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In May 1968, Lars Leksell and Erik-Olof Backlund achieved a pioneering breakthrough by performing the first Gamma Knife radiosurgery (GKRS) on a craniopharyngioma (CP). Today, more than 50 years later, this patient remains under continuous monitoring, providing the longest documented follow-up of a GKRS-treated CP. This case report provides a complete record of the patient's preoperative presentation, surgical assessment, GKRS, and an extensive long-term follow-up with multiple interventions. The investigation involved analysis of archived and digitalized patient records and radiological images. The patient was a 21-year-old female who presented with amenorrhea and low levels of gonadotropins. Pneumoencephalography showed a calcified 2 × 2.5 cm mass located in the suprasellar region, indicative of a CP. Subsequent stereotactic puncture confirmed a predominantly solid nature of the CP. Given the size and composition of the tumor, the surgical team opted for GKRS. Dose planning was performed manually, with coordinates determined using Leksell's stereotactic frame. The tumor was targeted with a total dose of 50 Gy using 179 beams of 60 Co. Over the subsequent 55 years, the patient underwent radiological and clinical follow-ups. Throughout this period, 4 cystic tumor recurrences occurred and were managed by stereotactic puncture and Yttrium-90 instillation radiotherapy. The solid component remained stable without repeated GKRS. The patient suffered lateral quadrant anopsia and endocrinological deficits, necessitating pharmaceutical intervention. Despite these challenges, the patient is still living an active life at age 76 years. This case stands as historic evidence of long-term safety and efficacy of GKRS for CPs., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

In December of 2016, a Consensus Conference on unruptured AVM treatment, involving 24 members of the three European societies dealing with the treatment of cerebral AVMs (EANS, ESMINT, and EGKS) was held in Milan, Italy. The panel made the following statements and general recommendations: (1) Brain arteriovenous malformation (AVM) is a complex disease associated with potentially severe natural history; (2) The results of a randomized trial (ARUBA) cannot be applied equally for all unruptured brain arteriovenous malformation (uBAVM) and for all treatment modalities; (3) Considering the multiple treatment modalities available, patients with uBAVMs should be evaluated by an interdisciplinary neurovascular team consisting of neurosurgeons, neurointerventionalists, radiosurgeons, and neurologists experienced in the diagnosis and treatment of brain AVM; (4) Balancing the risk of hemorrhage and the associated restrictions of everyday activities related to untreated unruptured AVMs against the risk of treatment, there are sufficient indications to treat unruptured AVMs grade 1 and 2 (Spetzler-Martin); (5) There may be indications for treating patients with higher grades, based on a case-to-case consensus decision of the experienced team; (6) If treatment is indicated, the primary strategy should be defined by the multidisciplinary team prior to the beginning of the treatment and should aim at complete eradication of the uBAVM; (7) After having considered the pros and cons of a randomized trial vs. a registry, the panel proposed a prospective European Multidisciplinary Registry.

Object: This report has been prepared to ensure more uniform reporting of Gamma Knife radiosurgery treatment parameters by identifying areas of controversy, confusion, or imprecision in terminology and recommending standards., Methods: Several working group discussions supplemented by clarification via email allowed the elaboration of a series of provisional recommendations. These were also discussed in open session at the 16th International Leksell Gamma Knife Society Meeting in Sydney, Australia, in March 2012 and approved subject to certain revisions and the performance of an Internet vote for approval from the whole Society. This ballot was undertaken in September 2012., Results: The recommendations in relation to volumes are that Gross Target Volume (GTV) should replace Target Volume (TV); Prescription Isodose Volume (PIV) should generally be used; the term Treated Target Volume (TTV) should replace TVPIV, GTV in PIV, and so forth; and the Volume of Accepted Tolerance Dose (VATD) should be used in place of irradiated volume. For dose prescription and measurement, the prescription dose should be supplemented by the Absorbed Dose, or DV% (for example, D95%), the maximum and minimum dose should be related to a specific tissue volume (for example, D2% or preferably D1 mm3), and the median dose (D50%) should be recorded routinely. The Integral Dose becomes the Total Absorbed Energy (TAE). In the assessment of planning quality, the use of the Target Coverage Ratio (TTV/ GTV), Paddick Conformity Index (PCI = TTV2/[GTV · PIV]), New Conformity Index (NCI = [GTV · PIV]/TTV2), Selectivity Index (TTV/PIV), Homogeneity Index (HI = [D2% –D98%]/D50%), and Gradient Index (GI = PIV0.5/PIV) are reemphasized. In relation to the dose to Organs at Risk (OARs), the emphasis is on dose volume recording of the VATD or the dose/volume limit (for example, V10) in most cases, with the additional use of a Maximum Dose to a small volume (such as 1 mm3) and/or a Point Dose and Mean Point Dose in certain circumstances, particularly when referring to serial organs. The recommendations were accepted by the International Leksell Gamma Knife Society by a vote of 92% to 8%., Conclusions: An agreed-upon and uniform terminology and subsequent standardization of certain methods and procedures will advance the clinical science of stereotactic radiosurgery.

