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.

A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival.

OBJECT: The extent of tumor resection that should be undertaken in patients with glioblastoma multiforme (GBM) remains controversial. The purpose of this study was to identify significant independent predictors of survival in these patients and to determine whether the extent of resection was associated with increased survival time. METHODS: The authors retrospectively analyzed 416 consecutive patients with histologically proven GBM who underwent tumor resection at the authors' institution between June 1993 and June 1999. Volumetric data and other tumor characteristics identified on magnetic resonance (MR) imaging were collected prospectively. CONCLUSIONS: Five independent predictors of survival were identified: age, Karnofsky Performance Scale (KPS) score, extent of resection, and the degree of necrosis and enhancement on preoperative MR imaging studies. A significant survival advantage was associated with resection of 98% or more of the tumor volume (median survival 13 months, 95% confidence interval [CI] 11.4-14.6 months), compared with 8.8 months (95% CI 7.4-10.2 months; p < 0.0001) for resections of less than 98%. Using an outcome scale ranging from 0 to 5 based on age, KPS score, and tumor necrosis on MR imaging, we observed significantly longer survival in patients with lower scores (1-3) who underwent aggressive resections, and a trend toward slightly longer survival was found in patients with higher scores (4-5). Gross-total tumor resection is associated with longer survival in patients with GBM, especially when other predictive variables are favorable.

The double-catheter technique for intrathecal medication trial: a brief technical note and report of five cases.

A method for intrathecal (IT) trials using a double-catheter technique is described. This technique involves placement of an IT and epidural catheter simultaneously. The rationale for this technique is the ability to treat a postdural puncture headache promptly should one develop during the trial.

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.

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.

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.

Stereotactic radiosurgery for brain metastases: results and prognostic factors.

This study was conducted to determine prognostic factors for tumor response and patient survival after stereotactic radiosurgery (SRS) for brain metastasis. Eighty-four patients with brain metastasis underwent SRS at a single institution. After fixation of the head with a stereotactic frame, computed tomography treatment planning was performed. The metastatic lesion was treated with multiple arcs to a median dose of 19 Gy. Forty-seven patients (56%) had a solitary brain lesion. Fifty-nine patients (70%) had evidence of extracranial disease at the time of SRS. The median survival duration from SRS was 7 months. Sixty-three percent of the patients had an objective radiographic response to SRS, which in turn was associated with superior central nervous system control. Age, collimator size, number of arcs, tumor location, and histology did not influence objective response rates. Patients who had a solitary lesion or who received treatment within 2 weeks after diagnosis were more likely to have an objective response than were those who did not (P < 0.05). Progressive brain disease accounted for 37% of the deaths. Nineteen patients (23%) had an in-field relapse. Four severe complications were attributed to SRS. This study confirms the role of SRS as an acceptable treatment option for patients with solitary or limited brain metastases. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 157-162 (2000).

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.

Cost modeling for alternate routes of administration of opioids for cancer pain.

The economic considerations relative to neuraxial infusion can be looked at with different types of economic models, including cost-minimization, cost-effectiveness, and cost-benefit analyses. A theoretical predictive model was developed about 2 years ago using a computer spreadsheet and based on four levels of supportive data. The model shows that the breakeven point at which it becomes less expensive to administer opioids with an intrathecal/implanted pump, rather than an epidural/external pump, is between 3 and 6 months after the start of pain management. In addition, the break even point between systemic treatment and spinal delivery with an implanted system is between 1 1/2 and 2 1/2 years from start of pain treatment.

A sheep model for continuous intrathecal infusion of test substances.

Pharmaceutical research and new drug development rely extensively on animal research. The development of novel agents for intrathecal administration requires preclinical studies of toxic effects in an animal model. We have developed a nonrodent animal model for this purpose. Our sheep model: 1 Is an animal whose neural axis is similar to the human 2 Allows for the percutaneous placement of intrathecal catheters 3 Has minimal possibilities of infection because the infusion system is totally implanted 4 Provides continuous infusion of the test agent 5 Generates behavioral, motor, neurological and histopathological information so that safety guidelines can be established prior to preclinical studies.

Cost effectiveness of intrathecal therapy for pain.

