Resistant Seizures Research Articles

Vagus Nerve Stimulation.

BACKGROUND:The vagus nerve stimulation (VNS) is an approach mainly used in cases of intractable epilepsy despite all the efforts. Also, its benefits have been shown in severe cases of depression resistant to typical treatment.AIM:The aim of this study was to present current knowledge of vagus nerve stimulation.MATERIAL AND METHODS:A new value has emerged just at this stage: VNS aiming the ideal treatment with new hopes. It is based on the placement of a programmable generator on the chest wall. Electric signals from the generator are transmitted to the left vagus nerve through the connection cable. Control on the cerebral bioelectrical activity can be achieved by way of these signal sent from there in an effort for controlling the epileptic discharges.RESULTS:The rate of satisfactory and permanent treatment in epilepsy with monotherapy is around 50%. This rate will increase by one-quarters (25%) with polytherapy. However, there is a patient group roughly constituting one-thirds of this population, and this group remains unresponsive or refractory to all the therapies and combined regimes. The more the number of drugs used, the more chaos and side effects are observed. The anti-epileptic drugs (AEDs) used will have side effects on both the brain and the systemic organs. Cerebral resection surgery can be required in some patients. The most commonly encountered epilepsy type is the partial one, and the possibility of benefiting from invasive procedures is limited in most patients of this type. Selective amygdala-hippocampus surgery is a rising value in complex partial seizures. Therefore, as epilepsy surgery can be performed in very limited numbers and rather developed centres, success can also be achieved in limited numbers of patients. The common ground for all the surgical procedures is the target of preservation of memory, learning, speaking, temper and executive functions as well as obtaining a good control on seizures. However, the action mechanism of VNS is still not exactly known. On the other hand, it appears to be a reliable method that is tolerated well in partial resistant seizures. It has been observed that adverse effects are generally of mild-medium severity, and most of the problems can be eliminated easily through the re-adjustment of the stimulator.CONCLUSION:VNS, which is a treatment modality that will take place it deserves in epilepsy treatment with “the correct patient” and “correct reason”, must be known better and its applications must be developed.

Voltage gated potassium channel antibody(VGKC)-associated encephalopathy and psychiatric symptoms (case report)

Introduction and ObjectivesThe limbic system is primarily responsible for modulating behaviour, emotions and neuro-endocrine functions. Limbic encephalopathy involves this part of the brain and is characterised by the acute or sub-acute onset of seizures, recent memory loss, confusion and psychiatric symptoms. Here we describe an unusual presentation of a well-functioning elderly man, who presented with sudden onset of confusion, cognitive impairment, treatment resistant hyponatremia, seizures and psychiatric symptoms.Methods (Presentation)This 79 year old gentleman, previously well and independent was admitted to the acute hospital with a 3 week history of sudden onset of confusion, odd behaviour and weight loss. On admission he was hyponatremic (Na-118), developed treatment resistant seizures and progressive cognitive impairment. He was referred to the Liaison Psychiatry team with increasing paranoia, agitation and persecutory delusions.ResultsMRI and CT brain remained normal. Lumbar puncture revealed a positive VGKC antibody and his blood titres for VGKC was more than 3000. His hyponatremia and seizures remained chronic, but improved with plasmapheresis, oral corticosteroids and cyclophosphamide. He was commenced on aripiprazole for psychiatric symptoms, but was transferred to the acute psychiatric unit after being detained under section 2 of the MHA due to risks of aggression and absconsion.ConclusionsPsychiatric symptoms related to this form of encephalitis have not been emphasised in literature. His aggression improved over time on aripiprazole, but was transferred to a residential care home setting due to persisting cognitive deficits and social care needs This case highlights the importance of recognising multimorbidity, joint working and more research required in the area.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs.

The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.

