Complete Seizure Control Research Articles

Electroclinical presentation and genotype–phenotype relationships in patients with Unverricht‐Lundborg disease carrying compound heterozygous CSTB point and indel mutations

Unverricht-Lundborg disease (EPM1A) is frequently due to an unstable expansion of a dodecamer repeat in the CSTB gene, whereas other types of mutations are rare. EPM1A due to homozygous expansion has a rather stereotyped presentation with prominent action myoclonus. We describe eight patients with five different compound heterozygous CSTB point or indel mutations in order to highlight their particular phenotypical presentations and evaluate their genotype-phenotype relationships. We screened CSTB mutations by means of Southern blotting and the sequencing of the genomic DNA of each proband. CSTB messenger RNA (mRNA) aberrations were characterized by sequencing the complementary DNA (cDNA) of lymphoblastoid cells, and assessing the protein concentrations in the lymphoblasts. The patient evaluations included the use of a simplified myoclonus severity rating scale, multiple neurophysiologic tests, and electroencephalography (EEG)-polygraphic recordings. To highlight the particular clinical features and disease time-course in compound heterozygous patients, we compared some of their characteristics with those observed in a series of 40 patients carrying the common homozygous expansion mutation observed at the C. Besta Foundation, Milan, Italy. The eight compound heterozygous patients belong to six EPM1A families (out of 52; 11.5%) diagnosed at the Laboratory of Genetics of the Galliera Hospitals in Genoa, Italy. They segregated five different heterozygous point or indel mutations in association with the common dodecamer expansion. Four patients from three families had previously reported CSTB mutations (c.67-1G>C and c.168+1_18del); one had a novel nonsense mutation at the first exon (c.133C>T) leading to a premature stop codon predicting a short peptide; the other three patients from two families had a complex novel indel mutation involving the donor splice site of intron 2 (c.168+2_169+21delinsAA) and leading to an aberrant transcript with a partially retained intron. The protein dose (cystatin B/β-actin) in our heterozygous patients was 0.24 ± 0.02, which is not different from that assessed in patients bearing the homozygous dodecamer expansion. The compound heterozygous patients had a significantly earlier disease onset (7.4 ± 1.7 years) than the homozygous patients, and their disease presentations included frequent myoclonic seizures and absences, often occurring in clusters throughout the course of the disease. The seizures were resistant to the pharmacologic treatments that usually lead to complete seizure control in homozygous patients. EEG-polygraphy allowed repeated seizures to be recorded. Action myoclonus progressively worsened and all of the heterozygous patients older than 30 years were in wheelchairs. Most of the patients showed moderate to severe cognitive impairment, and six had psychiatric symptoms. EPM1A due to compound heterozygous CSTB mutations presents with variable but often markedly severe and particular phenotypes. Most of our patients presented with the electroclinical features of severe epilepsy, which is unexpected in homozygous patients, and showed frequent seizures resistant to pharmacologic treatment. The presence of variable phenotypes (even in siblings) suggests interactions with other genetic factors influencing the final disease presentation.

VOLTAGE-GATED POTASSIUM CHANNEL (VGKC) ANTIBODIES IN EPILEPSY: DIAGNOSTIC YIELD AND THERAPEUTIC IMPLICATIONS

BackgroundRecent studies have identified serum VGKC antibodies in various cohorts of patients with epilepsy, and have suggested a potential aetiological role for VGKC antibodies in epilepsy.MethodsWe have undertaken systematic testing...