Objective: The current study retrospectively assessed delayed gamma knife radiosurgery (GKRS) in the management of high-grade glioma recurrences., Methods: A total of 55 consecutive patients with high-grade glioma comprising 68 World Health Organization (WHO) III and WHO IV were treated with GKRS for local recurrences between 2001 and 2007. All patients had undergone microsurgery and radiochemotherapy, considered as standard therapy for high-grade glioma. Complete follow-up was available in all patients; median follow-up was 17.2 months (2.5-114.2 months). Median tumor volume was 5.2 mL, prescription dose was 20 Gy (14-22 Gy), and median max dose was 45 Gy (30-77.3 Gy)., Results: The patients with WHO III tumors showed a median survival of 49.6 months with and a 2-year survival of 90%. After GKRS of the recurrences, these patients showed a median survival of 24.2 months and a 2-year survival of 50%. The patients with WHO IV tumors had a median survival of 24.5 months with a 2-year survival of 51.4%. After the recurrence was treated with GKRS, the median survival was 11.3 months and a 2-year survival: 22.9% for the WHO IV patients., Conclusion: The current study shows a survival benefit for high-grade glioma recurrences when GKRS was administered after standard therapy. This is a relevant improvement compared with earlier studies that had had not been able to provide a beneficial effect timing radiosurgery in close vicinity to EBRT., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chemotherapy has made substantial progress in the therapy of systemic cancer, but the pharmacological efficacy is insufficient in the treatment of brain metastases. Fractionated whole brain radiotherapy (WBRT) has been a standard treatment of brain metastases, but provides limited local tumor control and often unsatisfactory clinical results. Stereotactic radiosurgery using Gamma Knife, Linac or Cyberknife has overcome several of these limitations, which has influenced recent treatment recommendations. This present review summarizes the current literature of single session radiosurgery concerning survival and quality of life, specific responses, tumor volumes and numbers, about potential treatment combinations and radioresistant metastases. Gamma Knife and Linac based radiosurgery provide consistent results with a reproducible local tumor control in both single and multiple brain metastases. Ideally minimum doses of ≥18Gy are applied. Reported local control rates were 90-94% for breast cancer metastases and 81-98% for brain metastases of lung cancer. Local tumor control rates after radiosurgery of otherwise radioresistant brain metastases were 73-90% for melanoma and 83-96% for renal cell cancer. Currently, there is a tendency to treat a larger number of brain metastases in a single radiosurgical session, since numerous studies document high local tumor control after radiosurgical treatment of >3 brain metastases. New remote brain metastases are reported in 33-42% after WBRT and in 39-52% after radiosurgery, but while WBRT is generally applied only once, radiosurgery can be used repeatedly for remote recurrences or new metastases after WBRT. Larger metastases (>8-10cc) should be removed surgically, but for smaller metastases Gamma Knife radiosurgery appears to be equally effective as surgical tumor resection (level I evidence). Radiosurgery avoids the impairments in cognition and quality of life that can be a consequence of WBRT (level I evidence). High local efficacy, preservation of cerebral functions, short hospitalization and the option to continue a systemic chemotherapy are factors in favor of a minimally invasive approach with stereotactic radiosurgery., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Radiosurgery is the main alternative to microsurgical resection for benign meningiomas., Objective: To assess the long-term efficacy and safety of radiosurgery for meningiomas with respect to tumor growth and prevention of associated neurological deterioration. Medium- to long-term outcomes have been widely reported, but no large multicenter series with long-term follow-up have been published., Methods: From 15 participating centers, we performed a retrospective observational analysis of 4565 consecutive patients harboring 5300 benign meningiomas. All were treated with Gamma Knife radiosurgery at least 5 years before assessment for this study. Clinical and imaging data were retrieved from each center and uniformly entered into a database by 1 author (A.S.)., Results: Median tumor volume was 4.8 cm³, and median dose to tumor margin was 14 Gy. All tumors with imaging follow-up < 24 months were excluded. Detailed results from 3768 meningiomas (71%) were analyzed. Median imaging follow-up was 63 months. The volume of treated tumors decreased in 2187 lesions (58%), remained unchanged in 1300 lesions (34.5%), and increased in 281 lesions (7.5%), giving a control rate of 92.5%. Only 84 (2.2%) enlarging tumors required further treatment. Five- and 10-year progression-free survival rates were 95.2% and 88.6%, respectively. Tumor control was higher for imaging defined tumors vs grade I meningiomas (P < .001), for female vs male patients (P < .001), for sporadic vs multiple meningiomas (P < .001), and for skull base vs convexity tumors (P < .001). Permanent morbidity rate was 6.6% at the last follow-up., Conclusion: Radiosurgery is a safe and effective method for treating benign meningiomas even in the medium to long term.

