Our recently published pilot trial demonstrated that Gamma Knife® RS for MTLE was a well-tolerated procedure with seizure remission rates similar to those published for standard open temporal lobectomy. In the current report, we examined the development of the RS-induced radiologic changes and their association with clinical outcomes. We found that MRI indicators of vasogenic edema occurred approximately 9 months after RS and showed a significant relationship with seizure remission. Evidence of vasogenic changes, as well as diffusion and biochemical alterations detected by spectroscopy, are consistent with a mechanism of temporal lobe radiation injury mediated by local vascular insult and tissue necrosis. The extent of these alterations at 12 months was dose-dependent and predicted seizure remission in the third year of follow-up. The extent of the radiographic lesion did not correlate with long-term or sustained impairments in measures of language function or neurocognition.
Our results help to explain the outcomes reported in previous trials of RS for MTLE. With few exceptions, high-dose protocols (>20 Gy) yielded better short-term seizure remission than lower dose protocols.8
In the current report, high-dose RS treatments resulted in larger radiologic changes; accordingly, the presence of a “significant” T2 hyperintensity lesion (volume >200 mL) at the 12-month postoperative mark strongly predicted good seizure and quality of life outcomes.
While the neuroimaging changes documented in the current study are consistently associated with seizure control, the mechanisms by which RS reduces or eliminates seizures are unclear. Diffusion and proton spectroscopic data may help in this task, as well as shed light on the findings of “radionecrosis” in general. ADC maps at 12 months showed increased perilesional diffusion consistent with vasogenic edema, and within the target, decreased diffusion, consistent with the development of cytotoxic edema as seen with ischemia. Proton spectroscopic data support this interpretation: losses of NAA, choline, and creatine peaks and the development of lactate within the target indicated lack of normal oxidative metabolism, and thus, ischemic loss of neuronal parenchyma. Therefore, our data demonstrated a progression of ischemic vascular injury with subsequent necrosis, leading to increased vascular permeability, vasogenic edema within and around the radiosurgical target, and finally focal encephalomalacia. These findings are somewhat unexpected, since preclinical investigations with the use of rat models of limbic epilepsy demonstrate that seizure reduction is not associated with tissue necrosis or a concomitant loss of neurons,30–32
though most animals achieved improvement rather than remission of seizures. On the other hand, in humans, seizure remission after RS of other epileptic lesions—hypothalamic hamartomas or vascular malformations—does not require radiologic changes consistent with radionecrosis.33,34
Similarly, histopathology of hippocampal specimens obtained from open temporal lobectomy after failed RS for MTLE1,3,7
demonstrates perivascular sclerosis and hyalinization, rather than necrosis. However, since these specimens were obtained from unsuccessful RS, they may not be sufficient to explain the changes required for successful RS in MTLE. Our data indicate that RS does not result in remission of temporal lobe seizures unless there is significant injury to neural tissue in the presumed seizure focus. Whether there is an antiepileptic effect in the human temporal lobe that does not require neuronal damage has not been demonstrated.
Although our data provide guidance in the prediction of seizure remission by 12-month neuroimaging criteria, they do not explain the biologic variability among patients exposed to very similar treatment protocols. Of course, the factors that predict failure of standard temporal lobectomy may also apply to RS, including incomplete hippocampal “resection” or bilateral disease. On the other hand, sensitivities to radiation may differ among patients. Radiation injury mediated by vascular endothelial insult may be affected by genetic factors, such as DNA repair mechanisms, or even acquired conditions such as intracranial atherosclerosis.
The lack of neurocognitive impairments that correspond to peak neuroimaging changes has implications in the overall morbidity of RS. The development of transient, perilesional edema is expected after RS, but short-term cognitive morbidities have not been described.22
Studies of cognition or behavior after RS for tumors,35
or mesial temporal lobe epilepsy4,23,37
all demonstrate stabilization, relative sparing, or improvements in various markers of cognitive function, but these studies focus on final outcomes with little emphasis on interim or peak effects. Studies of patients treated with RS for metastatic tumors show that the majority of survivors, most of whom are impaired in categories of executive function, motor dexterity, or learning and memory at presurgical baseline, demonstrate stability or improvements 200 days following treatment35
; however, the majority of subjects died of their disease. Patients tested 1 year after RS for vascular malformations demonstrated no significant changes.36
We found a weak trend between the severity of temporal lobe edema and measures of language function when involving the dominant hemisphere, though the study was not powered to make definitive conclusions. A larger trial currently underway will address this issue in detail.