First clinical experiences with perampanel--the Kork experience in 74 patients.

Perampanel (PER) has been approved for adjunctive treatment of partial-onset seizures in patients age 12 years and older. In Germany, PER was licensed and marketed in September of 2012. At our tertiary referral epilepsy center, a couple of difficult-to-treat patients were awaiting this introduction of PER; therefore, we were able to initiate treatment in many patients within a short period of time. For this report we collected and analyzed the data of the first patients who had been started on add-on PER between September and December of 2012, so that we were able to evaluate at least 6 months of treatment when we made this analysis. At cutoff in June of 2013, 74 patients could be analyzed. Mean age was 38.4 years (range 15-71 years). PER doses ranged from 4 to 14 mg (mean 8.8 mg). All patients took PER once daily at bedtime. Seventy-one patients had focal epileptic seizures; the remaining four patients had Lennox-Gastaut syndrome. Considering the last 3 months of observation compared with baseline, 34 patients (46%) were responders with a reduction of seizure frequency of at least 50%. Ten patients of these (14% of all) were seizure-free. Adverse events were reported in 40 patients (54%). Leading side effects were somnolence (n = 31, 42%) and dizziness (n = 13, 18%), followed by ataxia, irritability, falls, cognitive slowing, and depression in single cases. Six-month retention rate was 70%. Our first clinical experiences with add-on PER in a highly selected group of difficult-to-treat epilepsies are promising.

Clinical experience of abrupt discontinuation of perampanel: a case series.

With an elimination half-life of 105 hours, perampanel (PER) allows a once-daily dosing regimen. In pivotal trials, when PER was tapered, it was therefore usually discontinued abruptly. Thus, in our hospital we have always practiced abrupt cessation. In this case series, we investigated how long PER serum concentrations still remain measurable after abrupt discontinuation of PER and whether withdrawal symptoms, such as an increase in seizures or status epilepticus, occur. PER serum levels and the clinical course of 15 adult in-patients were monitored for three weeks based on a retrospective study design following abrupt discontinuation of PER. After one week, PER was still detected in 13 of 15 patients, after two weeks in 10, and after three weeks in three. Neither a severe increase in seizure frequency nor status epilepticus occurred. However, modifications of the concomitant antiseizure drugs were necessary. The abrupt discontinuation of PER leads to a slow decrease in plasma concentration, thus resembling self-evident gradual discontinuation of PER. In some cases, PER may still be measurable and thus clinically active even weeks after its discontinuation. Efficacy and safety of other antiseizure drugs can be estimated appropriately only thereafter.

Is the anticonvulsant activity of levetiracetam dose-dependent?

PURPOSE: Although levetiracetam (LEV) is globally established as a leading antiseizure medication (ASM) it is still a controversial matter whether dose increases correspond with an increased efficacy if LEV in the recommended dose range did not show satisfying efficacy. In our clinical perception we questioned the value of dose increases in such non-responders. METHODS: In this retrospective monocenter study we analyzed the data of adult people with epilepsies (PWE) with focal-onset seizures who had been treated at the department of adults of the Kork Epilepsy Center between 2009 and 2019, who had been on a stable daily LEV dose and in whom LEV was further increased due to further seizures in spite of baseline LEV in a recommended daily dose range. For reasons of data homogeneity, we included only PWE with at least two definite seizures during the hospital stay under the baseline LEV dose who were treated and observed as in-patients after the increase of LEV for a period at least three-fold longer than the baseline interval before. Additional data acquisition comprised clinical data including adverse events, serum concentrations of LEV and other ASMs, and additional laboratory findings. The primary outcome variable was the change of seizure frequency prior to and after the increase of LEV. RESULTS: Out of 518 PWE who had been on LEV during their hospital stay, a total of 61 PWE fulfilled the inclusion criteria. After a gradual dose increment, 91,8 % of PWE showed a reduced seizure frequency, 73,8 % had a reduction of seizures of 50 % or more, and 21,3 % were seizure-free during the observation period. A significant seizure reduction could be shown with a seizure count of 2,5/week prior to the increment and 0,7/week after dose increment (p < 0,00001). Seven PWE reported minor adverse events and ten PWE showed slight laboratory changes (within normal levels). CONCLUSION: Contrary to our long-term clinical impression, LEV dose increments were reasonable and improved the seizure situation in PWE, usually without additional safety hazards.

