Refractory Absence Research Articles

Home recording of 3-Hz spike-wave discharges in adults with absence epilepsy using the wearable Sensor Dot.

Home monitoring of 3-Hz spike-wave discharges (SWDs) in patients with refractory absence epilepsy could improve clinical care by replacing the inaccurate seizure diary with objective counts. We investigated the use and performance of the Sensor Dot (Byteflies) wearable in persons with absence epilepsy in their home environment. Thirteen participants (median age = 22 years, 11 female) were enrolled at the university hospitals of Leuven and Freiburg. At home, participants had to attach the Sensor Dot and behind-the-ear electrodes to record two-channel electroencephalogram (EEG), accelerometry, and gyroscope data. Ground truth annotations were created during a visual review of the full Sensor Dot recording. Generalized SWDs were annotated if they were 3 Hz and at least 3 s on EEG. Potential 3-Hz SWDs were flagged by an automated seizure detection algorithm, (1) using only EEG and (2) with an additional postprocessing step using accelerometer and gyroscope to discard motion artifacts. Afterward, two readers (W.V.P. and L.S.) reviewed algorithm-labeled segments and annotated true positive detections. Sensitivity, precision, and F1 score were calculated. Patients had to keep a seizure diary and complete questionnaires about their experiences. Total recording time was 394 h 42 min. Overall, 234 SWDs were captured in 11 of 13 participants. Review of the unimodal algorithm-labeled recordings resulted in a mean sensitivity of .84, precision of .93, and F1 score of .89. Visual review of the multimodal algorithm-labeled segments resulted in a similar F1 score and shorter review time due to fewer false positive labels. Participants reported that the device was comfortable and that they would be willing to wear it on demand of their neurologist, for a maximum of 1 week or with intermediate breaks. The Sensor Dot improved seizure documentation at home, relative to patient self-reporting. Additional benefits were the short review time and the patients' device acceptance due to user-friendliness and comfortability.

Refractory absence epilepsy due to rare in born error of metabolism

Refractory absence epilepsy due to rare in born error of metabolism

Efficacy and Tolerability of Ultra Rapid Duty Cycling Vagus Nerve Stimulation for Medically Refractory Absence Seizures

BackgroundSignificant knowledge gap exists on vagus nerve stimulation (VNS) efficacy and tolerability in medically refractory absence seizures (MRAS). This retrospective review of patients with MRAS aims to narrow this knowledge gap by comparing ultra rapid duty cycling ([URDC] ON time seven seconds, OFF time 0.2 minutes) with less frequent stimulations of rapid duty cycling (RDC, OFF time <1.1 minutes) and normal duty cycling (NDC, OFF time ≥1.1 minutes). MethodsPatients with MRAS aged less than 21 years who underwent VNS implantation were identified. Patient demographics, antiepileptic medications, seizure types, frequency, VNS parameters, outcomes of seizure reduction rate (SRR), and seizure freedom were extracted and compared among NDC, RDC, and URDC patient cohorts. ResultsThirty-six patients with MRAS were identified. After a mean follow-up of 32.6 months, responder rate ([RR], SRR ≥50%) for URDC was 80% for absence seizures and 80% for all seizure types versus 66.67% and 66.77% for NDC and 78.57% and 57.14% for RDC, respectively. Six of 10 patients (60%) on URDC achieved complete seizure freedom. A higher rate of subjective improvement in academic performance, attention, and developmental gain was noted in the URDC group. Patients on URDC tolerated higher output current (mean 3.025 mA) with minimal side effects but required a battery change sooner. ConclusionsVNS is a safe and effective nonpharmacologic management choice in patients with MRAS. The data presented demonstrate that the combination of URDC and high output current provides better RR and seizure freedom. Apart from a reduced battery life, this parameter modality seems to be well-tolerated.

Acetazolamide responsive early-onset absence epilepsy and ataxia in a toddler with a KCNA2 genetic variant; a case report

