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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 219-234

Complications of stereotactic radiosurgery: Avoidable or inevitable?


1 Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Neurosurgery, National Institute of Medical Health and Neurosciences, Bangalore, India

Date of Web Publication02-Nov-2021

Correspondence Address:
Dr. Sunil K Gupta
Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, Bangalore
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_431_21

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  Abstract 


Gamma knife radiosurgery (GKRS) is a popular radiosurgical tool for various benign and malignant intracranial pathologies. Our objective was to evaluate the spectrum of complications of GKRS, the timeline of adverse events, and the outcome following the radiosurgical intervention. We systematically searched for articles related to various complications using the following keywords: “Vascular complications”, “Gamma-knife”, “stereotactic”, “radiosurgery”, “complications”, “edema”, “vascular changes”, “malignancy”, and “alopecia”. The literature was separately evaluated for 'early ' (within 12 weeks of GKRS)' or 'delayed' (after 12 weeks of GKRS) sequalae. We separately evaluated the relevant animal studies for literature analysis, and for the histopathological changes that take place after radiosurgery. Following the systematic analysis, 543 articles were evaluated. With the predetermined criteria, we identified 36 studies detailing 72 cases. Vascular complications, radiosurgery induced malignancy, radiation necrosis and radiation induced edema were the major reported complications. A delayed hemorrhage after a latency period was the most common complication while administering GKRS for arteriovenous malformations. A repeat radiosurgical intervention was identified as the significant factor responsible for delayed hemorrhage. Post-radiosurgery intratumoral hemorrhage was observed in meningiomas, vestibular schwannomas, pituitary adenomas, pineocytomas and cerebellar astrocytomas. Following the administration of single fraction stereotactic radiosurgery (SRS) for brain metastases, necrosis was observed in 5.2% patients at 6 months, in 17.2% at 12 months, and in 34% patient population at 24 months. Delayed occlusive or proliferative vasculopathy, malignancy, necrosis and edema are rare, albeit probable, complications that occur after GKRS. There are no definite identifiable markers for determining the probability of developing these complications. The risks of radiosurgery-induced complications are more in patients with a history of prior radiation therapy, a large tumor volume, and the usage of non-conformal dose plans. The risk of radiation-induced tumour formation after a single-function radiosurgery is very low and should not be used as a reason to choose alternative treatment strategies for appropriate patients. The clinician should explain these probable risks to the patient before considering GKRS as a treatment option.

Keywords: Gamma knife radiosurgery; vascular complications; radiation necrosis; radiation induced malignancy, edema


How to cite this article:
Tripathi M, Deora H, Gupta SK. Complications of stereotactic radiosurgery: Avoidable or inevitable?. Int J Neurooncol 2021;4, Suppl S1:219-34

How to cite this URL:
Tripathi M, Deora H, Gupta SK. Complications of stereotactic radiosurgery: Avoidable or inevitable?. Int J Neurooncol [serial online] 2021 [cited 2021 Nov 27];4, Suppl S1:219-34. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/3/219/329826



“We look for medicine to be an orderly field of knowledge and procedure. But it is not. It is an imperfect science, an enterprise of constantly changing knowledge, uncertain information, fallible individuals, and at the same time, lives on the line. There is science in what we do, yes, but also habit, intuition, and sometimes, plain old guessing. The gap between what we know and what we aim for persists. And this gap complicates everything we do.”

Atul Gawande: Complications: A Surgeon's Notes on an Imperfect Science


  Introduction Top


In the last four decades, we have witnessed a paradigm shift in the philosophy of management of neurosurgical ailments, thanks to the improved understanding of neurobiological behaviour of the diseases, and an enhancement in the armamentarium of a neurosurgeon. Stereotactic radiosurgery (SRS) is an advancement in the field of neurooncology that has gained tremendous popularity not only among neurosurgeons but also radiation therapists, due to its easy applicability, improved accessibility, cost-effectiveness, and long-term results. This is because it provides a comparable or better lesion control with an improved quality of life compared to the conventional surgical/radiation techniques.

