H.-J. Reulen

Technical Principles for Protoporphyrin-IX-Fluorescence Guided Microsurgical Resection of Malignant Glioma Tissue

Summary Malignant gliomas accumulate fluorescing protoporphyrin IX intracellularly after exposure to 5-aminolevulinic acid, a metabolic precursor of haem. This phenomenon has been exploited for intra-operative identification of residual tumour to enable greater completeness of tumour removal. The present report describes the necessary modifications to the operating microscope to enable microsurgical, fluorescence-guided tumour removal. The system consists of a xenon light source coupled to the microscope, which can be switched from normal white light to violet-blue excitation light (375–440 nm). A longpass filter is introduced into the observer light path to enable observation of tumour fluorescence. Transmission characteristics of excitation and observation filters are chosen to transmit part of the remitted excitation light. Thereby the observer retains an impression of tissue detail, next to tumour porphyrin fluorescence. An integrating three chip CCD camera optimized for red light detection enables documentation of fluorescence findings. The present modifications allow uncomplicated and rapid recognition of red tumour fluorescence and its borders to normal tissue, without interrupting the course of the operation. Tissue detail is great enough to enable tumour resection under violet-blue excitation light during parts of the operation. The system appears to constitute a useful tool for optimizing removal of malignant gliomas on a routine basis.

In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid

Several malignant tissues synthesize endogenous porphyrins after exposure to 5-aminolevulinic acid (5-ALA). The present experiments have been designed to elucidate whether the C6 glioma cell, a model cell for human malignant glioma, similarly synthesizes porphyrins when exposed to 5-ALA, and whether specific synthesis occurs when C6 cells are inoculated into rat brains to form a tumor. In this situation the blood-brain barrier may interfere with 5-ALA availability, and spreading of porphyrins with edema outside the tumor may occur. Flow cytometry is used to determine the course of cell volume and porphyrin fluorescence intensities in cultured C6 cells which are incubated in 1 mM 5-ALA. For the induction of experimental brain tumors, 10(4) untreated C6 cells are inoculated into the brains of rats. After 9 days animals receive 100 mg 5-ALA/kg body weight. Brains are removed after 3, 6, or 9 h and frozen coronal sections obtained for H/E staining or fluorescence spectography. Cultured C6 cells show a linear increase of protoporphyrin IX fluorescence after exposure to 5-ALA, which begins to plateau after 85 min. Marked fluorescence is also observed in solid and infiltrating experimental tumor. However, faint fluorescence also occurs in normal tissue, basal pia, choroid plexus, and, more obviously, in white-matter tracts bordering the tumor (maximal distance: 1.5 +/- 0.7 mm). The observations demonstrate that C6 cells synthesize protoporphyrin IX after exposure to 5-ALA in vitro and in vivo. However, when utilizing 5-ALA for fluorescence detection or photodynamic therapy of brain tumors, attention should be paid to the possibility of protoporphyrin IX occurring outside the tumor.

Cavernous Haemangiomas of the Spinal Cord. A Review of 117 Cases

 The data of 48 studies (published between 1903 and 1996), presenting information of all together 107 patients (108 lesions) regarding pre-treatment clinical and radiological factors, treatment strategies, and the outcome, plus our own experience of nine patients were retrospectively re-analyzed. The prognostic influence of pre-treatment factors was estimated with the chi-square statistics. Clinical evaluation before/after treatment was performed using the Frankel scale. The average bleeding rate was obtained from the ratio of percentage of first bleeding events in the population to the mean age of the population. There were 47 males and 69 females (aged from twelve to 88 years). Thirty nine percent of the lesions were found in the cervical, 54% in the thoracic (30% upper, 24% lower) and 7% in the lumbar cord. The peak age of presentation was in the fourth decade, the median duration of symptoms was 32 months. Clinical symptoms before treatment were progressive in all cases. Three patterns of clinical presentation could be identified: a) episodes of stepwise clinical deterioration (30%), b) slow progression of neurological decline (41%), c) acute onset with rapid or gradual decline over weeks or months (26%). 58% of the lesions showed clinical or radiological signs of haemorrhage. In 66% of surgical patients (91 efficiently documented cases), clinical improvement was achieved, 28% remained unchanged and 6% deteriorated. Whereas age, sex and lesion location had no influence on the results, duration of symptoms (<three years) correlated significantly to a better outcome (p<0.02). Surgical management in symptomatic patients is recommended. Once clinical signs caused by the malformation have appeared, the patients tend to experience progressive neurological deterioration.