Is brivaracetam-induced elevation of carbamazepine-epoxide levels common and clinically relevant? - A case series.

Brivaracetam (BRV) was recently introduced for the treatment of patients with focal epilepsy. BRV undergoes relatively few interactions, but one of them leads to the elevation of carbamazepine (CBZ)-10,11-CBZ-epoxide (CBZ-E) if BRV is co-administered with CBZ. This interaction has been considered to be clinically negligible. We present a case series of nine patients. In eight of them, levetiracetam (LEV) was switched to BRV. In the remaining case, oxcarbazepine was replaced by CBZ and added to a stable BRV dose. A marked increase of CBZ-E occurred in every case and was associated with clinically relevant symptoms including blurred vision, diplopia, dizziness, or fatigue in three of them. However, in the remaining six, the elevated CBZ-E levels were not associated with any tolerability problems. The importance of CBZ-E for adverse events under CBZ may have been overemphasized in the past and is not clinically impairing in most cases treated with the combination of BRV and CBZ.

Plasma concentration and clinical effects of perampanel-The Kork experience.

PURPOSE: To investigate the correlation between steady-state plasma concentrations of perampanel (PER) with efficacy and tolerability in adult patients with difficult-to-treat epilepsy. METHODS: PER plasma concentrations were assessed at steady-state conditions in 92 adult patients (57% female, 43% male, mean age 39,5 years, age range 20-73 years). All patients had been treated with PER at a stable dose for at least 3 weeks. Clinical efficacy was assessed on the day of measuring the plasma concentrations by a retrospective analysis of the seizure frequency and adverse effects. RESULTS: The mean overall plasma concentration was 323,5 ng/ml (range 19 ng/ml - 2436 ng/ml). The corresponding mean dose was 7,5 mg (range 2 mg - 12 mg). PER dose and plasma concentration showed a close linear correlation. Plasma levels and doses varied widely concerning both efficacy and tolerability of PER. The differences between plasma levels of responders and non-responders were not statistically significant. Therefore a clinically useful general reference range could not be defined. CONCLUSION: Our data do not indicate a reliable therapeutic range for PER plasma concentrations. Individual reference ranges varied widely. Therapeutic drug monitoring (TDM) may still be helpful in certain clinical situations.

Abnormal response of motor cortex to photic stimulation in idiopathic generalized epilepsy.

BACKGROUND: Intermittent photic stimulation (IPS) shortens the cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) over the primary motor hand area (M1(HAND)). This response is absent in healthy individuals with a photoparoxysmal response (PPR). Here we combined TMS of the M1(HAND) with IPS to examine whether patients with idiopathic generalized epilepsy (IGE) exhibit an abnormal cortical response pattern to IPS. METHODS: In 13 PPR-positive and 12 PPR-negative patients with IGE and in 13 PPR-negative healthy controls, we used focal TMS to the M1(HAND) to study how cortical excitability is changed by concurrent IPS at 50 Hz. RESULTS: IPS at 50 Hz reduced the duration of the CSP in healthy PPR-negative individuals, whereas IPS had no effect on the CSP in PPR-positive and PPR-negative patients with generalized epilepsy. The failure of IPS to shorten the CSP was independent of antiepileptic medication. Single-pulse or paired-pulse TMS only without concurrent IPS showed a higher motor threshold in PPR-positive patients with epilepsy, presumably caused by antiepileptic medication. No additional differences in cortical excitability were found among groups. CONCLUSIONS: Because the CSP is mediated by intracortical GABAergic mechanisms, our results indicate that IGEs are associated with an altered responsiveness of GABAergic inhibitory circuits in the M1(HAND). This electrophysiological trait is independent of photosensitivity. Excitability changes at the cortical or thalamic level may mediate this abnormal cortical response pattern in patients with IGE.

