however, "a simple febrile seizure does not usually require further evaluation, specifically electroencephalography, blood studies, or neuroimaging," the AAP Subcommittee on Febrile Seizures wrote in the February 2011 issue of Pediatrics.

The new guideline replaces the 1996 AAP practice parameter for the neurodiagnostic evaluation of healthy infants and children 6-60 months of age who have had a simple febrile seizure and who present for evaluation within 12 hours of the event (Pediatrics 1996;97:769-72).

The new document is based on a comprehensive review of the evidence-based literature published from 1996 to February 2009, with an emphasis on research that differentiated simple febrile seizures from other seizure types. The final recommendations, presented as action statements relating to the use of lumbar puncture, electroencephalography, laboratory testing, and neuroimaging, were developed based on the quality of supporting evidence and the balance of benefit and harm if the given policy is carried out, said lead author Dr. Patricia K. Duffner, professor of neurology and pediatrics at the State University of New York at Buffalo, and associates (Pediatrics 2011 Jan. 31 [doi: 10.1542/peds.2010-3318]).

According to the document:

• Lumbar puncture. It is strongly recommended for children who present with febrile seizure and have meningeal signs and symptoms, including neck stiffness, Kernig signs, or Brudzinski signs, or those whose history or exam suggests possible meningitis or intracranial infection. The procedure is optional for infants between 6 and 12 months who have not received scheduled Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae immunizations or when immunization status is unknown, and for children with febrile seizure who have been pretreated with antibiotics, which could potentially mask the signs and symptoms of meningitis.

Since the previous practice parameter was published, there has been widespread immunization in the United States for two of the most common causes of bacterial meningitis in this age range: Hib and S. pneumoniae. Compliance with all recommended immunizations does not completely eliminate the possibility of bacterial meningitis from the differential diagnosis, but "current data no longer support routine lumbar puncture in well-appearing, fully immunized children who present with a simple febrile seizure. Moreover, although approximately 25% of young children with meningitis have seizures as the presenting sign of the disease, some are either obtunded or comatose when evaluated by a physician for the seizure, and the remainder most often have obvious clinical signs of meningitis (focal seizures, recurrent seizures, petechial rash, or nuchal rigidity)," the guideline says.

• Electroencephalography (EEG). It should not be used routinely in the evaluation of simple febrile seizures in otherwise neurologically healthy children. "There is no evidence that EEG readings performed either at the time of presentation after a simple febrile seizure or within the following month are predictive of either recurrence of febrile seizures or the development of afebrile seizures/epilepsy within the next 2 years," the authors wrote.

• Measurement of serum electrolytes, calcium, phosphorus, magnesium, blood glucose, or complete blood cell count. Such measurements should not be performed routinely for the sole purpose of identifying the cause of a simple febrile seizure. "When fever is present, the decision regarding the need for laboratory testing should be directed toward identifying the source of the fever rather than as part of the routine evaluation of the seizure itself," Dr. Duffner and her associates concluded.

• Neuroimaging. It is not recommended for the routine evaluation of children who present with simple febrile seizures. "The literature does not support the use of skull films in evaluation of the child with a febrile seizure," they explained, nor have data been published that support or negate the need for CT or MRI in this population.

Data do show that "CT scanning is associated with radiation exposure that may escalate future cancer risk. MRI is associated with risks from required sedation and high cost," Dr. Duffner and her associates said. Additionally, extrapolation of data from CT studies in neurologically healthy children with generalized epilepsy "has shown that clinically important intracranial structural abnormalities in this patient population are uncommon," they noted.

All of the authors filed conflict of interest statements with the AAP, and any conflicts have been resolved through a process approved by the Board of Directors. The AAP reported having neither solicited nor accepted any commercial involvement in the development of the revised guideline.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.

Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.

Perampanel

In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.

At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.

"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.

Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.

In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.

Clobazam

The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.

"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.

Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.

In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.

Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.

High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.

The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.

Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.

Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.

SAN ANTONIO – Switching from the modified Atkins diet to the stricter ketogenic diet may improve seizure control in some patients with intractable epilepsy, a multinational, retrospective study has shown.

In particular, patients with myoclonic-astatic epilepsy, an idiopathic generalized epilepsy syndrome of early childhood, appeared to have the greatest likelihood of further improvement after making the switch, Dr. Eric Kossoff reported at the annual meetingof the American Epilepsy Society.

Previous studies have suggested that children who have achieved seizure control with the stringent, high-fat, low-carbohydrate ketogenic diet can maintain that status when they transition to the less-restrictive modified Atkins diet; however, the possibility of achieving additional seizure control by switching from the modified Atkins to the ketogenic diet has not been investigated, said Dr. Kossoff of Johns Hopkins University, Baltimore.

The modified Atkins diet differs from the traditional Atkins program in its further restriction of carbohydrates and stronger encouragement of fat intake. Compared with the ketogenic diet, the modified Atkins diet does not restrict fluid, calories, or protein, and it relies on carbohydrate counts rather than food weight and measurement, Dr. Kossoff explained.

Dr. Kossoff and colleagues from Denmark, Germany, and South Korea found that 9 of 28 patients who made the change reduced the frequency of seizures by more than 10%; 5 of the 9 subsequently became seizure free.

The ketogenic diet did not improve seizures in another five children who previously had no improvement while on the modified Atkins diet.

The likelihood of improvement as a result of the dietary switch was 78% for patients with myoclonic-astatic epilepsy, which was significantly higher than the 11% reported for all other etiologies combined. All five children who became seizure free after transitioning to the ketogenic diet had myoclonic-astatic epilepsy.

"We also observed a trend toward greater likelihood of improvement if a child had fasted at the onset of the ketogenic diet, but this did not reach statistical significance," he said.

Further research into the mechanisms underlying the anticonvulsant effect of the diets is needed to determine when and in which patients to use them, Dr. Kossoff said.

Some insight into this question was provided at the meeting by Susan Masino, Ph.D., of Trinity College in Hartford, Conn., who presented the findings of a study that confirmed adenosine as a key factor in the anticonvulsant effect of the ketogenic diet.

Dr. Masino and her colleagues found that mice with normal levels of adenosine A1 receptor (A1R) and a transgenic overexpression of adenosine kinase, an intracellular enzyme that negatively influences extracellular levels of adenosine, had a "near complete" reduction in the number and duration of spontaneous seizures. But mice with reduced A1R levels and those that lacked A1Rs were partially or completely resistant to the diet therapy.

"When we injected glucose, which blocks A1Rs, into the mice with reduced seizures from the ketogenic diet, the seizure frequency returned to previous levels within 30-90 minutes," she said.

The ketogenic diet appears to reduce seizures by increasing A1R-mediated inhibition through its low carbohydrate nature, Dr. Masino said. The suggestion that ketogenic metabolism increases the activity of adenosine at the A1 receptor subtype "may offer insight into new therapies for epilepsy as well as other clinical conditions in which adenosine is known to have clinical benefits."

Dr. Kossoff has received consultant fees from Atkins Nutritionals Inc. Dr. Masino reported having no relevant financial disclosures.

SAN ANTONIO – Switching from the modified Atkins diet to the stricter ketogenic diet may improve seizure control in some patients with intractable epilepsy, a multinational, retrospective study has shown.

In particular, patients with myoclonic-astatic epilepsy, an idiopathic generalized epilepsy syndrome of early childhood, appeared to have the greatest likelihood of further improvement after making the switch, Dr. Eric Kossoff reported at the annual meetingof the American Epilepsy Society.

