Determination of changes in tumor blood perfusion after hydralazine treatment by dynamic paramagnetic-enhanced magnetic resonance imaging.

Magnetic resonance imaging, using the paramagnetic chelate gadopentetate dimeglumine as a perfusing agent, was used to investigate the effect of the vasoactive drug hydralazine on tumor blood perfusion. The method requires measurements of the magnetic resonance image intensity changes with time on a pre-selected region of interest in the tumor image, immediately following intravenous injection of gadopentetate dimeglumine. The present study showed that the initial slope of the intensity-time curve can be used, to a first approximation, to infer tumor blood perfusion. With the dynamic imaging technique, it was demonstrated that, in the KHT sarcoma implanted intramuscularly in the hind leg of C3H/HeN mice, intraperitoneal administration of hydralazine reduced the volume-averaged tumor blood perfusion in a dose-dependent manner. The intrinsically high spatial resolution of magnetic resonance imaging allows a detailed study of the heterogeneous nature of tumor blood perfusion. The potential applications of this imaging technique to study the differential effects of hydralazine on perfusion between tumor and normal tissues will be discussed. The clinical utility of the technique should be promising because of its non-invasive nature.

Anaplastic astrocytoma with granular cell differentiation: case report and review of the literature.

In contrast to the relatively common soft tissue form of granular cell tumor (GCT), intercerebral GCTs are rare neoplasms. The Schwann cell is the accepted cell of origin for soft tissue GCTs. However, the origin of intracerebral tumors is controversial. We report a case of a GCT intimately associated with an anaplastic astrocytoma. Immunohistochemical staining with glial fibrillary acidic protein demonstrated focal positive staining within the granular cells. Six GCTs from other body sites were stained with glial fibrillary acidic protein for comparison and all were negative. The granular cell component was diffusely positive for S-100 and negative for epithelial membrane antigen and cytokeratin. Ultrastructurally, filaments characteristic of astrocytic cells were demonstrated within some granular cells. Based on our light microscopic, electron microscopic, and immunohistochemical findings, the granular cell component of this anaplastic astrocytoma is likely astrocytic in origin. We propose that these tumors be designated astrocytic neoplasms with granular cell differentiation and their prognoses dictated by the grade of the glial component.

A reservoir model for repeated CSF access in the rabbit.

A simple, reliable and inexpensive subcutaneously implanted reservoir-catheter system method was developed for repeated sterile access to the rabbit brain ventricular system. The system provides an avenue for the repeated intrathecal administration of drugs and for the withdrawal of cerebrospinal fluid (CSF). Reservoirs were subcutaneously implanted under the scalp and connected to tubing inserted into the cisterna magna or the lateral ventricle. The systems successfully functioned in 38 of 41 animals (12 with cisternal magna catheters and 29 with lateral ventricle catheters), for up to 12 weeks following implantation. Patency of the systems were documented with X-rays and radiopaque injected contrast medium.

Cost-effectiveness of long-term intrathecal morphine therapy for pain associated with failed back surgery syndrome.

A decision analytic study was conducted using computer simulation to project the outcomes in a simulated cohort of patients whose treatment for back surgery had failed. The objective of this study was to estimate the direct cost of intrathecal morphine therapy (IMT) delivered via an implantable pump relative to alternative therapy (medical management) over a 60-month course of treatment. IMT administered by way of an implantable pump can provide effective pain relief for selected patients whose less invasive treatment modalities have failed. Previous research suggested that a pump implant is less costly than alternative methods providing comparable analgesia for treatment exceeding 12 to 18 months. However, those analyses did not include the cost of complications or pump replacement. Scenarios representing the course of IMT, devised by a panel of experts, were represented as treatment pathways in a Monte Carlo simulation. Adverse event rates were drawn from published data supplemented by expert judgment. Direct costs were based on a health insurer paid claims perspective (direct costs) discounted at a 5% annual rate. The cost-effectiveness of IMT was calculated based on a report of 65% to 81% "good to excellent" pain relief relative to alternative (medical) management. With both adverse event probabilities and costs set at most likely (base case) values, the expected total cost of IMT over 60 months was $82,893 (an average of $1382 per month). In a sensitivity analysis, the best case (low adverse event rate, low cost) estimate was $53,468 ($891/mo), whereas the worst case (high adverse event rate, high cost) estimate was $125,102 ($2085/mo). Cost-effectiveness estimates ranged from $7212 (best case) to $12,276 (worst case) per year of pain relief. Results from a computer simulation designed to collect the costs not included in previous empiric research indicate that IMT appears to be cost-effective when compared with alternative (medical) management for selected patients when the duration of therapy exceeds 12 to 22 months.

