Refractory Complex Research Articles

Vigabatrin therapy for refractory complex partial seizures: review of major European trials

Complex partial seizures (CPS) are a form of localization-related seizures associated with serious comorbidities and risks. CPS can be difficult to treat and may remain refractory to treatment with antiepileptic drugs (AEDs). Refractory CPS (rCPS) can be hazardous because of the potential for severe dysfunction and bodily harm, sometimes with fatal consequences. Control of seizure activity is critical to the clinical management of CPS. Vigabatrin is a unique AED approved in both Europe and the United States as adjunctive therapy for adult patients with rCPS who have responded inadequately to several alternative treatments. This review focuses on appropriately controlled studies of vigabatrin conducted in Europe. Several double-blind studies randomized those with rCPS to treatment with vigabatrin vs placebo, and two evaluated durability of response to long-term, open-label vigabatrin. Endpoints included seizure frequency, treatment satisfaction, and adverse events (AEs). Efficacy outcomes demonstrated that vigabatrin add-on therapy significantly reduced the frequency of seizures. Long-term studies indicated durability of response and tolerability of vigabatrin therapy for up to several years. Treatment satisfaction data indicated a preference for vigabatrin vs placebo for both physicians and study participants. Vigabatrin was well-tolerated with generally mild AEs considered common to AEDs. Vision effects were not formally monitored in these studies. In European trials, vigabatrin was efficacious as adjunctive therapy for rCPS.

Non-vision adverse events with vigabatrin therapy

Vigabatrin is an effective antiepileptic drug (AED) for the treatment of refractory complex partial seizures (rCPS) and infantile spasms (IS). In clinical trials, vigabatrin was generally well-tolerated with an adverse event profile similar to that of other AEDs. The most common treatment-related adverse events were central nervous system effects, including drowsiness, dizziness, headache, and fatigue, with adjunctive vigabatrin in adults with rCPS, and sedation, somnolence, and irritability with vigabatrin monotherapy in infants with IS. Vigabatrin had little effect on cognitive function, mood, or behavior in a battery of neuropsychologic tests for rCPS. In placebo-controlled clinical trials, the incidence of depression and psychosis, but not other psychiatric adverse events, was greater with vigabatrin than placebo. Intramyelinic edema (IME) was initially identified in rats and dogs and led to a temporary suspension of clinical trials in the United States. IME was subsequently correlated with delays in evoked potential (EP) and increased T(2) -weighted signals on magnetic resonance imaging (MRI). Clinical trials of vigabatrin were allowed to resume after IME was not detected by neuropathologic assessments of autopsy and neurosurgical specimens or by serial EP or MRI assessments in older children and adults receiving vigabatrin. Subsequently, MRI abnormalities characterized by increased T(2) intensity and restricted diffusion were identified in infants treated with vigabatrin for IS. These abnormalities generally resolved with discontinuation of vigabatrin and, in some cases, during continued therapy. The benefit of improved seizure control must be balanced against the potential risks associated with vigabatrin, including abnormal MRI changes and other vigabatrin-related safety issues.

Vigabatrin therapy for refractory complex partial seizures: review of clinical trial experience in the United States

Vigabatrin is an antiepileptic drug used in more than 50 countries as adjunctive therapy for the treatment of refractory complex partial seizures (rCPS) in adults. First approved in the United Kingdom in 1989, vigabatrin was approved for use in the United States by the Food and Drug Administration in 2009. Although most clinical trials of vigabatrin have been conducted in Europe, three major trials, including two pivotal trials, were conducted in the United States. These trials have demonstrated efficacy and tolerability findings similar to those observed from the European trials. Results of the US trials have demonstrated vigabatrin to be an effective and generally well-tolerated therapy for rCPS in adults, with an optimal dosage of 3 g/day for most patients, and an onset of response generally within 2 weeks. This review focuses on the design and results of the three major US trials of vigabatrin in adults with rCPS.