Genetic variants in KCNA2 (potassium voltage-gated channel subfamily A member 2) have been associated with a spectrum of symptoms such as epileptic encephalopathy, myoclonic seizures, intellectual disability, and cerebellar ataxia [ [1] Pena S.D. Coimbra R.L. Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy. Clin Genet. 2015; 87: e1-e3 Crossref PubMed Scopus (58) Google Scholar , [2] Perilli L. Mastromoro G. Murciano M. Amedeo I. Avenoso F. Pizzuti A. Guido C.A. Spalice A. Myoclonic Epilepsy: Case Report of a Mild Phenotype in a Pediatric Patient Expanding Clinical Spectrum of KCNA2 Pathogenic Variants. Front Neurol. 2021; 12806516 PubMed Google Scholar ]. Individuals with KCNA2 gain-of-function genetic variants could benefit from tailored-treatment regimens [ [1] Pena S.D. Coimbra R.L. Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy. Clin Genet. 2015; 87: e1-e3 Crossref PubMed Scopus (58) Google Scholar , [3] Hedrich U.B.S. Lauxmann S. Wolff M. Synofzik M. Bast T. Binelli A. Serratosa J.M. Martínez-Ulloa P. Allen N.M. King M.D. Gorman K.M. Zeev B.B. Tzadok M. Wong-Kisiel L. Marjanovic D. Rubboli G. Sisodiya S.M. Lutz F. Ashraf H.P. Torge K. Yan P. Bosselmann C. Schwarz N. Fudali M. Lerche H. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. Science Translational Medicine. 2021; 13: eaaz4957 Crossref PubMed Scopus (0) Google Scholar ]. Here, we report a 2-year-old boy with early-onset drug refractory absence seizures and gait ataxia. The clinical exome sequencing revealed a gain-of-function genetic variant in the KCNA2 gene. The child responded remarkably well to acetazolamide and was seizure-free.

CLINICAL AND MOLECULAR REPORT OF A RARE RAM POSITIVE NON-DOWN SYNDROME INFANT CBFA2T3-GLIS2 NEGATIVE, PRESENTING THE DRIVER P210-BCR-ABL1

Pediatric Acute Megakaryoblastic Leukemia (AMKL) comprises 4%‒15% of Acute Myeloid Leukemia (AML) cases. Down Syndrome (DS)-AMKL usually displays a favorable outcome, whereas the prognosis of non-DS-AMKL is generally poor. Here we present the clinical and genomic data of a rare non-DS-AMKL infant with p210-BCR-ABL1 fusion, co-occurring with a high-risk WT1 mutation. The baby was RAM positive and CBFA2T3-GLIS2 negative, showing refractoriness to treatment. A 1-year-old girl was referred to the Hospital with a history of fever and motor developmental delay for four months. On admission, she presented ecchymosis, swelling, and organomegaly (spleen and liver). The WBC count was 26.5 × 10 3 /μL, hemoglobin level was 7.6 g/dL, platelet count was 25 × 10 3 /μL, and LDH was 2.887. At diagnosis, she showed bilateral myeloid sarcoma. Morphological analysis of the Bone Marrow (BM) showed clustered cytoplasmic blebs. Flow cytometry analysis revealed 83% of blast cells and a profile compatible with AMKL and RAM phenotype. The patient was treated under the high-risk AML-BFM-2004. Imatinib was incorporated into the treatment after BCR-ABL1 detection. However, minimal residual disease remained positive throughout the treatment, making BM transplantation unfeasible. Disease refractoriness was persistent even with the administration of Dasatinib, FLAG-IDA and Venetoclax. The patient died one year after diagnosis due to sepsis during BM aplasia. We performed G-banding, FISH, and Multiplex RT-PCR experiments. The molecular response was assessed by absolute quantification via RT-qPCR assays. Sanger sequencing and NGS were performed on a targeted approach. The karyotype was 46,XX,t(9;22)(q21;q34). We observed polyploidy (3‒20N). FISH in polyploid Nuclei (8N) showed four BCR-ABL1 fusion signals. In diploid metaphases, we observed two BCR-ABL1 signals. Multiplex RT-PCR detected the p210- BCR - ABL1 . RT-qPCR monitoring detected persistent high levels of BCR-ABL1 transcripts associated with disease refractoriness. Sanger sequencing showed no GATA1 mutation. NGS revealed a missense WT1 pathogenic mutation, and CBFA2T3-GLIS2 was not present. RAM phenotype is characterized by overexpression of CD56 and under-expression of CD38, CD45, and HLA-DR. This phenotype is characteristic of children, usually associated with AML-M7 (38%) and intermediate-risk cytogenetics not associated with prognostic subgroups. RAM is related to a poor prognosis with high MRD and induction failure rates compared to non-RAM patients. This phenotype is associated with the CBFA2T3-GLIS2 fusion, which is related to extramedullary involvement, a particular blast morphology, and a worse outcome as compared to fusion-negative AML pediatric patients, including a high frequency of disease refractoriness and relapse. NGS studies did not show CBFA2T3-GLIS2 in our patient. Thus, our results indicate that RAM+ associated with the driver p210-BCR-ABL1, even with specific targeted therapy, may lead to treatment resistance regardless of CBFA2T3-GLIS2+. Here we highlight for the first time the presence of p210-BCR-ABL1 associated with RAM phenotype in the absence of CBFA2T3-GLIS2 and disease refractoriness in a non-DS-AMKL infant.

