Interleukin (IL)-4-independent immunoglobulin class switch to immunoglobulin (Ig)E in the mouse.

Immunoglobulin (Ig) class switching in B cells is regulated by stimuli transduced by cytokines and cell-cell contact. Among these stimuli, interleukin (IL)-4 has been considered an absolute prerequisite for class switching to IgE in the mouse. Here we report that IL-4-deficient (IL-4-/-) and wildtype mice had comparably elevated serum IgE levels during the course of a murine retrovirus-induced immunodeficiency syndrome, MAIDS. IgE switching in IL-4-/- mice was also induced by injection of anti-IgD antibody. Treatment with anti-IgD induced germline epsilon (g epsilon) transcripts with comparable efficiency in IL-4-/- mice and controls, but the levels of productive epsilon transcripts (p epsilon) were lower by a factor of 200 and serum IgE levels were lower by a factor of 300 in IL-4-/- mice as compared with controls. Induction of g epsilon after anti-IgD treatment of IL-4-/- mice was unaffected by simultaneous treatment with monoclonal antibodies to IL-4 and IL-4 receptor alpha chain. Infection of IL-4-/- mice with Nippostrongylus brasiliensis, a potent stimulus for IgE production, resulted in induction of g epsilon transcripts; however, p epsilon transcripts were barely detectable and serum IgE was not detected. These findings establish a novel IL-4-independent pathway for IgE switching in the mouse that is strongly activated in retroviral infection but weakly in nematode infection. This pathway appears to be dependent on distinct factors that separately control induction of g epsilon transcription and switch recombination to p epsilon.

Preradiation intracarotid cisplatin treatment of newly diagnosed anaplastic gliomas. The CNS Cancer Consortium.

PURPOSE: This phase II study was performed to assess the response of patients with newly diagnosed, untreated malignant gliomas (anaplastic astrocytoma [AA] and glioblastoma multiforme [GBM]) to intracarotid (IC) cisplatin. PATIENTS AND METHODS: Eligibility criteria included surgical intervention limited to biopsy only, measurable contrast-enhancing tumor, and unilateral tumor location within the vascular territory of one internal carotid artery. Patients were scheduled to receive four infusions of IC cisplatin (75 mg/m2 every 4 weeks) before beginning standard radiotherapy. Twenty-six patients were treated, and 22 were assessable for response. RESULTS: Ten patients (45%) showed a greater than 25% decrease in the enhancing tumor area before radiotherapy with stabilization or improvement of neurologic deficits, and three patients (14%) had a greater than 70% decrease in tumor area. The likelihood of response to IC cisplatin was not clearly linked to patient age, tumor histology, or pretreatment tumor size. Myelosuppression, nephrotoxicity, and ototoxicity were mild. Optic neuropathy occurred in one patient, seizures in two, and fatal postinfusion cerebral edema in one. CONCLUSION: This study design, which permits assessment of the drug sensitivity of the untreated glioma, has shown definite antitumor activity of IC cisplatin in newly diagnosed malignant glioma patients.

Randomized comparison of diaziquone and carmustine in the treatment of adults with anaplastic glioma.

PURPOSE: We conducted a phase III trial comparing intravenous (IV) diaziquone (AZQ) and carmustine (BCNU) as single agents in patients with cerebral anaplastic gliomas who had received surgery and radiotherapy. Its purpose was to compare the efficacy of AZQ with that of BCNU, the standard agent for brain tumor chemotherapy. PATIENTS AND METHODS: Randomization between the two regimens occurred 8 weeks after completion of radiotherapy. A total of 251 patients were randomized to receive either AZQ or BCNU, and there were no significant differences between the two treatment arms in any of the known prognostic variables, including age, histologic grade, and Karnofsky performance status (KPS). RESULTS: There was no significant difference in either time to tumor progression or survival between the two treatment arms. Age and histology were strong predictors of outcome, whereas KPS had relatively less effect. Three groups of patients with distinctly different outcomes could be identified: (1) older age (45+) and glioblastoma/gliosarcoma (GBM/GS) patients had a median survival of 37 weeks after randomization; (2) patients with either older age or GBM/GS had a median survival of 61 weeks; and (3) younger age (< 45) and non-GBM/GS (usually anaplastic astrocytoma) patients had a median survival of 147 weeks. Toxicity was primarily hematologic, although acute gastrointestinal toxicity and chronic pulmonary toxicity were more common with BCNU. Patients randomized to AZQ who had significant hematologic toxicity that required dose reduction after the first treatment cycle had significantly longer time to tumor progression and survival than those who did not require dose reduction (P = .011 and .016, respectively). CONCLUSION: There was no significant difference in efficacy between AZQ and BCNU in patients with anaplastic gliomas as tested in this study, although AZQ was somewhat better tolerated.

