Developing a new animal model of temporal lobe epilepsy

Epilepsy affects 1-2 % of the population. For 30 % of these patients, their syndrome will be refractory to medical treatment. To improve our understanding and treatment of the epilepsies, we need to develop clinically relevant animal models. As temporal lobe epilepsy is often preceded by prolonged febrile seizures and in our population associated with a focal cortical dysplasia, we hypothesised that an underlying predisposing anatomical lesion would predispose individuals to develop prolonged febrile seizures and that temporal lobe epilepsy would later develop. As predicted, all the lesioned animals developed prolonged febrile seizures, while all other control groups only showed simple febrile seizures. After a latent period, 86 % of the animals who had experienced a prolonged seizure developed spontaneously recurrent limbic seizures. We now need to understand the anatomical and electrophysiological changes underlying this new epilepsy model to try and develop more effective treatments for the condition.     

Prevalence of mood dysfunction in epilepsy patients in Croatia

Fifty consecutive and consenting epilepsy patients from the Zagreb Epilepsy Center were examined for the presence of depressive symptoms using the Beck Depression Inventory (BDI). This questionnaire has been previously validated for use in the Croatian population. Mean age of the patients was 30.8 +/- 13.5 years, 60.4% were females. Majority of them were employed (72.9%) and single (62.5%), and 35.4% had a university degree. Most of them had complex partial seizures (n=40, 80%), and 6 (12%) were diagnosed with idiopathic generalized epilepsy. Assessment with the BDI showed that 33.3% of patients had recent depressive symptoms: 6.3% had mild depressive symptoms, 8.4% moderate and 18.6% severe depressive symptoms. Three patients (6.4%) attempted suicide in the past, two of them had current suicidal ideation, and all of them were severely depressed. This is the first and preliminary study assessing mood dysfunction in epilepsy patients in Croatia. Increased prevalence of depression in epilepsy patients suggests specific approach and need for early treatment.     

Complicated relationship between autism with regression and epilepsy

We retrospectively evaluated a set of 205 children with autism and compared it to the partial sub-set of 71 (34.6%) children with a history of regression. From 71 children with regression, signs of epileptic processes were present in 43 (60.6%), 28 (65.12%) suffered clinical epileptic seizures, and 15 (34.9%) just had an epileptiform abnormality on the EEG. In our analysis, autistic regression is substantially more associated with epileptic process symptoms than in children with autism and no history of regression. More than 90% of children with a history of regression also show IQ < 70 and reduced functionality. Functionality and IQ further worsens with the occurrence of epileptic seizures (98% of children with regression and epilepsy have IQ < 70). We proved that low IQ and reduced functionality significantly correlate rather with epileptic seizures than just sub-clinical epileptiform abnormality on EEG. Clinical epileptic seizures associated with regression significantly influence the age of regression and its clinical type. The age of regression is higher compared to children with regression without epileptic seizures (in median: 35 months of age in patients with seizures while only 24 months in other patients). Patients with seizures revealed regression after 24th months of age in 68% of cases, while patients without seizures only in 27%. However, coincidence with epilepsy also increased the occurrence of regression before the 18th month of age (23% of patients), while only 4% of patients without epilepsy revealed regression before the 18th month. Epileptic seizures are significantly associated especially with behaviour regression rather than speech regression or regression in both behaviour and speech. Also epileptic seizures diagnosed before correct diagnosis of autism were significantly associated with delayed regression (both behavioural and speech regression).     

Neuroprotection in epilepsy

Brain damage and neuronal loss caused by traumatic brain injury, ischemic stroke, and symptomatic status epilepticus can lead to severe long-term consequences, such as impairment in learning and memory and cognitive functions, and development of chronic epilepsy. This can be the result of morphologic and functional changes underlying temporal lobe epilepsy. Epilepsy patients have increased risk of status epilepticus. It is a life-threatening condition when seizures last for more than 30 min and trigger processes leading to neuronal apoptosis and necrosis in various parts of brain. Administration of neuroprotective drugs preventing these pathologic processes could improve the prognosis for such patients. However despite of active research of neuroprotective drugs, the effective ways to prevent brain damage resulting from prolonged seizures are yet to be found. Studies of neuroprotective properties of classic and novel anticonvulsant drugs showed that most of them do not have the sufficient neuroprotective effect and are not able to prevent epileptogenesis. Thus the studies of other potential neuroprotective drugs seem to be promising.     

