Late-onset seizures and epilepsy: Electroclinical features suggestive of autoimmune etiology.

Introduction: Late-onset epilepsy (LOE) has recently become a topic of intense research. Besides stroke, tumors, and dementia, autoimmune encephalitis (AE) has emerged as another possible cause of recurrent seizures in the elderly, and may account for a proportion of cases of LOE of unknown origin (LOEUO). This 24-h ambulatory electroencephalography (AEEG)-based study compared patients with LOEUO and AE to identify features suggestive of immune-mediated seizures in the elderly. Materials and methods: We retrospectively reviewed 232 AEEG examinations performed in patients over 55 years with ≥6-month follow-up, and selected 21 subjects with AE and 25 subjects with LOEUO. Clinical charts and AEEG recordings were carefully analyzed. Results: Twenty-five patients with LOEUO (12 women, mean age at onset 67.9 years) and 21 AE subjects (8 women, mean age at onset 65.7 years) were enrolled. High-frequency seizures were reported in 20/21 AE and 7/25 LOEUO cases (p < 0.00001). Focal aware seizures were more common in AE (14/21 vs. 6/25, p = 0.00058), whereas "isolated" focal-to-bilateral tonic-clonic seizures occurred in 5/25 patients with LOEUO only (p = 0.053). AE subjects reported ictal autonomic manifestations more frequently (p = 0.0033). Three-hundred-seventy and 24 seizures were recorded in 13/21 patients with AE and 3/25 patients with LOEUO, respectively (p = 0.0006). Interictal epileptiform discharges were observed in 70% of both groups, but their sleep activation was more common in AE (p = 0.06). Conclusion: Our study shows that high-frequency focal seizures with autonomic manifestations should raise the suspicion of AE in the elderly with new-onset seizures. It also highlights the relevant contribution of AEEG, which might reduce the diagnostic delay and provide useful clues to recognize AE.

Generalized Fast Discharges Along the Genetic Generalized Epilepsy Spectrum: Clinical and Prognostic Significance.

Objective: To investigate the electroclinical characteristics and the prognostic impact of generalized fast discharges in a large cohort of genetic generalized epilepsy (GGE) patients studied with 24-h prolonged ambulatory electroencephalography (paEEG). Methods: This retrospective multicenter cohort study included 202 GGE patients. The occurrence of generalized paroxysmal fast activity (GPFA) and generalized polyspike train (GPT) was reviewed. GGE patients were classified as having idiopathic generalized epilepsy (IGE) or another GGE syndrome (namely perioral myoclonia with absences, eyelid myoclonia with absences, epilepsy with myoclonic absences, generalized epilepsy with febrile seizures plus, or GGE without a specific epilepsy syndrome) according to recent classification proposals. Results: GPFA/GPT was found in overall 25 (12.4%) patients, though it was significantly less frequent in IGE compared with other GGE syndromes (9.3 vs. 25%, p = 0.007). GPFA/GPT was found independently of seizure type experienced during history, the presence of mild intellectual disability/borderline intellectual functioning, or EEG features. At multivariable analysis, GPFA/GPT was significantly associated with drug resistance (p = 0.04) and with a higher number of antiseizure medications (ASMs) at the time of paEEG (p < 0.001) and at the last medical observation (p < 0.001). Similarly, GPFA/GPT, frequent/abundant generalized spike-wave discharges during sleep, and a higher number of seizure types during history were the only factors independently associated with a lower chance of achieving 2-year seizure remission at the last medical observation. Additionally, a greater number of GPFA/GPT discharges significantly discriminated between patients who achieved 2-year seizure remission at the last medical observation and those who did not (area under the curve = 0.77, 95% confidence interval 0.57-0.97, p = 0.02). Conclusion: We found that generalized fast discharges were more common than expected in GGE patients when considering the entire GGE spectrum. In addition, our study highlighted that GPFA/GPT could be found along the entire GGE continuum, though their occurrence was more common in less benign GGE syndromes. Finally, we confirmed that GPFA/GPT was associated with difficult-to-treat GGE, as evidenced by the multivariable analysis and the higher ASM load during history.

Olfactory impairment in autoimmune encephalitis: another piece of the puzzle.