Preoperative activation and intraoperative stimulation of language-related areas in patients with glioma

OBJECTIVE Evaluation of the accuracy of preoperative localization of language-related cortex by magnetic resonance imaging-guided positron emission tomography. METHODS Patients with gliomas in the left dominant hemisphere were examined preoperatively with magnetic resonance imaging-guided positron emission tomography and intraoperatively by electrical stimulation of cortex. RESULTS A verb generation task yielded more intense and better lateralized local increases of cerebral blood flow in the positron emission tomographic examination than did a naming task. Significant correspondence of preoperative and intraoperative findings was observed for the verb generation task. Cortical sites with aphasic disturbance during electrical stimulation had a significantly higher cerebral blood flow increase during preoperative activation than did sites without intraoperative language impairment. Areas with cerebral blood flow increases above an optimum threshold had 73% sensitivity and 81% specificity to predict aphasic disturbance during intraoperative stimulation. CONCLUSION The data suggest that with further technical improvements, imaging of language function may become a preoperative diagnostic tool for patients with tumors close to language-related brain structures.

Safe surgery of lesions near the motor cortex using intra-operative mapping techniques : a report on 50 patients

SummaryIn 50 patients lesions located in or adjacent to the motor strip were microsurgically removed with the help of intra-operative electrophysiological mapping of the sensorimotor cortex. Mapping consisted of cortical stimulation and/or recording of somatosensory evoked potentials. Depending on the patients pre-operative neurological status, surprisingly good results could be achieved: The surgery resulted in increased permanent sensorimotor deficit in only 4% of cases and in improved neurological status in 30% of cases.It is concluded that surgical removal of centrally located lesions using a microsurgical technique and intra-operative mapping of the motor cortex is safe and permits extensive or radical resection of lesions, even those in the motor cortex itself.

The Risk of Haemorrhage after Image Guided Stereotactic Biopsy of Intra-Axial Brain Tumours – A Prospective Study

Summary Objective. To analyze prospectively the frequency and the risk of symptomatic and asymptomatic haemorrhage after image guided stereotactic biopsy of intra-axial brain tumours. Methods. The study was conducted within a time frame of 24 months (April 1998–April 2000). 326 patients (150 males, 176 females; mean age 56.8 years) were included and 345 computerized tomography (CT)-guided stereotactic biopsies were performed/supervised by a specialized stereotactic neurosurgeon. A modified Riechert Stereotaxy System and a workstation for multiplanar trajectory planning were used in all patients. Serial biopsies (median, 5 samples) were done with small forceps (diameter 1 mm), smear preparations of the biopsy specimens were intra-operatively examined. Frequency, size, and location of any detectable bleeding were analyzed by post-biopsy CT-scan investigation. For risk estimation, logistic regression analysis was performed. The chi-square statistic was used for comparative analysis of the study results with available data from the literature. Results. A conclusive tissue diagnosis could be achieved in 98%. Overall treatment morbidity was 3.1%. There was no mortality. Haemorrhage related morbidity was 0.9%. Age, Karnofsky score, mass effect of the tumour, tumour histology, tumour location and the number of specimens taken did not have any prognostic significance. The clinically silent bleeding rate was 9.6% and more often seen in patients with high grade gliomas (p=0.03). Both the silent and non-silent bleeding rate were significantly lower as compared to available prospective data in the literature. (p<0.01). Conclusion. Using multiplanar image guided trajectory planning, small biopsy forceps and intra-operative smear preparations the risk of major haemorrhage related morbidity after stereotactic brain tumour biopsy is extremely low (<1%) in experienced hands.

Fluorescence-guided resections of malignant gliomas — an overview

Radical resections of contrast-enhancing tumour in patients with malignant gliomas may be pertinent for survival but are often difficult to achieve due to uncertainties in distinguishing tumour margins intra-operatively. In this respect a number of novel methods are being examined which aim at enhancing resections. Among these methods, resections that exploit the accumulation of fluorescent porphyrins within malignant glioma tissue in response to exogenous administration of a metabolic percursor, 5-aminolevulinic acid, may offer particular advantages. This article summarises the clinical background and current status of 5-ALA drug development for fluorescence-guided resections of malignant gliomas and analyses the available literature with regard to possible mechanisms that govern the highly specific accumulation of fluorescent porphyrins in malignant glioma tissue in response to 5-ALA administration.

