Quantifying and visualizing uncertainty in EEG data of neonatal seizures.

This paper presents an approach to quantifying and visualizing uncertainty in EEG data of neonatal seizures. This approach exploits the inherent ability of trained quantum neural networks (QNNs) to learn arbitrary membership profiles from sample data. The ability of QNNs to quantify uncertainty in data is combined with the ability of ordered self-organizing maps (SOMs) to recognize structure in data and allow its visualization in two dimensions. The proposed approach is evaluated using EEG data of neonates monitored for seizures.

Quantifying motion in video recordings of neonatal seizures by feature trackers based on predictive block matching.

This work introduces predictive block matching, a method developed to track motion in video by exploiting the advantages of block motion estimation and adaptive block matching. The proposed method relies on a pure translation motion model to estimate the displacement of a block between two successive video frames before initiating the search for the best match of the block tracked throughout the frame sequence. The search for the best match relies on adaptive block matching, which employs an update strategy based on Kalman filtering to account for the changing appearance of the block. Predictive block matching was used to extract motor activity signals from video recordings of neonatal seizures.

Discrete optical flow estimation methods and their application in the extraction of motion strength signals from video recordings of neonatal seizures.

This work presents a methodology for the development of regularized optical flow computation methods for video. The proposed methodology is based on a discrete formulation of the optical flow problem. The optical flow computation methods produced by the proposed methodology are utilized to extract temporal motion strength signals from video recordings of neonatal seizures.

Extraction of motion strength and motor activity signals from video recordings of neonatal seizures.

This paper presents two methods developed to extract quantitative information from video recordings of neonatal seizures in the form of temporal motion strength and motor activity signals. Motion strength signals are extracted by measuring the area of the body parts that move during the seizure and the relative speed of motion using a combination of spatiotemporal subband decomposition of video, nonlinear filtering, and segmentation. Motor activity signals are extracted by tracking selected anatomical sites during the seizure using a modified version of a feature-tracking procedure developed for video, known as the Kanade-Lucas-Tomasi (KLT) algorithm. The experiments indicate that the temporal signals produced by the proposed methods provide the basis for differentiating myoclonic from focal clonic seizures and distinguishing these types of neonatal seizures from normal infant behaviors.

An IL-2/Ig fusion protein influences CD4+ T lymphocytes in naive and simian immunodeficiency virus-infected Rhesus monkeys.

The T cell-stimulatory cytokine interleukin 2 (IL-2) is being evaluated as a therapeutic in the clinical settings of HIV infection and cancer. However, the clinical utility of IL-2 may be mitigated by its short in vivo half-life, toxic effects, and high production costs. We show here that an IL-2/Ig fusion protein possesses IL-2 immunostimulatory activity in vitro and a long in vivo half-life. IL-2/Ig treatment of healthy rhesus monkeys induced significant increases in CD4(+) T lymphocyte counts and expression of CD25 by these cells. Short courses of IL-2/Ig treatment of simian immunodeficiency virus (SIV)-infected rhesus monkeys in conjunction with antiretroviral drugs resulted in increased CD25 expression on T lymphocytes, and transient increases in CD4(+) T lymphocyte counts. Plasma viremia did not increase in these treated animals. Treatment of healthy or SIV-infected rhesus monkeys with a plasmid encoding the IL-2/Ig protein did not affect CD4(+) T lymphocytes. These results demonstrate that IL-2/Ig has potential utility as an immunostimulatory therapeutic.

Augmentation of immune responses to HIV-1 and simian immunodeficiency virus DNA vaccines by IL-2/Ig plasmid administration in rhesus monkeys.

