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Open access

Władysław Lasoń, Joanna Ślusarczyk, Magdalena Regulska, Monika Leśkiewicz and Agnieszka Basta-Kaim

Summary

Introduction. An increasing body of evidence points to an important role of neuroinflammatory processes in the pathomechanism of epilepsy. This hypothesis is mainly supported by data showing an increase of pro-inflammatory cytokine levels and glia activation in animal models of epilepsy and in brain tissue of epileptic patients. On the other hand, less emphasis has been put on pharmacological verification of this hypothesis.

Aim. The aim of this review is to summarize current knowledge on potential usefulness of microglia regulators and anti-inflammatory agents in designing antiepileptic/antiepileptogenic drugs, with the primary mechanism of action based on the inhibition of neuroinflammation.

Methods. We reviewed PubMed and MEDLINE databases to select publications in the topic: epilepsy, neuroinflammation, microglia and microglia regulators with antiepileptic properties. We searched the databases up to April 2017 with no date restrictions.

Review and Discussion. In the present paper, we will discuss new concepts of epileptogenesis which focus not only on changes in neurons but also take into consideration the role of activation of glial cells: microglia and astrocytes. Neuroinflammation, mainly through increased production of pro-inflammatory factors such as cytokines or chemokines, may play an important role in the development of epilepsy. Drugs regulating glial cells activation and consequently inflammatory status in the central nervous system have beneficial effects in different animal models of epilepsy as well as in clinical study in patients. The most promising compound seems to be minocycline which in some studies has been shown to possess antiepileptogenetic action. On the other hand, some antiepileptic drugs exhibit marked anti-inflammatory potency.

Conclusions. There are much data to suggest that there is significant opportunity for designing new antiepileptic drugs whose primary mechanism of action entails the inhibition of neuroinflammatory processes.

Open access

Matthias Wittstock, Uwe Walter, Daniela Schirrmeister, Kyrylo Kurtieiev, Jan Klinke, Annette Grossmann and Johannes Rösche

Summary

Introduction. The differentiation between the clinical and electroencephalographic changes in nonconvulsive status epilepticus (NCSE) and those in sporadic Creutzfeldt-Jakob disease (sCJD) is a crucial question.

Case report. A 77-year old woman was admitted because of fluctuating behavioural chancaseges, adynamia and apraxia since several months for diagnostic. The diagnosis of sCJD was suggested. Subsequently, she had a generalized tonic clonic seizure (GTCS) and the EEG revealed periodic lateralized epileptiform discharges and NCSE was considered.

Discussion. The presented case illustrates the dilemma in the differential diagnosis of sCJD and (symptomatic) NCSE in the light of the recently published new Salzburg consensus criteria and unified EEG terminology. Concerning these criteria, the patient showed after an initial generalized seizure and substantial clinical improvement after administration of antiepileptic drugs, persisting epileptic discharges and only subtle clinical ictal phenomena during the EEG patterns with typical spatiotemporal evolution as a correlate of a symptomatic NCSE. During the further course of the disease in the presented patient the picture changed into an encephalopathic pattern.

Conclusion. EEG criteria for the diagnosis of NCSE are complex. In our case the EEG resembled the pattern of NCSE in the postictal phase of a GTCS according to a classification of NCSE in use at this time. After initial responsiveness to antiepileptic medication the patient lost responsiveness to therapy displaying the typical encephalopathic EEG findings in sCJD. These findings may support the hypothesis of initial NCSE and transformation into prion protein induced encephalopathic EEG and demonstrated clinical usefulness of the Salzburg consensus criteria for NCSE.

Open access

Duncan Palka, Mahinda Yogarajah, Hannah R. Cock and Marco Mula

Summary

Background. Epilepsy is among the most frequent neurological conditions and it is estimated that approximately 8% of the population experience a seizure at some time in their lives.

Aim. To examine the characteristics of patients referred to a First Seizure Clinic (FSC) at a University Hospital in South-West London.

Methods. All subjects referred to the FSC at St George’s University Hospitals between January and December 2015 were included in this audit.