Schizencephaly: A study of 16 patients

ObjectiveTo present 16 patients with schizencephaly and neurological involvement, and analyse their characteristics and neuroimages. Material and methodsThe study included 16 patients, 8 males and 8 females, all of whom were diagnosed with schizencephaly at less than 3 years of age; 2 patients were diagnosed prenatally. Schizencephaly was identified by computerised tomography (CT) in 1 patient and by MR or three-dimensional MR (3DMR) with a 1.5tesla apparatus in the others. Most patients were referred for evaluation because of psychomotor delay, motor disabilities and/or seizures. ResultsFive patients had bilateral schizencephaly with open lips (2 of them had suffered intrauterine cytomegalovirus infections); 2 showed unilateral schizencephaly with separated lips, 8 presented unilateral schizencephaly with fused lips, and 1 had schizencephaly with open lips on one side and fused lips on the other. Prenatal cytomegalovirus infection was diagnosed in 2 patients. A cerebral malformation that affected the midline was diagnosed by routine ultrasound studies in 2 patients. Eight patients (50%) presented with seizures that were focal, except for one patient who showed secondary generalisation. The latter was the only patient whose disease was refractory to complete seizure control with antiepileptic medication. All patients had some degree of motor deficit, which was either unilateral (hemiparesis) or bilateral (tetraparesis). Conclusion3DMR imaging was very important in diagnosing of schizencephaly in our patients because it showed the polymicrogyria that covered the area of the cleft and permitted us to rule out porencephaly. Neuronal migration disorders such as heterotopias and, more frequently, cortical dysplasias, were observed in several patients. Half of the patients had epilepsy which was controlled with antiepileptic medication, except in 1 patient.

Treatment changes in a cohort of people with apparently drug-resistant epilepsy: an extended follow-up

BackgroundThe seizure response to the addition of a previously unused antiepileptic drug in a cohort of 155 people with refractory epilepsy was previously reported after a median of 18 months...

Complete remission of seizures after corpus callosotomy

Corpus callosotomy is usually intended to alleviate-not to achieve total control of-epileptic seizures. A few patients experience complete seizure control after callosotomy, but the associated clinical factors are unknown. The object of this study was to investigate clinical factors associated with long-term seizure remission after total corpus callosotomy in patients with infantile or early childhood onset epilepsy. Thirteen consecutive patients with infantile or early childhood onset epilepsy underwent 1-stage total corpus callosotomy for alleviation of seizures. Their age at surgery ranged from 1 year and 5 months to 24 years (median 7 years). Eleven patients had West syndrome at the onset of disease, and the other 2 had Lennox-Gastaut syndrome. All patients suffered from spasms, axial tonic seizures, or atonic seizures. Six patients had proven etiology of epilepsy, including tuberous sclerosis, polymicrogyria, trauma, and Smith-Magenis syndrome. The association between postoperative seizure freedom and preoperative factors including age at surgery, no MRI abnormalities, proven etiology, and focal electroencephalographic epileptiform discharges was examined. Postoperative seizure freedom was achieved in 4 of 13 patients for a minimum of 12 months. All 4 patients had no MRI abnormalities and no identified etiology. None of the 8 patients with MRI abnormality, 6 patients with known etiology of epilepsy, or 4 patients aged older than 10 years at surgery achieved seizure freedom. Two of the 7 patients with focal electroencephalographic abnormalities became seizure free. Absence of MRI abnormalities was significantly associated with postoperative seizure freedom (p < 0.01). Complete seizure remission is achieved after total corpus callosotomy in a subgroup of patients with intractable epilepsy following West syndrome or Lennox-Gastaut syndrome. One-stage total corpus callosotomy at a young age may provide a higher rate of seizure freedom, especially for patients with no MRI abnormalities and no identified etiology of epilepsy.

Malignant migrating partial seizures of infancy controlled by stiripentol and clonazepam

The syndrome of malignant migrating partial seizures of infancy (MMPSI) is characterized by early onset of multiple seizure types and overall poor prognosis. Seizures are markedly drug resistant and few reports have suggested the efficacy of some antiepileptic drugs. We report one case of MMPSI in which prolonged seizure control is obtained with an association of clonazepam, levetiracetam and stiripentol, confirming thus the possibility of complete sustained seizure control in this epileptic syndrome. Of more than 60 cases reported to date, ours is the forth in which sustained complete control of seizures was obtained.

Kombinationstherapie bei Epilepsie

Use of Monotherapy is acknowledged as the standard anticonvulsant therapy although no more than about 65% of patients become seizure-free with a single antiepileptic drug. Therefore, up to 50% of patients with epilepsy are treated at least intermittently with more than one antiepileptic drug. The percentage of patients achieving complete seizure control with combination therapy after ineffective monotherapy is small. Monotherapy and combination therapy are not always contrary to each other; many anticonvulsants have different modes of action and are effectively a combination therapy in one drug. Combinations of anticonvulsants with differing mechanisms of action are called "rational polypharmacy". A superior efficacy of these combinations over combinations of anticonvulsants with identical or similar mechanisms of action have not been proved by randomised trials. Add-on trials with lacosamide and the combination of lamotrigine and valproic acid, however, suggest a superior tolerability and/or efficacy of combinations with differing mechanisms of action. Treatment with drug combinations should take into account, above all, efficacy and safety, interactions, and costs of each antiepileptic drug as well as comorbidity.