The potential utility of plasmid DNA as an HIV-1 vaccination modality currently is an area of active investigation. However, recent studies have raised doubts as to whether plasmid DNA alone will elicit immune responses of sufficient magnitude to protect against pathogenic AIDS virus challenges. We therefore investigated whether DNA vaccine-elicited immune responses in rhesus monkeys could be augmented by using either an IL-2/Ig fusion protein or a plasmid expressing IL-2/Ig. Sixteen monkeys, divided into four experimental groups, were immunized with (i) sham plasmid, (ii) HIV-1 Env 89.6P and simian immunodeficiency virus mac239 Gag DNA vaccines alone, (iii) these DNA vaccines and IL-2/Ig protein, or (iv) these DNA vaccines and IL-2/Ig plasmid. The administration of both IL-2/Ig protein and IL-2/Ig plasmid induced a significant and sustained in vivo activation of peripheral T cells in the vaccinated monkeys. The monkeys that received IL-2/Ig plasmid generated 30-fold higher Env-specific antibody titers and 5-fold higher Gag-specific, tetramer-positive CD8+ T cell levels than the monkeys receiving the DNA vaccines alone. IL-2/Ig protein also augmented the vaccine-elicited immune responses, but less effectively than IL-2/Ig plasmid. Augmentation of the immune responses by IL-2/Ig was evident after the primary immunization and increased with subsequent boost immunizations. These results demonstrate that the administration of IL-2/Ig plasmid can substantially augment vaccine-elicited humoral and cellular immune responses in higher primates.

Pharmacokinetics and stability of the ch14.18-interleukin-2 fusion protein in mice.

The fusion protein formed from ch14.18 and interleukin-2 (ch14.18-IL-2), shown to exhibit antitumor efficacy in mouse models, consists of IL-2 genetically linked to each heavy chain of the ch14.18 chimeric anti-GD2 monoclonal antibody. The purpose of this study was to determine the pharmacokinetics of ch14.18-IL-2 in mice and assess its stability in murine serum. Following i.v. injection, the fusion protein was found to have a terminal half-life of 4.1 h. Detection of IL-2 following injection of the ch14.18-IL-2 fusion protein showed a similar half-life, indicating that the fusion protein prolongs the circulatory half-life of IL-2. Detection of human IgG1 following injection of ch14.18-IL-2 showed a terminal half-life of 26.9 h. These data suggested that the native fusion protein is being altered in vivo, resulting in a somewhat rapid loss of detectable IL-2, despite prolonged circulation of its immunoglobulin components. In vitro incubation of the ch14.18-IL-2 fusion protein in pooled mouse serum at 37 degrees C for 48 h resulted in a loss of its IL-2 component, as detected in enzyme-linked immunosorbent assay systems and in proliferation assays. Polyacrylamide gel electrophoresis and Western blot analysis of the fusion protein incubated in mouse serum at 37 degrees C indicated that the ch14.18-IL-2 is cleaved, resulting in a loss of the 67-kDa band (representing the IL-2 linked to the IgG1 heavy chain) and the detection of a band of more than 50 kDa, slightly heavier than the IgG1 heavy chain itself. This suggests that the fusion protein is being cleaved in vitro within the IL-2 portion of the molecule. These studies show that (1) ch14.18-IL-2 prolongs the circulatory half-life of IL-2 (compared to that of soluble IL-2) and (2) the in vivo clearance of the fusion protein occurs more rapidly than the clearance of the ch14.18 antibody itself, possibly reflecting in vivo cleavage within the IL-2 portion of the molecule, resulting in loss of IL-2 activity.

An automated system for epileptogenic focus localization in the electroencephalogram.

This paper describes an automated system for the detection and localization of foci of epileptiform activity in the EEG. The system detects sharp EEG transients (STs) in the process, but the emphasis is on epileptic focus localization. A combination of techniques involving signal processing, pattern recognition, and the expert rules of an experienced electroencephalographer, involving considerable spatiotemporal context information, is applied to multichannel EEG data. An overall emphasis on minimizing the number of false-positive sharp transient detections drives the system design. Tested on data from 13 subjects with epileptiform activity and 5 controls, all areas of focal epileptiform activity were detected by the system, although not all of the contributing foci were reported separately. Two false-positive foci were detected as well due to nonfocal spike activity and normal spike-like activity not present in the training set. The system detected 95.7% of the epileptiform events constituting the correctly detected foci, with a false detection rate of 11.1%.

