Hemodynamic responses to interictal epileptiform discharges in children with symptomatic epilepsy

PURPOSE: Simultaneous electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) (EEG-fMRI) recording is a noninvasive tool for investigating epileptogenic networks. Most EEG-fMRI studies in epilepsy have been performed in adults. Childhood epilepsies, however, differ from those in adults due to interactions between epileptogenic and developmental processes. The purpose of this study was to investigate EEG-fMRI in children with lesional epilepsies. METHODS: Thirteen children with symptomatic epilepsy underwent a 20-min EEG-fMRI acquisition at 3 T under sedation-induced sleep. Statistical analysis was performed using the timing of spikes as events, modelled with hemodynamic response functions (HRFs) that peaked at 3, 5, 7, and 9 s after the spike. RESULTS: Each spike type was analyzed separately, resulting in 25 studies. In 84% of the studies, blood oxygenation level-dependent (BOLD) responses were localized in the lesion or brain area presumably generating spikes. Activation (positive BOLD) corresponding with the lesion was seen in 20% and deactivation (negative BOLD) in 52% of the studies. In the area of spike generation, activation was found in 48% of studies and deactivation in 36%. CONCLUSIONS: Despite the necessarily short recording times (20 min), good results could be obtained from the EEG-fMRI recordings, performed in sedated children using a high field scanner and individual HRFs. In contrast to studies in adults, deactivations in the lesion and the irritative zone were more common than activations. The impact of age, sleep, and sedation on the BOLD response might explain these findings, but future studies in children should not disregard the importance of deactivations in relation to the epileptogenic network.     

Cost-effectiveness of strong opioids focussing on the long-term effects of opioid-related fractures: a model approach

Opioid analgesics are known to impact on the central nervous system (CNS). These CNS side effects, such as dizziness and confusion, have been shown to lead to an increased risk of falling with subsequent fractures in elderly patients being treated with opioids. The risk of experiencing fractures has been shown to be dependent on the substance administered. Therefore, a health economic model was developed to investigate the cost-effectiveness of the most commonly used strong opiods in Germany, focussing on opioid-related fractures. By means of a Markov model, the consequences of hip, spine and forearm fractures due to the prior administration of transdermal (TD) buprenorphine, TD fentanyl, oral oxycodone as well as oral morphine were assessed from the perspectives of the German statutory health insurance (SHI) and the German social security (GSS) system over a time horizon of 6 years. The most frequently prescribed strength/package-size combinations of these opioids were taken into consideration, including generics where available. The results of the present analysis predict that TD buprenorphine is dominant compared to TD fentanyl and oxycodone by showing better effects [life years gained/quality adjusted life years (QALY) gained] at lower cost. From the SHI perspective, the incremental cost-effectiveness ratio (ICER) compared to morphine is € 6,801.61 per life year gained, and € 7,766.11 per QALY gained. From the GSS perspective, the ICER is € 2,496.77 per life year gained and € 2,850.83 per QALY gained. The model is robust regarding probabilistic variations of all parameters in the sensitivity analyses. Focussing on fractures due to the prior administration of strong opioids, TD buprenorphine is less costly and more effective than TD fentanyl and oxycodone and represents a cost-effective treatment option versus morphine in patients with chronic pain from both the SHI and GSS perspective in Germany.     

Dyschromatosis ptychotropica: an unusual pigmentary disorder in a boy with epileptic encephalopathy and progressive atrophy of the central nervous system—a novel entity?

The skin and the central nervous system are tissues of common ectodermal origin and share a close ontogenetic relationship. Genetic diseases primarily affecting both organ systems are regularly encountered in both dermatological and neurological settings. Here, we report on a boy with epileptic encephalopathy, severe intellectual disability, optic atrophy, and progressive cerebellar and supratentorial atrophy, reminiscent of progressive encephalopathy with edema and hypsarrythmia (PEHO) syndrome displaying a previously undescribed dyschromatosis in the form of progressive reticulate and mottled hyper- and hypopigmentation of the neck and the inguinal and axillary regions. We hypothesised that this combination of neurological and cutaneous findings has a common aetiology and represents a novel recognisable entity. Because of the unusual dermatological findings, we suggest the term dyschromatosis ptychotropica. Recognition of further cases may help elucidate the aetiology of this condition and give insight into the pathophysiology of both pigmentation disorders and epileptic encephalopathies.     

Photosensitivity in epileptic syndromes of childhood and adolescence.