Focal cortical dysplasias

Focal cortical dysplasias (FCDs) are localized malformations of cortical development associated with refractory epilepsies. Seizure onset most commonly occurs in the first decade of life and the clinical presentation varies according to the localization of the lesion. Neuropsychological impairment often accompanies the high seizure burden. Drug- resistant seizures can be controlled in a significant percentage of patients if adequate surgical treatment is possible. Although some clinical, electroencephalographic and neuroimaging characteristics of the FCDs are well understood, the differences among the histological subtypes of FCDs remains to be better determined.

Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies

We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel’s classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients.

Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations.

Early-onset epileptic encephalopathy caused by biallelic SLC13A5 mutations is characterized by seizure onset in the first days of life, refractory epilepsy and developmental delay. Little detailed information about the brain MRI features is available in these patients. Observational study describing the neuro-imaging findings in eight patients (five families) with mutations in the SLC13A5 gene. Seven infants had an MRI in the neonatal period, two had a follow-up MRI at the age of 6 and 18 months and one only at 13 months. One patient had follow-up MRIs at 11 and 16 months and 3 and 6 years of age, but no neonatal MRI. All patients presented with refractory neonatal seizures on the first day of life after an uncomplicated pregnancy and term delivery. Six out of seven infants with a neonatal MRI had a characteristic MRI pattern, with punctate white matter lesions (PWML), which were no longer visible at the age of 6 months, but led to gliotic scarring visible on MRI at the age of 18 months. The same pattern of gliotic scarring was seen on the MRIs of the infant without a neonatal scan. One infant had signal abnormalities in the white matter suspected of PWML on T2WI, but these could not be confirmed on other sequences. In infants presenting with therapy resistant seizures in the first days after birth, without a clear history of hypoxic-ischemic encephalopathy, but with PWML on their neonatal MRI, a diagnosis of SCL13A5 related epileptic encephalopathy should be considered.

Predicting seizures from local field potentials recorded via intracortical microelectrode arrays.

The need for new therapeutic interventions to treat pharmacologically resistant focal epileptic seizures has led recently to the development of closed-loop systems for seizure control. Once a seizure is predicted/detected by the system, electrical stimulation is delivered to prevent seizure initiation or spread. So far, seizure prediction/detection has been limited to tracking non-invasive electroencephalogram (EEG) or intracranial EEG (iEEG) signals. Here, we examine seizure prediction based on local field potentials (LFPs) from a small neocortical patch recorded via a 10×10 microelectrode array implanted in a patient with focal seizures. We formulate the seizure (ictal) prediction problem in terms of discriminating between interictal and preictal neural activity. Using deep Convolutional Neural Networks (CNNs), we show that periods of preictal activity can be successfully discriminated (80% detection; no false positives) from periods of interictal activity several (2-18) minutes prior to seizure onset. CNN input features consisted of the spectral power of LFP channels (1-second time windows) computed in 50 frequency bands (0-100 Hz; 2 Hz steps). Our preliminary results show that intracortical LFPs may be a promising neural signal for seizure prediction in focal epilepsy.

Wernicke-Korsakoff syndrome

To study the diagnosis and treatment of non-alcoholic Wernicke-Korsakoff syndrome (WKS). Eight patients (5 men and 3 women), mean age 38,9±1,4 years, with WKS developed due to acute gastrointestinal tract (GIT) disease (3 patients), the exacerbation of chronic GIT disease with malabsorption (2 patients) and after surgery on the upper GIT (3 patients) were included in the study. The disease manifested with consciousness disturbance, symptoms of ataxia, eye movement disorders and bulbar syndrome that developed after 24-48 h. Treatment resistant tonic-clonic seizures were developed in 1 patient. MRI revealed hyper intensive signals on T2-weighted images in the hypothalamus, mamillar bodies, brain stem, hippocampus as well as contrast accumulation in the mamillar bodies. Treatment with vitamin B complex (neurobion) and thiamine exerted a positive effect. Patients with GIT disease with malabsorption are at risk of WKS. Consciousness disturbance, symptoms of ataxia, eye movement disorders indicate the necessity of treatment with thiamine that allows to prevent the development of stable cognitive deficit.