BACKGROUND: Despite being long neglected, olfaction has recently become a focus of intense research in neuroscience, as smell impairment has been consistently documented in both neurodegenerative and neuroinflammatory diseases. Considering the close anatomo-functional correlations between the limbic system and the central olfactory structures, we investigated olfaction in a population of patients with autoimmune encephalitis (AE). METHODS: Nineteen adult subjects (14 males, median age 64 years) diagnosed with definite (14/19) or possible (5/19) AE and followed for ≥ 6 months were enrolled. The Brief Smell Identification Test (B-SIT), a 12-item, forced-choice, scratch-and-sniff measure, was used to assess the patients' olfactory function in comparison with a group of sex- and age-matched healthy controls (HC). According to the B-SIT score, subjects were classified as anosmic (< 6), hyposmic (6-8) and normal (≥ 9). Electro-clinical, laboratory and neuroimaging findings were reviewed. RESULTS: Smell impairment was revealed in 15/19 patients (9 hyposmic, 6 anosmic), compared with 5/19 HC (p = 0.0029). Age, gender and smoking habits did not affect the participants' performance at B-SIT. Olfactory dysfunction appeared more common among patients with definite AE (p = 0.0374), regardless of autoantibody status. Subjects with higher modified Rankin Scale (mRS) scores at AE onset more likely presented hyposmia/anosmia (p = 0.033), and so did those with bilateral ictal/interictal EEG abnormalities (p = 0.006). CONCLUSIONS: We found olfaction to be impaired in a significantly large proportion of AE cases. Smell deficits appeared more common in subjects with severe AE (as indicated by both definite diagnosis and higher mRS score), and might represent an additional feature of immune-mediated encephalitis.

High rates of early remission pattern in adult-onset compared with earlier-onset idiopathic generalized epilepsy: A long-term follow-up study.

OBJECTIVE: To investigate electroclinical characteristics and prognostic patterns of adult-onset vs. younger-onset idiopathic generalized epilepsy (IGE) patients during long-term follow-up. METHODS: In this single-center retrospective cohort comparative study, adult-onset IGE was defined as onset after 20 years of age. Patients with a follow-up duration between 10 and 30 years from epilepsy diagnosis were enrolled. Maximum follow-up duration was limited to 30 years to ensure a better comparison of prognostic data between adult-onset and younger-onset patients. The Benjamini-Hochberg false discovery rate (FDR) method was applied to obtain FDR-adjusted p-values. RESULTS: A total of 177 IGE patients were recruited and 27 adult-onset IGE patients were identified (15.3%). Follow-up duration was similar between younger- and adult-onset IGE patients and 74% of subjects performed at least one 24-hour EEG recording. Of adult-onset IGE patients, 8/27 were diagnosed with juvenile myoclonic epilepsy, while 19/27 were diagnosed with generalized tonic-clonic seizures (GTCS) only. EEG photosensitivity and absence seizures were significantly less frequent among adult-onset IGE patients as compared with younger subjects. When considering prognostic patterns, an early remission pattern was significantly higher among adult-onset IGE patients as compared with younger-onset IGE patients (55.6% vs. 24%, adjusted p value = 0.007). Antiseizure medication withdrawal was attempted in 3/27 adult-onset patients, and all had GTCS relapses. CONCLUSION: Our study contributes to better defining the electroclinical characteristics and long-term follow-up of adult-onset IGE patients. A favorable long-term seizure outcome was found in adult-onset IGE patients, as evidenced by the high rates of early remission pattern when compared with younger onset patients.

Seizure outcome trajectories in a well-defined cohort of newly diagnosed juvenile myoclonic epilepsy patients.

