Subnecrotic stereotactic radiosurgery controls epilepsy produced by kainic acid injection in rats

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Object. Any analysis of the potential role of stereotactic radiosurgery for epilepsy requires the experimental study of its potential antiepileptogenic, behavioral, and histological effects. The authors hypothesized that radiosurgery performed using subnecrotic tissue doses would reduce or abolish epilepsy without causing demonstrable behavioral side effects. The kainic acid model in rats was chosen to test this hypothesis.

Methods. Chronic epilepsy was successfully created by stereotactic injection of kainic acid (8 µg) into the rat hippocampus. Epileptic rats were divided into three groups: high-dose radiosurgery (60 Gy, 16 animals), low-dose (30 Gy, 15 animals), and controls. After chronic epilepsy was confirmed by observation of the seizure pattern and by using electroencephalography (EEG), radiosurgery was performed on Day 10 postinjection. Serial seizure and behavior observation was supplemented by weekly EEG sessions performed for the next 11 weeks. To detect behavioral deficits, the Morris water maze test was performed during Week 12 to study spatial learning and memory. Tasks involved a hidden platform, a visible platform, and a probe trial.

After radiosurgery, the incidence of observed and EEG-defined seizures was markedly reduced in rats from either radiosurgically treated group. A significant reduction was noted after high-dose (60 Gy) radiosurgery in Weeks 5 to 9 (p < 0.003). After low-dose (30 Gy) radiosurgery, a significant reduction was found after 7 to 9 weeks (p < 0.04). During the task involving the hidden platform, kainic acid—injected rats displayed significantly prolonged latencies compared with those of control animals (p < 0.05). Hippocampal radiosurgery did not worsen this performance. The probe trial showed that kainic acid—injected rats that did not undergo radiosurgery spent significantly less time than control rats in the target quadrant (p = 0.03). Rats that had undergone radiosurgery displayed no difference compared with control rats and demonstrated better performance than rats that received kainic acid alone (p = 0.04). Radiosurgery caused no adverse histological effects.

Conclusions. In a rat model, radiosurgery performed with subnecrotic tissue doses controlled epilepsy without causing subsequent behavioral impairment.

Article Information

Address reprint requests to: Douglas Kondziolka, M.D., Department of Neurological Surgery, Suite B400, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213. email: Kondziol@neuronet.pitt.edu.

© AANS, except where prohibited by US copyright law.

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Figures

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    Schematic drawing of the coronal plane of the rat brain 2.5 mm posterior to the bregma. The radiation isocenter is targeted at a depth of 3.5 mm below the dura. The isocenter is located in the CA3 area of the dorsal hippocampus. DG = dentate gyrus.

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    Graph demonstrating the percentages of rats exhibiting seizures on EEG (y axis) over an 11-week period. After radiosurgery was performed on Day 10 (RS, arrow), the incidence of seizures on EEG recordings was reduced markedly in the rats that underwent radiosurgery (Groups A [KA+60Gy] and B [KA+30Gy]). KA = kainic acid.

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    Representative bilateral hemispheric EEG tracings recorded after kainic acid injection before radiosurgery (upper) and 7 weeks after 60-Gy radiosurgery (lower). Note that in the preradiosurgery EEG tracings there are numerous high-frequency spiking events followed by postictal EEG signal depression. Spiking is noted bilaterally, indicating a spread of epileptiform activity to both hemispheres. Also note that there are no epileptiform discharges postradiosurgery. Large-amplitude slow waves seen in the upper panel represent motion artifacts occurring during the recording session.

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    Graph showing the average number of observed seizures during a 30-minute interval in each week. The number of observed seizures was reduced significantly after radiosurgery (Groups A and B).

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    Graph showing the average latency (in seconds) to find the platform in the Morris water maze test. During the first 5 days of the evaluation, the invisible platform task was performed. Rats that received kainic acid (KA+60Gy, KA+30Gy, and KA alone) performed worse than control animals (saline injection or needle insertion). There was no significant difference among the kainic acid—injected groups.

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    Bar graph demonstrating percentages of time spent searching the quadrant where the platform had been located. Kainic acid—injected rats that received no treatment (Group C [KA alone]) spent significantly less time in the target quadrant. Rats that underwent radiosurgery (Groups A [KA+60Gy] and B [KA+30Gy]) performed similar to control rats, which received no kainic acid (Groups D [saline injection] and E [needle insertion]).

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    Computerized map of rat movement during the probe trial. The black circle represents the site where the platform was located before the trial; the rat attempts to remember this location. After receiving kainic acid alone, rat movement is randomly distributed among all quadrants, but mainly occurs at the outer edge of the pool. This type of swimming is consistent with that of a rat with no experience in the maze. In control animals and in animals that received a kainic acid—induced lesion followed by 30-Gy radiosurgery, a higher proportion of time is spent by the rat searching the target quadrant.