Mechanism of action of vigabatrin: correcting misperceptions

Discovered more than three decades ago, vigabatrin is approved in more than 50 countries as adjunctive therapy for adult patients with refractory complex partial seizures who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month to 2 years with infantile spasms. Contrary to a fairly common misperception, the compound's mechanism of action is very well-characterized in animal models and cell cultures. γ-Aminobutyric acid (GABA)-ergic synapses comprise approximately 30% of all synapses within the central nervous system, and therein underlies the primary mode of synaptic inhibition. Vigabatrin was rationally designed to have a specific effect on brain chemistry by inhibiting the GABA-degrading enzyme, GABA transaminase, resulting in a widespread increase in GABA concentrations in the brain. The increase in GABA functions as a brake on the excitatory processes that can initiate seizure activity. Despite the short half-life of vigabatrin in the body (5-7 h) and its relatively low concentration in cerebrospinal fluid (10% of the concentration observed in plasma), it has the profound effect of increasing GABA concentration in the brain for more than a week after a single dose in humans. This effect persists steadily over years of vigabatrin administration and results in significant and persistent decreases in seizure activity. Vigabatrin can be effective with once-daily dosing. Because of its specificity, vigabatrin has helped researchers explore the specific mechanisms within the brain that underlie seizure activity.

Registry initiated to characterize vision loss associated with vigabatrin therapy

The vigabatrin patient registry was implemented in August 2009 in conjunction with Food and Drug Administration approval of vigabatrin. All US vigabatrin-treated patients must enroll in the registry. Data on prescriber specialty/location, patient demographics, and clinical characteristics are collected. Benefit–risk assessments are required early in the course of therapy. Vision assessments are required at baseline (≤4weeks after therapy initiation), every 3months during therapy, and 3 to 6months after discontinuation. As of February 1, 2011, 2473 patients (1500 with infantile spasms, 846 with refractory complex partial seizures, 120 with other diagnoses) had enrolled; 30.4% were previously exposed to vigabatrin. Kaplan–Meier analysis of time in registry indicated that 83 and 97% of all enrolled patients with refractory complex partial seizures and infantile spasms remained beyond 3 and 1month, respectively. The ongoing registry will provide visual status and other information on vigabatrin-treated patients for both the infantile spasm and refractory complex partial seizure indications.

Spontaneously Resolving Seronegative Autoimmune Limbic Encephalitis

We describe a patient with seronegative autoimmune limbic encephalitis (SNALE) masquerading as glioma. Brain magnetic resonance imaging (MRI) abnormalities, distinctive pathological findings, and spontaneous remission are highlighted. There are 15 previously reported SNALE cases, 1 with pathology. A 66-year-old man presented with prominent amnestic syndrome, progressive cognitive decline, and refractory complex partial seizures. Initial brain MRI suggested herpes limbic encephalitis. A 3-week course of intravenous acyclovir was ineffective. Cerebrospinal fluid analysis revealed no pleocytosis. Repeat brain MRI showed a left uncal-hippocampal, contrast-enhancing lesion with mass effect, which was resected. Pathology revealed perivascular and parenchymal mixed lymphocytic inflammatory infiltrates, microglial nodules, neuronophagia, microglial activation, astrocytosis, and lymphocyte emperipolesis within neurons. Thorough searches for infectious pathogens and autoantibodies were negative. Six weeks later, a new enhancing right mesial temporal lesion appeared, with increased seizure activity and further cognitive impairment. Although immune therapy was declined, spontaneous resolution of the new enhancing lesion, with full seizure control and significant cognitive improvement, occurred. SNALE may masquerade as glioma. Pathologic changes in our case of SNALE are distinctive. Spontaneous resolution of a focal SNALE lesion may potentially occur without immune therapy.

H-NS mediates the dissociation of a refractory protein-DNA complex during Tn10/IS10 transposition

Tn10/IS10 transposition takes place in the context of a protein–DNA complex called a transpososome. During the reaction, the transpososome undergoes several conformational changes. The host proteins IHF and H-NS, which also are global regulators of gene expression, play important roles in directing these architectural changes. IHF binds tightly to only one of two transposon ends within the transpososome, folding this end into a DNA loop structure. Unfolding this DNA loop is necessary for excising the transposon from flanking donor DNA and preventing integration of the transposon into itself. We show here that efficient DNA loop unfolding relies on the continuity of the flanking donor DNA on the side of the transpososome opposite to the folded transposon end. We also show this same donor DNA is a preferred binding site for H-NS, which promotes opening of the IHF-loop, which is required for productive target interactions. This is counter to the usual mode of H-NS action, which is repressive due to its propensity to coat DNA. The interplay between IHF and H-NS likely serves to couple the rate of transposition to the host cell physiology as both of these proteins are integrated into cellular stress response pathways.

