Radiosurgery effects and adverse effects in symptomatic eloquent brain-located Cavernomas.

In this study, the dose schedule efficacy, safety and late adverse effects of stereotactic radiosurgery (SRS) were evaluated for patients with symptomatic cavernomas who were not eligible for surgery and treated with SRS. Between January 2013 and December 2018, 53 patients with cavernomas were treated using SRS with the CyberKnife® system. Patients' diseases were deeply located or were in subcortical functional brain regions. In addition to bleeding, 23 (43.4%) patients had epilepsy, 12 (22.6%) had neurologic symptoms and 16 patients (30.2%) had severe headaches. The median volume was 741 (range, 421-1351) mm3, and the median dose was 15 (range, 14-16) Gy in one fraction. After treatment, six (50%) of 12 patients with neurologic deficits still had deficits. Rebleeding after treatment developed in only two (3.8%) patients. The drug was completely stopped in 14 (60.9%) out of 23 patients who received epilepsy treatment, and the dose of levetiracetam decreased from 2000 mg to 1000 mg in four (17.3%) of nine patients. Radiologically, complete response (CR) was observed in 13 (24.5%) patients, and partial responses (PR) were observed in 32 (60.2%) patients. Clinical response of CR was observed in 30 (56.6%) patients, PR was observed in 16 (30.2%), stable disease (SD) was observed in three (5.7%) and four (7.5%) patients progressed. In conclusion, SRS applied in the appropriate dose schedule may be an effective and reliable method in terms of symptom control and prevention of rebleeding, especially in patients with inoperable cavernomas.

Stereotactic radiosurgery as the initial management option for small-volume hypothalamic hamartomas with intractable epilepsy: a 35-year institutional experience and systematic review.

OBJECTIVE: Young patients with hypothalamic hamartomas (HHs) often present with intractable epilepsy. Currently there are no established management guidelines for HH. The authors retrospectively reviewed their single-institution experience to delineate the role of stereotactic radiosurgery (SRS). METHODS: Seven patients with HHs (4 females; median age 13.7 years, range 2.5-25 years) with no prior resection underwent SRS between 1987 and 2022. The clinical history, epilepsy profile, radiographic findings, and neurological outcomes were characterized. HH topographical types were classified according to the Régis classification. Outcome measures included Engel seizure classification, HH response, and the need for additional surgical interventions. RESULTS: All patients had Engel class IV epilepsy. A Leksell Gamma Knife was used to deliver a median margin dose of 18 Gy (range 16-20 Gy) to a median hamartoma volume of 0.37 cm3 (range 0.20-0.89 cm3). Seizure reduction was confirmed in 6 patients, and 2 patients had regression of their hamartoma. Two patients underwent resection and/or laser interstitial thermal therapy after SRS. At follow-up, 1 patient was seizure free, 4 patients achieved Engel class II, 1 patient had Engel class III, and 1 patient had Engel class IV seizure outcomes. CONCLUSIONS: SRS as the initial management option for HH was associated with a low risk of adverse effects. In this institutional series reviewing small-volume HHs treated with SRS, no adverse radiation effect was detected, and the majority of patients experienced seizure reduction. SRS should be considered as the first-line treatment for seizure control in patients with small-volume HHs.

[Functional stereotactic radiosurgery: Indications and perspectives]. / Radiochirurgie fonctionnelle : indications et perspectives.

Stereotactic radiosurgery (SRS) is a non-invasive technique that enables to create brain focal lesions with a high precision and localization. Thus, functional brain disorders can be treated by SRS in case of pharmacoresistance or inoperability. To date, treatment of trigeminal neuralgia is the most described and known indication. Other indications will be developed in the future like movement disorders, refractory epilepsy, obsessive compulsive disorder and severe depression. We present here a review of actual and future indications of functional brain SRS with their level of evidence. All these SRS treatments have to be strictly conducted by trained teams with an excellent collaboration between radiation physicists, medical physicists, neurosurgeons, neurologists, psychiatrists and probably neuroradiologists.

Oscillotherapeutics - Time-targeted interventions in epilepsy and beyond.

Oscillatory brain activities support many physiological functions from motor control to cognition. Disruptions of the normal oscillatory brain activities are commonly observed in neurological and psychiatric disorders including epilepsy, Parkinson's disease, Alzheimer's disease, schizophrenia, anxiety/trauma-related disorders, major depressive disorders, and drug addiction. Therefore, these disorders can be considered as common oscillation defects despite having distinct behavioral manifestations and genetic causes. Recent technical advances of neuronal activity recording and analysis have allowed us to study the pathological oscillations of each disorder as a possible biomarker of symptoms. Furthermore, recent advances in brain stimulation technologies enable time- and space-targeted interventions of the pathological oscillations of both neurological disorders and psychiatric disorders as possible targets for regulating their symptoms.

