Gösta Blennow

Vagus Nerve Stimulation in 16 Children with Refractory Epilepsy

Summary: Purpose: Vagus nerve stimulation (VNS) has been reported to produce >90% reduction in the number of seizures in children with intractable epilepsy. These encouraging results need confirmation.

Carbohydrate-deficient glycoprotein syndromes: peculiar group of new disorders.

A new group of metabolic disorders, the carbohydrate-deficient glycoprotein (CDG) syndromes, is reviewed with emphasis on the key condition, the CDG syndrome type I. This disease, an autosomal-recessive multisystem condition, has now been diagnosed in 45 Scandinavian patients. It is characterized by carbohydrate deficiencies of a number of glycoproteins, including uniform changes in transferrin. The transferrin alterations provide a distinct biologic marker and a practical and simple laboratory diagnostic means employing analysis of serum or blood spots from Guthrie-type filter paper. The syndrome presents differently through various life periods. A four-stage grouping system by age has been constructed and is presented. During infancy, internal organ symptoms are dominant; some may be life-threatening. In later childhood and adolescence, static mental deficiency, cerebellar ataxia, slowly progressive lower limb neuropathy, and pigmentary retinal degeneration, as well as secondary skeletal deformities, are the most prominent findings. Two very recently described clinical and biologic variants, CDG syndromes II and III, are summarized and compared to CDG type I.

Vagus nerve stimulation in 15 children with therapy resistant epilepsy; its impact on cognition, quality of life, behaviour and mood

PURPOSE Vagus nerve stimulation (VNS) is a neurophysiologic treatment for patients with refractory epilepsy. There is growing evidence of additional quality of life (QOL) benefits of VNS. We report the effects of VNS on seizure frequency and severity and how these changes are related to cognitive abilities, QOL, behaviour and mood in 15 children with medically refractory and for surgery not eligible epilepsy. METHODS Initially, and after 3 and 9 months of VNS-treatment, 15 children were investigated with Bayley Scales of Infant Development (BSID), Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R), Wechlser Intelligence Scales for Children (WISC-III) depending on the childs level of functioning, a Visual Analogue Scale for validating QOL, Child Behaviour Checklist (CBCL) for quantifying behaviour problems, Dodrill Mood Analogue Scale and Birleson Depression Self-Rating Scale, and the National Hospital Seizure Severity Scale (NHS3). A diary of seizure frequency was collected. RESULTS Six of 15 children showed a 50% or more reduction in seizure frequency; one of these became seizure-free. Two children had a 25-50% seizure reduction. Two children showed increased seizure frequency. In 13 of 15 children there was an improvement in NHS3. The parents reported shorter duration of seizure and recovery phase. There were no changes in cognitive functioning. Twelve children showed an improvement in QOL. Eleven of these also improved in seizure severity and mood and five also in depressive parameters. CONCLUSION This study has shown a good anti-seizure effect of VNS, an improvement in seizure severity and in QOL and a tendency to improvement over time regarding behaviour, mood and depressive parameters. The improvement in seizure severity, QOL, behaviour, mood and depressive parameters was not related to the anti-seizure effect.

