Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy. METHODS: For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045. FINDINGS: The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; WCRfinal/baseline=0·25) in patients who received pitolisant and 38% (WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p<0·0001). Treatment-related adverse events were significantly more common in the pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51; p=0·048). There were no serious adverse events, but one case of severe nausea in the pitolisant group. The most frequent adverse events in the pitolisant group (headache, irritability, anxiety, and nausea) were mild or moderate except one case of severe nausea. No withdrawal syndrome was detected following pitolisant treatment; one case was detected in the placebo group. INTERPRETATION: Pitolisant was well tolerated and efficacious in reducing cataplexy. If confirmed in long-term studies, pitolisant might constitute a useful first-line therapy for cataplexy in patients with narcolepsy, for whom there are currently few therapeutic options. FUNDING: Bioprojet, France.

Differential diagnosis of a paroxysmal neurological event: Do neurologists know how to clinically recognize it?

PURPOSE: To investigate ability to recognize paroxysmal neurological events (PNE) based on video-recorded events alone in a group of physicians treating prevalent neurological conditions. METHODS: Total of 12 patients' videos (6 epileptic seizures (ES), 4 psychogenic nonepileptic seizures (PNES), 2 other nonepileptic seizures (oNES)) were selected. Videos were displayed once to physicians blind to clinical data and final diagnosis. Physicians determined their clinical choice: ES, PNES, oNES, and I don't know (IDK). When ES was chosen, subjects determined type of ES: focal ES, secondary generalized tonic-clonic seizure (GTCS), primary GTCS, and IDK. RESULTS: In total 145 physicians (62% female, mean age 46.2±9years) (neurologists 58.6%, neuropsychiatrists 25.5%, psychiatrists 5%, and neurology residents 10.3%) were enrolled. Physician's exposure to patients with epilepsy per week was diverse: ≤1 patient (43.7%); 1-7 patients (37.2%); >7 patients (14.5%). Reported frequency of observation of PNE was as follows: frequent (21.4%), sometimes (47.6%); rarely (26.9%); never (2.1%). Majority of subjects were not EEG readers (60.7%). Median percentage (Mdn%) of correct answers (CA) was 75% (range 25-100). Predictor of better PNE recognition was higher frequency of clinical exposure to PNE (OR 1.65; CI95% 1.11-2.45; p=0.013). Mdn% of ES CA was 83.3%, (range 33.3-100), and of PNES CA was 50% (range 0-100). Physicians were more accurate in ES than PNES identification (p<0,001). Mdn% of type of ES CA was 50%, (range 0-100). CONCLUSIONS: We demonstrate the need for education about clinical features of PNE across subgroups of physicians who deliver neurological service, with emphasis on PNES and ES type classification.

Validation of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) Serbian version.

The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was developed and proven efficient for the rapid detection of a major depressive episode in people with epilepsy. This study describes the development, validation, and psychometric properties of the NDDI-E Serbian version. A consecutive sample of 103 patients with epilepsy was assessed using the Beck Depression Inventory (BDI) and the NDDI-E. All patients had no major difficulties in understanding or answering the questions of the Serbian version. Cronbach's alpha coefficient was 0.763. Receiver operating characteristic analysis showed an area under the curve of 0.943 (95% CI; 0.826 to 0.951), a cutoff score of ≥14, a sensitivity of 72.2%, a specificity of 95.2%, a positive predictive value of 81.3%, and a negative predictive value of 94.3%. The NDDI-E Serbian version scores were significantly and positively correlated with those of the BDI (p<0.001). The NDDI-E Serbian version constitutes a concise and consistent depression screening instrument for patients with epilepsy.

Polysomnographic sleep patterns in depressive, schizophrenic and healthy subjects.

BACKGROUND: Sleep disorders are frequent symptoms described in psychiatric patients with major depression and schizophrenia. These patients also exhibit changes in sleep architecture measured by polysomnography (PSG) during sleep. The aim of the present study was to identify potential biomarkers to facilitate diagnosis based on PSG measurements. SUBJECTS AND METHODS: Thirty (30) patients with schizophrenia, 30 patients with major depression and 30 healthy control subjects were investigated in the present study. All subjects underwent PSG measurements for a minimum time of 8 hours according to the criteria of Rechtscahffen & Kales (1968). We tested the potential of multiple sleep variables to predict diagnosis in different groups by using linear discriminant analysis (LDA). RESULTS: There were significant differences in PSG variables between healthy control subjects and psychiatric patients (total sleep time, sleep latency, number of awakenings, time of awakening after sleep onset, REM 1 latency, REM 1 and index of endogenous periodicity). Importantly, LDA was able to predict the correct diagnosis in 88% of all cases. CONCLUSIONS: The presented analysis showed commonalities and differences in PSG changes in patients with major depressive disorder and in patients with schizophrenia. Our results underline the potential of PSG measurements to facilitate diagnostic processes.