Immunologic havoc induced by the 60 kD Gag protein of the MAIDS defective virus.

The mechanisms responsible for development of profound immunodeficiency and extensive lymphoproliferation that characterize infection of different species with retroviruses are only partially understood. In mice, it has been shown the activities of an unusual Gag protein are necessary and sufficient to induce these abnormalities in a syndrome designated mouse AIDS (MAIDS). Current studies suggest that complex, antigen-driven interactions between T cells and B cells result in polyclonal activation of both types of lymphocytes, aberrant cytokine production and late lymphomas.

Transient focal ischemia in subhuman primates. Neuronal injury as a function of local cerebral blood flow.

Unilateral, transient (30, 60, and 120 minutes (min)) middle-cerebral-artery (MCA) occlusion was induced via transorbital craniotomy in 11 waking subhuman primates. Local cerebral blood flow (LCBF) was calculated from hydrogen clearance curves obtained through the use of intracerebral platinum microelectrodes. Unilateral MCA occlusion decreased LCBF in the territory of the ipsilateral MCA. Within minutes of the arterial occlusion all monkeys developed contralateral neurologic deficits that began disappearing three hours (h) after reopening the MCA. Regional ischemia, followed by 24 h of reperfusion, produced varying degrees of tissue vacuolation which correlated (r = 0.60, p less than 0.01, n = 49) with the percent reduction in LCBF multiplied by the occlusion time. Neurons were classified according to the structural features of their perikaryon. A plot of neuron types versus percent vacuolation suggested that normal neurons become increasingly scalloped under increasingly severe ischemic conditions. The number of scalloped neurons decreased precipitously in areas of marked sponginess coincident with the appearance of irreversibly damaged neurons. Local tissue edema values exceeding 30% correlated with irreversible injury to all neurons in the same area. Regional cerebral ischemia of increasing severity was acompanied by increasing numbers of lethally injured neurons.

A protein kinase-encoding gene, pkt1, from Trichoderma reesei, homologous to the yeast YPK1 and YPK2 (YKR2) genes.

A gene (pkt1) was isolated from the filamentous fungus Trichoderma reesei, which exhibits high homology with the yeast YPK1 and YKR2 (YPK2) genes. It contains a 2123-bp ORF that is interrupted by two introns, and it encodes a 662-amino-acid protein with a calculated M(r) of 72,820. During active growth, pkt1 is expressed as two mRNAs of 3.1 and 2.8 kb which differ in the 3' untranslated region due to the use of two different polyadenylation sites.

Predictive value of magnetic resonance imaging in temporal lobe epilepsy surgery.

The predictive value of magnetic resonance imaging (MRI) was assessed by a prospective study of 34 patients selected for surgical treatment of temporal lobe epilepsy. The MRIs were interpreted using standardized visual diagnostic criteria and the imaging findings were correlated with the surgical outcome. Lateralized MRI abnormalities were found in 25 (74%) of 34 patients. Significant associations were found between either the presence of a restricted foreign-tissue lesion or hippocampal atrophy and an excellent surgical outcome. An abnormal MRI had an 82% predictive value and a normal MRI had a 56% predictive value for surgical success. A history of febrile convulsions and the presence of hippocampal atrophy best predicted outcome (predictive value, 86%). These results suggest that specific MRI findings in candidates for temporal lobe epilepsy surgery are predictive of surgical outcome. The information provided by MRI may be of value for counseling patients prior to surgical intervention.

