Dilemmas in diagnostics and therapy of rolandic epilepsy

Introduction. It is considered that around 20%-30% of patients of all ages and in all continents have wrong epilepsy diagnoses. Diagnostic and consequential therapeutic errors appear, most often, when an adequate diagnostics is not applied. Benign focal epilepsy of childhoods with centrotemporal spikes-rolandic epilepsy, brings very often to diagnostic and therapeutic problems because of persistence of epilepticforms changes in an electroencephalography (EEG) recording, several years after establishment of good control over seizures. Case report. We presented 8.5 years-old girl, with the first and the only epileptic seizure at the age of 5, during her sleep. With a clear correlation of EEG record, benign rolandic epilepsy was diagnosed, so the therapy with valproate was introduced. There were no seizures after three years of its implementation. Because of epileptic-forms changes that still persisted in EEG record during her sleep, it was suggested to further use valproate. However, after reconsidering all circumstances it was concluded that the AED should bee slowly reduced up to its exclusion. After a complete stoppage of the therapy, the patient did not have any epileptic seizure for nine months, although EEG still remained pathologically changed during her sleep. Conclusion. A changed EEG record in a patient with rolandic epilepsy must not be a predictor of continuation of antiepileptic drugs therapy, after 2-3 years of successful seizures remission

Distribution and role of metals in sclerotic hippocampi of patients with mesial temporal lobe epilepsy

The accumulating evidence on the relation between the disturbed metal homeostasis and epilepsy urges the need for data regarding the total metal concentrations, as well as metal distribution in the brain itself, in order to indicate where to direct the potential therapy, to metal supplementation or chelation. This paper summarizes our results on the measurements of some important essential metals in hippocampi of patients with mesial temporal lobe epilepsy (mTLE) who underwent amigdalohippocampectomy. The key findings point out that levels of copper and manganese are deficient in hippocampi of mTLE patients, and that their concentrations correlated positively with neuronal loss in affected regions of sclerotic hippocampus. In addition, the Cu concentration was decreased in the areas of total neuronal loss. Iron and zinc total hippocampal levels were neither accumulated nor deficient compared to control. Our results contribute to deeper insight of metals biology in the epilepsy and may represent the initial point of new and non-invasive therapy of drug resistant epilepsy

Application of Counter-propagation Artificial Neural Networks in Prediction of Topiramate Concentration in Patients with Epilepsy

Purpose: The application of artificial neural networks in the pharmaceutical sciences is broad, ranging from drug discovery to clinical pharmacy. In this study, we explored the applicability of counter-propagation artificial neural networks (CPANNs), combined with genetic algorithm (GA) for prediction of topiramate (TPM) serum levels based on identified factors important for its prediction. Methods: The study was performed on 118 TPM measurements obtained from 78 adult epileptic patients. Patients were on stable TPM dosing regimen for at least 7 days; therefore, steady-state was assumed. TPM serum concentration was determined by high performance liquid chromatography with fluorescence detection. The influence of demographic, biochemical parameters and therapy characteristics of the patients on TPM levels were tested. Data analysis was performed by CPANNs. GA was used for optimal CPANN parameters, variable selection and adjustment of relative importance. Results: Data for training included 88 measured TPM concentrations, while remaining were used for validation. Among all factors tested, TPM dose, renal function (eGFR) and carbamazepine dose significantly influenced TPM level and their relative importance were 0.7500, 0.2813, 0.0625, respectively. Relative error and root mean squared relative error (%) and their corresponding 95% confidence intervals for training set were 2.14 [(-2.41) - 6.70] and 21.5 [18.5 - 24.1]; and for test set were 6.21 [(-21.2) - 8.77] and 39.9 [31.7 - 46.7], respectively. Conclusions: Statistical parameters showed acceptable predictive performance. Results indicate the feasibility of CPANNs combined with GA to predict TPM concentrations and to adjust relative importance of identified variability factors in population of adult epileptic patients

Pragmatic study of efficiency of controlled-release carbamazepine (TEGRETOL CR 400) in the treatment of patients with partial seizures

In patients with partial seizures controlled-release vs. conventional carbamazepine had better efficiency, based on an excellent tolerance favorable daily dosage and superior compliance

Concussive convulsions as differential diagnosis of posttraumatic epilepsy

Concussive convulsions are motor manifestations in acute head injury. This clinical phenomenon should be distin- guished from epileptic seizures. We present two young men with motor and convulsive manifestations in acute head injury. Patient 1. A18-year old basketball player felt on the parquet during a game. Initially he was struck on the right shoulder which caused brief and vigorous twitch of the head towards the ground and additional temporal impact. At the moment of impact he lost consciousness and developed tonic leg and arm posturing with both clenched fists. His legs were extended during next 20 seconds. Thereafter he was still and his loss of consciousness lasted 3 minutes. Patient 2. A 26-year old man felt on the wooden ground from a 4 m high ferry. He got head impact and lost consciousness. In a few seconds he had tonic/clonic convulsions for the next 10-15 seconds. Ten minutes later he awaked. Results of subsequent neurological examination, electroencephalography and cerebral magnetic resonance imaging studies were normal in both patients. They returned to their occupations after four weeks without problems for a further one year. Conclusion. Described motor manifestations present concussive convulsions. These clinical features are due to transient functional decerebration and corticomedullary dissociation during cerebral concussion. Concussive convulsions are a non-epileptic phenomenon, they are not associated with structural brain injury and have good prognosis. Antiepileptic treatment is not indicated

