Epileptogenic Tubers Are Associated with Increased Kurtosis of Susceptibility Values: A Combined Quantitative Susceptibility Mapping and Stereoelectroencephalography Pilot Study.

BACKGROUND AND PURPOSE: Prior studies have found an association between calcification and the epileptogenicity of tubers in tuberous sclerosis complex. Quantitative susceptibility mapping is a novel tool sensitive to magnetic susceptibility alterations due to tissue calcification. We assessed the utility of quantitative susceptibility mapping in identifying putative epileptogenic tubers in tuberous sclerosis complex using stereoelectroencephalography data as ground truth. MATERIALS AND METHODS: We studied patients with tuberous sclerosis complex undergoing stereoelectroencephalography at a single center who had multiecho gradient-echo sequences available. Quantitative susceptibility mapping and R2* values were extracted for all tubers on the basis of manually drawn 3D ROIs using T1- and T2-FLAIR sequences. Characteristics of quantitative susceptibility mapping and R2* distributions from implanted tubers were compared using binary logistic generalized estimating equation models designed to identify ictal (involved in seizure onset) and interictal (persistent interictal epileptiform activity) tubers. These models were then applied to the unimplanted tubers to identify potential ictal and interictal tubers that were not sampled by stereoelectroencephalography. RESULTS: A total of 146 tubers were identified in 10 patients, 76 of which were sampled using stereoelectroencephalography. Increased kurtosis of the tuber quantitative susceptibility mapping values was associated with epileptogenicity (P = .04 for the ictal group and P = .005 for the interictal group) by the generalized estimating equation model. Both groups had poor sensitivity (35.0% and 44.1%, respectively) but high specificity (94.6% and 78.6%, respectively). CONCLUSIONS: Our finding of increased kurtosis of quantitative susceptibility mapping values (heavy-tailed distribution) was highly specific, suggesting that it may be a useful biomarker to identify putative epileptogenic tubers in tuberous sclerosis complex. This finding motivates the investigation of underlying tuber mineralization and other properties driving kurtosis changes in quantitative susceptibility mapping values.

Headache in children with Sturge-Weber syndrome - Prevalence, associations and impact.

BACKGROUND: Sturge-Weber syndrome (SWS) is a congenital neurovascular disorder characterised by capillary-venous malformations involving the skin, brain and eye. Patients experience headache, however little is known about its characteristics or associations. We aimed to estimate prevalence, associations and the impact of headache in children with SWS. MATERIALS AND METHODS: Case notes of all patients in a national tertiary paediatric SWS clinic were retrospectively reviewed. Patients were categorised into those with or without a history of headache, with an analysis performed of clinical stigmata of their disease and headache symptomology, associations and treatment. A multivariable logistic regression analysis was undertaken to elicit independent predictors of headache. RESULTS: 37% of patients with SWS (n = 84) reported headaches that were variably associated with seizures, a preceding blow to the head and a minority had migraine features. In those reporting headaches, headaches interfered with daily activities of a quarter of the children and 39% experienced headaches frequently (more than 1/month). Headache was associated with glaucoma and aspirin administration while children with monoplegia and hemiplegia were less likely to have headache. CONCLUSIONS: Headache is common in children with SWS, often without classical migraine features and affects daily activities. Awareness of headache and its associations in SWS may improve management of this complex population.

Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information.

Cognitive impairment is a common comorbidity in temporal lobe epilepsy (TLE) and is often considered more detrimental to quality of life than seizures. While it has been previously shown that the encoding of memory during behavior is impaired in the pilocarpine model of TLE in rats, how this information is consolidated during the subsequent sleep period remains unknown. In this study, we first report marked deficits in spatial memory performance and severe cell loss in the CA1 layer of the hippocampus lower spatial coherence of firing in TLE rats. We then present the first evidence that the reactivation of behavior-driven patterns of activity of CA1 place cells in the hippocampus is intact in TLE rats. Using a template-matching method, we discovered that real-time (3-5 s) reactivation structure was intact in TLE rats. Furthermore, we estimated the entropy rate of short time scale (∼250 ms) bursting activity using block entropies and found that significant, extended temporal correlations exist in both TLE and control rats. Fitting a first-order Markov Chain model to these bursting time series, we found that long sequences derived from behavior were significantly enriched in the Markov model over corresponding models fit on randomized data confirming the presence of replay in shorter time scales. We propose that the persistent consolidation of poor spatial information in both real time and during bursting activity may contribute to memory impairments in TLE rats.

Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus.