Clinical Outcome of Supratentorial Astrocytoma WHO Grade II

Summary Objective. There are divergent opinions about the prognostic value of the extent of surgery and of different histological subtypes in supratentorial astrocytomas WHO grade II. Methods. We reviewed 75 consecutive patients (36 females, 39 males) with supratentorial astrocytomas WHO grade II (59 primary and 16 recurrent tumours) operated on between 1991 and 1995. Results. Gross total resection could be achieved in 40 astrocytomas, subtotal resection (including biopsy) was performed in 35 cases. Histological assessment confirmed 60 fibrillary, 6 gemistocytic, 9 oligo-astrocytic and no protoplasmic astrocytomas. There were no postoperative deaths. Early outcome 6 to 12 weeks after surgery according to the Glasgow Outcome Scale was good in 46 patients, 24 patients had moderate, and 5 had severe neurological deficits. Survival rates 1, 2, 3, and 4 years following surgery were 100%, 96%, 96%, 96% for patients who underwent gross total tumour resection and 86%, 77%, 77%, 64% for patients with subtotal tumour resection. The cumulative recurrence or progression rates after 4 years were 26% after gross total resection and 80% after subtotal resection, and this result is statistically significant. Recurrences after gross total resection or progressions after subtotal resection occurred more often in gemistocytic astrocytomas (40% and 100%, respectively) than in other subtypes. Dedifferentiation to a more malignant tumour seems to be more prominent in the gemistocytic subtype. Conclusion. Gross total resection should be the leading therapeutic option for patients with astrocytomas WHO grade II. For the gemistocytic subtype further studies will have to prove whether additional radiotherapy is of any benefit.

Locoregional radioimmunotherapy in selected patients with malignant glioma: experiences, side effects and survival times.

AbstractPrognosis of malignant glioma is very unfavourable mainly due to minimal tumour remnants in the peritumoural tissue. Intralesionally applied radioimmunotherapy is a possible therapeutical option with the potential to improve survival of patients with malignant glioma. We investigated side effects and survival after surgery, conventional radiotherapy and additional radioimmunotherapy with labelled tenascin-antibodies in patients with malignant glioma. Methods: Since 1995, 37 patients were treated with radioimmunotherapy after resection and radiotherapy of a malignant glioma. Patients received antibodies labelled with yttrium-90 and iodine-131 in different doses into the tumour cavity via a previously implanted ommaya-reservoir. Treatment was applied in up to 8 cycles (mean 2.96 cycles) in time intervals of 6–8 weeks. Mean age was 46 years, histology was anaplastic astrocytoma in 13 patients and glioblastoma in 24 patients. Results: For the whole group median survival time has not yet been reached. For glioblastoma the median survival time is 17 months, 5-year survival probability for anaplastic astrocytoma is 85% approximately. Quality of life was acceptable. Acute side effects following treatment were headache, seizures and worsening of pre-existing neurological symptoms. Late side effects were skin necrosis and, in 1 case, a delayed aphasia probably due to a vascular lesion. Conclusion: Radioimmunotherapy prolonged survival time in a selected group of patients with malignant gliomas as compared to a historical control group. Patients with anaplastic astrocytomas seem to have more benefit from this therapy than patients with glioblastomas.

Transcallosal Interforniceal-Transforaminal Approach for Removing Lesions Occupying the Third Ventricular Space: Clinical and Neuropsychological Results

OBJECTIVE The present study was undertaken to describe the clinical and prospective neuropsychological results for our group of 30 patients who were treated using a transcallosal interforniceal-transforaminal microsurgical approach. METHODS The transcallosal interforniceal and transcallosal-transforaminal approaches were used to treat 30 patients with space-occupying lesions located in the anterior part of the third ventricle. We used a modified anterior transcallosal microsurgical approach, as described recently. The patients underwent extensive, pre- and postoperative, prospective neuropsychological testing, using a specially designed test battery. RESULTS Twenty-three of 30 patients (77%) experienced excellent clinical outcomes (Glasgow Outcome Scale Grade V). The surgical procedures described in this report did not themselves impair attentional function. In both the early and late postoperative neuropsychological testing sessions, deficits in verbal memory were only rarely observed and were not noted to be correlated with the surgical procedures. The most relevant neuropsychological results for individual patients are reported in detail. CONCLUSION The approach described here can be successfully used for the resection of various space-occupying lesions in the anterior part of the third ventricle. The anatomic landmarks we recently defined and described (for example, the midline vessel on the trunk of the corpus callosum, to direct the callosotomy) guide the surgical path. Furthermore, we recommend the use of neuropsychological test batteries for both scientific and rehabilitative purposes.