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Faught E. Vigabatrin therapy for refractory complex partial seizures: review of clinical trial experience in the United States. Acta Neurol Scand: 2011: 124 (Suppl. 192): 29-35. © 2011 John Wiley & Sons A/S. 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. [ABSTRACT FROM AUTHOR]

Objective: To characterize protein binding in patients with epilepsy who achieve transient high (>150 mg/L) total plasma concentrations following rapid valproate infusion at very high doses. Methods: Patients with epilepsy ( n = 40) were administered 20 or 30 mg/kg loading doses (6 or 10 mg/kg/min) of undiluted valproate sodium injection. Total and unbound valproic acid (VPA) concentrations were used to assess VPA binding to plasma albumin. One- and two-binding site models were explored in a nonlinear mixed effects population analysis framework. The relative importance of weight, age, sex, race and enzyme-inducing comedications on the binding site association constant ( K) was examined using the likelihood ratio test. Intersubject and intrasubject variabilities were characterized using exponential or proportional error models. Results: Optimal characterization of the data was achieved using the one-binding site model. Population binding parameter estimates (standard error) for number of binding sites ( N) and K were 1·98 (0·0865) and 15·5 [2·28 (1/mM)], respectively. No significant covariates were identified for VPA protein binding. The intersubject and intrasubject coefficients of variation were 32% and 14%, respectively. Conclusions: A one-binding site model without any significant covariates for binding constants optimally described VPA protein binding. As the estimated dissociation constant (1/ K, 64·5 μ m or 9·3 mg/L) was within the therapeutic range (5–15 mg/L) for unbound VPA concentrations, protein binding was nonlinear. Although the range of unbound fraction and VPA concentrations were much higher than previous studies, the dissociation constant was consistent with historical data in normal healthy adults and epilepsy patients receiving lower doses. [ABSTRACT FROM AUTHOR]

Seizures are extremely common in the elderly, with an annual incidence reaching 100 per 100 000 people aged over 60 years. Most are precipitated by acute symptomatic illnesses such as stroke or systemic disease. Chronic neurological diseases such as Alzheimer's disease may also cause seizures. The aetiology of seizures in many patients is unknown. Seizures may be situational and subside quickly, but the prevalence of chronic seizures - epilepsy - is as high as 1% in the elderly. The majority of seizures are of partial onset, especially complex partial. Complex partial seizures at this age may be very subtle and hard to diagnose. Generalised-onset seizures also occur, perhaps as a result of diffuse changes with aging or degenerative disease or to a combination of genetic and environmental factors. The prognosis for complete seizure control in this population is relatively favourable. Physiological and disease-related changes with aging result in complex pharmacokinetics. Most changes lead to a need for gentler drug treatment with cautious initiation of drugs at lower dosages. Consideration must be given to renal and hepatic function, protein binding and drug interactions. Determinations of free (unbound) drug concentrations are helpful for highly protein bound drugs. The dosages of newer drugs excreted renally must be adjusted based on creatinine clearance. The dosage of most drugs is determined empirically by careful observation of seizure control and adverse effects. Carbamazepine, valproic acid (sodium valproate), gabapentin and lamotrigine have certain theoretical advantages, but comparative trials of anticonvulsants in the elderly are needed. The ideal drug for older patients would be effective, without neurological toxicity, with low protein binding, a nonparticipant in drug interactions and amenable to once daily administration. [ABSTRACT FROM AUTHOR]

