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BACKGROUND: Assumptions about the damaging effects of radiotherapy (XRT) are based on studies in which total dose, dose fraction, treatment volume, degree of malignancy, chemotherapy, tumor recurrence, and neurologic comorbidity interact with XRT effects. This is a prospective, long-term study of XRT effects in adults, in which total dose and dose fraction were constrained and data related to tumor recurrence and neurologic comorbidity (e.g., hypertension) were excluded. METHODS: The effects of XRT on the cognitive and radiographic outcomes of 26 patients with low-grade, supratentorial, brain tumors yearly from baseline (6 weeks after surgery and immediately before XRT) and yearly to 6 years were examined. Radiographic findings were examined regionally. RESULTS: Selective cognitive declines (in visual memory) emerged only at 5 years, whereas ratings of clinical MRI (T2 images) showed mild accumulation of hyperintensities with post-treatment onset from 6 months to 3 years, with no further progression. White matter atrophy and total hyperintensities demonstrated this effect, with subcortical and deep white matter, corpus callosum, cerebellar structures, and pons accounting for these changes over time. About half of the patients demonstrated cognitive decline and treatment-related hyperintensities. CONCLUSIONS: There was no evidence of a general cognitive decline or progression of white matter changes after 3 years. Results argue for limited damage from XRT at this frequently used dose and volume in the absence of other clinical risk factors.

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OBJECTIVE: The neurocognitive sequelae of therapeutic cranial irradiation are not well characterized in adults with primary brain tumors. To address this problem, we prospectively examined neuropsychological findings during two phases of radiation effects. BACKGROUND: Investigations of radiation effects have revealed variable outcomes that range from no radiation-associated morbidity to severe cognitive impairment, but have relied on case reports or retrospective studies of late-delayed changes in white matter or in cognition. No reliable radiographic or neurocognitive tools exist to describe the multiple phases of radiation effects. METHOD: Twenty adult patients (median age, 39 years) from a university hospital were treated with radiotherapy (RT) for low-grade primary brain tumors. Prospective longitudinal neuropsychological studies were compared at baseline (after surgery and before irradiation) and at 3, 6, and 12 months after RT to examine early-delayed effects, including verbal memory changes in 20 patients and visual memory changes in 11 patients. We also examined cognitive changes during the late-delayed phase for up to 3 years after RT and determined whether early-delayed memory deficit predicted late-delayed memory deficit in a small subset of patients. A comprehensive neuropsychological battery was used, including verbal and visual memory tests designed to compare learning, storage, and retrieval. RESULTS: Patients demonstrated normal verbal memory at baseline, decrement, and then rebound in verbal retrieval. Deficit at baseline and recovery up to 1 year after RT defined visual memory. Together, these observations constitute a double dissociation of memory functions. No changes over time were observed in other neurocognitive tests or in fatigue or mood measures. Time-dependent patterns of each long-term memory test were examined in relation to lesion site in individual patients. CONCLUSIONS: The double dissociation of memory functions after RT may provide markers for the damaging and facilitative early-delayed effects of RT. Late-delayed effects were not predicted based on early-delayed changes in a small sample.

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PURPOSE: To assess the efficacy and safety profile of high-dose (0.3 mmol/kg cumulative dose) gadoteridol in patients with suspected central nervous system metastatic disease. METHODS: We studied 67 patients using an incremental-dose technique. Patient monitoring included a medical history, physical examination, vital signs, and extensive laboratory tests within 24 hours before and after the MR examination. Precontrast T1- and T2-weighted spin-echo studies were performed, followed by intravenous injection of 0.1 mmol/kg of gadoteridol. T1-weighted images were acquired immediately after and at 10 and 20 minutes after injection. At 30 minutes an additional 0.2 mmol/kg of gadoteridol was administered (0.3-mmol/kg cumulative dose), and T1-weighted images were acquired. Cases demonstrating abnormal MR findings were assessed for efficacy by unblinded and blinded reviewers and were analyzed quantitatively. RESULTS: Three adverse effects in two patients were considered to be related to gadoteridol administration. No adverse effects were serious; all self-resolved. Forty-nine cases showed abnormal MR findings and were included in the efficacy analysis. A significantly greater number of lesions was seen on the high-dose as opposed to the standard-dose images. Blinded and unblinded readers identified 5 and 8 patients, respectively, with solitary lesions on standard-dose examination and multiple lesions on high-dose examination. Two patients who had normal standard-dose findings had lesions identified on high-dose studies. Quantitative analysis of 133 lesions in 45 patients demonstrated significant increases in lesion signal intensity on high-dose studies when compared with standard-dose studies. CONCLUSION: Gadoteridol can be safely administered up to a cumulative dose of 0.3 mmol/kg. High-dose contrast studies provide improved lesion detectability and additional diagnostic information over studies performed in the same patients with a 0.1-mmol/kg dose and aid in patient diagnosis and treatment. High-dose gadoteridol study may facilitate the care of patients with suspected central nervous system metastasis.

