Dystrophin Distribution and Expression in Human and Experimental Temporal Lobe Epilepsy

Objective: Dystrophin is part of a protein complex that connects the cytoskeleton to the extracellular matrix. In addition to its role in muscle tissue, it functions as an anchoring protein within the central nervous system such as in hippocampus and cerebellum. Its presence in the latter regions is illustrated by the cognitive problems seen in Duchenne Muscular Dystrophy (DMD). Since epilepsy is also supposed to constitute a comorbidity of DMD, it is hypothesized that dystrophin plays a role in neuronal excitability. Here, we aimed to study brain dystrophin distribution and expression in both, human and experimental temporal lobe epilepsy (TLE). Method: Regional and cellular dystrophin distribution was evaluated in both human and rat hippocampi and in rat cerebellar tissue by immunofluorescent colocalization with neuronal (NeuN and calbindin) and glial (GFAP) markers. In addition, hippocampal dystrophin levels were estimated by Western blot analysis in biopsies from TLE patients, post-mortem controls, amygdala kindled (AK)-, and control rats. Results: Dystrophin was expressed in all hippocampal pyramidal subfields and in the molecular-, Purkinje-, and granular cell layer of the cerebellum. In these regions it colocalized with GFAP, suggesting expression in astrocytes such as Bergmann glia (BG) and velate protoplasmic astrocytes. In rat hippocampus and cerebellum there were neither differences in dystrophin positive cell types, nor in the regional dystrophin distribution between AK and control animals. Quantitatively, hippocampal full-length dystrophin (Dp427) levels were about 60% higher in human TLE patients than in post-mortem controls (p < 0.05), whereas the level of the shorter Dp71 isoform did not differ. In contrast, AK animals showed similar dystrophin levels as controls. Conclusion: Dystrophin is ubiquitously expressed by astrocytes in the human and rat hippocampus and in the rat cerebellum. Hippocampal full-length dystrophin (Dp427) levels are upregulated in human TLE, but not in AK rats, possibly indicating a compensatory mechanism in the chronic epileptic human brain

An Unusual Triad in Pediatric Neurology:A Case Report on Cerebral Palsy, Epilepsy, and Duchenne Muscular Dystrophy

We present a case of an unusual triad in pediatric neurology: a currently 12-year-old boy with cerebral palsy and epilepsy who was later also diagnosed with Duchenne muscular dystrophy. We describe the clinical path that resulted in this exceptional diagnosis. This case report illustrates how different neurological disorders may overshadow each other. In addition, it demonstrates that every child with cerebral palsy and either an atypical clinical course or with inexplicable laboratory values-as well as every infant boy born to a theoretical Duchenne muscular dystrophy carrier-should be subjected to additional investigations.</p

Periaqueductal Grey Stimulation Induced Panic-Like Behaviour Is Accompanied by Deactivation of the Deep Cerebellar Nuclei

Until recently, the cerebellum was primarily considered to be a structure involved in motor behaviour. New anatomical and clinical evidence has shown that the cerebellum is also involved in higher cognitive functions and non-motor behavioural changes. Functional imaging in patients with anxiety disorders and in cholecystokinin tetrapeptide-induced panic-attacks shows activation changes in the cerebellum. Deep brain stimulation of the dorsolateral periaqueductal grey (dlPAG) and the ventromedial hypothalamus (VMH) in rats has been shown to induce escape behaviour, which mimics a panic attack in humans. We used this animal model to study the neuronal activation in the deep cerebellar nuclei (DCbN) using c-Fos immunohistochemistry. c-Fos expression in the DCbN decreased significantly after inducing escape behaviour by stimulation of the dlPAG and the VMH, indicating that the DCbN were deactivated. This study demonstrates that the DCbN are directly or indirectly involved in panic attacks. We suggest that the cerebellum plays a role in the selection of relevant information, and that deactivation of the cerebellar nuclei is required to allow inappropriate behaviour to occur, such as panic attacks

Intra-Amniotic LPS Induced Region-Specific Changes in Presynaptic Bouton Densities in the Ovine Fetal Brain

Rationale. Chorioamnionitis has been associated with increased risk for fetal brain damage. Although, it is now accepted that synaptic dysfunction might be responsible for functional deficits, synaptic densities/numbers after a fetal inflammatory challenge have not been studied in different regions yet. Therefore, we tested in this study the hypothesis that LPS-induced chorioamnionitis caused profound changes in synaptic densities in different regions of the fetal sheep brain. Material and Methods. Chorioamnionitis was induced by a 10 mg intra-amniotic LPS injection at two different exposure intervals. The fetal brain was studied at 125 days of gestation (term = 150 days) either 2 (LPS2D group) or 14 days (LPS14D group) after LPS or saline injection (control group). Synaptophysin immunohistochemistry was used to quantify the presynaptic density in layers 2-3 and 5-6 of the motor cortex, somatosensory cortex, entorhinal cortex, and piriforme cortex, in the nucleus caudatus and putamen and in CA1/2, CA3, and dentate gyrus of the hippocampus. Results. There was a significant reduction in presynaptic bouton densities in layers 2-3 and 5-6 of the motor cortex and in layers 2-3 of the entorhinal and the somatosensory cortex, in the nucleus caudate and putamen and the CA1/2 and CA3 of the hippocampus in the LPS2D compared to control animals. Only in the motor cortex and putamen, the presynaptic density was significantly decreased in the LPS14 D compared to the control group. No changes were found in the dentate gyrus of the hippocampus and the piriforme cortex. Conclusion. We demonstrated that LPS-induced chorioamnionitis caused a decreased density in presynaptic boutons in different areas in the fetal brain. These synaptic changes seemed to be region-specific, with some regions being more affected than others, and seemed to be transient in some regions

