Transduction profiles in minipig following MRI guided delivery of AAV-5 into thalamic and corona radiata areas.

BACKGROUND: As a step towards clinical use of AAV-mediated gene therapy, brains of large animals are used to settle delivery parameters as most brain connections, and relative sizes in large animals and primates, are reasonably common. Prior to application in the clinic, approaches that have shown to be successful in rodent models are tested in larger animal species, such as dogs, non-human primates, and in this case, minipigs. NEW METHOD: We evaluated alternate delivery routes to target the basal ganglia by injections into the more superficial corona radiata, and, deeper into the brain, the thalamus. Anatomically known connections can be used to predict the expression of the transgene following infusion of AAV5. For optimal control over delivery of the vector with regards to anatomical location in the brain and spread in the tissue, we have used magnetic resonance image-guided convection-enhanced diffusion delivery. RESULTS: While the transduction of the cortex was observed, only partial transduction of the basal ganglia was achieved via the corona radiata. Thalamic administration, on the other hand, resulted in widespread transduction from the midbrain to the frontal cortex COMPARISON WITH EXISTING METHODS: Compared to other methods, such as delivery directly to the striatum, thalamic injection may provide an alternative when for instance, injection into the basal ganglia directly is not feasible. CONCLUSIONS: The study results suggest that thalamic administration of AAV5 has significant potential for indications where the transduction of specific areas of the brain is required.

Lesion evolution after gamma knife irradiation observed by magnetic resonance imaging.

PURPOSE: Our study is focused on the magnetic resonance imaging (MRI) observation of lesion development and hippocampus related functional impairments in rats after irradiation with a Leksell Gamma knife (LGK). MATERIALS AND METHODS: We exposed 32 three-month-old Long-Evans rats to various radiation doses (25 Gy, 50 Gy or 75 Gy). The rats were scanned by a 4.7 T magnetic resonance (MR) spectrometer at several timepoints (1 - 18 months) after irradiation. The lesion size was evaluated by manual segmentation; the animals were behaviorally tested in a Morris water maze and examined histologically. RESULTS: We found that a dose of 25 Gy induced no edema, necrosis or behavioral change. The response of the rats to higher doses was not uniform; the first occurrence of lesions in the rat brains irradiated with 50 and 75 Gy was detected six months post-irradiation. Functional impairment correlated well with the lesion size and histology. CONCLUSIONS: Rat brains showed the development of expanding delayed lesions after 50 or 75 Gy doses from the LGK during the first year after irradiation.

Gamma knife radiosurgery for endocrine-inactive pituitary adenomas.

BACKGROUND: The goal of nonsecreting pituitary adenoma radiosurgery is to halt tumour growth and to maintain normal performance of the hypophysis and the functionally important structures around the sella. The effectiveness of gamma knife radiosurgery was evaluated. METHOD: Over a period of 10 years (1993-2003), 140 patients with nonsecreting pituitary adenoma were treated by Leksell gamma knife at our Centre. Seventy-nine of them were followed up for longer than 3 years. Their age range was 24-73 years, with a median of 54 years. Eighty-five percent of them had previous open surgery. Fifteen patients had adenoma contact with the optic tract. Fourteen patients had a normally functioning hypophysis, 48 patients had complete panhypopituitarism, while the rest retained partial functions of the normal hypophysis. Adenoma volumes ranged between 0.1 and 31.3, the median being 3.45 ccm. The marginal dose ranged between 12 and -35 Gy, with a median of 20 Gy. FINDINGS: The follow-up ranged from 36 to 122 months, with a median of 60 months. No adenoma growth was detected; 89% of treated adenomas decreased in size, with a median volume reduction of 61%. There was no perimeter vision impairment after radiosurgery, while 4 out of 52 patients with abnormal perimeter vision reported improvement. There was no impairment of oculomotor nerve function. Impairment of hypophysis function was observed in 2 patients. CONCLUSIONS: Radiosurgery has a reliable antiproliferative effect on nonsecreting pituitary adenomas. It is a safe treatment with a low risk of morbidity. Short contact between a nonsecreting pituitary adenoma and the optic pathway is not an absolute contraindication for Gamma knife radiosurgery.

Penile block in children, our first experience.

