J. S. H. Vles

Animal models for vagus nerve stimulation in epilepsy

Vagus nerve stimulation (VNS) is a moderately effective adjunctive treatment for patients suffering from medically refractory epilepsy and is explored as a treatment option for several other disorders. The present review provides a critical appraisal of the studies on VNS in animal models of seizures and epilepsy. So far, these studies mostly applied short-term VNS in seizure models, demonstrating that VNS can suppress and prevent seizures and affect epileptogenesis. However, the mechanism of action is still largely unknown. Moreover, studies with a clinically more relevant setup where VNS is chronically applied in epilepsy models are scarce. Future directions for research and the application of this technology in animal models of epilepsy are discussed.

Intrathecal baclofen therapy in children with intractable spastic cerebral palsy: a cost-effectiveness analysis

In a Dutch national study, we recently established the effectiveness and safety of continuous intrathecal baclofen infusion (CITB) in children with intractable spastic cerebral palsy (CP). Because prospective studies on the cost‐effectiveness of CITB in children with spastic CP are lacking, we conducted a cost‐effectiveness analysis alongside our prospective national study. We compared the costs and health effects of CITB with those of standard treatment only, from the health care perspective for a 1‐year period. Health effects were expressed in terms of a visual analogue scale for individual problems and quality‐adjusted life years (QALYs). We included eight females and seven males, aged between 7 and 17 years (mean age 13y 8mo [SD 3y]). Eleven children had spastic CP and four had spastic‐dyskinetic CP. One child was clsssified on the Gross Motor Function Classification System at Level III, two at Level IV, and 12 at Level V. CITB was more effective and more costly than standard treatment only. Gaining one QALY cost on average €32 737. We conclude that based on the threshold‐willingness to pay for one QALY in the Netherlands (€80 000), our results confirm the cost‐effectiveness of CITB for carefully selected children with intractable spastic CP.

Impaired language performance as a precursor or consequence of Rolandic epilepsy

OBJECTIVES A correlation between language impairment and Rolandic epilepsy is frequently reported. It is unknown whether this language impairment develops gradually as a consequence of Rolandic epilepsy or precedes the onset of seizures. In the latter case both language impairment and Rolandic epilepsy may be symptoms of an underlying syndrome or both develop during the process of epileptogenesis. METHODS Non-comparative clinical cohort study of 48 children with Rolandic epilepsy (childrens mean age is 9 years, and 7 months; SD is 1 year, and 8 months). They were screened for previous and current language impairment and their reading skills were examined. RESULTS 23% of children with Rolandic epilepsy had speech therapy in the past and 35% repeated a year on primary school, which is more often compared to the Dutch population of children. Their results on a reading task revealed lower scores. CONCLUSIONS Language is impaired in children with Rolandic epilepsy. In some children this impairment of language may even be a precursor, for the Rolandic epilepsy. It is undecided however, whether the language impairment develops gradually after the onset of epilepsy, whether Rolandic epilepsy and language impairment are both symptoms of an underlying syndrome or both develop during the process of epileptogenesis as we observed in some children the onset of language impairment before the onset of epilepsy.

Electrocortical brain activity, cerebral haemodynamics and oxygenation during progressive hypotension in newborn piglets

OBJECTIVES To investigate the relationships between systemic and cerebral haemodynamics and oxygenation, and electroencephalogram (EEG) amplitude and frequency analysis studied by the cerebral function analyzing monitor (CFAM) during progressive hypovolemic hypotension. METHODS Six piglets of 1 week of age, weighing 1.9-3.4 kg were mechanically ventilated under 1-1.5% halothane anaesthesia. After 1 h stabilization, blood was withdrawn in aliquots of 10 ml/kg over 15 min up to a total of 40-60 ml/kg. Arterial oxygenation was maintained at normal levels. Thereafter, the total blood volume previously withdrawn, was reinfused. Changes in near infrared spectroscopy (NIRS) parameters [cerebral oxidized cytochrome aa3 (Cytaa3), cerebral blood volume (CBV) or total haemoglobin (tHb: oxy- + deoxyhaemoglobin)], carotid blood flow (Q(car)), maximal EEG amplitude and EEG frequency percentages were analyzed continuously. RESULTS The EEG amplitude remained stable until the mean arterial blood pressure (MAP), Q(car) and tHb dropped below 30 mmHg (41% of baseline), 20 ml/min (33% of baseline) and 82% of baseline, respectively. Delta (delta) wave frequency percentage of the CFAM increased significantly at MAP below 30 mm Hg. EEG amplitude remained depressed after blood reinfusion and haemodynamic recovery. Cytaa3 changes were not statistically significant, reflecting sufficient neuronal oxygenation. CONCLUSION Our results show that electrocortical function is affected only by profound systemic hypotension. This occurred at a higher level of cerebral oxygen delivery than the level associated with neuronal hypoxia and secondary cell damage.

