Spinal cord compression by catheter granulomas in high-dose intrathecal morphine therapy: case report.

OBJECTIVE AND IMPORTANCE: The use of chronic intrathecal morphine for the treatment of intractable, nonmalignant pain is becoming more prevalent. A rare but devastating complication of this therapy is the development of spinal cord compression secondary to the formation of intrathecal granulomas. CLINICAL PRESENTATION: We report three cases of intrathecal granuloma formation in the thoracic subarachnoid space, associated with intrathecal morphine pumps. These three patients were receiving high doses of morphine to control their pain (25 mg/d, 28 mg/d, and 45 mg/d, respectively) when they presented with signs and symptoms of thoracic spinal cord compression. Myelography and postmyelographic computed tomography of the spine revealed masses causing spinal cord compression. INTERVENTION: Two patients underwent thoracic laminectomies for resection of these masses, and the other patient had the intrathecal catheter removed. A pathological examination revealed sterile granulomas in the resected masses. CONCLUSION: Intrathecal granulomas are likely to occur with increasing frequency as the use of chronic intrathecal morphine delivery increases in patients with nonmalignant pain. The cause of intrathecal granulomas is unknown, although it is likely that morphine plays a major role in their formation. We think that those patients receiving high doses of morphine are at greater risk for developing this complication.

Neurosurgery at the University of Michigan.

Neurosurgery at the University of Michigan was established as a specialty three-quarters of a century ago by Max Minor Peet. It developed under the successive leadership of Edgar Allan Kahn, Richard Coy Schneider, and Julian T. Hoff. Each has made unique contributions to the program, which has a strong tradition of teaching, research, and patient care. This article traces the development of the training program in neurosurgery at Michigan, focusing on its historical background, past accomplishments, present structure, and future directions.

3D laser scanning for image guided stereotactic neurosurgery.

While this work is in its very early stages, the 3D laser scanner shows significant promise as a surgical localization device with advantages over other sensing methods. Accurate 3D surface extraction and matching, a central problem in computer vision, is the key to frameless stereotaxic neurosurgery using this technique.

Late local and remote structural changes after capsulotomy for obsessive compulsive disorder.

Stereotactic subcaudate capsulotomy (SC) is used to treat medically intractable obsessive compulsive disorders (OCD). Although clinical improvement has been observed, post-SC structural correlates are lacking in this biological disorder. Our study provides imaging evidence for local and distant alterations in structures which may have an important role in the manifestations of OCD. Five OCD patients treated with SC received MR imaging for pre-SC planning, early (1-7 days) post-SC assessment, and late (5-12 months) follow-up. The volumes of the anterior limb of the internal capsules, caudate heads, third ventricle, mamillary bodies, thalami, and hippocampal formations were digitally computed. Volumes from each of the serial imaging studies were compared. At 5-12 months post-SC, all patients showed reduction in volume of the anterior limbs of the internal capsules, caudate heads, thalami, and increased volume of the third ventricle (reflecting thalamic/caudate atrophy). 2-5 patients showed reduction in hippocampal formation volume. The post-SC reduction in volume of these structures, some far distant to the stereotactic lesion, suggests that the interrelationships of the anterior limb of the internal capsule, the caudate/thalamic nuclei, and possibly the pallidal and limbic systems are necessary for the manifestations of OCD and their variants.

Stereotactic localization using fast spin-echo imaging in functional disorders.

Fast Spin-Echo Magnetic Resonance Imaging facilitates multiplanar target and trajectory selection in functional disorders by rapidly delineating gray matter, white matter, vascular, and ventricular structures. Errors due to anatomic variation or co-existing lesions can be avoided as are movement artifacts. Although not a substitute for physiologic target corroboration, the method facilitates safety and efficacy of "functional" stereotactic procedures.

Distribution of [32P]-chromic phosphate colloid in cystic brain tumors.

To suppress cyst formation in 42 brain tumors, 32P has been stereotactically instilled in doses calculated to deliver 20,000-40,000 rad to the cyst wall, assuming uniform dispersal of the radioisotope. However, samples of cyst fluid obtained at varying intervals after injection showed lower than expected activity levels, suggesting early 'plating' of 32P. To accommodate this phenomenon, a surface-area-dependent dosimetric calculation is compared with a volume-dependent calculation which assumes uniform dispersal. These two approaches represent lower and upper extremes. It appears that in small cysts there is less difference in the required administered dose, but in larger cysts potentially very large differences exist and caution should be exercised if uniform suspension is assumed.