Bálint-like syndrome as an unusual representation of non-convulsive status epilepticus.

The clinical signs of posterior cortex dysfunction are, due to their paucity and subtlety, very often ignored as non-specific during clinical evaluation of non-convulsive status epilepticus. Therefore, focal non-convulsive status epilepticus emerging from the posterior cortex, and especially the parietal lobes, can be fairly under-recognised. We report a 66-year-old patient with focal non-convulsive status epilepticus presenting as isolated Bálint-like syndrome, successfully treated to full clinical and electrophysiological recovery. The diagnostic and pathophysiological features are discussed. Focal non-convulsive status epilepticus can be associated with negative phenomena such as neuropsychological deficits mimicking those detected more often in degenerative and vascular brain diseases. [Published with video sequences].

[Evolutionary approach to the interpretation of sleep function].

Evolutionary approach to the interpretation of sleep function seems more promising than the contemporary theories which, in nature, are more utilitarian. The basis of biological approach rest first on the existance of neuronal networks opearting in most primitive (even few cells) organisms. Under an evolutionary pressure, multifunctional neuronal networks developed in response to the need to elaborate more complex tasks relevant to the vital functioning of more complex organisms. As an answer to the need to process the sonsory input a state of calm wakefulness, as a precursor state to the primitive sleep, developed. At a certain point of evolution, coincident with the development of focal vision, the sonsory input relevant to the well-being of the organisms overcame the processing capacity of the existant neuronal networks. A new state of vigilance developed corresponding to the state of primitive sleep in which animals withdrew to the security of an ecological niche. With the advance of focal vision and homeothermy a novel state of vigilance corresponding to 'sleep' developed. The enormous amounts of sensory (specially visual) input relevant for the animal, were moved for processing to the newly developed vigilance state of sleep. This sleep state was able to process memory and perform synaptic strengthening within neuronal networks, without coming into collision with the more vital activities performed at wakefulness (like surveillance of the surrounding, flee reaction, preying, etc). Sleep developed in more complex and higher organisms as an answer to the evolutionary pressures to process the sensory input which would otherwise interfere with the processing capacities of the multifunctional neuronal networks in wakefulness.

Hippocampal metabolic dysfunction in juvenile myoclonic epilepsy: 3D multivoxel spectroscopy study.

PURPOSE: To investigate the metabolic differences in hippocampi of patients with juvenile myoclonic epilepsy (JME) and healthy controls using magnetic resonance spectroscopy (MRS). METHODS: A 3D multivoxel SE 135 MRS study on 1.5 T scanner of both hippocampi was performed in 17 patients with JME and normal brain MRI and in 19 age and sex matched controls. Three dominant signals were measured: Choline (Cho), Creatine (tCr) and N-Acetylaspartate (NAA) and expressed as ratios of Cho:tCr, NAA:tCr, NAA:Cho and NAA:(Cho+tCr). Metabolite ratios in head, body and tail of each hippocampus in the JME group of patients were compared with ratios from corresponding structures in the control group. RESULTS: We found a significant difference in metabolite ratios of both hippocampi between the JME and the control groups. We detected significant differences of Cho:tCr in the head, NAA:tCr in the head, body and tail, NAA:Cho and NAA:(Cho+tCr) in the body and tail of the left hippocampus, and NAA:Cho and NAA:(Cho+tCr) in the body and tail of the right hippocampus. DISCUSSION: Although not previously recognized as a part of the epileptogenic network, our results suggest that the hippocampus, well recognized as a key player in focal epilepsies, may have a certain role in the pathogenesis of JME.

[Transient lesion in the splenium of the corpus callosum and a sudden antiepileptic drugs withdrawal: a case with focal epilepsy in presurgical evaluation].

