Why Are So Few Patients With Pharmacoresistant Epilepsy Referred to Epilepsy Centers?

VANCOUVER—Neurologists’ best chance to reduce disability in patients with pharmacoresistant epilepsy lies in early recognition of pharmacoresistance and early referral of patients to full-service epilepsy centers, according to a lecture delivered at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Fewer than 1% of patients with refractory epilepsy are referred to epilepsy centers each year, and many patients are referred too late to significantly affect disability, said Jerome Engel Jr, MD, PhD, Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences and Director of the Seizure Disorder Center at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Misconceptions about epilepsy centers and epilepsy surgery may be partly responsible for the dearth of referrals.

“I think a major misconception—and I have to take partial blame for this because of all the talking I’ve done about surgery in the last three decades or more—is that all epilepsy centers do is surgery. I think a common attitude among referring neurologists is, ‘My patient is not a surgical candidate or doesn’t want surgery, so there’s no reason to refer him or her to an epilepsy center,’” Dr. Engel said.

Beyond performing surgery, specialized centers can recognize pseudopharmacoresistance, diagnose nonepileptic seizures, identify specific epilepsy syndromes, and provide psychosocial support. Dr. Engel noted that, given his position as the director of an epilepsy center, his message might seem self-serving and critical of his audience, but he asked neurologists to keep an open mind. “Early, effective intervention offers the best chance to prevent irreversible psychosocial problems, a lifetime of disability, and premature death,” he said.

A Serious Burden

Refractory epilepsy can lead to developmental delays and interfere with interpersonal and vocational skills. Patients may have interictal behavioral problems, most commonly depression, or neurologic impairment. “The mortality rate for uncontrolled epilepsy is five to 10 times that of the general population, not only because of sudden unexpected death in epilepsy and accidents, but also suicide,” Dr. Engel said. Although more than 20 new antiseizure drugs have been approved in the last three decades, the percentage of patients with pharmacoresistant epilepsy has not changed.

According to the International League Against Epilepsy, a patient has drug-resistant epilepsy when he or she fails two trials of appropriate antiseizure drugs, either alone or in combination, due to inefficacy and not intolerance. Of the approximately three million people with epilepsy in the United States, about one-third have pharmacoresistant epilepsy. According to the National Association of Epilepsy Centers, about 4,000 patients are referred to epilepsy centers per year, Dr. Engel said.

The publication of evidence-based recommendations for epilepsy center referrals has not had an obvious effect on clinical practice. In 2003, Dr. Engel and colleagues in the Quality Standards Subcommittee of the AAN published a practice parameter for temporal lobe resections. Based on a randomized controlled trial and 24 case series, they concluded that surgery provides greater benefit than medical treatment, with risks that are at least comparable. The trial by Wiebe et al found that, after a year, 64% of the patients who had surgery were seizure-free, compared with 8% of patients in the medical arm. An analysis of the case series, which included 1,952 patients, yielded nearly the same results. They recommended that patients with drug-resistant temporal lobe seizures be referred to an epilepsy center, and that surgical candidates undergo surgery.

The practice parameter, however, did not lead to earlier referrals for surgery evaluations at UCLA’s epilepsy center. Haneef et al found that in the four years before publication of the practice parameter, patients’ average time from diagnosis to referral was 17 years, compared with 18.6 years in the four years after publication.

More Than Surgery

Epilepsy centers can identify pseudopharmacoresistance in patients who are not compliant in taking their medication or who are prescribed the wrong drugs or dosage. Furthermore, a third of patients admitted to epilepsy centers do not have epilepsy, Dr. Engel said. Patients’ apparent pharmacoresistance may be caused by lifestyle issues, such as substance abuse or frequent sleep deprivation, or other conditions.

Many patients, even if their condition improves, continue to have seizures and disability. “Epilepsy centers have psychologists, psychiatrists, social workers, and counselors who help patients deal with problems that are caused by their seizures,” Dr. Engel said.

Other treatments that epilepsy centers provide include experimental drug trials and stimulation techniques, such as vagus nerve stimulation, trigeminal nerve stimulation, and responsive neurostimulation. In addition, epilepsy centers can identify patients who might benefit from the ketogenic diet or modified Atkins diet.

Surgical Candidates?

