Gamma knife radiosurgery for patients with multiple cerebral metastases.

Although efficacy of gamma knife radiosurgery has been demonstrated in numerous studies, the policies in patients with multiple metastases seem to be unequivocal. The maintained quality of life, the possibility of short hospitalization and the continuation of a systemic chemotherapy are increasingly important arguments in favor of a minimally invasive radiosurgical approach. These factors are particularly emphasized in patients with a dismal prognosis. The current retrospective analysis was undertaken to summarize the clinical results of radiosurgery in patients with multiple cerebral metastases of various primary cancer. Fractionated whole brain radiotherapy (WBRT) was omitted as prophylactic treatment and applied only in cases with general tumor spread. Clinical data of all consecutive patients (n = 215) who received gamma knife radiosurgery for cerebral metastases between January 2001 and January 2003 at the gamma knife Centers of the Karolinska Hospital and H.M. Queen Sophia Hospital (Sophiahemmet) Stockholm were analyzed retrospectively. 172 patients were treated for multiple metastases (198 treatments). The median prescription dose was 22 Gy (range 14-34 Gy). The Kaplan Meier plot shows a median survival (MST) of 7.8 months for patients with multiple cerebral metastases and 13.7 months for patients with single metastases. There was no relation between survival and number of metastases in patients with multiple metastases. Within this group 11.6% (20/172 patients) developed adverse radiation reactions. Tumor recurrences were documented by FDG-PET in 7 patients (out of 172 patients: 4.1%) after a median latency of 10 months after radiosurgery. In summary, gamma knife radiosurgery provides a highly effective and minimally invasive method to treat patients with multiple cerebral metastases even without prophylactic WBRT. Local control and patient survival in the present series of patients is in accordance with other retrospective series of patients with single and multiple metastases.

Subdural-atrial and subdural-peritoneal shunting in infants with chronic subdural fluid collections.

BACKGROUND: In symptomatic infants with chronic subdural fluid collections a variety of treatment strategies, such as observation, repeated subdural tapping, external or internal subdural drainage, and craniotomy have been advocated. Until now, the ideal management for this etiologically heterogenous group of children seems controversial. METHODS: The authors present their treatment with subdural-peritoneal and subdural-atrial shunts and the follow-up in 8 infants (mean age, 7 months) with bifrontal subdural hygromas and hematomas caused by different etiologic conditions. RESULTS: Initially, all children were symptomatic, and repeated subdural taps showed no clinical and neuroradiologic benefit. Shunting resulted in disappearance of all clinical signs in all infants, with complete removal of the chronic subdural fluid collections in 6 cases and remarkable improvement in 2 cases. In all infants the shunt system was removed after disappearance of signs and decrease of fluid collections. As the only complication the shunt system had to be removed in 1 case on the fourth postoperative day because of infection without any further disadvantages. In none of the cases was a recurrence of the fluid collections seen during the follow-up. CONCLUSION: These results suggest that in infants with symptomatic chronic subdural fluid collections who fail to respond to repeated tapping, the early placement of an unilateral subdural-peritoneal shunt with a low pressure valve represents a safe, benign, and effective treatment option.

Angiographic long-term follow-up data for arteriovenous malformations previously proven to be obliterated after gamma knife radiosurgery.

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.

Lesion topography and outcome after thermocapsulotomy or gamma knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere.

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.

Morphological asymmetry in anterior limb of human internal capsule revealed by confocal laser and polarized light microscopy.

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.

Radiosurgical lesions in the normal human brain 17 years after gamma knife capsulotomy.

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.

Obsessive compulsive disorder and the right hemisphere: topographic analysis of lesions after anterior capsulotomy performed with thermocoagulation.

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.

Cytogenetic analysis of gliomas by in situ hybridization of stereotactic biopsy material.

Chromosome analysis of brain tumours can provide important pathobiological data; however, cytogenetic tools are so far not routinely applied for diagnosis. In the present study 25 paraffin embedded stereotactic biopsies from 19 glioma patients were studied using in situ hybridization of chromosome #10 and #15 using biotinylated pericentromeric probes. Numerical changes of chromosome #10 are frequent alterations in glioblastoma. Quantification of chromosome #15 served as a control in order to exclude artificial monosomies or nonspecific changes. The number of chromosomes in at least 200 cells were counted for each specimen. 18 of 25 biopsies could be evaluated quantitatively. The small volume of probes was not a limiting factor for analysis. Quantification of "nonspecific" chromosome #15 revealed single spots in 22-41% of all cells in the 18 biopsies. Chromosome #10 showed single spots in a range between 34 and 44% of counted nuclei in 13/18 biopsies. In 5 out of 18 biopsies 51-60% monosomies were found: in this subgroup were 4 high grade gliomas. These cases were interpreted as monosomy of chromosome #10. The results demonstrate feasibility and quantitative evaluability of cytogenetic analysis in stereotactic biopsy material using in situ hybridization.