OBJECTIVE: To investigate the temporal course of medication response and associated prognostic factors in a cohort of juvenile myoclonic epilepsy (JME) patients over a long-term follow-up. MATERIALS AND METHODS: Data from 113 JME patients diagnosed according to recently proposed class II criteria were retrospectively reviewed. Early sustained remission was defined as 4-year seizure remission starting within 2 years from the first antiseizure medication (ASM) intake, as opposed to delayed sustained remission. Spontaneous relapse rate (ie, not related to ASM withdrawal) was also investigated, along with factors associated with seizure relapse. RESULTS: Four-year seizure remission was obtained by 76/113 (67.3%) subjects. Early sustained remission was achieved by 45/76 (59.2%) patients. Absence seizures were significantly associated with no-remission at multivariable multinomial logistic regression analysis. Catamenial seizures and earlier age at epilepsy onset significantly predicted delayed sustained remission. Spontaneous seizure relapse after 4-year remission occurred in 15.7% of patients with early sustained remission and in 35.5% of those with delayed sustained remission (p = 0.045). The most common concomitant factors for a spontaneous relapse were irregular lifestyle habits and pregnancy-related switch from valproate to another ASM. Patients with a history of catamenial seizures were more likely to experience a spontaneous generalized tonic-clonic seizure relapse after 4-year remission at univariable analysis. SIGNIFICANCE: Our data support the prognostic relevance of early medication response in JME patients. Furthermore, the prognostic significance of catamenial seizures and the impact of valproate switch on seizure relapse after a prolonged remission account for the challenging therapeutic management of women with childbearing potential.

Functional Gastrointestinal Disorders in Patients With Epilepsy: Reciprocal Influence and Impact on Seizure Occurrence.

Introduction: The complex relationship between the microbiota-gut-brain axis (MGBA) and epilepsy has been increasingly investigated in preclinical studies. Conversely, evidence from clinical studies is still scarce. In recent years, the pivotal role of MGBA dysregulation in the pathophysiology of functional gastrointestinal disorders (FGID) has been recognized. With this background, we aimed to investigate the prevalence of FGID in patients with epilepsy (PWE) and the possible impact of bowel movement abnormalities on seizure recurrence. Methods: A total of 120 PWE and 113 age-, sex-, and BMI-matched healthy subjects (HS) were consecutively enrolled. A questionnaire to evaluate the presence of FGID (according to Rome III diagnostic criteria) was administrated to all participants. In a subgroup of drug-resistant patients, we administered an ad-hoc questionnaire combining Bristol stool charts and seizure diaries to evaluate seizure trends and bowel movement changes. Results: A higher prevalence of FGID in PWE (62.5%) than in HS (39.8%) was found (p < 0.001). The most frequently observed disorder was constipation, which was significantly higher in PWE than in HS (43.3 vs. 21.2%, p < 0.001), and was not associated with anti-seizure medication intake according to multivariable analysis. In drug-resistant patients, most seizures occurred during periods of altered bowel movements, especially constipation. A significant weak negative correlation between the number of days with seizures and the number of days with normal bowel movements was observed (p = 0.04). According to multivariable logistic regression analysis, FGID was significantly associated with temporal lobe epilepsy as compared with other lobar localization (p = 0.03). Conclusions: Our clinical findings shed new light on the complex relationship between epilepsy and the MGBA, suggesting a bidirectional link between bowel movement abnormalities and seizure occurrence. However, larger studies are required to better address this important topic.

Persistent treatment resistance in genetic generalized epilepsy: A long-term outcome study in a tertiary epilepsy center.

OBJECTIVE: To assess prognostic patterns and investigate clinical and electroencephalography (EEG) variables associated with persistent treatment resistance in a population of genetic generalized epilepsy (GGE) patients with a long-term follow-up. METHODS: Data from GGE patients followed from 1975 to 2019 were reviewed retrospectively. Subjects with a follow-up >10 years, starting from epilepsy diagnosis, were included. Persistent treatment resistance was defined as the absence of any period of remission ≥1 year despite treatment with two appropriate and adequate antiepileptic drugs (AEDs). RESULTS: One hundred ninety-nine patients were included. The median age was 39.5 years (interquartile range [IQR] 30-49) and the median follow-up was 27 years (IQR 18-35). The most common syndrome was juvenile myoclonic epilepsy (JME), diagnosed in 44.2% of patients. During follow-up, 163 subjects (81.9%) experienced 3-year remission from any seizure type, whereas 5- and 10-year remission occurred in 141 (70.8%) and 92 (46.2%) cases, respectively. The most common prognostic pattern was a relapsing-remitting course, observed in 80 patients (40.2%), whereas 29 (14.6%) displayed persistent treatment resistance. According to multivariable logistic regression analysis, febrile seizures (FS), specific EEG patterns (namely generalized paroxysmal fast activity, GPFA) and valproate (VPA) resistance were the only variables significantly associated with persistent treatment resistance. JME was the only epilepsy syndrome statistically associated with persistent treatment resistance in univariable logistic regression analysis. SIGNIFICANCE: Persistent treatment resistance was observed in almost 15% of GGE patients followed in a tertiary epilepsy center. A worse outcome was associated with specific clinical variables (JME, FS) and EEG patterns (GPFA).