PCSM-08EFFICACY AND TOLERABILITY OF LACOSAMIDE IN PATIENTS WITH GLIOMA AND SEIZURES: A PROSPECTIVE STUDY

BACKGROUND: Lacosamide (LCM) has been suggested to improve seizure control as add-on treatment in brain tumor patients. We present the results of a prospective study on the efficacy and tolerability of LCM in a cohort of patients with low (LGG) and high grade (HGG) gliomas with active epilepsy, either on chemotherapy or radiotherapy or during observation alone with MRI. METHODS: We enrolled 62 adult patients with persisting seizures (seizures > 1 per month) despite an adequate treatment with other antiepileptic drugs. The endpoints of the study were a significant reduction of seizure frequency (> 50% compared with baseline) and seizure freedom (SF) at 3 and 6 months, being concomitant AEDs and steroids unchanged or reduced. RESULTS: Among grade II gliomas a significant reduction of seizures was observed in 5/22 patients (22.7.%) and 7/22 (36.8%) at 3 and 6 months after start of LCM, respectively; a SF was obtained in 6/22 (23.3%) and 8/22 (42.1%) at 3 and 6 months after start of LCM, respectively. Among HGG a significant reduction of seizures was obtained in 10/41 patients (24.4%) and 7/33 patients (21.1%) at 3 and 6 months after start of LCM, respectively; a SF was obtained in 19/40 (47.5%) and 15/40 (45.5%) at 3 and 6 months after the start of LCM, respectively. Four out of 11 and 7/15 patients with LGG who responded to LCM did not receive any antineoplastic treatment, whereas 18/40 patients with HGG had the tumor stable or responding on MRI (RANO criteria) following antineoplastic treatment. A resolution of a status epilepticus was obtained in 7 patients. In 2 cases only LCM was withdrawn due to dizziness and fatigue or resistant seizures. CONCLUSIONS: This is the first prospective study showing a significant activity of LCM as add-on therapy in gliomas with different grades of malignancy.

Epilepsy with myoclonic-atonic seizures (Doose syndrome): When video-EEG polygraphy holds the key to syndrome diagnosis.

An electroclinical epilepsy syndrome diagnosis enables physicians to predict outcomes as well as select appropriate treatment options. We report a child who presented with reflex myoclonus at the age of 9 months and was initially diagnosed with myoclonic epilepsy in infancy. After 9 years of medically resistant myoclonic seizures, extensive investigations, and emerging learning difficulties, she was referred for video-telemetry to characterize her seizures in an attempt to make a syndromic diagnosis. A three-day video-telemetry assessment was performed to document seizures. Neck and deltoid EMG channels were applied from the onset of the recording.Frequent generalized bursts of 3- to 5-Hz spike/polyspike and slow wave discharges, associated with clinical manifestations, mostly myoclonic seizures, were noted. In addition, definite atonic components were noted on the neck EMG as well as the deltoids associated with the slow component of the ictal discharges.The EEG and polygraphy findings are suggestive of a generalized epilepsy characterized by predominantly myoclonic seizures with atonic components. This raises the possibility whether a variant of epilepsy with myoclonic–atonic seizures (Doose syndrome) may be the underlying diagnosis for this girl. A trial of the ketogenic diet would therefore be considered as an option in her future management in view of its beneficial effect in this condition.

Meta-analysis of vagus nerve stimulation treatment for epilepsy: correlation between device setting parameters and acute response.