Utilizing neuronavigation for virtual electrode representation and safe resection following SEEG; a technical report.

Purpose: One of the most effective treatments for epilepsy is resection, but it remains underutilized. Efforts must be made to increase the ease, safety, and efficacy of epilepsy resection to improve utilization. Studies have shown an improved risk profile of stereoelectroencephalography (SEEG) over subdural grids (SDG) for invasive monitoring. One limitation to increased adoption of SEEG at epilepsy centers is the theoretical difficulty of planning a delayed resection once electrodes are removed. Our objective was to develop and present a technique using readily available neuronavigation technology to guide a cortical, non-lesional epilepsy resection with co-registration of imaging during invasive monitoring to imaging in an explanted patient, allowing for virtual visualization of electrodes. Methods: An example case taking advantage of the technique described above as an adjunct for an anatomically guided resection is presented with technical details and images. Results: Intraoperative neuronavigation was successfully used to virtually represent previously removed SEEG electrodes and accuracy could be easily verified by examining scars on the scalp, bone, dura and pia. Conclusions: The simple technique presented can be a useful adjunct to resection following SEEG. This may help increase the adoption of SEEG, even when resection is planned.

Rat sensorimotor cortex tolerance to parallel transections induced by synchrotron-generated X-ray microbeams.

Microbeam radiation therapy is a novel preclinical technique, which uses synchrotron-generated X-rays for the treatment of brain tumours and drug-resistant epilepsies. In order to safely translate this approach to humans, a more in-depth knowledge of the long-term radiobiology of microbeams in healthy tissues is required. We report here the result of the characterization of the rat sensorimotor cortex tolerance to microradiosurgical parallel transections. Healthy adult male Wistar rats underwent irradiation with arrays of parallel microbeams. Beam thickness, spacing and incident dose were 100 or 600 µm, 400 or 1200 µm and 360 or 150 Gy, respectively. Motor performance was carried over a 3-month period. Three months after irradiation rats were sacrificed to evaluate the effects of irradiation on brain tissues by histology and immunohistochemistry. Microbeam irradiation of sensorimotor cortex did not affect weight gain and motor performance. No gross signs of paralysis or paresis were also observed. The cortical architecture was not altered, despite the presence of cell death along the irradiation path. Reactive gliosis was evident in the microbeam path of rats irradiated with 150 Gy, whereas no increase was observed in rats irradiated with 360 Gy.

Radiosurgery for epilepsy: Systematic review and International Stereotactic Radiosurgery Society (ISRS) practice guideline.

BACKGROUND: While there are many reports of radiosurgery for treatment of drug-resistant epilepsy, a literature review is lacking. OBJECTIVE: The aim of this systematic review is to summarize current literature on the use of stereotactic radiosurgery (RS) for treatment of epilepsy. METHODS: Literature search was performed using various combinations of the search terms "radiosurgery", "stereotactic radiosurgery", "Gamma Knife", "epilepsy" and "seizure", from 1990 until October 2015. Level of evidence was assessed according to the PRISMA guidelines. RESULTS: Fifty-five articles fulfilled inclusion criteria. Level 2 evidence (prospective studies) was available for the clinical indications of mesial temporal lobe epilepsy (MTLE) and hypothalamic hamartoma (HH) treated by Gamma Knife (GK) RS. For remaining indications including corpus callosotomy as palliative treatment, epilepsy related to cavernous malformation and extra-temporal epilepsy, only Level 4 data was available (case report, prospective observational study, or retrospective case series). No Level 1 evidence was available. CONCLUSION: Based on level 2 evidence, RS is an efficacious treatment to control seizures in MTLE, possibly resulting in superior neuropsychological outcomes and quality of life metrics in selected subjects compared to microsurgery. RS has a better risk-benefit ratio for small hypothalamic hamartomas compared to surgical methods Delayed therapeutic effect resulting in ongoing seizures is associated with morbidity and mortality risk. Lack of level 1 evidence precludes the formation of guidelines at present.

[Brain X-radiation for Childhood Epilepsy, Hydrocephalus or Mental Retardation? Research at Tuebingen University, 1940-1946]. / Röntgenbestrahlung des Gehirns zur Behandlung von kindlicher Epilepsie, Hydrocephalus oder Schwachsinn? Forschungen an der Tübinger Universitätsklinik von 1940-1946.

