Efficacy and safety of lidocaine for treatment of neonatal seizures.

AIM: Treatment of neonatal seizures still relies primarily on phenobarbital, despite an estimated efficacy of less than 50% and concern over neurodegenerative side effects. The objective of this study was to evaluate the efficacy and safety of lidocaine as second-line treatment of neonatal seizures in infants following benzodiazepine treatment but without previous treatment with phenobarbital. METHODS: In a 10-year cohort, a retrospective chart review was conducted for all infants (gestational age ≥ 37 w, age ≤ 28 days) who had received lidocaine as second-line treatment of neonatal seizures prior to treatment with phenobarbital between January 2000 and June 2010. Infants were included if they had electroencephalographic seizures. RESULTS: Cessation of seizure activity was seen in 16 of 30 infants based on clinical and electroencephalographic features, and a probable response was seen in an additional 3 of 30 patients. Suspected adverse effects were seen in only one patient, who developed a transient bradycardia. CONCLUSION: Lidocaine has a moderate efficacy as second-line therapy following benzodiazepines for treating neonatal seizures and is not frequently associated with cardiovascular adverse effects. Lidocaine should therefore be considered in the treatment of seizures in the neonatal period to a higher extent than is the case today.

Relationship of mixed lymphocyte culture response to HL-A histocompatibility antigens. Effect of allele plus one antigen match.

The influence of varying degrees of incompatibility for HL-A antigens on one-way mixed lymphocyte cultures (MLC) has been investigated. Reactions have been compared to a simple expression of HL-A antigens, allele compatibility, and a proposal considering the potential influence of antigen matching in relationship to allele compatibility. As expected, HL-A compatibility was associated with nonstimulated cultures, but significant correlation was not observed when incompatibility was expressed in terms of HL-A antigen or allele mismatching. When the relationship of both was considered, however, a second distinctive group was demonstrated that shared one allele plus one antigen of the second allele. Within this group no stimulation, even with augmented culture conditions, was observed in some families. Employing these same criteria, there was no significant difference in the MLC response in those groups that were incompatible for both alleles regardless of the number of matched antigens or the group that shared an allele but differed by both antigens of the second allele. These results support the concept of an intimate relationship between the loci coding for HL-A antigens and mixed culture reactions. They suggest that HL-A haplotype incompatibility acting as a unit is the primary stimulus of the MLC response, and that the immunogenicity of the haplotype also relates to whether or not one antigen is common to the stimulating and responding cell.

Clinical, neuroimaging and neurophysiological features in addicts with manganese-ephedrone exposure.

OBJECTIVE: To identify biomarkers supporting the clinical diagnosis of manganism in patients several years after exposure to manganese (Mn). METHODS: Neurophysiological examinations, magnetic resonance imaging (MRI), single-photon emission computed tomography and fluorodeoxyglycose (FDG) positron emission tomography were performed in four former ephedrone addicts with extrapyramidal symptoms. RESULTS: Peripheral nervous system was not affected. No patients had reduced uptake of (123)I Ioflupane in the striatum. MRI signal intensities were slightly changed in the basal ganglia. All patients showed a widespread, but not uniform, pathological pattern of FDG uptake with changes mainly located to the central part of the brain including the basal ganglia and the surrounding white matter. CONCLUSIONS: Presynaptic neurons in the nigrostriatal pathway are intact in Mn-induced parkinsonism after prolonged abstinence from ephedrone. The diagnosis is principally based on clinical signs and the history of drug abuse.

Heterogeneity of antibody response to human platelet transfusion.

To study the antibody response to human platelet transfusions, nine thrombocytopenia patients with bone marrow failure were given 6 U (3X10(11)) of random platelet concentrates twice a week. Before transfusion, none of the patients had preexisting antibodies detectable with lymphocytotoxicity, platelet aggregation, or capillary leukoagglutination techniques. After receiving 18-78 U of platelets, they became refractory to further transfusions of random platelets and alloantibodies were detectable. Two patterns of antibody response could be identified. In three patients, the sera were not lymphocytotoxic with a panel of standard cells in which all the known HLA antigens in the first and second series were represented at least once. Yet, they caused platelet aggregation with 30, 24, and 60%, respectively, of a donor population studied. The aggregating activities were inhibited by antihuman IgG but not by antihuman IgA or antihuman IgM antiserum. The aggregating antibodies could be absorbed out with donor platelets but not lymphocytes or granulocytes. Antibodies from two of these patients aggregated platelets of their respective siblings matched for both HLA haplotypes. Transfusion of platelets from these two siblings did not increase the platelet count while platelets obtained from aggregation-negative donors did. The sera from the remaining six patients were lymphocytotoxic with 15-100% of the panel of standard cells. They also had aggregating antibodies, which could be absorbed out by both platelets and lymphocytes, suggesting that they were HLA antibodies. These data suggest that the development of platelet-specific antibodies may play an important role in the immunological rejection of isologous platelets, and should be considered in the selection of donors for patients who are refractory to platelets from random donors.