Placebo controlled utility and feasibility study of the H-reflex and flexor reflex in spastic children treated with intrathecal baclofen

OBJECTIVE To evaluate feasibility and utility of the soleus H-reflex and tibialis anterior flexor reflex (FR) in identifying spinal cord neuronal response to intrathecal baclofen (ITB) in children with severe spastic cerebral palsy. METHODS During a randomized, double-blind, placebo-controlled dose-escalation test treatment, maximum H amplitude/maximum M amplitude (H/M ratio) and FR parameters were bilaterally recorded at baseline and 2-3 h after intrathecal bolus administration of placebo and increasing doses of baclofen until both an improvement in the individual treatment goal(s) and a one-point reduction on the Ashworth scale were observed. RESULTS Electrophysiological data of 14 children were studied. The H-reflex was feasible in 13 children, the FR threshold area in 9 and the FR, elicited with supramaximal stimulation, in only one child. After ITB, the H/M ratio significantly decreased (left: 0.67+/-0.47 to 0.15+/-0.18, P=0.005; right: 0.55+/-0.32 to 0.14+/-0.19, P=0.002) without placebo effect. FR threshold area after ITB, only decreased significantly in children not taking oral baclofen (left: 146+/-53 to 41+/-54 mV ms, P=0.000; right: 156+/-80 to 66+/-48 mV ms, P=0.002). CONCLUSIONS This is the first randomized, double-blind, placebo-controlled dose-escalation study in spastic children demonstrating the soleus H-reflex to be a feasible and objective measure to quantify the decreasing motoneuron excitability in response to ITB bolus administration. Only in children not taking oral baclofen, FR threshold area can also be used as an objective outcome measure, yet feasibility is limited. SIGNIFICANCE We suggest introducing the H-reflex as the electrophysiological gold standard for the evaluation of the effect of ITB in spastic children.

Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy

Tonic GABAA receptors are a subpopulation of receptors that generate long-lasting inhibition and thereby control network excitability. In recent years, these receptors have been implicated in various neurological and psychiatric disorders, including Parkinson’s disease, schizophrenia, and epilepsy. Their distinct subunit composition and function, compared to phasic GABAA receptors, opens the possibility to specifically modulate network properties. In this review, the role of tonic GABAA receptors in epilepsy and as potential antiepileptic target will be discussed.

The Effects of Vagus Nerve Stimulation on Pro- and Anti-Inflammatory Cytokines in Children with Refractory Epilepsy: An Exploratory Study

Objectives: The vagus nerve has important immunological and anti-inflammatory actions that might be relevant to the beneficial effects of vagus nerve stimulation (VNS). Therefore, we conducted an exploratory study on VNS effects on cytokine levels in plasma and cerebrospinal fluid of children suffering from refractory epilepsy. Moreover, as predictors of the response are lacking, we also aimed to determine if cytokine changes predict the clinical response. Methods: VNS was performed according to a randomized double-blind design: plasma levels were compared between patients who received 20 weeks of high output (therapeutic) (n = 21) or low output (active control) stimulation (n = 20). Thereupon, all patients received high output stimulation for another 19 weeks; levels during this period were compared to baseline. Interictal interleukin-1β, interleukin-6, and interleukin-10 were determined by ELISA. Results: No significant changes were found between high and low output groups and between the last 19 weeks of stimulation and baseline. Changes in interleukin-1β correlated with improved IQ (τ = 0.42, p < 0.01). Lower baseline plasma levels of interleukin-6 were associated with more seizure frequency reduction [R2 = 0.105 (1, 35), p = 0.050]. Conclusion: Interictal cytokine levels were not altered by VNS but baseline interleukin-6 predicted the clinical response. In the future, patient selection may be aided by determination of the cytokine profile of the patient.