Seizures in autoimmune encephalitis: Findings from an EEG pooled analysis.

PURPOSE: Seizures are common in autoimmune encephalitis (AE), and an extensive work-up is required to exclude alternative etiologies. The aim of our study was to identify possible clinical/EEG peculiarities suggesting the immune-mediated origin of late-onset seizures. METHODS: Thirty patients diagnosed with AE (19 men, median age 68 years, 18 seronegative) were included. Overall 212 video-electroencephalographic (EEG) and 31 24-h ambulatory EEG (AEEG) recordings were retrospectively reviewed. Posterior dominant rhythm, interictal epileptiform discharges (IEDs), clinical (CSs) and subclinical seizures (SCSs) were analyzed. RESULTS: Six-hundred-nineteen ictal events were recorded in 19/30 subjects, mostly (568/619) during AE acute stage. Among ten patients with CSs other than faciobrachial dystonic seizures, 7 showed prominent autonomic and emotional manifestations. SCSs were detected in 11 subjects, mainly via AEEG (260/287 SCSs vs 150/332 CSs, p < 0.001). Eight patients presented seizures during hyperventilation. IEDs, documented in 21 cases, were bilateral in 14 and focal temporal in 13. Multiple ictal EEG patterns were detected in 9/19 patients, 6 of whom had both CSs and SCSs, bilateral asynchronous seizures and ictal activities arising from temporal and extra-temporal regions. No correlation was found between the lateralization of MRI alterations and that of EEG findings. CONCLUSION: Our study confirms that adult-onset, high frequency focal seizures with prominent autonomic and emotional manifestations should be investigated for AE. Multiple ictal EEG patterns could represent a 'red flag', reflecting a widespread neuronal excitability related to the underlying immune-mediated process. Finally, our work enhances the crucial role of long-lasting EEG monitoring in revealing subclinical and relapsing seizures.

Valproate impact and sex-dependent seizure remission in patients with idiopathic generalized epilepsy.

BACKGROUND: Idiopathic Generalized Epilepsy (IGE) management has become increasingly challenging due to the restricted use of Valproate (VPA) in females. The aim of the study was to assess possible differences in terms of seizure outcome between men and women suffering from IGE. METHODS: A cohort of IGE patients (age range: 13-50 years) followed from 1980 to 2018 were included. Their medical history was retrospectively reviewed to investigate possible factors influencing seizure outcome. Seizure Remission (SR) was defined as the absence of any seizure type over 18 months prior to the last medical observation. The primary outcome was to evaluate sex differences in terms of SR at last observation. A multivariable logistic regression model was elaborated using SR as dependent variable. RESULTS: Three-hundred and sixty patients were included, 204 (56.7%) of whom were women. The median age at the end of follow-up was 30. At last medical observation, fewer women were receiving VPA compared with men (females 39.7% vs males 79.5%, p < .001). Overall SR was 70.6%. SR was significantly different according to sex (females 62.3% vs males 81.4%, p < .001). Multivariable logistic regression model showed that female sex (Odds Ratios [OR] = 0.52, 95% Confidence Interval [CI] = 0.29-0.94; p = .03), VPA treatment at last observation (OR = 0.44, 95% CI = 0.25-0.76; p = .003) and epilepsy syndrome (p < .001) were the factors independently associated with SR. CONCLUSIONS: Recent modifications in VPA prescribing patterns may have determined a worse seizure control among IGE female patients. Comparative clinical trials assessing the best therapeutic options for women with childbearing potential are urgently needed.

Anxiety as the only manifestation of focal non-convulsive status epilepticus: case report and review of the literature.

Psychiatric disorders represent common comorbidities in epileptic patients. Sometimes anxiety is part of the ictal semiology, especially during seizures arising from/involving frontal or temporal lobes. We describe a patient with focal epilepsy and recurrent hyperkinetic seizures who also presented prolonged episodes characterized by massive anxiety, alarm and fear. A Video-Electroencephalographic monitoring performed during one of these attacks revealed a continuous epileptiform activity over the right frontal regions, consistent with a focal non-convulsive status epilepticus accounting for the patient's psychiatric symptoms. Our case confirms the complex relationship between epilepsy and anxiety. A review of the literature is also included.