Complications are very rare with gamma knife radiosurgery (GKRS). Anecdotal reports highlighting the development of vascular occlusion, malignancy, necrosis and edema are observed in literature. Long-term studies have proven excellent results with GKRS; the chances of an infrequent collateral damage (ranging from incomplete nidus obliteration, cyst formation, development of neuropathy, radiosurgery induced edema to radiation-induced tumors in rare instances), however, always coexist.[1],[2],[3],[4],[5] A comprehensive review on the reporting of complications following GKRS is lacking. In order to fill this void, the authors reviewed available literature to highlight complications and their management following radiosurgical intervention in neurosurgical ailments.


  Methods Top


A comprehensive search was carried out among all English language articles on PubMed/Medline (until December 2020) using the keywords: “Gamma-knife”, “radiosurgery”, “complications”, “edema”, “vascular complications”, “vascular changes”, “radiosurgery”, “stereotactic radiosurgery”, “malignancy”, and “alopecia”. Relevant articles were filtered and reviewed for their suitability to be included in this review. Only the articles, where the primary modality of treatment used was GKRS were included, while other modalities such as linear accelerator (LINAC), cyber-knife based, or conventional radiotherapy were excluded [Figure 1]. References of the included articles were also studied for the inclusion of additional cases. Relevant animal studies on the effect of radiation on cerebral vasculature; and, those on the histological changes that take place following GKRS administration, have also been reviewed.
Figure 1: The research methodology for vascular complications of gamma knife radiosurgery

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  Results Top


The systematic analysis revealed 543 articles on the topic, out of which 518 were excluded, based on a predetermined inclusion/exclusion criterion. We finally identified 36 studies, detailing 72 cases, that were deemed appropriate to be included in this study.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] We evaluated these studies to identify the mentioned complications, the treatment parameters and the long-term outcomes [Table 1] and [Table 2].[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49]
Table 1: Compilation of various adverse vascular effects of gamma knife radiosurgery reported in literature

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Table 2: Characteristics of cases with vascular complications

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Delayed haemorrhage

Radiation-induced changes in the vascular wall and intimal hyperplasia help in the arteriovenous malformation (AVM) obliteration following GKRS.[49],[50],[51],[52] Among the 'cafeteria choices' for AVM treatment, the strongest reason for not using GKRS is the inherent risk of 'interval bleed' following the latter treatment. The criteria of cure following treatment of an AVM is the angiographic proof of complete nidus obliteration and the absence of an early draining vein.[53] There are anecdotal case reports of the occurrence of a remote bleed after documented AVM obliteration, that may be precipitated even 5-years after the administration of GKRS. The retrospective analysis of these patients has proven the persistence of an early draining vein; and/or, the histopathologic evidence of patent vascular channels within or surrounding the nidus.[4],[14],[16],[17],[18],[20] The most common complication that occurred in the study was delayed haemorrhage (encountered in 37/72 patients). This complication should be given due consideration while dealing with vascular pathologies, like an AVM, a cavernous malformation, or other vascular lesions. The 25/72 patients had delayed hemorrhage, with varying reasons being ascribed to it, such as the development of venous thrombosis, the presence of an occult residue, the occurrence of radiation-induced angiopathy or the resurgence of a recurrent AVM.

In AVMs, there were many causes of delayed hemorrhage reported. These include venous thrombosis as an adverse effect of radiation, occult residues, recurrent AVM, and cyst formation. It has been shown histologically and via immunohistochemical analysis[37] that despite angiographic cure, the nidus remains microscopically patent in some cases, with evidence of neo-vascularization as well as the already mentioned radiological markers. Almost all such cases had rebleeding after 5 years (range 4-11 years) of the treatment. These histological and immunohistochemical characteristics do not seem to be influenced by the location or size of the AVM. The only factor that seems to correlate with vascular events is a repeat treatment with radiosurgery. The hemorrhage in 50% of cases usually responds to medical management with only 13 out of 25 cases needing surgical decompression.[16]