Sialyltransferase ST3Gal IV deletion protects against temporal lobe epilepsy

Temporal lobe epilepsy (TLE) often becomes refractory, and patients with TLE show a high incidence of psychiatric symptoms, including anxiety and depression. Therefore, it is necessary to identify molecules that were previously unknown to contribute to epilepsy and its associated disorders. We previously found that the sialyltransferase ST3Gal IV is up‐regulated within the neural circuits through which amygdala‐kindling stimulation propagates epileptic seizures. In contrast, this study demonstrated that kindling stimulation failed to evoke epileptic seizures in ST3Gal IV‐deficient mice. Furthermore, approximately 80% of these mice failed to show tonic–clonic seizures with stimulation, whereas all littermate wild‐type mice showed tonic–clonic seizures. This indicates that the loss of ST3Gal IV does not cause TLE in mice. Meanwhile, ST3Gal IV‐deficient mice exhibited decreased acclimation in the open field test, increased immobility in the forced swim test, enhanced freezing during delay auditory fear conditioning, and sleep disturbances. Thus, the loss of ST3Gal IV modulates anxiety‐related behaviors. These findings indicate that ST3Gal IV is a key molecule in the mechanisms underlying anxiety – a side effect of TLE – and may therefore also be an effective target for treating epilepsy, acting through the same circuits.

     

Neurosurgical management of epilepsy: a personal perspective in 1983

The therapeutic goal in the neurosurgical treatment of medically intractable epilepsy is complete seizure control, for both biologic and psychosocial reasons. Cortical resections are more likely to accomplish this than other surgical alternatives for epilepsy. Although abnormalities on new imaging techniques (CT, positron emission scanning) aid in identifying the epileptic focus, interictal epileptiform EEG changes remain the main indicator of focal origin of the seizures. Where this is equivocal, direct brain recording of spontaneous seizures with subdural electrodes is of value in identifying the side and lobe of seizure onset. The cortical resection is then tailored by the extent of the interictal electrocorticographic abnormalities and functional identification of essential areas such as those for language, using an electrical stimulation mapping technique, under local anesthesia. With this approach, half of the patients with temporal lobe foci are seizure-free since the time of operation, over two-thirds become so with time, and over three-quarters have at least very major reductions in seizure frequency.     

Early prognosis of epilepsy.

In 94 previously untreated new referrals to a neurological clinic with tonic-clonic or partial seizures or both the failure rate for optimum single-drug treatment with phenytoin or carbamazepine after a median of 32 months was 17%. Failure of single-drug treatment was associated especially with the presence of additional neuropsychiatric handicaps but also with partial or mixed seizures, symptomatic epilepsy, and a higher number and frequency of tonic-clonic or partial seizures before treatment. Analysis of the recurrence of seizures suggested that the first year of treatment may be crucial in determining the long-term prognosis. These findings are in keeping with the concept that seizures may predispose to further seizures, and imply that early, effective treatment may be important to prevent evolution into chronic and more intractable epilepsy.     

Gene therapy in epilepsy: the focus on NPY

Gene therapy represents an innovative and promising alternative for the treatment of epileptic patients who are resistant to conventional antiepileptic drugs. Among the various approaches for the application of gene therapy in the treatment of CNS disorders, recombinant viral vectors have been most widely used so far. Several gene targets could be used to correct the compromized balance between inhibitory and excitatory transmission in epilepsy. Transduction of neuropeptide genes such as galanin and neuropeptide Y (NPY) in specific brain areas in experimental models of seizures resulted in significant anticonvulsant effects. In particular, the long-lasting NPY over-expression obtained in the rat hippocampus using intracerebral application of recombinant adeno-associated viral (AAV) vectors reduced the generalization of seizures from their site of onset, delayed acquisition of fully kindled seizures and afforded neuroprotection. These results establish a proof-of-principle for the applicability of AAV-NPY vectors for the inhibition of seizures in epilepsy. Additional investigations are required to demonstrate a therapeutic role of gene therapy in chronic models of seizures and to address in more detail safety concerns and possible side-effects.     