A dose gradient index (GI) is proposed that can be used to compare treatment plans of equal conformity. The steep dose gradient outside the radiosurgical target is one of the factors that makes radiosurgery possible. It therefore makes sense to measure this variable and to use it to compare rival plans, explore optimal prescription isodoses, or compare treatment modalities. The GI is defined as the ratio of the volume of half the prescription isodose to the volume of the prescription isodose. For a plan normalized to the 50% isodose line, it is the ratio of the 25% isodose volume to that of the 50% isodose volume. The GI will differentiate between plans of similar conformity, but with different dose gradients, for example, where isocenters have been inappropriately centered on the edge of the target volume. In a retrospective series of 50 dose plans for the treatment of vestibular schwannoma, the optimal prescription isodose was assessed. A mean value of 40% (median 38%, range 30-61%) was calculated, not 50% as might be anticipated. The GI can show which of these prescription isodoses will give the steepest dose falloff outside the target. When planning a multiisocenter treatment, there may be a temptation to place some isocenters on the edge of the target. This has the apparent advantage of producing a plan of good conformity and a predictable prescription isodose; however, it risks creating a plan that has a low dose gradient outside the target. The quality of this dose gradient is quantified by the GI.

Radiosurgery is considered one of the most revolutionary recent developments in the therapy of certain intracranial tumors. It is generally accepted that radiosurgery with the Gamma Knife or stereotactic Linac is the least invasive effective treatment for cerebral metastases. The Gamma Knife provides so far the highest possible and practically applicable precision of radiation. Radiosurgery of brain metastases with a size of less than 12 cm3 results in excellent local tumor control rates and very low associated morbidity. The Gamma Knife has been shown to be highly effective also against multiple metastases and is likewise effective even for tumors that are relatively resistant to traditional external beam radiation therapy. Radiosurgery replaces open tumor operation in some indications. As an additive therapy it allows the conventional surgeon to operate less radically resulting in a lower complication rate. The goal is short hospitalization time and increased quality of life.

Object: The purpose of this study was to assess the long-term treatment efficacy and morbidity of patients who undergo gamma knife radiosurgery (GKS) for craniopharyngioma., Methods: Twenty-one consecutive Swedish patients were evaluated retrospectively: 11 children (< or = 15 years) and 10 adults. The time from diagnosis to the most recent follow-up imaging study was 6.3 to 34.3 years (mean 18.2 years, median 16.8 years). Tumor volumes and morbidity from GKS or other treatments were assessed at the time of the most recent imaging study or at the time of a subsequent new treatment. The observation period ranged from 0.5 to 29 years (mean 7.5 years, median 3.5 years). The prescription dose ranged from less than 3 Gy to 25 Gy. The mean tumor volume was 7.8 cm3 (range 0.4-33 cm3). There were 22 tumors in 21 patients treated with GKS. Five of these tumors were reduced in size, three were unchanged, and 14 increased. Tumor progression correlated with a low dose to the tumor margin. Eleven (85%) of 13 tumors that received a dose of less than 6 Gy to the margin increased in size, whereas only three (33%) of nine tumors that received 6 Gy increased. This difference was statistically significant (p = 0.01). In five of six patients tumors that became smaller after GKS there were no recurrences within a mean follow-up period of 12 years. Nine (82%) of 11 tumors in children ultimately increased after GKS, compared with five (50%) of 10 in adults. In eight patients there was a deterioration of visual function. In all except one this could be related to a volume increase but radiation-induced damage could not be excluded as a factor in any of them. Four patients developed pituitary deficiencies., Conclusions: Gamma knife radiosurgery is effective in controlling growth of craniopharyngiomas with a minimum dose of 6 Gy. The findings also suggest that other stereotactic techniques, such as cyst aspiration and intracystic treatment, are only of value in reducing tumor volume in preparation for safe GKS.