The presence of CD34+ cell clusters predicts impending relapse in children with acute lymphoblastic leukemia receiving maintenance chemotherapy.

Early detection of relapse in children with acute lymphoblastic leukemia (ALL), as well as distinction of leukemic blasts from hematogones, can be difficult by morphologic examination alone. Using CD34 and terminal deoxynucleotidyl transferase (TdT) immunoperoxidase stains, we studied specimens from 25 children with ALL in morphologic remission to determine if we could identify children at risk of relapse. We studied morphologic remission bone marrow specimens from 9 patients who experienced relapse during the subsequent 6 months and 16 children who remained in complete remission, including 10 specimens with increased numbers of hematogones. Despite morphologic remission, clusters of more than 5 CD34+ and/or TdT-positive cells were identified before overt relapse in 6 of 9 cases of relapse, but were noted in only 1 of 10 specimens from children in continuous complete remission and none of 10 specimens with increased numbers of hematogones. Clusters of CD34+ or TdT-positive cells can identify individual patients at risk for imminent relapse. Hematogones may be differentiated from lymphoblasts by this method.

Rett syndrome: characterization of seizures versus non-seizures.

Epileptic seizures are reported to occur frequently in Rett syndrome (RS). We evaluated the hypothesis that many events classified as seizures in RS represent other paroxysmal, non-epileptic events; thus, the overall incidence of seizures in RS is overestimated. We conducted video/polygraphic/EEG monitoring sessions (8-120 h duration) in 82 RS females (ages 2-30 years). Fifty-five patients (67%) had a history of seizures and 43 (52%) were receiving anticonvulsants. All had abnormal EEGs. These abnormalities included epileptiform findings, the frequency of which ranged from 60% of patients in clinical stage IV to 97% of patients in clinical stage III. During monitoring, electrographic seizures were recorded in only 13 patients (16%) and included both partial and generalized events. Clinical events correlating with EEG seizure discharges were identified by parents during only 5 of these recordings. The parents of 23 (42%) of the 55 patients with a history of seizures identified events during monitoring that they felt were representative of the child's typical 'seizures', but which were not associated with EEG seizure discharges. These 'non-seizure' events included episodes of motor activity, such as twitching, jerking, head turning, falling forward, and trembling, as well as episodes of staring, laughing, pupil dilatation, breath holding and hyperventilation. These studies confirm that the occurrence of epileptic seizures is overestimated in RS, and further suggest that actual seizures may be under-recognized. Video/EEG monitoring can provide definitive information regarding the need for anticonvulsant therapy in RS.

A phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus interleukin-2 in children with refractory neuroblastoma: a report of the Children's Cancer Group.

BACKGROUND: The murine monoclonal antibody (MoAb) 14.G2a recognizes GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and facilitates antibody dependent cellular cytotoxicity (ADCC) in vitro. When given in vivo, interleukin-2 (IL-2) can increase ADCC by enhancing the activity and number of circulating lymphocytes. METHODS: Thirty-three pediatric patients with GD2 positive malignancies, ranging in age from 2 to 17 years (median, 9.9 years), received IL-2 and 14.G2a in this Phase I/IB study of the Children's Cancer Group (CCG) and were monitored for toxicities and response to therapy. Seven of these patients also received granulocyte-macrophage-colony stimulating factor. RESULTS: The maximum tolerated dose (MTD) of 14.G2a with IL-2 was 15 mg/m2/day. The most prevalent Grade 3-4 toxicities were generalized pain (n = 14 [42%]) and fever without documented infection (n = 17 [52%]). IL-2 was thought to be the causative agent in most cases of fever. Toxicities attributed to 14.G2a included pain, allergic or anaphylactic reactions, and rash. Human antimouse antibodies were demonstrated in 9 of 21 evaluated patients. One patient with neuroblastoma had a partial response, and one patient with osteosarcoma had a complete response. Immunocytology demonstrated that the number of neuroblastoma cells in bone marrow decreased in three patients. CONCLUSIONS: The murine MoAb 14.G2a was well tolerated at the MTD and appeared to have some antitumor activity. Further development of this approach will involve additional engineered forms of the antibody as well as testing in the adjuvant and minimal residual disease setting.