Myoclonic epilepsy, parkinsonism, schizophrenia and left-handedness as common neuropsychiatric features in 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is considered as the genetic model of schizophrenia. However, its polymorphic nature has led researchers to further investigate its neuropsychiatric manifestations. METHODS: We enrolled 56 adults (38 men, 18 women) diagnosed with 22q11.2DS. All subjects were evaluated by a multidisciplinary team. The neuropsychiatric features were investigated by means of clinical and neurophysiological evaluation (video-EEG). RESULTS: Thirty per cent of our patients were left-handed. Fifty-eight per cent had a low IQ, and 22 of 56 subjects had psychotic disorders (13 of 22 with schizophrenia). Eighteen patients reported at least one seizure in their lifetime, and ten were diagnosed with epilepsy; among them, seven had genetic generalised epilepsy (GGE), and five of seven showed features suggestive of juvenile myoclonic epilepsy (JME). Video-EEG recordings revealed generalised epileptiform abnormalities in 24 of 56 cases. Besides, only one patient with epilepsy had a cardiac malformation. Lastly, 31 of 56 subjects presented with parkinsonism, 16 of whom were taking neuroleptics. None of the 15 patients with parkinsonism not related to neuroleptic therapy was diagnosed with epilepsy, compared with 6 of those taking antipsychotics. CONCLUSIONS: 22q11.2DS is characterised by left-handedness and neuropsychiatric features such as cognitive impairment, schizophrenia, epilepsy and parkinsonism. GGE, mostly the JME phenotype, is the predominant epilepsy type. The significant association between 22q11.2DS and parkinsonian features confirms these patients' genetic susceptibility to parkinsonism. Despite the lack of any conclusive evidence, our study suggests a possible relationship between the analysed clinical variables: (1) an inverse correlation between low IQ/psychosis/epilepsy and major cardiac diseases; (2) a direct association between psychosis and both mental delay and epilepsy; and (3) an inverse correlation between parkinsonism and epilepsy.

Doing without valproate in women of childbearing potential with idiopathic generalized epilepsy: Implications on seizure outcome.

OBJECTIVE: Valproate (VPA) use in women with idiopathic generalized epilepsy (IGE) who are of reproductive age has been a matter of concern and debate, which eventually led to the recent restrictions by regulatory agencies. The aim of our study was to investigate the relationship between VPA avoidance/switch and seizure outcome in women of childbearing potential. METHODS: We retrospectively reviewed data from female patients with IGE, 13-50 years of age, followed since 1980. We evaluated the prescription habits, and the rate of VPA switch for other antiepileptic drugs (AEDs) and its prognostic implications. Seizure remission (SR) was defined as the absence of any seizure type more than 18 months before the last medical observation. The main aim of the study was to assess (a) possible changes in seizure outcome related to VPA switch for other AEDs, especially in patients planning a pregnancy; and (b) possible differences in SR based on the presence/absence of VPA at last observation. RESULTS: One hundred ninety-eight patients were included in the study. Overall SR at last medical observation was 62.7%. SR significantly differed between subjects taking and those not taking VPA (P < .001) at last visit. Multiple regression models showed that taking VPA at last medical observation was strongly associated with SR in both the general population (P < .001) and the juvenile myoclonic epilepsy (JME) group (P < .001). Thirty-six (70.6%) of 51 patients who switched from VPA during follow-up experienced a clinical worsening. Switching back to VPA was more frequently associated with SR at last observation (P < .001). In those patients who substituted VPA in view of a pregnancy, SR and drug burden (monotherapy vs polytherapy) differed significantly before and after the switch. SIGNIFICANCE: Our study suggests that VPA avoidance/switch might be associated with unsatisfactory seizure control in women with IGE who are of childbearing potential. Our findings further highlight the complexity of the therapeutic management of female patients of reproductive age.

Ictal atrial fibrillation during focal seizures: a case report and literature review.