Diagnostic Value of Long-Term Video-EEG Monitoring in Children with Refractory Absence Epilepsy

Diagnostic Value of Long-Term Video-EEG Monitoring in Children with Refractory Absence Epilepsy

Amantadine for the Treatment of Refractory Absence Seizures in Children.

Introduction:Childhood epilepsy is a generalized epilepsy syndrome with a favorable response to antiepileptic drugs; however, a small percentage of typical absence seizures remain refractory to drugs. We studied the safety and efficacy of amantadine in children with refractory absence seizures.Materials and Methods:Of 48 children with typical absence seizures attending the outpatient department of a tertiary care neurological center over a period of 3 years from July 2013 to June 2016, 4 children who were refractory to standard treatment for at least 1 year were selected and were started on amantadine 4–6 mg/kg/day, after obtaining informed consent.Observations:The children, aged between 7 and 14 years, had more than 10 episodes of seizures per day in spite of polytherapy with valproate, lamotrigine, clonazepam, levetiracetam, and topiramate in various combinations. Electrographically, all showed the typical generalized 3 Hz spike wave discharges activated by hyperventilation. All the children became seizure free within 1 week after starting amantadine, and there was improvement in their school performance. The children continue to remain seizure free for 6–30 months now. No significant adverse effects were observed on addition of amantadine.Discussion:Amantadine can be tried as a safe add-on drug for children with absence epilepsy refractory to multiple drugs. Further multicenter trials may be needed to prove its effectiveness, as the numbers are small.

Restitution slope is principally determined by steady-state action potential duration.

AimsThe steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF.Methods and resultsExperiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM – to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope.Conclusion(s)Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death.

Refractory absence seizures: An Italian multicenter retrospective study.

To evaluate evidence and prognosis of refractory cases of absence seizures. Subjects with refractory absence seizures were identified retrospectively in 17 Italian epilepsy pediatrics Centers. We analyzed age at onset, family history, presence of myoclonic components, seizure frequency, treatment with antiepileptic drugs (AEDs), interictal electroencephalography (EEG) and neuropsychological assessment. Two subgroups were identified: one with patients with current absence seizures and another with patients that had become seizure free with or without AED treatment. The chi-square test was applied. A total of 92 subjects with drug-resistant absence seizures were analyzed. 45 subjects still show absence seizures (49%) and the other 47 became seizure free (51%) after a period of drug-resistance. The statistical analysis between these two groups showed no correlation between age of onset, family history and abnormalities at interictal EEG. Statistically significant differences were observed with regard to the number of AEDs used and intellectual disability. Typical absence epilepsy classifiable as Childhood Absence Epilepsy could not be considered so "benign", as suggested in literature. A longer duration of disease and a higher frequency of seizure seem to be correlated with a higher presence of cognitive impairment. No significant risk factor was observed to allow the faster and better recognition of patients with worse prognosis.

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

Adjunctive Madopar for ultrarefractory epilepsy? Preliminary observations

BackgroundThe optimum drug treatment for ultrarefractory epilepsy after failure of seven prior antiepileptic drugs (AEDs) remains uncertain. Prompted by reports that adjunctive amantadine or l-dopa has been useful for children with refractory absence seizures and Lennox–Gastaut syndrome, we studied the utility of dopaminergic agents for adults with ultrarefractory epilepsy. MethodsWe assessed seizure control following adjunctive treatment for up to 12months with the dopaminergic agent Madopar© in three adult patients with ultrarefractory epilepsy following brain injury or with Lennox–Gastaut syndrome, who had not achieved sustained seizure remission during past treatment with at least seven lifetime AEDs. FindingsThe adjunctive use of Madopar was associated with a reduction or remission of tonic–clonic seizures in two patients. However, Madopar seemed to have aggravated absence seizures in the patient with Lennox–Gastaut syndrome. InterpretationAlthough our preliminary observations do not and cannot establish the efficacy or safety of adjunctive Madopar, it may be an option for treatment of ultrarefractory focal seizures in adults if confirmed by randomized controlled trials.

