Evaluating the impact of pain management (PM) education on physician practice patterns--a continuing medical education (CME) outcomes study.

California Assembly Bill AB487 mandates that all practicing physicians are required to obtain 12 h of Continuing Medical Education in Pain Management and End of Life Care before the year 2006 in order to renew their state license to practice medicine. In order to determine the effectiveness of this bill in influencing the practice of medicine, we conducted the first of five planned annual Pain Management seminars and utilized physician questionnaires to determine possible practice changes as a result of this seminar. Eighty-one physicians representing 17 multiple specialties of medicine enrolled in this seminar. The topics included: management of malignant and non-malignant pain, pharmacology and management of side effects of opiate and non-opiate analgesics, and adjunctive therapies including depression management and spirituality issues. Physicians were asked to respond to an immediate post-seminar questionnaire and were subsequently queried 4 months following the conference. Fifty-one out of 81 physician registrants responded to an immediate post-attendance questionnaire, and 31 responded to the 4-month follow-up questionnaire. Responses included: [Please see text]. This audience represents the most motivated group of practitioners electing to receive Pain Management Education long before the mandated deadline. Sixty-seven percent expressed an interest in changing their practice following this intensive educational experience. Ninety percent responding to the follow-up evaluation indicated that their practices had changed, suggesting that this seminar series is effective in altering physician practice patterns (supported by Cancer Center Support Grant CA 33572 and Sarnat Foundation).

Donepezil in the treatment of opioid-induced sedation: report of six cases.

Donepezil, an oral acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease, was given to 6 cancer pain patients having sedation related to the analgesic use of opioids. Each patient was taking more than 200 mg of oral morphine equivalents per day, and several were receiving complex analgesic regimens consisting of multiple adjuvant medications. Sedation improved at least moderately in 5 of the patients and mildly in 1 after they began taking donepezil. Patients reported a decrease in episodes of spontaneous sleeping during the day, fewer myoclonic twitches, improved daily function and greater social interaction. Several also reported improved sleep at night. Analgesia was not compromised by the use of donepezil, and in some cases it appeared improved. Donepezil may be a valuable alternative to psychostimulants in the treatment of opioid-induced sedation. A prospective controlled trial comparing the treatment effects of psychostimulants and donepezil on patients having opioid-induced sedation is underway.

Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis.

PURPOSE: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. METHODS: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200-1500 mg/m2, followed by a 23-h infusion of 800-6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. RESULTS: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 microM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 +/- 41 ml/min per m2) versus without CNS disease (59 +/- 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. CONCLUSION: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (> 1 microM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.

Eye movement disorders in bone marrow transplant patients on cyclosporin and ganciclovir.

After 582 allogeneic bone marrow transplants, we have encountered four patients (0.7%) who developed transient unilateral or bilateral sixth nerve palsies. Three of the four patients also had bilateral ptosis. These signs resolved 24-48 h after cyclosporin and ganciclovir were discontinued. One patient had MRI T2 abnormalities compatible with cyclosporin neurotoxicity. We postulate that cyclosporin, possibly together with ganciclovir, can produce transient brain stem or neuromuscular dysfunction with eye movement abnormality in occasional patients.

Acute polyneuropathy after high dose cytosine arabinoside in patients with leukemia.