Epilepsy in Korean patients with Angelman syndrome

PurposeThe aim of this study was to investigate the natural history of epilepsy and response to anti-epileptic drug treatment in patients with Angelman syndrome (AS) in Korea.MethodsWe retrospectively reviewed the clinical records of 14 patients diagnosed with epilepsy out of a total of 17 patients with a genetic diagnosis of AS. These patients were seen at the Department of Pediatric Neurology at Severance Children's Hospital from March 2005 to March 2011.ResultsFourteen (9 males and 5 females) subjects (82.3%) were diagnosed with epilepsy in AS. The most common seizure types were generalized tonic-clonic (n=9, 27%) and myoclonic (n=9, 27%), followed by atonic (n=8, 24%), atypical absence (n=4, 12%) and complex partial seizure (n=3, 9%). The most commonly prescribed antiepileptic drug (AED) was valproic acid (VPA, n=12, 86%), followed by lamotrigine (LTG, n=9, 64%), and topiramate (n=8, 57%). According to questionnaires that determined whether each AED was efficacious or not, VPA had the highest response rate and LTG was associated with the highest rate of seizure exacerbation. Complete control of seizures was achieved in 6 patients. Partial control was achieved in 7 patients, while one patient was not controlled.ConclusionEpilepsy is observed in the great majority of AS patients. It may have early onset and is often refractory to treatment. There are few reports about epilepsy in AS in Korea. This study will be helpful in understanding epilepsy in AS in Korea.

Lecture: profile of risks and benefits of new antiepileptic drugs in brain tumor-related epilepsy

In patients with brain tumor, seizures are the onset symptom in 20-40% of the patients, while a further 20-45% of the patients will present them during the course of the disease. These data are important when considering the choice of antiepileptic drugs for this particular patient population, because brain tumor-related epilepsy (BTRE) is often drug resistant, has a strong impact on the quality of life and weighs heavily on public health expenditures. In brain tumor patients, the presence of epilepsy is considered as the most important risk factor for long-term disability. For this reason, the problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control can significantly improve the patient's psychological and relational sphere. In these patients, new generation drugs such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, and zonisamide are preferred, because they have fewer drug interactions and cause fewer side effects. Among the recently marketed drugs, lacosamide has demonstrated promising results and should be considered as a possible treatment option. Therefore, it is necessary to develop a customized treatment plan for each patient with BTRE, whose goals are complete seizure control, minimal or no side effects, and elimination of cognitive impairment and/or psychosocial problems.

Esquisencefalia. Estudio de 16 pacientes

ObjectiveTo present 16 patients with schizencephaly and neurological involvement, and analyse their characteristics and neuroimages. Material and methodsThe study included 16 patients, 8 males and 8 females, all of whom were diagnosed with schizencephaly at less than 3 years of age; 2 patients were diagnosed prenatally. Schizencephaly was identified by computerized tomography (CT) in 1 patient and by MR or three-dimensional MR (3DMR) with a 1.5tesla apparatus in the others. Most patients were referred for evaluation because of psychomotor delay, motor disabilities and/or seizures. ResultsFive patients had bilateral schizencephaly with open lips (2 of them had suffered intrauterine cytomegalovirus infections); 2 showed unilateral schizencephaly with separated lips, 8 presented unilateral schizencephaly with fused lips, and 1 had schizencephaly with open lips on one side and fused lips on the other. Prenatal cytomegalovirus infection was diagnosed in 2 patients. A cerebral malformation that affected the midline was diagnosed by routine ultrasound studies in 2 patients. Eight patients (50%) presented with seizures that were focal, except for one patient who showed secondary generalisation. The latter was the only patient whose disease was refractory to complete seizure control with antiepileptic medication. All patients had some degree of motor deficit, which was either unilateral (hemiparesis) or bilateral (tetraparesis). Conclusion3D MR imaging was very important in diagnosing of schizencephaly in our patients because it showed the polymicrogyria that covered the area of the cleft and permitted us to rule out porencephaly. Neuronal migration disorders such as heterotopias and, more frequently, cortical dysplasias, were observed in several patients. Half of the patients had epilepsy which was controlled with antiepileptic medication, except in 1 patient.