Previous studies have suggested that children who have achieved seizure control with the stringent, high-fat, low-carbohydrate ketogenic diet can maintain that status when they transition to the less-restrictive modified Atkins diet; however, the possibility of achieving additional seizure control by switching from the modified Atkins to the ketogenic diet has not been investigated, said Dr. Kossoff of Johns Hopkins University, Baltimore.

The modified Atkins diet differs from the traditional Atkins program in its further restriction of carbohydrates and stronger encouragement of fat intake. Compared with the ketogenic diet, the modified Atkins diet does not restrict fluid, calories, or protein, and it relies on carbohydrate counts rather than food weight and measurement, Dr. Kossoff explained.

Dr. Kossoff and colleagues from Denmark, Germany, and South Korea found that 9 of 28 patients who made the change reduced the frequency of seizures by more than 10%; 5 of the 9 subsequently became seizure free.

The ketogenic diet did not improve seizures in another five children who previously had no improvement while on the modified Atkins diet.

The likelihood of improvement as a result of the dietary switch was 78% for patients with myoclonic-astatic epilepsy, which was significantly higher than the 11% reported for all other etiologies combined. All five children who became seizure free after transitioning to the ketogenic diet had myoclonic-astatic epilepsy.

"We also observed a trend toward greater likelihood of improvement if a child had fasted at the onset of the ketogenic diet, but this did not reach statistical significance," he said.

Further research into the mechanisms underlying the anticonvulsant effect of the diets is needed to determine when and in which patients to use them, Dr. Kossoff said.

Some insight into this question was provided at the meeting by Susan Masino, Ph.D., of Trinity College in Hartford, Conn., who presented the findings of a study that confirmed adenosine as a key factor in the anticonvulsant effect of the ketogenic diet.

Dr. Masino and her colleagues found that mice with normal levels of adenosine A1 receptor (A1R) and a transgenic overexpression of adenosine kinase, an intracellular enzyme that negatively influences extracellular levels of adenosine, had a "near complete" reduction in the number and duration of spontaneous seizures. But mice with reduced A1R levels and those that lacked A1Rs were partially or completely resistant to the diet therapy.

"When we injected glucose, which blocks A1Rs, into the mice with reduced seizures from the ketogenic diet, the seizure frequency returned to previous levels within 30-90 minutes," she said.

The ketogenic diet appears to reduce seizures by increasing A1R-mediated inhibition through its low carbohydrate nature, Dr. Masino said. The suggestion that ketogenic metabolism increases the activity of adenosine at the A1 receptor subtype "may offer insight into new therapies for epilepsy as well as other clinical conditions in which adenosine is known to have clinical benefits."

Dr. Kossoff has received consultant fees from Atkins Nutritionals Inc. Dr. Masino reported having no relevant financial disclosures.

SAN ANTONIO – Switching from the modified Atkins diet to the stricter ketogenic diet may improve seizure control in some patients with intractable epilepsy, a multinational, retrospective study has shown.

In particular, patients with myoclonic-astatic epilepsy, an idiopathic generalized epilepsy syndrome of early childhood, appeared to have the greatest likelihood of further improvement after making the switch, Dr. Eric Kossoff reported at the annual meetingof the American Epilepsy Society.

Previous studies have suggested that children who have achieved seizure control with the stringent, high-fat, low-carbohydrate ketogenic diet can maintain that status when they transition to the less-restrictive modified Atkins diet; however, the possibility of achieving additional seizure control by switching from the modified Atkins to the ketogenic diet has not been investigated, said Dr. Kossoff of Johns Hopkins University, Baltimore.

The modified Atkins diet differs from the traditional Atkins program in its further restriction of carbohydrates and stronger encouragement of fat intake. Compared with the ketogenic diet, the modified Atkins diet does not restrict fluid, calories, or protein, and it relies on carbohydrate counts rather than food weight and measurement, Dr. Kossoff explained.

Dr. Kossoff and colleagues from Denmark, Germany, and South Korea found that 9 of 28 patients who made the change reduced the frequency of seizures by more than 10%; 5 of the 9 subsequently became seizure free.

The ketogenic diet did not improve seizures in another five children who previously had no improvement while on the modified Atkins diet.

The likelihood of improvement as a result of the dietary switch was 78% for patients with myoclonic-astatic epilepsy, which was significantly higher than the 11% reported for all other etiologies combined. All five children who became seizure free after transitioning to the ketogenic diet had myoclonic-astatic epilepsy.

"We also observed a trend toward greater likelihood of improvement if a child had fasted at the onset of the ketogenic diet, but this did not reach statistical significance," he said.

Further research into the mechanisms underlying the anticonvulsant effect of the diets is needed to determine when and in which patients to use them, Dr. Kossoff said.

Some insight into this question was provided at the meeting by Susan Masino, Ph.D., of Trinity College in Hartford, Conn., who presented the findings of a study that confirmed adenosine as a key factor in the anticonvulsant effect of the ketogenic diet.

Dr. Masino and her colleagues found that mice with normal levels of adenosine A1 receptor (A1R) and a transgenic overexpression of adenosine kinase, an intracellular enzyme that negatively influences extracellular levels of adenosine, had a "near complete" reduction in the number and duration of spontaneous seizures. But mice with reduced A1R levels and those that lacked A1Rs were partially or completely resistant to the diet therapy.

"When we injected glucose, which blocks A1Rs, into the mice with reduced seizures from the ketogenic diet, the seizure frequency returned to previous levels within 30-90 minutes," she said.

The ketogenic diet appears to reduce seizures by increasing A1R-mediated inhibition through its low carbohydrate nature, Dr. Masino said. The suggestion that ketogenic metabolism increases the activity of adenosine at the A1 receptor subtype "may offer insight into new therapies for epilepsy as well as other clinical conditions in which adenosine is known to have clinical benefits."

Dr. Kossoff has received consultant fees from Atkins Nutritionals Inc. Dr. Masino reported having no relevant financial disclosures.

SAN ANTONIO – Frequent generalized tonic-clonic seizures, the use of multiple antiepileptic drugs, a 15-year or longer duration of epilepsy, and an epilepsy diagnosis before age 16 were among the statistically significant risk factors for sudden unexplained death in epilepsy.

The associations were detected in a pooled analysis of four published case-control studies presented at the annual meeting of the American Epilepsy Society.

In patients with idiopathic generalized epilepsy, lamotrigine therapy also was associated with an increased risk of death. In addition, male gender was associated with increased mortality, as were stroke, infection, traumatic brain injury, and brain tumor, reported epidemiologist Dale Hesdorffer, Ph.D., of Columbia University in New York.

Sudden unexplained death in epilepsy (SUDEP) is the most common cause of death in chronic epilepsy. Yet most studies that have attempted to identify risk factors have been limited by the small number of cases in each study. To address this deficiency, Dr. Hesdorffer and her colleagues in the Epidemiology Task Force of the International League Against Epilepsy combined data from four similarly designed case-control studies conducted in the United States, Sweden, Scotland, and England. The number of cases of sudden death ranged from 20-149 cases in each study. All cases had a history of epilepsy with at least one seizure during a 5-year period and unexpected death that occurred suddenly and remained unexplained after further investigation, including autopsy.