[Germinoma of the pineal area. Long-term follow-up after stereotaxic biopsy]. / Germinome der Pinealisregion. Langzeitverlauf nach stereotaktischer Biopsie.

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.

PET-study of intracranial meningiomas: correlation with histopathology, cellularity and proliferation rate.

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.

Monosomy 1p is correlated with enhanced in vivo glucose metabolism in meningiomas.

The 2-[18F]fluoro-2-deoxy-D-glucose (FDG) uptake of 25 human meningiomas was preoperatively evaluated in vivo by positron-emission tomography (PET). After surgery, meningioma biopsies were analyzed cytogenetically. Five meningiomas showed partial monosomy for chromosome 1p additional to other typical chromosome aberrations. This aberrant karyotype was correlated with increased FDG uptake. Three of five meningiomas with monosomy 1p were classified as grade II according to WHO, while only one of 20 tumors without monosomy 1p was classified as grade II. Thus, monosomy 1p and elevated FDG uptake in PET are to be regarded as cytogenetic and metabolic parameters for the aggressiveness of meningiomas.

A model for experimental interstitial radiotherapy using intracerebral D-54MG glioma xenografts in athymic mice.

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.

Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms.

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.

[18FDG-PET in intracranial meningiomas versus grading, proliferation index, cellular density and cytogenetic analysis]. / 18FDG-PET bei intrakraniellen Meningeomen versus Grading, Proliferationsindex, Zelldichte und zytogenetische Analyse.

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.

Chronic electrical stimulation of the VL-VPL complex and of the pallidum in the treatment of movement disorders: personal experience since 1982.

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.

Lysis of basal ganglia haematoma with recombinant tissue plasminogen activator (rtPA) after stereotactic aspiration: initial results.

In a series of 10 patients with stereotactically treated basal ganglia haematoma rtPA was used to dissolve remaining clots. Pre-operative haematoma volume ranged between 39 and 111 cm3 (average 56 cm3). Stereotactic aspiration alone yielded an average volume reduction of 60% (range 23 to 78%). Haematoma cavity was instillated with rtPA repeatedly beginning 24 hours after the stereotactic intervention. At the end of rtPA therapy between 2 and 4 days after onset of the haemorrhage 67 to 92% (average 84%) of the initial haematoma was removed in all patients. More than 80% of the pre-operative clot could be removed in 8 out of 10 patients between day 2 and 4. There were no signs of rtPA related toxicity. At the end of the follow-up period (between 4 and 17 months--mean 8 months) 6 patients were awake, oriented and with a residual hemiparesis able to live in their familiar environment. It is concluded that local rtPA instillation is an effective additional treatment to further resolution of deep seated intracerebral haematomas after stereotactic aspiration.

Effect of recombinant tissue plasminogen activator on clot lysis and ventricular dilatation in the treatment of severe intraventricular haemorrhage.

Twelve patients with severe intraventricular haemorrhage (IVH) underwent intraventricular thrombolysis with recombinant tissue plasminogen activator (rtPA). External ventricular drainage was performed in all patients within 24 hours of haemorrhage. Fibrinolytic therapy was started within 24 hours from the onset of symptoms in ten cases, and in two further cases after 48 hours and 5 days, respectively. Two to 5 mg of rtPA were injected via the ventricular catheter into one or both lateral ventricles. The injection was repeated at intervals ranging from 6 to 24 hours until CT scans demonstrated a substantial reduction of intraventricular blood. The total rtPA doses per patient ranged from 3 to 31 mg. CT scans showed a marked reduction of intraventricular blood and normalization of ventricular size within 24 to 48 hours from the beginning of the fibrinolytic therapy. Rapid reduction of elevated intracranial pressure by continuous diversion of cerebrospinal fluid could be achieved in all patients, because the ventricular catheters never became obstructed by clotted blood during the fibrinolytic therapy. During the period of treatment, the level of consciousness, as classified according to the Glasgow Coma Scale, improved from a mean value of 7 to 12. One fatal case of meningitis most probably due to the ventriculostomy was the only complication related to the treatment. This method of treatment might improve the prognosis in patients in whom a large intraventricular haematoma volume, ventricular dilatation, and impaired cerebrospinal fluid circulation are major determinants for the outcome.

Bilateral chronic subdural haematomas following traumatic cerebrospinal fluid leakage into the thoracic epidural space.

This report describes a patient who developed bilateral chronic subdural haematomas after a stab injury to the thoracic meninges causing prolonged cerebrospinal fluid leakage into the epidural space. Diagnostic findings and therapeutic management are presented and possible pathogenic mechanisms are discussed. This case suggests that patients who have symptoms or signs of increased intracranial pressure after a penetrating spinal injury should be studied for subdural haematoma.

The effect of an amino acid-lowering diet on the rate of melphalan entry into brain and xenotransplanted glioma.

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.