Magnetic resonance spectroscopic imaging in temporal lobe epilepsy: neuronal dysfunction or cell loss?

BACKGROUND: Magnetic resonance spectroscopy (MRS) has demonstrated consistent metabolic abnormalities in temporal lobe epilepsy. The reason for decreases in N-acetylated compounds are thought to be related to neuronal hippocampal cell loss as observed in hippocampal sclerosis. However, mounting evidence suggest that the N-acetylated compound decreases may be functional and reversible. OBJECTIVE: To establish whether the metabolic changes measured by MRS correlate to hippocampal cell loss in temporal lobe epilepsy. SUBJECTS AND METHODS: We prospectively performed quantitative hippocampal MR imaging volumetry and MRS imaging in 33 patients with intractable mesial temporal lobe epilepsy who were undergoing surgery. A neuronal-glial ratio of cornu ammonis and fascia dentata was obtained and correlated while validating the pathologic analysis by comparisons with specimens of age-matched autopsy control-case hippocampus (n = 14). RESULTS: The neuronal-glial ratio of the patient group was statistically significantly lower than in the control group for the cornu ammonis region (P<.001). Correlations of hippocampal volumes with cornu ammonis and neuronal-glial ratios revealed a significant interdependence (P<.01). However, correlations of the resected hippocampal creatine-N-acetylated compound ratio with the cornu ammonis or fascia dentata neuronal-glial ratios showed no significant interdependence (P>.8). CONCLUSIONS: Our findings support the concept that the metabolic dysfunction measured by MRS imaging and the hippocampal volume loss detected by MR imaging volumetry do not have the same neuropathologic basis. These findings suggest that the MRS imaging metabolic measures reflect neuronal and glial dysfunction rather than neuronal cell loss as previously assumed.

Proton spectroscopic imaging at 4.1 tesla in patients with malformations of cortical development and epilepsy.

We used proton magnetic resonance spectroscopic imaging (MRSI) at 4.1 tesla in patients with malformations of cortical development (MCDs) and epilepsy. We compared the spectroscopic results with normative data using 2 SDs (95% confidence) above normal values for detection of significant abnormalities for creatine-N-acetylated compounds (Cr/NA) ratio and choline-N-acetylated compounds (Cho/NA). The results were correlated with clinical, EEG, and histologic findings. Patients with focal cortical dysplasia showed significant metabolic abnormalities in correspondence with the structural lesions, whereas patients with heterotopia and polymicrogyria demonstrated no subcortical MRSI abnormalities. Significant correlations were found between the metabolic abnormalities and the frequency of seizures but not with the degree of interictal EEG discharges. Quantitative neuronal and glial cell counts revealed no statistically significant correlation between cell loss and the abnormal metabolic ratios in those who underwent surgery. These preliminary findings suggest that MRSI-based metabolic abnormalities in patients with MCDs are variable and are likely to be associated with complex cellular mechanisms involving the regulation of NA, total Cr content, and Cho.

Multimodality MRI in mesial temporal sclerosis: relative sensitivity and specificity.

Our objectives were to determine the relative sensitivity and specificity of different MRI sequences and analysis techniques for the detection of mesial temporal sclerosis (MTS). Mesial temporal sclerosis is the most common pathologic finding in patients undergoing temporal lobe epilepsy surgery. Magnetic resonance imaging is the most reliable preoperative imaging technique for the detection of MTS. We analyzed the abnormalities in preoperative MRIs of 44 consecutive patients who had undergone temporal lobectomy and who had pathologic confirmation of MTS. Techniques included inversion recovery (IR); T1-weighted, volume-acquired images; hippocampal T2 relaxometry (HT2); volumetric assessment; and visual analysis. Sensitivity was 86% with IR, 90% with T1-weighted qualitative visual analysis, and 97% with quantitative volumetry. Pathologic prolongation of HT2 (> 2 SD of normal) was present in 79%. Analysis of variance showed statistically significant differences in sensitivity between HT2, volumetric measurements (p < 0.01), and qualitative visual atrophy (p < 0.05). Concordance between all MRI modalities was 68%. Inversion recovery and qualitative analysis lateralized the side of surgery in 93%. The combination of IR and T1-weighted images correctly identify MTS in most patients. Hippocampal volumetry provided localization in an additional small number of patients.