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    Photomicrographs. Upper: Tissue obtained in a rat with a kainic acid—induced lesion that underwent 60-Gy radiosurgery. Lower: Tissue obtained in a rat with a kainic acid—induced lesion that received no treatment. The rat brains demonstrate similar findings, including marked neuron loss in CA3 and unilateral hippocampal atrophy. At 13 weeks, there was no evidence of radiation necrosis after irradiation (upper). H & E, original magnification × 5.

References

  • 1.

    Babb TLPereira-Leite JMathern GWet al: Kainic acid induced hippocampal seizures in rats: comparisons of acute and chronic seizures using intrahippocampal versus systemic injections. Ital J Neurol Sci 16:39441995Babb TL Pereira-Leite J Mathern GW et al: Kainic acid induced hippocampal seizures in rats: comparisons of acute and chronic seizures using intrahippocampal versus systemic injections. Ital J Neurol Sci 16:39–44 1995

    • Search Google Scholar
    • Export Citation
  • 2.

    Barcia-Salorio JLBarcia JAHernández Get al: Radiosurgery of epilepsy. Long-term results. Acta Neurochir Suppl 62:1111131994Barcia-Salorio JL Barcia JA Hernández G et al: Radiosurgery of epilepsy. Long-term results. Acta Neurochir Suppl 62:111–113 1994

    • Search Google Scholar
    • Export Citation
  • 3.

    Barcia-Salorio JLBarcia JARoldán Pet al: Radiosurgery of epilepsy. Acta Neurochir Suppl 58:1951971993Barcia-Salorio JL Barcia JA Roldán P et al: Radiosurgery of epilepsy. Acta Neurochir Suppl 58:195–197 1993

    • Search Google Scholar
    • Export Citation
  • 4.

    Barcia-Salorio JLVanaclocha VCerdá Met al: Response of experimental epileptic focus to focal ionizing radiation. Appl Neurophysiol 50:3593641987Barcia-Salorio JL Vanaclocha V Cerdá M et al: Response of experimental epileptic focus to focal ionizing radiation. Appl Neurophysiol 50:359–364 1987

    • Search Google Scholar
    • Export Citation
  • 5.

    Behrens ESchramm JZentner Jet al: Surgical and neurological complications in a series of 708 epilepsy surgery procedures. Neurosurgery 41:1101997Behrens E Schramm J Zentner J et al: Surgical and neurological complications in a series of 708 epilepsy surgery procedures. Neurosurgery 41:1–10 1997

    • Search Google Scholar
    • Export Citation
  • 6.

    Ben-Ari Y: Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:3754031985Ben-Ari Y: Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375–403 1985

    • Search Google Scholar
    • Export Citation
  • 7.

    Cavalheiro EARiche DALe Gal La Salle G: Long-term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol 53:5815891982Cavalheiro EA Riche DA Le Gal La Salle G: Long-term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol 53:581–589 1982

    • Search Google Scholar
    • Export Citation
  • 8.

    Chen QMLamproglou IPoisson Met al: Long-term effects of cranial irradiation in the rat: a behavioral study. Neurology 239:1161992 (Abstract)Chen QM Lamproglou I Poisson M et al: Long-term effects of cranial irradiation in the rat: a behavioral study. Neurology 239:116 1992 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 9.

    Czurkó ACzéh BSeress Let al: Severe spatial navigation deficit in the Morris water maze after single high dose of neonatal x-ray irradiation in the rat. Proc Natl Acad Sci USA 94:276627711997Czurkó A Czéh B Seress L et al: Severe spatial navigation deficit in the Morris water maze after single high dose of neonatal x-ray irradiation in the rat. Proc Natl Acad Sci USA 94:2766–2771 1997

    • Search Google Scholar
    • Export Citation
  • 10.

    Gaiarsa JLZagrean LBen—Ari Y: Neonatal irradiation prevents the formation of hippocampal mossy fibers and the epileptic action of kainate on rat CA3 pyramidal neurons. Neurophysiology 71:2042151994Gaiarsa JL Zagrean L Ben—Ari Y: Neonatal irradiation prevents the formation of hippocampal mossy fibers and the epileptic action of kainate on rat CA3 pyramidal neurons. Neurophysiology 71:204–215 1994

    • Search Google Scholar
    • Export Citation
  • 11.

    Gayoso MJPrimo CAl-Majdalawi Aet al: Brain lesions and water-maze learning deficits after systemic administration of kainic acid to adult rats. Brain Res 653:921001994Gayoso MJ Primo C Al-Majdalawi A et al: Brain lesions and water-maze learning deficits after systemic administration of kainic acid to adult rats. Brain Res 653:92–100 1994

    • Search Google Scholar
    • Export Citation
  • 12.