Various common misconceptions about contraindications for surgery also may prevent patients from being referred to specialized centers. For instance, bilateral interictal spikes are not a contraindication for surgery because in most patients with this finding, all seizures originate from one side. A normal MRI is not a contraindication for surgery because techniques such as PET-MRI fusion and magnetoencephalography can identify epileptogenic regions that do not appear on MRI. If a patient has multiple or diffuse lesions, only one of the lesions might be epileptogenic, or if a patient has a large lesion, only part of the lesion might be epileptogenic. When an abnormality is in a primary cortex, there are ways to identify cortex that cannot be removed and still obtain good results with surgery, Dr. Engel said.

In patients with existing memory deficits, surgery typically does not worsen memory and can improve it. In patients who do not have memory deficits, however, surgery of the language-dominant temporal lobe may worsen memory, and this complication may be a concern.

Chronic psychosis is not a contraindication for surgery. “If it’s postictal psychosis, it will go away after seizures stop. If it’s interictal psychosis, a patient with schizophrenia is better off without epilepsy than with epilepsy, even if they’ll still have schizophrenia,” Dr. Engel said. An IQ less than 70 was once considered a contraindication for surgery, but that is no longer necessarily the case.

Another issue that may be increasingly common is the removal of lesions at hospitals that perform few epilepsy surgeries (ie, low-volume hospitals). “The outcomes are not as good. There’s more morbidity, and there’s mortality, which we don’t see very much in the epilepsy centers,” Dr. Engel said. In addition, many lesions are incidental findings. “You really need to demonstrate when you see a lesion that that lesion is the source of the habitual seizures,” Dr. Engel said.

In an analysis of 6,200 epilepsy surgery procedures published in the August issue of Epilepsy Research, Rolston et al observed higher rates of adverse events when low- and high-volume centers were examined together, compared with high-volume centers alone.

ERSET Outcomes

Some 100,000 to 500,000 patients with epilepsy in the US are potential surgical candidates, and about 2,000 epilepsy surgeries are performed per year. Surgical outcomes have improved over the last few decades, and new surgical techniques have been developed, including laser thermal ablation, which can be performed through a small drill hole, Dr. Engel said.

To determine whether surgery soon after failure of two antiepileptic drug trials is superior to continued medical management, Dr. Engel and colleagues conducted the Early Randomized Surgical Epilepsy Trial (ERSET), which was published in JAMA in 2012. The multicenter trial was stopped early due to slow study recruitment. It included 38 participants (ages 12 and older, 18 men) who had mesial temporal lobe epilepsy and disabling seizures for no more than two consecutive years after their two failed drug trials. Only surgical candidates were randomized. In an intent-to-treat analysis, all of the patients in the medical arm continued to have seizures, while 11 patients in the surgical arm (73%) were seizure-free during year two of follow-up. In an analysis that included only patients for whom researchers had complete data, 85% of patients in the surgical group were seizure-free. Compared with the medical treatment group, patients in the surgical group had improved quality of life. Adverse events included three episodes of status epilepticus in the medical group and a transient stroke in the surgical group. Memory decline occurred in four participants after surgery, but the sample was too small to assess the effect of treatment on cognitive function.

“All people with refractory epilepsy deserve a timely consultation at an epilepsy center,” Dr. Engel said. “Many are not refractory. Many are surgical candidates. And the remainder of them deserve psychosocial support.”

—Jake Remaly

VANCOUVER—Neurologists’ best chance to reduce disability in patients with pharmacoresistant epilepsy lies in early recognition of pharmacoresistance and early referral of patients to full-service epilepsy centers, according to a lecture delivered at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Fewer than 1% of patients with refractory epilepsy are referred to epilepsy centers each year, and many patients are referred too late to significantly affect disability, said Jerome Engel Jr, MD, PhD, Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences and Director of the Seizure Disorder Center at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Misconceptions about epilepsy centers and epilepsy surgery may be partly responsible for the dearth of referrals.

“I think a major misconception—and I have to take partial blame for this because of all the talking I’ve done about surgery in the last three decades or more—is that all epilepsy centers do is surgery. I think a common attitude among referring neurologists is, ‘My patient is not a surgical candidate or doesn’t want surgery, so there’s no reason to refer him or her to an epilepsy center,’” Dr. Engel said.

Beyond performing surgery, specialized centers can recognize pseudopharmacoresistance, diagnose nonepileptic seizures, identify specific epilepsy syndromes, and provide psychosocial support. Dr. Engel noted that, given his position as the director of an epilepsy center, his message might seem self-serving and critical of his audience, but he asked neurologists to keep an open mind. “Early, effective intervention offers the best chance to prevent irreversible psychosocial problems, a lifetime of disability, and premature death,” he said.