Aneurysm/pseudoaneurysm formation

Among non-AVM cases (12/72) with delayed haemorrhage, the prominent cause of late rebleeding was the aneurysm or pseudoaneurysm formation in the vessel in the close proximity to the targeted area.[54] The literature reports such occurrences in superior cerebellar artery (SCA) and anterior inferior cerebellar artery (AICA) in patients with trigeminal neuralgia (TN) (4;3 aneurysms and 1 pseudo-aneurysm)[30],[34], and in a patient with cerebellopontine angle meningioma (1/1, aneurysm).[7],[8],[28],[32],[34] One patient presented in a comatose status secondary to a ruptured pseudoaneurysm of the AICA following GKRS for a vestibular schwannoma (VS). He was successfully managed with immediate external ventricular drainage of cerebrospinal fluid (CSF), followed by endovascular management of the aneurysm.[32] Another patient developed a pseudoaneurysm in the petrous segment of internal carotid artery following GKRS for a pituitary adenoma (PA) (1/1, aneurysm/72). This patient needed a high flow bypass and trapping of the aneurysm and had a good recovery.[13] Another patient with a clival meningioma suffered from intratumoral bleed within 3 hours of undergoing GKRS. This patient was on aspirin and clopidogrel for his cardiac ailment and radiosurgery cannot be definitely attributed as a cause for the haemorrhage. The patient survived on conservative management with subtle lower cranial nerve deficits.[10]

An aneurysm or a pseudoaneurysm formation is a well-documented phenomenon after GKRS, with most cases occurring either after a high dose of radiation for TN or following GKRS for a VS. Interestingly, among patients of VS, aneurysms[8],[32],[33],[34] have occurred in the anterior inferior cerebellar artery (AICA). The etiopathogenesis has been attributed to vascular wall damage, that has only been proved pathologically in one case by Akamatsu et al.[32] The arterial wall adjacent to the aneurysm did not reveal any atheromatous change. The aneurysm had only a thin collagenous wall with loss of elastic layer and the media; thus, it was diagnosed as a pseudoaneurysm on histological grounds. The VS did not invade the arterial wall. This is in direct contrast to other radiation derived microangiopathic changes. Typically, radiation-induced aneurysms show atherosclerotic changes in the intima, collagenous fibrosis with loss of smooth muscle cells in the media, and macrophage infiltration within the intima and/or media.[32] Larger arteries are less susceptible to radiation-induced damage compared to the smaller arteries. These aneurysms are more common along the arteries rather than at branching points, and interestingly, doses as low as 5-9 Gy can induce sufficient changes to precipitate an aneurysm formation.[33] According to Kellner et al., in 2014, radiation-induced edema is present in 10-30% of this patient population. As the basic mechanism of aneurysm/pseudoaneurysm formation is chronic inflammation, patients who have had a higher sensitivity to radiation require a longer follow-up to rule out this complication.[7]

Most cases of aneurysm formation have either been managed conservatively or with endovascular coiling. The development of aneurysms may be as late as ten years after the treatment.[7] Regular follow-up visits and imaging are usually discontinued by that time as the rarity of these lesions do not warranty such a prolonged follow-up. However, if a patient previously treated with GKRS presents years later with a new-onset sudden and severe headache and/or focal deficits, the possibility of an aneurysm/pseudoaneurysm needs to be kept in mind. Factors that may help in further narrowing the possibilities to that of existence of an aneurysm are the presence of a vessel near the radiation hotspots, and the development of radiation-induced edema in the immediate postoperative period.

Occlusive vasculopathy

27/72 patients suffered from stenosis/obliteration of vessels, most commonly in the zone of radiation, and rarely (2/27) in the zone outside the area that has received direct radiation. Most of these patients were treated for AVM (11/27), cavernous sinus meningioma (CSM) (13/27), TN (2/27), and pituitary adenoma (1/27). The majority (16/27) of these patients remained asymptomatic. Of the 13 patients treated for a CSM, 9 were asymptomatic, while 4 were symptomatic; three of these patients showed symptoms of transient ishaemic attack, and a single patient suffered from a stroke after 39 months of the GKRS. In a case of TN reported by Maher et al., in 2000,[3] the patient underwent microvascular decompression after he was detected to be having a poor pain control following administration of medication. The intraoperative impression showed that the superior cerebellar artery, along with accompanying veins, had atheromatous changes, presumably secondary to the effects of radiation therapy.[55],[56]

Abeloos et al.,[1] reported an ipsilateral internal carotid artery (ICA) occlusion in a case of cavernous sinus hemangioma with 22.3 Gy radiation delivered to the cavernous ICA. Graffeo et al., in 2019[35] studied the relation between ICA occlusion, the dose of radiation, and the effect of tumor growth on ICA. They found that in a pathological entity like functional pituitary adenoma, no patient suffered from an ICA occlusion despite the higher radiation doses administered, compared to the non-functioning adenomas. When a patient with a CSM was irradiated, the five- and 10-year risk of ICA occlusion was 7.5% and 12.5% in groups with complete encasement of the ICA. The risk of ischemic stroke was 1.2% in both the groups.[35],[57].