INTRODUCTION: A sudden withdrawal of antiepileptic drugs gives higher rate of epileptic seizures in the settings of video electroencephalography (vEEG), monitoring that is a subject to further registration and analysis. A very rare complication of this method is transient lesion of the splenium of corpus callosum (SCC) detected with brain MRI. CASE REPORT: We presented a patient with a 5-year history of pharmacoresistant epilepsy admitted to the Institute of Neurology (August, 2008) for vEEG monitoring. Interictal epileptic discharges but none seizure were recorded after the sudden withdrawal of antiepileptic medications, during 5 days of vEEG monitoring Initial brain MRI three days after vEEG monitoring revealed focal lesion in SCC, hyperintense on T2 and FLAIR sequence. A longitudinal radiological follow-up (7 and 49 days after initial acquisition) confirmed transient nature of the lesion without diffusion coefficient changes. CONCLUSION: SCC lesion, reversible and harmless, may occur after a sudden antiepileptic withdrawal. Its early detection makes further extensive neuroradiological and clinical examinations unnecessary.

Long-term survival in patients with status epilepticus: a tertiary referral center study.

PURPOSE: To determine long-term survival in patients with status epilepticus (SE). METHODS: We prospectively followed patients admitted for the first (69.6%) or recursive episode of SE between January 1, 1989 and December 31, 1997 at the Institute of Neurology, Belgrade, Serbia, until death or study termination (December 31, 2006). Data were obtained for cause of death; etiology of SE-acute symptomatic (AS), progressive symptomatic (PS), remote symptomatic (RS), and idiopathic/cryptogenic (I/C); presence of epilepsy; and reoccurrence of SE. Standardized mortality rate (SMR), survival, and regression analysis were used. RESULTS: A total of 120 of 750 patients with an episode of SE (15.9%) died in the 30-day period following SE. Data for 207 of 630 (32.8%) surviving patients (35.7% with initial SE) were available at the end of follow-up [median 12 years; 95% confidence interval (CI) 11.1-12.8]. SMR was significantly increased (SMR = 1.81; 95% CI 1.32-2.41). There were 46 deaths (22.2%): 15 of 65 in the AS, 20 of 29 in the PS, 6 of 29 in the RS, and 5 of 75 in the I/C groups. Five-year survival rate was lowest in the PS (45%) compared to AS (91%), RS (87%), and I/C (99%) groups. The following characteristics increased long-term risk for mortality: older age [Exp(B) 1.05, 95% CI 1.029-1.072], PS and AS etiology [Exp(B) 15.6, 95% CI 5.8-41.6; 3.3, 95% CI 1.2-9.1], presence of epilepsy [Exp(B) 2.3, 95% CI 1.2-4.3], and initial SE [Exp(B) 2.4, 95% CI 1.4-4.4]. DISCUSSION: Approximately one of five patients die within 12 years after an episode of SE. Symptomatic SE (PS and AS), initial SE, age, and presence of epilepsy are associated with long-term increased risk of death.

Coexistence of Unverricht-Lundborg disease and congenital deafness: molecular resolution of a complex comorbidity.

PURPOSE: We report on genetic analysis of a complex condition in a Serbian family of four siblings, wherein two had progressive myoclonic epilepsy (PME) and congenital deafness (CD), one had isolated congenital deafness (ICD), and one was healthy. METHODS AND RESULTS: Molecular diagnosis performed by Southern blotting confirmed Unverricht-Lundborg disease in the available sibling with PME/CD. In the sibling with ICD (heterozygote for expansion mutation in CSTB) we demonstrated recombination event between the D21S2040 marker and the CSTB gene and identified c.207delC (p.T70Xfs) mutation in the fourth exon of the transmembrane protease, serine-3 (TMPRSS3) gene (maps in close proximity to CSTB), responsible for nonsyndromic deafness in the sibling with PME/CD as well. DISCUSSION: To the best of our knowledge this is the first genetic confirmation of the coexistence of these two mutations.

[REM sleep parasomnias and degenerative diseases of the central nervous system].

Parasomnias are defined as unpleasant and undesirable behavioral (in the sense of action) or experiential (in the sense of sensorial or perceptive) phenomena which overwhelmingly or exclusively happen during sleep. Former attitudes that parasomnias are closely related to psychiatric derangement are abandoned and newer polysomnographic research indicates that we are dealing with a number of totally different organically defined states, most of which are easy to diagnose and even cure. The frequency of parasomnias in population is much higher than so far supposed so that they are considered among the most frequent disturbance of the CNS. Another inglorious record tightly connected to parasomnias is that they belong to the most frequently undiagnosed or misdiagnosed diseases. Clinically the most important and intriguing of the parasomnias associated with REM sleep, is REM sleep behavior disorder (RBD). In the last few decades in the field of human and animal sleep, researchers have noticed that RBD represents the omen of the more complex degenerative disorders of the central nervous system--the synucleinopathies and tauopathies. RBD can precede these disorders for decades before the florid clinical picture becomes obvious.