Penile block has been in use in penile surgery as a technique for perioperative analgesia for 25 years. The authors reintroduced penile block on the Department of Paediatric Anaesthetics and Intensive Care at the University Children's Hospital in Bratislava, Slovakia in June 2004 after 8 years. This prospective open observational study presents their experience with penile block for elective penile surgery in 96 paediatric patients (Tab. 3, Ref. 14).

Can morphological MRI differentiate between primary central nervous system lymphoma and glioblastoma?

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive brain neoplasm that accounts for roughly 2-6% of primary brain tumors. In contrast, glioblastoma (GBM) is the most frequent and severe glioma subtype, accounting for approximately 50% of diffuse gliomas. The aim of the present study was to evaluate morphological MRI characteristics in histologically-proven PCNSL and GBM at the time of their initial presentation. METHODS: We retrospectively evaluated standard diagnostic MRI examinations in 54 immunocompetent patients (26 female, 28 male; age 62.6 ± 11.5 years) with histologically-proven PCNSL and 54 GBM subjects (21 female, 33 male; age 59 ± 14 years). RESULTS: Several significant differences between both infiltrative brain tumors were found. PCNSL lesions enhanced homogenously in 64.8% of cases, while nonhomogeneous enhancement was observed in 98.1% of GBM cases. Necrosis was present in 88.9% of GBM lesions and only 5.6% of PCNSL lesions. PCNSL presented as multiple lesions in 51.9% cases and in 35.2% of GBM cases; however, diffuse infiltrative type of brain involvement was observed only in PCNSL (24.1%). Optic pathways were infiltrated more commonly in PCNSL than in GBM (42.6% vs. 5.6%, respectively, p <0.001). Other cranial nerves were affected in 5.6% of PCNSL, and in none of GBM. Signs of bleeding were rare in PCNSL (5.6%) and common in GBM (44.4%); p < 0.001. Both supratentorial and infratentorial localization was present only in PCNSL (27.7%). Involvement of the basal ganglia was more common in PCNSL (55.6%) than in GBM (18.5%); (p < 0.001). Cerebral cortex was affected significantly more often in GBM (83.3%) than in PCNSL (51.9%); mostly by both enhancing and non-enhancing infiltration. CONCLUSION: Routine morphological MRI is capable of differentiating between GBM and PCNSL lesions in many cases at time of initial presentation. A solitary infiltrative supratentorial lesion with nonhomogeneous enhancement and necrosis was typical for GBM. PCNSL presented with multiple lesions that enhanced homogenously or as diffuse infiltrative type of brain involvement, often with basal ganglia and optic pathways affection.

Progress in glaucoma treatment research: a nonrandomized prospective study of 102 patients with advanced refractory glaucoma treated by Leksell gamma knife irradiation.

OBJECT: The authors performed a study to characterize the effects of ciliary body gamma knife surgery (GKS) for advanced glaucoma. METHODS: In addition to a pilot project involving 14 patients, 88 other patients were treated. Four 8-mm isocenters were used. Blind eyes received 20 Gy to the 50% isodose. If there was preserved vision the dose was 15 Gy. The median follow up was 20 months (range 2-54 months). Severe pain was present in 93% of patients with secondary glaucoma; after GKS it was substantially improved in 89% of cases. In primary open angle glaucoma, the pain was less frequent and severe. In more than half the patients it disappeared during a median latency of 6 weeks. The median intraocular pressure value was lowered in patients with secondary glaucoma (from 51.3-27 mm Hg). The same values for primary glaucoma were 25.3 and 16.1 mm Hg, respectively, after a median latency of 12 weeks. Twenty-seven of 40 patients with neovascular glaucoma showed a marked reduction of neovascularization after a median latency of 18 weeks. Treatment complications were slight. There was postoperative lacrimation in 61%. Two patients underwent postirradiation cataract extraction. Noninfectious keratitis was observed in two patients. Pharmacotherapy could be reduced in all patients and ceased in approximately one third. There has been no recurrence of the initial symptoms and no worsening of visual acuity. CONCLUSIONS: Gamma knife surgery ameliorates the main symptoms in advanced glaucomas and precludes the need for eventual ocular enucleation.

Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radiosurgery Study Group.