PURPOSE: Photosensitivity, a reaction of the brain to external photic stimulation, can be graded from 1 to 4, and is most frequently seen in the first decades of life. This study investigated photosensitivity in children with epilepsy. METHODS: A retrospective study performed in the neuropaediatric department of the largest paediatric hospital in Kiel, treating patients at all medical care levels. The clinical data and EEG records of 566 patients with the most common epileptic syndromes were analyzed, in particular regarding photosensitivity. Their EEGs included application of intermittent light stimulation using standard techniques at twice the minimum. RESULTS: The proportion of photosensitive patients was significantly higher in the paediatric cohort than in adult patients, as published in the literature: 46% of patients with generalized epilepsies showed photosensitivity as compared to 20% with focal epilepsies. Photosensitivity was more common in idiopathic generalized epilepsy (IGE), (epilepsy with grand mal on awakening, 74%; juvenile absence epilepsy, 56%; juvenile myoclonic epilepsy, 50%; childhood absence epilepsy, 44%) than in focal types (idiopathic partial - Rolandic epilepsy, 23%; symptomatic/cryptogenic type of epilepsy, 16%), while in patients who experienced occasional seizures (neonatal/febrile seizures), this ranged between 40% and 23%, respectively. The generalized photoparoxysmal response, (PPR), grades 3 and 4 were found significantly more often in patients with IGE (92%) than in patients with focal epilepsies. Finally, the female preponderance was confirmed (37% to 27% of all epilepsies). CONCLUSIONS: Photosensitivity can be detected both in patients with IGE, with idiopathic and symptomatic/cryptogenic types of focal epilepsies, and with epileptic (occasional) seizures. PPR grades 3 and 4 are the most common in IGE.     

Mapping brain activity on the verge of a photically induced generalized tonic–clonic seizure

In a photosensitive patient intermittent photic stimulation (IPS) accidentally provoked a generalized tonic–clonic seizure during simultaneous recordings of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Before seizure onset, IPS consistently induced generalized photoparoxysmal responses (PPRs). These PPRs were associated with increases in blood oxygen level dependent (BOLD) signal in the visual cortex, the thalamus, and both superior colliculi, and a decrease in BOLD signal in the frontoparietal areas. The BOLD signal in the visual cortex increased in magnitude during consecutive epochs of IPS associated with PPRs. We propose that repeated IPS led to an excessive amount of neuronal activity in the visual cortex that evoked PPRs and finally exceeded a critical threshold and triggered a generalized seizure.     

Comparison of gait with and without shoes in children

Full body gait analysis was used to determine if differences exist in kinematic, kinetic, and temporal-spatial data with and without shoes in able-bodied children. The greatest difference noted between conditions was an increase in stride length with shoes. Minimal changes were seen in kinematics and kinetics with the addition of shoes. Due to the very tight standard deviations of the data, these minimal changes in the magnitude of the curves resulted in statistically significant differences, yet these changes do not appear to be clinically significant. It is believed that this study establishes that barefoot gait analysis is sufficient for most clinical studies, and an additional assessment undertaken while wearing shoes is not necessary.     

Identification of HLA class I dependent immunogenic peptides from clonotypic TCRbeta expressed in cutaneous T-cell lymphoma

The clonotypic T-cell receptor (TCR) is a potential target antigen for specific immunotherapy of cutaneous T-cell lymphoma (CTCL). We identified T-cell epitopes from the rearranged TCR beta chain of the malignant T-cell population by the "reverse immunology" approach. Peptide-specific T-cell lines were generated against predicted epitopes and tested for the recognition of tumor cells and cells transfected with the full-length DNA coding for TCRV beta chain. Two peptides derived from the clonotypic TCRVbeta of a HLA-A2 positive patient could induce peptide-specific T cells from peripheral blood mononuclear cells of healthy donors and the patient as assessed by IFN-gamma ELISpot assay. Furthermore, the reactive CTLs efficiently recognized autologous Sézary tumor cells, as well as HLA-A2 positive 293 cells transfected with recombinant plasmid expressing the corresponding TCRVbeta29 protein. Similar results were obtained in a HLA-A3+ patient for TCRVbeta7-Jbeta2.7. In conclusion, our experiments show that the TCR beta chain harbors epitopes suitable as targets for specific vaccination which might be a promising approach for the specific immunotherapy of cutaneous T-cell lymphoma patients.     

VHL mutations in renal cell cancer: does occupational exposure to trichloroethylene make a difference?

Occupational exposures have long been suspected to play a role in the incidence of renal cell carcinoma (RCC). Especially, the carcinogenicity of the industrial solvent trichloroethylene (TCE) has been controversially debated, both with respect to the epidemiological and the molecular studies. In order to further elucidate this issue, it appeared important to compare suitable RCC patient groups, i.e., TCE-exposed versus non-TCE-exposed patients. We evaluated RCC from a previous German study that had described differences in RCC risks between TCE-exposed (n=17) and non-exposed patients (n=21). We compared age at diagnosis and histopathologic parameters of tumors as well as somatic mutation characteristics in the kidney cancer causing VHL tumor suppressor gene. RCC did not differ with respect to histopathological characteristics in both patient groups. We noticed a younger age at diagnosis in TCE-exposed patients compared to non-exposed patients (P=0.01). Moreover, the non-TCE-exposed patients did not share the somatic VHL mutation characteristics of TCE-exposed patients such as the previously identified hot spot mutation 454 C > T P81S or multiple mutations. These data support the notion of a putative genotoxic effect of TCE leading to VHL gene damage and subsequent occurrence of RCC in highly exposed subjects.