"Across the studies, statistically significant risk factors for sudden unexplained death in epilepsy were a high number of generalized tonic-clonic seizures, poly-antiepileptic drug therapy, high seizure frequency, and young age at epilepsy onset," she said.

Using logistic regression analysis to identify risk factors, the researchers employed the largest study (149 cases, 602 controls) as the reference initially and then controlled for the largest study to eliminate the possibility that its size would bias the results, Dr. Hesdorffer explained. The investigators adjusted multivariate analyses for study, age of death, gender, and duration of epilepsy.

The analyses revealed that individuals with one or two generalized tonic-clonic seizures per year had a fivefold increased risk of sudden death compared with epilepsy patients with no history of generalized tonic-clonic seizures. "This risk was increased to 15-fold in patients who had three or more of these seizures per year," Dr. Hesdorffer reported. Male gender, onset of epilepsy before age 16, epilepsy duration of more than 15 years, and polytherapy also were associated with a significantly increased risk of sudden death, she said.

In patients with no history of generalized tonic-clonic seizures, polytherapy was associated with a 2.5-fold increased risk of sudden death. Those with a history of one or two generalized tonic-clonic seizures and polytherapy had a 10-fold increased risk. Three or more such seizures and polytherapy were associated with a 27-fold increased risk, Dr. Hesdorffer reported.

In patients on monotherapy, the sudden death risk for patients with one or two generalized tonic-clonic seizures was six times higher than that of controls; for those with three or more seizures, it was 12 times higher.

Idiopathic generalized epilepsy was associated with a decreased risk of sudden death. The exception was seen in patients taking lamotrigine, Dr. Hesdorffer said. Factors that were not significantly associated with SUDEP included levels of carbamazepine, valproate, or phenytoin, as well as age at death, epilepsy surgery, comorbid mental health disorders, learning difficulty, alcohol abuse, and comorbid pulmonary disease, she said.

The results provide an "emerging profile" of epilepsy patients who are at increased risk of SUDEP, said Dr. Hesdorffer. "The contribution of antiepileptic drug therapy – particularly that of lamotrigine therapy – should be further examined."

Dr. Hesdorffer reported having no financial conflicts of interest.

SAN ANTONIO – Frequent generalized tonic-clonic seizures, the use of multiple antiepileptic drugs, a 15-year or longer duration of epilepsy, and an epilepsy diagnosis before age 16 were among the statistically significant risk factors for sudden unexplained death in epilepsy.

The associations were detected in a pooled analysis of four published case-control studies presented at the annual meeting of the American Epilepsy Society.

In patients with idiopathic generalized epilepsy, lamotrigine therapy also was associated with an increased risk of death. In addition, male gender was associated with increased mortality, as were stroke, infection, traumatic brain injury, and brain tumor, reported epidemiologist Dale Hesdorffer, Ph.D., of Columbia University in New York.

Sudden unexplained death in epilepsy (SUDEP) is the most common cause of death in chronic epilepsy. Yet most studies that have attempted to identify risk factors have been limited by the small number of cases in each study. To address this deficiency, Dr. Hesdorffer and her colleagues in the Epidemiology Task Force of the International League Against Epilepsy combined data from four similarly designed case-control studies conducted in the United States, Sweden, Scotland, and England. The number of cases of sudden death ranged from 20-149 cases in each study. All cases had a history of epilepsy with at least one seizure during a 5-year period and unexpected death that occurred suddenly and remained unexplained after further investigation, including autopsy.

"Across the studies, statistically significant risk factors for sudden unexplained death in epilepsy were a high number of generalized tonic-clonic seizures, poly-antiepileptic drug therapy, high seizure frequency, and young age at epilepsy onset," she said.

Using logistic regression analysis to identify risk factors, the researchers employed the largest study (149 cases, 602 controls) as the reference initially and then controlled for the largest study to eliminate the possibility that its size would bias the results, Dr. Hesdorffer explained. The investigators adjusted multivariate analyses for study, age of death, gender, and duration of epilepsy.

The analyses revealed that individuals with one or two generalized tonic-clonic seizures per year had a fivefold increased risk of sudden death compared with epilepsy patients with no history of generalized tonic-clonic seizures. "This risk was increased to 15-fold in patients who had three or more of these seizures per year," Dr. Hesdorffer reported. Male gender, onset of epilepsy before age 16, epilepsy duration of more than 15 years, and polytherapy also were associated with a significantly increased risk of sudden death, she said.

In patients with no history of generalized tonic-clonic seizures, polytherapy was associated with a 2.5-fold increased risk of sudden death. Those with a history of one or two generalized tonic-clonic seizures and polytherapy had a 10-fold increased risk. Three or more such seizures and polytherapy were associated with a 27-fold increased risk, Dr. Hesdorffer reported.

In patients on monotherapy, the sudden death risk for patients with one or two generalized tonic-clonic seizures was six times higher than that of controls; for those with three or more seizures, it was 12 times higher.

Idiopathic generalized epilepsy was associated with a decreased risk of sudden death. The exception was seen in patients taking lamotrigine, Dr. Hesdorffer said. Factors that were not significantly associated with SUDEP included levels of carbamazepine, valproate, or phenytoin, as well as age at death, epilepsy surgery, comorbid mental health disorders, learning difficulty, alcohol abuse, and comorbid pulmonary disease, she said.

The results provide an "emerging profile" of epilepsy patients who are at increased risk of SUDEP, said Dr. Hesdorffer. "The contribution of antiepileptic drug therapy – particularly that of lamotrigine therapy – should be further examined."

Dr. Hesdorffer reported having no financial conflicts of interest.

SAN ANTONIO – Frequent generalized tonic-clonic seizures, the use of multiple antiepileptic drugs, a 15-year or longer duration of epilepsy, and an epilepsy diagnosis before age 16 were among the statistically significant risk factors for sudden unexplained death in epilepsy.

The associations were detected in a pooled analysis of four published case-control studies presented at the annual meeting of the American Epilepsy Society.

In patients with idiopathic generalized epilepsy, lamotrigine therapy also was associated with an increased risk of death. In addition, male gender was associated with increased mortality, as were stroke, infection, traumatic brain injury, and brain tumor, reported epidemiologist Dale Hesdorffer, Ph.D., of Columbia University in New York.

Sudden unexplained death in epilepsy (SUDEP) is the most common cause of death in chronic epilepsy. Yet most studies that have attempted to identify risk factors have been limited by the small number of cases in each study. To address this deficiency, Dr. Hesdorffer and her colleagues in the Epidemiology Task Force of the International League Against Epilepsy combined data from four similarly designed case-control studies conducted in the United States, Sweden, Scotland, and England. The number of cases of sudden death ranged from 20-149 cases in each study. All cases had a history of epilepsy with at least one seizure during a 5-year period and unexpected death that occurred suddenly and remained unexplained after further investigation, including autopsy.

"Across the studies, statistically significant risk factors for sudden unexplained death in epilepsy were a high number of generalized tonic-clonic seizures, poly-antiepileptic drug therapy, high seizure frequency, and young age at epilepsy onset," she said.

Using logistic regression analysis to identify risk factors, the researchers employed the largest study (149 cases, 602 controls) as the reference initially and then controlled for the largest study to eliminate the possibility that its size would bias the results, Dr. Hesdorffer explained. The investigators adjusted multivariate analyses for study, age of death, gender, and duration of epilepsy.