Cardiac arrhythmias are a common but often overlooked symptom that occur during or after epileptic seizures. The characterization of seizure-related heart rhythm disorders could shed light on the functional organization of the so-called "central autonomic network" and possibly on the pathophysiology of sudden death of epilepsy patients (SUDEP). Indeed, epileptic discharges may affect the heart through the involvement of cortical regions selectively driving autonomic functions. Ictal atrial fibrillation is an exceedingly rare phenomenon, usually associated with generalized tonic-clonic seizures. Here, we report a case of paroxysmal atrial fibrillation as a core presenting feature of a focal non-motor seizure in a 68-year-old man, at first misdiagnosed and treated for a typical cardiogenic arrhythmia. A brief literature review is included.

Factors underlying the development of chronic temporal lobe epilepsy in autoimmune encephalitis.

PURPOSE: Limbic encephalitis (LE) is an autoimmune condition characterized by amnestic syndrome, psychiatric features and seizures. Early diagnosis and prompt treatment are crucial to avoid long-term sequelae, including psycho-cognitive deficits and persisting seizures. The aim of our study was to analyze the characteristics of 33 LE patients in order to identify possible prognostic factors associated with the development of chronic epilepsy. METHODS: This is a retrospective cohort study including adult patients diagnosed with LE in the period 2010-2017 and followed up for ≥12 months. Demographics, seizure semiology, EEG pattern, MRI features, CSF/serum findings were reviewed. RESULTS: All 33 LE patients (19 M/14F, mean age 61.2 years) presented seizures. Thirty subjects had memory deficits; 22 presented behavioural/mood disorders. Serum and/or CSF auto-antibodies were detected in 12 patients. In 31 subjects brain MRI at onset showed typical alterations involving temporal lobes. All patients received immunotherapy. At follow-up, 13/33 had developed chronic epilepsy; predisposing factors included delay in diagnosis (p = .009), low seizure frequency at onset (p = .02), absence of amnestic syndrome (p = .02) and absence/rarity of inter-ictal epileptic discharges on EEG (p = .06). CONCLUSIONS: LE with paucisymptomatic electro-clinical presentation seemed to be associated to chronic epilepsy more than LE presenting with definite and severe "limbic syndrome".

Perampanel as adjunctive therapy in highly refractory epilepsies: Real-world data from an Italian tertiary care epilepsy centre.

Perampanel (PER) is a selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, licensed as adjunctive therapy in focal epilepsy and primary generalized tonic-clonic seizures (pGTCSs). We performed a retrospective study on highly refractory adult patients taking PER, with 1-year follow-up. Retention rate represented the primary outcome of our work; seizure frequency reduction (≥50%), "switch rate" and proportion of adverse events (AEs) were evaluated as secondary endpoints. Eighty-nine subjects (47 females, age range: 19-78 years) were included. Seventy-three had focal epilepsy (FE), 9 generalized epilepsy and 7 epileptic encephalopathy. All patients were highly drug-resistant (medication failures: 5-17). Retention rate was 87.6%, 63% and 51.7% at 3, 6 and 12 months. Responders were 27/89 (30.3%), with 8/27 seizure-free. The number of previous treatment failures and the concomitant use of enzyme inducers negatively influenced clinical response, whereas no correlation was documented between PER dose and outcome. Responder proportion was more satisfying in structural FE than in FE of unknown etiology (33% versus 20%), and in secondarily GTCSs than focal seizures (54% vs 28%), whereas pGTCSs showed a lower reponse rate (25%). Mild-to-moderate AEs (mainly dizziness, gait disturbances and psychiatric effects) were reported by 40% of patients; serious psychiatric AEs usually occurred in subjects with psychiatric comorbidities. Our study confirms the tolerability and effectiveness of PER in highly drug-resistant patients with different epilepsy syndromes and aetiologies.

A novel action of lacosamide on GABAA currents sets the ground for a synergic interaction with levetiracetam in treatment of epilepsy.