Vagus nerve stimulation (VNS) is an adjunctive neurophysiological treatment for those patients who have pharmacoresistant or surgically resistant partial onset epilepsy. The aim of this study is to determine the effects of high and low stimulation paradigms on a responder rate of ≥50 and ≥75% reduction in seizure frequency and associated adverse effects in adults and children. A literature search was performed using Medline, PubMed, EMBASE, and Cochrane library for studies using vagus nerve stimulation published from January 1980 until July 2014 for medically or surgically resistant partial onset seizures, in children and adults. No restrictions on languages were imposed. Four authors reviewed and selected studies for inclusion and exclusion. The search identified five randomized control trials that fit with our inclusion criteria. The following outcomes were evaluated: 50% or greater reduction in total seizure frequency, 75% or greater reduction in total seizure frequency, and adverse effects. Four randomized controlled trials were analyzed in this meta-analysis. Results indicate high stimulation is more effective in adult patients who experienced ≥50 and ≥75% reduction in seizure frequency with a significant difference within both high and low stimulation groups. In children, there was no significant difference between the two groups and patients with ≥50 % reduction in seizures. Adverse effects such as hoarseness and dyspnea were more common in the high stimulation group where the remaining side effects were not statistically different among both groups. High stimulation is more effective than low stimulation in producing a greater reduction in seizure frequency in patients with medically and surgically resistant epilepsy.

Vagus nerve stimulation for partial seizures.

Vagus nerve stimulation for partial seizures.

The AMPA receptor antagonist NBQX exerts anti-seizure but not antiepileptogenic effects in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy

The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy.

The late diagnosis of double cortex syndrome in a 36-year-old woman with resistant atonic seizures

Subcortical laminar heterotopia (double cortex syndrome) is an orphan disease with an incidence of 1 to 200,000 people in the population. The cause of the disease is mutation of the gene DCX (synonyms: DBCN, XLIS) in chromosome Xq22.3-q23. The type of inheritance is X-linked dominant. Correct diagnosis requires a high degree of skills of a neurologist/epileptologist and a radiologist. The paper describes a clinical case of the late diagnosis of double cortex syndrome in a 36-year-old woman with a long history of resistant atonic seizures and mental retardation.

Impact of cyclic nucleotides on the antiseizure activity of acute and chronic diazepam administration in isoniazid-induced seizures and pentylenetetrazole kindling in rats

BackgroundIt is estimated that ~10% of the population suffers a single convulsive episode during their lifetime. Epilepsy is the second most common chronic neurological disorder after stroke, affecting ~0.5% of the population in developed countries and 1.5-2% in developing countries. Diazepam (DZ) is among the benzodiazepines used most widely in status epilepticus as well as resistant and refractory seizures. However, tolerance to its antiseizure activity is among the obstacles facing it use on a wider basis. Exploration of the role of cyclic nucleotides in seizures might enable finding ways to combat tolerance as well as discover new treatment modalities.Materials and methodsSeizure severity, electroencephalography, and levels of γ-aminobutyric acid (GABA), glutamate, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) in brain homogenate were assessed upon single administration of isoniazid and repeated pentylenetetrazole injections, whether untreated or treated with DZ, either acutely or on a chronic basis, respectively.ResultsA single DZ injection, 10 min after single isoniazid, could significantly improve seizure severity, associated with increased power of the fast β wave, implying ameliorated cognitive functions, together with an equal GABA/glutamate ratio versus significant reduction in the cAMP/cGMP ratio. Repeated DZ injections, 10 min after each pentylenetetrazole injection, on alternate days for 1 month and every 2 days for another month produced a significant improvement in seizure severity, accompanied by reduced power of the fast β and the slow δ waves, associated with an increased GABA/glutamate ratio and an unchanged cAMP/cGMP ratio.ConclusionThe current study assumes that a certain interplay exists between GABA/glutamate on the one hand and cAMP/cGMP on the other so that DZ could exert an anticonvulsant effect on an acute basis despite an unchanged GABA/glutamate ratio as well as upon chronic administration in the presence of an unchanged cAMP/cGMP ratio. In addition, the unchanged cAMP/cGMP ratio associated with chronic DZ administration suggests that cyclic nucleotides might lead to loss of some of the effects of DZ, as shown by reduced β wave power, indicating a reduction in cognitive abilities, concentration, and learning abilities, in contrast to higher β power after single use.