Percutaneous retrogasserian glycerol rhizolysis for treatment of chronic intractable cluster headaches: long-term results.

OBJECTIVE: To analyze the long-term effectiveness and safety of percutaneous retrogasserian glycerol rhizolysis (PRGR) in the treatment of medically refractive chronic cluster headache (CH). The current mainstay of surgical intervention for these patients is percutaneous radiofrequency retrogasserian rhizotomy (PRFR). However, when performed for V1 distribution pathology, PRFR can lead to corneal anesthesia, which places the patient at risk for future visual loss. It also increases the risk of facial dysesthesia. METHODS: In a prospective, consecutive series, 18 patients with intractable CH were followed for a mean of 5.2 years (range, 40-78 mo) after they had undergone PRGR, performed using a standard technique. The significance of this technique as an alternative to PRFR is that it should result in a lower rate of both corneal and facial anesthesia and provide an acceptable degree of pain relief. RESULTS: Fifteen patients (83%) obtained immediate pain relief after one or two injections; the majority of them experienced relief after the first injection. CH recurred in seven patients (39%) over the course of the study. Two of these patients received a second injection, and both met with equal success. Two other patients underwent PRFR. Excluding those who underwent PRFR, the overall daily headache frequency decreased from 3.5 +/- 0.3 attacks per day preoperatively to 0.6 +/- 0.2 attacks per day at last follow-up. The severity of these headaches, as assessed by verbal pain scales, also decreased from 10 preoperatively to 4.4 +/- 1.4 at follow-up. None of the patients, including those who required a second procedure, experienced corneal anesthesia or facial dysesthesia. CONCLUSION: This study provides the first long-term evaluation of PRGR for the treatment of medically refractive chronic CH and lends support to both the safety and long-term efficacy of this procedure. Further investigations are needed to compare directly the relative efficacy and safety of PRGR and PRFR.

Brain tumor resection aided with markers placed using stereotaxis guided by magnetic resonance imaging and computed tomography.

In the operative resection of brain tumors, defining and locating edges of deep-seated tumors or those with indistinct color and consistency can be difficult. This report presents a simple yet precise, alternative method, using the basic Brown-Roberts-Wells or Cosman-Roberts-Wells stereotactic frame, for placement of visual markers to aid in tumor resections. The method can also be extended to the Leksell system. Using routine computed tomographic scanning or magnetic resonance imaging after stereotactic frame application, multiple points along tumor edges were used as target points. In the operating room, standard techniques were used for the skin incision, removal of the bone flap, and opening the dura. At each target point, after opening the dura and using stereotactic coordinates and equipment, a microbiopsy forceps was used to place "micropatties" (each with a string tail) or small catheters with pledgets or catheter tips located at tumor edges. After removing the arc, the tumor resection was accomplished in a conventional nonstereotactic manner by simply following string tails or catheters to the tumor. Gross tumor edges were determined from positions of actual patties or catheter tips. These simple but accurate techniques offer the possibility of tumor resections under stereotactic guidance with equipment readily available to most neurosurgeons. The fidelity of marker placement is also maintained in relation to tumor edges despite shifts in the tumor and/or brain as cystic areas are drained or large amounts of the tumor are resected.

Radiofrequency cingulotomy for intractable cancer pain using stereotaxis guided by magnetic resonance imaging.