A Serious Burden

Refractory epilepsy can lead to developmental delays and interfere with interpersonal and vocational skills. Patients may have interictal behavioral problems, most commonly depression, or neurologic impairment. “The mortality rate for uncontrolled epilepsy is five to 10 times that of the general population, not only because of sudden unexpected death in epilepsy and accidents, but also suicide,” Dr. Engel said. Although more than 20 new antiseizure drugs have been approved in the last three decades, the percentage of patients with pharmacoresistant epilepsy has not changed.

According to the International League Against Epilepsy, a patient has drug-resistant epilepsy when he or she fails two trials of appropriate antiseizure drugs, either alone or in combination, due to inefficacy and not intolerance. Of the approximately three million people with epilepsy in the United States, about one-third have pharmacoresistant epilepsy. According to the National Association of Epilepsy Centers, about 4,000 patients are referred to epilepsy centers per year, Dr. Engel said.

The publication of evidence-based recommendations for epilepsy center referrals has not had an obvious effect on clinical practice. In 2003, Dr. Engel and colleagues in the Quality Standards Subcommittee of the AAN published a practice parameter for temporal lobe resections. Based on a randomized controlled trial and 24 case series, they concluded that surgery provides greater benefit than medical treatment, with risks that are at least comparable. The trial by Wiebe et al found that, after a year, 64% of the patients who had surgery were seizure-free, compared with 8% of patients in the medical arm. An analysis of the case series, which included 1,952 patients, yielded nearly the same results. They recommended that patients with drug-resistant temporal lobe seizures be referred to an epilepsy center, and that surgical candidates undergo surgery.

The practice parameter, however, did not lead to earlier referrals for surgery evaluations at UCLA’s epilepsy center. Haneef et al found that in the four years before publication of the practice parameter, patients’ average time from diagnosis to referral was 17 years, compared with 18.6 years in the four years after publication.

More Than Surgery

Epilepsy centers can identify pseudopharmacoresistance in patients who are not compliant in taking their medication or who are prescribed the wrong drugs or dosage. Furthermore, a third of patients admitted to epilepsy centers do not have epilepsy, Dr. Engel said. Patients’ apparent pharmacoresistance may be caused by lifestyle issues, such as substance abuse or frequent sleep deprivation, or other conditions.

Many patients, even if their condition improves, continue to have seizures and disability. “Epilepsy centers have psychologists, psychiatrists, social workers, and counselors who help patients deal with problems that are caused by their seizures,” Dr. Engel said.

Other treatments that epilepsy centers provide include experimental drug trials and stimulation techniques, such as vagus nerve stimulation, trigeminal nerve stimulation, and responsive neurostimulation. In addition, epilepsy centers can identify patients who might benefit from the ketogenic diet or modified Atkins diet.

Surgical Candidates?

Various common misconceptions about contraindications for surgery also may prevent patients from being referred to specialized centers. For instance, bilateral interictal spikes are not a contraindication for surgery because in most patients with this finding, all seizures originate from one side. A normal MRI is not a contraindication for surgery because techniques such as PET-MRI fusion and magnetoencephalography can identify epileptogenic regions that do not appear on MRI. If a patient has multiple or diffuse lesions, only one of the lesions might be epileptogenic, or if a patient has a large lesion, only part of the lesion might be epileptogenic. When an abnormality is in a primary cortex, there are ways to identify cortex that cannot be removed and still obtain good results with surgery, Dr. Engel said.

In patients with existing memory deficits, surgery typically does not worsen memory and can improve it. In patients who do not have memory deficits, however, surgery of the language-dominant temporal lobe may worsen memory, and this complication may be a concern.

Chronic psychosis is not a contraindication for surgery. “If it’s postictal psychosis, it will go away after seizures stop. If it’s interictal psychosis, a patient with schizophrenia is better off without epilepsy than with epilepsy, even if they’ll still have schizophrenia,” Dr. Engel said. An IQ less than 70 was once considered a contraindication for surgery, but that is no longer necessarily the case.

Another issue that may be increasingly common is the removal of lesions at hospitals that perform few epilepsy surgeries (ie, low-volume hospitals). “The outcomes are not as good. There’s more morbidity, and there’s mortality, which we don’t see very much in the epilepsy centers,” Dr. Engel said. In addition, many lesions are incidental findings. “You really need to demonstrate when you see a lesion that that lesion is the source of the habitual seizures,” Dr. Engel said.

In an analysis of 6,200 epilepsy surgery procedures published in the August issue of Epilepsy Research, Rolston et al observed higher rates of adverse events when low- and high-volume centers were examined together, compared with high-volume centers alone.