Scalp EEG for the diagnosis of epilepsy and photosensitivity in the baboon

Spontaneous seizures have been observed in several baboon species housed at the Southwest National Primate Research Center (SNPRC), including Papio hamadryas anubis and cynocephalus/anubis, hamadryas/anubis, and papio/anubis hybrids. The goal of this study was to establish a noninvasive, reliable electroencephalographic technique to characterize epilepsy phenotypes and assess photosensitivity in these subspecies. Thirty baboons with witnessed seizures, and 15 asymptomatic baboons underwent scalp electroencephalograms (EEGs) with photic stimulation (PS). The sensitivity and specificity of surface EEG for identifying interictal epileptic discharges (IEDs) in baboons with witnessed seizures were examined. The morphology of IEDs, electroclinical features of seizures and responses to PS, reproducibility of EEG findings, and intrarater reliability were also evaluated. Twenty-three seizure baboons (77%) demonstrated IEDs, predominantly with frequencies of 4-6 Hz in 18 baboons and 2-3 Hz in six baboons. Two seizure animals had a mixture of 2-3-Hz and 4-6-Hz IEDs. All animals with 2-3-Hz IEDs were 3 years old or younger. Myoclonic seizures (MS) and generalized tonic-clonic seizures (GTCS) were recorded in 13 baboons (43%). PS activated IEDs in 15 baboons (50%) and seizures in nine baboons. The presence of IEDs or seizures was not associated with a particular gender or species (Fisher exact test, alpha=0.05). Seizures were more common in animals >3 years old, while PS-induced IEDs and seizures were more prevalent in P.h. anubis/cynocephalus crosses compared to P.h. anubis. In the asymptomatic controls, IEDs were recorded in five baboons (33%), and photoparoxysmal responses were observed in two (13%). Surface EEG is a sensitive and reliable instrument for characterizing the epilepsy encountered in Papio species. Electroclinically, the seizure animals had generalized epilepsy with photosensitivity. The variation in IED morphology may be age-related or it may reflect different epileptic phenotypes. Ketamine provoked IEDs and seizures in most seizure animals and only in a few asymptomatic baboons; therefore, it may enhance the sensitivity of surface EEG for detecting a predisposition to epilepsy.     

A cross-sectional study of people with epilepsy and neurocysticercosis in Tanzania: clinical characteristics and diagnostic approaches

Neurocysticercosis (NCC) is a major cause of epilepsy in regions where pigs are free-ranging and hygiene is poor. Pork production is expected to increase in the next decade in sub-Saharan Africa, hence NCC will likely become more prevalent. In this study, people with epilepsy (PWE, n=212) were followed up 28.6 months after diagnosis of epilepsy. CT scans were performed, and serum and cerebrospinal fluid (CSF) of selected PWE were analysed. We compared the demographic data, clinical characteristics, and associated risk factors of PWE with and without NCC. PWE with NCC (n=35) were more likely to be older at first seizure (24.3 vs. 16.3 years, p=0.097), consumed more pork (97.1% vs. 73.6%, p=0.001), and were more often a member of the Iraqw tribe (94.3% vs. 67.8%, p=0.005) than PWE without NCC (n=177). PWE and NCC who were compliant with anti-epileptic medications had a significantly higher reduction of seizures (98.6% vs. 89.2%, p=0.046). Other characteristics such as gender, seizure frequency, compliance, past medical history, close contact with pigs, use of latrines and family history of seizures did not differ significantly between the two groups. The number of NCC lesions and active NCC lesions were significantly associated with a positive antibody result. The electroimmunotransfer blot, developed by the Centers for Disease Control and Prevention, was more sensitive than a commercial western blot, especially in PWE and cerebral calcifications. This is the first study to systematically compare the clinical characteristics of PWE due to NCC or other causes and to explore the utility of two different antibody tests for diagnosis of NCC in sub-Saharan Africa.     