BACKGROUND: Peripheral nerve toxicity has been reported but is not a commonly recognized complication of high dose cytosine arabinoside (HDAC) therapy. This study was undertaken to estimate the prevalence and describe the clinical spectrum of acute polyneuropathy associated with HDAC therapy for leukemia. METHODS: Records of 153 acute leukemia patients who received 194 courses of HDAC at the City of Hope were reviewed for evidence of severe peripheral neuropathy with onset 2-3 weeks after HDAC therapy. RESULTS: Two patients were identified who developed motor disability 2-3 weeks after HDAC therapy, and the disability progressed in a monophasic course to quadriparesis. There was neurophysiologic evidence of peripheral nerve demyelination with slowed nerve conduction velocities and conduction block. One patient who was autopsied had demyelination identified in luxol-fast blue sections of peripheral nerve (with Bielschowsky-stained sections showing intact peripheral nerve axons). There were foamy macrophages in the peripheral nerve but no chronic inflammatory cells. For comparison, data from these two patients were combined with those from four published case reports of polyneuropathy associated with HDAC therapy. Quadriparesis occurred in five of six cases with the need for ventilatory support in four. Cerebrospinal fluid protein was elevated in five of six cases. Etiologic evidence incriminating HDAC included simultaneous cerebellar signs in two of six cases and a narrow interval of clinical onset after HDAC therapy. CONCLUSIONS: Demyelinating polyneuropathy occurs in approximately 1% of HDAC courses and produces severe motor disability. HDAC immunosuppression could trigger an immune-mediated neuropathy; alternatively, a direct neurotoxic effect of HDAC on Schwann cells is also an etiologic possibility.

Polymyositis as a manifestation of chronic graft-versus-host disease.

A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.

Immune-mediated myelopathy after allogeneic marrow transplantation.

We describe two patients who developed myelopathy 15 and 27 months after allogeneic marrow transplantation. Exacerbations of the myelopathy occurred, with the development of optic neuropathy in one patient when corticosteroid therapy was tapered. The other patient had two exacerbations, 28 months and 40 months after transplantation, both of which resolved with plasma-pheresis. These case reports suggest that immune-mediated disease after transplantation can affect the central nervous system.

Neoplastic meningitis as the presentation of occult primitive neuroectodermal tumors.

Seven children and young adults initially presented with subacute meningitis and/or increased intracranial pressure. The diagnosis of neoplastic meningitis secondary to a primitive neuroectodermal neoplasm was delayed by the absence of an obvious primary tumor. The neuroradiologic appearance was that of a basimeningeal infiltrative process, complicated by communicating hydrocephalus or "pseudotumor cerebri." Myelography was important in the diagnosis of disseminated meningeal malignancy in four cases. Cerebrospinal fluid cytologic diagnosis was insensitive but ultimately confirmed in five cases. All seven patients experienced progressive disease despite neuraxis radiotherapy and intensive chemotherapy; six have died. Systemic dissemination to bone and/or peritoneum occurred in three patients while on therapy. In two, a primary parenchymal brain or spinal cord tumor could not be identified at postmortem examination. The presentation of a primitive neuroectodermal tumor as subacute meningitis without an evident primary tumor heralds an aggressive and refractory neoplasm.

Exacerbation of inflammatory demyelinating polyneuropathy after bone marrow transplantation.

Two patients with hematologic malignancy and quiescent inflammatory demyelinating polyneuropathy developed severe exacerbations of polyneuropathy at the time of bone marrow transplantation. The clinical course in both patients was progressive despite therapy with immuno-suppressive agents, plasmapheresis, and high dose immunoglobulin. The polyneuropathy resulted in quadriplegia which contributed to the patients' deaths 175 and 48 days after transplantation. Sections of multiple peripheral nerves sampled post mortem in the first case revealed prominent demyelination with heavy infiltration of macrophages and lymphocytes. Immunohistochemical studies demonstrated that most of the lymphocytes were of the CD8+, cytotoxic/suppressor cell class and that many of the Schwann cells expressed class II (HLA-DR) antigen. This report suggests that bone marrow transplantation can exacerbate inflammatory demyelinating polyneuropathy.

Papilledema in the metastatic jugular foramen syndrome.

In a patient with Ewing's tumor, bilateral papilledema developed along with a left jugular foramen syndrome. Plain tomograms demonstrated a metastasis at the base of the skull. A digital intravenous angiogram showed an occlusion of the left transverse sinus at the level of the jugular foramen. The papilledema was explained by an increase in the intracranial pressure due to the rapid obstruction of venous drainage by the metastasis.