The analyses revealed that individuals with one or two generalized tonic-clonic seizures per year had a fivefold increased risk of sudden death compared with epilepsy patients with no history of generalized tonic-clonic seizures. "This risk was increased to 15-fold in patients who had three or more of these seizures per year," Dr. Hesdorffer reported. Male gender, onset of epilepsy before age 16, epilepsy duration of more than 15 years, and polytherapy also were associated with a significantly increased risk of sudden death, she said.

In patients with no history of generalized tonic-clonic seizures, polytherapy was associated with a 2.5-fold increased risk of sudden death. Those with a history of one or two generalized tonic-clonic seizures and polytherapy had a 10-fold increased risk. Three or more such seizures and polytherapy were associated with a 27-fold increased risk, Dr. Hesdorffer reported.

In patients on monotherapy, the sudden death risk for patients with one or two generalized tonic-clonic seizures was six times higher than that of controls; for those with three or more seizures, it was 12 times higher.

Idiopathic generalized epilepsy was associated with a decreased risk of sudden death. The exception was seen in patients taking lamotrigine, Dr. Hesdorffer said. Factors that were not significantly associated with SUDEP included levels of carbamazepine, valproate, or phenytoin, as well as age at death, epilepsy surgery, comorbid mental health disorders, learning difficulty, alcohol abuse, and comorbid pulmonary disease, she said.

The results provide an "emerging profile" of epilepsy patients who are at increased risk of SUDEP, said Dr. Hesdorffer. "The contribution of antiepileptic drug therapy – particularly that of lamotrigine therapy – should be further examined."

Dr. Hesdorffer reported having no financial conflicts of interest.

SAN ANTONIO – A diagnosis of epilepsy increases the risk of death from any cause, and mortality risk is highest for those diagnosed with epilepsy in the first year of life, according to neurologist Dr. Jakob Christensen.

Adverse birth outcomes account for some of the increased mortality. Even after excluding those with adverse birth outcomes from analysis, however, the risk is still 10 times greater than the background mortality rate.

The conclusion is based on findings from a large cohort study of all-cause mortality in people with epilepsy born in Denmark from 1977 to 2006. Dr. Christensen, of Aarhus (Denmark) University Hospital, used linked information from Danish civil service, health, and cause of death registries to examine mortality rates of those with and without epilepsy.

Among the 1.5 million people in the cohort, there were 10,648 deaths, and 806 were in people diagnosed with epilepsy, Dr. Christensen said at the annual meeting of the American Epilepsy Society. Based on 26.2 million person-years of follow-up, overall mortality was approximately 40 times higher in the epilepsy group. Risk was highest among people diagnosed with epilepsy in the first year of life, "approximately 60 times that of the background mortality," he said.

Mortality risk declined with increasing age at diagnosis, but the mortality rate in epilepsy patients never reached the background value seen in those without epilepsy, he said. Even those diagnosed after age 15 had a 5-10 times greater mortality risk.

After excluding from the analysis epilepsy patients with adverse birth outcomes, such as low birth rate, asphyxia, early birth, or malformations, mortality risk decreased relative to the epilepsy population as a whole. However, mortality was still 10 times higher than the background rate.

Investigation into specific causes of death was not part of the study. "We did look at the data to see if any causes were highly increased, and there were no surprises. For example, mortality was higher in patients with brain tumors, which is not unexpected," Dr. Christensen said.

"What we hope to do next is to look more closely at the 8%-10% of the epilepsy patients in this study whose cause of death was listed as ‘epilepsy,’ to gain insight into factors associated specifically with sudden unexpected death in epilepsy."

Dr. Christensen reported having no financial conflicts of interest.

SAN ANTONIO – A diagnosis of epilepsy increases the risk of death from any cause, and mortality risk is highest for those diagnosed with epilepsy in the first year of life, according to neurologist Dr. Jakob Christensen.

Adverse birth outcomes account for some of the increased mortality. Even after excluding those with adverse birth outcomes from analysis, however, the risk is still 10 times greater than the background mortality rate.

The conclusion is based on findings from a large cohort study of all-cause mortality in people with epilepsy born in Denmark from 1977 to 2006. Dr. Christensen, of Aarhus (Denmark) University Hospital, used linked information from Danish civil service, health, and cause of death registries to examine mortality rates of those with and without epilepsy.

Among the 1.5 million people in the cohort, there were 10,648 deaths, and 806 were in people diagnosed with epilepsy, Dr. Christensen said at the annual meeting of the American Epilepsy Society. Based on 26.2 million person-years of follow-up, overall mortality was approximately 40 times higher in the epilepsy group. Risk was highest among people diagnosed with epilepsy in the first year of life, "approximately 60 times that of the background mortality," he said.

Mortality risk declined with increasing age at diagnosis, but the mortality rate in epilepsy patients never reached the background value seen in those without epilepsy, he said. Even those diagnosed after age 15 had a 5-10 times greater mortality risk.

After excluding from the analysis epilepsy patients with adverse birth outcomes, such as low birth rate, asphyxia, early birth, or malformations, mortality risk decreased relative to the epilepsy population as a whole. However, mortality was still 10 times higher than the background rate.

Investigation into specific causes of death was not part of the study. "We did look at the data to see if any causes were highly increased, and there were no surprises. For example, mortality was higher in patients with brain tumors, which is not unexpected," Dr. Christensen said.

"What we hope to do next is to look more closely at the 8%-10% of the epilepsy patients in this study whose cause of death was listed as ‘epilepsy,’ to gain insight into factors associated specifically with sudden unexpected death in epilepsy."

Dr. Christensen reported having no financial conflicts of interest.

SAN ANTONIO – A diagnosis of epilepsy increases the risk of death from any cause, and mortality risk is highest for those diagnosed with epilepsy in the first year of life, according to neurologist Dr. Jakob Christensen.

Adverse birth outcomes account for some of the increased mortality. Even after excluding those with adverse birth outcomes from analysis, however, the risk is still 10 times greater than the background mortality rate.

The conclusion is based on findings from a large cohort study of all-cause mortality in people with epilepsy born in Denmark from 1977 to 2006. Dr. Christensen, of Aarhus (Denmark) University Hospital, used linked information from Danish civil service, health, and cause of death registries to examine mortality rates of those with and without epilepsy.

Among the 1.5 million people in the cohort, there were 10,648 deaths, and 806 were in people diagnosed with epilepsy, Dr. Christensen said at the annual meeting of the American Epilepsy Society. Based on 26.2 million person-years of follow-up, overall mortality was approximately 40 times higher in the epilepsy group. Risk was highest among people diagnosed with epilepsy in the first year of life, "approximately 60 times that of the background mortality," he said.

Mortality risk declined with increasing age at diagnosis, but the mortality rate in epilepsy patients never reached the background value seen in those without epilepsy, he said. Even those diagnosed after age 15 had a 5-10 times greater mortality risk.

After excluding from the analysis epilepsy patients with adverse birth outcomes, such as low birth rate, asphyxia, early birth, or malformations, mortality risk decreased relative to the epilepsy population as a whole. However, mortality was still 10 times higher than the background rate.

Investigation into specific causes of death was not part of the study. "We did look at the data to see if any causes were highly increased, and there were no surprises. For example, mortality was higher in patients with brain tumors, which is not unexpected," Dr. Christensen said.

"What we hope to do next is to look more closely at the 8%-10% of the epilepsy patients in this study whose cause of death was listed as ‘epilepsy,’ to gain insight into factors associated specifically with sudden unexpected death in epilepsy."