Reversible Carbamazapine Encephalopathy With Frontal Intermittent Rhythmic Delta Activity

Reversible Carbamazapine Encephalopathy With Frontal Intermittent Rhythmic Delta Activity

Differential diagnosis of grand mal seizures during puberty in neurologically healthy children

Epileptic syndromes that occur during puberty with grand mal (GM) seizures can present a diagnostic problem. The beginning of the disease is often marked by “big attack”. Juvenile myoclonic epilepsy (JME) in puberty is first characterized by the occurrence of myoclonic jerks mostly in the hand, then by GM, and more rarely by typical absence seizures. The aim is to describe the course of the same disease, JME, in a sister and brother but with a different diagnostic approach, and consequently different therapeutic success. The sister was found to have a GM attack during afternoon nap at the age of 14 years. She was first diagnosed with partial epilepsy with secondary generalization and then with generalized epilepsy. During two years of treatment with topiramate, GM did not recur, routine EEG did not show any epileptiform changes and she was not motivated to continue treatment, so she sought a second opinion. Medical documentation revealed a permanently neglected problem of objects “falling out” of her hand in the morning, especially after sudden awakening or short sleep. We used video EEG with provocation methods (morning awakening and active manipulation of objects with both hands) to record myoclonic hand jerks along with ictal EEG. We diagnosed JME, introduced valproate as the first choice drug (several drug combinations were tried later), but control of myoclonic seizures was never achieved. We did targeted search for “small” seizures in other family members. Shortly thereafter, “blinking” episodes were noticed in the brother, then aged 13.5; myoclonic jerks in his hands were recorded by diagnostic evaluation and video EEG, and valproate therapy was introduced. Seizures were completely stopped. Epileptic syndrome did not manifest the full clinical picture. The GM seizures would have likely prevented the boy from pursuing his desired professional athlete career. In conclusion, undetected and for a long time inappropriately treated JME in the sister resulted in inability to achieve complete seizure control. In her brother, complete seizure control was achieved by early introduction of appropriate JME treatment.

Possible new avenues in epilepsy treatment: the stimulation techniques deep brain stimulation, vagal nerve stimulation, transcranial magnetic stimulation

Summary Stimulation techniques have been extensively explored as new treatments for epilepsy, and their efficacy is still being investigated, albeit several approaches appear to be very promising. Vagal nerve stimulation (VNS) has been a well established palliative therapy for almost 20 years, however, complete seizure control is rarely obtained. Its favourable effect on mood has been noted in several studies, and VNS was FDA-approved for the treatment of major depression in 2005. Intracerebral electrical stimulation is currently being evaluated as ap otential treatment for patients with drug-resistan tf ocal epilepsy in whom surgery cannot be offered. We summarise the results of various studies applying deep brain stimulation (DBS) to different brain structures, particularly to the mesial temporal lobe. From these studies, it appears that the efficiency of DBS to reduce epileptic seizures is demonstrated in a sufficiently large patient population but the exact determinants (physical parameters, syndromes) of its success (or its absence) remain unknown. Repetitive Transcranial Magnetic Stimulation (rTMS) has been investigated as an antiepileptic treatment in patients with focal seizure onset by several groups, however, the clinical success is variable and in most studies rather low.