PURPOSE: To better predict permanent complications from arteriovenous malformation (AVM) radiosurgery. METHODS AND MATERIALS: Data from 85 AVM patients who developed symptomatic complications following gamma knife radiosurgery and 337 control patients with no complications were evaluated as part of a multi-institutional study. Of the 85 patients with complications, 38 patients were classified as having permanent symptomatic sequelae (necrosis). AVM marginal doses varied from 10-35 Gy and treatment volumes from 0.26-47.9 cc. Median follow-up for patients without complications was 45 months (range: 24-92). RESULTS: Multivariate analysis of the effects of AVM location and the volume of tissue receiving 12 Gy or more (12-Gy-Volume) allowed construction of a significant postradiosurgery injury expression (SPIE) score. AVM locations in order of increasing risk and SPIE score (from 0-10) were: frontal, temporal, intraventricular, parietal, cerebellar, corpus callosum, occipital, medulla, thalamus, basal ganglia, and pons/midbrain. The final statistical model predicts risks of permanent symptomatic sequelae from SPIE scores and 12-Gy-Volumes. Prior hemorrhage, marginal dose, and Marginal-12-Gy-Volume (target volume excluded) did not significantly improve the risk-prediction model for permanent sequelae (p >/= 0.39). CONCLUSION: The risks of developing permanent symptomatic sequelae from AVM radiosurgery vary dramatically with location and, to a lesser extent, volume. These risks can be predicted according to the SPIE location-risk score and the 12-Gy-Volume.

A multi-institutional analysis of complication outcomes after arteriovenous malformation radiosurgery.

PURPOSE: To better understand radiation complications of arteriovenous malformation (AVM) radiosurgery and factors affecting their resolution. METHODS AND MATERIALS: AVM patients (102/1255) who developed neurological sequelae after radiosurgery were studied. The median AVM marginal dose (Dmin) was 19 Gy (range: 10-35). The median volume was 5.7 cc (range: 0.26-143). Median follow-up was 34 months (range: 9-140). RESULTS: Complications consisted of 80/102 patients with evidence of radiation injury to the brain parenchyma (7 also with cranial nerve deficits, 12 also with seizures, 5 with cyst formation), 12/102 patients with isolated cranial neuropathies, and 10/102 patients with only new or worsened seizures. Severity was classified as minimal in 39 patients, mild in 40, disabling in 21, and fatal in 2 patients. Symptoms resolved completely in 42 patients for an actuarial resolution rate of 54% +/- 7% at 3 years post-onset. Multivariate analysis identified significantly greater symptom resolution in patients with no prior history of hemorrhage (p = 0.01, 66% vs. 41%), and in patients with symptoms of minimal severity: headache or seizure as the only sequelae of radiosurgery (p < 0.0001, 88% vs. 34%). CONCLUSION: Late sequelae of radiosurgery manifest in varied ways. Further long-term studies of these problems are needed that take into account symptom severity and prior hemorrhage history.

Solitary brain metastases treated with the Leksell gamma knife: prognostic factors for patients.

PURPOSE: To analyze treatment results, complications, prognostic factors and their statistical significance in surviving patients treated with the Leksell gamma knife (LGK) for solitary brain metastases. MATERIALS AND METHODS: Between 1992-1998, 237 patients were treated with solitary brain metastasis (SBM). The histological subtypes were as follows: 101 patients (42.6%) non small-cell lung cancer, 42 (17.7%) renal cell carcinoma, 36 (15.2%) breast carcinoma, 30 (12.7%) colorectal carcinomas and 28 (11.8%) melanoma. RESULTS: A complete or partial regression was observed in 193 (81.4%) patients, cessation of growth activity in 32 (13.5%) and local progression in 12 (5.1%). Local recurrence was observed in nine (4.7%) of 193 patients with complete or partial regression. Acute toxicity appeared in 24 (10%) patients (score 3.4), late complications (score 3.4) were observed in 13 patients (5.5%). Out of 237 patients, 182 patients died with a median survival of 6 months and 55 patients are still alive with a median survival 12 months and with a minimal follow up period of 10 months. The significant prognostic factors for longer survival in these series of patients were: Karnofsky performance status (70% or more), the extent of extra-cerebral disease (no extra-cerebral disease), pretreatment neurological symptoms neurological functional class (NFC 1), histology (renal cell and breast carcinomas) and the dose to the planning target volume (20 Gy and higher). CONCLUSIONS: Radiosurgery provides an effective local control for 90% of treated patients with low morbidity. Several significant prognostic factors were detected for patients' survival. These factors can help to predict better patients' survival after the LGK treatment.