Results. From a total of 257 patients, males 49.5%, age range 16–90, 30% referred by General Practices (GPs), 59.1% by the Accident & Emergency Department (A&E) and 10.9% by other hospital wards, 24.5% did not attend (DNA) the clinical appointment. Females who did not attend were significantly older than males (49.8 years old vs 39.7; p = 0.007). Among those who attended the clinical appointment, 17% were diagnosed first unprovoked seizure, 12.4% acute symptomatic seizure and 28.9% epilepsy. These patients were referred mainly by A&E while GPs referred seizure mimics especially non-epileptic attack disorder (NEAD) and syncope. Patients with NEAD were significantly younger than those with seizures (29.4 years old vs 44.2; p < 0.001) and had a previous psychiatric history (72.7% vs 16.8%; p < 0.001). The proportion of seizure mimics was similar in the older sample group (> 65 years). Regarding acute symptomatic seizures, 33.3% were alcohol-related, 20.8% acute brain insults and 12.5% drug-related (always overdose).

Conclusions. 1 in 4 patients referred to a FSC does not attend the clinical appointment, especially older females. More than 1 in 3 cases represent seizure mimics and are referred mainly by GPs.

Open access

Elena Belousova, Vladimir Sukhorukov, Marina Dorofeeva, Lev Shagam and Dmitrii V. Vlodavetz

Summary

Introduction. There are some genetic disorders with combination of mental retardation, epilepsy and autism in which the abnormal mammalian Target of Rapamycin (m-TOR) signaling is implicated. The most important of them is tuberous sclerosis complex (TSC), but the disturbances of the m-TOR pathway can also be detected in Rett syndrome (RS), Fragile X syndrome and Down syndrome. We describe the rare case of co-occurrence of TSC and RS.

Case study. The female child was born at term by normal delivery after a non-complicated pregnancy. Family history was negative for epilepsy and mental retardation. The neonatal period was uneventful and psychomotor development was normal before the child became 1.5 years old. At the age of 18 months the girl developed hand-wringing stereotypes, facial hypotonia, ataxia and gait apraxia. She lost eye-to-eye contact and verbal contact with relatives, and became indifferent to the surrounding environment. When she was 2 years old, focal adversive seizures started which were readily controlled with carbamazepine. Cerebral cortical and subcortical tubers, cerebral white-matter radial migration lines and subependymal nodules on brain MRI together with hypomelanotic macules suggested the presence of TSC. Diagnosis was confirmed at age of 3 years by a heterozygous mutation c.5161-2A>G in TSC2 gene on chromosome 16p13. But the rude regression of psychomotor development and speech, autistic features alongside with characteristic hand-wringing stereotypes were unexplained until at age of 4.5 years RS was diagnosed by finding a heterozygous missense mutation in exon 4 of the MECP2 gene c.455C>T, resulting in a P152R substitution in the methyl-binding domain of the protein. At age of 5 the patient is not able to walk independently and has no expressive speech, she is autistic, has ataxia, limb rigidity, hyperreflexia, lack of purposeful hand movements, verbal and motor stereotypies.

Discussion. The presence of two mutations (one characteristic for TSC2 and one – characteristic for RS) significantly worsened the developmental and motor delay and autistic features in our patient. Dysregulation of m-TOR way is well established in TSC and recently described in RS, Down syndrome and Fragile X syndrome.

Open access

Mirosław Jasiński, Magdalena Chrościńska-Krawczyk and Stanisław J. Czuczwar

Summary

Background. Adenosine is regarded as an endogenous anticonvulsant and its agonists have been proved to affect the anticonvulsant activity of a number of antiepileptic drugs (AEDs) in animal models of seizures.

Aim. To evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.

Methods. The following adenosine receptor agonists were used: A1 – cyclohexyladenosine, A2A – CGS 21 680, A3 – N6-benzyl-NECA and A1 (preferentially) and A2 – 2-chloroadenosine. Their possible anticonvulsant effects were studied in a threshold electroconvulsive test for maximal electroconvulsions. The protective activity of AEDs alone or in combinations with adenosine agonists was evaluated in the form of their respective ED50 values necessary to protect 50% of mice against tonic extension of the hind limbs, following maximal electroshock, delivered through ear electrodes. The specificity of interactions between AEDs and adenosine agonists was challenged with an adenosine receptor A1 and A2 antagonist, aminophylline (5 mg/kg). The effects of AEDs alone or with adenosine agonists were tested for the occurrence of adverse effects (AE) (impairment of motor coordination) in a chimney test. All combinations with an enhancement the protective activity of CBZ or VPA were verified with the free plasma or brain concentration of these AED.