Comparison between adaptive and fixed stimulus paired-pulse transcranial magnetic stimulation (ppTMS) in normal subjects.

OBJECTIVES: Paired-pulse TMS (ppTMS) examines cortical excitability but may require lengthy test procedures and fine tuning of stimulus parameters due to the inherent variability of the elicited motor evoked potentials (MEPs) and their tendency to exhibit a 'ceiling/floor effects' in inhibition trials. Aiming to overcome some of these limitations, we implemented an 'adaptive' ppTMS protocol and compared the obtained excitability indices with those from 'conventional' fixed-stimulus ppTMS. METHODS: Short- and long interval intracortical inhibition (SICI and LICI) as well as intracortical facilitation (ICF) were examined in 20 healthy subjects by adaptive ppTMS and fixed-stimulus ppTMS. The test stimulus intensity was either adapted to produce 500 µV MEPs (by a maximum likelihood strategy in combination with parameter estimation by sequential testing) or fixed to 120% of resting motor threshold (rMT). The conditioning stimulus was 80% rMT for SICI and ICF and 120% MT for LICI in both tests. RESULTS: There were significant (p < 0.05) intraindividual correlations between the two methods for all excitability measures. There was a clustering of SICI and LICI indices near maximal inhibition ('ceiling effect') in fixed-stimulus ppTMS which was not observed for adaptive SICI and LICI. CONCLUSIONS: Adaptive ppTMS excitability data correlates to those acquired from fixed-stimulus ppTMS. SIGNIFICANCE: Adaptive ppTMS is easy to implement and may serve as a more sensitive method to detect changes in cortical inhibition than fixed stimulus ppTMS. Whether equally confident data are produced by less stimuli with our adaptive approach (as already confirmed for motor threshold estimation) remains to be explored.

HLA antigens and schizophrenia.

We typed 45 schizophrenic patients for 35 HLA antigens and compared their frequencies with 1,263 population controls. No significant differences between schizophrenics and controls were found. When the schizophrenics were subtyped, a significant (P less than .05) excess of Aw26 was found among the hebephrenics, compared with the population controls. When the published literature on schizophrenia-HLA associations was surveyed, none of the reported associations were found to be consistent across studies. Some possible explanations for the heterogeneity among studies are discussed and it is concluded that an association between schizophrenia and any of the HLA antigens has not yet been demonstrated.

Intracerebral microdialysis of extracellular amino acids in the human epileptic focus.

Extracellular levels of aspartate (ASP), glutamate (GLU), serine (SER), asparagine (ASN), glycine (GLY), threonine (THR), arginine (ARG), alanine (ALA), taurine (TAU), tyrosine (TYR), phenylalanine (PHE), isoleucine (ILEU), and leucine (LEU) were monitored by using intracerebral microdialysis in seven patients with medically intractable epilepsy, undergoing epilepsy surgery. In association with focal seizures, dramatic increases of the extracellular ASP, GLU, GLY, and SER concentrations were observed. The other amino acids analyzed, including TAU, showed small changes. The results support the hypothesis that ASP, GLU, GLY, and possibly SER, play an important role in the mechanism of seizure activity and seizure-related brain damage in the human epileptic focus.

Different neuron populations in the feline lateral cervical nucleus: a light and electron microscopic study with the retrograde axonal transport technique.