Epilepsy is one of the most common chronic neurological diseases, and its pharmacological treatment holds great importance for both physicians and national authorities, especially considering the high proportion of drug-resistant patients (about 30%). Lacosamide (LCM) is an effective and well-tolerated new-generation antiepileptic drug (AED), currently licensed as add-on therapy for partial-onset seizures. However, LCM mechanism of action is still a matter of debate, although its effect on the voltage sensitive sodium channels is by far the most recognized. This study aimed to retrospectively analyze a cohort of 157 drug-resistant patients treated with LCM to describe the most common and effective therapeutic combinations and to investigate if the LCM can affect also GABAA-mediated neurotransmission as previously shown for levetiracetam (LEV). In our cohort, LEV resulted the compound most frequently associated with LCM in the responder subgroup. We therefore translated this clinical observation into the laboratory bench by taking advantage of the technique of "membrane micro-transplantation" in Xenopus oocytes and electrophysiological approaches to study human GABAA-evoked currents. In cortical brain tissues from refractory epileptic patients, we found that LCM reduces the use-dependent GABA impairment (i.e., "rundown") that it is considered one of the specific hallmarks of drug-resistant epilepsies. Notably, in line with our clinical observations, we found that the co-treatment with subthreshold concentrations of LCM and LEV, which had no effect on GABAA currents on their own, reduced GABA impairment in drug-resistant epileptic patients, and this effect was blocked by PKC inhibitors. Our findings demonstrate, for the first time, that LCM targets GABAA receptors and that it can act synergistically with LEV, improving the GABAergic function. This novel mechanism might contribute to explain the clinical efficacy of LCM-LEV combination in several refractory epileptic patients.

Switch From Originator to Equivalent Drug in the Era of Generic Antiepileptic Drugs: Study of Keppra Versus Epitiram Clinical Equivalence.

OBJECTIVES: Generic antiepileptic drugs represent a measure to maximize cost saving. Levetiracetam (LEV) is one of most commonly used and effective antiepileptic drugs. The objective of our work was to demonstrate the effectiveness and safety of overnight switch from monotherapy with Keppra (original drug) to epitiram (generic drug) at the same dose. METHODS: In our observational study, we consecutively enrolled 37 seizure-free patients with epilepsy who expressed the wish to switch to a generic drug for economic reasons. During the 6-month evaluation period, we assessed treatment efficacy, tolerability, compliance, and intersubject variability of LEV serum concentration. At each visit, clinical and neurological examination, scales, video-electroencephalogram, and blood sample analysis to evaluate LEV plasma level were performed. RESULTS: A total of 36 of 37 enrolled patients switched from Keppra to epitiram, which was administered at the same dose in monotherapy. Three of 36 patients dropped out during follow-up for adverse events. The other 33 subjects had neither seizures nor adverse events. No significant differences in electroencephalogram features and scale scores were revealed; the intersubject variability of LEV serum concentration did not differ significantly at follow-up evaluation (P = 0.53). All the patients expressed good clinical personal impression and continued to take epitiram. The switchback rate was 8 %. CONCLUSIONS: The switch from Keppra to epitiram was easy and safe in our population, and epitiram can be considered as effective and tolerable as Keppra. Only a slight, non-statistically significant variability in LEV serum concentration was documented after the switch from Keppra to epitiram. Larger epileptic populations should be studied to confirm these results.

Epileptic seizures heralding a relapse in high grade gliomas.

PURPOSE: Seizures are a common clinical symptom in high-grade gliomas (HGG). The aim of the study was to investigate the relationship between seizures and HGG relapse (HGG-R). METHODS: We retrospectively evaluated 145 patients who were surgically treated for HGG-R. By analyzing clinical characteristics in these patients (all operated and treated by the same protocol), we identified 37 patients with seizures during follow-up. This cohort was divided into four subgroups according to a) presence or absence of seizures at the time of diagnosis and b) temporal relationship between seizure occurrence and HGG-R during follow-up: subgroup A (25pts) had seizures at follow-up but not at onset, subgroup B (12pts) had seizures both at follow-up and onset, subgroup C (30pts) had seizures before MRI-documented HGG-R, and subgroup D (7pts) had seizures after MRI-documented HGG-R. RESULTS: Although the datum was not statistically significant, survival was longer in patients with seizures during follow-up than in those without seizures (59.3% vs 51.4% alive at 2 years). In 30 patients (subgroup C) seizures heralded HGG-R. In a correlation analysis for this last subgroup, the time interval between seizure and the HGG-R was significantly associated with the number of chemotherapy cycles (r=0.470; p=0.009) and follow-up duration (r=0.566; p=0.001). A linear regression model demonstrated a reciprocal association between the above factors and that it may be possible to estimate the timing of HGG-R by combining these data. CONCLUSIONS: Seizures may herald HGG-R before MRI detection of relapse, thus suggesting that seizures should always be considered a red flag during follow-up.