Brain X-radiation for Childhood Epilepsy, Hydrocephalus or Mental Retardation? Research at Tuebingen University, 1940-1946 We reconstructed 65 cases out of a series of "experimental" X-ray-therapy by chart review and reanalysis of publications from a contextual historical perspective. The research procedures in the context of NS-pressure for effectiveness soon dismissed structured scientific procedures and surrendered own standards, whereas radiation impact did not transgress the contemporary guidelines.

Effects of extremely low frequency electromagnetic field (50 Hz) on pentylenetetrazol-induced seizures in mice.

The electromagnetic fields (EMF) have various behavioral and biological effects on human body. There are growing concerns about the consequences of exposure to EMF. However, some studies have shown beneficial effects of these waves on human. In this paper, we study the effect of acute, sub acute and long-term exposure to 50 Hz, 0.1 mT magnetic fields (MF) on the seizure induction threshold in mice. 64 mice are used and divided into four groups. Eight mice in any group were selected to be exposed to MF for specific duration and the others were used as a control group. The duration of the applied exposures was as follows: (1) 1 day (acute), (2) 3 days (sub acute), (3) 2 weeks (sub acute), (4) 1 month (long term). The mice were exposed 2 h for a day. After exposure, the pentylentetrazol (PTZ) is injected to the mice to induce seizure and the needed dose for the seizure induction threshold is measured. In the acute exposure, the threshold to induce seizure in the exposed and sham-exposed groups was 44.25 and 46.5 mg, respectively, while the difference was not significant (p value = 0.5). In the sub acute exposure (3 days), the mean amount of drug to induce seizure was 47.38 mg in the exposed and 43.88 mg in the sham-exposed groups, however, the difference was not significant (p value = 0.3). The results were 52.38 and 46.75 mg after 2 weeks of exposure which were not significantly different either (p value = 0.2). After 1 month of exposure to MF, the threshold for the induction of seizure was significantly increased (p value < 0.05). The mean dosage to induce seizure in the exposed and control group was 54.3 and 45.75 mg, respectively. However, considering the p value, the difference in the seizure induction threshold between the exposed and sham-exposed groups after acute and sub acute exposure was not significant, analyzing the effects of acute, sub acute and long-term exposures totally indicates that increasing the exposure time increases the seizure induction threshold.

Long-term experience with fractionated stereotactic radiotherapy in pharmacoresistant epilepsy: neurological and MRI changes.

PURPOSE: Radiotherapy is an option in patients with difficult-to-treat epilepsy in which pharmacological and surgical alternatives have been exhausted. However, little is known about the long-term efficacy and side effects of radiotherapy in this context. Hence, we report for the first time on the long-term outcome (median 10 years) of fractionated stereotactic radiotherapy (FSRT) in 11 patients with drug-resistant epilepsy in a retrospective study. Primary endpoint is tolerability concerning neurological and MRI findings, secondary endpoint seizure frequency. PATIENTS AND METHODS: FSRT was performed in 11 patients with cryptogenic or symptomatic epilepsy from 1996 to 2009 using a conventional linear accelerator (LINAC) in seven cases and a dedicated NOVALIS(®) LINAC in four. The biologically equivalent dose ranged from 26.3 to 58.3 Gy (α/ß=10). RESULTS: (1) None of the patients developed temporary or permanent neurological deficits. No MRI changes occurred. (2)Treatment resulted in improvement of seizure frequency in seven patients, five of them had a decrease in seizure frequency, and two of them were seizure-free at last follow-up. CONCLUSIONS: If radiation is administered with proper fractionation, dose prescription and target volume definition, long-term neurological side effects are unlikely. (2) Radiotherapy has the potential to control the frequency and intensity of seizures in epilepsy patients.

Effect of infrared laser irradiation on amino acid neurotransmitters in an epileptic animal model induced by pilocarpine.

