Journal of Clinical Neuroscience xxx (2014) xxx–xxx

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Journal of Clinical Neuroscience

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Clinical Study

Delayed complications after Gamma Knife surgery for intractableepilepsy

http://dx.doi.org/10.1016/j.jocn.2013.11.0440967-5868/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +86 10 6709 6767; fax: +86 10 6705 7507.E-mail address: fgmeng@ccmu.edu.cn (F.-G. Meng).

Please cite this article in press as: Chen N et al. Delayed complications after Gamma Knife surgery for intractable epilepsy. J Clin Neurosci (2014),dx.doi.org/10.1016/j.jocn.2013.11.044

Ning Chen a, Shou-Qin Du b, Na Yan c, Chong Liu d, Jian-Guo Zhang a, Yan Ge d, Fan-Gang Meng d,⇑a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, Chinab Clinical Medical Examination, The Sixth People Hospital of Jinan, Shandong, Chinac School of Public Health and Family Medicine, Capital Medical University, Beijing, Chinad Beijing Neurosurgical Institute, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing 100050, China

a r t i c l e i n f o

Article history:Received 18 September 2013Accepted 13 November 2013Available online xxxx

Keywords:Gamma KnifeIntractable epilepsyRadiation necrosisRadiosurgery

a b s t r a c t

Despite the controversy concerning the clinical usefulness of Gamma Knife surgery (GKS; Elekta AB,Stockholm, Sweden) for intractable epilepsy, this treatment modality has attracted attention due to itslow invasiveness. We report the long-term outcomes of four patients, focusing particularly on the efficacyand complications of GKS. We reviewed the data of four patients with medically intractable epilepsy whounderwent GKS between 1998 and 2000 at our hospital. The marginal dose to the 50% isodose line was24 Gy in one patient and 20 Gy in the remaining three patients. Two of the four patients were treated inthe right temporal lobe, one was treated in the left parietal lobe, and one was treated in the right frontallobe. The mean follow-up was 12.5 years (range 12–14 years). One patient was seizure free (Engel classIA) 24 months after GKS, and two patients failed to show any seizure reduction (Engel class IVA). How-ever, a clear aggravation was evident in one patient (Engel class IVC). All four patients underwent resec-tive surgery due to radiation necrosis (RN) 7, 10, 10 and 12 years after GKS. Three patients were seizurefree (Engel class IA), and one was considered to have Engel class IB status following the resective surgery.GKS treatment resulted in insufficient seizure control and carried a significant risk of RN after severalyears. Drawbacks such as a delay in seizure control and the risk of RN should be considered when theclinical application of this treatment is evaluated.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Epilepsy surgery, an effective treatment for properly selectedpatients with intractable seizures, has achieved encouraging out-comes in the treatment of medically intractable epilepsy [1]. How-ever, there are associated risks, including intracranial hemorrhage,infection, neurological deficits, and anesthesia complications [2].Accordingly, the use of Gamma Knife surgery (GKS; Elekta AB,Stockholm, Sweden) for epilepsy has attracted attention as analternative treatment option. In a recent prospective multicenterpilot trial in which two different radiosurgery doses were com-pared, an overall seizure remission rate of 69% was observed atthe 3 year follow-up, a finding that is comparable to that reportedfor respective temporal lobectomy [3]. However, another reportwith 8 years of follow-up failed to demonstrate that GKS success-fully controlled seizures in the long term [4]. Accordingly, the clin-ical efficacy of GKS for medically intractable epilepsy remains

controversial, and its role in the treatment of medically intractableepilepsy needs to be further evaluated for efficacy and safety.

In this article, we report the long-term outcomes of fourpatients with intractable epilepsy who underwent GKS andrequired resective surgery due to radiation necrosis (RN).

2. Methods

Between 1998 and 2000, four patients underwent GKS. All fourpatients had medically intractable generalized tonic-clonic seizureor complex partial seizure epilepsy associated with sudden falls orother seizure types, documented by video-electroencephalographyanalysis and cranial MRI (Fig. 1a), and based on descriptions fromfamily members. Histological specimens obtained during theresective surgery were reviewed to confirm the diagnosis of RN.

Seizure outcome was classified according to a modified versionof the Engel classification [5]. For this evaluation stable status hadto be achieved for a minimum of 2 years before final outcome clas-sification. Antiepileptic drugs were initially continued, and an

http://

Fig. 1. (a) Axial T1-weighted MRI before Gamma Knife surgery (GKS; Elekta AB, Stockholm, Sweden) and (b) axial T2-weighted MRI showing a hyperintense region in theright temporal lobe 83 months after GKS in Patient 1. (c) Axial T2-weighted MRI showing a hyperintense region in the left parietal lobe 10 years after GKS in Patient 2. (d)Axial T2-weighted MRI showing a hyperintense region in the right frontal-temporal lobe 10 years after GKS in Patient 3. (e) Axial T2-weighted MRI showing a hyperintenseregion in the right temporal lobe 12 years after GKS in Patient 4. (f) Coagulation necrosis on a hematoxylin and eosin stained sample from Patient 1 (original magnification �200). (g) Protoplasmic astrocyte degeneration around the lateral wall of the cyst from Patient 3 (hematoxylin and eosin stain, original magnification � 100). (This figure isavailable in colour at www.sciencedirect.com)

2 N. Chen et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx

attempt to gradually decrease their dosage and number was madein patients with good results (Engel class I) after 2 years.