Valproic Acid and Warfarin: An Underrecognized Drug Interaction

Drug interactions in the neurosciences intensive care unit (NICU) may involve antiepileptic drugs and warfarin. Most commonly used antiepileptic drugs are either potent hepatic enzyme inducers or inhibitors and they affect the metabolism of warfarin. Valproic acid also displaces warfarin from the protein binding sites resulting in significant INR changes but this type of drug interaction is less well known. Case report. A 71 year-old female patient with a glioblastoma multiforme presented to the NICU with refractory partial complex seizures. Patient was on warfarin for a prior deep venous thrombosis. After treatment with levetiracetam, seizures recurred and intravenous loading with valproic acid was administered, but resulted in a rapid increase in international normalized ratio (INR) to 7.6. A MRI of the brain showed hemorrhagic tumor, but no new major bleeding. With both acidic drugs present, a loading dose of valproic acid may displace warfarin from the protein binding sites resulting in redistribution of warfarin in free active form and lead to a rapid increase in INR.

DNET as cause of symptomatic epilepsy

Dysembrioplastic Neuroepithelial Tumor (DNET) is a congenital, benign tumor due to a development abnormality of certain embryonic cells of the brain, frequently associated with epilepsy. These lesions typically cause refractory complex partial seizures with onset before age 20 years in neurologically normal individuals who have no evidence of neuro cutaneous syndrome. At least 80 % of patients are rendered seizure-free after resection of these lesions. We present the case of a 40 years old woman with complex partial seizures who underwent resective surgery for DNET, and had a good outcome after surgery. We would like to draw attention of the clinicians to this potentially curable type of symptomatic epilepsy.

Autism in two females with duplications involving Xp11.22-p11.23

We present two phenotypically similar females with Xp duplication who have autism and epilepsy. Case 1 is a 14-year-old Honduran female with autism and medically refractory complex partial, secondarily generalized epilepsy. Case 2 is a 3-year-old Austrian female with autism and medically refractory complex partial epilepsy. Both patients also share features of severe intellectual disability (case 1 has a developmental quotient of 23, case 2 has a developmental quotient of 42) and dysmorphic facial features. Autism was confirmed by thorough clinical evaluations and testing. Case 1 has a karyotype of 46,X,dup(X)(p11.2-p22.33) and a highly skewed X-inactivation pattern (94:6). Brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were abnormal. Case 2 has a 5-megabase duplication of Xp11.22-p11.23 on chromosome microarray analysis. The patient has a random X-inactivation pattern (77:23). Brain MRI was normal, but EEG was abnormal. Both patients have duplications involving the Xp11.22-p11.23 region, indicating that this is an area of interest for future translational autism research.

Electroencephalographic and seizure manifestations of pyridoxal 5′-phosphate-dependent epilepsy

We describe the electroencephalographic and clinical seizure manifestations of pyridoxal 5′-phosphate-dependent epilepsy (PLP-DE) in two patients [diagnosis confirmed by low cerebrospinal fluid (CSF) PLP, complete resolution of previously intractable seizures with PLP supplementation, negative pyridoxine-dependent epilepsy CSF biomarkers, and/or positive disease causing pyridox(am)ine 5′-phosphate oxidase gene mutation] along with a comprehensive review of the literature. One patient presented with neonatal tonic status epilepticus with subsequent generalized tonic–clonic seizures, and the second, with refractory complex partial seizures starting at 2years of age. The pretreatment EEG revealed, interictally, burst suppression, multifocal independent sharp waves, and electrical status epilepticus in sleep. Ictally and interictally, it revealed runs of unilateral spike/slow waves. Previously reported features include burst suppression, myoclonus, tonic seizures, clonic seizures, and spasms. In the appropriate clinical scenario, the aforementioned features should raise the possibility of PLP-DE and appropriate treatment should be initiated. The first late-onset case (at 2years) of PLP-DE is reported.

