Glutamate From Gliomas Sparks Seizures

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

The investigators detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration–approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators “that system x_c- does not contribute substantially to glutamate release in tumor-free brain.” Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

Patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs “would be most likely to benefit from SAS treatment,” the investigators noted.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. They also will undergo chemical shift MRI to determine the acute effect of oral SAS on glutamate release. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is “primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures.”

The National Institutes of Health funded the mouse study. None of the authors had relevant financial disclosures.

Adviser's Viewpoint

New Avenue for Treating Seizures

Seizures are often a presenting symptom or sometimes a contributing factor in morbidity for patients with primary brain tumors. Dr. Buckingham and her colleagues demonstrated, through a commonly used mouse model, that glutamate is released from glioblastoma cells, thereby altering the surrounding neuronal resting membrane potential. This hyperexcitable state is ultimately responsible for epileptogenesis. Tumors release glutamate via a transporter mechanism called system x_c-, which is a viable target for seizure treatment. In fact, this transporter mechanism has been downregulated through use of sulfasalazine (SAS), an FDA-approved drug for use in Crohn's disease.

In 32 of 86 mice, epileptogenic potentials were recorded. Only three experienced convulsions. The remaining mice had events that were characterized as freezing behavior, automatisms, and head tremor. Based on phenotype alone, these manifestations were not clearly epileptic. But activity seen by depth electrodes confirmed them as seizures. Once SAS was administered, the frequency of seizure activity was significantly decreased. This finding is exciting, given the prior dearth of data relating tumorigenesis and epilepsy. The subtle behavioral changes that were witnessed to correlate with epileptic activity may suggest that patients with glioblastoma are experiencing subclinical seizure activity and further morbidity that is often thought of as a direct result of tumor growth and/or sequelae of chemoradiation.

In vitro studies are needed to further assess feasibility and tolerability of SAS as an antiepileptic drug, given its short half-life and its impact on metabolism of chemotherapeutic agents. This drug has been looked at previously in patients with progressive glioblastoma in terms of activity against tumorigenesis, but not for antiepileptic activity.

ALYX B. PORTER, M.D., is an assistant professor of neurology at the Mayo Clinic in Phoenix. She specializes in neuro-oncology. She has no relevant disclosures.

Vitals

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

The investigators detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration–approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators “that system x_c- does not contribute substantially to glutamate release in tumor-free brain.” Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

Patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs “would be most likely to benefit from SAS treatment,” the investigators noted.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. They also will undergo chemical shift MRI to determine the acute effect of oral SAS on glutamate release. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is “primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures.”

The National Institutes of Health funded the mouse study. None of the authors had relevant financial disclosures.

Adviser's Viewpoint

New Avenue for Treating Seizures

Seizures are often a presenting symptom or sometimes a contributing factor in morbidity for patients with primary brain tumors. Dr. Buckingham and her colleagues demonstrated, through a commonly used mouse model, that glutamate is released from glioblastoma cells, thereby altering the surrounding neuronal resting membrane potential. This hyperexcitable state is ultimately responsible for epileptogenesis. Tumors release glutamate via a transporter mechanism called system x_c-, which is a viable target for seizure treatment. In fact, this transporter mechanism has been downregulated through use of sulfasalazine (SAS), an FDA-approved drug for use in Crohn's disease.

In 32 of 86 mice, epileptogenic potentials were recorded. Only three experienced convulsions. The remaining mice had events that were characterized as freezing behavior, automatisms, and head tremor. Based on phenotype alone, these manifestations were not clearly epileptic. But activity seen by depth electrodes confirmed them as seizures. Once SAS was administered, the frequency of seizure activity was significantly decreased. This finding is exciting, given the prior dearth of data relating tumorigenesis and epilepsy. The subtle behavioral changes that were witnessed to correlate with epileptic activity may suggest that patients with glioblastoma are experiencing subclinical seizure activity and further morbidity that is often thought of as a direct result of tumor growth and/or sequelae of chemoradiation.

In vitro studies are needed to further assess feasibility and tolerability of SAS as an antiepileptic drug, given its short half-life and its impact on metabolism of chemotherapeutic agents. This drug has been looked at previously in patients with progressive glioblastoma in terms of activity against tumorigenesis, but not for antiepileptic activity.