A comparative light and electron microscopic study was made of the two major neuron populations in the feline lateral cervical nucleus (LCN) that have an ascending projection--namely, the cervicothalamic and cervicomesencephalic neurons. The small population of neurons in the LCN that remained unlabelled after extensive injections into all known areas of LCN termination was also investigated. The intra-axonal retrograde tracing technique was employed and three different tracers were used: native horseradish peroxidase, horseradish peroxidase conjugated to wheat germ agglutinin, and cholera toxin subunit B (CTb). The diaminobenzidine and tetramethylbenzidine methods were used for the peroxidase reaction, and an immunocytochemical staining method with monoclonal antibodies was employed to localize CTb. The light microscopic cell count was performed on plastic-embedded semithin (2 micron) sections, and a section-embedding technique was used for sampling regions of interest for electron microscopy. The total number of neurons in the LCN was calculated to be 8,300, which is higher than numbers reported from other studies on frozen sections. It was concluded from control experiments that many neurons fail to counterstain in frozen sections. The average proportion of labelled cervicothalamic neurons was 94%, which accords with earlier reports. The frequency of labelled neurons projecting to the midbrain was 25-49%, depending on the method used. The highest number of labelled neurons was found with the immunocytochemical method with use of CTb as a tracer. In the electron microscopic study, the cell area, form factor, nuclear area, bouton covering ratio, mean appositional length of boutons, and bouton density were measured. There were no significant differences in these respects between the cervicothalamic and cervicomesencephalic neurons, but the unlabelled neurons differed significantly from the labelled ones, with a smaller somal area, a lower bouton covering ratio, and a larger relative nuclear area. The ascending neurons were scattered over the entire LCN, but the neurons that remained unlabelled after the extensive injections was found in its ventromedial part. It is suggested that these are interneurons. In the light microscopic study of the animals injected with CTb, the ventromedial part of the LCN displayed labelled structures resembling terminals. Electron microscopic examination of the sections revealed boutons synapsing on unlabelled neurons and dendrites. Occasionally labelled neurons and dendrites were also contacted.(ABSTRACT TRUNCATED AT 400 WORDS)

Postnatal development of the feline lateral cervical nucleus: I. A quantitative light and electron microscopic study.

With the aim of obtaining some basic information for future developmental studies, the lateral cervical nucleus (LCN) was investigated in 32 kittens of different ages by electron microscopic and stereologic methods. Corresponding light microscopic measurements of neuronal and nuclear profiles and of the total LCN volume were also performed. The total LCN volume increased sixfold between the ages of 12 hours and 120 days, the most rapid increase occurring during the first month. The neuronal size was fairly constant up to the age of 9 days, whereafter it showed greater variation. The mean profile area increased rapidly during the second week and then more slowly. The relative volume of boutons increased significantly between birth and the age of 34 days and then decreased slightly up to 120 days postnatally. The total bouton volume showed a steady increase, which was most pronounced between the ages of 9 and 34 days. The relative dendritic volume decreased during the 120 days of observation, whereas the total volume of dendrites increased up to the age of 92 days and then decreased. The total volume of glial cells increased during the 120-day observation period, as did both the relative and total volumes of myelinated axons. The changes in the relative volumes of mitochondria in boutons and dendrites were very similar, with increases that were most marked between the ages of 9 and 34 days and between 92 and 120 days.

Conductivity ratios of the scalp-skull-brain head model in estimating equivalent dipole sources in human brain.

The dipole tracing (DT) method estimates the position and vector dipole moment of an equivalent current dipole by minimizing the mean squared error of the dipole potentials at the surface electrode positions. In the scalp-skull-brain/DT (SSB/DT) method, which we have developed, the head model consists of three compartments of uniform conductors corresponding to the scalp, skull and brain. The accuracy of the calculations are mainly dependent on the ratios of the conductivities of the three compartments. The best result was obtained with the conductivity ratios of 1:1/80:1 for the scalp, skull and brain compartments, respectively.

The termination in the mesencephalon of fibres from the lateral cervical nucleus. An anatomical study in the cat.

The termination in the dorsal mesencephalon of fibres from the lateral cervical nucleus (LCN), recently discovered with the retrograde tracing technique, was investigated by both the degeneration method and anterograde transport of lectin-conjugated horseradish peroxidase. Both strategies gave similar results. The termination area was found to be situated at the level of transition between the superior and inferior colliculi and comprises mainly the intercollicular nucleus and the deep and intermediate layers of the posterolateral pole of the superior colliculus. The functional implication of the demonstrated projection from LCN is discussed in relation to somatosensory activity in the mesencephalic tectum.

Differences in the collateralization of neuronal projections from the dorsal column nuclei and lateral cervical nucleus to the thalamus and tectum in the cat: an anatomical study using two different double-labeling techniques.