Results. Adenosine receptor agonists (cycloheksyladenosine up to 4 mg/kg; CGS 21 680 – 8 mg/kg; N6-benzyl-NECA – 1 mg/kg; 2-chloroadenosine – 2 mg/kg) did not significantly affect the threshold for maximal electroconvulsions. Cycloheksyladenosine (1 mg/kg), N6-benzyl-NECA (0.5 and 1 mg/kg) and 2-chloroadenosine (1 mg/kg) potentiated the anticonvulsant activity of CBZ. Valproate’s protective action was enhanced by one adenosine agonist – cycloheksyladenosine (1 mg/kg). Only the combination of CBZ + N6-benzyl-NECA (1 mg/kg) was resistant to aminophylline (5 mg/kg). Pharmacokinetic interactions were evident in case of the combination of CBZ + N6-benzyl-NECA (1 mg/kg) and resulted in an increased free plasma concentration of this CBZ. Interestingly, total brain concentration of CBZ confirmed the pharmacokinetic interaction as regards CBZ + N6-benzyl-NECA (1 mg/kg).

Conclusion. The best profile was shown by the combination of CBZ + 2-chloroadenosine which involved no AE or a pharmacokinetic interaction. The remaining positive combinations in terms of anticonvulsant activity were associated with general profound AE and pharmacokinetic interactions in some of them.

Open access

Athanasios Covanis

Summary

The International Bureau for Epilepsy (IBE) Executive Committee for the term 2013–2017 began in June 2013 during the 30th International Epilepsy Congress in Montreal. From the beginning, our primary goals were to fulfil the mission of our organisation and address problems such as awareness, education, and social issues, while promoting and protecting the human rights of persons with epilepsy (PWE) and improving trans-regional equity in access to health care services, improved prevention, diagnosis and treatment and as a consequence, a reduction in the treatment gap and alleviation of stigma worldwide. By so doing, the quality of life of PWE and those who care of them will be significantly improved. In order to achieve these aims, the IBE joined forces with the International League Against Epilepsy (ILAE) and also the World Health Organisation (WHO), regional and national IBE organisations and other stakeholders.

In addition, the participation of the IBE President in many national epilepsy events worldwide has helped to promote care and human rights of PWE nationally. A major awareness event accomplished during our term in office was the launch of the International Epilepsy Day in 2015. An IBE-ILAE event celebrated the 2nd Monday in February each year at the European Parliament with the participation of many stakeholders, PWE and advocates for epilepsy MEPs.

In 2014 in order to improve access to care, treatment, appropriate treatment for PWE worldwide, particularly in developing countries, we developed our strategy plan becoming IBE’s roadmap up to 2019 and with strategic priorities to establish epilepsy as a health priority worldwide. In June 2014, in Troina, Italy, WHO, ILAE, IBE and the Global Outreach Research Task Force organised a workshop to discuss how to improve access to antiepileptic medicines in low- and middle-income countries and, as a consequence, to produce a white paper. A unique historical achievement during our term in office was the approval from WHO and subsequently from World Health Assembly (WHA) (May 26th, 2015) the Resolution on the Burden of epilepsy, and calls on United Nation Member States to implement the WHA68.20 actions and for WHO to report back in 2018. The creation by IBE/ILAE in 2016 the legal entity Epilepsy Alliance Europe has given the opportunity for both organizations to play a partnership role in many research projects aiming to reduce the epilepsy burden in Europe and worldwide.

Open access

Péter Halász

Summary

Introduction. Medial temporal lobe of epilepsy (MTLE) is considered as local/regional epilepsy. However, as was discussed in Part I of this review (Halász, 2016a) there is more evidence regarding the involvement of both temporal lobes so as to consider MTLE as one of the typical bilateral system epilepsies.

Aim. To provide contemporary review of MTLE in relation to the declarative memory system and the newly recognized hippocampo-frontal memory consolidation during slow wave sleep.

Methods. A review of the available literature on experimental and clinical data and also the authors own studies in MTLE patients.

Review, discussion and results. New experimental and clinical neurophysiological data have shown that MTLE is closely linked to the hippocampal memory system. It is likely that hippocampal spiking is the epileptic variations of the normal sharp wave ripple events mediating the encoding and consolidation of memory engrams by a hippocampo-frontal dialogue during slow wave sleep.