Progressive Langerhans cell histiocytosis in an infant with Klinefelter syndrome successfully treated with allogeneic bone marrow transplantation.

PURPOSE: We describe successful treatment of an infant with progressive Langerhans cell histiocytosis (LCH) with allogeneic bone marrow transplantation (BMT), and discuss a chromosomal abnormality discovered in his LCH-affected tissue. PATIENTS AND METHODS: A 4-month-old male infant with a seborrheic-appearing rash, respiratory collapse, and spontaneous pneumothorax is presented. LCH was diagnosed with primary involvement of skin and lungs. His disease progressed despite aggressive multiagent chemotherapy that included high-dose methylprednisolone, vinblastine, cyclophosphamide, methotrexate, 2-chlorodeoxyadenosine, and etoposide. RESULTS: The patient was successfully treated with myeloblative therapy and low-dose total body irradiation followed by allogeneic BMT at the age of 16 months, at which time he had multisystem involvement. One hundred percent 47XXY/14p+ cells were identified from a lung biopsy; peripheral blood chromosomal analysis demonstrated mosaic 47XXY/14p+, and normal 46XY. CONCLUSIONS: Allogeneic BMT may be used successfully in the treatment of refractory, progressive LCH in infants, who are at highest risk of mortality. The cytogenetic association between Klinefelter syndrome and LCH has not been described previously. Cytogenetic analysis of other patients with LCH may be beneficial in determining a genetic association between LCH and Klinefelter syndrome and/or abnormalities of chromosome 14.

Tetanus toxin-induced seizures in infant rats and their effects on hippocampal excitability in adulthood.

A new experimental model of developmental epilepsy is reported. Behavioral and EEG features of seizures produced by unilateral intrahippocampal injection of tetanus toxin in postnatal day 9-11 rats, are described. Within 24-72 h of tetanus toxin injection, rat pups developed frequent and often prolonged seizures which included combinations of repetitive wet dog shakes, and wild running-jumping seizures. Intrahippocampal and cortical surface EEG recordings showed that coincident with these behaviors, electrographic seizures occurred not only in the injected hippocampus, but also in the contralateral hippocampus and bilaterally in the neocortex. Analysis of the interictal EEG revealed multiple independent spike foci. One week following tetanus toxin injection, the number of seizures markedly decreased; however, interictal spiking persisted. After injection rats were allowed to mature some were observed to have unprovoked behavioral seizures and/or epileptiform EEG activity. Mature animals were also studied using in vitro slice techniques. Recordings from hippocampal slices demonstrated spontaneous epileptiform burst discharges in the majority of rats which had tetanus toxin induced seizures as infants. These events occurred in area CA3 and consisted of interictal spikes and intracellularly recorded paroxysmal depolarization shifts (PDSs). On rarer occasions, electrographic seizures were recorded. The use of the tetanus toxin model in developing rats may facilitate a better understanding of the unique features of epileptogenesis in the developing brain and the consequences early-life seizures have on brain maturation and the genesis of epileptic conditions in later life.

Alpha rhythm slowing during initiation of carbamazepine therapy: implications for future cognitive performance.

A prospective study comparing the immediate changes in occipital electroencephalographic (EEG) frequency following institution of carbamazepine therapy to long-term alterations of neuropsychological performance is reported. The patient group consisted of 16 previously untreated children in the 5-14-year age range who had recent onset partial seizures and were managed for at least 1 year with carbamazepine monotherapy. EEG changes following initiation of carbamazepine therapy, as compared to baseline, were determined by a computer-based quantitative method. Neuropsychological factors were assessed at baseline and after 1 year of therapy. While the alpha frequency decreased following institution of carbamazepine in most subjects, a greater decline (typically > 0.5 Hz) was observed in the subset who subsequently demonstrated decreased neuropsychological performance at 1 year. The major effects could be attributed to the Arithmetic and Picture Completion subtests of the Wechsler Intelligence Scale for Children-Revised (WISC-R). The findings suggest that quantitative EEG analysis may be useful for identifying individuals at increased risk for developing anticonvulsant-related long-term cognitive changes.