The dorsal column nuclei (DCN) and the lateral cervical nucleus (LCN) project to the diencephalon and tectum. In order to determine which neurons project to these targets and whether any of them have collateral projections, the double-retrograde labeling techniques developed by Hayes and Rustioni and Kuypers et al. were used. Both strategies produced similar results. Within DCN, neurons which projected to the diencephalon were located differently and had a different morphology than those which projected to the tectum. The diencephalic-projecting neurons, which were preferentially located within the middle part of the DCN complex were mainly large (> 15 micrometer diameter) and round. The tectal-projecting neurons, often located along the edges of the gracile and cuneate nuclei or between them, were most often found outside of the middle parts of the DCN complex (i.e. predominantly rostrally and frequently also caudally). These tectal-projecting neurons varied in size and were usually oval or fusiform in shape. In contrast to DCN, neurons in LCN which projected either to the tectum or diencephalon did not differ morphologically and in both groups were of various sizes and shapes. They were intermixed haphazardly, predominantly within the lateral two-thirds of the nucleus. In addition, another class of neurons, constituting more than 40% of the labeled population in some experiments, had collateral projections to both terminal targets. These double-labeled neurons were haphazardly mixed with other labeled neurons.

Epileptic seizure activity in the acute phase following cortical impact trauma in rat.

The aim of this investigation was to determine the incidence of seizure activity in the acute phase following traumatic brain injury. Compression contusion trauma was produced in the right parietal cortex in 19 artificially ventilated rats. Electroencephalographic recordings were carried out in 17 of the animals for 2 h following the impact. The extracellular levels of neuroactive amino acids were simultaneously monitored in 9 of the experiments using microdialysis. In 14 of the 17 animals a generalized seizure activity with an average duration of 59 s (range 30-101 s) was recorded. The mean time lag between trauma and seizure onset was 67 s (range 26-90 s). The seizure activity was consistently followed by post-ictal depression. The trauma was accompanied by a transient increase of aspartate, taurine, glutamate and glycine, in decreasing rank order. The seizure activity occurred when the levels of these neuroactive amino acids were elevated. It is concluded that the high incidence of seizure activity observed may be an important factor contributing to secondary ischemia after traumatic brain injury. Aspartate and glutamate, potentiated by glycine, may play a role in post-traumatic seizure activity.

Convergence on the same neurons in the feline ventrobasal thalamus of terminals from the dorsal column and the lateral cervical nuclei: an ultrastructural study combining orthograde degeneration and anterograde axonal transport of lectin conjugated horseradish peroxidase.

After electrocoagulation of the dorsal column nuclei (DCN) and injections of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) into the lateral cervical nucleus (LCN), two kinds of changes in fibers and boutons were observed in the dorsolateral part of the thalamic ventroposterolateral nucleus (VPL). The axons and boutons from neurons in the DCN demonstrated dark degeneration, while the fibers and synaptic terminals from the LCN-neurons contained the characteristic needle-shaped peroxidase reaction products following incubation with tetramethylbenzidine (TMB). Occasionally dark degenerating boutons and boutons with TMB-positive reaction products showed synaptic contact with the same dendritic profiles. After consideration of the possibility of an axoaxonal transfer of the tracer it is concluded that the findings demonstrate convergence of synaptic input both from the DCN and from the LCN on the same postsynaptic VPL neurons. The present results are in accordance with earlier light microscopic and neurophysiological findings. It is also concluded that the ultrastructural technique employed in this study is well suited to reveal convergence of different afferent systems on the same postsynaptic neurons.

Decreased cortical levels of astrocytic glutamate transport protein GLT-1 in a rat model of posttraumatic epilepsy.

The extracellular homeostasis of glutamate in the brain is maintained by the efficient uptake into astroglial cells. The high extracellular glutamate levels seen during seizures are therefore probably a result of both an increased synaptic release and a deranged glutamate uptake. In this study we used immuno-blotting technique to measure the cortical levels of the astrocytic glutamate transport protein (GLT-1) and of the glutamate and aspartate transporting protein (GLAST) in an epilepsy model induced by ferrous chloride injection in the cortex of rats. The levels of GLT-1 were lower in epileptic rats than in controls, day 1 and 5 after induction, but not at 3 months. Glial fibrillary protein (GFAP) levels increased with time in the epileptic model, whereas GLAST and beta-tubulin III remained unchanged compared to controls. The results suggest that the transient decrease of GLT-1 could play a role in epileptogenesis, while recurrent seizure activity may be maintained by other mechanisms.