Spreading photoparoxysmal EEG response is associated with an abnormal cortical excitability pattern.

Photosensitivity or photoparoxysmal response (PPR) is a highly heritable electroencephalographic trait characterized by an abnormal cortical response to intermittent photic stimulation (IPS). In PPR-positive individuals, IPS induces spikes, spike-waves or intermittent slow waves. The PPR may be restricted to posterior visual areas (i.e. local PPR with occipital spikes only) or spread to anterior non-visual cortical regions (i.e. PPR with propagation). The mechanisms underlying the PPR and causing its spread remain to be clarified. In unmedicated PPR-positive individuals and PPR-negative control participants without any history of previous seizures, we used focal transcranial magnetic stimulation (TMS) to investigate the excitability of the visual or primary motor cortex (M1). In the first experiment [18 healthy control subjects (i.e. without PPR in electroencephalography: 6 females, mean age 26.5 +/- 7.34 years) and 17 healthy participants with PPR (7 females, mean age 25.18 +/- 12.2 years) were studied], occipital TMS was used to elicit phosphenes or to suppress the visual perception of letter trigrams. PPR-positive individuals with propagation had lower phosphene thresholds and steeper stimulus-response curves than individuals without PPR or with occipital spikes only. Occipital TMS also induced a stronger suppression of visual perception in PPR-positive subjects with propagation relative to subjects without PPR or with occipital spikes. In the second experiment, we applied TMS over the right M1 without concurrent IPS and measured the motor threshold, the stimulus response curve, and the duration of the cortical silent period (CSP) in PPR positive individuals with propagation and in PPR-negative control participants [15 right-handed healthy subjects without PPR (3 males, mean age 17.7 +/- 3.6 years) and 14 right-handed healthy individuals showing a PPR with propagation (3 males, mean age 17.4 +/- 3.9 years)]. PPR-positive individuals showed no changes in these excitability measures relative to the PPR-negative control participants. We also measured the modifiability of the CSP by continuous IPS at a frequency of 18 or 50 Hz. While IPS reduced the duration of the CSP in PPR-negative control subjects, IPS had no effect on the duration of the CSP in PPR-positive individuals. Our results provide first time evidence that the propagation of the PPR is associated with increased excitability of the occipital but not the motor cortex. The stronger inhibitory effect of TMS on visual perception and the failure of IPS to shorten the CSP in PPR-positive participants may possibly reflect adaptive changes that prevent the provocation of seizures during the PPR.

Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients.

Focal cortical dysplasias (FCDs) are increasingly diagnosed as a cause of symptomatic focal epilepsy in paediatric and adult patients. However, little is known about the clinical characteristics of epilepsy in these patients. In order to elucidate the clinical characteristics of their epilepsy, 120 pharmacoresistant patients including children and adults with histologically proven FCD were studied retrospectively. Age at seizure onset was analysed in the total group and compared between subgroups with different localization and different histological subtypes of FCD. The role of febrile seizures with respect to dual pathology was investigated. Seizure semiology was analysed focusing on initial seizure type and change of seizure semiology during the course of disease. Finally, transient responsiveness to antiepileptic drug therapy was studied. In the majority of patients, epilepsy began in the first 5 years of life. However, onset of epilepsy could also occur in the second or third decade until the age of 60. Age at epilepsy onset was not significantly different between temporal, extratemporal and multilobar localization of FCD. Patients without cytoarchitectural abnormalities (mild malformations of cortical development, FCD 1a according to Palmini) had significantly later epilepsy onset (P= 0.001) compared with patients with cytoarchitectural abnormalities (FCD 1b, 2a and 2b according to Palmini). In patients with additional hippocampal sclerosis (dual pathology) febrile seizures were significantly more frequently reported (P = 0.02) than in patients without dual pathology. Moreover, patients with dual pathology and febrile seizures significantly more frequently presented with severe hippocampal sclerosis (Wyler Grade 3-4) as compared with patients with dual pathology in the absence of febrile seizures (P = 0.03). First observed seizures were mainly tonic or generalized tonic-clonic. A change of seizure semiology seemed to be age-dependent and occurred between the age of >1 and 14 years. About 15.8% of the patients presented with status epilepticus during the course of disease. About 17% of the patients showed transient responsiveness (> or =1 year seizure freedom) to antiepileptic drug therapy either after initial therapy (50%) or later in the course of epilepsy (50%). Patients with FCD represent a heterogeneous group. Different age at epilepsy onset and transient responsiveness to antiepileptic drugs in approximately 17% of patients may reflect different dynamics in epileptogenicity of the underlying FCD. Dual pathology may be associated with different pathomechanisms in patients with and without febrile seizures.