ERSET Outcomes

Some 100,000 to 500,000 patients with epilepsy in the US are potential surgical candidates, and about 2,000 epilepsy surgeries are performed per year. Surgical outcomes have improved over the last few decades, and new surgical techniques have been developed, including laser thermal ablation, which can be performed through a small drill hole, Dr. Engel said.

To determine whether surgery soon after failure of two antiepileptic drug trials is superior to continued medical management, Dr. Engel and colleagues conducted the Early Randomized Surgical Epilepsy Trial (ERSET), which was published in JAMA in 2012. The multicenter trial was stopped early due to slow study recruitment. It included 38 participants (ages 12 and older, 18 men) who had mesial temporal lobe epilepsy and disabling seizures for no more than two consecutive years after their two failed drug trials. Only surgical candidates were randomized. In an intent-to-treat analysis, all of the patients in the medical arm continued to have seizures, while 11 patients in the surgical arm (73%) were seizure-free during year two of follow-up. In an analysis that included only patients for whom researchers had complete data, 85% of patients in the surgical group were seizure-free. Compared with the medical treatment group, patients in the surgical group had improved quality of life. Adverse events included three episodes of status epilepticus in the medical group and a transient stroke in the surgical group. Memory decline occurred in four participants after surgery, but the sample was too small to assess the effect of treatment on cognitive function.

“All people with refractory epilepsy deserve a timely consultation at an epilepsy center,” Dr. Engel said. “Many are not refractory. Many are surgical candidates. And the remainder of them deserve psychosocial support.”

—Jake Remaly

VANCOUVER—Neurologists’ best chance to reduce disability in patients with pharmacoresistant epilepsy lies in early recognition of pharmacoresistance and early referral of patients to full-service epilepsy centers, according to a lecture delivered at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Fewer than 1% of patients with refractory epilepsy are referred to epilepsy centers each year, and many patients are referred too late to significantly affect disability, said Jerome Engel Jr, MD, PhD, Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences and Director of the Seizure Disorder Center at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Misconceptions about epilepsy centers and epilepsy surgery may be partly responsible for the dearth of referrals.

“I think a major misconception—and I have to take partial blame for this because of all the talking I’ve done about surgery in the last three decades or more—is that all epilepsy centers do is surgery. I think a common attitude among referring neurologists is, ‘My patient is not a surgical candidate or doesn’t want surgery, so there’s no reason to refer him or her to an epilepsy center,’” Dr. Engel said.

Beyond performing surgery, specialized centers can recognize pseudopharmacoresistance, diagnose nonepileptic seizures, identify specific epilepsy syndromes, and provide psychosocial support. Dr. Engel noted that, given his position as the director of an epilepsy center, his message might seem self-serving and critical of his audience, but he asked neurologists to keep an open mind. “Early, effective intervention offers the best chance to prevent irreversible psychosocial problems, a lifetime of disability, and premature death,” he said.

A Serious Burden

Refractory epilepsy can lead to developmental delays and interfere with interpersonal and vocational skills. Patients may have interictal behavioral problems, most commonly depression, or neurologic impairment. “The mortality rate for uncontrolled epilepsy is five to 10 times that of the general population, not only because of sudden unexpected death in epilepsy and accidents, but also suicide,” Dr. Engel said. Although more than 20 new antiseizure drugs have been approved in the last three decades, the percentage of patients with pharmacoresistant epilepsy has not changed.

According to the International League Against Epilepsy, a patient has drug-resistant epilepsy when he or she fails two trials of appropriate antiseizure drugs, either alone or in combination, due to inefficacy and not intolerance. Of the approximately three million people with epilepsy in the United States, about one-third have pharmacoresistant epilepsy. According to the National Association of Epilepsy Centers, about 4,000 patients are referred to epilepsy centers per year, Dr. Engel said.

The publication of evidence-based recommendations for epilepsy center referrals has not had an obvious effect on clinical practice. In 2003, Dr. Engel and colleagues in the Quality Standards Subcommittee of the AAN published a practice parameter for temporal lobe resections. Based on a randomized controlled trial and 24 case series, they concluded that surgery provides greater benefit than medical treatment, with risks that are at least comparable. The trial by Wiebe et al found that, after a year, 64% of the patients who had surgery were seizure-free, compared with 8% of patients in the medical arm. An analysis of the case series, which included 1,952 patients, yielded nearly the same results. They recommended that patients with drug-resistant temporal lobe seizures be referred to an epilepsy center, and that surgical candidates undergo surgery.