Fractionated stereotactic radiotherapy with the Leksell Gamma Knife: feasibility study.

The main aim of this study was to check feasibility of stereotactic radiotherapy, which is routinely practised on linear accelerators, using a fixed Leksell stereotactic frame and a Leksell Gamma Knife. The study refers to the first experiences with 48 patients treated by a fractionated regimen (in 2-6 days). Isoeffect relationships calculations based on the linear-quadratic model and the levels of applied radiation doses, taking into account radiobiology of the tumour, tumour volume, critical structures surrounding the treated lesion and other factors are discussed. The procedure for quality control during the whole fractionated regimen is described. The study has shown that stereotactic radiotherapy with the Leksell Gamma Knife is feasible. However, only early effects can be discussed and there are still questions remaining which should be carefully studied: tolerance doses for critical structures at fractionation, definition of an 'ideal' fractionation regimen, and justification of the linear-quadratic model in the case of stereotactic radiotherapy.

Radiosurgery for epilepsy associated with cavernous malformation: retrospective study in 49 patients.

OBJECTIVE: Microsurgical resection of a cavernous malformation (CM) with or without associated cortical resection can provide efficient treatment of drug-resistant associated epilepsy. To explore the potential alternative role of radiosurgery and to evaluate its safety and efficacy for this indication, we conducted a retrospective multicenter study. METHODS: We retrospectively reviewed the files of patients with long-lasting drug-resistant epilepsy, presumably caused by CM, who were treated by gamma knife (GK) surgery for the control of their epilepsy in five centers (Marseilles, Komaki City, Prague, Graz, and Sheffield). A satisfactory follow-up was available for 49 patients (mean follow-up period, 23.66 +/- 13 mo). The mean duration of epilepsy before the GK procedure was 7.5 (+/-9.3) years. The mean frequency of seizures was 6.9/month (+/-14). The mean marginal radiation dose was 19.17 Gy +/- 4.4 (range, 11.25-36). Among the 49 patients, 17 (35%) had a CM located in or involving a highly functional area. RESULTS: At the last follow-up examination, 26 patients (53%) were seizure-free (Engel's Class I), including 24 in Class IA (49%) and 2 patients with occasional auras (Class IB, 4%). A highly significant decrease in the number of seizures was achieved in 10 patients (Class IIB, 20%). The remaining 13 patients (26%) showed little or no improvement. The mediotemporal site was associated with a higher risk of failure. One patient bled during the observation period, and another experienced radiation-induced edema with transient aphasia. Postradiosurgery excision was performed in five patients, and a second radiosurgical treatment was carried out in one patient. CONCLUSION: This series is the first to specifically evaluate the capability of GK surgery to safely and efficiently treat epilepsy associated with CM. Seizure control can be reached when a good electroclinical correlation exists between CM location and epileptogenic zone. Although we do not recommend GK surgery for prevention of bleeding for a CM that has not bled previously, our findings suggest that GK surgery can be proposed for the treatment of epilepsy when the CM is located in a highly functional area.

Treatment of postherpetic trigeminal neuralgia with the gamma knife.

OBJECT: Postherpetic neuralgia is a syndrome characterized by intractable pain. Treatment of this pain has not yet been successful. Patients with postherpetic neuralgia will therefore benefit from any progress in the treatment strategy. The authors performed gamma knife radiosurgery (GKS) as a noninvasive treatment for postherpetic trigeminal neuralgia (TN) and evaluated the success rate for pain relief. METHODS: Between 1995 and February 1999, six men and 10 women were treated for postherpetic TN; conservative treatment failed in all of them. The median follow up was 33 months (range 8-34 months). The radiation was focused on the root of the trigeminal nerve in the vicinity of the brainstem (maximal dose 70-80 Gy in one fraction, 4-mm collimator). The patients were divided into five groups according to degree of pain relief after treatment. A successful result (excellent, very good, and good) was reached in seven (44%) patients and radiosurgery failed in nine (56%). Pain relief occurred after a median interval of 1 month (range 10 days-6 months). No radiation-related side effects have been observed in these patients. CONCLUSIONS: These results suggest that GKS for postherpetic TN is a relatively successful and safe method that can be used in patients even if they are in poor condition. In case this method fails, other treatment options including other neurosurgical procedures are not excluded.