All information concerning the clinical histories, symptoms,surgical approaches, drug treatments, outcomes, and follow-upwere retrospectively obtained by case note review and telephoneinterviews as appropriate. After GKS, all patients were observedfor seizure frequency and complications, and postoperativechanges were evaluated by periodic MRI examinations.

3. Results

3.1. Long-term efficacy

Four male patients with a mean age of 31.6 years (range 19–39 years) underwent GKS. Two were treated in the right temporallobe, one was treated in the left parietal lobe, and one was treatedin the right frontal lobe. The characteristics of the population arelisted in Table 1. The mean follow-up duration was 12.5 years(range 12–14 years). One patient was seizure-free (Patient 4, Engelclass IA) 24 months after GKS, and Patient 2 and Patient 3 failed toshow any seizure reduction (Engel class IVB), while a clear aggra-vation was observed in Patient 1 (Engel class IVC). The fourpatients underwent resective surgery for RN at 7, 10, 10, and12 years after GKS. Three patients were seizure-free (Patient 2, 3,

Table 1Characteristics of patients with medically intractable epilepsy who underwent Gamma Kn

Patient Age,years/Sex

Seizure origin onvideo-EEG

Preoperative MRIfinding

50%isodoseline

Volum(mm3

1 25/M RTL HSD 20 Gy 75002 19/M LPL NA 20 Gy 75003 39/M RFL NA 20 Gy 65004 37/M RTL NA 24 Gy 7500

EEG = electroencephalography, GKS = Gamma Knife surgery (Elekta AB, Stockholm, Sweabnormality, RFL = right frontal lobe, RTL = right temporal lobe.* Engel’s classification.

Please cite this article in press as: Chen N et al. Delayed complications after Gadx.doi.org/10.1016/j.jocn.2013.11.044

4, Engel class IA) and one patient (Patient 1) was considered tobe Engel class IB following resection surgery (Table 1).

3.2. Long-term side-effects

RN was the main long-term adverse effect after GKS. MRIrevealed a hyperintensity on T2-weighted images in the right tem-poral lobe 2.2 years after GKS treatment in Patient 1. Seven yearsafter GKS, MRI demonstrated a space-occupying mass in the righttemporal-occipital lobe (Fig. 1b). As the patient developed general-ized convulsive seizures, he underwent a right anterior temporallobectomy. The resected specimen showed hippocampus sclerosisand RN without malignant tumor cells (Fig. 1f).

Patient 2 presented with right limb weakness 10 years afterGKS, and MRI revealed a cystic lesion in the left parietal lobe(Fig. 1c). A lesion resection was performed 5 months later. Theresected specimen revealed RN without malignant tumor cells.

Patient 3 presented with headache 10 years after GKS, and MRIrevealed a cystic lesion in the right frontal-temporal lobe (Fig. 1d).A lesion resection was performed 1 month later. The resected spec-imen revealed RN without malignant tumor cells (Fig. 1g).

Patient 4 showed a cystic lesion in the right temporal lobe onMRI studies 12 years after GKS (Fig. 1e). A right temporal

ife surgery

e)

Outcomesafter GKS*

Interval between GKS andsurgery, years

Outcomes afterresective surgery*

Class IVC 7 Class IBClass IVB 10 Class IBClass IVB 10 Class IAClass IA 12 Class IA

den), HSD = hippocampal size decrease, LPL = left parietal lobe, M = male, NA = no

mma Knife surgery for intractable epilepsy. J Clin Neurosci (2014), http://

N. Chen et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx 3

lobectomy was performed. The resected specimen showed RNwithout malignant tumor cells.

4. Discussion

Stereotactic radiosurgery, which is commonly performed for theminimally invasive treatment of focal lesions that are otherwisehard to reach via open surgery, is becoming increasingly popularfor the treatment of focal epileptic lesions [6]. Although the clinicalsignificance of GKS for resistant-drug epilepsy is still under discus-sion, the treatment nonetheless attracts attention because it is lessinvasive than resective surgery. However, although epilepsy radio-surgery has been performed for decades [7], its real usefulnessremains debatable, and the rates of seizure-free patients reportedin previous studies vary.