The safety of evening primrose oil in epilepsy

The concern that evening primrose oil might cause epilepsy or seizures, or reduce the threshold for seizures, originated from two papers published in the early 1980s. These original reports are re-examined, and the association of evening primrose oil with seizures is shown to be spurious. Not only are linoleic acid and gamma-linolenic acid safe in epilepsy, with prolonged oral administration of linoleic acid and alpha-linolenic acid (in a 4:1 mixture) protecting rats from having seizures in four different epilepsy models, but the evening primrose oil-derived omega-6 fatty acid arachidonic acid inhibits sodium ion currents and synaptic transmission, while the evening primrose oil-derived eicosanoid prostaglandin E(1) appears to have anticonvulsant activity. In light of these findings, it is suggested that formularies should now remove seizures or epilepsy as a side-effect of evening primrose oil, and should remove a history of seizures or epilepsy as a contraindication to taking evening primrose oil.     

Sydney epilepsy incidence study to measure illness consequences: the SESIMIC observational epilepsy study protocol

Background  

Epilepsy affects an estimated 50 million people and accounts for approximately 1% of days lost to ill health globally, making it one of the most common, serious neurological disorders. While there are abundant global data on epilepsy incidence, prevalence and treatment, there is a paucity of Australian incidence data. There is also a general lack of information on the psychosocial impact and socioeconomic consequences of a new diagnosis of epilepsy on an individual, their family, household, and community which are often specific to the health and social system of each country.     

Deletion of FGF9 in GABAergic neurons causes epilepsy

Fibroblast growth factor 9 (FGF9) has long been assumed to modulate multiple biological processes, yet very little is known about the impact of FGF9 on neurodevelopment. Herein, we found that loss of Fgf9 in olig1 progenitor cells induced epilepsy in mice, with pathological changes in the cortex. Then depleting Fgf9 in different neural populations revealed that epilepsy was associated with GABAergic neurons. Fgf9 CKO in GABAergic neuron (CKO^VGAT) mice exhibited not only the most severe seizures, but also the most severe growth retardation and highest mortality. Fgf9 deletion in CKO^VGAT mice caused neuronal apoptosis and decreased GABA expression, leading to a GABA/Glu imbalance and epilepsy. The adenylate cyclase/cyclic AMP and ERK signaling pathways were activated in this process. Recombinant FGF9 proteoliposomes could significantly decrease the number of seizures. Furthermore, the decrease of FGF9 was commonly observed in serum of epileptic patients, especially those with focal seizures. Thus, FGF9 plays essential roles in GABAergic neuron survival and epilepsy pathology, which could serve as a new target for the treatment of epilepsy.Subject terms: Epilepsy, Molecular neuroscience     

Reduction in polypharmacy for epilepsy.

A two-year prospective study of 40 adult outpatients with chronic epilepsy was carried out in which blood drug concentrations were monitored, and anticonvulsant polypharmacy was reduced to treatment with a single drug in 29 patients (72%). In the year after the reduction of treatment the control of seizures was improved in 16 patients (55%), unchanged in eight(28%), and worse in five (17%). Mental function was improved in 16 (55%). The main reason for failure to reduce to or maintain treatment with a single drug was exacerbation of seizures during the difficult withdrawal period, especially in patients with frequent seizures, taking several drugs, or with additional neuropsychological handicaps. It is more difficult to reduce polypharmacy than to avoid it in the first place. Polypharmacy may sometimes aggravate control of seizures.     

Results of an action-research on epilepsy in rural mali

Purpose

To evaluate the RARE (Réseau Action-Recherche sur l’Epilepsie) program, a model of managing and treating people with epilepsy (PWE) at a primary health-care level in rural areas of Mali, we assessed treatment efficacy and compliance of patients who underwent the first year follow-up.