Sustained Reduction of Cerebellar Activity in Experimental Epilepsy

Clinical and experimental evidence suggests a role for the cerebellum in seizure control, while no data are available on cerebellar activity between seizures. We hypothesized that interictal regional activity of the deep cerebellar nuclei is reduced in epilepsy and tested this in an animal model by using ΔFosB and cytochrome oxidase (COX) (immuno)histochemistry. The expression of these two markers of neuronal activity was analysed in the dentate nucleus (DN), interpositus nucleus (IN), and fastigial nucleus (FN) of the cerebellum of fully amygdala kindled rats that were sacrificed 48 hours after their last seizure. The DN and FN of kindled rats exhibited 25 to 29% less ΔFosB immunopositive cells than their respective counterpart in sham controls (P<0.05). COX expression in the DN and FN of kindled animals was reduced by 32 to 33% compared to respective control values (P<0.05). These results indicate that an epileptogenic state is characterized by decreased activity of deep cerebellar nuclei, especially the DN and FN. Possible consequences may include a decreased activation of the thalamus, contributing to further seizure spread. Restoration of FN activity by low frequency electrical stimulation is suggested as a possible treatment option in chronic epilepsy

Percutaneous radiofrequency lesions adjacent to the dorsal root ganglion alleviate spasticity and pain in children with cerebral palsy: pilot study in 17 patients

BACKGROUND: Cerebral palsy (CP) may cause severe spasticity, requiring neurosurgical procedures. The most common neurosurgical procedures are continuous infusion of intrathecal baclofen and selective dorsal rhizotomy. Both are invasive and complex procedures. We hypothesized that a percutaneous radiofrequency lesion of the dorsal root ganglion (RF-DRG) could be a simple and safe alternative treatment. We undertook a pilot study to test this hypothesis. METHODS: We performed an RF-DRG procedure in 17 consecutive CP patients with severe hip flexor/adductor spasms accompanied by pain or care-giving difficulties. Six children were systematically evaluated at baseline, and 1 month and 6 months after treatment by means of the Modified Ashworth Scale (MAS), Gross Motor Function Measure (GMFM) and a self-made caregiver's questionnaire. Eleven subsequent children were evaluated using a Visual Analogue Scale (VAS) for spasticity, pain and ease of care. RESULTS: A total of 19 RF-DRG treatments were performed in 17 patients. We found a small improvement in muscle tone measured by MAS, but no effect on the GMFM scale. Despite this, the caregivers of these six treated children unanimously stated that the quality of life of their children had indeed improved after the RF-DRG. In the subsequent 11 children we found improvements in all VAS scores, in a range comparable to the conventional treatment options. CONCLUSION: RF-DRG is a promising new treatment option for severe spasticity in CP patients, and its definitive effectiveness remains to be defined in a randomised controlled trial

A Study on the Validity of a Computer-Based Game to Assess Cognitive Processes, Reward Mechanisms, and Time Perception in Children Aged 4-8 Years

BACKGROUND: A computer-based game, named Timo's Adventure, was developed to assess specific cognitive functions (eg, attention, planning, and working memory), time perception, and reward mechanisms in young school-aged children. The game consists of 6 mini-games embedded in a story line and includes fantasy elements to enhance motivation. OBJECTIVE: The aim of this study was to investigate the validity of Timo's Adventure in normally developing children and in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: A total of 96 normally developing children aged 4-8 years and 40 children with ADHD were assessed using the game. Clinical validity was investigated by examining the effects of age on performances within the normally developing children, as well as performance differences between the healthy controls and the ADHD group. RESULTS: Our analyses in the normally developing children showed developmental effects; that is, older children made fewer inhibition mistakes (r=-.33, P=.001), had faster (and therefore better) reaction times (r=-.49, P<.001), and were able to produce time intervals more accurately than younger children (ρ=.35, P<.001). Discriminant analysis showed that Timo's Adventure was accurate in most classifications whether a child belonged to the ADHD group or the normally developing group: 78% (76/97) of the children were correctly classified as having ADHD or as being in the normally developing group. The classification results showed that 72% (41/57) children in the control group were correctly classified, and 88% (35/40) of the children in the ADHD group were correctly classified as having ADHD. Sensitivity (0.89) and specificity (0.69) of Timo's Adventure were satisfying. CONCLUSIONS: Computer-based games seem to be a valid tool to assess specific strengths and weaknesses in young children with ADHD

A systematic review of studies measuring health-related quality of life of general injury populations

Background. It is important to obtain greater insight into health-related quality of life (HRQL) of injury patients in order to document people's pathways to recovery and to quantify the impact of injury on population health over time. We performed a systematic review of studies measuring HRQL in general injury populations with a generic health state measure to summarize existing knowledge. Methods. Injury studies (1995-2009) were identified with main inclusion criteri