Anti-inflammatory therapies are the current most plausible drug candidates for anti-epileptogenesis and neuroprotection following prolonged seizures. Given that vasogenic edema is widely considered to be detrimental for outcome following status epilepticus, the anti-inflammatory agent dexamethasone is sometimes used in clinic for alleviating cerebral edema. In this study we perform longitudinal magnetic resonance imaging in order to assess the contribution of dexamethasone on cerebral edema and subsequent neuroprotection following status epilepticus. Lithium-pilocarpine was used to induce status epilepticus in rats. Following status epilepticus, rats were either post-treated with saline or with dexamethasone sodium phosphate (10mg/kg or 2mg/kg). Brain edema was assessed by means of magnetic resonance imaging (T2 relaxometry) and hippocampal volumetry was used as a marker of neuronal injury. T2 relaxometry was performed prior to, 48 h and 96 h following status epilepticus. Volume measurements were performed between 18 and 21 days after status epilepticus. Unexpectedly, cerebral edema was worse in rats that were treated with dexamethasone compared to controls. Furthermore, dexamethasone treated rats had lower hippocampal volumes compared to controls 3 weeks after the initial insult. The T2 measurements at 2 days and 4 days in the hippocampus correlated with hippocampal volumes at 3 weeks. Finally, the mortality rate in the first week following status epilepticus increased from 14% in untreated rats to 33% and 46% in rats treated with 2mg/kg and 10mg/kg dexamethasone respectively. These findings suggest that dexamethasone can exacerbate the acute cerebral edema and brain injury associated with status epilepticus.

Prolonged febrile seizures cause reversible reductions in white matter integrity.

Prolonged febrile seizures (PFS) are the commonest cause of childhood status epilepticus and are believed to carry a risk of neuronal damage, in particular to the mesial temporal lobe. This study was designed to determine: i) the effect of prolonged febrile seizures on white matter and ii) the temporal evolution of any changes seen. 33 children were recruited 1 month following PFS and underwent diffusion tensor imaging (DTI) with repeat imaging at 6 and 12 months after the original episode of PFS. 18 age-matched healthy control subjects underwent similar investigations at a single time point. Tract-based spatial statistics (TBSS) was used to compare fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) between patients and controls on a voxel-wise basis within the white matter skeleton. Widespread reductions in FA along multiple white matter tracts were found at 1 and 6 months post-PFS, but these had resolved at 12 months. At one month post-PFS the main changes seen were reductions in AD but at 6 months these had predominantly changed to increases in RD. These widespread white matter changes have not previously been noted following PFS. There are many possible explanations, but one plausible hypothesis is that this represents a temporary halting of normal white matter development caused by the seizure, that then resumes and normalises in the majority of children.

Altered short-term plasticity in the prefrontal cortex after early life seizures.

Seizures during development are a relatively common occurrence and are often associated with poor cognitive outcomes. Recent studies show that early life seizures alter the function of various brain structures and have long-term consequences on seizure susceptibility and behavioral regulation. While many neocortical functions could be disrupted by epileptic seizures, we have concentrated on studying the prefrontal cortex (PFC) as disturbance of PFC functions is involved in numerous co-morbid disorders associated with epilepsy. In the present work we report an alteration of short-term plasticity in the PFC in rats that have experienced early life seizures. The most robust alteration occurs in the layer II/III to layer V network of neurons. However short-term plasticity of layer V to layer V network was also affected, indicating that the PFC function is broadly influenced by early life seizures. These data strongly suggest that repetitive seizures early in development cause substantial alteration in PFC function, which may be an important component underlying cognitive deficits in individuals with a history of seizures during development.

Epilepsy surgery in children under 3 years.

PURPOSE: Resective epilepsy surgery in early childhood has become an important treatment option for selected infants and children with epilepsy. We describe experience and clinical outcomes of children under 3 years undergoing epilepsy surgery at Great Ormond Street Hospital (GOSH). METHODS: All children under 36 months of age who had resective surgery for the purpose of treating epilepsy within the GOSH epilepsy surgery programme were ascertained using a departmental database. Aetiology, post-operative seizure frequency, pre and post-operative cognitive function, long-term complications and re-operation rates were analysed by retrospective examination of clinical records. RESULTS: Forty-two children were included in our cohort with a median age at surgery of 20 months (range 3-36 months). Surgical procedures comprised 25 functional hemispherectomies, two anatomical hemispherectomies, four multilobar resections, seven lobar resections and four focal resections. 7/42 (17%, 95% CI 8-31%) children underwent re-operation. 20/42 (48%, 95% CI 33-62%) children achieved seizure freedom. 18/42 (43%, 95% CI 29-58) demonstrated an improvement in seizure frequency and no children had an increase in seizure frequency. Post-operative complications included subsequent shunt procedure in 5/25 (20%, 95% CI 9-39%) children undergoing hemispherectomy. There were no mortalities. In 23 children pre- and post-operative DQ or IQ was determinable allowing longitudinal comparison. Five children had a decrease in DQ/IQ >15 and two children had an increase DQ/IQ >15. DISCUSSION: Epilepsy surgery in children under 3 years of age offers suitable candidates a good chance of significantly improved seizure outcome which compares with rates in older cohorts.