Coupling of focal electrical seizure discharges with infantile spasms: incidence during long-term monitoring in newly diagnosed patients.

To investigate the coupling of focal electrical seizure discharges (FS) and infantile spasms, we analyzed the video/polygraphic monitoring studies performed on 96 consecutive patients newly diagnosed with infantile spasms and hypsarrhythmic EEGs. A FS was considered to be coupled with infantile spasms if it occurred during a cluster of spasms (a series of individual spasms separated by < 1 min) or within 10 s of spasm onset or cessation. Ten patients demonstrated FS. In five patients (5% of the entire population) an apparent coupling of some FS with infantile spasms was observed during the baseline monitoring study. However, in three patients (only 3% of the entire population) was the observed coupling of FS and infantile spasms significant (p < 0.05). These results indicate that coupling of FS and infantile spasms occurs rarely, and that, in some instances, apparent couplings of FS and infantile spasms are best explained by chance coincidence. These findings do not support the hypothesis that the generation of infantile spasms at a subcortical level is dependent on a focal cortical discharge.

High-dose, long-duration versus low-dose, short-duration corticotropin therapy for infantile spasms.

Fifty patients in whom the diagnosis of infantile spasms had recently been made and who had hypsarrhythmic electroencephalographic findings were randomly assigned to receive either high- or low-dose therapy with corticotropin (adrenocorticotropic hormone; ACTH). Twenty-six patients receiving the high-dose therapy were treated as follows: 150 U/m2 per day for 3 weeks, 80 U/m2 per day for 2 weeks, 80 U/m2 every other day for 3 weeks, and 50 U/m2 per day every other day for 1 week, with the dosage then tapered to zero during a 3-week period. The 24 patients assigned to the low-dose therapy group received 20 to 30 U/day for 2 to 6 weeks; the dosage was then tapered to zero during a 1-week period. Population characteristics (cryptogenic vs symptomatic, treatment lag, and age at start of treatment) of the two groups were similar. Response, defined as cessation of spasms and disappearance of hypsarrhythmia, was determined objectively by serial prolonged video and polygraphic monitoring studies. Of the 26 patients treated with the high-dose therapy, 13 (50%) responded; of the 24 patients treated with the low-dose therapy, 14 (58%) responded (p value not significant). No significant difference in the relapse rate between the two groups was observed. The side effects seen in both treatment groups were similar, except that hypertension occurred more frequently in the high-dose group. These results indicate that there is no major difference in the effectiveness of these two regimens in the treatment of infantile spasms with respect to spasm cessation and improvement in the patients' electroencephalographic findings.

Rett syndrome: controlled study of an oral opiate antagonist, naltrexone.

HYPOTHESIS: The opiate antagonist, naltrexone, will be beneficial in Rett syndrome. SUBJECTS: Twenty-five individuals fulfilling the criteria for Rett syndrome. METHOD: Randomized, double-blind, placebo-controlled crossover trial with two treatment periods, 4 months each, and an intervening 1-month washout period. Clinical stage, motor and cognitive development, motor-behavioral analysis, neurophysiological parameters (computerized electroencephalographic analysis, breathing characteristics, quantification of stereotyped hand movements, and sleep characteristics), and cerebrospinal fluid beta-endorphin measurements were evaluated at baseline and at the end of each treatment period. RESULTS: Only data from the first period of this study were analyzed due to significant sequence effects in the crossover design. This analysis indicated positive effects on certain respiratory characteristics including decreased disorganized breathing during wakefulness. Four (40%) of the individuals receiving naltrexone progressed one or more clinical stages versus none of the individuals receiving placebo. The adjusted (for baseline value and Rett stage) end of treatment psychomotor test age (Bayley Scales) was significantly higher for the placebo group. There was no significant change for the other parameters. CONCLUSION: Naltrexone may modify some of the respiratory disturbance in Rett syndrome. Declines in motor function and more rapid progression of the disorder suggest a deleterious effect.