Clinical outcomes of perampanel vs. lacosamide in cohorts of consecutive patients with severely refractory epilepsies - A monocentric retrospective analysis of systematically collected data from the German Kork Epilepsy Center.

PURPOSE: Perampanel (PER) and lacosamide (LCM) are antiepileptic drugs (AEDs) approved for the adjunctive treatment of partial-onset seizures. At the time of market entry, information on clinical effectiveness of new AEDs is limited to results from pivotal trials, real-life or comparative data are missing. This analysis of data collected retrospectively in a German epilepsy center used unified evaluation criteria, and describes treatment outcomes with LCM and PER at 6 months. METHODS: Results of the first 70 consecutive patients who had received LCM or PER after their market entries in Germany were compared. Outcome measures comprised 50% responder rates, seizure freedom, retention, and incidence of adverse events (AEs). RESULTS: The mean number of previous AEDs was 8.7 in the PER group, and 7.3 in the LCM group. At 6 months, the 50% responder rate for all seizures was 48.6% for PER, and 28.6% for LCM, with seizure freedom in 14.3% of patients with PER, and 4.3% with LCM. Thirty-two AEs were reported for LCM, and 51 for PER, most commonly dizziness (22.9% of patients) for LCM, and somnolence/tiredness for PER (41.4%). AEs were reported as primary reason for discontinuation in 3 patients of the PER group. Retention rates were similar. CONCLUSIONS: This analysis describes initial comparative benefits of two newly available AEDs in two cohorts of patients with highly refractory epilepsies. Responder and seizure freedom rates were numerically higher for PER. The analysis suggests that new AEDs can provide a chance for seizure freedom in relevant subgroups of patients, despite previous failure of multiple AEDs.

Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy-A monocenter survey.

PURPOSE: To assess the efficiency of brivaracetam under real-world conditions in a tertiary referral epilepsy center. METHODS: We consecutively collected patients treated at our center with brivaracetam (BRV). After a minimum observation period of six months we retrospectively analyzed the efficiency of BRV. RESULTS: Data of 101 patients (mean age 42 years, range 18-81 years, 54 females,) were analyzed. The median number of antiepileptic drugs (AEDs) used prior to BRV was 10 (range 2-18). The initial dose of BRV was at least 50mg per day, the mean maintenance dose at cut-off was 168.6mg (median 200mg, range 50-400mg). Efficacy data were assessed for the last three months or at the time of the last observation carried forward if BRV had been discontinued prematurely. Responder rate was 27.8% (n=28) with 7% seizure-free patients. Adverse events (AEs) occurred in 37 patients (37%). Most frequent AEs were dizziness (16%) and somnolence (11%). Psychiatric adverse events comprised irritability, aggression, depression and psychosis in single cases. Retention rate after six months was 51.5%. Main reason for discontinuation was a lack of efficacy. In 43 cases LEV and BRV were switched. The switch was performed abruptly without complications. In 26 cases (60%) BRV was discontinued and re-switched to LEV within weeks, mainly due to a lack of better efficacy. After the switch from LEV to BRV we even saw an aggravation both of seizure frequency and severity in 5 cases. Retention rate in patients who had not been on LEV was 57%. CONCLUSION: In our hands BRV appeared to be well tolerated and easy to handle. The retention rate was influenced by patients who were switched from LEV and re-switched because BRV was not more efficient. Switching from and re-switching to LEV was easy.

Seizure anticipation by patients with focal and generalized epilepsy: a multicentre assessment of premonitory symptoms.