Histopathological examination of the normal cerebral arteries after irradiation disclosed a series of changes similar to that observed in the cerebral AVM specimens following radiation therapy, including vessel obliteration with hyalinization. Similar mechanisms may be applicable in cases of anterior inferior cerebellar artery (AICA) occlusion, (following radiation treatment of a VS).[32] A heterogeneous dose distribution inside the target may produce hot spots on the vessel wall, which can be avoided by adjusting the dosimetry planning.

Vascular occlusion requiring a bypass is rare, with only 2 reported cases observed in literature. This includes the development of moya-moya disease following GKRS of an AVM in one patient;[9] and, the development of petrous ICA occlusion in the other.[13] A vascular bypass procedure led to an improvement in symptoms in the two cases; due to the lack of a suffient follow-up, it remains to be seen whether these cases had re-appearance of an AVM. Interestingly, one case of cerebral AVM with the moya-moya disease was reported by Seol et al.,[49] in which a staged bilateral encephaloduromyosynangiosis (EDAMS) was performed for the moya-moya disease. This led to an increase in the size of the AVM, which was subsequently treated with GKRS, without the patient developing any other complication.

Proliferative vasculopathy

Proliferative vasculopathy includes the development of additional vascular pathologies after radiation owing to the proliferation of existing vessels and/or the occurrence of neovascularization. Proliferative vasculopathy includes the formation of a cavernous malformation (7/10),[25],[27],[28] the development of angiomatous changes (1/10),[24] the formation of a capillary hemangioma (1/10),[23] and the development of moya-moya vascular proliferation (1/10). Uozumi et al., reported the development of moya-moya disease in a case of AVM of the left occipital lobe, Spetzler Martin grade III. The patient underwent GKRS after a staged embolization, and a dose of 20 Gy was administered at the periphery of the lesion at 50% isodose. The supraclinoid ICA bifurcation and the M1 segment of middle cerebral artery received a dose of 2.1 Gy and 1.9 Gy, respectively. The patient suffered a transient ischaemic attack (TIA) 30 months post-GKRS. The angiographic evaluation showed occlusion of the M1 segment of the ipsilateral ICA for which the patient underwent both direct and indirect revascularization with a good functional outcome.[9] It was observed that the number of isocenters (1-20), target volume (2.3ml to 20ml), or radiation dose (13Gy-90Gy) did not influence the development of vascular effects due to radiation.[10] [Table 2].

The formation of moya-moya disease after GKRS for an AVM[9] can be explained by the altered circulation brought about by the high cerebral blood flow to the AVM. The radiation-induced changes may cause a slow occlusion of the AVM with the need to maintain cerebral hemodynamics. This is brought about by an increase in the factors stimulating angiogenesis, such as vascular endothelial growth factor (VEGF), leading to pial collateral vasculature formation. The irradiated tissue may develop chronic oxidative changes with an increased expression of cytokines and growth factors. This inflammation is a chronic phenomenon that has been suggested by the Guidelines of Research on Intractable Diseases of the Ministry of Health Labor and Welfare, Japan, to cause the moya-moya syndrome.[48] It would be interesting to note if the anti-VEGF therapy, as a prophylactic or therapeutic treatment modality, has any effect on the prevention of this neovascularization.

The development of cavernous malformation (CM) following radiosurgery has been reported in 7 instances,[36] out of which GKRS induced CM accounts for 6 of them. The development of CM has been reported after administering GKRS for treating a VS, pineocytoma,[28] metastasis,[27] dysgerminoma, pituitary adenoma, and AVM.[25]