Objective: To investigate whether angiograms obtained 2 years after radiosurgery, proving total arteriovenous malformation (AVM) occlusion, represent the final state of treated AVMs and adjacent normal vessels., Methods: Angiograms were obtained for 48 patients 5 to 24 years after gamma knife radiosurgery and 4 to 17 years after the AVMs had been proven to be totally occluded after the treatment; changes in normal vessels and signs of recanalization were recorded. Ten of the patients developed clinical symptoms attributable to the AVMs or the treatment after having been declared cured, whereas the other patients did not exhibit symptoms., Results: There was evidence of AVM nidi at the sites of previously occluded AVMs for two patients and of nidi adjacent to those sites for another two patients. Three of the four recurrent AVMs were associated with hemorrhaging. All patients who experienced hemorrhaging from previously occluded AVMs were < or = 14 years of age at the time of gamma knife radiosurgery. There were signs of segmental narrowing in normal vessels that had been irradiated with high doses (nine patients) or a low dose (one patient). The segmental narrowing decreased with time for four of these patients, was unchanged for four, and increased for two. These vascular changes did not produce clinical symptoms in any of the patients., Conclusion: There is a small possibility that AVMs may reappear after having been totally occluded after radiosurgery, especially in pediatric patients. Segmental narrowing in normal arteries after radiosurgery is a benign condition that rarely progresses and does not produce clinical symptoms.

The fiber structure in the anterior limb of the internal capsule was investigated in a region where stereotactic lesions (anterior capsulotomy) result in successful treatment of obsessive-compulsive disorder (OCD). Eight human hemispheres were sectioned in comparable planes parallel to the ACPC plane. Microscopic slices were labeled with DiI and analyzed with confocal laser and polarized light microscopy. Three distinct systems of fibers were detected. Single fibers run from the caudate nucleus to the lentiform nucleus. The anterior thalamic peduncle connects the mediodorsal and partially the anterior thalamic nucleus with the frontal lobe. The frontopontine tract system connects the frontal lobe with the pons. This fiber tract occupies 38% of the anterior limb and is arranged in small bands. Right-left comparison of morphometric parameters of these bundles demonstrated that more and smaller bundles were located on the left-hand side than on the right-hand side. Tendencies for this configuration were noticeable in all brains investigated, with statistical significance in one brain. These morphological differences correlate with functional differences, as it was possible to demonstrate right hemispheric dysfunctions in cases of OCD. The benefit of anterior capsulotomy in OCD is generally seen in the interruption of fronto-basal ganglia-thalamic loops by disconnecting the anterior thalamic peduncle. In addition, the frontopontine fiber tract is disconnected in this stereotactic procedure.