A Patient with Anti-LGI1 Related Autoimmune Limbic Encephalitis who had Frequent and Drug Resistant Seizures

A Patient with Anti-LGI1 Related Autoimmune Limbic Encephalitis who had Frequent and Drug Resistant Seizures

Age and Gender-Related Changes in Biogenic Amine Metabolites in Cerebrospinal Fluid in Children.

Metabolites of cerebrospinal biogenic amines (dopamine and serotonin)are an important tool in clinical research and diagnosis of children with neurotransmitter disorders. In this article we focused on finding relationships between the concentration of biogenic amine metabolites, age, and gender. We analyzed 148 samples from children with drug resistant seizures of unknown etiology and children with mild stable encephalopathy aged 0-18 years. A normal profile of biogenic amineswas found in 107 children and those children were enrolled to the study group. The CSF samples were analyzed by HPLC with an electrochemical detector. The concentrations of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively, were high at birth, gradually decreasing afterward until the 18 years of age. Nevertheless, the HVA/5-HIAA ratio did not vary with age, except in the children below 1 year of age. In the youngest group we observed a strong relationship between the HVA/5-HIAA ratio and age (r = 0.69, p < 0.001). There were no statistical differences in the level of both dopamine and serotonin metabolites between boys and girls, although a tread toward lower HVA and 5-HIAA in the boys was noticeable. Significant inter-gender differences in the level of HVA and 5-HIAA were noted only in the age-group of 1-4 years, with 5-HIAA being higher in the girls than boys (p = 0.004). In conclusion, the study revealed that the concentration of biogenic amine metabolites is age and sex dependent.

Rasmussen′s encephalitis: A rare case report

Rasmussen's encephalitis (RE) is a chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex leading to progressive neurological and cognitive deterioration. Advances in neuroimaging suggest that progression of the inflammatory process seen with magnetic resonance imaging (MRI) might be a good biomarker in RE. We present here a case of 8-year-old male child presented with repeated episodes of drug resistant seizures leading to intellectual impairment and cognitive deterioration. Further MRI was done which shows diffuse left cerebral atrophy.

Progressive dysembryoplastic neuroepithelial tumour

Dysembryoplastic neuroepithelial tumour (DNET) is a benign tumour characterised by cortical location and presentation with drug resistant partial seizures in children. Recently the potential for malignant transformation has been reported, however progression without malignant transformation remains rare. We report a case of clinical and radiologic progression of a DNET in a girl 10years after initial biopsy.

Antiepileptic efficacy of lamotrigine in phenobarbital-resistant and -responsive epileptic rats: A pilot study

About 25% of patients with epilepsy are refractory to treatment, so that new, more effective antiepileptic drugs (AEDs) are urgently needed. Animal models that simulate the clinical situation with individuals responding and not responding to treatment are important to determine mechanisms of AED resistance and develop novel more effective treatments. We have previously developed and characterized such a model in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. In this model, prolonged treatment of epileptic rats with phenobarbital (PB) results in two subgroups, PB responders and PB nonresponders. When PB nonresponders were treated in previous experiments with phenytoin (PHT), 83% of the PB-resistant rats were also resistant to PHT. In the present study we examined if rats with PB resistant seizures are also resistant to lamotrigine (LTG), using continuous EEG/video recording of spontaneous seizures over 10 consecutive weeks. For this purpose, a new group of epileptic rats was produced and selected by treatment with PB into responders and nonresponders. As in previous studies, PB nonresponders had a significantly higher seizure frequency before onset of treatment. During subsequent treatment with LTG, all PB nonresponders and 60% of the PB responders exhibited >75% reduction of seizure frequency and were therefore considered as LTG responders. Plasma levels of LTG did not differ significantly between responders and nonresponders. The data of this pilot study indicate that LTG is more effective than PHT to suppress seizures in PB nonresponders in this model, but that not all PB responders also respond to LTG. Overall, our data provide further evidence that AED studies in post-SE TLE models are useful in determining and comparing AED efficacy and investigating predictors and mechanisms of pharmacoresistance.