Products of cells from gliomas: VIII. Multiple-well immunoperoxidase assay of immunoreactivity of primary hybridoma supernatants with human glioma and brain tissue and cultured glioma cells.

To test the feasibility of primary screening of hybridoma supernatants against human glioma tissue, over 5000 combinations of hybridoma supernatants with glioma tissue, cultured glioma cells, and normal central neural tissue were screened with a new multiple-well (M-well) screening system. This is an immunoperoxidase assay system with visual endpoints for screening 20-30 hybridoma supernatants per single microscope slide. There were extensive differences between specificities to tissue and to cultured glioma cells when both were screened with M-wells and when cultured cells were screened with standard semi-automated fluorescence. Primary M-well screening with glioma tissue detected seven hybridoma supernatants that specifically identified parenchymal cells of glioma tissue and that were not detected with cultured cells. Immunoreactivities of individual supernatants for vascular components (nine supernatants), necrosis (five supernatants), and nuclei (three supernatants) were detected. Other supernatants bound multiple sites on glioma tissue and/or subpopulations of neurons and glia of normal tissue. The results show that primary screening with glioma tissue detects a number of different specificities of hybridoma supernatants to gliomas not detected by conventional screening with cultured cells. These are potentially applicable to diagnosis and therapy.

Management of anteriorly located C1-C2 neurofibromata.

The authors discuss their recent experience with anteriorly located C1-C2 neurofibromata in five patients with cervical myelopathy and magnetic resonance scans consistent with intradural extramedullary masses in this region. Surgery was performed using a posterolateral approach with microscopic intradural exploration. Gross total intradural tumor removal was achieved in all cases. Improvement in cervical myelopathy occurred in all patients. This report concludes that C1-C2 neurofibromata located anterior to the spinal cord can be totally and safely removed using a posterolateral approach. Improvement in neurologic dysfunction accompanies posterior decompression and gross total intradural tumor removal.

Direct stereotactic intracerebral injection of monoclonal antibodies and their fragments: a potential approach to brain tumor immunotherapy.

Delivery of monoclonal antibodies (Mab) to brain tumors is restricted by the blood:brain barrier. To circumvent this problem, we studied direct stereotactic injection of the Mab into the brain. An anti-melanoma intact Mab and its Fab fragments, which do not react with normal rat brain, were radioiodinated and injected either intracerebrally (IC) or intravenously (IV) into rats. At 5 days after injection, IC delivery of intact antibody was 101 times higher than IV delivery. The ratio of radioantibody in injected cerebrum:blood was 14:1. With IC delivered Fab fragments, the radioantibody ratio in injected cerebrum:blood was 242:1 at 5 days after IC injection, with a 680-fold delivery advantage over IV injection. These data demonstrate a dramatic regional delivery advantage for intact Mab and especially for Fab fragments injected directly into the brain. This route of Mab delivery may have therapeutic potential for brain tumors.

Visual outcome in cystic craniopharyngiomas treated with intracavitary phosphorus-32.

Seven patients with cystic craniopharyngiomas were treated with stereotactic instillation of radioactive phosphorus-32 (32P). Five patients had been previously treated with various combinations of surgery and external beam irradiation, whereas two had the 32P instillation at a primary therapy. Visual acuity improved in 13 eyes and remained stable in 1. Visual fields normalized in three patients, improved in two, and remained stable in two. Two patients received single treatments with 32P, whereas five required multiple instillations for recurrent cyst expansion.

From manual to 3-D computerized treatment planning for 125-I stereotactic brain implants.

Aspects of planning for the treatment of high grade primary or recurrent brain tumors with stereotactically placed catheters afterloaded with high activity 125-I seeds are discussed. At our institution, planning has evolved from a simple manual process, which assumed geometric symmetry, through a more advanced manual process, that took advantage of certain mechanical properties of the stereotactic frame used, into a sophisticated, computerized planning approach that includes optimization of the source distribution and 3-D displays. Use of the simple manual method is limited to the rare situations where target volumes are quite regular in shape. The advanced manual method provides some customization for irregularly shaped volumes, but is slow and tedious to implement. The interactive, computerized approach permits identification of target volumes directly on CT slices, reconstructions in arbitrary planes, and optimization of catheter placement, source separation along each catheter, and selection of source strengths from an available inventory. A multi-format display feature which includes a probe's eye view perspective is provided to aid in planning. Integral dose-volume histograms for the target volume point out the advantages in using sophisticated, 3-D, computerized planning systems for these implants.

