Johan Lundgren

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.

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.

Ketogenic Diet Improves Sleep Quality in Children with Therapy-resistant Epilepsy.

Summary:  Purpose: The study purpose was to evaluate sleep structure during ketogenic diet (KD) treatment in children with therapy‐resistant epilepsy and to correlate possible alterations with changes in clinical effects on seizure reduction, seizure severity, quality of life (QOL), and behavior.

Aspiration: A Potential Complication to Vagus Nerve Stimulation

Summary: Purpose: Vagus nerve stimulation (VNS) is reported to reduce the frequency of seizures in children and adults without causing serious side effects. However, clinical observation of swallowing difficulties in 2 children treated with VNS made further investigation necessary.

Classification, incidence and survival analyses of children with CNS tumours diagnosed in Sweden 1984-2005

Aim:  Primary tumours in the central nervous system (CNS) are the second most common malignancy in childhood after leukaemia. Sweden has a high incidence and a high‐survival rate in international comparative studies. This has raised the question about the type of tumours included in the Swedish Cancer registry. We therefore compared international data to the Swedish Childhood Cancer registry.

Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations

Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3′,5‐triiodothyronine (T3). Mutations in MCT8 are associated with severe psychomotor retardation, high serum T3 and low 3,3′,5′‐triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3‐responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations. Hum Mutat 0,1‐10, 2008.

Acidosis-Induced Ischemic Brain Damage: Are Free Radicals Involved?

Substantial evidence exists that reactive oxygen species participate in the pathogenesis of brain damage following both sustained and transient cerebral ischemia, adversely affecting the vascular endothelium and contributing to the formation of edema. One likely triggering event for free radical damage is derealization of protein-bound iron. The binding capacity for some iron-binding proteins is highly pH sensitive and, consequently, the release of iron is enhanced by acidosis. In this study, we explored whether enhanced acidosis during ischemia triggers the production of reactive oxygen species. To that end, enhanced acidosis was produced by inducing ischemia in hyperglycemic rats, with normoglycemic ones serving as controls. Production of H2O2, estimated from the decrease in catalase activity after 3-amino-1,2,4-triazole (AT) administration, was measured in the cerebral cortex, caudoputamen, hippocampus, and substantia nigra (SN) after 15 min of ischemia followed by 5, 15, and 45 min of recovery, respectively (in substantia nigra after 45 min of recovery only). Free iron in cerebrospinal fluid (CSF) was measured after ischemia and 45 min of recovery. Levels of total glutathione (GSH + GSSH) in cortex and hippocampus, and levels of α-tocopherol in cortex, were also measured after 15 min of ischemia followed by 5, 15, and 45 min of recovery. The results confirm previous findings that brief ischemia in normoglycemic animals does not measurably increase H2O2 production in AT-injected animals. Ischemia under hyperglycemic conditions likewise failed to induce increased H2O2 production. No difference in free iron in CSF was observed between animals subjected to ischemia under hyper- and normoglycemic conditions. The moderate decrease in total glutathione or α-tocopherol levels did not differ between normo- and hyperglycemic animals in any brain region or at any recovery time. Thus, the results failed to give positive evidence for free radical damage following brief periods of ischemia complicated by excessive acidosis. However, it is possible that free radical production is localized to a small subcellular compartment within the tissue, thereby escaping detection. Also, the results do not exclude the possibility that free radicals are pathogenetically important after ischemia of longer duration.

INFLUENCE OF MODERATE HYPOTHERMIA ON ISCHEMIC BRAIN DAMAGE INCURRED UNDER HYPERGLYCEMIC CONDITIONS

SummaryPreischemic hyperglycemia aggravates brain damage following transient ischemia, and adds some special features to the damage incurred, notably a high frequency of postischemic seizures, cellular edema, and affectation of additional brain structures, such as the substanta nigra pars reticulata (SNPR). We raised the question whether mild intra-ischemic hypothermia (32–33° C), known to reduce selective neuronal vulnerability in normoglycemic subjects, also ameliorates the characteristic damage observed in hyperglycemic animals. To that end, two series of experiments were performed. In the first, normo- and hypothermic animals were subjected to 10 min of ischemia during hyperglycemic conditions (plasma glucose 20–25 mmol · 1-1), and allowed either 15 h or 1 week of recovery. In the second, both normo- and hyperglycemic animals were subjected to 15 min of ischemia (at normal or reduced temperature) and surviving animals were studied after 1 week of recovery. All normothermic, hyperglycemic animals developed postischemic seizures and died within the first 24 h. Mild hypothermia afforded substantial protection. Thus, 6/7 hypothermic animals subjected to 10 min of ischemia survived 1 week of recovery and none developed postischemic seizures. Of the hypothermic animals subjected to 15 min of ischemia 6/11 survived for 1 week, only one of which developed seizures. Protection by hypothermia was also shown by the histopathological analysis. Experiments with 10 min of ischemia and 15 h of recovery showed the expected damage in normothermic, hyperglycemic subjects. Hypothermia markedly reduced damage in all vulnerable structures, including the cingulate cortex and SNPR. The protection was most pronounced in the caudoputamen, where no affected neurons were seen in the hypothermic subjects. The experiments with 15 min of ischemia confirmed previous findings that mild hypothermia protects normoglycemic animals against the insult. The results also showed that hypothermia prevented most of the exaggeration of damage caused by hyperglycemia. However, under hypothermic conditions hyperglycemia still augmented damage in the cingulate cortex, medial and lateral venteroposterior thalamic nuclei, and SNPR, structures specifically damaged under hyperglycemic, normothermic conditions. This suggests that hypothermia has less of a protective effect on mechanisms causing such damage than on neuronal damage in the classic selectively vulnerable regions, particularly the caudoputamen.

Chapter 3 Acidosis-related brain damage

Publisher Summary This chapter updates information on the coupling among hyperglycemia, intra and extracellular acidosis and brain damage because of ischemia or hypoxia, and discusses cellular and molecular mechanisms that may be involved. When ischemia is complicated by excessive acidosis, the ischemic damage encompasses post-ischemic seizures, edema, and pannecrosis. The cellular and molecular mechanisms responsible for these alterations have not been adequately defined. However, it seems likely that the acidosis causes damage to inhibitory GABAergic cells by raising Ca i 2+ to levels, which will overload the buffering systems and cause cell death, thereby explaining the proclivity to post-ischemic seizure discharge. The rapidly evolving damage following long periods of ischemia is probably caused by several adverse effects of a raised H + activity: inhibition of Na + /H + exchange and lactate – oxidation, inhibition of mitochondria1 respiration, and acceleration of coupled Na + /H + and Cl – /HCO 3 – exchange. However, an important factor may be a lingering rise in Ca i 2+ in cells whose pH i is reduced over a longer period, predisposing to Ca 2+ -related damage. The molecular mechanisms underlying delayed acidosis-related damage probably comprise Fe 2+ and NO · -related production of free radicals that have the microvessels as their main target.