OBJECTIVE: The aim of the present study was to investigate the effect of daily laser irradiation on the levels of amino acid neurotransmitters in the cortex and hippocampus in an epileptic animal model induced by pilocarpine. BACKGROUND DATA: It has been claimed that at specific wavelengths and energy densities, laser irradiation is a novel and useful tool for the treatment of peripheral and central nervous system injuries and disorders. MATERIALS AND METHODS: Adult male albino rats were divided into three groups: control rats, pilocarpinized rats (epileptic animal model), and pilocarpinized rats treated daily with laser irradiation (90 mW at 830 nm) for 7 d. The following parameters were assayed in cortex and hippocampus: amino acid neurotransmitters (excitatory: glutamic acid and aspartate; and inhibitory: gamma-aminobutyric acid [GABA], glycine, and taurine) by high-performance liquid chromatography (HPLC), glucose content, and the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), using a spectrophotometer. RESULTS: Significant increases in the concentrations of glutamic acid, glutamine, glycine, and taurine were recorded in the cortices of pilocarpinized rats, and they returned to initial levels after laser treatment. In the hippocampus, a moderate increase in aspartate accompanied by a significant increase in glycine were observed in the epileptic animal model, and these dropped to near-control values after laser treatment. In addition, a significant increase in cortical AST activity and a significant decrease in ALT activity and glucose content were obtained in the pilocarpinized animals and pilocarpinized rats treated with laser irradiation. In the hippocampus, significant decreases in the activity of AST and ALT and glucose content were recorded in the epileptic animals and in the epileptic animals treated with laser irradiation. CONCLUSION: Based on the results obtained in this study, it may be suggested that nearinfrared laser irradiation may reverse the neurochemical changes in amino acid neurotransmitters induced by pilocarpine.

Influence of ionizing radiation on the course of kindled epileptogenesis.

Several clinical and experimental reports suggest that low-dose irradiation of an established epileptic focus can reduce the occurrence of spontaneous seizures. Conversely, some recent reports suggest that under some conditions low-dose irradiation may have disinhibitory effects on seizure expression. Here, we have investigated mechanistic aspects of this phenomenon in the kindling model of epilepsy by applying focal irradiation at various points during kindling development. Rats were kindled to stage 5 by afterdischarge-threshold electrostimulation of the left amygdala. Treatment groups were irradiated using a collimated X-ray beam (18 MV) either prior to kindling, at kindling stage 3, or at kindling stage 5, by exposure of the left amygdala to a single-fraction central-axis dose of 25 Gy. Generalized seizure thresholds (GSTs) were subsequently assayed at weekly intervals for 10 weeks and at monthly intervals for an additional 3 months, along with the severity of the evoked seizures. Irradiation produced no significant effects on seizure threshold, but did produce persistent changes in seizure severity which varied as a function of the timing of irradiation. Relative to sham irradiated controls, the occurrence of stage 6 seizures was significantly increased by irradiation prior to kindling, but was unaffected by irradiation at kindling stage 3, and significantly reduced by irradiation at kindling stage 5. Quantitative immunohistochemical assays for neuron and astrocyte densities within the amygdala and hippocampus revealed only subtle changes in neuronal density within the dentate granule cell layer. These results are discussed in relation to mechanisms of seizure- and radiation-induced plasticity.

Gamma knife radiosurgery for refractory epilepsy caused by hypothalamic hamartomas.

BACKGROUND: Hypothalamic hamartomas are associated with precocious puberty and chronic epilepsy characterized by gelastic seizures. The seizure disorder is usually refractory to most antiepileptic drugs. Gamma knife surgery has emerged as an alternative to microsurgical removal or radiofrequency ablation to improve seizure control. We present our experience with radiosurgery in 4 patients afflicted by this disorder. METHODS: Using gamma knife radiosurgery, 4 patients with intractable gelastic seizures and complex epilepsy were managed. Patient age varied from 5 to 29 years. The duration of symptoms was 4-28 years. A conformal radiosurgery plan was designed with a mean of 4.25 isocenters to cover the hamartoma at the 50% isodose line. A mean margin dose of 17.5 Gy was used. The clinical outcome was evaluated with the Engel scale. RESULTS: No complication occurred. After a median follow-up of 22 months, 3 patients had shown some improvement, with 2 attaining Engel class II status. CONCLUSION: Gamma knife surgery is a promising alternative to microsurgical removal for patients with refractory epilepsy caused by hypothalamic hamartomas.

FLAIR-/T1-/T2-co-registration for image-guided diagnostic and resective epilepsy surgery.

OBJECTIVE: For technical reasons, T2-weighted and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) sequences do not allow morphological orientation with high anatomic resolution, but they may show small epileptogenic lesions. Considering the peculiarities of diagnostic and resective epilepsy surgery the present study focused on the co-registration of various magnetic resonance sequences for guided epilepsy surgery. METHODS: Fifty patients (24 men; 26 women) aged 2 to 74 years (mean, 32 yr), in whom epileptogenic lesions were not readily identifiable on three-dimensional T1-weighted MRI scans underwent additional two-dimensional T2-weighted and FLAIR sequences before diagnostic and/or resective epilepsy surgery. FLAIR and/or T2-weighted images were co-registered to the T1-weighted data set and were displayed on the navigation station on site for guided invasive diagnostics and for resection according to an individualized resection plan. Postoperative MRI scanning was routinely performed for assessment of resection extent. RESULTS: Co-registered T1- and FLAIR-/T2-images allowed for image-guided intraoperative identification of all lesions (n = 50). Control MRI scans revealed that complete resection was performed as planned before the operation in 49 patients and incomplete resection was performed in one patient. Preliminary seizure outcome with a mean follow up of 14 months (range, 7-24 mo) was assigned according to the Engel classification: Class I, 78%; Class II, 12%; Class III, 4%; Class IV, 6%. CONCLUSION: Image guidance on the basis of image fusion/co-registration of T1- and FLAIR-/T2-images allows for intraoperative identification of otherwise poorly visible lesions on standard MRI sequences in good spatial resolution. Recall of this information during surgery from the navigation system's screen assists in achieving the goal of precise electrode placement, or complete resection of the lesion as well as of the perilesional epileptogenic tissue and improves the surgeon's intraoperative orientation.