Most of these cases have presented with headaches and focal deficits, corresponding to the area of hemorrhage. Interestingly, only 13/25 patients needed a surgical intervention. This low rate of surgery in the group may be attributed to the limited amount of hemorrhage that the patients had with either little or no mass effect and vasospasm. Also, multiple treatments being administered to patients again seemed to be an inciting factor, as 4/72 patients had undergone multiple treatments. Many patients suffered from loco-regional hemorrhage even after a conclusive angiographic proof of there being no residual lesion, and with a good long-term follow-up after GKRS (more than five years).[14],[16],[17],[18],[20],[21] Szeifert et al., showed recanalization of the vessels in the lesion that had previously been subjected to radiation. This change may either signify an angiographically occult disease or the development of new radiation-induced vasculopathy. In retrospect, it remains difficult to differentiate between the two; however, the immunohistochemical analysis showed an increase in Factor VIII (von Willebrand factor) and cluster of differentiation (CD) 34 positivity, owing to neoformation of the thin and fragile vasculature. Even angiographically occult nidi may suffer from delayed hemorrhage, and autopsy studies have indeed shown reorganization of the thrombus inside the nidus lumina.[37]

Radiation induced cranial neuropathy

Radiation induced neuropathy is a possible complication following the administration of high dose radiation in a single fraction. Skull base pathologies, such as the perioptic lesions,[58] seller-parasellar lesions,[59],[60] cavernous sinus lesions, cerebellopontine angle lesions,[61],[62] and paragangliomas[63] are critical lesions that occur in regions where the pathology remains in close proximity with critical neurovascular structures. Some of these lesions invade the fascicles of cranial nerves, and occasionally, push these nerves to the periphery of the tumor.[64] Radiation-induced neuropathy may occur either by the generation of an accidental hotspot on the cranial nerve or by irradiating a longer segment of the nerve. A sensory nerve is more radiosensitive than a pure motor nerve.[65],[66] Neuropathy may be gradual or sudden in onset. Radiation induced optic neuropathy may manifest as anterior optic neuropathy in the form of pale edema of the disc with the presence of incidental splinter hemorrhages, or as posterior optic neuropathy, with a loss of visual acuity with or without field defects. One should avoid exposing the optic pathway to more than 8 Gy radiation. The radiation tolerance dose of motor nerves is not well defined. The conventional practice suggests an acceptable radiation tolerance of 25Gy in a single fraction for pure motor nerves. The authors have reported the development of an acute-onset facial paralysis in patients with a vestibular schwannoma after GKRS. The time of development of the post-radiosurgery clinical improvement or of the cranial neuropathy remains debatable (with the range being from 2 months–3 years). Most of these neuropathies remain a transient phenomenon. They usually respond favourably to steroids, with complete neurological recovery.

Radiation induced malignancy

It is well known that the risk of malignancy after GKRS is exceedingly small.[67] However, the possibility of GKRS contributing to the development of this serious effect warrants a careful long-term evaluation of the treatment [Table 3].[68],[69] Patel and Chiang[70] recently reviewed the literature and described 36 cases of SRS-induced neoplasms [Table 4].[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103] These authors extrapolated that the risk of SRS-induced neoplasm was 0.04% at 15 years, based on an estimation of the total worldwide number of patients treated with SRS for a benign disease. To produce a secondary neoplasm, the radiation delivered to the adjacent normal tissue must be mutagenic (i.e., induce a change in the genetic material/DNA) but not cytotoxic. If the radiation dose delivered is too high, the normal cells will simply die and have no opportunity to become neoplastic. It is postulated that the high level of a single dose delivered during the SRS therapy preferentially leads to cytotoxicity over mutagenicity. Animal and clinical studies have demonstrated that there is an increasing rate of secondary neoplasm development when the maximum dose escalates to between 3 and 10 Gy. This is followed by a decrease in the risk of development of a neoplasm, once the dose increases beyond this range. Furthermore, the volumes irradiated in SRS are small, and there are small entrance and exit bystander doses; all these factors contribute to a smaller volume of tumor tissue at risk of developing a neoplasia. This data suggests why, despite the higher amounts of radiation doses delivered, the risk of developing radiation-induced neoplasms following SRS is much lower than with external beam radiotherapy (EBRT). It may also explain why vestibular schwannomas, which traditionally are treated with lower doses, are associated with a greater rate of development of a secondary neoplasm than would otherwise be expected.
Table 3: Recommended timings and duration of follow up in specific cases of post GKRS

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Table 4: Recorded cases of malignant transformation after SRS