Congenital porencephaly and hippocampal sclerosis. Clinical features and epileptic spectrum.

We studied clinical features and seizure localization in 14 patients with porencephaly and intractable seizures. Perinatal complications were present in nine patients, childhood febrile convulsions in two, congenital hemiparesis in 12, and intellectual impairment in seven. Ten patients had psychoparetic complex partial seizures (CPS), three had sensorimotor simple partial seizures, and one had generalized tonic-clonic seizures. Surface EEG showed temporal onset in nine patients (one bitemporal) and extratemporal onset in four. MRI showed porencephaly in the distribution of the middle cerebral artery in eight patients, posterior cerebral in three, internal carotid in one, and multiple vessels in two. MR-based volumetry revealed hippocampal formation atrophy in 13 patients (eight unilateral and five bilateral) and amygdalar atrophy in 10 patients (nine unilateral and one bilateral). Hippocampal formation atrophy was concordant with CPS semiology in 10 patients (71%) and with EEG temporal localization in nine patients. Two patients had pathologic confirmation of mesial temporal sclerosis and were seizure free after temporal lobectomy. We conclude that mesial temporal sclerosis often coexists with porencephaly and is the likely seizure focus in the presence of concordant electroclinical data. This recognition implies that effective surgical intervention can be offered to certain patients with porencephaly-related seizure disorders. The dual pathology and association with perinatal cerebral vascular occlusion suggest a common ischemic pathogenesis.

Patient-oriented outcome assessment after temporal lobectomy for refractory epilepsy.

OBJECTIVE: To determine patient-oriented outcome after anterior temporal lobectomy (ATL) for refractory epilepsy. BACKGROUND: Health-related quality of life (HRQOL) is an important component of the assessment of outcome from epilepsy surgery, but prior controlled studies of the effect of surgery on HRQOL are inconclusive. Direct assessment of the effect of surgery on patient concerns of living with epilepsy has not been reported. METHODS: We used reliable and valid instruments to compare HRQOL and patient concerns of 125 patients who had received an ATL more than than one year previously to a clinically similar group of 71 patients who were awaiting ATL. All patients were selected for surgery based on similar criteria. We also used bivariate correlation analysis and multivariate regression modeling to determine the association of traditional outcome variables with HRQOL. RESULTS: Patients who had undergone ATL reported significantly less concern of living with epilepsy in 16 of 20 items of the EFA Concerns Index and better HRQOL in 8 of 11 scales of the Epilepsy Surgery Inventory-55. Regression analysis in the postoperative group demonstrated that mood status, employment, driving, and antiepileptic drug (AED) cessation, but not seizure-free status or IQ, were associated with better HRQOL. CONCLUSIONS: Our findings support a positive affect of ATL on patient concerns and HRQOL in refractory temporal lobe epilepsy, although longitudinal studies are needed to corroborate these results. Mood, employment, driving ability, and AED use are important postoperative predictors of HRQOL.

Predictive value of 1H MRSI for outcome in temporal lobectomy.