ALYX B. PORTER, M.D., is an assistant professor of neurology at the Mayo Clinic in Phoenix. She specializes in neuro-oncology. She has no relevant disclosures.

Vitals

New evidence suggests that excessive glutamate released from glioma cells causes epileptic activity in peritumoral neurons, which may be stopped by a drug that blocks the release of glutamate from tumor cells.

Previous studies have suggested that tumor-associated seizures arise from increased levels of glutamate near areas of epileptiform activity in the peritumoral border where invading cells surround neurons, but this is the first study to establish that the activity is associated with glutamate release from the system x_c- cystine-glutamate transporter that is expressed on tumor cells, according to Susan C. Buckingham, Ph.D., and her associates at the University of Alabama at Birmingham.

The investigators detected abnormal EEG activity in 37% of immunodeficient mice 1 week after they underwent intracranial implantation of human glioma cells, but not in any mice that underwent sham implantation. This abnormal activity manifested itself as subtle changes in behavior such as freezing, facial automatisms, and tremor. Tumor-bearing cortical slices from these mice revealed a time-dependent increase in glutamate concentration (Nat. Med. 2011 Sept. 11 [doi:10.1038/nm.2453]).

Sulfasalazine (SAS), a Food and Drug Administration–approved drug that is known to inhibit system x_c-, blocked the release of glutamate from the tumor cells but not from sham slices, which suggested to the investigators “that system x_c- does not contribute substantially to glutamate release in tumor-free brain.” Electrode recordings revealed spontaneous paroxysmal discharges near tumor cells in 23% of the cortical slices, but not in sham slices. Patch-clamp recordings from neurons in these areas demonstrated increased excitability. When the researchers applied SAS to these neurons, the mean duration of epileptiform activity declined significantly. Mice with xenografted tumors that received intraperitoneal injections of SAS also showed decreased epileptic activity on EEG.

Patients with low-grade, slow-growing tumors that can become refractory to traditional antiepileptic drugs “would be most likely to benefit from SAS treatment,” the investigators noted.

Based on the approved status and tolerable side effects of SAS, the investigators are planning a trial using it as an adjuvant treatment for peritumoral epilepsy in approximately 50 patients with gliomas. They also will undergo chemical shift MRI to determine the acute effect of oral SAS on glutamate release. Although the trial is open to patients with all grades of glioma, senior author Dr. Harald Sontheimer said in an interview that his team is “primarily interested in newly diagnosed patients with low-grade gliomas who present with seizures.”

The National Institutes of Health funded the mouse study. None of the authors had relevant financial disclosures.

Adviser's Viewpoint

New Avenue for Treating Seizures

Seizures are often a presenting symptom or sometimes a contributing factor in morbidity for patients with primary brain tumors. Dr. Buckingham and her colleagues demonstrated, through a commonly used mouse model, that glutamate is released from glioblastoma cells, thereby altering the surrounding neuronal resting membrane potential. This hyperexcitable state is ultimately responsible for epileptogenesis. Tumors release glutamate via a transporter mechanism called system x_c-, which is a viable target for seizure treatment. In fact, this transporter mechanism has been downregulated through use of sulfasalazine (SAS), an FDA-approved drug for use in Crohn's disease.

In 32 of 86 mice, epileptogenic potentials were recorded. Only three experienced convulsions. The remaining mice had events that were characterized as freezing behavior, automatisms, and head tremor. Based on phenotype alone, these manifestations were not clearly epileptic. But activity seen by depth electrodes confirmed them as seizures. Once SAS was administered, the frequency of seizure activity was significantly decreased. This finding is exciting, given the prior dearth of data relating tumorigenesis and epilepsy. The subtle behavioral changes that were witnessed to correlate with epileptic activity may suggest that patients with glioblastoma are experiencing subclinical seizure activity and further morbidity that is often thought of as a direct result of tumor growth and/or sequelae of chemoradiation.

In vitro studies are needed to further assess feasibility and tolerability of SAS as an antiepileptic drug, given its short half-life and its impact on metabolism of chemotherapeutic agents. This drug has been looked at previously in patients with progressive glioblastoma in terms of activity against tumorigenesis, but not for antiepileptic activity.

ALYX B. PORTER, M.D., is an assistant professor of neurology at the Mayo Clinic in Phoenix. She specializes in neuro-oncology. She has no relevant disclosures.

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