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This issue may be different for patients with phacomatoses, such as neurofibromatosis type 2 (NF-2) or von Hippel-Lindau (VHL) disease. As these syndromes manifest due to abnormalities in the tumor suppressor genes, these patients are postulated to be at greater risk for radiation-induced malignancies, based on the “two-hit” hypothesis. Given the increased rate of malignant peripheral nerve sheath tumors (MPNSTs) in our reviewed literature, one might be concerned that the underlying NF2-related mutations in patients with vestibular schwannomas may increase the risk of developing a secondary malignancy. However, the largest study till date, of patients with familial NF2 treated with SRS, did not conclusively demonstrate an increased risk of developing secondary neoplasms in this category of patients. In fact, only two cases on SRS- induced malignancies have been reported in patients with NF2 and von Hippel- Lindau; and, of these tumors, one was thought to be present before the SRS procedure was performed. This relatively low incidence of the reported cases of secondary malignancy in patients with NF-2 disease may be due, in part, to the shorter life expectancy for these patients. NF1 genetic mutation has been conclusively associated with the malignant peripheral nerve sheath (MPNST) transformation.

Radiation necrosis

With any radiation treatment, radiation necrosis may be found as a bystander effect.[104] The manifestations of radiation necrosis may range from being completely asymptomatic and present as a mere radiological diagnosis, to the development of a florid clinical entity. In its presentation, any radiation necrosis might manifest clinically as an acute, a subacute or a chronic phenomenon, depending on the temporal relationship of the development of symptomatology with the radiation exposure. An acute injury is defined as injury that develops either during or immediately after completion of radiation therapy. Necrosis is characterized by edema on MRI. It usually remains a reversible phenomenon and resolves with or without a short course of steroids. An early delayed injury (also known as pseudoprogression) is the development of radiation necrosis up to 12 weeks after radiation therapy. It is again characterized by hyperintensity on FLAIR and T2 weighted MRI images. Any late injury usually occurs after a few months-to-years after the radiation exposure. A late injury is often irreversible in nature. It may manifest as a focal lesion after a session of focused radiation therapy; or, in a diffuse pattern with wide-spread periventricular white matter changes, in cases where whole brain radiation therapy has been administered.[105],[106],[107],[108]

The exact incidence of radiation necrosis is still unknown due to the inherent difficulties in establishing the diagnosis of radiation induced necrosis (RIN). Despite advancements in imaging tools, the definitive diagnosis of RIN can only be established after obtaining a biopsy from the representative area. Following a single fraction SRS for brain metastases, RIN has been observed in 5.2% patients at 6 months, in 17.2% patients at 12 months, and in 34% patients at 24 months after the radiation session.[109] The pathophysiology of RIN is proposed to be radiation-induced injury to the vascular endothelial growth factor (VEGF), which leads to acute tissue hypoxia and increased tumor cell death. Injury to endothelium secondarily increases the permeability of blood brain barrier with the release of proinflammatory cytokines, further aggravating the edema. The secondary effect of RIN is astrocytic hyperplasia, resulting in predominantly white matter edema. Animal experiments have shown that white matter necrosis is a function of the duration of exposure and the cumulative dose delivered during radiation therapy.[110] The perinecrotic tissues show strong positivity for VEGF positive astrocytes. This phenomenon indirectly explains the role of bevacizumab in the management of RIN.[111] RIN also leads to overexpression of proinflammatory cytokines such as interleukin (IL) 6, tumor necrosis factor (TNF) alpha and IL1 alpha in the perinecrotic tissues.