This study presents a new and simplified method of creating cingulate gyrus lesions by using stereotaxis guided by magnetic resonance imaging (MRI). Previous methods have utilized ventriculogram-guided stereotaxis requiring indirect cingulate gyrus localization and general anesthesia. With the present technique a BRW stereotactic frame was applied with the patient under local anesthesia. An MRI scan was performed using a T1 signal (TR, 600 ms; TE, 30 ms) in the coronal plane with 5-mm thick sections spaced every 6 mm. The coronal slice 24 mm posterior to the anterior tip of lateral ventricle was identified. The center of each (right and left) cingulate gyrus was identified as a target area, and appropriate coordinates were determined. Approach parameters were calculated for the right and left gyri using an azimuth of 45 degrees and 315 degrees, respectively, and a declination of 45 degrees. A radiofrequency electrode was stereotactically placed so that the electrode tip was at a target point which was the center of the cingulate gyrus. A radiofrequency lesion (75 degrees, 60 seconds) was made in each hemisphere's cingulate gyrus. Four patients with intractable terminal cancer pain have been initially treated in this manner. The lesions were well-localized on postoperative MRI scans. There have been no complications except for perilesional edema for 10 days in 1 patient (treated with longer radiofrequency settings that have subsequently been modified).(ABSTRACT TRUNCATED AT 250 WORDS)

Sufentanil citrate and morphine/bupivacaine as alternative agents in chronic epidural infusions for intractable non-cancer pain.

Intraspinal narcotic (usually intrathecal morphine) infusions with implanted pumps are increasingly used in patients with intractable chronic pain not caused by cancer. In some patients, pain control is difficult with infusions of morphine. Seven patients with diagnoses of arachnoiditis, epidural scarring, and/or vertebral body compression fracture were treated with alternative solutions in an epidural route. For maximal flexibility, Medtronic implanted programmable infusion pumps with catheters to T6-T10 were used, and pain was monitored by verbal pain scales. In three patients, epidural infusions of morphine in 0.5% bupivacaine (MS-MARC) resulted in little or no pain relief without significant side effects (e.g., headache, nausea, or vomiting). In these same patients, epidural infusions of sufentanil citrate resulted in pain scale reductions of 92%, 82%, and 40%, respectively, with no side effects. Four other patients found more effective pain relief when switched from initial sufentanil citrate infusions to MS-MARC. Pain scale reductions (with no side effects) were 92%, 76%, 59%, and 47% in these patients. Pain relief and minimal side effects with sufentanil citrate is theorized to result from its higher lipophilicity promoting local transdural diffusion to spinal cord and limiting upward diffusion to the brain stem. Sufentanil citrate is also advantageous for programmable pumps because it is 100 times more potent than morphine and therefore allows longer pump refill times and higher infusion doses. Although this study was done on a limited number of patients, sufentanil citrate and MS-MARC in epidural infusions using programmable infusion pumps for non-cancer patients provide significant alternative drug combinations and routes.

Trigeminal cisternal injection of glycerol for treatment of chronic intractable cluster headaches.

Medical treatment of chronic cluster headaches (cluster headaches that occur frequently without remission) can be very difficult. In many patients, the pain remains severe despite all medication trials. For these patients, previous reports recommend radiofrequency trigeminal rhizotomy, which risks corneal anesthesia and subsequent corneal decompensation. As a safer, yet effective, treatment, retro-Gasserian injections of glycerol were given to eight patients having intractable chronic cluster headaches. Needle penetration into the trigeminal cistern, glycerol amount (0.55 ml), and length of patient elevation after the procedure (80-90 degrees upright for 10 h) were modified for maximal exposure of the V1 division. Three patients required one additional injection, and one patient required two additional injections. Verbal pain scales (means +/- 1 standard error of the mean) were: 9.1 +/- 0.30 (preoperative), 2.6 +/- 1.10 (1 mo postoperative), and 2.1 +/- 0.64 (1 yr postoperative). Daily headache frequency decreased from 6.0 +/- 2.0 (preoperative) to 0.2 +/- 0.09 (i.e., one headache every 5 days) (1 yr postoperative). Three of the eight patients had no headaches after 1 year. There were no instances of corneal or facial anesthesia. One year postoperatively, five patients required no medication, and three remained on low doses of medication for headache treatment. In contrast to previous limited reports of glycerol injections for cluster headaches, results with these patients having chronic cluster headaches support the use of glycerol injections as a viable treatment alternative, with significant pain relief and corneal safety.