Objectives: Obsessive-compulsive disorder is a common mental disorder, notorious for its chronicity and intractability. Stereotactic lesions within the anterior limb of the internal capsule have been shown to provide symptomatic relief in such refractory cases, but only few systematic evaluations have correlated anatomic lesion location with individual postoperative outcome., Patients and Methods: Between 1976 and 1989, extremely disabled and otherwise intractable patients with a chronic deteriorating clinical course of obsessive-compulsive disorder underwent bilateral thermocapsulotomy (n = 22) or radiosurgical gamma knife capsulotomy (n = 13) at the Karolinska Hospital, Stockholm. Clinical morbidity was monitored prospectively pre- and postoperatively by using standardized psychiatric rating scales. In 29 patients (thermocapsulotomy, n = 19; gamma knife capsulotomy, n = 10), both psychiatric and magnetic resonance imaging follow-up data (median, 8.4 yr) were available., Results: A right-sided anatomically defined lesion volume was identified in all successfully treated patients. This common topographic denominator was defined in the approximate middle of the anterior limb of the internal capsule on the plane parallel to the anterior commissure-posterior commissure line at the level of the foramen of Monro and 4 mm above on the plane defined by the internal cerebral vein. This region was unaffected in patients with poor outcomes. On the left side, no particular lesion topography was associated with clinical outcome. Topographic differences of lesion overlap between good and poor outcome groups were significant for the right side (Fisher's exact test, P < 0.005)., Conclusion: The current anatomic long-term analysis after thermocapsulotomy or gamma knife capsulotomy for obsessive-compulsive disorder reveals common topographic features within the right-sided anterior limb of the internal capsule independent of treatment modality.

Objective: To our knowledge, this is the first long-term follow-up study of high-dose single-session irradiation to the human brain and provides new data concerning late tissue reactions after irradiation to small target volumes. The long-term lesional brain changes in 14 patients subjected to bilateral gamma knife capsulotomy for otherwise intractable anxiety disorders were retrospectively analyzed by magnetic resonance imaging., Methods: The prototype gamma unit was used for the radiosurgical procedure, and the collimators provided rectangular cross-sectional fields with an anteroposterior diameter of 3 mm and a transverse diameter of 5 or 11 mm. Maximum target doses were 120 to 180 Gy. Magnetic resonance imaging was performed 15 to 18 years (mean, 17 yr) after treatment, and dose-volume histograms were calculated for the dose distributions., Results: One patient had been irradiated twice on one side. In all but one of the remaining 27 targets, lesions with a volume of less than 100 mm3 were revealed by magnetic resonance imaging. The volumes of the lesions were confined within the volume corresponding to a minimum dose of approximately 110 Gy, with one exception. In one of three targets receiving a maximum dose of 120 Gy, no lesion was detected. There were no late radiation effects such as cyst formations, telangiectasias, hemorrhagic infarctions, or neoplasms., Conclusion: This investigation indicates that a minimum dose of 110 Gy, with the currently used 4-mm collimator, to the edge of the target volume is required to create a lesion. The results prove that gamma knife surgery can be used in functional neurosurgery for producing small permanent lesions in the normal human brain.

Considerable but uncontrolled evidence suggests that stereotactic capsulotomy by means of thermolesions may provide symptomatic relief for patients with otherwise therapy refractory "malignant" obsessive compulsive disorder (OCD). Unlike in other functional stereotactic interventions, target localization for capsulotomy is based upon anatomical definition only. Few systematic attempts have been made to correlate the site and size of the capsular lesions with postoperative clinical outcome. Between 1976 and 1989 bilateral thermo-capsulotomy (TC) was performed in 22 OCD patients. In 19 patients complete quantitative pre- and postoperative psychiatric rating of OCD symptoms and long-term postoperative MRI studies were available. Cohorts of patients fulfilling criteria for good or poor outcome were contrasted, cases with intermediate treatment effect being excluded. Median postoperative MRI follow-up was 8.4 years (2.4-20.3 y). 9/19 patients fulfilled criteria for good postoperative outcome. In these patients all lesion sites overlapped covering a small area within the right anterior limb of the internal capsule. Lesions within the group of patients with poor outcome (n = 5) were located elsewhere, mostly further anterior in the internal capsule. Differences of lesion overlap between the two outcome groups were significant for the right side (Fisher's Exact Test: p < 0.005). Common topographic features of lesion sites within the right internal capsule were identified in OCD patients responding favourably to capsulotomy.

The current study analyses the long-term clinical course of 12 patients with pineal germinomas. The histological diagnosis was established by stereotactic biopsy in all cases. In 11 of the 12 cases the diagnosis was correct. There was no operative mortality or morbidity. All patients were treated by external radiotherapy. The median follow-up period for the surviving patients is 5.9 years (range 4.5-8.8 years). After radiotherapy, CT and MRI follow-up examinations showed complete tumor remissions with no local tumor recurrences in all cases. Two patients died of other, unrelated, illnesses 1.4 and 5.8 years after diagnosis of the pineal germinoma. Since long-term survival and morbidity do not document any superiority of operative resection of germinomas, the minimally invasive approach with stereotactic biopsy and radiotherapy is strongly advocated. There is no longer any justification for irradiating pineal tumors to check the diagnosis now that stereotactic biopsy is available.