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Spontaneous regression of hematologic malignancies is not uncommon and occurs in a wide variety of lymphomas and leukemias. In contrast, spontaneous remission of neurologic symptoms produced by these tumors is exceedingly rare. We report a patient with central nervous system acute lymphoblastic leukemia who experienced at least one spontaneous remission of papilledema and sixth nerve palsy. This represents, to our knowledge, the first case of spontaneous remission of neuro-ophthalmologic signs in a patient with acute leukemia. We conclude that meningeal leukemia may have a protracted course, and that spontaneous remission of neuro-ophthalmologic findings should not be so readily ascribed to a benign process in a patient with preexisting leukemia.

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The peripheral nervous system is frequently impaired in patients who have cancer. This impairment often results from toxicity of treatment but may also be due to direct invasion by tumor or may be part of a paraneoplastic syndrome. This review summarizes the recent literature regarding peripheral neuropathies and myopathies that are seen in patients with cancer. Highlights include the neuromuscular toxicity of some of the newer chemotherapeutic agents and immune mediators such as taxol and interleukin-2; a discussion of some of the agents being investigated for chemoprotection and rescue; an assessment of the evidence supporting the concept of motor neuron disease as a paraneoplastic disorder; and an interesting case report of megakaryoblastic leukemia invading peripheral nerves. Also summarized are some nice reviews and prospective studies of the toxicity of more conventional treatments.

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We report a biopsy-diagnosed patient with Creutzfeldt-Jacob disease showing on magnetic resonance images bilateral increased signal intensity in the basal ganglia on long repetition time images. Creutzfeldt-Jacob disease (CJD) is a degenerative process of the brain, induced by a novel infectious agent, and is usually characterized by a rapidly progressive dementia. We report a biopsy-diagnosed patient with CJD with a distinctive magnetic resonance (MR) appearance.

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Mood and behavioral changes have been reported in patients with thalamic tumors. We report a case in which an infiltrating mass lesion of both thalami was manifested by an alteration in personality with relative motor and sensory sparing. These personality changes, unlike many such cases reported in the literature, were not related to increased intracranial pressure and hydrocephalus. Magnetic resonance imaging (MRI) demonstrated the lesion that was subtle and nearly inapparent on contrast-enhanced computerized tomography (CT).

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A prospective study of patients receiving cis-diaminedichloroplatin II (DDP) was carried out to determine if risk factors could be identified related to the patient's living habits or past medical history that would predict in which patients DDP neuropathy might develop. Sixty-nine patients receiving six different combinations of chemotherapeutic agents, including DDP were examined. Twenty-eight of these patients received DDP in combination with the radioprotective agent S-2-(3-aminopropylamino)-ethylphosporothioic acid (WR 2721). No risk factors were identified relating to personal habits or past medical history of the patients. However, patients receiving DDP (40 mg/m2) on 5 consecutive days had a significantly higher incidence of neuropathy. Patients receiving DDP in combination with WR 2721 had a significantly lower incidence of neuropathy, and the mean dose at onset was significantly higher than the mean dose at onset of neuropathy for all other groups. In addition, five of six patients who were available for long-term follow-up demonstrated nearly complete reversal of the signs and symptoms of neuropathy.

