In the July 30, 2012, Neurology articles ahead of print, Drs. Yuen and colleagues from the Royal Melbourne Hospital in Australia presented an important analysis looking at the relationship between glutamate and the glutamate transporter expression in human gliomas and the surrounding peritumoral brain, and the presence of tumor-associated seizures. The investigators studied two groups of patients who underwent a craniotomy (an operation in which the skull is opened) for a type of brain tumor known as glioma. The tumors, and specimens around the tumor, were sent to pathology and analyzed for glutamate concentration and expression of glial glutamate transporters.
A Little Bit of Background…
Glutamate, as you may recall, is an important excitatory neurotransmitter and is felt to be important in the onset of seizures with elevated levels in epilepsy.
The researchers then compared the group who had seizures and those who were seizure free for characteristics in glutamate concentration and expression of these glial glutamate transporters or compounds that help to transport glutamate across the cells. The aim being to see if there was a relationship existing, and therefore the effect of brain tumors on seizures.
A total of 42% of patients had tumor-associated seizures with 95% of seizures first occurring preoperatively or before the operation. Clinical factors associated with the risk of tumor-associated seizures were being at a younger age, the location of the tumor being in the temporal lobe and tumors that have cells that are known as oligodendroglial.
The molecular features in the tumor specimens associated with tumor-associated seizures were higher glutamate concentrations, reduced expression of EAAT2, an increased system xc- expression.
These results were also replicated in the peritumoral tissue. An analysis identified that raised glutamate concentrations in tumor and peritumoral tissue and increased expression of the peritumoral system xc-, younger age, temporal lobe location and tumors with oligodendroglial components as predictive of preoperative seizures.
The scientist concluded that relative increased glutamate concentrations in gliomas and altered glutamate transporter expression are associated with the presence of tumor-associated seizures and may play a role in how seizures and epilepsy develop in patients who have primary brain tumors.
Why is this Important?
This study is important because seizures are among the most common clinical conditions found in patients who have brain tumors. About half of patients who present with brain tumors will experience at least one seizure during the course of their disease and oftentimes seizures are the presenting symptoms that tell the physician that a tumor is either going to occur or has occurred and requires diagnosis. How tumors lead to seizures is unknown and answering that question would help not only to prevent seizures associated with tumors, but perhaps may shed light as to how to manage seizures and epilepsy in patients who do not have any tumors at all. There has been significant attention recently on the role of glutamate and this particular study highlights how glutamate may lead to certain types of epilepsy.
In an accompanying editorial by Drs. Rüegg and colleagues, the editorialists find that this study aligns with recently published animal data showing that glutamate increased in certain animal models and seizures can be abolished by applying a blocking agent that stops the transporter from working.
This blocking agent, known as sulfasalazine, is a well known and currently approved drug for inflammatory bowel diseases and used by gastroenterologist. By the same mechanism, glioma growth can also be inhibited. Perhaps taken together, this potentially suggests, at least according to the accompanying editorial, that sulfasalazine might be tested as a seizure-suppressing agent in patients who have tumor-associated seizures. Since these seizures are often resistant to typical anti-seizure drugs, perhaps looking at a different approach to management would be beneficial in this particular instance.
Pay Attention to This!
This study merits attention because:
It highlights a group of patients that are often discussed in the world of oncology, but are difficult to manage by epilepsy specialists, given that the manner in which seizures occur in brain tumor patients may need to be treated differently from those who simply present with epilepsy without a tumor.
The study also highlights a unique mechanism by which seizures may be stopped and perhaps provides a glimpse as to a different approach for managing seizures in this particular population. Clearly more work is needed but another glimmer of hope is presented by the work of Dr. Yuen.
by Joseph I. Sirven, MD
Last Reviewed: 8/29/2012
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