Successful management of chronic cancer and nonmalignant pain remains a challenge to clinicians, and cost effectiveness is an important consideration for clinical decision making. Although the oral route was previously considered the optimal method of chronic opioid administration, emerging evidence demonstrates a therapeutic advantage to intrathecal opioid delivery compared to alternative modalities. Intrathecal drug delivery uses an implantable drug infusion system to deliver very low doses of opioids and other analgesics directly into the intrathecal space. Although the initial costs of surgical implantation of an intrathecal pump appear to be substantial, maintenance costs of intrathecal drug delivery over time are significantly lower than other routes of administration, including oral and intravenous drug delivery. Cost analyses of alternate routes of opioid administration indicate that intrathecal delivery is the most cost-effective route of opioid administration for patients who require long-term management of cancer (≥ 3-6 months) or nonmalignant pain (≥ 11-22 months).

Alternative intrathecal agents for the treatment of pain.

There is a need to develop alternative agents for intrathecal pain therapy for patients who either cannot tolerate the side effects of or who no longer obtain sufficient analgesia with opioids. The experimental use of several compounds in intrathecal drug delivery is currently in progress, with the development of clonidine as the single most important advance in the improvement of pain treatment. Clonidine, an α(2) -adrenergic receptor agonist, appears to be safe and effective in the treatment of cancer and nonmalignant pain, with its effects most pronounced in patients whose pain consists of a neuropathic component. Other possible effective agents for intrathecal delivery include bupivacaine, octreotide, and SNX-111. The preclinical and clinical profiles for these promising new intrathecal pain medications are discussed.

Future trends in the development of local drug delivery systems: intraspinal, intracerebral, and intraparenchymal therapies.

Due to successful use of intrathecal drug delivery in the management of refractory pain and spasticity, new agents and indications are now being investigated. Preclinical studies of neurotrophic factors, molecules necessary for neuroneal survival and development, suggest that these agents may be beneficial for patients with neurologic disorders. Because neurotrophic factors do not cross the blood-brain barrier following systemic administration, local delivery routes, including intrathecal, intracerebroventrical, and intraparenchymal routes, are being studied; research is being conducted on intrathecal delivery for amyotrophic lateral sclerosis (ALS), intracerebroventricular delivery for Parkinson's disease and Alzheimer's disease, and intrahippocampal delivery for seizure disorders. Treatment of other neurologic disorders, such as brain tumors and HIV-related viral infections, also may be optimized by methods of local drug delivery, including intratumoral and intraparenchymal administration of potentially effective agents. Intraspinal, intratumoral, and intraparenchymal routes of administration are speculated to become critical components of treatment for a variety of neurological indications.

Preclinical toxicity study of intrathecal administration of the pain relievers dextrorphan, dextromethorphan, and memantine in the sheep model.

Objectives To determine the toxicity window for the continuous intrathecal administration of dextrorphan, dextromethorphan, and memantine via an implanted delivery pump. Materials and Methods Using 48 sheep with programmable continuous intrathecal infusion systems we determined the behavioral, motor, neurological, and histopathological changes produced by a 43-day continuous infusion study of dextrorphan, dextromethorphan, and memantine dissolved in 0.9% NaCl. Daily doses of each N-methyl-D-aspartate (NMDA) antagonist were 0.013, 0.051, 0.203, 0.510, 0.811, and 2.533 mg/kg/day, flow rates ranged from 13.25 ml/day to 0.051 ml/day at a concentration of 10 mg/ml. Control animals received saline in the range of 7.9985 ml/day to 1 ml/day. Conclusions Infusion of saline in the control animals produced no behavioral or motor changes. However, infusion of dextrorphan, dextromethorphan, and memantine at the higher doses (> 0.051 mg/kg/day) produced dose-dependent negative behavioral, motor, and histopathologic changes as indicated by a series of nonparametric statistical analyses. The minimal toxic doses were dextrorphan dose 3, dextromethorphan dose 1 and memantine dose 1. This study suggests that continuous intrathecal infusion of dextrorphan, dextromethorphan, and memantine via an implantable pump system can cause significant toxicities at the higher doses studied.

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.

Palliation of intractable cancer pain by MRI-guided cingulotomy.

CASE REPORT: Three cases of intractable pain arising from widespread metastatic cancer with poor response to opioids were treated with MRI-guided cingulotomy. RESULTS AND CONCLUSIONS: In most cases, MRI-guided cingulotomy was associated with significant pain relief and reduced opioid use. To provide insight into the role of MRI-guided cingulotomy in oncologic pain refractory to more conservative measures, the relative risks and benefits of cingulotomy are discussed, along with the course of one patient who experienced postoperative cognitive impairment. This report also describes the relevant neurosurgical and pharmacotherapeutic issues associated with management of pain in patients with widespread metastatic disease.