Frequency, causes and phenomenology of late seizure recurrence in patients with juvenile myoclonic epilepsy after a long period of remission.

PURPOSE: To determine frequency, causes, and phenomenology of late seizure recurrence (SR) in patients with juvenile myoclonic epilepsy (JME) after remission of at least 1 year. METHODS: Among 2722 epileptic patients from tertiary referral center, we retrospectively identified 105 patients (62 females; mean age 22.3+/-7.2 years) with an established diagnosis of JME. All patients were treated with valproates (83.3%), or lamotrigine, topiramate, phenobarbital, add-on clobazam, or combinations (16.2%). RESULTS: The median period of follow-up was 4.2+/-3.2 (range: 1-17) years. SR occurred in 74 patients (70.5%) after median period of 2.4+/-3.2 years. Twenty-two patients (29.7%) experienced myoclonic seizures (MS), 13 (17.7%) generalized tonic-clonic seizures (GTCS), 37 (50%) a combination of MS and GTCS, and two (2.6%) a combination of MS, GTCS and absence seizures. SR was associated most frequently with sleep deprivation and AED withdrawal, and rarely with alcohol intake, drug abuse, photostimulation, or menstruation. No provoking factors for SR were identified in 31.1% and 45% of cases with MS and GTCS, respectively. The majority of patients (59/74) had a single SR. A second SR occurred less frequently in patients in whom valproate dosage was increased after the first SR (p=0.0048). CONCLUSION: Late SR (mainly MS and GTCS) is detected frequently after prolonged follow-up in patients with JME despite the use of best-known therapy, usually due to AED withdrawal or erratic life style. Instead of futile efforts to persuade the patient to conform to restrictive life style, it is probably more efficient to use initial higher doses of AEDs.

The frequency of reversible parkinsonism and cognitive decline associated with valproate treatment: a study of 364 patients with different types of epilepsy.

PURPOSE: We report the frequency of parkinsonism and cognitive decline (P/CD) in patients treated with valproate (VPA) after 1 year of treatment and at least 1 year of follow-up. METHODS: Three hundred sixty-four patients with various epileptic syndromes and seizure types were treated with VPA mono- or polytherapy for more than 1 year. RESULTS: We found five cases of P/CD (1.37%; 95% CI, 0.18-2.56%). Among 140 patients with different adverse effects (AEs) of VPA, P/CD were among the rarest in frequency but significant in terms of drug discontinuation (five of 17). CONCLUSIONS: Early identification of this type of AE and discontinuation of the drug led to complete recovery in affected patients.

[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. In 1972, Passouant et al. described sleep with eye movements and persistent tonic muscle activity induced by tricyclic antidepressant medication, and Tachibana et al., in 1975, the preservation of muscle tone during REM sleep in the acute psychosis induced by alcohol and meprobamate abuse. wever, the first formal description of RBD in humans as new parasomnia was made by Schenck et al in 1986. Subsequently, in 1990, the International Classification of Sleep Disorders definitely recognized RBD as new parasomnia. To our knowledge, arts and literature do not mention RBD. Except for the quotation, made by Schenck et al [n 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. 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". 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, orjactatio capitis noctuma 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. AC KNOWLEDGEMENT TheauthorsthankDr. NikolaTrajanovid, ABSM, FAASM (Canada) for valuable suggestions, and Dr. Carlos Schenck from the Minnesota Regional Sleep Disorders Center (USA) for reading the manuscript.

[Generalized epilepsy with febrile seizures plus: clinical and genetic analysis of three Serbian families].