    Handelmann GEOlton DS: Spatial memory following damage to hippocampal CA3 pyramidal cells with kainic acid: impairment and recovery with preoperative training. Brain Res 217:41581981Handelmann GE Olton DS: Spatial memory following damage to hippocampal CA3 pyramidal cells with kainic acid: impairment and recovery with preoperative training. Brain Res 217:41–58 1981

    • Search Google Scholar
    • Export Citation
  • 13.

    Heikkinen ERHeikkinen MISotaniemi K: Stereotactic radiotherapy instead of conventional epilepsy surgery. A case report. Acta Neurochir 119:1591601992Heikkinen ER Heikkinen MI Sotaniemi K: Stereotactic radiotherapy instead of conventional epilepsy surgery. A case report. Acta Neurochir 119:159–160 1992

    • Search Google Scholar
    • Export Citation
  • 14.

    Hellstrand DEAbraham-Fuchs KJernberg Bet al: MEG localization of interictal epileptic focal activity and concomitant stereotactic radiosurgery. A non-invasive approach for patients with focal epilepsy. Physiol Meas 14:1311361993Hellstrand DE Abraham-Fuchs K Jernberg B et al: MEG localization of interictal epileptic focal activity and concomitant stereotactic radiosurgery. A non-invasive approach for patients with focal epilepsy. Physiol Meas 14:131–136 1993

    • Search Google Scholar
    • Export Citation
  • 15.

    Hodges HKatzung NSowinski Pet al: Late behavioural and neuropathological effects of local brain irradiation in the rat. Behav Brain Res 91:991141998Hodges H Katzung N Sowinski P et al: Late behavioural and neuropathological effects of local brain irradiation in the rat. Behav Brain Res 91:99–114 1998

    • Search Google Scholar
    • Export Citation
  • 16.

    Imamura STanaka STojo Het al: Kainic acid-induced perirhinal cortical seizures in rats. Brain Res 800:3233271998Imamura S Tanaka S Tojo H et al: Kainic acid-induced perirhinal cortical seizures in rats. Brain Res 800:323–327 1998

    • Search Google Scholar
    • Export Citation
  • 17.

    Invik RJSharbrough FWLaws ER Jr: Effects of anterior temporal lobectomy on cognitive function. J Clin Psychol 43:1281371987Invik RJ Sharbrough FW Laws ER Jr: Effects of anterior temporal lobectomy on cognitive function. J Clin Psychol 43:128–137 1987

    • Search Google Scholar
    • Export Citation
  • 18.

    Ishikawa SOtsuki TKaneki Met al: Dose-related effects of single focal irradiation in the medial temporal lobe structures in rats—magnetic resonance imaging and histological study. Neurol Med Chir 39:171999Ishikawa S Otsuki T Kaneki M et al: Dose-related effects of single focal irradiation in the medial temporal lobe structures in rats—magnetic resonance imaging and histological study. Neurol Med Chir 39:1–7 1999

    • Search Google Scholar
    • Export Citation
  • 19.

    Katz AAwad IAKong AKet al: Extent of resection in temporal lobectomy for epilepsy. II. Memory changes and neurologic complications. Epilepsia 30:7637711989Katz A Awad IA Kong AK et al: Extent of resection in temporal lobectomy for epilepsy. II. Memory changes and neurologic complications. Epilepsia 30:763–771 1989

    • Search Google Scholar
    • Export Citation
  • 20.

    Kitchen N: Experimental and clinical studies on the putative therapeutic efficacy of cerebral irradiation (radiotherapy) in epilepsy. Epilepsy Res 20:1101995Kitchen N: Experimental and clinical studies on the putative therapeutic efficacy of cerebral irradiation (radiotherapy) in epilepsy. Epilepsy Res 20:1–10 1995

    • Search Google Scholar
    • Export Citation
  • 21.

    Kondziolka D: Functional radiosurgery. Neurosurgery 44:12221999Kondziolka D: Functional radiosurgery. Neurosurgery 44:12–22 1999

    • Search Google Scholar
    • Export Citation
  • 22.

    Lamproglou IChen QMBoisserie Get al: Radiation-induced cognitive dysfunction: an experimental model in the old rat. Int J Radiat Oncol Biol Phys 31:65701995Lamproglou I Chen QM Boisserie G et al: Radiation-induced cognitive dysfunction: an experimental model in the old rat. Int J Radiat Oncol Biol Phys 31:65–70 1995

    • Search Google Scholar
    • Export Citation
  • 23.

    Lindquist CKihlstrom LHellstrand E: Functional neurosurgery— a future for the gamma knife? Stereotact Funct Neurosurg 57:72811991Lindquist C Kihlstrom L Hellstrand E: Functional neurosurgery— a future for the gamma knife? Stereotact Funct Neurosurg 57:72–81 1991

    • Search Google Scholar
    • Export Citation
  • 24.