Travelling waves in a neural field model with refractoriness

At one level of abstraction neural tissue can be regarded as a medium for turning local synaptic activity into output signals that propagate over large distances via axons to generate further synaptic activity that can cause reverberant activity in networks that possess a mixture of excitatory and inhibitory connections. This output is often taken to be a firing rate, and the mathematical form for the evolution equation of activity depends upon a spatial convolution of this rate with a fixed anatomical connectivity pattern. Such formulations often neglect the metabolic processes that would ultimately limit synaptic activity. Here we reinstate such a process, in the spirit of an original prescription by Wilson and Cowan (Biophys J 12:1–24, 1972), using a term that multiplies the usual spatial convolution with a moving time average of local activity over some refractory time-scale. This modulation can substantially affect network behaviour, and in particular give rise to periodic travelling waves in a purely excitatory network (with exponentially decaying anatomical connectivity), which in the absence of refractoriness would only support travelling fronts. We construct these solutions numerically as stationary periodic solutions in a co-moving frame (of both an equivalent delay differential model as well as the original delay integro-differential model). Continuation methods are used to obtain the dispersion curve for periodic travelling waves (speed as a function of period), and found to be reminiscent of those for spatially extended models of excitable tissue. A kinematic analysis (based on the dispersion curve) predicts the onset of wave instabilities, which are confirmed numerically.Electronic supplementary materialThe online version of this article (doi:10.1007/s00285-013-0670-x) contains supplementary material, which is available to authorized users.

Vagus nerve stimulation for medically refractory absence epilepsy

PurposeA proportion of patients with childhood and juvenile absence epilepsies (CAE, JAE) are likely to be classified as medically refractory. In view of evidence gap for the treatment of such patients, this series is reported to generate estimate for efficacy of vagus nerve stimulation (VNS) in this patient population. MethodsPatients were identified by a chart review of all VNS recipients between January 1, 2006 and December 31, 2011. The diagnosis of CAE and JAE was based on conventional criteria. Details of demography, epilepsy phenomenology, management and outcomes were extracted. The outcome measures included reduction in daily seizure frequency measured as a percentage of pre-VNS seizure frequency and classified on International League Against Epilepsy (ILAE) outcome scale. ResultsNine patients (7 CAE, 2 JAE) with a mean age of seizure onset of 5.4 years (±3.9) were identified. Mean duration of epilepsy prior to VNS implant was found to be 3.9 years (±1.4). These patients had failed a median of 5 anti-epileptic drugs before being referred for consideration of surgical treatment. After a mean follow-up of 33.9 months (±25.5, minimum 4 months), 1 patient attained complete seizure freedom (ILAE class 1), 6 had ILAE class 4 and 2 had ILAE class 5 outcomes, respectively. Mean reduction in daily seizure frequency was found to be 53.5±60.3% (1-sided p-value for paired t-test=0.04), with a 50% responder rate of 55.6%. ConclusionVNS may be considered as a therapeutic option in patients with medically refractory absence epilepsy.

Teaching Neuro Images : Hemispheric epilepsy

A 48-year-old woman was evaluated for a 40-year history of medically refractory absence and generalized tonic-clonic seizures. Neurologic examination and brain MRI were normal. Awake interictal EEG showed generalized fast spike-wave complex, always right hemispheric maximal ([figure 1][1]).

Intractable Absence Seizures in Hyperinsulinism-Hyperammonemia Syndrome

A girl with intractable absence seizures and facial myoclonia at age 7 years was eventually diagnosed with hyperinsulinism-hyperammonemia syndrome because of hypoglycemia, hyperinsulinism, hyperammonemia, and the results of an oral l-leucine loading test. Her seizures occurred even during periods of relatively normal blood glucose levels, and were completely suppressed by diazoxide treatment only. Her diagnosis of hyperinsulinism-hyperammonemia syndrome was confirmed by a loss of sensitivity of glutamate dehydrogenase for guanosine 5'-triphosphate. Genetic studies identified the I444M mutation in the GLUD1 gene, which encodes glutamate dehydrogenase. This case illustrates the complex relationship between seizures and hypoglycemia in hyperinsulinism-hyperammonemia syndrome that can create diagnostic difficulties. The possibility of hyperinsulinism-hyperammonemia syndrome should be considered in patients with refractory absence seizures with myoclonia.

