topiramate and Sclerosis

Mammalian central neurons regulate their intracellular pH (pHi) strongly and even slight pHi-fluctuations can influence inter-/intracellular signaling, synaptic plasticity and excitability.. For the first time, we investigated topiramate´s (TPM) influence on pHi-behavior of human central neurons representing a promising target for anticonvulsants and antimigraine drugs.. In slice-preparations of tissue resected from the middle temporal gyrus of five adults with intractable temporal lobe epilepsy, BCECF-AM-loaded neocortical pyramidal-cells were investigated by fluorometry. The pHi-regulation was estimated by using the recovery-slope from intracellular acidification after an Ammonium-Prepulse (APP).. Among 17 pyramidal neurons exposed to 50 μM TPM, seven (41.24%) responded with an altered resting-pHi (7.02±0.12), i.e., acidification of 0.01-0.03 pH-units. The more alkaline the neurons, the greater the TPM-related acidifications (r=0.7, p=0.001, n=17). The recovery from APPacidification was significantly slowed under TPM (p<0.001, n=5). Further experiments using nominal bicarbonate-free (n=2) and chloride-free (n=2) conditions pointed to a modulation of the HCO3 -- driven pHi-regulation by TPM, favoring a stimulation of the passive Cl-/HCO3 --antiporter (CBT) - an acid-loader predominantly in more alkaline neurons.. TPM modulated the bicarbonate-driven pHi-regulation, just as previously described in adult guinea-pig hippocampal neurons. We discussed the significance of the resulting subtle acidifications for beneficial antiepileptic, antimigraine and neuroprotective effects as well as for unwanted cognitive deficits.

Topics: Acid-Base Equilibrium; Adult; Anticonvulsants; Bicarbonates; Chloride-Bicarbonate Antiporters; Epilepsy, Temporal Lobe; Female; Fluorometry; Hippocampus; Humans; Hydrogen-Ion Concentration; Male; Malformations of Cortical Development; Neocortex; Neurons; Pyramidal Cells; Sclerosis; Temporal Lobe; Topiramate; Young Adult

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS.. Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS.. Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia.. Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS.

Topics: Adolescent; Adult; Aged; Amines; Anticonvulsants; Ataxia; Benzodiazepines; Carbamazepine; Clobazam; Cyclohexanecarboxylic Acids; Databases, Factual; Diplopia; Dizziness; Epilepsy, Temporal Lobe; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Hippocampus; Humans; Lamotrigine; Lethargy; Male; Middle Aged; Oxcarbazepine; Pregabalin; Retrospective Studies; Sclerosis; Topiramate; Treatment Outcome; Triazines; Valproic Acid; Vertigo; Vigabatrin; Vision Disorders; Young Adult

To clarify the role of hippocampal sclerosis (HS) in developing psychiatric and cognitive adverse events during therapy with topiramate (TPM) in patients with temporal lobe epilepsy (TLE).. We analyzed the data of 70 patients with TLE and HS and 128 patients with cryptogenic TLE matched for age, sex, starting dose, and titration schedule of TPM. They were selected from the first consecutive 431 patients started on TPM between 1995 and 1999.. Patients with HS were more likely to develop cognitive adverse events (CAEs; p = 0.002) and depression (p = 0.018) and to be receiving a polytherapy regimen (p = 0.007). However, regression analysis demonstrated that only HS was a predictive factor for the occurrence of CAEs (OR = 2.4; p < 0.001) and depression (OR = 2.3; p = 0.02).. Patients with TLE and HS were more prone to develop CAEs and depression than were patients with cryptogenic TLE, during TPM therapy, despite the same titration schedule. The presence of HS and not duration of epilepsy or polytherapy regimen represented the main risk factor.

Topics: Adult; Anticonvulsants; Cognition Disorders; Depressive Disorder; Drug Therapy, Combination; Epilepsy, Temporal Lobe; Female; Fructose; Hippocampus; Humans; Male; Middle Aged; Regression Analysis; Risk Factors; Sclerosis; Topiramate