Hyperthermia aggravates and hypothermia ameliorates epileptic brain damage

The influence of hyperthermia and hypothermia on epileptic brain damage was studied in rats, in which status epilepticus was induced by flurothyl. Histopathological changes were examined by light microscopy after 1 or 7 days of recovery. Two series of animals were studied. In the first, short periods of seizures (20 and 25 min) were employed to examine whether moderate hyperthermia (39.5° C) would aggravate epileptic brain damage, and a longer period (45 min) was used to investigate whether moderate hypothermia (32.5° C) would ameliorate the damage. The second series investigated whether brief periods of status epilepticus (10 min) would cause brain damage if hyperthermia were high or excessive. For this series, animals with body temperatures of 37.0, 39.0, and 41.0° C were studied. Data from normothermic animals (37.5° C) confirmed previously described neuronal damage. Although hyperthermic animals failed to showe increased damage in the CA1 sector, or in the hilar region of the dentate gyrus, they showed enhanced damage in the neocortex and globus pallidus (GP). In substantia nigra pars reticulata (SNPR) four out of five hyperthermic animals had bilateral infarcts after 20 min of status epilepticus, whereas no normothermic animal showed such damage. Hypothermia seemed to ameliorate epileptic brain damage in the neocortex (n.s.) and GP (P < 0.05) following status epilepticus for 45 min. Three out of seven hypothermic animals had mild SNPR involvement compared to severe infarction of the nucleus in five out of six normothermic animals (P < 0.05). Thus, hyperthermia aggravated and hypothermia ameliorated epileptic brain damage both in regions showing selective neuronal necrosis (neocortex) and in regions developing pan-necrosis (GP and SNPR). The second series displayed an unexpected result of excessive hyperthermia. Animals subjected to only 10 min of status epilepticus at a temperature of 41° C showed not only neocortical lesions, but also moderate to extensive damage to the hippocampus (CA1, subiculum, and dentate gyrus). It is concluded that at high body and brain temperature, brief periods of status epilepticus can yield extensive brain damage, primarily affecting the hippocampus.

Sleep and wakefulness in preadolescent children with deficits in attention, motor control and perception

In 10 children with deficits in attention, motor control and perception (DAMP), the relation between daytime vigilance and night‐time sleep quality was examined with polygraphic sleep recordings, multiple sleep latency tests and measurements of reaction times. Two girls and eight boys, 6–12 years of age were studied. Eighteen normal children served as controls. Normal sleep regulation and sleep quality was found, but the children with DAMP tolerated the recording procedure less well than the controls. Most patients did not suffer from increased daytime sleepiness, but at MSLT 3, patients had short sleep latencies as in daytime hypersomnolence. Reaction times were significantly longer among the patients than among the controls. It is proposed that the findings may be related to functional changes in the forebrain.

Effects of reduced cerebral blood flow upon EEG pattern, cerebral extracellular potassium, and energy metabolism in the rat cortex during bicuculline-induced seizures

Progressive cerebral ischemia was induced by blood pressure (BP) reduction in rats during status epilepticus, and the sequence of cerebral functional (EEG, extracellular K+ activity) and metabolic (levels of high energy phosphates, glucose, glucose-6-phosphate, lactate, pyruvate, alpha-ketoglutarate) changes were determined. Very moderate reductions of BP were accompanied by tissue lactate accumulation and a decrease of the rate of re-uptake of K+ extruded during discharges. These changes were pronounced at BP about 50 mm Hg, when also the energy state showed some deterioration, and the EEG activity changed from one of bursts and suppressions into single spikes. At BP about 30 mm Hg EEG activity was abolished, but not until a slightly lower BP level was there a severe energy depletion and a massive K+ release, indicating generalized membrane depolarization. The results show an increased susceptibility to ischemia during seizures with changes of membrane pump function, and energy metabolism appearing at moderate reductions of BP. Concomitant decrease of seizure activity delayed to some extent the development of massive energy failure and membrane depolarization.

Cerebral metabolic and circulatory changes in the rat during sustained seizures induced bydl-homocysteine