Dr. Christensen reported having no financial conflicts of interest.

BOSTON – Clinical application of the first consensus-based criteria for neuroleptic malignant syndrome should expedite the diagnosis of the life-threatening complication of antipsychotic drug treatment by replacing current "ad hoc approaches," Dr. Ronald J. Gurrera said at the American Psychiatric Association Institute on Psychiatric Services.

Additionally, the new criteria, developed using the Delphi technique by a 17-member international expert panel of psychiatrists, neurologists, anesthesiologists, and emergency medicine specialists convened by the Neuroleptic Malignant Syndrome Information Service, will facilitate clinical research, which has been hampered by the lack of universally accepted criteria, said Dr. Gurrera, a geriatric psychiatrist affiliated with the VA Boston Healthcare System.

The expert panel reached consensus on the following diagnostic criteria for neuroleptic malignant syndrome (NMS), derived through five iterations of group sampling with controlled feedback:

• Exposure to a dopamine agonist, or dopamine-agonist withdrawal, within the past 72 hours.

• Hyperthermia.

• Rigidity.

• Mental status alteration.

• Elevated creatine phosphokinase.

• Sympathetic nervous system lability, defined as the presence of two or more of these features: elevated blood pressure, blood pressure fluctuation, diaphoresis, or urinary incontinence.

• Tachycardia and tachypnea.

• Negative work-up for infectious, toxic, metabolic, and neurologic causes.

Although NMS is rare – prevalence estimates range from 0.02% to 2.44% among patients taking neuroleptic drugs – it is a significant source of morbidity and mortality in these patients, Dr. Gurrera said, noting that mortality is estimated to be as high as 12%. Morbidity from NMS includes rhabdomyolysis, pneumonia, renal failure, seizures, arrhythmias, disseminated intravascular coagulation (DIC), and respiratory failure. Mortality usually results from respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, or DIC, he said in a poster presentation.

Although the condition is thought to occur more frequently with the use of high-potency conventional antipsychotics, NMS is a potential adverse effect of any antipsychotic agent, including the newer atypical antipsychotics, Dr. Gurrera said, noting that there is no evidence to suggest an association with any particular neuroleptic agent over another.

Despite the availability of DSM-IV-TR research criteria for NMS, which require that both severe muscle rigidity and elevated temperature be present after recent administration of an antipsychotic as well as two associated signs, symptoms, or laboratory findings that are not better accounted for by a substance-induced, neurologic, or general medical condition, it can be difficult to distinguish the symptoms of NMS from some of the other, more common side effects of antipsychotic medications, such as dystonias, parkinsonism, and akathisia, and from other conditions that present with the same symptoms, Dr. Gurrera said. Given the potential severity of the disorder, however, antipsychotic medication should be discontinued in any patient with symptoms of NMS, "even before the diagnosis is definitive," he said.

The rate of mortality associated with NMS has decreased in recent years, from an estimated high of 30%, most likely reflecting an increased awareness of the condition and more conservative antipsychotic prescribing practices, as well as the use of atypical antipsychotics, Dr. Gurrera said. The increased recognition of the disorder can lead to earlier diagnosis and treatment, reducing the number of lethal cases of NMS, he said, stressing the need for clinicians to be aware of the early signs and clinical features of the condition.

Dr. Gurrera reported having no relevant conflicts of interest.

BOSTON – Clinical application of the first consensus-based criteria for neuroleptic malignant syndrome should expedite the diagnosis of the life-threatening complication of antipsychotic drug treatment by replacing current "ad hoc approaches," Dr. Ronald J. Gurrera said at the American Psychiatric Association Institute on Psychiatric Services.

Additionally, the new criteria, developed using the Delphi technique by a 17-member international expert panel of psychiatrists, neurologists, anesthesiologists, and emergency medicine specialists convened by the Neuroleptic Malignant Syndrome Information Service, will facilitate clinical research, which has been hampered by the lack of universally accepted criteria, said Dr. Gurrera, a geriatric psychiatrist affiliated with the VA Boston Healthcare System.

The expert panel reached consensus on the following diagnostic criteria for neuroleptic malignant syndrome (NMS), derived through five iterations of group sampling with controlled feedback:

• Exposure to a dopamine agonist, or dopamine-agonist withdrawal, within the past 72 hours.

• Hyperthermia.

• Rigidity.

• Mental status alteration.

• Elevated creatine phosphokinase.

• Sympathetic nervous system lability, defined as the presence of two or more of these features: elevated blood pressure, blood pressure fluctuation, diaphoresis, or urinary incontinence.

• Tachycardia and tachypnea.

• Negative work-up for infectious, toxic, metabolic, and neurologic causes.

Although NMS is rare – prevalence estimates range from 0.02% to 2.44% among patients taking neuroleptic drugs – it is a significant source of morbidity and mortality in these patients, Dr. Gurrera said, noting that mortality is estimated to be as high as 12%. Morbidity from NMS includes rhabdomyolysis, pneumonia, renal failure, seizures, arrhythmias, disseminated intravascular coagulation (DIC), and respiratory failure. Mortality usually results from respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, or DIC, he said in a poster presentation.

Although the condition is thought to occur more frequently with the use of high-potency conventional antipsychotics, NMS is a potential adverse effect of any antipsychotic agent, including the newer atypical antipsychotics, Dr. Gurrera said, noting that there is no evidence to suggest an association with any particular neuroleptic agent over another.

Despite the availability of DSM-IV-TR research criteria for NMS, which require that both severe muscle rigidity and elevated temperature be present after recent administration of an antipsychotic as well as two associated signs, symptoms, or laboratory findings that are not better accounted for by a substance-induced, neurologic, or general medical condition, it can be difficult to distinguish the symptoms of NMS from some of the other, more common side effects of antipsychotic medications, such as dystonias, parkinsonism, and akathisia, and from other conditions that present with the same symptoms, Dr. Gurrera said. Given the potential severity of the disorder, however, antipsychotic medication should be discontinued in any patient with symptoms of NMS, "even before the diagnosis is definitive," he said.

The rate of mortality associated with NMS has decreased in recent years, from an estimated high of 30%, most likely reflecting an increased awareness of the condition and more conservative antipsychotic prescribing practices, as well as the use of atypical antipsychotics, Dr. Gurrera said. The increased recognition of the disorder can lead to earlier diagnosis and treatment, reducing the number of lethal cases of NMS, he said, stressing the need for clinicians to be aware of the early signs and clinical features of the condition.

Dr. Gurrera reported having no relevant conflicts of interest.

BOSTON – Clinical application of the first consensus-based criteria for neuroleptic malignant syndrome should expedite the diagnosis of the life-threatening complication of antipsychotic drug treatment by replacing current "ad hoc approaches," Dr. Ronald J. Gurrera said at the American Psychiatric Association Institute on Psychiatric Services.

Additionally, the new criteria, developed using the Delphi technique by a 17-member international expert panel of psychiatrists, neurologists, anesthesiologists, and emergency medicine specialists convened by the Neuroleptic Malignant Syndrome Information Service, will facilitate clinical research, which has been hampered by the lack of universally accepted criteria, said Dr. Gurrera, a geriatric psychiatrist affiliated with the VA Boston Healthcare System.