Cerebral blood flow changes during pilocarpine-induced status epilepticus activity in the rat hippocampus.

INTRODUCTION: There is a known relationship between convulsive status epilepticus (SE) and hippocampal injury. Although the precise causes of this hippocampal vulnerability remains uncertain, potential mechanisms include excitotoxicity and ischaemia. It has been hypothesised that during the early phase of seizures, cerebral blood flow (CBF) increases in the cortex to meet energy demand, but it is unclear whether these compensatory mechanisms occur in the hippocampus. In this study we investigated CBF changes using perfusion MRI during SE in the pilocarpine rat. METHODS: First, we determined whether SE could be induced under anaesthesia. Two anaesthetic protocols were investigated: isoflurane (n=6) and fentanyl/medetomidine (n=7). Intrahippocampal EEG electrodes were used to determine seizure activity and reflex behaviours were used to assess anaesthesia. Pilocarpine was administered to induce status epilepticus. For CBF measurements, MRI arterial spin labelling was performed continuously for up to 3h. Either pilocarpine (375 mg/kg) (n=7) for induction of SE or saline (n=6) was administered. Diazepam (10mg/kg) was administered i.p. 90 min after the onset of SE. RESULTS AND DISCUSSION: We demonstrated time-dependent significant (p<0.05) differences between the CBF responses in the parietal cortex and the hippocampus during SE. This regional response indicates a preferential distribution of flow to certain regions of the brain and may contribute to the selective vulnerability observed in the hippocampus in humans.

Statin-induced myopathy in the rat: relationship between systemic exposure, muscle exposure and myopathy.

Rare instances of myopathy are associated with all statins, but cerivastatin was withdrawn from clinical use due to a greater incidence of myopathy. The mechanism of statin-induced myopathy with respect to tissue disposition was investigated by measuring the systemic, hepatic, and skeletal muscle exposure of cerivastatin, rosuvastatin, and simvastatin in rats before and after muscle damage. The development of myopathy was not associated with the accumulation of statins in skeletal muscle. For each statin exposure was equivalent in muscles irrespective of their fibre-type sensitivity to myopathy. The low amount of each statin in skeletal muscle relative to the liver does not support a significant role for transporters in the disposition of statins in skeletal muscle. Finally, the concentration of cerivastatin necessary to cause necrosis in skeletal muscle was considerably lower than rosuvastatin or simvastatin, supporting the concept cerivastatin is intrinsically more myotoxic than other statins.

Childhood convulsive status epilepticus: epidemiology, management and outcome.

Convulsive status epilepticus (CSE) in childhood is a medical emergency and its aetiology and outcome mean that it should be studied separately from adult CSE. The incidence in developed countries is between 17 and 23/100,000 with a higher incidence in younger children. Febrile CSE is the commonest single group with a good prognosis in sharp distinction to CSE related to central nervous system infections which have a high mortality. The aim of treatment is to intervene at 5 min and studies indicate that intravenous (i.v.) lorazepam may be a better first-line treatment than rectal diazepam and i.v. phenytoin a better second-line treatment than rectal paraldehyde. An epidemiological study strongly supports the development of prehospital treatment with buccal midazolam becoming a widely used but unlicensed option in the community. More than two doses of benzodiazepines increase the rate of respiratory depression without obvious benefit. The 1 year recurrence rate is 17% and the hospital mortality is about 3%.

Childhood convulsive status epilepticus: epidemiology, management and outcome.

Convulsive status epilepticus (CSE) in childhood is a medical emergency and its aetiology and outcome mean that it should be studied separately from adult CSE. The incidence in developed countries is between 17 and 23/100,000 with a higher incidence in younger children. Febrile CSE is the commonest single group with a good prognosis in sharp distinction to CSE related to central nervous system infections which have a high mortality. The aim of treatment is to intervene at 5 min and studies indicate that intravenous (i.v.) lorazepam may be a better first-line treatment than rectal diazepam and i.v. phenytoin a better second-line treatment than rectal paraldehyde. An epidemiological study strongly supports the development of prehospital treatment with buccal midazolam becoming a widely used but unlicensed option in the community. More than two doses of benzodiazepines increase the rate of respiratory depression without obvious benefit. The 1 year recurrence rate is 17% and the hospital mortality is about 3%.

Meningitis is a common cause of convulsive status epilepticus with fever.