Conclusions. The source of memory impairment in MTLE patients is not merely the cell loss and synaptic transformation of the hippocampal structure, but the every night interference with memory consolidation due to interictal spiking.

Open access

Dorota Talarska, Michał Michalak and Patrycja Talarska

Summary

Background. Every chronic illness, including epilepsy, has a negative effect on both the quality of life of the sufferer as well as on their relationship with their surroundings.

Aims. To investigate the quality of life of children suffering from epilepsy and analyse how they assessed and scored their experiences compared to their parents.

Materials and methods. The study included 209 children with epilepsy and their parents. The research tool was a questionnaire for gathering demographic and clinical data as well as the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0) questionnaire in two versions, one for 8–12 year olds and one for 13–18 year olds and their parents.

Results. Cronbach’s alpha coefficient for the entire PedsQL 4.0 questionnaire was 0.91 and 0.93 for children with epilepsy and their parents respectively. Children rated their Total Scale Score higher (67.5 points) than their parents (62.5 points). Whilst analyzing children’s functioning in different areas it was observed that girls’ assessments were higher than boys’, except for Emotional Functioning. Both parents and children scored School Functioning the lowest. The greatest agreement of responses was observed in the domain of Physical Functioning, the smallest in the domain of Emotional Functioning.

Conclusions. Quality of life was rated higher by both age groups of children suffering from epilepsy than by their parents. A statistically significant difference was found when comparing the assessment scores of children and parents in light of the following variables; child age, gender, illness duration, seizure frequency and treatment effectiveness.

Open access

Heinz Gregor Wieser

Summary

Introduction. Numerous reviews of the currently established concepts, strategies and diagnostic tools used in epilepsy surgery have been published. The focus concept which was initially developed by Forster, Penfield and Jasper and popularised and enriched by Lüders, is still fundamental for epilepsy surgery.

Aim. To present different conceptual views of the focus concept and to discuss more recent network hypothesis, emphasizing so-called “critical modes of an epileptogenic circuit”.

Method. A literature search was conducted using keywords: presurgical evaluation, epileptic focus concepts, cortical zones, diagnostic tools.

Review and remarks. The theoretical concepts of the epileptic focus are opposed to the network hypothesis. The definitions of the various cortical zones have been conceptualized in the presurgical evaluation of candidates for epilepsy surgery: the seizure onset zone versus the epileptogenic zone, the symptomatogenic zone, the irritative and functional deficit zones are characterized. The epileptogenic lesion, the “eloquent cortex” and secondary epileptogenesis (mirror focus) are dealt with. The current diagnostic techniques used in the definition of these cortical zones, such as video-EEG monitoring, non-invasive and invasive EEG recording techniques, magnetic resonance imaging, ictal single photon emission computed tomography, and positron emission tomography, are discussed and illustrated. Potential modern surrogate markers of epileptogenicity, such as High frequency oscillations, Ictal slow waves/DC shifts, Magnetic resonance spectroscopy, Functional MRI, the use of Magnetized nanoparticles in MRI, Transcranial magnetic stimulation, Optical intrinsic signal imaging, and Seizure prediction are discussed. Particular emphasis is put on the EEG: Scalp EEG, semi-invasive and invasive EEG (Stereoelectroencephalography) and intraoperative electrocorticography are illustrated. Ictal SPECT and 18F-FDG PET are very helpful and several other procedures, such as dipole source localization and spike-triggered functional MRI are already widely used. The most important lateralizing and localizing ictal signs and symptoms are summarized. It is anticipated that the other clinically valid surrogate markers of epileptogenesis and epileptogenicity will be further developed in the near future. Until then the concordance of the results of seizure semiology, localization of epileptogenicity by EEG and MRI remains the most important prerequisite for successful epilepsy surgery.

Conclusions and future perspectives. Resective epilepsy surgery is a widely accepted and successful therapeutic approach, rendering up to 80% of selected patients seizure free. Although other therapies, such as radiosurgery, and responsive neurostimulation will increasingly play a role in patients with an unresectable lesion, it is unlikely that they will replace selective resective surgery. The hope is that new diagnostic techniques will be developed that permit more direct definition and measurement of the epileptogenic zone.