Thallium-201 tumor/cardiac ratio estimation of residual astrocytoma.

Treatment of high-grade astrocytoma includes surgery, chemotherapy, and various methods of irradiation. Radiation therapy usually results in necrosis and edema around the primary tumor site. Contrast-enhanced computerized tomography (CT) and standard radionuclide imaging techniques are unable to reliably distinguish recurrent tumor from necrosis or edema since these images depict localization of contrast material or tracer, which primarily depends on blood-brain barrier breakdown. Thallium-201 (201Tl) appears to incorporate into viable tumor cells more rapidly than into normal brain cells. This report describes a new method to quantify the uptake of 201T1 in the tumor: the tumor-to-cardiac uptake ratio (T/C). Twenty-three 201T1 brain scans were performed on eight patients to differentiate recurrent viable high-grade astrocytoma from posttherapy changes. Planar images of the head and heart were obtained in order to calculate the ratio of tumor counts to cardiac counts. This ratio represents a numerical estimation of 201T1 uptake in the brain tumor relative to cardiac counts and is expressed as the T/C index. The T/C index correlated well with the clinical course in all eight patients. In general, however, CT suggested more extensive regrowth of tumor than the actual clinical status suggested. In one patient's course of radiological monitoring, tumor recurrence was detected by means of 201T1 imaging four months prior to its appearance on CT. In conclusion, when performed serially, the T/C index can provide an accurate estimate of residual tumor burden or recurrence, and detect and quantify viable tumor during therapy.

Products of cells cultured from gliomas. VI. Immunofluorescent, morphometric, and ultrastructural characterization of two different cell types growing from explants of human gliomas.

Explants derived from human gliomas have been characterized with respect to their cellular outgrowth pattern after 1-22 weeks in culture. A mat of cells which were fibronectin (FN)-positive and glial fibrillary acidic protein (GFAP)-negative (hereafter designated FN+ cells) with a polygonal, flat morphology covered the growth substrate in a swirling pattern for a mean diameter of 9.2 mm around FN+ explants. FN+ cells showed ruffled plasmalemma, dilated rough endoplasmic reticulin (RDR), and extracellular filamentous strands. Rare desmosomes were compatible with at most minor leptomeningeal components or differentiation. FN+ cells predominated in six of seven cultures at passage 2, and their features were the same from various high-grade gliomas and gliosarcoma. Around other explants, elongated or stellate cells which were GFAP+ and FN- grew in a netlike pattern with little cell-to-cell contact. These GFAP+ cells surrounded explants at a mean diameter of 2 mm, substantially less than FN+ cells (P less than 0.005), and they grew more slowly than FN+ cells around explants. GFAP+ cells had an area/perimeter ratio which was less than that of FN+ cells. GFAP+ cells contained abundant intracellular filaments, rare desmosomes, and narrow RER cisternae. In mixed explants, GFAP+ cells often grew on top of FN+ cells. Individual cells which stained for both GFAP and FN were evident only from one glioma (8% doubly positive). Cells negative for both proteins resembled FN+ cells morphologically. Frozen sections of original glioma tissue showed FN+ vessel walls and GFAP+ parenchyma. Results are evidence for very early overgrowth of a preexistent FN+ cell type distinct from the GFAP+ parenchymal cell. The features of this distinct cell type are mesenchymal and resemble the proliferating vascular elements of gliomas in situ. The tendency for GFAP+ cells to grow on top of these FN+ cells suggests a feeder layer interaction. More knowledge of the origins and interactions of these two cell types may increase our understanding of the mechanism of antigenic changes in gliomas and may provide clues to improved therapeutic approaches.

Products of cells cultured from gliomas. V. Cytology and morphometry of two cell types cultured from glioma.