AIMS: In children with convulsive status epilepticus (CSE) with fever, to determine the likelihood of acute bacterial meningitis (ABM), the proportion that are treated with antibiotics, and the proportion that have diagnostic CSF sampling. METHODS: Patients with an incident episode of CSE with fever were identified as part of an ongoing prospective population based study of CSE in childhood. RESULTS: There were 49 incident cases of CSE in the first six months. Ascertainment was 96%. Twenty four had CSE with fever, 16 had early parenteral antibiotics, nine had diagnostic CSF sampling, and four had ABM. The population risk of ABM in CSE with fever was significantly higher than that of short seizures with fever (17% v 1.2%). CONCLUSIONS: The classical symptoms and signs of ABM may be absent in CSE with fever. A high index of suspicion for ABM in the child with CSE with fever is paramount. The most appropriate management is suggested to be early parenteral antibiotics and a lumbar puncture when there are no contraindications.

Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.

OBJECTIVES: To characterise the clinical features, emergency pre-paediatric intensive care (PIC) treatment, and course of status epilepticus (SE) in children admitted to PIC. This may provide insight into reasons for admission to PIC and provide a framework for the development of strategies that decrease the requirement for intensive care. DESIGN: Cross sectional, retrospective study. SETTING: A tertiary paediatric institution's intensive care unit. PARTICIPANTS: The admission database and all discharge summaries of each admission to a tertiary paediatric institution's PIC over a three year period were searched for children aged between 29 days and 15 years with a diagnosis of SE or related diagnoses. The case notes of potential cases of SE were systematically reviewed, and clinical and demographic data extracted using a standard data collection form. RESULTS: Most children with SE admitted to PIC are aged less than 5 years, male to female ratio 1:1, and most (77%) will have had no previous episodes of SE. Prolonged febrile convulsions, SE related to central nervous system infection, and SE associated with epilepsy occur in similar proportions. Contrary to the Advanced Paediatric Life Support guidelines many children admitted to PIC for SE receive over two doses, or inadequate doses, of benzodiazepine. There is a risk of respiratory depression following administration of over two doses of benzodiazepine (chi2 = 3.4, p = 0.066). Children with SE admitted to PIC who had prehospital emergency treatment are more likely to receive over two doses of benzodiazepines (chi2 = 11.5, p = 0.001), and to subsequently develop respiratory insufficiency (chi2 = 6.2, p = 0.01). Mortality is low. Further study is required to determine the morbidity associated with SE in childhood requiring intensive care. CONCLUSIONS: As the risk of respiratory depression is greater with more than two doses of benzodiazepines, clinicians should not disregard prehospital treatment of SE. As pre-PIC treatment of SE is inadequate in many cases, appropriate audit and modifications of standard guidelines are required.

A systematic review of the epidemiology of status epilepticus.

Population-based data on the incidence, aetiology, and mortality associated with status epilepticus (SE) are required to develop preventative strategies for SE. Through a systematic review, we aimed to assess the methodological quality as well as similarities, and differences between available population based studies in order to arrive at conclusions on the epidemiology of SE. All population-based studies where primary outcome was incidence, aetiology or mortality of SE were identified through a systematic search and synthesized. Methodological quality of studies were independently rated by two examiners using a unique scoring system. Seven population-based projects on SE yielding nine published reports and five abstracts were reviewed. Quality scores were in the range of 19-34 with a possible maximum of 40 (kappa scores 0.67-1.0). The incidence of SE has a bimodal distribution with peaks in children aged less than a year and the elderly. Most SE were acute symptomatic. Short-term mortality was 7.6-22% and long-term mortality was 43%. Age and aetiology were the major determinants of mortality. There are few population-based studies on SE but most are of good quality. Most studies are primarily or exclusively based on adult populations. There is limited information on the association of ethnicity and socio-economic status and SE.

Quantitative magnetic resonance characterization of mesial temporal sclerosis in childhood.

OBJECTIVE: To investigate whether quantitative MR techniques can be used to distinguish between mesial temporal sclerosis in patients with a history of prolonged febrile convulsion and in patients without such a history. METHODS: Quantitative hippocampal T2 relaxometry, hippocampal volumetry, and single voxel (1)H-MRS data were acquired from 16 children who subsequently underwent temporal lobe resections for intractable temporal lobe epilepsy and histologically were shown to have sclerosis of the horn of Ammon. Eight children had a history of prolonged febrile convulsion in early childhood and eight children had other or no associations. RESULTS: Patients with a history of prolonged febrile convulsion had smaller hippocampi (p = 0.02) and prolonged T2 relaxation time (p = 0.03) ipsilateral to the seizure focus when compared with patients without such a history. There was also more side-to-side asymmetry of T2 relaxation time (p = 0.004) and hippocampal volume (p = 0.02) in the patients with a history of prolonged febrile convulsion than in those with other or no associations. No differences between the groups were identified using (1)H-MRS. CONCLUSIONS: These data support the view that there are at least two types of mesial temporal sclerosis. There may be several pathogenetic pathways from initial insult to later mesial temporal sclerosis, and these pathways are, at least in part, dependent on the initial insult.