Interictal paroxysmal EEG abnormalities in childhood absence epilepsy

The aim of this study is to analyze the graphic features and the clinical significance of the focal interictal paroxysmal abnormalities (FIPA) which can be found in the EEG of patients with typical absences, on the basis of 29 personal cases. The children (15 female; mean age at the first evaluation = 8.2 years, range 4.8–14.3 years) were particularly selected, because they only showed absence seizures. In all subjects the ictal clinical and EEG features were typical for childhood absence epilepsy (CAE). The interictal EEG showed a normal background activity in all children and in 11 patients the presence of FIPA specially on frontal areas. The graphic aspects of FIPA and their spatial and temporal variability, often in the same subject, were in agreement with a functional form. Furthermore the excellent response to valproic acid and ethosuximide, with a complete seizure control also in the follow-up in 26 among 28 treated children, confirms the opinion that our cases are affected by a typical form of CAE. In conclusion FIPA probably are not uncommon in typical idiopathic CAE and their presence does not seem to change the benign prognosis. There is a relationship between our data and the experimental models proposed in the literature.

Pharmacotherapy for children and adolescents with epilepsy

Introduction: Childhood epilepsies are the most frequent neurological problems that occur in children. Despite the introduction of new antiepileptic drugs (AEDs) 25 – 30% of children with epilepsy remain refractory to medical therapy.Areas covered: This review aims to highlight the main published data on the treatment of childhood epilepsy. The electronic database, PubMed, and abstract proceedings were used to identify studies. The aim of antiepileptic therapy should be to provide complete seizure control, if possible without the burden of any side effect. Since 1993, new agents have been approved for use as an antiepileptic. Although there are few published data (especially in pediatric populations) to establish that the second-generation AEDs are more efficacious than the older AEDs, they appear to have better tolerability.Expert opinion: Old AEDs are efficacious agents that continue to play a major role in the current treatment of epilepsy. These agents actually remain the first-line treatment for many specific seizure types or epileptic syndromes. The new AEDs were initially approved as adjunct agents and – subsequently – as monotherapy for various seizure types in the adult and children. Despite these improvements, few AEDs are now considered to be a first-choice for the treatment of epilspsy in children.

Reversible Carbamazapine Encephalopathy With Frontal Intermittent Rhythmic Delta Activity

Reversible Carbamazapine Encephalopathy With Frontal Intermittent Rhythmic Delta Activity

Epilepsy in a child with Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder characterized by facial dismorphy, multiple congenital anomalies, delayed psychomotor development and pharmaco-resistant epilepsy. We present a 5-year-old girl with severe delay in growth and development, microcephaly, mild facial dismorphy and epilepsy. The pregnancy was complicated by intrauterine growth retardation. Generalized muscle hypotonia was observed at birth. First seizures started at age of 9 months as unilateral convulsive status epilepticus (SE), sometimes with bilateral generalization. Seizures were often triggered by fever and were resistant to antiepileptic treatment. Introduction of lamotrigine and valproate therapy led to complete seizure control at the age of 33 months. Electroencephalographic (EEG) finding was typical at the beginning. After transitory improvement between age four and five years, epileptiform EEG activity appeared again at the age of five years, without observed clinical seizures. Magnetic resonance imaging showed diffuse brain atrophy and delay in myelination. Using Multiplex ligation-dependent probe amplification (MLPA) method, we disclosed heterozygote microdeletation of the distal part of the short arm of chromosome 4 (4p16). We present a clinical course of epilepsy in a patient with Wolf-Hirschhorn syndrome. The diagnosis was verified by modern molecular technique. This is the first molecular characterization of a patient with WHS performed in our country.

Rufinamide in children and adults with Lennox–Gastaut syndrome: First Italian multicenter experience