The expert panel reached consensus on the following diagnostic criteria for neuroleptic malignant syndrome (NMS), derived through five iterations of group sampling with controlled feedback:

• Exposure to a dopamine agonist, or dopamine-agonist withdrawal, within the past 72 hours.

• Hyperthermia.

• Rigidity.

• Mental status alteration.

• Elevated creatine phosphokinase.

• Sympathetic nervous system lability, defined as the presence of two or more of these features: elevated blood pressure, blood pressure fluctuation, diaphoresis, or urinary incontinence.

• Tachycardia and tachypnea.

• Negative work-up for infectious, toxic, metabolic, and neurologic causes.

Although NMS is rare – prevalence estimates range from 0.02% to 2.44% among patients taking neuroleptic drugs – it is a significant source of morbidity and mortality in these patients, Dr. Gurrera said, noting that mortality is estimated to be as high as 12%. Morbidity from NMS includes rhabdomyolysis, pneumonia, renal failure, seizures, arrhythmias, disseminated intravascular coagulation (DIC), and respiratory failure. Mortality usually results from respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, or DIC, he said in a poster presentation.

Although the condition is thought to occur more frequently with the use of high-potency conventional antipsychotics, NMS is a potential adverse effect of any antipsychotic agent, including the newer atypical antipsychotics, Dr. Gurrera said, noting that there is no evidence to suggest an association with any particular neuroleptic agent over another.

Despite the availability of DSM-IV-TR research criteria for NMS, which require that both severe muscle rigidity and elevated temperature be present after recent administration of an antipsychotic as well as two associated signs, symptoms, or laboratory findings that are not better accounted for by a substance-induced, neurologic, or general medical condition, it can be difficult to distinguish the symptoms of NMS from some of the other, more common side effects of antipsychotic medications, such as dystonias, parkinsonism, and akathisia, and from other conditions that present with the same symptoms, Dr. Gurrera said. Given the potential severity of the disorder, however, antipsychotic medication should be discontinued in any patient with symptoms of NMS, "even before the diagnosis is definitive," he said.

The rate of mortality associated with NMS has decreased in recent years, from an estimated high of 30%, most likely reflecting an increased awareness of the condition and more conservative antipsychotic prescribing practices, as well as the use of atypical antipsychotics, Dr. Gurrera said. The increased recognition of the disorder can lead to earlier diagnosis and treatment, reducing the number of lethal cases of NMS, he said, stressing the need for clinicians to be aware of the early signs and clinical features of the condition.

Dr. Gurrera reported having no relevant conflicts of interest.

Wegener’s granulomatosis is a systemic vasculitis that primarily affects small- to medium-size vessels. The antineutrophil cytoplasmic antibody–associated disease typically involves the upper and lower respiratory tracts and the kidneys. But the disease can potentially involve any organ, including the central and peripheral nervous systems, according to Dr. Philip Seo. "When most general rheumatologists ask me about Wegener’s, they generally stick to the canonical manifestations [sinus, lungs, kidneys], but nervous system involvement is certainly relevant to the management of these patients, and probably underappreciated," he said.

Nervous system manifestations present in approximately 22%-54% of Wegener’s patients, according to a recent report. The report’s authors noted that the majority of the complications reflected in this estimate are cases involving the peripheral nervous system – specifically, polyneuropathy or mononeuritis multiplex (Curr. Opin. Rheumatol. 2011;23:7-11).

Central nervous system involvement is relatively uncommon in Wegener’s, affecting an estimated 7%-11% of patients, according to an investigation into mechanisms of CNS complications in which the authors identified three separate pathogenic patterns: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and CNS vasculitis (Medicine. 2006;85: 54-65).

In this month’s column, Dr. Seo discusses the diagnosis and management of neurologic complications associated with Wegener’s disease that are most likely to present in clinical practice.

Question: What are the potential neurologic complications that clinicians must have on their radar?

Dr. Seo: The most common complication is a sensory peripheral neuropathy. Although this can be associated with pain, many patients will complain about a lack of sensation, which they will describe as a cold feeling in their feet, or the feeling that their feet are wrapped in plastic wrap or covered in wax. Some patients might also describe this as a feeling akin to rubber bands being stretched over their feet. A more serious form of peripheral neuropathy is a mononeuritis multiplex, which can lead to a "wrist drop" or a "foot drop."

Question: What are the important diagnostic considerations? What signs and symptoms should clinicians look for?

Dr. Seo: Many patients learn to accommodate these symptoms subconsciously, or they won’t have the vocabulary to describe these problems clearly to you. Thus, it is important to test both strength and sensation explicitly, especially when you are meeting a patient for the first time. Often, the patient will be surprised to learn that they have had a neuropathy and just never realized it was a problem.

Question: How does the occurrence of neurologic manifestations affect patient management?

Dr. Seo: Sensory neuropathy in particular is difficult to manage, because immunosuppression halts the progression of symptoms but does not actually repair the damaged nerves. Most medications that are advertised for sensory neuropathy address only the pain associated with this phenomenon. Some patients do not complain that their feet and lower legs continue to feel numb, even after many years of being in remission.

Question: Is the damage caused by nervous system involvement reversible?

Dr. Seo: Unfortunately, the role of treatment is to arrest progression of the disease. So, although we hope that immunosuppression will prevent the neuropathy from becoming worse, it does not actually help repair the damaged nerves. I think that recovery does occur in these cases, but it can be excruciatingly slow. Recovery of motor function in a patient with mononeuritis multiplex is considerably faster, and patients can often regain normal function of the affected limbs with time. Currently, the early diagnosis and treatment of Wegener’s are the best ways to prevent or reduce potential damage associated with neurologic involvement.

Dr. Seo is in the division of rheumatology and is codirector of the vasculitis center at Johns Hopkins University in Baltimore. He reported having no relevant financial disclosures.

Wegener’s granulomatosis is a systemic vasculitis that primarily affects small- to medium-size vessels. The antineutrophil cytoplasmic antibody–associated disease typically involves the upper and lower respiratory tracts and the kidneys. But the disease can potentially involve any organ, including the central and peripheral nervous systems, according to Dr. Philip Seo. "When most general rheumatologists ask me about Wegener’s, they generally stick to the canonical manifestations [sinus, lungs, kidneys], but nervous system involvement is certainly relevant to the management of these patients, and probably underappreciated," he said.

Nervous system manifestations present in approximately 22%-54% of Wegener’s patients, according to a recent report. The report’s authors noted that the majority of the complications reflected in this estimate are cases involving the peripheral nervous system – specifically, polyneuropathy or mononeuritis multiplex (Curr. Opin. Rheumatol. 2011;23:7-11).

Central nervous system involvement is relatively uncommon in Wegener’s, affecting an estimated 7%-11% of patients, according to an investigation into mechanisms of CNS complications in which the authors identified three separate pathogenic patterns: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and CNS vasculitis (Medicine. 2006;85: 54-65).

In this month’s column, Dr. Seo discusses the diagnosis and management of neurologic complications associated with Wegener’s disease that are most likely to present in clinical practice.

Question: What are the potential neurologic complications that clinicians must have on their radar?

Dr. Seo: The most common complication is a sensory peripheral neuropathy. Although this can be associated with pain, many patients will complain about a lack of sensation, which they will describe as a cold feeling in their feet, or the feeling that their feet are wrapped in plastic wrap or covered in wax. Some patients might also describe this as a feeling akin to rubber bands being stretched over their feet. A more serious form of peripheral neuropathy is a mononeuritis multiplex, which can lead to a "wrist drop" or a "foot drop."