OBJECTIVE: To investigate the predictive value of 1H MRSI for outcome in patients with mesial temporal lobe epilepsy (MTLE). BACKGROUND: 1H MRSI has been shown to be highly sensitive in the lateralization of temporal lob epilepsy. METHODS: The authors analyzed the relationship between the 1H MRSI findings and surgical outcome in 40 consecutive patients who underwent temporal lobe surgery for MTLE. Outcome at a mean of 24 months (range 18 to 40 months) was classified as seizure free or not seizure free. RESULTS: At follow-up, 78% of patients were seizure free. Correlations showed no predictive value for the creatine/N-acetylated compound (Cr/NA) ratio of the operated temporal lobe and outcome. However, a relationship was found between surgical failure and the Cr/NA ratio of the nonoperated temporal lobe and with a Cr/NA ratio in the nonoperated lobe above 1.21 in patients with bilateral abnormalities (p < 0.01). CONCLUSIONS: Preoperative elevations in the Cr/NA ratio in the nonoperated temporal lobe or the presence of higher metabolic ratios contralateral to the proposed surgery are associated with surgical failure. The predictive value of 1H MRSI absolute metabolite concentrations for outcome in MTLE requires further investigation.

Cognitive consequences of coexisting temporal lobe developmental malformations and hippocampal sclerosis.

OBJECTIVE: To characterize patterns of cognitive functioning in a well-defined group of patients with MRI-identified coexisting left temporal lobe developmental malformations (TLDM) and mesial temporal sclerosis (MTS), and to examine neuropsychological outcome in this dual-pathology group following epilepsy surgery. METHODS: Cognitive functioning in patients with left TLDM and MTS (n = 15) was compared with patients with isolated left MTS (n = 40). TLDM and MTS were identified by high-quality MRI protocol. Patients were administered a battery of neuropsychology tests as part of their presurgical workup for possible epilepsy surgery. Unilateral temporal lobe resection was performed on 10 of the dual-pathology patients and 34 of the isolated MTS patients. Postoperative cognitive performance was also assessed. RESULTS: Both groups displayed impairments in verbal and visual memory, language, and academic achievement. Performance on measures of psychometric intelligence, executive function, and attention were not impaired and were similar between groups. Presence of dual pathology was associated with a significantly less efficient verbal encoding strategy on the word list learning task. Postoperatively, declines were noted for both groups across tasks of verbal memory and language. Groups were not different significantly in terms of neuropsychological outcome after surgery. CONCLUSION: Patients with coexisting TLDM and MTS have impaired cognitive functioning similar to MTS patients-in particular, with regard to episodic memory and language deficits. Temporal lobe resection produces similar cognitive changes in both groups.

Amygdala atrophy and seizure outcome after temporal lobe epilepsy surgery.

Surgical outcome in hippocampal atrophy (n = 44) and amygdalohippocampal atrophy (n = 14) were compared. Hippocampal atrophy had better seizure-free outcome than amygdalohippocampal atrophy (80% versus 50%, p = 0.043). Severity of hippocampal atrophy correlated with duration of epilepsy in patients with hippocampal atrophy (r = 0.4, p = 0.007), but not in those with amygdalohippocampal atrophy, suggesting that these two groups may have a different pathogenesis.

Temporal lobe developmental malformations and hippocampal sclerosis: epilepsy surgical outcome.

BACKGROUND: Temporal lobe developmental malformations coexist with mesial temporal sclerosis in the form of dual pathology with a high frequency of bilateral amygdala or hippocampal abnormalities. OBJECTIVE: The aim of this study was to correlate and compare the MRI findings and the surgical outcome in patients with temporal lobe developmental malformations (n = 20) and isolated mesial temporal sclerosis (n = 36). METHODS: MRI-based normalized volumetry of the amygdala and hippocampal formation in patients with unilateral temporal lobe developmental malformations and isolated mesial temporal sclerosis who underwent temporal lobe resections was performed. Seizure outcome was compared between groups at follow-up. RESULTS: The frequency of bilateral hippocampal or amygdala atrophy (p < 0.04) and combined hippocampal-amygdala atrophy (p < 0.02) was higher in patients with temporal lobe developmental malformations. Although no significant difference in postsurgical seizure-free status was found between the temporal lobe developmental malformations and isolated mesial temporal sclerosis groups (70% versus 91%), patients with temporal lobe developmental malformations and bilateral amygdala or hippocampal-amygdala atrophy had a significantly worse outcome (p < 0.02). CONCLUSION: Bilateral hippocampal atrophy is frequent in patients with temporal lobe developmental malformations. However, it is the presence of bilateral amygdala or amygdalo-hippocampal atrophy that is associated with a higher risk of seizure recurrence.

