Is radiosurgery a neuromodulation therapy?
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Radiosurgery is commonly considered to be effective through a destructive physical mechanism on neural tissue. Since its invention by Leksell in the 1950s, clinical and experimental experience of radiosurgery has demonstrated that for classical indications, for example arteriovenous malformations and benign tumors, radiosurgery is effective because of its specific histological effects of thrombotic endothelial proliferation and apoptosis, not simple coagulative necrosis. In functional neurosurgery, the strategy is either to target a small volume of normal tissue (i.e., ventrointermediate nucleus, capsulotomy, trigeminal neuralgia, etc.) with a high dose (80–140 Gy at maximum) or to target a large volume of tissue (i.e., 5–9 cc in epilepsy radiosurgery) with a moderate dose (17–24 Gy at the marginal isodose). These procedures have been proposed, technically performed, and evaluated on the basis of the hypothesis that their mechanism of action is purely destructive. However, modern neurophysiological, radiological and histological studies are leading us to question this assumption. Tissue destruction is turning out to be either absent or minimal and in almost all cases insufficient to explain the clinical effects obtained. Therefore, one possibility is that radiosurgery is inducing changes in the functioning of the neural tissue, by inducing remodeling of the glial environment, and is leading to the modulation of function while preserving basic processing. Thus, most radiosurgery procedures may induce the desired biological effect without requiring the histological destructive effect for completion of the therapeutic objective. Therefore the concept of “lesional” radiosurgery may be incorrect and a completely hidden world of neuromodulatory effects may remain to be discovered.
KeywordsApoptosis Gamma knife Glia Plasticity Radiosurgery Subnecrotic
From the beginning, neurosurgery has been a specialty field dealing with the “ablation, removal or reduction” of structural conditions affecting neurological function . Perhaps one of the first attempts at therapeutic neuromodulation was the use of electrical fish by the ancient Egyptians in 500 BC for pain management. However, only recently has the idea of restoration of function through modulation of neuronal function or restoration of damaged neurological circuitry been given consideration, thus marking a significant milestone in the intellectual and therapeutic course of neurosurgery . Twenty years ago concepts of neuromodulation, gene therapy, and cellular grafting were being introduced to our field [30, 55]. Electrical stimulation, direct installation of substances in the central nervous system (CNS), and grafting are now regarded as the main avenues for technical development in neuromodulation. However, radiosurgery has always been considered as a purely ablative treatment. This article explores some of the documented and theoretical mechanisms involved in the responses of neural tissues to radiosurgery from the perspective of an experienced user.
Lesional versus non-lesional effect
Radiosurgery, in the mind of its inventor Lars Leksell, was clearly intended to mimic the lesional effects of a surgeon’s knife, hence the name “Gamma Knife” given to the first completed instrument. The high doses initially selected for the thalamotomies  or capsulotomies  or benign tumors [33, 60] were rapidly identified as being unnecessarily toxic. The first vestibular schwannoma treated with the Gamma Knife in Stockholm by Leksell and Meyerson on June 16, 1969 was treated with 35 Gy at the periphery ! Gradually, neurosurgeons in Karolinska came to appreciate that it was possible to provide very long-term tumor control for benign tumors using much lower doses. In 1992, we were taught by George Noren  to treat these tumors with 11–13 Gy at the margin, a lower dose than originally recommended but only implemented in Stockholm from April, 1989. This dose reduction policy resulted in a dramatic decrease in facial palsy rate from 27% to less than 1%, and an increase in hearing preservation to 80% with no loss of tumor control [10, 49, 53]. With this new regimen of lower doses for benign tumors, the predominant mechanism of action was presumed to be cell death mediated by DNA breakage in the populations of cells which were entering mitosis [2, 22, 25].
The objective of arteriovenous malformation (AVM) radiosurgery is to create thrombosis of the nidus thus preventing further hemorrhage. This clinical effect is obtained because of a histological change marked by endothelial proliferative thrombosis [56, 65]. This is typically a biological effect specifically induced by radiosurgery without simple destruction of vascular tissue but rather a proliferative response within the arterial wall of the vessels to radiation injury. This histological and clinical evidence consequently led Steiner  to propose a modification to Leksell’s historical definition of radiosurgery as follows: “radiosurgery is the neurosurgical procedure where narrow ionizing beams, given in a single high dose fraction, are used either to destroy a predetermined target volume or to induce a desired biological effect in this target volume, …”. Furthermore, the much lower rate of hemorrhage after AVM radiosurgery (compared with embolization) may have something to with modulation of another specific biological effect, namely a decrease in the angiogenic response to injury with a reduction of the expression of the vascular endothelial growth factor .