Initial experience with gamma knife radiosurgery for advanced glaucoma.

OBJECT: The authors assessed the affect of gamma knife radiosurgery on patients with glaucoma. METHODS: Fifteen eyes in 14 patients were treated with gamma knife radiosurgery during a 14-month period. Ocular pain was alleviated in all patients and intraocular pressure was decreased. There were no early side effects. CONCLUSIONS: Further studies are needed to elucidate the best treatment parameters, long-term results, and some of the pathophysiological effects.

Gamma knife radiosurgery of skull base meningiomas.

Meningiomas are the most frequent benign tumors treated by gamma knife radiosurgery and the majority of them are located on the skull base. Between 1992 and 1999, 197 skull base-located meningiomas in 192 patients were treated by gamma knife in Prague. Contact with the chiasma or optic tract was not regarded as a contraindication for gamma knife radiosurgery and such contact was observed in 32% of the skull base meningiomas treated. 176 patients were monitored during a median of 36 months, of whom 73% showed a decrease in tumor volume; no change was observed in 25% and continued growth was observed in 2%. Neurodeficit improved in 63% of patients, temporary morbidity occurred in 11% and persistent morbidity remained in 4.5%. Radiosurgery induced edema in 11%. Significantly lower edema occurrence was observed after radiosurgery in patients with no history of edema prior to radiosurgery, where the tumor was located in the posterior skull base and where the dosage to the tumor margin was lower than or equal to 14 Gy. Radiosurgery of skull base meningiomas has been proven to be safe and efficient. We consider gamma knife treatment for skull base meningiomas to be the method of choice whenever tumors are within the volume limits and there is no need for an urgent decompressive effect from the open operation.

[Radiosurgical hypophysectomy in painful bone metastases of breast carcinoma]. / Radiochirurgická hypofyzektomie u bolestivých kostních metastáz karcinomu prsu.

Radiosurgical hypophysectomy using Leksell gamma knife was performed to the patient with cancer pain from bone metastases of the breast cancer, relief of the pain was achieved. Patient survived 26 months after hypophysectomy. Review of the literature concerning relief of the pain after hypophysectomy is presented.

[Radiosurgical treatment of meningioma with the Leksell gamma knife]. / Radiochirurgická lécba meningiomu s uzitím Leksellova gama noze.

BACKGROUND: Up to the present time radical microsurgery of the tumour was considered the most satisfactory treatment. Now an ever more important part in the treatment of these tumours is played by radiosurgery. It involves minimal surgical stress, a minimal rate of complications and minimal change of lifestyle during the postoperative period. The objective of the submitted work was to evaluate the authors' results with the use of Leksell's gamma knife. METHODS AND RESULTS: In 1992-1994 48 patients with meningiomas were indicated for treatment with a gamma knife. The group comprised 12 men (25%) and 36 women (75%) aged 18-73 years (mean age 52.8 years which did not differ significantly in the two groups). In 19 patients (39.6%) one or more neurosurgical operations were carried out previously, in 4 patients (8.3%) fractionated radiotherapy. Karnofski's score, as an indicator of the general condition, varied between 30-90%, the mean value for the whole group being 71%. The calculated volume of the meningioma was between 0.7 and 25.8 cm3, the average being 7.4 cm3. Collateral oedema in the adjacent area of the tumour was found in 6 patients (12.5%). In 19 patients (39.6%) the tumour was at the base of the skull, in 29 patients (60.4%) at other sites. The radiosurgically administered dose was within the range of 6.5-24 Gy, on average 14,2 Gy, on the isodose on average 50.7% (range 40-75%). The dose below the maximum was within the range of 13-45 Gy), on average 28.3 Gy. Only in two patients fractionated administration of the dose was used. After a 6-month interval following operation 30 patients were examined. In 7 patients (23.3%) partial wrinkling of the meningioma occurred (range 6-18 months), Karnofski's score improved by 10% in 8 (26.6%) and deteriorated in 3 patients (10%). The neurodeficit improved in 7 (23.3%) and deteriorated in 4 patients (13.3%). Collateral oedema developed in 5 patients (16.6%) 5-7 months after operation, in about half the patients it was symptom free. During the follow up period 2 patients died (8 and 5 months following surgery): in one the cause of death was not associated with the basic disease, in the second patient (where radiotherapy was the third neurosurgical operation) the radiosurgical operation could not reverse tha fatal course of the disease. CONCLUSIONS: Radiosurgery of meningiomas is a safe therapeutic method with zero mortality, minimal surgical stress, a minimal rate of complications and a minimal morbidity. It is indicated in meningiomas and possibly their residues after subtotal neurosurgery up to a maximal volume of 30 cm3. It is primary treatment suitable in particular in old.patients, patients with a high per- and postoperative risk and in patients refusing open neurosurgery.