PURPOSE: To assess subjective seizure anticipation in patients with focal and generalized epilepsy. METHODS: Five hundred consecutively recruited out-patients (251 male, 249 female, mean age 38.1 year) from three German tertiary epilepsy referral centres filled out questionnaires regarding subjective anticipation of seizures by at least 30 min and to timing and semiologic characteristics of their premonitory symptoms versus those of ictal phenomena. Patients were not regarded as having prodromi if the semiology of symptoms reported long before a seizure was identical to auras. RESULTS: 6.2% of patients reported that they were able to anticipate seizures. Premonitory symptoms were classified as stereotyped in all but one patient. An intraindividual semiologic analysis showed that the majority of these patients had symptoms, which were distinct from ictal experiences during auras. Seizure anticipation was reported both by patients with focal and idiopathic generalized epilepsy. The median estimated time interval between occurrence of premonitory symptoms and seizure onset was 90 min. CONCLUSIONS: This study gives evidence that both patients with focal and idiopathic generalized epilepsy may subjectively anticipate the occurrence of epileptic seizures. Premonitory symptoms are distinct from auras in terms of semiology and time of occurrence. The lower percentage of patients regarded as having premonitory symptoms as compared to some earlier reports may be related to stricter criteria and to the exclusion of auras, which could directly evolve into seizures, and other ictal events. Premonitory symptoms occur at similar periods prior to seizures as anticipatory EEG-changes have been reported using methods from time series analysis.

Add-on perampanel in Lance-Adams syndrome.

Perampanel (PER) is the first-in-class selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that has been licensed and marketed as antiepileptic drug (AED) indicated for patients with partial-onset and primary generalized tonic-clonic seizures. A positive effect was reported in some patients with epileptic myoclonic jerks in idiopathic generalized epilepsy and in progressive myoclonic epilepsy. We treated a male patient with posthypoxic nonepileptic myoclonus (Lance-Adams syndrome) with add-on PER and achieved an almost complete cessation of jerks. This effect was reproducible and, therefore, we suggest that it might be worth trying PER in comparable cases.

Analysis of hippocampal atrophy in alcoholic patients by a Kohonen feature map.

We investigated the correlation of hippocampal volume with homocysteine, folate, vitamin B12 and B6 in alcoholic patients and healthy controls applying a Kohonen feature map (KFM) and conventional statistics. Representation of subjects on the KFM suggested an inverse correlation of hippocampal volume with blood levels of homocysteine and correlation with folate and vitamin B6. In conventional statistical analyses (t-test) reduced folate and increased homocysteine was found in alcoholics compared to healthy controls (p < 0.01). In female alcoholics vitamin B6 was reduced significantly (p = 0.03). Multiple linear regression analyses showed a significant correlation between average hippocampal volume and homocysteine (p < 0.001). KFM proved to be a sensitive tool for visualisation of statistical correlations in data sets even if no further statistical information is available.

Quality control of elective surgery for drug-resistant epilepsy in a German reference centre--a long-term outcome study.

PURPOSE: Resective epilepsy surgery is the recommended treatment for a well-defined group of patients with drug-resistant epilepsy. Long-term outcome studies are an appropriate quality control to assess the value of elective surgical procedures ethically and economically. This paper reports the long-term post-surgical follow-up of adult patients of the Kork Epilepsy Centre. METHOD: Data collection was performed by means of a questionnaire to obtain updated information about postsurgical outcome, frequency and postsurgical seizure semiology in case of relapse, postsurgical use of antiepileptic drugs, social issues and satisfaction rates. We classified seizure outcome according to the ILAE surgery outcome scale (OC 1-OC 6). RESULTS: Outcome data of 340 adult patients were obtained. Mean post-operative follow-up was 6.7 years (range 1.0-21.6 years). Seizure remission was 67% if comprising patients with postoperative auras only (OC 1+OC 2). Sixty-two per cent of patients were completely seizure free. The majority of patients (78%) underwent temporal lobe resections. Sixty-four per cent of these and 52% of the patients with extra-temporal resections became completely seizure-free (OC 1). Only 34% of the patients with negative MRI achieved complete seizure-freedom. CONCLUSION: In line with others our huge cohort sample that covers decades of experience with epilepsy surgery revealed satisfying long-term outcome results. Best results were obtained in lesional temporal lobe epilepsy, least favourable results in MRI-negative epilepsy.