Temporal lobe developmental malformations and epilepsy: dual pathology and bilateral hippocampal abnormalities.

Temporal lobe developmental malformations (TLDM) with focal cortical dysplasia and balloon cells may coexist with mesial temporal sclerosis. The true incidence of this dual pathology is unknown. Our aim was to assess the frequency of amygdala (AM)-hippocampal abnormality in a homogeneous population with this specific developmental malformation. MRI-based volumetry of the AM and hippocampal formation (HF) in 30 patients with unilateral TLDM and intractable partial epilepsy was performed. A volume normalization process defined a normal range of HF and AM volumes in control subjects, and enabled the detection of bilateral volume loss. Normalized volumes detected HF atrophy in 26 patients (nine unilateral and 17 bilateral) and AM atrophy in 18 patients (three unilateral and 15 bilateral). Visual analysis detected unilateral HF abnormality in 21 patients and bilateral abnormality in two. When compared with a group of patients with temporal lobe epilepsy and pure hippocampal sclerosis (N = 92), where volumetry revealed bilateral HF atrophy in 18%, a significant difference in the frequency of bilateral HF atrophy was found (p < 0.0001). Dual pathology is frequent in patients with TLDM (87%), and the AM-HF abnormality is often bilateral (57%). Our data suggest that more widespread and potentially epileptogenic lesions coexist with visibly detectable unilateral TLDM. This has implications for the selection of patients for temporal lobe surgery and may influence surgical strategies.

Magnetic resonance imaging in childhood intractable partial epilepsies: pathologic correlations.

We conducted a retrospective single-blind study assessing the value of MRI in 44 children surgically treated for partial epilepsy, and correlated the MRI findings with the pathology in all cases. MRI revealed abnormalities in concordance with the clinical and electroencephalographic data in 84% of patients. Developmental neuronal migration pathology was present in 25% of patients and was relatively more common in the sensorimotor cortex. There was hippocampal sclerosis in 50% of patients with temporal lobe resection; however, only two of the 10 children with hippocampal sclerosis were below the age of 12 years. Similarly, ganglio-glial tumors were more common than astrocytomas in children below age 12. These results indicate that MRI is sensitive in the detection of pathologic abnormalities in most pediatric candidates for epilepsy surgery, and that the distribution and type of pathology appear to be age related in this population.

Subjective versus objective memory change after temporal lobe epilepsy surgery.

OBJECTIVE: To examine subjective versus objective memory change after anterior temporal lobectomy (ATL). METHODS: A prospective, controlled study. Controls included 39 unoperated patients with intractable temporal lobe epilepsy (TLE) who were administered a series of cognitive and health-related quality of life measures at baseline and at 12-month follow-up intervals. The surgery sample included 65 patients with intractable, focal TLE who had undergone either a right or left ATL. These patients were tested preoperatively and at 6-month follow-up intervals. Subjective and objective memory change was quantified using a newly developed methodology to control for practice effect and regression to the mean. RESULTS: Measures of subjective and objective memory change were not significantly related in the surgery sample. Prevalence of significant subjective memory decline 1 year after surgery ranged from 3 to 7%, whereas prevalence of significant objective memory decline ranged from 26 to 55%. Postoperative levels of emotional distress significantly predicted self-reported memory decline 1 year after ATL. Postoperative medication side effect and seizure outcome were also related significantly to subjective memory change in patients who had undergone left ATL. CONCLUSIONS: Subjective and objective memory change after temporal lobectomy are not related. Complaints of significant memory decline after ATL are infrequent and may serve as a marker for depression or other mood disorder rather than organically based memory decline.