Question: What are the important diagnostic considerations? What signs and symptoms should clinicians look for?

Dr. Seo: Many patients learn to accommodate these symptoms subconsciously, or they won’t have the vocabulary to describe these problems clearly to you. Thus, it is important to test both strength and sensation explicitly, especially when you are meeting a patient for the first time. Often, the patient will be surprised to learn that they have had a neuropathy and just never realized it was a problem.

Question: How does the occurrence of neurologic manifestations affect patient management?

Dr. Seo: Sensory neuropathy in particular is difficult to manage, because immunosuppression halts the progression of symptoms but does not actually repair the damaged nerves. Most medications that are advertised for sensory neuropathy address only the pain associated with this phenomenon. Some patients do not complain that their feet and lower legs continue to feel numb, even after many years of being in remission.

Question: Is the damage caused by nervous system involvement reversible?

Dr. Seo: Unfortunately, the role of treatment is to arrest progression of the disease. So, although we hope that immunosuppression will prevent the neuropathy from becoming worse, it does not actually help repair the damaged nerves. I think that recovery does occur in these cases, but it can be excruciatingly slow. Recovery of motor function in a patient with mononeuritis multiplex is considerably faster, and patients can often regain normal function of the affected limbs with time. Currently, the early diagnosis and treatment of Wegener’s are the best ways to prevent or reduce potential damage associated with neurologic involvement.

Dr. Seo is in the division of rheumatology and is codirector of the vasculitis center at Johns Hopkins University in Baltimore. He reported having no relevant financial disclosures.

Wegener’s granulomatosis is a systemic vasculitis that primarily affects small- to medium-size vessels. The antineutrophil cytoplasmic antibody–associated disease typically involves the upper and lower respiratory tracts and the kidneys. But the disease can potentially involve any organ, including the central and peripheral nervous systems, according to Dr. Philip Seo. "When most general rheumatologists ask me about Wegener’s, they generally stick to the canonical manifestations [sinus, lungs, kidneys], but nervous system involvement is certainly relevant to the management of these patients, and probably underappreciated," he said.

Nervous system manifestations present in approximately 22%-54% of Wegener’s patients, according to a recent report. The report’s authors noted that the majority of the complications reflected in this estimate are cases involving the peripheral nervous system – specifically, polyneuropathy or mononeuritis multiplex (Curr. Opin. Rheumatol. 2011;23:7-11).

Central nervous system involvement is relatively uncommon in Wegener’s, affecting an estimated 7%-11% of patients, according to an investigation into mechanisms of CNS complications in which the authors identified three separate pathogenic patterns: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and CNS vasculitis (Medicine. 2006;85: 54-65).

In this month’s column, Dr. Seo discusses the diagnosis and management of neurologic complications associated with Wegener’s disease that are most likely to present in clinical practice.

Question: What are the potential neurologic complications that clinicians must have on their radar?

Dr. Seo: The most common complication is a sensory peripheral neuropathy. Although this can be associated with pain, many patients will complain about a lack of sensation, which they will describe as a cold feeling in their feet, or the feeling that their feet are wrapped in plastic wrap or covered in wax. Some patients might also describe this as a feeling akin to rubber bands being stretched over their feet. A more serious form of peripheral neuropathy is a mononeuritis multiplex, which can lead to a "wrist drop" or a "foot drop."

Question: What are the important diagnostic considerations? What signs and symptoms should clinicians look for?

Dr. Seo: Many patients learn to accommodate these symptoms subconsciously, or they won’t have the vocabulary to describe these problems clearly to you. Thus, it is important to test both strength and sensation explicitly, especially when you are meeting a patient for the first time. Often, the patient will be surprised to learn that they have had a neuropathy and just never realized it was a problem.

Question: How does the occurrence of neurologic manifestations affect patient management?

Dr. Seo: Sensory neuropathy in particular is difficult to manage, because immunosuppression halts the progression of symptoms but does not actually repair the damaged nerves. Most medications that are advertised for sensory neuropathy address only the pain associated with this phenomenon. Some patients do not complain that their feet and lower legs continue to feel numb, even after many years of being in remission.

Question: Is the damage caused by nervous system involvement reversible?

Dr. Seo: Unfortunately, the role of treatment is to arrest progression of the disease. So, although we hope that immunosuppression will prevent the neuropathy from becoming worse, it does not actually help repair the damaged nerves. I think that recovery does occur in these cases, but it can be excruciatingly slow. Recovery of motor function in a patient with mononeuritis multiplex is considerably faster, and patients can often regain normal function of the affected limbs with time. Currently, the early diagnosis and treatment of Wegener’s are the best ways to prevent or reduce potential damage associated with neurologic involvement.

Dr. Seo is in the division of rheumatology and is codirector of the vasculitis center at Johns Hopkins University in Baltimore. He reported having no relevant financial disclosures.

Wegener’s granulomatosis is a systemic vasculitis that primarily affects small- to medium-size vessels. The antineutrophil cytoplasmic antibody–associated disease typically involves the upper and lower respiratory tracts and the kidneys. But the disease can potentially involve any organ, including the central and peripheral nervous systems, according to Dr. Philip Seo. "When most general rheumatologists ask me about Wegener’s, they generally stick to the canonical manifestations [sinus, lungs, kidneys], but nervous system involvement is certainly relevant to the management of these patients, and probably underappreciated," he said.

Nervous system manifestations present in approximately 22%-54% of Wegener’s patients, according to a recent report. The report’s authors noted that the majority of the complications reflected in this estimate are cases involving the peripheral nervous system – specifically, polyneuropathy or mononeuritis multiplex (Curr. Opin. Rheumatol. 2011;23:7-11).

Central nervous system involvement is relatively uncommon in Wegener’s, affecting an estimated 7%-11% of patients, according to an investigation into mechanisms of CNS complications in which the authors identified three separate pathogenic patterns: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and CNS vasculitis (Medicine. 2006;85: 54-65).

In this month’s column, Dr. Seo discusses the diagnosis and management of neurologic complications associated with Wegener’s disease that are most likely to present in clinical practice.

Question: What are the potential neurologic complications that clinicians must have on their radar?

Dr. Seo: The most common complication is a sensory peripheral neuropathy. Although this can be associated with pain, many patients will complain about a lack of sensation, which they will describe as a cold feeling in their feet, or the feeling that their feet are wrapped in plastic wrap or covered in wax. Some patients might also describe this as a feeling akin to rubber bands being stretched over their feet. A more serious form of peripheral neuropathy is a mononeuritis multiplex, which can lead to a "wrist drop" or a "foot drop."

Question: What are the important diagnostic considerations? What signs and symptoms should clinicians look for?

Dr. Seo: Many patients learn to accommodate these symptoms subconsciously, or they won’t have the vocabulary to describe these problems clearly to you. Thus, it is important to test both strength and sensation explicitly, especially when you are meeting a patient for the first time. Often, the patient will be surprised to learn that they have had a neuropathy and just never realized it was a problem.

Question: How does the occurrence of neurologic manifestations affect patient management?

Dr. Seo: Sensory neuropathy in particular is difficult to manage, because immunosuppression halts the progression of symptoms but does not actually repair the damaged nerves. Most medications that are advertised for sensory neuropathy address only the pain associated with this phenomenon. Some patients do not complain that their feet and lower legs continue to feel numb, even after many years of being in remission.