Abstract: Introduction:: Proton magnetic resonance spectroscopy (1H MRS) has been proposed as a lateralizing method for the presurgical evaluation of patients with medically intractable temporal lobe epilepsy (TLE). Studies have shown correlations between temporal lobe (TL) NAA and seizure frequency, and TL NAA/Cr and the duration of epilepsy in patients with TLE. This latter finding may suggest that progressive neuronal dysfunction may occur in both temporal lobes in patients with TLE, even when the seizures originate in only one temporal lobe. We analyzed our data in an attempt to find a possible correlation between extension of neuronal dysfunction based on NAA measures and duration of epilepsy. Methods:: We studied 45 consecutive patients with the diagnosis of TLE, who were referred for presurgical evaluation. Duration of epilepsy was defined as the interval between the age of seizure onset and the time of the MRS examination. All studies were performed in the inter-ictal state, prior to intracranial monitoring or resection. We performed two-tailed Pearson correlation analysis between ipsilateral NAA/Cr and extension of the abnormality (voxels involved) and the duration of the seizure disorder in years. Results:: The average duration of epilepsy in this group was 20 years. No significant correlation was found between duration of epilepsy and mean hippocampal NAA/Cr (r =−.131, p =.390); nor was a correlation found between duration of epilepsy in years or the extent of metabolic lesion (voxels involved) (r =−.264, p =.079). Conclusions:: Hippocampal NAA/Cr does not correlate with duration of epilepsy in TLE. Our findings suggest that cross-sectional group measures of hippocampal neuronal function do not suggest damage progression. [Copyright &y& Elsevier]

Summary: Ideal antiepileptic drugs (AEDs) are designed to stop seizures with limited central nervous system (CNS) side effects. However, CNS-related treatment-emergent adverse events (TEAEs) often occur in patients receiving AEDs. Topiramate (TPM) is an AED proven to be safe and effective as adjunctive treatment for epilepsy patients with partial seizures. Double-blind, placebo-controlled, multicenter trials demonstrated potential effects on cognition. The P.A.D.S. (post-marketing antiepileptic drug survey) group, a cooperative group of 14 epilepsy centers that collaborate on obtaining data about new AEDs and devices, prospectively collected standardized data forms before and during treatment with TPM for epilepsy, and analyzed the postmarketing experience of CNS TEAEs with TPM. Our results from 701 treated patients show that cognitive complaints were the most common reason to discontinue TPM. The presence of complaints did have predictive value if the patient would discontinue TPM, although was not specific as to when discontinuation would occur. The spectrum of complaints in our open-label prospective multicenter postmarketing study was similar to those observed in controlled clinical trials. We were unable to demonstrate a specific population, dose titration, or concomitant AED that was at risk to discontinue treatment. We conclude that most patients treated with TPM will continue therapy beyond 6 months. Cognitive complaints and not efficacy reflect the primary reason for discontinuing therapy. Psychomotor slowing was the most common complaint, yet most patients elect to continue treatment, with “better” or “much better” ratings of both seizure and global improvement during treatment. [ABSTRACT FROM AUTHOR]

We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p. L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein ( CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old. [ABSTRACT FROM AUTHOR]

Amyloid fibril formation is generally associated with many neurodegenerative disorders, including Alzheimer's disease (AD). Although fibril plaque formation is associated with biological membranes in vivo, the role of the cell surfaces in amyloid fibril formation and the molecular mechanism of amyloid toxicity are not well understood. Understanding the details of amyloid interaction with lipid membrane may shed light on the mechanism of amyloid toxicity. Using atomic force microscopy, we investigated aggregation of amyloid-β1-42 (Aβ1-42) on model phospholipid membranes as a function of time and membrane composition. Neutral, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), anionic - 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt) (DOPG), and cationic - 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), were used to study the effect of lipid type on amyloid binding. We showed that both the charge on the lipid head group and lipid phase affect the interaction of amyloid oligomers with the membrane surface changing the rate of adsorption and causing changes in membrane structure and structure of amyloid deposits. We observed that amyloid aggregates progressively accumulate in a similar manner on the surface of neutral DPPC gel phase membrane and on the surface of fluid phase negatively charged DOPG membrane. In contrast to DPPC and DOPG, positively charged fluid DOTAP membrane and neutral fluid phase DOPC membrane contain amyloid deposits with reduced height, which suggests fusing of Aβ1-42 into the lipid membrane surface. [ABSTRACT FROM AUTHOR]

Examines the correlation between scalp electroencephalogram (EEG) and proton magnetic resonance spectroscopy (H-MRS) in temporal lobe epilepsy. Degree on the concordance of H-MRS with the lateralization side; H-MRS in patients with normal EEG spikes; Observation on the anterior predominance of the H-MRS abnormalities.