Size and Morphology Control of Ultrafine Refractory Complex Oxide Crystals

High-temperature complex oxides are of considerable interest as their applications cover a broad spectrum from catalytic to optical technology. Indeed, new exciting opportunities might emerge if these high-temperature complex oxides, in which structure crystallization is achieved at temperatures T > 1000 °C, could be synthesized as nonaggregated, ultrafine building blocks. In general, such refractory complex oxide particles are difficult to synthesize as ultrafine crystals because of the strong driving force available for sintering and coarsening in this high-temperature range. This paper reports a new synthetic process for the preparation of nonaggregated, ultrafine barium hexa-aluminate, BaO, 6Al2O3, (BHA), and Ba0.9Eu0.1MgAl10O17, (BAM) crystals in which structure crystallization occurs around 1300 °C. Our process is based on the Ba2+ and Al3+ ions high-temperature controlled diffusion from carbon−inorganic hybrid compounds prepared from soft chemistry routes. Control of morphology of these refractory complex aluminates displaying nanoplatelets morphology was achieved via the tailoring of high-temperature diffusion lengths of the various cations involved in the formation of these ultrafine refractory crystals.

Association of apolipoprotein E polymorphisms with temporal lobe epilepsy in a Chinese Han population

Apolipoprotein E (ApoE) has been implicated as one of the susceptibility genes for temporal lobe epilepsy (TLE). Previous studies indicate that ApoE ɛ4 is associated with several disease-related traits including the increased risk of late posttraumatic seizures, earlier onset of TLE, refractory complex partial seizures, and postictal confusion. Contradictory data were also reported regarding the association between ApoE polymorphisms and TLE. The present study was designed to investigate whether ApoE ɛ4 is a risk factor for TLE and the above clinical variables, as well as to determine whether -491A/T polymorphism may independently alter the risk for TLE in a Chinese Han population. The ApoE and -491A/T polymorphisms were genotyped in 558 controls and 735 patients including 560 TLE patients using polymerase chain reaction-restriction fragment length polymorphism. A significant association was detected between prior trauma and the ApoE ɛ4 allele in TLE patients. However, no significant differences were observed in the genotype and haplotype distributions and allele frequencies of these two polymorphisms between cases and controls. Furthermore, there were no significant associations between these two polymorphisms and the other clinical variables examined. The study illustrates that the ApoE ɛ4 allele may be involved in the development of TLE in those patients with prior trauma in the Chinese Han population.

Study of DSM-IV Axis I psychiatric disorders in patients with refractory complex partial seizures using a short structured clinical interview

Psychiatric disorders are a source of significant comorbidity in patients with refractory epilepsy, yet are often underrecognized. We assessed the prevalence of DSM-IV Axis I psychiatric disorders using a short structured clinical interview (Mini-International Psychiatric Interview [MINI]) in patients with medically refractory complex partial seizures. Consecutive patients with refractory epilepsy being evaluated with video/EEG monitoring and imaging for seizure focus localization and lateralization underwent MINI evaluation to assess for the presence of psychiatric disorders. Among 117 patients (74 male, 43 female) studied, 57 (48.7%) had at least one psychiatric disorder; 19 (16.2%) had depression, 10 (8.5%) dysthymia, 27 (23.0%) anxiety disorder, and 11(9.4%) other disorders. Most clinical features and epilepsy-related variables had no significant association with psychiatric disorder on logistic regression analysis. Almost half of the patients with refractory focal seizures have a coexistent psychiatric disorder, and its presence or absence cannot be predicted by their clinical profiles. All patients should be assessed and treated for psychiatric comorbidity to improve overall quality of life.