Methods

A network of rural general practitioners (GPs) settled in six rural districts of the regions of Koulikoro, Segou and Sikasso, was involved in the diagnosis, evaluation and monitoring of all the identified PWE and in the distribution of phenobarbital (PB). All the participants were included in a prospective database and followed-up by GPs at 4 months intervals during the first year. Seizure frequency, treatment doses and appearance of adverse events (AEs) were systematically recorded. Efficacy was evaluated in terms of reduction of seizures frequency while noncompliance in terms of time to study withdrawal for any cause.

Key findings

596 patients treated with PB were included in the analysis. Of these, 74.0% completed the first year follow-up. At the final visit, 59.6% were seizure-free: 31.0% for 12 months, 10.2% for 8 months and 18.4% for 4 months. Adults and patients with convulsive seizures were the most drug-resistant (p<0.002). Few AEs were recorded. The multivariate analysis showed that being a woman, presenting convulsive seizures, having more than 5 seizures/month and had never be treated were predictors of withdrawal (p≤0.05) at 12 months.

Significance

This study showed a good response and compliance to the treatment and allowed the identification of some factors associated with failure of management in a setting very near to clinical practice. Awareness campaigns are needed to assure a broader accessibility to treatment and to improve the compliance and continuity with treatment programs.     

Stability of synchronization clusters and seizurability in temporal lobe epilepsy

Purpose

Identification of critical areas in presurgical evaluations of patients with temporal lobe epilepsy is the most important step prior to resection. According to the “epileptic focus model”, localization of seizure onset zones is the main task to be accomplished. Nevertheless, a significant minority of epileptic patients continue to experience seizures after surgery (even when the focus is correctly located), an observation that is difficult to explain under this approach. However, if attention is shifted from a specific cortical location toward the network properties themselves, then the epileptic network model does allow us to explain unsuccessful surgical outcomes.

Methods

The intraoperative electrocorticography records of 20 patients with temporal lobe epilepsy were analyzed in search of interictal synchronization clusters. Synchronization was analyzed, and the stability of highly synchronized areas was quantified. Surrogate data were constructed and used to statistically validate the results. Our results show the existence of highly localized and stable synchronization areas in both the lateral and the mesial areas of the temporal lobe ipsilateral to the clinical seizures. Synchronization areas seem to play a central role in the capacity of the epileptic network to generate clinical seizures. Resection of stable synchronization areas is associated with elimination of seizures; nonresection of synchronization clusters is associated with the persistence of seizures after surgery.

Discussion

We suggest that synchronization clusters and their stability play a central role in the epileptic network, favoring seizure onset and propagation. We further speculate that the stability distribution of these synchronization areas would differentiate normal from pathologic cases.     

Clinical course of untreated tonic-clonic seizures in childhood: prospective,hospital based study.

OBJECTIVE: To assess decleration and acceleration in the disease process in the initial phase of epilepsy in children with new onset tonic-clonic seizures. STUDY DESIGN: Hospital based follow up study. SETTING: Two university hospitals, a general hospital, and a children''s hospital in the Netherlands. PATIENTS: 204 children aged 1 month to 16 years with idiopathic or remote symptomatic, newly diagnosed, tonic-clonic seizures, of whom 123 were enrolled at time of their first ever seizure; all children were followed until the start of drug treatment (78 children), the occurrence of the fourth untreated seizure (41 children), or the end of the follow up period of two years (85 untreated children). MAIN OUTCOME MEASURES: Analysis of disease pattern from first ever seizure. The pattern was categorised as decelerating if the child became free of seizures despite treatment being withheld. In cases with four seizures, the pattern was categorised as decelerating if successive intervals increased or as accelerating if intervals decreased. Patterns in the remaining children were classified as uncertain. RESULTS: A decelerating pattern was found in 83 of 85 children who became free of seizures without treatment. Three of the 41 children with four or more untreated seizures showed a decelerating pattern and eight an accelerating pattern. In 110 children the disease process could not be classified, mostly because drug treatment was started after the first, second, or third seizure. The proportion of children with a decelerating pattern (42%, 95% confidence interval 35% to 49%) may be a minimum estimate because of the large number of patients with an uncertain disease pattern. CONCLUSIONS: Though untreated epilepsy is commonly considered to be a progressive disorder with decreasing intervals between seizures, a large proportion of children with newly diagnosed, unprovoked tonic-clonic seizures have a decelerating disease process. The fear that tonic-clonic seizures commonly evolve into a progressive disease should not be used as an argument in favour of early drug treatment in children with epilepsy.     