[The first year of use of the Leksell gamma knife at the Hospital Na Homolce--results after 5 years]. / První rok provozu Leksellova gama noze v Nemocnici na Homolce--5 let poté.

The first Leksell gamma knife procedure was performed in Prague on 26th October 1992 and during the first year 156 patients were treated at the department of stereotactic and radiation neurosurgery. 42% patients suffered from a vascular lesion, 39% of patients from a benign tumour and 19% patients from a malignant tumour. Radiosurgery using the gamma knife is a non-invasive stereotactic neurosurgical procedure. Radiosurgery, as microsurgery, must be evaluated not only early, but also the late effect after the treatment some years. Evaluation of the results is therefore an ongoing process and results of the first year with the 5-year follow up are presented. At this time radiosurgery has a zero treatment mortality and the present morbidity with regard to the diagnosis 0-10%.

[The Leksell gamma knife--a radiosurgery instrument]. / Lekselluv gama nuz--radiochirurgický nástroj.

Radiosurgery means delivery of a single dose of precisely directed ionizing radiation to a small volume of intracranial tissue without opening of the skull after the stereotactic localisation of the preselected target. Leksell gamma knife is a device enabling to deliver focused radiation toward the intracranial volume with the gamma rays emitted by the 201 sources of the isotope Co 60. Suitable indications for radiosurgery are cerebral arteriovenous malformations, benign and malignant intracranial tumors and functional diseases of the brain.

[Use of the radiosurgery knife in the treatment of hypophyseal adenomas]. / Uplatnení radiochirurgie gama nozem pri lécení adenomu hypofýzy.

BACKGROUND. Surgery of pituitary adenomas did not produce quite satisfactory results. Therefore radiosurgery using Leksell's gamma knife has become the most widely used method which-with the contribution of MRI-meets the most important demands of aimed irradiation: a sufficiently high dose of radiation of the tumour and minimal radiation load of functionally important surrounding structures. The objective of the investigation was to assemble experience with this therapeutic method. METHODS AND RESULTS. During the period between October 1992 and September 1994 a total of 41 patients were treated: 16 men, 12-66 years old, mean age 40.8 years; 25 women age 16-76 years, mean age 50.2 years. Female:male ratio 1.5 : 1. In 30 patients (73.2%) a microsurgical operation had preceded, in 5 (12.2%) conventional fractionated radiotherapy and in 11 patients (26.9%) primary radiosurgery. As far as the type of pituitary adenoma is concerned, it conditioned acromegaly in 30, Cushing's syndrome in 3 or Nelson's syndrome in 1, or a prolactinoma was involved (in 2 patients). In five instances the adenoma was hormonally inactive. Its localization was most frequently intrasellar (36), less frequently parasellar (5). The range of administered doses varied as regards the maximum between 12.5 and 80 Gy, the average being 46.8 Gy, to the periphery of the adenoma a dose of 10-49 Gy was administered, on average 24.7 Gy using a 50-80% isodose. The time interval after treatment is relatively short for detailed analysis or evaluation. During current evaluation the authors did not observe in any of the patients progression of the disease, and in several patients diminution of the tumour was found. Karnofski's score seemed to improve. CONCLUSIONS. Radiosurgery, using Leksell's gamma knife, is after failure of conservative and microsurgical therapeutic possibilities suitable further treatment of pituitary adenoma. In indicated cases it may be the first choice. Postirradiation follow up indicates promising effects, for more detailed evaluation a several years' interval is necessary.