Pharmacodynamic Profiles of Ketamine (R)- and (S)- with 5-Day Inpatient Infusion for the Treatment of Complex Regional Pain Syndrome

Background: Ketamine might be effective in blocking central sensitization of pain transmission neurons through its effect on NMDA receptors in refractory Complex Regional Pain Syndrome (CRPS) patients. At higher doses, ketamine infusions can be associated with significant risks; outpatient therapy requires return visits for a 10-day period with variable efficacy and duration. Objective: This study determined the efficacy of a 5-day moderate dose, continuous racemic ketamine infusion. The pharmacodynamic responses to racemic ketamine and norketamine were examined. Design: Observational study Methods: In this study, ketamine was titrated from 10-40 mg/hour in 16 CRPS patients, and maintained for 5 days. Pain was assessed daily. Ketamine and norketamine concentrations were obtained on Day 1 before starting the infusion; at 60 to 90 minutes, 120 to 150 minutes, 180 to 210 minutes, and 240 to 300 minutes after the initiation of the infusion on Days 2, 3, 4, and 5; and on Day 5 at 60 minutes after the conclusion of the infusion. The plasma concentrations of (R)-ketamine, (S)-ketamine, (R)-norketamine and (S)-norketamine were determined using an enantioselective liquid chromatography – mass spectrometry method. Results: Ketamine and norketamine infusion rates stabilized 5 hours after the start of the infusion. The subjects showed no evidence of significant tachycardia, arterial oxygen desaturation, or hallucinatory responses. Subjects generally experienced minimal pain relief on day one followed by significant relief by day 3. Mean pain scores decreased from the 8-9 to 3-5 ranges; however, the analgesic response to ketamine infusion was not uniform. On day 5, there was little or no change in the pain measure assessed as the worst pain experienced over the last 24 hours in 37% of the subjects. (R)- and (S)-ketamine concentrations peaked at 240-300 min. (R)- and (S)-norketamine concentrations were lower and peaked on Day 2 of the infusion, as opposed to Day 1 for (R)- and (S)-ketamine. Significant pain relief was achieved by the second day of infusion and correlated with the maximum plasma levels of ketamine and norketamine. Pain relief continued to significantly improve over the 5 day infusion at concentrations of 200-225 ng/mL for (R)- and (S)-ketamine, and 90-120 ng/mL for(R)- and (S)-norketamine. Conclusions: A 5-day ketamine infusion for the treatment of severe CRPS provided significant (P <0.05) pain relief by Day 3 compared to baseline. The pain relief experienced on Day 2 of the infusion continued to improve over the 5-day infusion period and correlated with the maximum plasma levels of ketamine and norketamine. We speculate that downstream metabolites of ketamine and norketamine might be playing a role in its therapeutic efficacy. Key words: ketamine, norketamine, CRPS, pharmacodynamics, chronic pain, enantiomers

Dissolution kinetics of low grade complex copper ore in ammonia-ammonium chloride solution

The leaching kinetics of Tang-dan refractory low grade complex copper ore was investigated in ammonia-ammonium chloride solution. The concentration of ammonia and ammonium chloride, the ore particle size, the solid-to-liquid ratio and the temperature were chosen as parameters in the experiments. The results show that temperature, concentration of ammonia and ammonium chloride have favorable influence on the leaching rate of copper oxide ores. But, leaching rate decreases with increasing particle size and solid-to-liquid ratio. The leaching process is controlled by the diffusion of the lixiviant and the activation energy is determined to be 23.279 kJ/mol. An equation was also proposed to describe the leaching kinetics.

Management of refractory complex partial seizures: current state of the art

Diagnosis of complex partial epilepsy is based on the clinical history, and laboratory tests, including EEG and neuroimaging studies, corroborate the diagnosis. The goal of epilepsy management is to make the patient completely seizure-free without drug-induced side effects, even in the patient with refractory complex partial seizures. Frequently this can be accomplished by choice of the optimal antiepileptic drug (AED) or a combination of drugs, the use of strategies to maximize the effectiveness of drug treatment, or by surgical removal of the seizure focus. Currently there are five "classical" first-line AEDs and 11 new AEDs available in the US and in many other countries for the treatment of localization-related epilepsy. The current state of the evidence is that no AED is clearly superior to other AEDs in the management of refractory complex partial seizures. Therefore the choice of which drug to use in an individual patient has to be based on other considerations, including the potential adverse reactions that may occur in that patient. There are a number of strategies for optimal use of AEDs in the management of refractory complex partial seizures. These include verification of the diagnosis of epilepsy and classification of specific seizure types, use of monotherapy if possible but polytherapy if necessary, starting with a low dose and raising it slowly but, until complete seizure control is achieved, pushing to the maximum tolerated dose, changing timing of dosing to reduce toxicity, using pharmacokinetic principles to fine-tune AED doses, adjusting dose for drug-drug interactions, and never giving up in the pursuit of better seizure control. Resection of the seizure focus can be curative in the majority of patients with seizures localized to one mesial temporal lobe. Success rates for resection of extratemporal seizure foci are lower. Vagus nerve stimulation (VNS) devices result in a significant reduction of seizure frequency in many patients, but patients rarely become completely seizure-free as a result of VNS device implantation. Management of refractory complex partial seizures continues to improve with the identification of new drugs and the development of new approaches to their control and cure.