This is the first multicenter Italian experience with rufinamide as an adjunctive drug in children, adolescents and adults with Lennox-Gastaut syndrome. The patients were enrolled in a prospective, add-on, open-label treatment study from 11 Italian centers for children and adolescent epilepsy care. Forty-three patients (26 males, 17 females), aged between 4 and 34 years (mean 15.9 ± 7.3, median 15.0), were treated with rufinamide for a mean period of 12.3 months (range 3-21 months). Twenty patients were diagnosed as cryptogenic and 23 as symptomatic. Rufinamide was added to the baseline therapy at the starting dose of 10mg/kg body weight, evenly divided in two daily doses and then increased by 10mg/kg approximately every 3 days up to a maximum of 1000 mg/day in children aged ≥4 years with a body weight less than 30 kg. In patients more than 30 kg body weight, rufinamide could be titrated up to 3200 mg/day. After a mean follow-up period of 12.3 months (range 3-21 months), the final mean dose of rufinamide was 33.5mg/kg/24h (range 11.5-60) if combined to valproic acid, and of 54.5mg/kg/24h (range 21.8-85.6) without valproic acid. The response rate (≥50% decrease in countable seizures) was 60.5% (26 of 45 patients) in total; 51.1% experienced a 50-99% reduction in seizure frequency and complete seizure control was achieved in the last 4 weeks follow-up by 9.3% of patients. Two patients (4.7%) had a 25-50% seizure reduction, while seizure frequency remained unchanged in 13 (30.2%) and increased in 2 (4.7%). Reliable data for atypical absence seizures and myoclonic seizures were not available, as these are usually impossible to count. Ten patients (23.2%) reported adverse side effects, while taking rufinamide. They were generally mild and transient and most frequently included vomiting, drowsiness, irritability and loss of appetite. In conclusion, rufinamide as an adjunctive therapy reduced the number of drop attacks and major motor seizures in about 60% of patients with Lennox-Gastaut syndrome and produced only mild or moderate adverse side effects.

Reoperation after selective amygdalohippocampectomy: an MRI analysis of the extent of temporomesial resection in ten cases

Selective amygdalohippocampectomy (SAHE) yields 60-80% of patients with medically refractory mesial temporal lobe epilepsy seizure-free and seems to be equally effective compared to the more extended temporal lobe resections. The resection of the entire entorhinal cortex (EC) is of crucial importance to warrant complete seizure control for those patients. Thus, evidence of residual EC could be a predictor of a potentially successful reoperation in patients with recurrent seizures after SAHE. We performed an analysis of preoperative and postoperative magnetic resonance imaging (MRI) in patients who underwent a reoperation after an unsuccessful transsylvian SAHE to assess the presence of residual EC before reoperation and to determine whether certain anatomical variants may dispose patients to incomplete resection of EC. Ten patients who underwent reoperation after SAHE for the recurrence of medically refractory seizures were studied. MRI after SAHE was assessed for the presence of residual EC using T2-weighted and inversion recovery sequences perpendicularly to the main axis of the hippocampus. The results were compared with a control group of ten patients who became seizure-free after SAHE. In the nine patients of the study group, the sulcal anatomy of the basal temporal lobe was graphically outlined and analysed on MRI scans performed before SAHE to characterise the sulcal boundaries of the EC. Residual EC was found in nine of ten patients and was absent in the control group. After reoperation (median follow-up of 36.5 months), eight out of ten patients were completely seizure-free. In seven out of nine patients, a discontinuous course of the lateral sulcal boundaries of the EC was determined. Careful analysis of MRI verified residual mesiotemporal structures in the majority of patients who became seizure-free after reoperation. Certain temporobasal sulcal patterns might dispose for a higher risk of incomplete resection of the EC. The study confirms that reoperation is an effective treatment modality for patients with recurrent seizures after transsylvian SAHE.

Epileptic nystagmus: Description of a pediatric case with EEG correlation and SPECT findings

Epileptic nystagmus (EN) describes repetitive eye movements that result from seizure activity. We describe a patient with EN and vertigo first noted at the age of 4 yr and 10 mo. Brain MRI did not show anomalies. Ictal EEG recordings revealed epileptic activity during three episodes of horizontal, left-beating nystagmus not crossing the midline. Ictal 99mTc-ECD SPECT demonstrated the presence of active foci in multiple cerebral regions including bilateral prefrontal, bilateral parieto-temporo-occipital and the left parieto-insular-vestibular areas. A wide area of hypoperfusion was also evident in the right hemisphere, prevailing in the parieto-occipital regions and the medial prefrontal gyrus. Topiramate was started at a dose of 2 mg/kg/d with complete seizure control after 14 d. EEG and SPECT were repeated after a seizure-free period of 1 mo; disappearance of epileptic activity and modification of cerebral perfusion were evident. This case reaffirms the cortical origin and involvement of temporo-occipital and frontal cortex in the genesis of saccadic epileptic nystagmus. Rapid complete control of clinical events coincided with the normalization of EEG and improvement of the SPECT pattern.