Pallidotomy: a comparison of responders and nonresponders.

OBJECTIVE: We reviewed a prospective series of 32 unilateral, large-volume, microelectrode-guided posteroventral pallidotomies to determine the differences between responsive and nonresponsive patients. METHODS: Our patients underwent extensive pre- and postoperative evaluations. One year postoperatively, we correlated the outcomes of 25 patients with their histories, physical findings, neuropsychological assessments, and lesion characteristics to further understand the indications, limitations, and pitfalls of unilateral pallidotomy. Our group judged responsiveness by comparing the preoperative total Unified Parkinson's Disease Rating Scale off-state scores with those obtained 1 year postoperatively. A score indicating greater than 20% improvement at 1-year follow-up was rated a good outcome; improvement of greater than 40% was rated an excellent outcome. RESULTS: Although most patients sustained long-term benefits, some demonstrated little or no improvement. Patient and lesion factors influenced outcome. Younger age (<60 yr), tremor, unilateral predominance, L-dopa responsiveness, motor fluctuations with dyskinesia, and good lesion placement predicted a good response to unilateral pallidotomy. Advanced age (>70 yr), absence of tremor, increased duration of disease, reduced responsiveness to L-dopa, frontal behavioral changes, prominent apraxic phenomena, and improper lesion placement predicted a poor response. CONCLUSION: Unilateral, large-volume pallidotomy with precise lesion control provides long-lasting benefits for carefully selected patients.

Epidural and subarachnoid administration of opioids for nonmalignant pain: technical issues, current approaches and novel treatments.

As intraspinal opioid infusions are being offered to an increasing number of patients with chronic noncancer pain, technical considerations and complications have become important. For these technical considerations, there are points that are unclear and controversial and others that appear to be "minor" but, if missed, can lead to disastrous pump complications. Among the controversial areas are type of testing for a spinal infusion, method for needle placement in the spine, and type of pump. For the apparently minor considerations, important areas are attention to the method of puncture of the paraspinal fascia, anchoring of catheter, pump placement, and initial filling of the pump. As experience with these infusions is accumulated, and as the financial climate in medicine changes, the approaches to these techniques appear to be changing toward a general consensus. Recent scientific advances, both in newer analgesic substances and in innovative methods for intraspinal delivery of these substances, also are affecting these approaches.

Current practices in intraspinal therapy--a survey of clinical trends and decision making.

Practice patterns were assessed via an internet-based survey distributed to physicians who manage implantable infusion pumps for pain management. Respondents consisted of 413 physicians who represented management of 13,342 patients, predominantly in the U.S. The survey used a standard questionnaire format plus two clinical vignettes to assess decision-making practices. The responding physicians chose morphine most often, but many other drugs were selected without clear indications. There was evidence of wide variations in clinical practice among physicians who use this modality. These findings highlight the need for practice guidelines based on research outcomes and expert experience to establish pathways for optimal management.

Future directions in the management of pain by intraspinal drug delivery.

Management of pain by intraspinal delivery of drugs enables physicians to target specific sites of action. While this novel approach is gaining increasing use, well-designed studies are needed. A major limitation is the lack of published information on existing drugs used for intrathecal delivery. (The strengths and weaknesses of this information are reviewed in the accompanying literature review article.) Promising agents such as bupivacaine, hydromorphone, and morphine/clonidine combinations warrant further research in large prospective (ideally randomized and double-blind) clinical safety and efficacy studies. These studies may provide data for pain management guidelines, such as those included in the preceding paper. Research must also address issues of formulation, chemical stability/compatibility, pharmacokinetics, and toxicology during clinical development and drug approval. Finally, more basic studies and early phase trials of other potential agents for intrathecal pain management (e.g., gabapentin) are needed.

Long-term intraspinal infusions of opioids in the treatment of neuropathic pain.