Vigabatrin in Refractory Complex Partial Seizures: The Evidence of its Therapeutic Value

Vigabatrin (Sabril®) has recently been granted approval in the Unites States for the adjunctive treatment of complex-partial seizures in adults. The drug was first evaluated as a potential therapy for this population decades ago, and it has been available in other parts of the world for some time. Well controlled studies demonstrate that at doses up to 3 g/day, the drug is efficacious as add-on therapy for treatment resistant seizures. However, vigabatrin has been associated with significant side-effects limiting its use, and relegating it to a late therapeutic alternative. Specifically, vigabatrin has been implicated in the development of irreversible peripheral vision loss in a significant number of patients. For this reason, the approval of the drug in the United States was contingent upon the introduction of a rigorous monitoring protocol that must accompany its use. Additionally, the drug has been associated with a relatively high incidence of psychiatric disturbances, although there is disagreement about a direct correlation of these symptoms to the drug. Still, the drug remains a viable alternative for patients who have failed therapy with traditional anti-seizure medications.

Clinical profile of vigabatrin as monotherapy for treatment of infantile spasms

Vigabatrin, the first therapeutic agent to be approved by the Food and Drug Administration for the treatment of infantile spasms, as well as for adjunctive use in the treatment of refractory complex partial epilepsy, represents an important advance for patients with difficult-to-manage epilepsy. This review summarizes the complex history, chemistry, and pharmacology, as well as the clinical data leading to the approval of vigabatrin for infantile spasms in the US. The long path to its approval reflects the visual system and white matter toxicity concerns with this agent. This review provides a brief description of these concerns, and the regulatory safety monitoring and mitigation systems that have been put in place to enhance benefit over risk.

S31-04 - Mapping complex hallucinations using fMRI to guide rTMS treatment

BackgroundHallucinations are extremely distressing erroneous percepts accompanied by a powerful sense of reality. In schizophrenia, hallucinations were functionally explored in the verbal domain even if they may emerge outside the range of auditory. In the present study, we used advanced-Independent Component Analysis for fMRI-data-sets (ICA) to explore complex hallucinations and define potential rTMS targets beyond the conventional temporo-parietal junction.Methods16 adolescents with early-onset schizophrenia and suffering from refractory complex hallucinations were included. They all benefited from a 30-min. rest fMRI examination after which they were accurately interviewed about their psycho-sensory experiences during scanning. Using cortex-based ICA, BOLD signals related to the hallucinatory experience were extracted at the subject level and then submitted to a self-organizing-group ICA procedure to extract clusters at the group-level on the basis of a pure similarity matrix.ResultsThis method highlighted auditory, visual and multisensory hyper-active clusters after decomposition by random-effect sog-ICA (ǀZǀ=2.2; p< 0.01). The increased BOLD-signal measured in association sensory areas during hallucinations was concomitant of the de-engagement of the “resting-state” network in hallucinating subjects.DiscussionData-driven analysis methods for rest-fMRI-data allowed evidencing the neural correlates of complex hallucinations in adolescents with schizophrenia. Despite inter-individual variability, sog-ICA clearly demonstrates that the hallucinatory experience emerges from increased activity within modality-dependent associative sensory cortices and can be fused in cross-modal areas. These brain regions constitute good candidates to guide dimensional treatment of hallucinations like rTMS.