Explants of cells of a human glioma were evaluated with the nuclear fluorochrome 4',6-diamidino-2-phenylindole, by phase-contrast illumination, and by Giemsa staining correlated with double immunofluorescence for glial fibrillary acidic protein (GFAP) and fibronectin (FN). FN-positive (FN+) cells lacked GFAP detectable by immunofluorescence. Their mean nuclear-to-cytoplasmic ratio was large (0.192). Actual mean areas of nuclei (1,252 microns2) and cytoplasm (8,376 microns2) of FN+ cells compared with mean areas of fibroblasts suggested that the high nuclear-to-cytoplasmic ratio of FN+ cells was due to their microscopically evident reduced cytoplasmic spreading rather than to larger nuclei. Some FN+ cells showed marked variation in nuclear and nucleolar size and shape. Others had abnormal mitoses or hyperchromatic nuclei. GFAP-positive (GFAP+) cells lacked FN detectable by immunofluorescence. GFAP+ cells were smaller and less round than FN+ cells. Their usual location was growing on a layer of FN+ cells. The mean nuclear-to-cytoplasmic ratio (0.245) of GFAP+ cells was the highest in the study, surpassing the ratio of the continuous glioma line LM (0.176). Mean areas of nuclei (289 microns2) and of cytoplasm (1,350 microns2) of GFAP+ cells suggested that their high nuclear-to-cytoplasmic ratio was due to their microscopically evident reduced cytoplasmic spreading. Reduced spreading was associated with extension of long, thin cytoplasmic processes. The majority of GFAP+ cells showed marked cytoplasmic basophilia, nuclear hyperchromasia, and clumped chromatin. Features observed in both FN+ and GFAP+ cells from this high-grade astrocytoma are features associated with malignant transformation in more thoroughly studied tumor systems.

Treatment of cystic astrocytomas with intracavitary phosphorus 32.

Cyst formation by astrocytomas can cause progressive neurological deficit and can necessitate multiple surgical procedures. Before the advent of computed tomography (CT) preoperative diagnosis of cystic astrocytomas was difficult and stereotactic management of these lesions was limited. CT-guided stereotaxy provides a safe approach to all cystic astrocytomas including brain stem lesions. Based upon the experience of intracavitary radiation of craniopharyngioma cysts, the authors treated nine patients presenting with cystic astrocytomas utilizing colloidal chromium phosphorus 32 (32P). Control of cyst formation was achieved in eight patients. Our preliminary data suggest that intracavitary 32P may provide a significant adjunctive therapy in the management of cystic astrocytomas.

Phosphorus-32 therapy of cystic Grade IV astrocytomas: technique and preliminary application.

Instillation of [32P]chromic phosphate to cystic brain tumors was performed in six patients. Three patients had craniopharyngioma, two had Grade IV astrocytoma and one had Grade II astrocytoma. The cyst volumes ranged from 2 to 44 cc. A calculated dose of 20,000 rad was delivered to the cyst wall. The [32P]chromic phosphate dose given to achieve this dose ranged from 0.11 mCi to 2.5 mCi. Radionuclide leakage was not detected in either the central nervous system or the reticuloendothelial system by bremsstrahlung scanning. Stereotactic instillation was done in some cases, others had indwelling catheters. The frequency of cyst fluid aspiration in the three patients with craniopharyngioma decreased postinstillation. In the two patients with Grade IV astrocytoma, reductions in both the CT documented cyst size as well as the frequency of cyst aspiration were noted. We conclude that [32P]chromic phosphate installation by stereotactic or indwelling catheter method is a safe and helpful procedure in the management of cystic brain tumors.

Benefit from and tolerance to continuous intrathecal infusion of morphine for intractable cancer pain.

A patient with painful bilateral metastatic lumbosacral plexopathy from cervical cancer was treated with levorphanol tartrate (Levo-Dromoran), 4 mg orally every 4 hours, with poor pain relief. A lumbar subarachnoid catheter was then placed percutaneously. A bolus of 1 mg of morphine gave complete pain relief for 17 hours. Over the next week, the dose requirement increased to 10 mg/day, infused by an external pump. A permanently implantable infusion pump with a 50-cc drug chamber and flow rate of 3.4 cc/day was placed in the abdomen and attached to the lumbar subarachnoid catheter. The pump was refilled by percutaneous injection. Morphine was infused continuously at 15 mg/day, affording the patient increased mobility and no pain for 7 days. When the pain returned, the morphine dose was increased to 17.5 mg/day, and the patient was allowed to take oral Levo-Dromoran for pain. The intrathecal morphine dose was constant within 2-week periods, but was increased from 17.5 to 96 mg/day because of inadequate pain relief. Oral Levo-Dromoran intake averaged 3.4 mg/day. Levo-Dromoran intake was less during the 1st week of each 2-week cycle than the last week (mean 15.0 versus 38.0 mg/wk, p less than 0.05). No sedation or respiratory depression was seen.