Temporary non-cicatricial focal alopecia

Post radiation alopecia is a well-known phenomenon in EBRT. Post-GKRS alopecia is relatively rare due to the sharp dose fallout and focused radiation, which are the hallmarks of GKRS. Post-radiation alopecia is a dose-dependent phenomena, which may be temporary or permanent depending on the radiation exposure to the dermal and epidermal appendages. A 3 Gy exposure leads to reversible anagen alopecia; while, permanent alopecia starts at a 5 Gy exposure.[112] For superficial lesions, occasionally it becomes impossible to spare hair follicles in the dermis from a 3 Gy exposure. Post-radiosurgery alopecia starts within a month, which usually remains temporary, noncicatricial and focal, overlying the targeted area [Figure 2]. Usually the hair recovery is complete by the end of 2 months. The hair regrowth has a similar growth pattern, quality and texture to that prior to the administration of GKRS. Loss of hair may lead to significant psychological issues and an altered quality of life in the patients. SRS is preferred to the conventional radiation as chances of alopecia are significantly less in the former procedure. A careful dose and site planning, with the sparing of dermal appendages and hair roots within 4 to 6 mm depth in the skin, may prevent this complication. Patients with superficial lesions should be informed about this possible complication prior to their being administered the GKRS. They should be assured that there is a possibility of near-normal hair growth within 2 months of treatment.
Figure 2: (a) Right jugular paraganglioma treated with gamma knife radiosurgery; (b) Focal non-cicatricial alopecia within two weeks of GKRS; and, (c) Complete hair growth within two months

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  Discussion Top


GKRS is currently an indispensable tool in the neurosurgical armamentarium, being used for wide-ranging indications, including tumors, vascular malformations, as well as functional ailments. With the frameless technology, the horizon has expanded further, as fractionated radiosurgery with GKRS has become a norm. Along with the ease of usability, we need to be equally aware of the possibility of complications developing, and for the care-seekers and providers to be realistic about the expectations of GKRS. The essential need is to understand the mechanism of action of GKRS and the radiobiological changes brought about by the procedure.

The VEGF protein is overexpressed in a variety of central nervous system diseases, including tumor, ischemia, and traumatic brain injury.[38],[39] It has been demonstrated to increase in expression following irradiation, even in normal tissues in a rat model. The increase is time-dependent, initially increasing over a period of 8 weeks, reaching the maximal expression 16 weeks after radiosurgery. This over-expression of VEGF begins to decrease 20 weeks after radiosurgery.[40] Furthermore, radiosurgery and radiotherapy may both increase VEGF expression but the effect of radiosurgery on the VEGF overexpression is longer lasting. This increase may explain the formation of vascular lesions (earlier reported in 2 case reports of epilepsy due to medial temporal sclerosis).[23],[24] Another phenomenon observed is a decrease in the endothelial cell number within one day of irradiation, when a dose in the range of 25 Gy has been administered. This loss of endothelial cells is very evident at four weeks post irradiation.[41] All these changes may contribute to an increased incidence of edema of the irradiated tissue.

Other changes include fibrous thickening of the tunica adventitia, intimal hyperplasia, and exuberant loose connective tissue production with relative sparing of the tunica media of the blood vessels. In a review, the mechanism of radiation injury has been proposed to be mediated by phenotypic changes in the vessel walls secondary to expression or suppression of specific genes and protein products. These alterations result in cellular proliferation or death through cytotoxic injury or apoptosis.[42] Consequently, cellular proliferation, especially neo-intimal hyperplasia, following a session of single-fraction irradiation may be the cause of vascular occlusion in many of the cases reported.

Radiation induced vasculopathy

Most of the vascular changes seen in post-GKRS cases can be explained from the available data on pathological changes after radiosurgery. However, these are few and far between. [43],[44],[45] In a comprehensive review Attebery et al.,[46] proposed that GKRS is believed to cause a proliferative vasculopathy within the blood vessels of an AVM, and parallel effects can be seen in benign tumors. The process of vasculopathy originates with endothelial cell injury secondary to exposure to the high doses of ionizing radiation, following which the vessels become hyalinised and thickened, causing luminal stenosis and occlusion. In the experimental model, this endothelial cell proliferation starts as early as three hours after irradiation and can continued throughout the observation period (i.e. 90 days) after radiation.[47] These changes are dose-related, and high-dose radiation can induce radionecrosis but the exact threshold is unknown.

In the cases where the CT/MRI shows a visible radiological change, such as edema, subarachnoid hemorrhage or infarction, an immediate digital subtraction angiogram (DSA) is warranted to delineate the vessel and for considering the possibility of intervention. Early treatment of the infarction with revascularization, and edema with intracranial pressure lowering measures usually ensures a good prognosis. Aneurysm formation is better managed either with parent vessel occlusion or by its trapping, as the vessel wall may be too fragile for direct clipping or coiling. A structured protocol for follow-up of these cases may help in the early detection of an aneurysm [Table 3].