A differential biologic effect
Kurita et al. in 2002 studied radiation-induced apoptosis of oligodendrocytes in the adult rat brain, relying on the counting of TUNEL-positive cells with apoptotic morphology (GFAP−, CNP+). They reported rapid apoptotic depletion of the oligodendrocytes (maximum after 8 h) and a significant decrease in cell density in the white matter 24 h after irradiation. These changes are dose, time, and location-dependant, because more intense changes are seen in the external capsule than in the genus of the corpus callosum, the internal capsule, and the cerebellum .
The genetic profile of the individual is certainly crucial. In thalamotomies, the treatment is completely standard in terms of the volume of the target, location, and dose. Although the tissue reaction to radiosurgery is reportedly very focal in some series [19, 67], up to 10% of the patients can have a much larger radiographic reaction, as seen on MR imaging, and these imaging changes may be associated with hemiparesis, usually transient. Kondziolka et al. [21, 23] have demonstrated the radio-protective effect of the 21-aminosteroid U-74389G in an experimental study in rats. They report that this drug reduces the cytokine expression normally seen after radiation injury and which may be over-expressed in patients having a greater reaction to radiosurgery seen clinically.
Main functional radiosurgery indications: a review
Jenrow et al.  have reported in epileptic rats (kindling model) that the selective reduction of densities in the dentate granular cell layer and the medial CA3 pyramidal cell layer was prevented or reversed by the irradiation at 25 Gy but not at 18 Gy. These experimental studies tended to support the dose effect we have found in man . Several magnetic resonance spectroscopy studies are showing, at around 12 months (usual delay for clinical and radiological major changes), a strong reduction of choline, creatine, and N-acetylaspartate with elevation of the lactate, pointing to lack of normal oxidative metabolism (ischemia) [11, 15, 36, 38, 61, 62]. Dr Jason Sheehan and his group report that for epileptic rats irradiated with 40 Gy to the medial temporal lobe, immunohistochemical findings suggest that at least one subtype of hippocampal interneurons are selectively vulnerable to GKR. Neuronal cells seem to have undergone a phenotypic shift with regard to calbindin and GAD-67 expression (K. Lee, personal communication, 2009). Thus, this work suggests a selective vulnerability of some neuronal subtypes to our proposed “neuromodulative” effect.
Hypothalamic hamartoma radiosurgery for epilepsy control is an even more convincing example of the functional, non-lesional effect in GKR. As an international referral center for this rare pathology, we have treated more than 80 patients. Theoretically, the question of epileptogenic zone (EZ) definition is straightforward. The hamartoma itself, usually quite well delineated on a high resolution MRI, is supposed to be the EZ [31, 51] and defines the limits of the target, thus making the targeting simpler than for MTLE. After the first multi-centered retrospective trial , we have organized a prospective trial . In these case series, the vast majority of the patients do not show any radiographic changes on their follow-up MRI. More than 50% of the patients are seizure-free and a large portion of the patients have had a significant reduction in their seizure frequency and associated significant improvement of their quality of life. Interestingly, the psychiatric  and neuropsychological symptoms are also improving dramatically or resolving completely, in a larger percentage of the patients, even in those with no complete seizure cessation. This effect on the co-morbidities usually occurs before the effect on seizure control and in the absence of any changes in the MRI. The clinical observation of profound therapeutic effect with absolutely no histological necrosis induced by radiosurgery is encouraging and is again indicative of a neuromodulatory effect of radiosurgery on the surrounding brain .
The CNS is known not to be capable of meaningful regeneration of lost neurons or axons and dendritic connections after injury. Thus a lesion in the brain may result in permanent and severe loss of neurological function. Classically, the CNS regenerative process fails, in our opinion, for at least three reasons:
neurons are highly susceptible to death after CNS injury;
the CNS extracellular matrix contains multiple inhibitory factors making growth impossible; and
the intrinsic growth capacity of post-mitotic neurons are constitutively reduced by factors that inhibit CNS regeneration and its potential strategies to overcome those obstacles .
A radical change in the phenotype of the glial environment may allow a functional readjustment phenomenon. Neurons may have a more impressive capacity for adjusting than previously suggested. Their intracellular machinery may be able to adapt in response to changes in their environment and some sort of retained developmental state may have an amazing ability to correct internal errors, battling the effects of such mistakes as mutations or mis-folded proteins . Our hypothesis is that radiosurgery, under certain conditions, relying on non-necrotizing dose conditions, may induce an important turnover of the glial environment of neurons, enabling functional connections the opportunity to reset, reorganize, and overcome errors disturbing their functional capability. Thus, let us create “Glial Chaos” in the system!
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