The glucose metabolism of 62 meningiomas was measured by fluorine -18-2-fluorodeoxyglucose (FDG) PET and correlated with proliferation rate (Ki-67 index) and tumor cellularity. The mean metabolic rate (MRGlu) for meningiomas was 0.26 +/- 0.13 mikromol/g/min (range 0.08-0.62 mikromol/g/min). The relative tumor FDG-uptake (Q-MRGlu) (tumor/contralateral cortex) of all meningiomas was calculated with 0.73 +/- 0.37 (0.24-1.79). Differences of Q-MRGlu were significant between the groups with high vs. low cellularity (p < 0.01), increased vs. normal proliferation rate (p < 0.025) and low (WHO grade I) vs. higher (WHO grades II, III) graded tumors. In recurrent meningiomas (14 tumors) the glucose metabolism was not increased. The data show that 18 FDG-PET is suitable to serve as non-invasive predictor of tumor growth characteristics in meningiomas.

Due to its constant glial morphology and small variability as to tumor location and growth characteristics, the intracerebral D-54MG tumor xenograft provides the predictability and reproducibility needed by models for the study of stereotactic interstitial radiotherapy. Development and results of experimental brachytherapy in an intracerebral human gliomas derived xenograft tumor model are reported. Tumor homogenate prepared from homogenized subcutaneous D-54MG xenografts was inoculated into the frontal lobe of athymic BALB/c mice (nu/nu genotype). The D-54MG glioma xenografts grew at the site of inoculation without intraventricular or subarachnoid spread. The increase of median survival (IMS) was 58.33% for the highest dose (9370 cGy) and 33.3% for the intermediate dose (5654 cGy). In both experiments the survival prolongation was statistically significant (p < 0.05) as calculated by the Log Rank Rest for Kaplan Meier Survival Distributions. In the low dose group (3159 cGy) only a small and not significant IMS was achieved (16.67%). The results of the present investigation demonstrate the accuracy of the stereotactic operative procedure and the efficacy of experimental intracerebral interstitial radiotherapy with I 125 seeds. Using a constant dose rate, experimental interstitial brachytherapy in brain-tumor bearing nude mice was shown to result in a dose dependant survival prolongation for the treated animals. The model may help to optimize the rational basis of clinical brain tumor therapy and is well suited to simulate dose and dose rate related therapeutic effects.

The global improvement of all parkinsonian symptoms after stereotactic pallidotomy has been demonstrated by Leksell. Recently, Laitinen, re-evaluating this target in the neurosurgical treatment of Parkinson's disease, confirmed the real value of this approach, and emphasized the necessity of locating the lesion in the ventroposterolateral part of the pallidum internum. Because we know that high-frequency stimulation of the ventrolateral part of the thalamus has the same clinical effect on tremor as high-frequency coagulation, this technique has now been applied bilaterally in one session in three patients who have severe Parkinson's disease, with akinesia and levodopa-induced dyskinesias in the foreground. The very satisfactory clinical results, up to 12 months in the first case, confirm the observation of Laitinen, but with the difference that the approach discussed here is both nondestructive and reversible, and unwanted side effects are avoided.

62 intracranial meningiomas in 60 patients were studied with 18FDG-PET prior to neurosurgery in order to evaluate the relationship between 18FDG uptake and biological aggressiveness of the tumors. Histopathological grading, cellular density, Ki-67 proliferation index and evidence of chromosomal aberrations were used to assess tumor aggressiveness. Significantly elevated 18FDG uptake was found in grade 2- and 3- compared to grade 1-meningiomas, in tumors of high cellularity compared with those of low cellularity, and in meningiomas with an elevated Ki-67 proliferation index (above 2%). The two meningiomas with the most pronounced chromosomal aberrations revealed the highest 18FDG uptake of all cytogenetically studied meningiomas. We conclude that 18FDG-PET is useful for estimating the biological aggressiveness of intracranial meningiomas.