Long-term intraspinal infusions of opioid drugs are being increasingly utilized in patients with noncancer pain. Despite this, there is a lack of long-term information, including success and failure rates for pain relief and technical problems. During a 5-year period, 18 noncancer patients underwent implantation of programmable infusion pumps for long-term intrathecal opioid infusion. Patients had (a) neuropathic pain, (b) had failed or been ineligible for noninvasive treatments, and (c) obtained greater than 50% pain relief with intrathecal trial infusions of morphine sulfate or sufentanil citrate. A disinterested third-party reviewer evaluated patients at the most recent follow-up. Sixty-one percent (11/18) of patients had good or fair pain relief with mean follow-up 2.4 +/- 0.3 years (0.8-4.7 years). Average numeric pain scores decreased by 39% +/- 4.3%. Five of the 11 responders required lower opioid doses (12-24 mg/day morphine) and the remaining six patients required higher opioid doses (> 34 mg/day morphine). Failure of long-term pain relief occurred in 39% (7/18) despite good pain relief in trial infusions and the use of both morphine and sufentanil. Technical problems developed in 6/18 patients but appeared to be preventable with further experience. Long-term intrathecal opioid infusions can be effective in treatment of neuropathic pain but might require higher infusion doses.

Clinical realities and economic considerations: economics of intrathecal therapy.

The estimated annual cost of medical management of chronic back pain is $25 billion. Such management is often ineffective and overly costly. Most physicians who have employed intrathecal pain therapy attest to its efficacy in the management of intractable chronic pain. However, few economic analyses are available to evaluate the cost effectiveness of different modalities and to aid in clinical decision making and third-party reimbursement policies. Current analyses tend to focus on short-term cost-benefit measurements and to ignore variables such as quality of life and patient functioning. This bias has impaired the ability of payers to make appropriate decisions regarding the safety, cost effectiveness, and efficacy of intrathecal pain therapy in noncancer patients. Clinical data demonstrate that for cancer patients whose expectancies exceed 3 months, the overall costs of intrathecal pain therapy may be less than those of tunneled epidural catheters or external infusion devices. In nonmalignant pain, intrathecal therapy appears to be cost effective compared to conventional medical management at 22 months. Further debate and fine tuning of these economic models from all perspectives are required.

Evidence-based review of the literature on intrathecal delivery of pain medication.

Evidence-based medicine depends on the existence of controlled clinical trials that establish the safety and efficacy of specific therapeutic techniques. Many interventions in clinical practice have achieved widespread acceptance despite little evidence to support them in the scientific literature; the critical appraisal of these interventions based on accumulating experience is a goal of medicine. To clarify the current state of knowledge concerning the use of various drugs for intraspinal infusion in pain management, an expert panel conducted a thorough review of the published literature. The exhaustive review included 5 different groups of compounds, with morphine and bupivacaine yielding the most citations in the literature. The need for additional large published controlled studies was highlighted by this review, especially for promising agents that have been shown to be safe and efficacious in recent clinical studies.

Clinical guidelines for intraspinal infusion: report of an expert panel. PolyAnalgesic Consensus Conference 2000.

Consensus guidelines developed by an expert panel are helpful to clinicians when there is variation in practice and lack of a firm evidence base for an intervention, such as intraspinal therapy for pain. An internet-based survey of practitioners revealed remarkable variation in practice patterns surrounding intraspinal therapy. This prompted an interdisciplinary panel with extensive clinical experience in intraspinal infusion therapy to evaluate the results of the survey, the systematic reviews of the literature pertaining to this approach, and their own clinical experience with long-term spinal infusions. The panel proposed a scheme for the selection of drugs and doses for intraspinal therapy, and suggested guidelines for administration that would increase the likelihood of a successful outcome. These expert panel guidelines were designed to provide an initial structure for clinical decision making that is based on the best available evidence and the perspectives of experienced clinicians.

Long-term results of peripheral nerve stimulation for reflex sympathetic dystrophy.