    Martin RCSawrie SMRoth DLet al: Individual memory change after anterior temporal lobectomy: base rate analysis using regression-based outcome methodology. Epilepsia 39:107510821998Martin RC Sawrie SM Roth DL et al: Individual memory change after anterior temporal lobectomy: base rate analysis using regression-based outcome methodology. Epilepsia 39:1075–1082 1998

    • Search Google Scholar
    • Export Citation
  • 25.

    Mori YKondziolka DBalzer Jet al: The effects of stereotactic radiosurgery on an animal model of hippocampal epilepsy. Neurosurgery 46:1571682000Mori Y Kondziolka D Balzer J et al: The effects of stereotactic radiosurgery on an animal model of hippocampal epilepsy. Neurosurgery 46:157–168 2000

    • Search Google Scholar
    • Export Citation
  • 26.

    Morris R: Developments of a water maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47601984Morris R: Developments of a water maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60 1984

    • Search Google Scholar
    • Export Citation
  • 27.

    Morris RGMGarrud PRawlins JNPet al: Place navigation impaired in rats with hippocampal lesions. Nature 297:6816831982Morris RGM Garrud P Rawlins JNP et al: Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683 1982

    • Search Google Scholar
    • Export Citation
  • 28.

    Regis JKerkerian-Legoff LRey Met al: First biochemical evidence of differential functional effects following gamma knife surgery. Stereotact Funct Neurosurg 66 (Suppl 1):29381996Regis J Kerkerian-Legoff L Rey M et al: First biochemical evidence of differential functional effects following gamma knife surgery. Stereotact Funct Neurosurg 66 (Suppl 1):29–38 1996

    • Search Google Scholar
    • Export Citation
  • 29.

    Regis JPeragui JCRey Met al: First selective amygdalohippocampal radiosurgery for ‘mesial temporal lobe epilepsy.’ Stereotact Funct Neurosurg 64 (Suppl 1):1932011995Regis J Peragui JC Rey M et al: First selective amygdalohippocampal radiosurgery for ‘mesial temporal lobe epilepsy.’ Stereotact Funct Neurosurg 64 (Suppl 1):193–201 1995

    • Search Google Scholar
    • Export Citation
  • 30.

    Sun BFDe Salles AFMedin PMet al: Reduction of hippocampal-kindled seizure activity in rats by stereotactic radiosurgery. Exp Neurol 154:6916951998Sun BF De Salles AF Medin PM et al: Reduction of hippocampal-kindled seizure activity in rats by stereotactic radiosurgery. Exp Neurol 154:691–695 1998

    • Search Google Scholar
    • Export Citation
  • 31.

    Sutherland RJMcDonald RJ: Hippocampus, amygdala, and memory deficits in rats. Behav Brain Res 37:57791990Sutherland RJ McDonald RJ: Hippocampus amygdala and memory deficits in rats. Behav Brain Res 37:57–79 1990

    • Search Google Scholar
    • Export Citation
  • 32.

    Sutherland RJWhishaw IQKolb B: A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-injected damage to the hippocampal formation in the rat. Behav Brain Res 7:1331531983Sutherland RJ Whishaw IQ Kolb B: A behavioural analysis of spatial localization following electrolytic kainate- or colchicine-injected damage to the hippocampal formation in the rat. Behav Brain Res 7:133–153 1983

    • Search Google Scholar
    • Export Citation
  • 33.

    Tanaka TKaijima MYonemasu Yet al: Spontaneous secondarily generalized seizures induced by a single microinjection of kainic acid into unilateral amygdala in cats. Electroencephalogr Clin Neuropsysiol 61:4224291985Tanaka T Kaijima M Yonemasu Y et al: Spontaneous secondarily generalized seizures induced by a single microinjection of kainic acid into unilateral amygdala in cats. Electroencephalogr Clin Neuropsysiol 61:422–429 1985

    • Search Google Scholar
    • Export Citation
  • 34.

    Tanaka TTanaka SFujita Tet al: [Experimental complex partial seizures induced by microinjection of kainic acid into limbic structures.] Progr Neurobiol 38:3173441992 (Jpn)Tanaka T Tanaka S Fujita T et al: [Experimental complex partial seizures induced by microinjection of kainic acid into limbic structures.] Progr Neurobiol 38:317–344 1992 (Jpn)

    • Search Google Scholar
    • Export Citation
  • 35.

    Whang CJKwon Y: Long-term follow-up of stereotactic Gamma Knife radiosurgery in epilepsy. Stereotact Funct Neurosurg 66 (Suppl 1):3493561996Whang CJ Kwon Y: Long-term follow-up of stereotactic Gamma Knife radiosurgery in epilepsy. Stereotact Funct Neurosurg 66 (Suppl 1):349–356 1996

    • Search Google Scholar
    • Export Citation

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