Few prognostic studies involving patients with medicallyintractable epilepsy have been reported. In one study, after a meanfollow-up of 8 years, 60% of patients (nine of 16) who were treatedwith a marginal dose of 24 Gy for medically intractable epilepsywere considered seizure free [8]. A multicenter, prospective pilotstudy of GKS for medically intractable epilepsy demonstrated that76.9% of patients (10 of 13) who were treated with a marginal doseof 24 Gy were seizure free and that 58.8% of patients (10 of 17) whowere treated with a marginal dose of 20 Gy were seizure free at the36 month follow-up evaluation [9]. In another study with a meanfollow-up of 60 months, 46.7% of patients (seven of 15) whoreceived a dose of 21 Gy at the margin for intractable temporallobe epilepsy were free of disabling seizures [10]. However, Srikij-vilaikul et al. reported that GKS at the 20 Gy dose level did not leadto seizure control in patients with medial temporal lobe epilepsy(MTLE) [11].

In the present study, one patient, who received 24 Gy for intrac-table MTLE, was seizure free; however, another two patients, whoreceived 20 Gy for the treatment of intractable frontal epilepsy orparietal epilepsy showed no reduction in seizure frequency.Finally, a clear aggravation was observed in one patient whoreceived 20 Gy for intractable MTLE. These results suggest agreater success rate can be obtained with 24 Gy to the 50% isodoseline than with 20 Gy to the 50% isodose line and that the type ofepilepsy may be related to the prognosis after GKS. Chang et al.reported that a greater proportion of patients who received24 Gy (76.9%) than 20 Gy (58.8%) were seizure free, although thedifference did not reach statistical significance [3]. Therefore, anappropriate dose should be adopted for patients with medicallyintractable epilepsy, and 24 Gy to the 50% isodose line may resultin a better outcome.

Although studies concerning GKS in the treatment of drug-resistant epilepsy show encouraging results, significant side effectshave been reported. In most patients who underwent GKS forintractable epilepsy, edema appeared approximately 1 year aftertreatment and regressed within a few years. Furthermore, approx-imately 15% of patients experience headaches with nausea andvomiting, the symptoms of which can largely be controlled by ste-roids [9]. However, in one GKS series with long-term follow-up,one MTLE patient who received 24 Gy was reported to requireearly medial temporal lobectomy for worsening papilledemadespite steroid administration; nonetheless, no RN was noted [8].In 2011, Jeremy et al. reported a patient who, although seizure freeand able to discontinue antiepileptic drugs 2 years after being trea-ted with 24 Gy GKS for MTLE, developed profound RN, leading toblindness 4 years later [12].

Most of the reported cases of RN were detected within 3 yearsof radiosurgical intervention [13–15], although RN may occur morethan 5 years after GKS [16,17], as in our patients. The mechanismunderlying such late RN remains unclear. The most widely

Please cite this article in press as: Chen N et al. Delayed complications after Gadx.doi.org/10.1016/j.jocn.2013.11.044

accepted theory attributes the delayed RN to endothelial cell dam-age. In the early stages, fibrinoid necrosis of blood vessel wallsoccurs, followed by vessel wall thickening, hyalinization, and tel-angiectasia. Such sclerotic damage to the capillary walls resultsin porosity that is associated with the progressive destruction ofthe blood–brain barrier. An influx of leukocytes to damaged areasleads to over-production of various cytokines, inducing oligoden-drocyte apoptosis. Serum leakage into the brain parenchymathrough abnormal capillaries causes glial injury and extensivefibrinoid coagulative degeneration, predominantly of the whitematter [18–21]. We found similar pathological changes in ourpatients.

Treatment variables beyond dose (as explored in this protocol)include the treatment volume (defined as that within the 50% iso-dose). The 50% isodose volume ranged from 5500 to 9000 mm3 in apreviously reported protocol for intractable epilepsy [22–24];however, in our patients, the isodose volume was 7500 mm3 inPatient 1, 2 and 4, and was 6500 mm3 in Patient 3. The smaller vol-umes have been reported to rarely be effective, and greater vol-umes may lead to RN [25]. Additionally, predictive factors for RNwere demonstrated to be associated with the dose and volume incases of arteriovenous malformations and tumors [26,27]. DelayedRN was also observed in cases of arteriovenous malformation afterGKS [28,29]. Our protocol relied heavily on that of Regis and col-leagues [22], but the volumes in Patient 1, 2 and 4 were slightlyhigher. One possible reason why RN occurred in the delayed phasemight be the increased irradiation volume. Too large a target mightmake the RN develop over a long period.

Our patients demonstrated that an appropriate dose and vol-ume should be adopted for patients with medically intractable epi-lepsy and that, at the same time, the risk of delayed developmentof RN of the targeted brain should be considered. These patientsstress the need to evaluate the long-term effects of GKS in thetreatment of medically intractable epilepsy in a larger populationas well as the requirement for MRI studies in patients who undergoGKS for intractable epilepsy even after complete seizure control.

Conflicts of Interest/Disclosures

The authors declare that they have no financial or other con-flicts of interest in relation to this research and its publication.

Acknowledgements

This work was supported in part by the China Postdoctoral Sci-ence Foundation (20060400094), the Beijing Outstanding TalentTraining Program (2009D003034000002), and the Beijing HealthSystem Advanced Health Technology Talent Cultivation Plan(2011-3-032).

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mma Knife surgery for intractable epilepsy. J Clin Neurosci (2014), http://