This prospective, consecutive series describes peripheral nerve stimulation (PNS) for treatment of severe reflex sympathetic dystrophy (RSD) or complex regional pain syndrome, in patients with symptoms entirely or mainly in the distribution of one major peripheral nerve. Plate-type electrodes were placed surgically on affected nerves and tested for 2 to 4 days. Programmable generators were implanted if 50% or more pain reduction and objective improvement in physical changes were achieved. Patients were followed for 2 to 4 years and a disinterested third-party interviewer performed final patient evaluations. Of 32 patients tested, 30 (94%) underwent permanent PNS placement. Long-term good or fair relief was experienced in 19 (63%) of 30 patients. In successfully treated patients, allodynic and spontaneous pain was reduced on a scale of 10 from 8.3 +/- 0.3 preimplantation to 3.5 +/- 0.4 (mean +/- standard error of the mean) at latest follow up (p<0.001). Changes in vasomotor tone and patient activity levels were markedly improved but motor weakness and trophic changes showed less improvement. Six (20%) of the 30 patients undergoing PNS placement returned to part-time or full-time work after being unemployed prestimulator implantation. Initial involvement of more than one major peripheral nerve correlated with a poor or no relief rating (p<0.01). Operative modifications that minimize technical complications are described. This study indicates that PNS can provide good relief for RSD that is limited to the distribution of one major nerve.

Constant infusion of morphine for intractable cancer pain using an implanted pump.

In the past, pain control for chronic pain syndromes using narcotic infusion has been carried out primarily via the intrathecal (subarachnoid) route. This report presents one of the first large series of terminally ill cancer patients with intractable pain treated with continuous epidural morphine infusions by means of implanted pumps and epidural spinal catheters. The purpose of the study was to demonstrate that the epidural route is effective with minimal complications, and that screening with temporary epidural catheter infusions results in a high rate of subsequent pain relief. A multidisciplinary team (neurosurgeon, anesthesiologists, psychiatrists, oncologists, and nurse clinicians) evaluated and treated all of the patients studied. Percutaneous placement of temporary epidural catheters for a trial assessment was performed by the anesthesiologists. Pain evaluations were conducted independently by psychiatrists using both verbal and visual analog scales. From 1982 to 1988, 41 (59.4%) of 69 patients evaluated for eligibility experienced good pain control during trial assessment and were subsequently implanted with Infusaid infusion pumps. Preinfusion pain analog values were 8.6 +/- 0.3 and postimplantation values at 1 month were 3.8 +/- 0.4 (p less than 0.001). Over this same 1-month period. requirements of systemic morphine equivalents decreased by 79.3% with epidural infusions as compared to preinfusion requirements (p less than 0.001). There were no instances of epidural scarring, respiratory depression, epidural infections, meningitis, or catheter blockage. One patient developed apparent drug tolerance and three patients required further catheter manipulations. This series strongly suggests that significant reductions in cancer pain can be obtained with few complications and a low morphine tolerance rate using chronic epidural morphine infusion. Anesthesiology and psychiatry input, along with temporary catheter infusion screening and quantitative pain evaluations using analog scales, are essential.

Surgery versus radiosurgery in the treatment of brain metastasis.

Surgery and radiosurgery are effective treatment modalities for brain metastasis. To compare the results of these treatment modalities, the authors followed 13 patients treated by radiosurgery and 62 patients treated by surgery who were retrospectively matched. Patients were matched according to the following criteria: histological characteristics of the primary tumor, extent of systemic disease, preoperative Karnofsky Performance Scale score, time to brain metastasis, number of brain metastases, and patient age and sex. For patients treated by radiosurgery, the median size of the treated lesion was 1.96 cm3 (range 0.41-8.25 cm3) and the median dose was 20 Gy (range 12-22 Gy). The median survival was 7.5 months for patients treated by radiosurgery and 16.4 months for those treated by surgery; this difference was found to be statistically significant using both univariate (p = 0.0018) and multivariate (p = 0.0009) analyses. The difference in survival was due to a higher rate of mortality from brain metastasis in the radiosurgery group than in the surgery group (p < 0.0001) and not due to a difference in the rate of death from systemic disease (p = 0.28). Log-rank analysis showed that the higher mortality rate found in the radiosurgery group was due to a greater progression rate of the radiosurgically treated lesions (p = 0.0001) and not due to the development of new brain metastasis (p = 0.75). On the basis of their data, the authors conclude that surgery is superior to radiosurgery in the treatment of brain metastasis. Patients who undergo surgical treatment survive longer and have a better local control. The data lead the authors to suggest that the indications for radiosurgery should be limited to surgically inaccessible metastatic tumors or patients in poor medical condition. Surgery should remain the treatment of choice whenever possible.