The practice parameter, however, did not lead to earlier referrals for surgery evaluations at UCLA’s epilepsy center. Haneef et al found that in the four years before publication of the practice parameter, patients’ average time from diagnosis to referral was 17 years, compared with 18.6 years in the four years after publication.

More Than Surgery

Epilepsy centers can identify pseudopharmacoresistance in patients who are not compliant in taking their medication or who are prescribed the wrong drugs or dosage. Furthermore, a third of patients admitted to epilepsy centers do not have epilepsy, Dr. Engel said. Patients’ apparent pharmacoresistance may be caused by lifestyle issues, such as substance abuse or frequent sleep deprivation, or other conditions.

Many patients, even if their condition improves, continue to have seizures and disability. “Epilepsy centers have psychologists, psychiatrists, social workers, and counselors who help patients deal with problems that are caused by their seizures,” Dr. Engel said.

Other treatments that epilepsy centers provide include experimental drug trials and stimulation techniques, such as vagus nerve stimulation, trigeminal nerve stimulation, and responsive neurostimulation. In addition, epilepsy centers can identify patients who might benefit from the ketogenic diet or modified Atkins diet.

Surgical Candidates?

Various common misconceptions about contraindications for surgery also may prevent patients from being referred to specialized centers. For instance, bilateral interictal spikes are not a contraindication for surgery because in most patients with this finding, all seizures originate from one side. A normal MRI is not a contraindication for surgery because techniques such as PET-MRI fusion and magnetoencephalography can identify epileptogenic regions that do not appear on MRI. If a patient has multiple or diffuse lesions, only one of the lesions might be epileptogenic, or if a patient has a large lesion, only part of the lesion might be epileptogenic. When an abnormality is in a primary cortex, there are ways to identify cortex that cannot be removed and still obtain good results with surgery, Dr. Engel said.

In patients with existing memory deficits, surgery typically does not worsen memory and can improve it. In patients who do not have memory deficits, however, surgery of the language-dominant temporal lobe may worsen memory, and this complication may be a concern.

Chronic psychosis is not a contraindication for surgery. “If it’s postictal psychosis, it will go away after seizures stop. If it’s interictal psychosis, a patient with schizophrenia is better off without epilepsy than with epilepsy, even if they’ll still have schizophrenia,” Dr. Engel said. An IQ less than 70 was once considered a contraindication for surgery, but that is no longer necessarily the case.

Another issue that may be increasingly common is the removal of lesions at hospitals that perform few epilepsy surgeries (ie, low-volume hospitals). “The outcomes are not as good. There’s more morbidity, and there’s mortality, which we don’t see very much in the epilepsy centers,” Dr. Engel said. In addition, many lesions are incidental findings. “You really need to demonstrate when you see a lesion that that lesion is the source of the habitual seizures,” Dr. Engel said.

In an analysis of 6,200 epilepsy surgery procedures published in the August issue of Epilepsy Research, Rolston et al observed higher rates of adverse events when low- and high-volume centers were examined together, compared with high-volume centers alone.

ERSET Outcomes

Some 100,000 to 500,000 patients with epilepsy in the US are potential surgical candidates, and about 2,000 epilepsy surgeries are performed per year. Surgical outcomes have improved over the last few decades, and new surgical techniques have been developed, including laser thermal ablation, which can be performed through a small drill hole, Dr. Engel said.

To determine whether surgery soon after failure of two antiepileptic drug trials is superior to continued medical management, Dr. Engel and colleagues conducted the Early Randomized Surgical Epilepsy Trial (ERSET), which was published in JAMA in 2012. The multicenter trial was stopped early due to slow study recruitment. It included 38 participants (ages 12 and older, 18 men) who had mesial temporal lobe epilepsy and disabling seizures for no more than two consecutive years after their two failed drug trials. Only surgical candidates were randomized. In an intent-to-treat analysis, all of the patients in the medical arm continued to have seizures, while 11 patients in the surgical arm (73%) were seizure-free during year two of follow-up. In an analysis that included only patients for whom researchers had complete data, 85% of patients in the surgical group were seizure-free. Compared with the medical treatment group, patients in the surgical group had improved quality of life. Adverse events included three episodes of status epilepticus in the medical group and a transient stroke in the surgical group. Memory decline occurred in four participants after surgery, but the sample was too small to assess the effect of treatment on cognitive function.

“All people with refractory epilepsy deserve a timely consultation at an epilepsy center,” Dr. Engel said. “Many are not refractory. Many are surgical candidates. And the remainder of them deserve psychosocial support.”

—Jake Remaly