The long-term prognosis in cases were the aneurysm has gone undetected, is usually poor. However, its early detection and efficient management have improved the outcome in recent years. The need for this review can be emphasized by the fact that awareness regarding the possibility of a vascular event following GKRS is often not present, and hence, the entity may be missed, sometimes with fatal consequences.

Management of secondary malignancies

For patients who develop secondary malignant tumors, the prognosis remains grim. In the 36 cases reviewed, the average survival was less than 12 months from the time of diagnosis, despite the additional intervention performed in the form of surgical resection, radiation and chemotherapy. The prognosis subsequent to the development of a second malignancy appears identical to that seen in the primary lesion at a similar location and having identical histological appearance. Ideally, open surgery would allow curative resection of these secondary neoplasms, but in patients with a tumor at surgically difficult locations, there are case reports suggesting that secondary tumors can be treated with radiosurgery. What remains unknown is whether or not additional radiation further increases the risk of developing secondary neoplasms, and if so, then to what extent?


  Management of Radiation Necrosis Top


Radiological diagnosis of radiation induced necrosis

The diagnosis of RIN needs dedicated MRI sequences, which include T1, T2, T1 contrast, FLAIR, and SWI/DWI sequences. Radiation necrosis appears as a ring enhancing lesion in the radiated area with perilesional white matter edema. Radiologically, it becomes difficult to differentiate tumour recurrence from radiation induced edema [Figure 3]. Desquesada et al.,[113] defined the radiation necrosis lesion quotient, i.e., ratio of the nodule seen on the T2-weighted MR sequence to the total enhancing area seen on T1-weighted sequences. A legion quotient of 0.6 or greater was observed in all cases of recurrent tumours, where as, a lesion quotient of 0.3 or less was seen in 80% cases of radiation necrosis. This criteria may be used to distinguish radiation necrosis from tumour recurrence. However, the same results could not be reproduced by the later studies. Mitsuya et al.,[114] assessed cerebral blood volume (CBV) as a useful tool to distinguish RIN from recurrent brain metastases. The optimal regional cerebral blood volume (rCBV) value is 2.1 with the sensitivity of 100% and specificity of 95.2%. The rCBV ranged from 2.1-10 in the case of tumor recurrence, and from 0.39-2.57 in the case of radiation necrosis. The accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating between RIN and tumor recurrence is controversial. Proton magnetic resonance spectroscopy (MRS) may help in differentiating RIN from tumour recurrence, as necrosis selectively leads to elevated lipids and lactate levels. Thus, none of these investigations can definitively differentiate between RIN and its radiological masquerades, and a conclusive diagnosis can only be ascertained on histopathological analysis from the representative area.
Figure 3: (a) Right medial temporal arteriovenous malformation treated with GKRS; (b) Radiation necrosis in the irradiated zone; and (c) complete radiologic resolution after two months treatment of pentoxyphylline and vitamin E combination

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Treatment of radiation necrosis/radiation induced brain edema

Since RIN is associated with significant brain edema, steroids remain the cornerstone of treatment. However, long-term steroid usage may have its own detrimental effects. There is no specific guideline for the second line medication or manoeuvre for the management of steroid resistant cases. In resource-constrained cases, a combination of pentoxifylline and vitamin E, an anticoagulant, Celecoxib, free radical scavengers, VEGF inhibitors (e.g. bevacizumab), and hyperbaric oxygen therapy, have been used by different radiosurgeons in different capacities and protocols. There is no level one evidence to prove or disapprove the superiority of one treatment modality over the other. In resistant cases, surgery remains the salvage procedure.


  Conclusion Top


De-novo development of aneurysms, post-obliteration rupture of AVMs, vessel occlusion requiring a bypass, and the initiation of moya-moya disease are the established vascular complications following GKRS. Radiation induced edema and necrosis are rare and should be continuously assessed on a long-term basis as these can be managed with appropriate pharmacological treatment. The development of a secondary malignancy, although disastrous, has a very low incidence. A constant vigil for the development of a neoplasm is necessary on a long-term basis following GKRS. Apart from unforeseen and unexpected complications, a poor patient selection, the inappropriate definition of target volume and dose selection are recipes for disaster. Though GKRS remains one of the safest and most effective tools in the hands of a neurosurgeon, more research is required in the field of radiation and its effect on the human body.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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