Frontal lobe tumoral epilepsy: clinical,neurophysiologic features and predictors of surgical outcome

PURPOSE: To review the clinical, neurophysiologic features and surgical outcomes in patients with frontal lobe tumors and chronic intractable seizures. METHODS: Medical records of patients with intractable epilepsy who underwent resection or stereotactic biopsy of frontal lobe tumor (confirmed by surgical pathology) seen between 1985 and 1999 at Yale University School of Medicine Epilepsy Center were reviewed for age at diagnosis, age at onset of seizures, delay between seizure onset and tumor diagnosis, types and frequencies of seizures, EEG results, use of anticonvulsants, extent of surgery, pathological diagnosis, and tumor recurrence. RESULTS: Thirty-seven patients were included. Mean age at seizure onset was 31.6 years, and at tumor diagnosis was 36.2 years. Mean duration between onset of seizures and tumor diagnosis was 6.1 years. Seventeen patients had auras. Seizure frequency averaged 7.6 seizures per week, with 58% of patients having more than one seizure type. All patients used anticonvulsants, with 90% eventually using polytherapy. All patients eventually underwent at least one surgical procedure. Only 13 (35.1%) patients were class I. Twelve (32.4%) patients were class II, seven (18.9%) class III, and five (13.5%) class IV. No statistically significant differences were seen between good and poor long-term seizure outcome in relation to specific tumor pathology, seizure types, or type of resection. CONCLUSIONS: Long-term surgical outcomes in tumoral frontal lobe epilepsy are more favorable than those in nontumoral intractable frontal lobe epilepsy (65% class I or II) and less favorable than those in other tumoral epilepsy (overall, 70% class I). Frontal location of intracranial neoplasm may predict a less favorable long-term epilepsy prognosis than tumoral epilepsy in general, an observation for which several explanations are proposed.     

Identification of the key amino acids of gliai cell line-derived neurotrophic factor family receptor alpha 1 involved in its biological function

Glial cell line-derived neurotrophic factor （GDNF） plays a critical role in neurodevelopment and survival of midbrain dopaminergic and spinal motor neurons in vitro and in vivo. The biological actions of GDNF are mediated by a two-receptor complex consisting of a glycosylphosphatidylinositol-linked cell surface molecule, the GDNF family receptor alpha 1 （GFR alpha 1）, and receptor protein tyrosine kinase Ret. Although structural analysis of GDNF has been extensively examined, less is known about the structural basis of GFR alpha 1 function. In this study, based on evolutionary trace method and relative solvent accessibility prediction of residues, a set of trace residues that are solvent-accessible was selected for site-directed mutagenesis. A series of GFR alpha 1 mutations was made, and PC12 cell lines stably expressing different GFR alpha 1 mutants were generated. According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNF- GFR alpha 1-Ret interaction assay, residues 152NN153, Arg259, and 316SNS318 in the GFR alpha 1 central region were found to be critical for GFR alpha 1 binding to GDNF and eliciting downstream signal transduction. The single mutation R259A in the GFR alpha 1 molecule simultaneously lost its binding ability to GDNF and Ret. However N152A/N153A or S316A/N317A/ S318A mutation in the GFR alpha 1 molecule still retained the ability to bind with Ret. These findings suggest that distinct structural elements in GFR alpha 1 may be involved in binding to GDNF and Ret.     

Reversible findings of restricted diffusion in 5‐flourouracil neurotoxicity

A 35‐year‐old woman presented with neurotoxicity correlated to an i.v. regimen of 5‐fluorouracil as episodes of acute confusional state and abnormalities of symmetrically restricted diffusion in the periventricular white matter and corpus callosum. On discontinuing the medication, the areas of severely restricted diffusion had entirely resolved, with minimal residual T2 signal abnormality. In this case, immediate discontinuation of the chemotherapeutic agent apparently reversed the patient's symptoms and findings on MRI. The scant information available in the published literature regarding this phenomenon is reviewed with regard to 5‐fluorouracil.     

Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis

Stroke is a major cause of long-term disability, the severity of which is directly related to the numbers of neurons that succumb to the ischemic insult. The signaling cascades activated by cerebral ischemia that may either promote or protect against neuronal death are not well-understood. One injury-responsive signaling pathway that has recently been characterized in studies of non-neural cells involves cleavage of membrane sphingomyelin by acidic and/or neutral sphingomyelinase (ASMase) resulting in generation of the second messenger ceramide. We now report that transient focal cerebral ischemia induces large increases in ASMase activity, ceramide levels, and production of inflammatory cytokines in wild-type mice, but not in mice lacking ASMase. The extent of brain tissue damage is decreased and behavioral outcome improved in mice lacking ASMase. Neurons lacking ASMase exhibit decreased vulnerability to excitotoxicity and hypoxia, which is associated with decreased levels of intracellular calcium and oxyradicals. Treatment of mice with a drug that inhibits ASMase activity and ceramide production reduces ischemic neuronal injury and improves behavioral outcome, suggesting that drugs that inhibit this signaling pathway may prove beneficial in stroke patients.     

High pretreatment serum concentration of basic fibroblast growth factor is a predictor of poor prognosis in small cell lung cancer.

Basic fibroblast growth factor (bFGF) is a secreted multifunctional cytokine and a potent stimulator of angiogenesis. We measured bFGF concentrations from serum samples taken from 103 patients with small cell lung cancer at the time of diagnosis. Serum concentration of bFGF (S-bFGF) ranged from undetectable to 54 pg/ml (median, 6 pg/ml). S-bFGF was not associated with age, sex, performance status, or stage. A high pretreatment S-bFGF was associated with poor overall survival. The 1- and 2-year survival rates of the patients within the highest quartile of S-bFGF (>or=17 pg/ml) were only 26% and 11%, respectively, in contrast to the 49% and 20% 1- and 2-year survival rates of those patients with S-bFGF < 17 pg/ml (P = 0.013). The 1- and 2-year survival rates of the patients with extensive-stage disease were 33% and 10%, respectively (P = 0.0091). Interestingly, S-bFGF provided additional prognostic information to the stage because the 1- and 2-year survival rates of patients with extensive-stage disease and a high S-bFGF (>or=17 pg/ml) were as low as 16% and 5%, respectively (P = 0.0026). Similarly, in the multivariate model of survival analysis, patients with both extensive-stage disease and a high S-bFGF (>or=17 pg/ml) were found to have a particularly poor prognosis (relative risk of death, 2.1; 95% confidence interval, 1.2-3.6; P = 0.0057). We conclude that a high S-bFGF at diagnosis is associated with poor outcome in small cell lung cancer, possibly reflecting active angiogenesis and rapid tumor growth, and may complement prognostic information obtained by staging.     

Evaluation of pleural disease using MR and CT. With special reference to malignant pleural mesothelioma

Purpose: To evaluate MR imaging and CT in differentiating malignant pleural mesothelioma from other malignancies or benign pleural disease.Material and Methods: Thirty-four patients (18 pleural mesotheliomas, 9 other malignancies, 7 benign pleural diseases) were examined using enhanced CT and MR. Two radiologists reviewed the CT and two others the MR images. Comparisons were made between the diagnostic groups and the imaging methods.Results: The abnormalities commonly found in malignant disease, but significantly less frequently in benign pleural disease, were focal thickening and enhancement of interlobar fissures. In mesothelioma, enhancement of interlobar fissures, tumour invasion of the diaphragm, mediastinal soft tissue or chest wall, were significantly more often observed than in other malignancies and MR was the most sensitive method. In other malignancies, invasion of bony structures was a more common finding and was also better shown by MR. The contrast-enhanced T1 fat-suppressed (CET1fs) sequence detected these features better than other MR sequences.Conclusion: MR, especially the CET1fs sequence in three planes, gave more information than enhanced CT. Focal thickening and enhancement of interlobar fissures were early abnormalities indicating malignant pleural disease. MR could be clinically useful for differentiating mesothelioma from other pleural diseases.