Quantification of changes in electroencephalographic power spectra in a patient with Budd-Chiari-syndrome after implantation of a transjugular intrahepatic portosystemic stent shunt (TIPSS).

We examined a 41-year-old female with a subacute Budd-Chiari Syndrome (BCS) before and after implantation of a transjugular intrahepatic portosystemic stent shunt (TIPSS) by means of digital electroencephalography (EEG). After TIPSS implantation hepatic decompression had been achieved and the liver function as well as the clinical status improved daily. Simultaneously, the digital EEG showed a decrease in the power of the theta band and an increase in the physiological alpha frequency band. The theta/alpha ratio decreased after TIPSS, despite an elevated arterial ammonia level. The patient had a well-preserved liver parenchyma before the occurrence of the BCS. After portal decompression by TIPSS, the liver function normalized and the liver resumed efficient synthesis and parts of its detoxification task. This regeneration capacity was documented by a rise in cholinesterase after TIPSS. After temporary substitution of albumin the serum albumin concentration returned to normal. Thus, some neurotoxic substances with high albumin-binding capacity may not be absorbed by the central nervous system (CNS). Furthermore, it appears likely that the length of time the brain is exposed to neurotoxic substances plays a role in the clinical and electroencephalographic changes. Compared to the conventional EEG the theta/alpha ratio reflected better metabolically conditioned electroencephalographic changes after TIPSS.

Sonographic imaging of foramen ovale electrodes.

OBJECTIVE: In patients with medically intractable partial epilepsy of mesiotemporal origin, video electroencephalographic monitoring with foramen ovale electrodes is necessary to plan neurosurgical interventions. Imaging of these electrodes after implantation hitherto required conventional radiography, magnetic resonance imaging, or computed tomography of the skull. These methods are expensive. Therefore, the aim of our work was to show the capability of more cost-effective transcranial B-mode sonography for visualization of the electrodes. METHODS: In this pilot study, a 42-year-old female patient with implanted foramen ovale electrodes was examined transtemporally with a 2-MHz sector transducer to visualize the intracranially implanted electroencephalographic recording device. RESULTS: Foramen ovale electrodes could be detected easily in the patient, and bedside monitoring of explantation was possible. CONCLUSIONS: We were able to show the applicability of transcranial B-mode sonography for visualization of foramen ovale electrodes in preoperative electroencephalographic monitoring of patients with epilepsy. Further evaluation of this method in additional patients will follow.

Quantification of the electroencephalographic theta/alpha ratio for the assessment of portal-systemic encephalopathy following implantation of transjugular intrahepatic portosystemic stent shunt (TIPSS).

The aim of the study was the quantification of metabolically caused electroencephalographic changes of portal-systemic encephalopathy, a prototype of hepatic encephalopathy. We examined 12 patients with liver cirrhosis before and after implantation of a transjugular intrahepatic portosystemic stent shunt (TIPSS) by means of quantitative digital electroencephalography (EEG). One month after TIPSS implantation, all patients showed an increase in the power of the theta frequency band as well as a decrease in the power of the alpha frequency band. To reduce the error variance, we formed the quotient of the relative power of the theta and alpha frequency band. Theta/alpha quotient values over 0.7 indicate a general change of the EEG with a sensitivity of 93% and a specificity of 87%. The results we have to hand indicate a correlation between the albumin concentration and the theta/alpha quotient 1 and 3 months after TIPSS. No significant correlation was revealed with regard to the Child-Pugh score or the liver function parameters cholinesterase, bilirubin, and prothrombin time. Neither the arterial ammonia concentration nor the performance in the psychometric test showed significance in relation to the theta/alpha quotient. Substances with a high albumin bond and potential neurotoxicity may--in the case of lower albumin levels--be absorbed with increased frequency in the CNS and may be responsible for the observed EEG change.