Sustained, generalized seizure activity was induced in anaesthetized (70% N2O), paralyzed and artifically ventilated rats by i.p. DL-homocysteine thiolactone in a dose of 11 mmol/kg. Epileptic discharges in the EEG were accompanied by marked perturbation of tissue metabolites. There was a fall in phosphocreatine concentration to 40% of control but only moderate changes in adenine nucleotides, a marked rise in lactate concentration, and a pronounced increase in the lactate/pyruvate ratio. Excessive amounts of dihydroxyacetone phosphate (and glyceraldehyde phosphate) accumulated, indicating that depletion of NAD+ occurred. There was marked accumulation of ammonia, glutamine and alanine, and reduction in glutamate and aspartate concentrations. Administration of a subconvulsive dose of homocysteine (7.5 mmol/kg) gave rise to changes in ammonia and amino acids, qualitatively similar to those occurring during seizures. It is concluded that although changes in the metabolites of the energy reserve were mainly caused by the induced seizures, those affecting amino acid concentrations were significantly influenced by accumulation of ammonia, secondary to metabolism of injected homocysteine. Cerebral blood flow (CBF) and oxygen utilization (CMRO2) were measured during sustained seizures. CMRO2 rose to 150% of control, with a corresponding increase in CBF.

Low risk of seizure recurrence after early withdrawal of antiepileptic treatment in the neonatal period.

The risk of seizure recurrence within the first year of life was evaluated in infants with neonatal seizures diagnosed with a combination of clinical signs, amplitude-integrated electroencephalogram (EEG) monitoring, and standard EEG. Fifty eight of 283 (4.5%) neonates in tertiary level neonatal intensive care had seizures. The mortality in the infants with neonatal seizures was 36.2%. In 31 surviving infants antiepileptic treatment was discontinued after one to 65 days (median 4.5 days). Three infants received no antiepileptic treatment, two continued with prophylactic antiepileptic treatment. Seizure recurrence was present in only three cases (8.3%)--one infant receiving prophylaxis, one treated for 65 days, and in one infant treated for six days. Owing to the small number of infants with seizure recurrence, no clinical features could be specifically related to an increased risk of subsequent seizures. When administering antiepileptic treatment, one aim was to abolish both clinical and electrographical seizures. Another goal was to minimise the duration of treatment and to keep the treatment as short as possible. It is suggested that treating neonatal seizures in this way may not only reduce the risk of subsequent seizure recurrence, but may also minimise unnecessary non-specific prophylactic treatment for epilepsy.

Neuromotor deviation in offspring of psychotic mothers: A selective developmental deficiency in two groups of children at heightened psychiatric risk?

As part of a longitudinal investigation begun in the neonatal period, selected neuromotor behaviors and different facets of general mental development were investigated blind at 6 years of age in 64 index offspring of women with a history of schizophrenic, schizoaffective, affective and unspecified functional psychosis and in 95 control offspring of women with no history of psychosis. Compared with the controls, the offspring of psychotics (total index group) showed a significantly increased frequency of both multiple and specific neuromotor deviations. The offspring of women with schizophrenia and with unspecified functional psychosis showed increased rates of multiple neuromotor deviations, not found in the offspring of women with schizoaffective and affective psychoses. The neuromotor deviations were confirmed on Griffiths Developmental Test subscales reflecting gross and fine motor performance, and the deficits did not extend to subscales measuring cognitive ability and personal-social competence. No relationship was found between the individual subjects neonatal and 6-year deviation scores. The results suggest the existence of a selective neuromotor developmental deviation in the offspring of schizophrenics and women with unspecified functional psychosis. Different possible etiological factors are discussed.

Spect Findings in Children with Specific Language Impairment

Findings from 99mTc-HMPAO SPECT measurements at rest in a group of 19 school-age children with specific language impairment (SLI) were compared to a group of 12 children with attention-deficit hyperactivity disorder (ADHD). The regional cerebral blood flow (CBF) distributions were different in the two groups. Children with SLI showed significantly lower CBF values in the right parietal region and in the subcortical region compared to the ADHD group. In addition, the SLI group had symmetric CBF distributions in the left and right temporal regions, whereas the ADHD group showed the usual asymmetry with left-sided hemispheric predominance in the temporal regions. The findings give further evidence for anomalous neurodevelopment with deviant hemispheric lateralization as an important factor in the aetiology of SLI. They also point to the role of subcortical structures in language impairment in childhood. Earlier focus on cortical structures in SLI research needs to be widened to include subcortical regions as well.