The first film presentation of REM sleep behavior disorder precedes its scientific debut by 35 years

The perplexing and tantalizing disease of rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by peculiar, potentially dangerous behavior during REM sleep. It was described both in animals and humans. RBD in mammals was first described by Jouvet and Delorme in 1965, based on an experimental model induced by lesion in pontine region of cats [1]. In 1972, Passouant et al. described sleep with eye movements and persistent tonic muscle activity induced by tricyclic antidepressant medication [2], and Tachibana et al., in 1975, the preservation of muscle tone during REM sleep in the acute psychosis induced by alcohol and meprobamate abuse [3]. However, the first formal description of RBD in humans as new parasomnia was made by Schenck et al in 1986 [4-7]. Subsequently, in 1990, the International Classification of Sleep Disorders definitely recognized RBD as new parasomnia [8]. To our knowledge, arts and literature do not mention RBD. Except for the quotation, made by Schenck et al [6] in 2002, of Don Quixote de la Mancha whose behavior in sleep strongly suggested that Miguel de Servantes actually described RBD, no other artistic work has portrayed this disorder. Only recently we become aware of the cinematic presentation of RBD which by decades precedes the first scientific description. The first presentation of RBD on film was made prior to the era of advanced electroencephalography and polysomnography, and even before the discovery of REM sleep by Aserinsky and Kleitman in 1953. [9]. The artistic and intuitive presentation of RBD was produced in Technicolor in a famous film "Cinderella" created by Walt Disney in 1950, some 35 years prior to its original publication in the journal "Sleep" [2]. Since there is an earlier version of the film initially produced in 1920, presumably containing this similar scene, we can only speculate that the first cinematic presentation of RBD might precede its scientific debut by 65 years. In a scene in a barn, clumsy and goofy dog Bruno is, as dogs usually do, lying on a mat deeply asleep and obviously dreaming of his enemy cat Lucifer. This is clearly implied by a preceding scene showing Lucifer being extremely frightened while observing the dreaming dog in action. The cat Lucifer is instantly aware that the dog is chasing him in a dream and is horrified (Pictures 1-3). In a film sequence lasting only 16 seconds, we see Cinderella being aware that Bruno is firmly asleep, apparently having a terrible dream. While lying on the ground with total absence of any muscle atonia, the dog Bruno chases the cat Lucifer in his dream. He is running and barking, and when in his dream he catches Lucifer, he tries to devour the cat. Cinderella tries to wake him up by calling his name twice, first gently and then more vigorously, as she becomes aware of the content of Lucifer’s dream and his intention. The dog is deeply asleep and does not awake in spite of being exposed to sunlight through the opening door of the barn, and called by name by Cinderella (Pictures 4-14). For such a behavior he is reprimanded by Cinderella who definitely recognized the content of his dream (Pictures 15-36). Immediately upon awakening, Bruno shows his good natured temper and amiable character (Pictures 37-40). The film shows that the producer (Walt Disney) and film directors (Wilfred Jackson, Clyde Geronimi and Hamilton Luske) were obviously aware that a dog might enact the content of a dream. It also implies that their observation from day-to-day (better to say night-to-night) life of the dream enactment is not a rare phenomenon, and that it deserves to be shown in the film. These authors were also aware that dogs having RBD were good-natured during wakefulness and that only in dreams they showed unrestrained aggression; while awake, dog Bruno was only an opponent or enemy to the cat Lucifer, but in dreams the animosity grew to aggression. Disney noticed this peculiar kind of sleep behavior and most probably was aware of its frequency and importance, and certainly not knowing it is a disease, he used it to color his cartoon character making it more likable to the observer. Since the film was nominated for Best Score, Best Song and Best Sound, it not only reflected the artistic and observational abilities of the producer, but also his sense of the importance of the phenomenon, awareness of its frequency and presence in animals. The onlooker is tempted to speculate that Disney, while obviously having been aware of such a behavior in animals, might also have knowledge of its presence in humans. Even more, since Disney’s films frequently present different sleep disturbances (e.g., obstructive sleep apnea (OSA) in dwarfs, hypersomnolence in the dwarf Sleepy, or jactatio capitis nocturna in the dwarf Dopey in film "The Snow White"), it seems plausible that he first observed RBD in man, and then artistically transferred it to his cartoon animal characters. Since the whole incident took place during the day, we assume that Bruno, apart from suffering from RBD, had another sleep disorder causing daytime REM intrusions (possibly narcolepsy and probably not OSA, as is frequent in Disney’s films, since there is no excessive daytime sleepiness). The odd thing about RBD is that it may easily, as it probably did for centuries, go as peculiar behavior in sleep – rather than disease. While Lucifer was presented as sober and prudent cat, Bruno was clumsy and forgetful dog. We will refrain from speculating that dog’s clumsy nature could be the consequence of the CNS involvement by neuro-degenerative disease (i.e., synucleinopathy). Although we are aware that, in interpreting this episode we assumed to be at least as imaginative as the cartoon films of Walt Disney are, the fact remains that the artistic film presentation of RBD precedes its scientific description by at least 35 years

Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients

Background: Topiramate (TPM) is a sulfamate-substituted monosaccharide that is structurally different from other antiepileptic drugs. TPM inhibits carbonic anhydrase activity, which is associated with loss of bicarbonate from the kidney and consequently metabolic acidosis or electrolyte imbalance. Objective: The objectives of the study were to investigate the influence of TPM therapy on bicarbonate and potassium levels in adult epileptic patients. Methods: Data were collected from 59 adult patients on monotherapy or co-therapy of TPM and other antiepileptic drugs. Serum bicarbonate and potassium levels were available from all patients. Steady-state TPM trough concentrations were determined in blood samples by high-performance liquid chromatography. Data analysis was performed by SPSS software (version 17, Chicago, IL). Results: Patients were divided into group A (duration of therapy shorter than or equal to 5 years) and group B (duration of therapy longer than 5 years). Significant difference (P lt 0.05) in serum bicarbonate levels was observed between these 2 groups. Bicarbonate levels were linearly related to the TPM therapy duration. No correlation was found between the TPM dose or patient age and bicarbonate or potassium levels, as well as between therapy duration and potassium level. Linear regression analysis showed no significant association among 54 available TPM trough concentrations and bicarbonate or potassium levels. Conclusions: Results highlight the frequent occurrence of lower bicarbonate level associated with prolonged TPM therapy. Monitoring bicarbonate levels in patients on long-term TPM therapy might be useful

Population pharmacokinetics of topiramate in adult patients with epilepsy using nonlinear mixed effects modelling

The objective of the study was to develop population pharmacokinetic model of topiramate (TPM) using nonlinear mixed effects modelling approach. Data were collected from 78 adult epileptic patients on mono- or co-therapy of TPM and other antiepileptic drugs, such as carbamazepine (CBZ), valproic acid, lamotrigine, levetiracetam, phenobarbital and pregabalin. Steady-state TPM concentrations were determined in blood samples by high performance liquid chromatography with fluorescence detection. A one-compartment model with first order absorption and elimination was used to fit the concentration-time TPM data. Volume of distribution of TPM was estimated at 0.575 l/kg. The influence of demographic, biochemical parameters and therapy characteristics of the patients on oral clearance (CL/F) was evaluated. Daily carbamazepine dose (DCBZ) and renal function estimated by Modification of diet in renal disease (MDRD) formula significantly (p lt 0.001) influenced CL/F and were included in the final model: CL/F . (l/h) = 1.53(1/h) . [1 + 0.476 . DCBZ(mg/day)/1000(mg/day)] . EXP[0.00476 . [MDRD(ml/min) -95.72(ml/ mm)]]. Increase of CL/F with DCBZ and MDRD was best described by linear and exponential models. Mean TPM CL/F during CBZ co-therapy was 2.46 l/h, which is higher for 60.8% than in patients not co-treated with CBZ. Evaluation by bootstrapping showed that the final model was stable. The predictive performance was evaluated by adequate plots and indicated satisfactory precision. This model allows individualisation of TPM dosing in routine patient care, especially useful for patients on different CBZ dosing regimen

Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients

Background: Topiramate (TPM) is a sulfamate-substituted monosaccharide that is structurally different from other antiepileptic drugs. TPM inhibits carbonic anhydrase activity, which is associated with loss of bicarbonate from the kidney and consequently metabolic acidosis or electrolyte imbalance. Objective: The objectives of the study were to investigate the influence of TPM therapy on bicarbonate and potassium levels in adult epileptic patients. Methods: Data were collected from 59 adult patients on monotherapy or co-therapy of TPM and other antiepileptic drugs. Serum bicarbonate and potassium levels were available from all patients. Steady-state TPM trough concentrations were determined in blood samples by high-performance liquid chromatography. Data analysis was performed by SPSS software (version 17, Chicago, IL). Results: Patients were divided into group A (duration of therapy shorter than or equal to 5 years) and group B (duration of therapy longer than 5 years). Significant difference (P lt 0.05) in serum bicarbonate levels was observed between these 2 groups. Bicarbonate levels were linearly related to the TPM therapy duration. No correlation was found between the TPM dose or patient age and bicarbonate or potassium levels, as well as between therapy duration and potassium level. Linear regression analysis showed no significant association among 54 available TPM trough concentrations and bicarbonate or potassium levels. Conclusions: Results highlight the frequent occurrence of lower bicarbonate level associated with prolonged TPM therapy. Monitoring bicarbonate levels in patients on long-term TPM therapy might be useful