Neonatal electrocortical brain activity and cerebral tissue oxygenation during non-acidotic, normocarbic and normotensive graded hypoxemia

OBJECTIVE Neonates are commonly exposed to isolated hypoxemic episodes. In order to identify the risk of this, we correlated cerebral oxygen delivery and electrocortical brain activity during isolated graded and repetitive hypoxemia in 1-week-old piglets. METHODS Six halothane-anesthetized piglets were subjected to two episodes of graded hypoxemia of 45 min duration. The fractional concentration of inspired oxygen (FiO(2)) was stepwise decreased at 15 min intervals from 0.21 to 0.15, 0.10 and 0.05. A second identical hypoxemic event was induced after 1 h of normoxemia (FiO(2) 0.21). Mean arterial pressure (MAP) and pH were maintained at baseline values during the whole experiment. We measured near infrared spectroscopy parameters (cerebral oxidized cytochrome aa(3) (Cytaa3), total hemoglobin (tHb: oxy- +deoxyhemoglobin)) corresponding to cerebral blood volume (CBV), carotid blood flow (Q(car)), intra-arterial oxygen saturation (SaO(2)), and mean maximal EEG amplitude and relative spectral power. RESULTS Delta (delta) power increased significantly and the EEG amplitude dropped below 10 and 5 microV at the end of the first and the second hypoxemic period (PaO(2) 2.68+/-1.08 (P<0.05) and 2.87+/-0.58 kPa, respectively). Both EEG variables normalized during recovery (FiO(2) 0.21). Q(car), CBV and Cytaa3 were not changed. CONCLUSION Acute isolated hypoxemia has to be sustained to induce neuronal hypofunction in normotensive animals. Hypoxic hypoxemia led to acute changes in neuronal activity, whereas cellular oxygenation remained unaffected.

Postural behaviour of term SGA and AGA newborn infants

The authors studied the body posture at rest of 15 healthy term infants with birthweights appropriate for gestational age (AGA) and 15 infants who were small for gestational age (SGA). In both groups, there was wide inter‐individual variability in pos:ural behaviour. Apart from a preference for a position with all limbs in abduction between I and 90°, independent of the degree of flexion or extension and internal/external rotation, no dominant preference posture could be seen for either group. The SGA infants showed a more flexed position of the arms, ccrnpared with the AGA group. One of the factors contributing to this difference might be the influence of intrauterine malnutrition on the development of the central nervous system.

The influence of head position and head position change on spontaneous body posture and motility in full-term AGA and SGA newborn infants

No consensus exists concerning the influence of head position and head position change on body posture and motility. Especially the existence of an asymmetric tonic neck reflex (ATNR) in full-term newborns is an issue of discussion. Three-hour video recordings were made of 15 full-term appropriate for gestational age (AGA) and 15 full-term small for gestational age (SGA) infants between the third and eight postnatal day. During a playback of the video recording head position, head position change and several movement patterns of the four limbs were fed into a computer using an event-detecting program. Furthermore, spontaneous head turnings were selected and body posture just before, immediately at and 1 min after the head turning were sketched. The data were analyzed concerning: (1) influence of head position on symmetry of movement of the four limbs; (2) the existence of an ATNR and ATNR-related patterns. In both AGA and SGA infants all movement patterns except hand-face and hand-mouth contact showed a symmetrical distribution, independent of head position. Furthermore, the occurrence of an ATNR following a spontaneous head turning in both AGA and SGA infants was rare. From our results it may be concluded that the ATNR is rare in full-term AGA and SGA newborns. Furthermore, this study demonstrates that head position is not a major factor influencing quantitative aspects of spontaneous motor behaviour. The results are of clinical importance as they imply that in the examination of the neurological condition of the full-term newborn infant by means of observation of spontaneous posture and motility, head position is not of major importance.