Generator mechanisms of epileptic potentials analyzed by dipole tracing method.

A new dipole tracing method, based on a realistic head model, was used to determine dipole locations and vector moments of interictal convexity sharp waves recorded (with conventional EEG technique) from the right fronto-temporal region in a patient with partial complex seizures. When the dipole locations in the head model were compared to MRI scans, the majority of the sharp wave dipoles were found to be located in the right hippocampal area. For individual sharp waves, the hippocampal dipoles moved along tracks corresponding to the vector moment directions, suggesting that the electrical sources of the convexity sharp waves were somato-dendritic currents which spread rapidly from one neuron group to the next in the hippocampal area. Previous long-term subdural recording had shown seizure onset in this area. After right-sided anterior temporal lobectomy including the hippocampus the patient has been seizure-free for three months.

Extracellular amino acid levels measured with intracerebral microdialysis in the model of posttraumatic epilepsy induced by intracortical iron injection.

An iron induced model of posttraumatic chronic focal epilepsy in rats was studied with respect to extracellular amino acids, electrophysiology, and morphology, approx. 6 months after intracortical injection of ferrous chloride. Twenty-six of the twenty-eight (93%) rats developed spontaneous epileptiform EEG-activity and electrical cortical stimulation done in eight animals evoked seizure activity in five animals (62.5%). Epileptic brain tissue displayed significantly higher extracellular interictal levels of aspartate (ASP), compared to normal brain, measured with intracerebral microdialysis. The interictal levels of serine (SER) were significantly higher at the lesion side compared to the contralateral cortex in epileptic animals. Spontaneous elevations of ASP and glutamate (GLU) levels up to 8 times the basal level were found in 4/5 (80%). There was no consistent amino acid pattern following the electrically induced seizures, but in association with more intense seizure activity ASP and GLU were elevated. Histopathologically, the necrotic lesions in the cortex contained small vessels and iron pigment loaded astrocytes. Scattered eosinophilic neurons were found in the hippocampus, bilaterally in 37% of the animals. The results show that a focal epileptiform activity developed in a high percentage of animals that received an intracortical iron injection. The observed amino acid changes in epileptic animals may be involved in the development of seizures in this model of posttraumatic epilepsy.

Long-term neurological dysfunction and neonatal hypoglycaemia after diabetic pregnancy.

AIM: To determine if children born to mothers with diabetes mellitus during pregnancy, who subsequently developed neonatal hypoglycaemia, experienced long-term neurological dysfunction. METHODS: Thirteen children with, and 15 without, neonatal hypoglycaemia (blood glucose < 1.5 mmol/l) were randomly selected from a larger cohort and investigated at the age of 8 years. They were also compared with 28 age matched healthy controls. RESULTS: Children with neonatal hypoglycaemia had significantly more difficulties in a validated screening test for minimal brain dysfunction than controls and were also more often reported to be hyperactive, impulsive, and easily distracted. On psychological assessment, they had a lower total development score than normoglycaemic children born to diabetic mothers, and control children. CONCLUSIONS: Neonatal hypoglycaemia in diabetic pregnancy was associated with long-term neurological dysfunction related to minimal brain dysfunction/deficits in attention, motor control, and perception.

Electric stimulation of a transsected nerve does not seem to prevent loss of sensory neurons: an experimental study in cats.

Injury to a sensory nerve often results in a clinically poor long term outcome, possibly as a result of the extensive loss of neurons within the dorsal root ganglia (DRG), which has been shown in several experimental studies. This loss is possibly caused by interruption of the sensory input and axonal transport in the damaged afferent nerve. To investigate the importance of sensory afferent input into a nerve a pulsed electric stimulation was applied on the proximal part of the superficial radial nerve after transsection and microsurgical repair. The purpose was to simulate nerve impulses and thereby mask the severity of the injury. To test this hypothesis a pilot study was undertaken in eight cats. The neuronal tracer showed that the median neuronal loss was 38% of the neurons of the dorsal root ganglia that received afferents from the nerve investigated, which corresponds to the figure in a previous study in which electric stimulation was not used. Artificial sensory stimulation during regeneration in a transsected and repaired peripheral nerve therefore does not seem to reduce neuronal loss.