Bodo Lippitz

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 Parkinsons 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 Parkinsons 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.

Cytokine patterns in patients with cancer: a systematic review

Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types, but owing to the heterogeneity of cancer theories of common reaction mechanisms seem to be obsolete. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor β (TGFβ), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4). Clinical data were analysed in a non-quantitative descriptive manner and interpreted with regard to experimentally established physiological cytokine interactions. The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFβ. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12-interferon-γ-HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patients prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer.

Bilateral Chronic Electrostimulation of Ventroposterolateral Pallidum

: 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 Parkinsons 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 Parkinsons 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.

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 Parkinsons 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 Parkinsons disease with severe hypokinesia, speech and gait disturbances, and on-off phenomenon have been globally improved by a bilateral chronic stimulation of the pallidum.

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.

Stereotactic radiosurgery in the treatment of brain metastases: The current evidence

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.

Long-term Tumor Control of Benign Intracranial Meningiomas After Radiosurgery in a Series of 4565 Patients

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.

Anti-Tumour TreatmentStereotactic radiosurgery in the treatment of brain metastases: The current evidence

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.

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.

Standardization of terminology in stereotactic radiosurgery: Report from the Standardization Committee of the International Leksell Gamma Knife Society: special topic.

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.