Electrolyte therapy reduces spike-and-wave discharges in the WAG/Rij rat model of absence epilepsy

Although antiepileptic drugs are often effective in the control of seizures, some patients show little or no improvement. As alternative treatments, different dietary modifications were shown to be beneficial for patients with poor tolerance for AEDS. Previous reports have shown that rice-based oral electrolyte hydration therapy is effective in seizure control in patients with refractory absence seizures. In the present study, using an animal model of absence epilepsy, we showed that the occurrence of spike-and-wave discharges significantly decreases upon switching to electrolyte therapy. We also showed that consumption of solution with the same osmolarity as rice-based oral electrolyte solution leads to a decrease in the number of spike-and-wave discharges per hour. We suggest that the antiepileptic effect of rice-based oral electrolyte hydration therapy can be at least in part due to hyperosmolarity of the ingested solution.

Amantadine for the Treatment of Refractory Absence Seizures in Children

Amantadine has demonstrated efficacy in small series for absence and myoclonic type seizures. We examined the efficacy of amantadine for treating refractory absence seizures in a cohort of pediatric patients. We retrospectively reviewed medical records for patients with absence seizures treated with amantadine at Cook Children's Medical Center after January 2007. Abstracted data included sex, age at initiation, concomitant antiepileptic drugs, amantadine dosing, and seizure frequency. Outcomes at 3, 6, and 12 months after initiation were categorized as >90%, ≥50%, or <50% reduction in seizure frequency. Of 13 patients included in the study, many were exposed to multiple antiepileptic drugs (median, 3; range, 1-6). Three were implanted with a vagus nerve stimulator. A response of at least 50% seizure reduction was reported in more than 50% of patients reviewed at 3, 6, and 12 months after initiating treatment. Among responders, a majority had >90% reduction in seizure frequency. Amantadine may constitute an efficacious alternative treatment for refractory absence seizures.

Refractory absence epilepsy associated with GLUT-1 deficiency syndrome

GLUT-1 deficiency syndrome (GLUT-1 DS) is a disorder of cerebral glucose transport associated with early infantile epilepsy and microcephaly. We report two boys who presented with refractory absence epilepsy associated with hypoglycorrhachia, both of whom have genetically confirmed GLUT-1 DS. We propose that these children serve to expand the phenotype of GLUT-1 DS and suggest that this condition should be considered as a cause of refractory absence seizures in childhood.

Pharmacological principles as a basis for polytherapy.

Most patients with newly diagnosed epilepsy can be optimally controlled by prescribing a single anti-epilepsy drug, selected on the basis of its efficacy and safety profile. In about one-third of patients, however, seizures persist during monotherapy, despite the intake of the maximally tolerated drug dose. In such cases, substantial therapeutic benefit may be achieved by prescribing appropriate drug combinations. Safe use of multiple drug therapy requires a good knowledge of clinical pharmacology, particularly an awareness of potentially adverse drug interactions. As many older anti-epilepsy drugs have similar modes of action, their interaction may not always be of clinical benefit, because drug side-effects may also be additive. There is, however, evidence that specific combinations may be particularly advantageous; for example, valproate and ethosuximide in the management of refractory absence seizures. Compared with older drugs, some of the recently developed agents possess different and more selective mechanisms of action, which may result in enhanced therapeutic benefit when specific combinations are used. Preliminary observations do suggest that, in some cases, the efficacy exhibited by certain new drugs could be explained in terms of their pharmacological effect being 'complementary' to that of concurrently used agents.

DynamicI-VCurves Are Reliable Predictors of Naturalistic Pyramidal-Neuron Voltage Traces

Neuronal response properties are typically probed by intracellular measurements of current-voltage (I-V) relationships during application of current or voltage steps. Here we demonstrate the measurement of a novel I-V curve measured while the neuron exhibits a fluctuating voltage and emits spikes. This dynamic I-V curve requires only a few tens of seconds of experimental time and so lends itself readily to the rapid classification of cell type, quantification of heterogeneities in cell populations, and generation of reduced analytical models. We apply this technique to layer-5 pyramidal cells and show that their dynamic I-V curve comprises linear and exponential components, providing experimental evidence for a recently proposed theoretical model. The approach also allows us to determine the change of neuronal response properties after a spike, millisecond by millisecond, so that postspike refractoriness of pyramidal cells can be quantified. Observations of I-V curves during and in absence of refractoriness are cast into a model that is used to predict both the subthreshold response and spiking activity of the neuron to novel stimuli. The predictions of the resulting model are in excellent agreement with experimental data and close to the intrinsic neuronal reproducibility to repeated stimuli.