Effects of kindling and irradiation on neuronal density in the rat dentate gyrus.

Low-dose radiosurgery is presently in use as a treatment modality for focal epilepsy, but the mechanisms underlying the associated changes in seizure expression are poorly understood. We investigated whether total and parvalbumin expressing (PV+) neuronal densities within the hippocampus and amygdala are affected by analogous focal irradiation in amygdala-kindled rats. Adult rats were kindled by electrical stimulation through 10 stage 5 seizures. The kindled amygdala was then focally irradiated at 18 or 25 Gy, and generalized seizure thresholds were subsequently monitored for approximately 6 months. Histological and immunohistochemical assays of total and PV+ neuronal densities were performed bilaterally throughout the hippocampus and within the basolateral amygdala. PV+ neuronal densities were unaffected by kindling or irradiation in these regions. Kindling selectively reduced neuronal densities in the dentate granule cell layer, and medial CA3 pyramidal cell layer. Irradiation at 25 Gy, but not at 18 Gy, prevented or reversed this kindling-associated reduction in density.

Emerging surgical and radiotherapeutic techniques for treating epilepsy.

PURPOSE OF REVIEW: Recent advances in epilepsy surgery have developed a resurgence of interest in the use of surgical techniques for the treatment of intractable epilepsy. RECENT FINDINGS: More invasive procedures such as hemispherectomy and multiple subpial transection have become more popular. Disconnective techniques such as multiple subpial transection have provided a surgical option for patients whose epileptogenic zone resides in the eloquent cortex. Alternatively, new minimally invasive neurostimulation therapies have been introduced to preserve maximal cerebral tissue. Radiosurgery has been recently utilized in the treatment of epilepsy with preliminary promising results. SUMMARY: In this analysis, the authors will attempt to review the more recent surgical approaches and their indications for the treatment of medically intractable epilepsy. For patients with the epileptogenic zone in the noneloquent cortex, seizure focus resection remains the most reasonable approach to therapy.

Radiosurgical treatment of intractable epilepsy with low radiation dose.

OBJECTIVE: To localize the epileptic foci with positron emission tomography (PET), and study the principles of target definition and method to determine the optimal range of exposure in radiosurgery for intractable epilepsy. METHODS: This study included 176 patients with intractable epilepsy, who received linear accelerator radiosurgery after (18)F-FDG PET for epileptic foci localization. The patients were divided according to different peripheral doses used in the treatment into Group A in which radiation dose of 9 to 11 Gy was used, Group B with 11 to 13 Gy and Group C with exposure to over 13 Gy. Follow-up study was conducted in all the patients for a period ranging from 3 to 16 months, during which the frequency of seizure after treatment was recorded to evaluate the therapeutic effect. RESULTS: The seizure frequency significantly decreased after radiosurgical treatment in all the groups, but between the groups, the decrement evinced no significant difference. According to Wieser's classification of the effect after operation, 46.9% cases belonged to grade I to II and 41.5% to grade III to IV. Obvious complications were not observed, nor did disability or mortality occurred in these cases. CONCLUSIONS: Stereotactic radiosurgery with low radiation dose under the guidance of PET provides a safe, effective and minimally invasive surgical approach for patients with intractable epilepsy, and peripheral radiation doses of 9 to 11 Gy for the epileptic foci localized by PET is sufficient to ensure good clinical outcome.

[The delayed effects of modulated and non-modulated electromagnetic field on epileptiformic activity in rats]. / Otdalennye posledstviia deistviia modulirovannogo i nemodulirovannogo elektromagnitnogo polia na epileptiformnuiu aktivnost' krys.

The modifying influence of the weak electromagnetic field on the development of the audiogenic spasmodic activity in rats was shown. The decrease of lifetime of experimental rats exposed to electromagnetic fields with different parameters and development of tumours (in one set of experiments) was found.