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Symptoms and signs of cis-diamminedichloroplatinum II (DDP) neuropathy usually develop during treatment and stabilize or improve when DDP is stopped. We report three patients whose symptoms began 3 to 8 weeks after the last dose of DDP and progressed over 1 or 2 months to moderate-marked disability. The clinical picture in each was consistent with DDP neuropathy, and no other cause could be identified. Two of the patients improved over 8 and 27 months to become asymptomatic; the other died 2 months after presentation. It is important to recognize that DDP neuropathy can present after treatment has been discontinued since the clinical picture mimics the paraneoplastic dorsal root ganglionitis, which has a different prognosis.

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A 27 year old male with metastatic testicular carcinoma was treated with cisplatin, vinblastine, and bleomycin (PVB) chemotherapy. After receiving a cumulative dose of 500 mg/m2 of cisplatin, he developed severe nausea and vomiting and had clinical evidence of a cisplatin-induced peripheral neuropathy. His vomiting resolved five weeks after discontinuation of cisplatin. We believe this case represents the first report of gastric autonomic neuropathy induced by cisplatin.

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An abnormality in myoplasmic Ca2+ regulation has frequently been proposed in 20,25-diazacholesterol (20,25-D) myotonia. We report here the results of several studies of transmembrane Ca2+ movement in this animal model. (i) Physiologic Ca2+ release by intact sarcoplasmic reticulum (SR) was examined in chemically skinned single muscle fibers preloaded in EGTA-buffered Ca2+ solutions (pCa2+7.0 to 6.4). Isometric tension development and Ca2+ release thresholds in response to Cl- or caffeine showed no differences between control and 20,25-D fibers at any pCa2+. (ii) The kinetics of energy-dependent Ca2+ accumulation in purified SR vesicles were followed spectrophotometrically using Ca2+-sensitive dyes. The apparent rate for ATP-dependent Ca2+ uptake and Ca2+ sequestering capacity were unchanged in SR from 20,25-D animals vs. controls. (iii) Surface membrane Ca2+ATPase activity was measured in red blood cell ghosts and sarcolemma. Enzyme Vmax was decreased by 25 to 50% in both membranes in the 20,25-D-treated animals with a compensatory increase in the number of Ca2+ATPase molecules. In general, the SR handling of Ca2+ appears normal in 20,25-D myotonia, although the activity of Ca2+ATPase in membranes with high sterol content may be altered in response to changes in the lipid environment in this model.

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We studied calcium transport in inside-out erythrocyte vesicles from patients with myotonic or facioscapulohumeral dystrophy and age- and sex-matched controls. No significant difference was noted in the affinity of the transporter for calcium or the maximum reaction velocity. Under identical conditions, we previously found that Duchenne dystrophy membranes differed from controls in affinity for calcium and maximum velocity. The results reported here imply that the abnormality in Duchenne dystrophy is specific and not an abnormality found in all forms of dystrophy.

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Erythrocyte calcium transport as a function of free [Ca++] was examined using inside-out vesicles from eight pairs of patients with Duchenne dystrophy and age- and sex-matched controls. The Km for Ca++ of the transport protein and the Vmax were higher in the Duchenne vesicles in seven of the eight pairs. The mean Km and Vmax were significantly higher in the Duchenne group.

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Inside-out vesicles from human erythrocytes were used to study the kinetics of calcium transport. The amounts of total ATP, MgCl2, and CaCl2 required to yield particular concentrations of MgATP2-, free Mg2+, and free Ca2+ were determined mathematically, and the final concentration of free Ca2+ was confirmed using the calcium indicator dye arsenazo III. Calcium accumulation was linear for 40 min in the presence of ATP and for at least 60 min in the presence of ATP and oxalate. When the calcium ionophore A-23187 was added at the end of an uptake experiment, 95% of accumulated calcium was released. There was a single affinity for calcium with a Km of 3.4 +/- 0.4 microM. Rduced glutathione in the assay medium increased the Vmax but did not alter the Km. The optimal pH was 6.9 to 7.3, and the optimal temperature was 40 degrees C with an Ea of 14.3 kcal/mol. The dependence of calcium accumulation on [MgATP2-] and [ATP4-] could not be measured separately in this assay system. At half-maximal transport rate [MgATP2-] = 1.0 MM and [ATP4-] = 0.1 mM. The data suggest a complex kinetic mechanism.

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