Question: Is the damage caused by nervous system involvement reversible?

Dr. Seo: Unfortunately, the role of treatment is to arrest progression of the disease. So, although we hope that immunosuppression will prevent the neuropathy from becoming worse, it does not actually help repair the damaged nerves. I think that recovery does occur in these cases, but it can be excruciatingly slow. Recovery of motor function in a patient with mononeuritis multiplex is considerably faster, and patients can often regain normal function of the affected limbs with time. Currently, the early diagnosis and treatment of Wegener’s are the best ways to prevent or reduce potential damage associated with neurologic involvement.

Dr. Seo is in the division of rheumatology and is codirector of the vasculitis center at Johns Hopkins University in Baltimore. He reported having no relevant financial disclosures.

Wegener’s granulomatosis is a systemic vasculitis that primarily affects small- to medium-size vessels. The antineutrophil cytoplasmic antibody–associated disease typically involves the upper and lower respiratory tracts and the kidneys. But the disease can potentially involve any organ, including the central and peripheral nervous systems, according to Dr. Philip Seo. "When most general rheumatologists ask me about Wegener’s, they generally stick to the canonical manifestations [sinus, lungs, kidneys], but nervous system involvement is certainly relevant to the management of these patients, and probably underappreciated," he said.

Nervous system manifestations present in approximately 22%-54% of Wegener’s patients, according to a recent report. The report’s authors noted that the majority of the complications reflected in this estimate are cases involving the peripheral nervous system – specifically, polyneuropathy or mononeuritis multiplex (Curr. Opin. Rheumatol. 2011;23:7-11).

Central nervous system involvement is relatively uncommon in Wegener’s, affecting an estimated 7%-11% of patients, according to an investigation into mechanisms of CNS complications in which the authors identified three separate pathogenic patterns: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and CNS vasculitis (Medicine. 2006;85: 54-65).

In this month’s column, Dr. Seo discusses the diagnosis and management of neurologic complications associated with Wegener’s disease that are most likely to present in clinical practice.

Question: What are the potential neurologic complications that clinicians must have on their radar?

Dr. Seo: The most common complication is a sensory peripheral neuropathy. Although this can be associated with pain, many patients will complain about a lack of sensation, which they will describe as a cold feeling in their feet, or the feeling that their feet are wrapped in plastic wrap or covered in wax. Some patients might also describe this as a feeling akin to rubber bands being stretched over their feet. A more serious form of peripheral neuropathy is a mononeuritis multiplex, which can lead to a "wrist drop" or a "foot drop."

Question: What are the important diagnostic considerations? What signs and symptoms should clinicians look for?

Dr. Seo: Many patients learn to accommodate these symptoms subconsciously, or they won’t have the vocabulary to describe these problems clearly to you. Thus, it is important to test both strength and sensation explicitly, especially when you are meeting a patient for the first time. Often, the patient will be surprised to learn that they have had a neuropathy and just never realized it was a problem.

Question: How does the occurrence of neurologic manifestations affect patient management?

Dr. Seo: Sensory neuropathy in particular is difficult to manage, because immunosuppression halts the progression of symptoms but does not actually repair the damaged nerves. Most medications that are advertised for sensory neuropathy address only the pain associated with this phenomenon. Some patients do not complain that their feet and lower legs continue to feel numb, even after many years of being in remission.

Question: Is the damage caused by nervous system involvement reversible?

Dr. Seo: Unfortunately, the role of treatment is to arrest progression of the disease. So, although we hope that immunosuppression will prevent the neuropathy from becoming worse, it does not actually help repair the damaged nerves. I think that recovery does occur in these cases, but it can be excruciatingly slow. Recovery of motor function in a patient with mononeuritis multiplex is considerably faster, and patients can often regain normal function of the affected limbs with time. Currently, the early diagnosis and treatment of Wegener’s are the best ways to prevent or reduce potential damage associated with neurologic involvement.

Dr. Seo is in the division of rheumatology and is codirector of the vasculitis center at Johns Hopkins University in Baltimore. He reported having no relevant financial disclosures.

Wegener’s granulomatosis is a systemic vasculitis that primarily affects small- to medium-size vessels. The antineutrophil cytoplasmic antibody–associated disease typically involves the upper and lower respiratory tracts and the kidneys. But the disease can potentially involve any organ, including the central and peripheral nervous systems, according to Dr. Philip Seo. "When most general rheumatologists ask me about Wegener’s, they generally stick to the canonical manifestations [sinus, lungs, kidneys], but nervous system involvement is certainly relevant to the management of these patients, and probably underappreciated," he said.

Nervous system manifestations present in approximately 22%-54% of Wegener’s patients, according to a recent report. The report’s authors noted that the majority of the complications reflected in this estimate are cases involving the peripheral nervous system – specifically, polyneuropathy or mononeuritis multiplex (Curr. Opin. Rheumatol. 2011;23:7-11).

Central nervous system involvement is relatively uncommon in Wegener’s, affecting an estimated 7%-11% of patients, according to an investigation into mechanisms of CNS complications in which the authors identified three separate pathogenic patterns: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and CNS vasculitis (Medicine. 2006;85: 54-65).

In this month’s column, Dr. Seo discusses the diagnosis and management of neurologic complications associated with Wegener’s disease that are most likely to present in clinical practice.

Question: What are the potential neurologic complications that clinicians must have on their radar?

Dr. Seo: The most common complication is a sensory peripheral neuropathy. Although this can be associated with pain, many patients will complain about a lack of sensation, which they will describe as a cold feeling in their feet, or the feeling that their feet are wrapped in plastic wrap or covered in wax. Some patients might also describe this as a feeling akin to rubber bands being stretched over their feet. A more serious form of peripheral neuropathy is a mononeuritis multiplex, which can lead to a "wrist drop" or a "foot drop."

Question: What are the important diagnostic considerations? What signs and symptoms should clinicians look for?

Dr. Seo: Many patients learn to accommodate these symptoms subconsciously, or they won’t have the vocabulary to describe these problems clearly to you. Thus, it is important to test both strength and sensation explicitly, especially when you are meeting a patient for the first time. Often, the patient will be surprised to learn that they have had a neuropathy and just never realized it was a problem.

Question: How does the occurrence of neurologic manifestations affect patient management?

Dr. Seo: Sensory neuropathy in particular is difficult to manage, because immunosuppression halts the progression of symptoms but does not actually repair the damaged nerves. Most medications that are advertised for sensory neuropathy address only the pain associated with this phenomenon. Some patients do not complain that their feet and lower legs continue to feel numb, even after many years of being in remission.

Question: Is the damage caused by nervous system involvement reversible?

Dr. Seo: Unfortunately, the role of treatment is to arrest progression of the disease. So, although we hope that immunosuppression will prevent the neuropathy from becoming worse, it does not actually help repair the damaged nerves. I think that recovery does occur in these cases, but it can be excruciatingly slow. Recovery of motor function in a patient with mononeuritis multiplex is considerably faster, and patients can often regain normal function of the affected limbs with time. Currently, the early diagnosis and treatment of Wegener’s are the best ways to prevent or reduce potential damage associated with neurologic involvement.

Dr. Seo is in the division of rheumatology and is codirector of the vasculitis center at Johns Hopkins University in Baltimore. He reported having no relevant financial disclosures.