The results of clinical and genetic analysis of three Serbian families (pedigrees) with autosomal dominant inheritance, incomplete penetrance and phenotypic features of GEFS+ are presented in this study. Mutation analysis of the SCN1A, SCN1B and GABRG2 genes was performed in all affected and some unaffected members of these three families. Twenty-six exons of SCN1A, five exons of SCN1B and nine exons of GABRG2 were individually amplified using primers based on intronic sequence. PCR products were sequenced in both forward and reverse directions. Subsequently, the samples were run and analyzed using 377 DNA automated sequencer. No consanguinity was noticed. The MM and OM family members live in Republic of Srpska while KS family originates from the central Serbia. No mutations of the exons of SCN1A, SCN1B and GABRG2 genes were found in tested subjects. Obligate carriers in MM family (III-1, III-2, and III-4) exhibit variable expressivity or incomplete penetrance rather than proof of polygenetic inheritance. OM pedigree follows autosomal dominant pattern despite reduced penetrance. Bilinear transmission may assume the possibility of multigenetic mode of inheritance in KS family. The fact that all affected members in three Serbian families were negative for mutations in SCN1A, SCN1B and GABRG2 genes strongly supports the hypothesis of significant genetic heterogeneity of GEFS+. Recognizing GEFS+ on clinical grounds contributes to more precise integration of this syndrome into already existing classification of epileptic syndromes.

[Phenomenology and psychiatric origins of psychogenic non-epileptic seizures]. / Fenomenologija i psihijatrijska osnova psihogenih neepilepticnih napada.

INTRODUCTION: Psychogenic nonepileptic seizure (PNES) is a sudden change in a person's behavior, perception, thinking, or feeling that is usually time limited and resembles, or is mistaken for, epilepsy but does not have the characteristic electroencephalographic (EEG) changes that accompanies a true epileptic seizure [1]. It is considered that PNES is a somatic manifestation of mental distress, in response to a psychological conflict or other stressors [2]. A wide spectrum of clinical presentation includes syncope, generalized tonic-clonic seizure, simple and complex partial seizure, myoclonic seizure, frontal lobe seizures and status epilepticus [3]. Coexistence of epilepsy and PNES is seen in approximately 9% of cases [5]. Between 25-30% of patients referred to tertiary centers and initially diagnosed as refractory epilepsy were on further examination diagnosed as PNES [6, 7]. In DSM-IV [12] PNES are usually categorized under conversion disorder with seizures or convulsions. However, psychiatric basis of PNES may be anxiousness (panic attack), somatization or factitious disorder, simulation, dissociative disorders and psychosis [1]. AIM: The aim of the study was to establish clinical phenomenology and EEG characteristics as well as basic psychiatric disorder in patients with PNES. METHOD: In a retrospective study covering the period from January 1st 1999 till April 31st 2003, 24 patients (22 female, 2 male) treated at the institute of Neurology in Belgrade were analyzed. PNES were defined as sudden change in behavior incoherent with epileptiform activity registered on EEG. Possible PNES were determined on the basis of history data and clinical examination during the attack but definitive confirmation was established only by the finding of no ictal EEG changes during typical seizure of each patient. Patients with coexisting epilepsy were included in the study, too. At least two standard EEG (range 2-6, median 4) were performed at the beginning of diagnostic evaluation. Demographic data, clinical presentation (apparent loss of consciousness, type of convulsion and associated clinical signs) and placebo-induced seizures (administration of saline near the cubital vein) with EEG or video-EEG monitoring were analyzed. Basic psychiatric disorder was classified according to DSM IV classification criteria. RESULTS: Duration of PNES was 4.7 years (range from 2 months to 30 years). The time from onset to the diagnosis of PNES was 4.5 years. Epilepsy comorbidity was diagnosed in 9 patients (37.5%). The average time of use of antiepileptic drugs (AED) in the group of isolated PNES was 2.4 years and 20% of patients were treated with two or more AED. The vast majority of patients presented with bilateral convulsions (54.16%) with apparent loss of consciousness found in 91.6% of cases. Ictal iwury (16.7%), tongue bite (4.2%) and premonition of the seizure (17.4%) were uncommon. Variability in clinical presentation of seizures was found in over half of patients (57%). Psychological trigger could be determined in over 60% of patients. EEG findings in a group with isolated PNES suggesting the existence of epileptiform activity was found in one case. EEG monitoring of placebo-induced seizure was performed in 20 patients, of whom 19 (95%) showed typical habitual attack with no electroclinical correlate. In 70% of cases conversion disorder DSM-IV criteria were fulfilled. Somatization disorder and undifferentiated somatoform disorder were found in 3 patients. The diagnosis of factitious disorder was made in one case and only two patients were undiagnosed according to DSM-IV. DISCUSSION: Average delay from onset to diagnosis of PNES in larger studies was estimated to be approximately 7 years [8]. Even though diagnostic delay in our study was shorter, organizational reasons for this could not be found. Longer duration of a typical attack (compared to the epileptic seizure), apparent loss of consciousness, bilateral convulsion behavior and significant clinical variability in absence of typical epileptic elements such as tongue bite and ictal iwury could be the main clinical manifestation of PNES. We found rare interictal abnormalities (6.7%) in the group with isolated PNES and significant percentage (77.7%) in patients with coexisting epilepsy which is coherent with other reports [8]. The latest could lead to prolonged delay in appropriate diagnosis and suitable treatment. Clear psychological trigger wasn't noted in whole group of patients (61%). This, however, is not unusual since PNES represents a chronic disorder with repeated triggering that could lead to less significant role of the same psychological trigger in developed PNES. Even insufficiently resolved in ethical terms, placebo-induced procedure was of huge sensitivity. In clinical practice conversion disorder is hard to differ from malingering or implementation of secondary gain. One could make the conclusion only on the basis of detailed and careful estimation of the symptoms developing context. Conversion disorder is more prevalent among women (from 2:1 to 10:1) [4, 13] but modest percentage of affected men could be explained only by limited sample in this study. CONCLUSION: PNES is often replaced with epilepsy and in number of cases clinical differentiation is not easy. One should be acquainted with clinical presentation of PNES as well as its psychiatric origin in order to adequately recognize and treat the disorder.