Higher risk of seizures in offspring of mothers than of fathers with epilepsy.

Seizure risk has consistently been found to be higher in offspring of mothers than of fathers with epilepsy. This pattern cannot be explained by any simple genetic model. The present study examined the possibility that the pattern arises from differences between affected mothers and fathers in the characteristics of their epilepsy that influence offspring seizure risk. The study population comprised 687 offspring of parents with epilepsy from the Rochester-Olmsted County Record Linkage Project. Cumulative incidences of unprovoked seizures to age 25 were 8.7% and 2.4% in offspring of affected mothers and fathers, respectively. Cox proportional hazards analysis was used to calculate rate ratios (RRs) for unprovoked seizures in offspring. In the univariate analysis, risk of unprovoked seizures was higher if the affected parent was the mother (RR = 2.8, 95% confidence interval [ci] 1.1-7.2) or if the parent's onset was before age 20 (RR = 2.5, 95% ci 1.1-5.9), but there was no effect on offspring risk of either parent's etiology (idiopathic vs. remote symptomatic) or parent's seizure type (generalized vs. partial). These findings were not substantially changed in the multivariate analysis. Thus, differences between affected mothers and fathers in these characteristics did not account for the higher risk in offspring of affected mothers. Anticonvulsant use during pregnancy was not associated with increased offspring seizure risk.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures

SCN1A is the most relevant epilepsy gene. Mutations of SCN1A generate phenotypes ranging from the extremely severe form of Dravet syndrome (DS) to a mild form of generalized epilepsy with febrile seizures plus (GEFS+). Mosaic SCN1A mutations have been identified in rare familial DS. It is suspected that mosaic mutations of SCN1A may cause other types of familial epilepsies with febrile seizures (FS), which are more common clinically. Thus, we screened SCN1A mutations in 13 families with partial epilepsy with antecedent febrile seizures (PEFS+) using denaturing high-performance liquid chromatography and sequencing. The level of mosaicism was further quantified by pyrosequencing. Two missense SCN1A mutations with mosaic origin were identified in two unrelated families, accounting for 15.4% (2/13) of the PEFS+ families tested. One of the mosaic carriers with ~25.0% mutation of c.5768A>G/p.Q1923R had experienced simple FS; another with ~12.5% mutation of c.4847T>C/p.I1616T was asymptomatic. Their heterozygous children had PEFS+. Recurrent transmission occurred in both families, as noted in most of the families with germline mosaicism reported previously. The two mosaic mutations identified in this study are less destructive missense, compared with the more destructive truncating and splice-site mutations identified in the majority of previous studies. This is the first report of mosaic SCN1A mutations in families with probands that do not exhibit DS, but manifest only a milder phenotype. Therefore, such families with mild cases should be approached with caution in genetic counseling and the possibility of mosaicism origin associated with high recurrence risk should be excluded.     

Clinical use of the embryonic brain tissue grafts in epilepsy

Brain and spinal nerve tissue grafts of 5- to 10-week human embryos obtained during legal abortions were transplanted in the last 2.5 years to 15 patients with epilepsy and other paroxysmal disorders. Different forms of epilepsy were found in these patients. The latter were examined to determine their somatic, neurological, and psychological status. This made it possible to divide the patients into groups. Embryonic nerve tissue transplantation (ENTT) was found to be among efficient ways of treatment of patients with different forms of epilepsy. The positive results differed by degree and attested to the marked recovery activity of the impaired central nervous system (CNS). In patients with epilepsy resistant to medical treatment, embryonic nerve tissue implantation was found to cause a stable remission lasting from eight months to 2.5 years in 12 patients and to significantly decrease the frequency of seizures in three patients. Improvement of cognitive functions was observed in all cases. The changes in EEG were always positive, sometimes lagging behind the clinical effect, though more often progressing parallel to it. The possible biological mechanisms causing the above positive effect are discussed.