Since 1982, we have been able to control involuntary movements associated with deaf-ferentation by means of chronic electrical stimulation of the thalamic sensory nucleus through implanted programmable neuropacemakers. Since 1987, we have been using the same system with electrodes chronically implanted in the VL for treating selected cases of tremor due to Parkinson's disease, multiple sclerosis and in cases of essential tremor. In our series of 60 patients, suppression of tremor was achieved in almost all cases; however, due to dysarthria in 30% of the cases (cases after previous thalamotomy in the other side or with bilateral stimulation), the amplitude of stimulation was corrected and thus some tremor was still observed. The rigidity of parkinsonism was in all cases improved. One case of hemiballism was perfectly controlled with the same technique. Finally, 3 cases of Parkinson's disease with severe hypokinesia, speech and gait disturbances, and on-off phenomenon have been globally improved by a bilateral chronic stimulation of the pallidum.

Melphalan (L-phenylalanine mustard, L-PAM, alkeran; molecular weight, 305,000) is transported across tumor cell membranes and the blood-brain barrier by the large neutral amino acid (LNAA) transport system. Normally, plasma LNAA levels are high enough and the affinity low enough that this system does not transport much melphalan into the brain. However, plasma amino acids can be reduced by fasting and protein-free diet. We used this method to reduce competition and to increase melphalan transport into brain tumors. In nude mice fasted for 12 h and then fed a protein-free diet for 2 and 6 h, mean plasma LNAA levels were 46% and 42% of control values. Nude mice with xenotransplanted D-54MG human gliomas were used to study tissue distribution and uptake kinetics of [3H]melphalan in a control group and a diet group (after a 12-h fast and 2 h of a 0% protein diet). The K1 (blood-to-tissue transfer constant) of melphalan, determined by graphical analysis and by nonlinear fitting to a 2-compartment model, was higher in the diet group in all tumor regions except the necrotic center of subcutaneous tumors; the increase was significant in the tumor periphery of brain and s.c. tumors. The ratio of K1s (diet to control) varied from 1.2 to 1.3 in brain tumors, 1.9 to 2.1 in subcutaneous tumors, and 1.8 to 3.1 in tumor-free brain. The apparent [3H]melphalan distribution space was significantly higher in the tumor periphery of both brain and subcutaneous tumors of the 15- and 30-min diet group. We also measured blood-brain barrier transport of [alpha-14C]aminoisobutyric acid and blood flow (with [131I]iodoantipyrine): the K1 of [alpha-14C]aminoisobutyric acid was 28.1 +/- 6.6 (SE) in brain tumors and 24.3 +/- 8.9 microliters/g/min in subcutaneous tumors. Blood flow was 58.2 --> 3.9 in brain tumors and 5.2 +/- 0.4 ml/100 g/min in subcutaneous tumors. Fasting, when combined with a protein-free diet, reduces plasma amino acid levels and thereby reduces competition between melphalan and LNAAs. This may increase the amount of melphalan that can enter a brain tumor without increasing the administered drug dose and suggests a therapeutic manipulation that can be used to increase the delivery of melphalan.

It is always difficult to interpret abnormalities in pupillary reflexes when a patient who has suffered injuries to the upper part of the face is unconscious. Nevertheless, thorough examination of pupillary reflexes can provide vital information about possible damage to the central nervous system. Decisions about treatment of and prognosis for patients with multiple injuries can be made more accurately when the status of the nerves supplying the eye are taken into account. Anatomical and physiological relationships of pupillary reflexes and oculomotor reactions in a patient with multiple injuries are discussed.

In previous studies we demonstrated that administration of buthionine sulfoximine (BSO) to athymic BALB/c mice bearing intracranial human glioma xenografts resulted in highly selective depletion of glutathione in neoplastic tissue with minimal effects on contralateral normal brain tissue. In the present study we treated athymic BALB/c mice bearing intracranial human glioma (D-54 MG) or medulloblastoma (TE-671) xenografts with melphalan alone or BSO followed by melphalan. Administration of BSO depleted intracellular glutathione to 7.5% of the control level. BSO plus melphalan resulted in a significant increase in median survival over that produced by melphalan alone: 45.3% versus 26.4% in TE-671 and 69% versus 27.6% in D-54 MG. These studies justify further efforts to modulate chemotherapeutic and radiotherapeutic interventions of primary malignant brain tumors by depletion of glutathione.