[A practical study of the efficacy of a delayed-action preparation of carbamazepine (Tegretol CR 400) in the treatment of patients with partial epilepsy ]. / Pragmaticna studija efikasnosti retard-preparata karbamazepina (Tegretol CR 400) u lecenju bolsenika s parcijalnim napadima epilepcije.

INTRODUCTION: Carbamazepine (CBZ) is the first choice antiepileptic drug in the treatment of partial seizures. Many clinical studies show high efficacy and good tolerance of CBZ in the majority of patients. However, poor water solubility and erratic absorption as well as autoinduction of its metabolism, cause wide and unpredictable fluctuations in CBZ serum concentration. In order to avoid these problems controlled-release formulations of CBZ (Tegretol CR 400) were developed. PURPOSE: The aim of this study was to evaluate the efficacy, tolerance and practicality of the therapy of partial seizures in adults with controlled-release CBZ (Tegretol CR 400). PATIENTS AND METHODS: Over a three-year period we conducted an open pragmatic study of controlled-release CBZ in the therapy of 141 adult patients with established diagnosis of localized related epilepsy. Patients with progressive brain or systemic disease were excluded. All patients had unacceptable seizure frequency and were divided into four groups: 1) 34 with newly-diagnosed epilepsy; 2) 42 with chronic epilepsy and no previous antiepileptic medication; 3) 27 with chronic epilepsy previously treated with conventional preparations of carbamazepine (CBZ); and 4) 38 with chronic epilepsy previously treated with other antiepileptic medications. Patients were switched to controlled-release CBZ and the dosage was slowly adjusted. Baseline evaluation included the analysis of efficacy, tolerance and practicality of the controlled-release CBZ therapy. Three categories of efficiency were defined: 1) successful (patients without seizures); 2) partially successful (patients with improvement of at least 50% in frequency and severity of seizures); and 3) unsuccessful therapy (same or worse than before controlled-release CBZ). Tolerance and practicity were evaluated through the analysis of side effects and frequency of daily doses, respectively. These variables were compared to the corresponding ones after a period of at least three months of full dosage controlled-release CBZ therapy. RESULTS: In all four groups the therapy was successful in 76%, 52%, 30% and 29%, partially successful in 18%, 43%, 30% and 32%, and unsuccessful in 6%, S%, 40% and 39%, respectfully. Side effects occurred less frequently in all 4 groups during the therapy with controlled-release CBZ. We found reduced frequency of drug administration (once or twice daily) in 97.9% of our patients. DISCUSSION: Due to its slow and irregular absorption, short half life, wide and unpredictable fluctuation in plasma levels CBZ has decreased ability to control seizures, with the appearance of the intermittent side-effects such as diplopia, ataxia, headache and dizziness. Controlled-release formulation of CBZ sustains stable absorption and reduces fluctuations in carbamazepine serum concentration. Steady serum levels permit to the majority of patients to tolerate a higher total daily dose by reducing peak-dependent side-effects and improve compliance as a result of less frequent daily doses (1 or 2). CONCLUSION: In patients with partial seizures controlled-release vs. conventional carbamazepine had better efficiency, based on an excellent tolerance, favorable daily dosage and superior compliance.