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Cenobamate is a new antiseizure medication (ASM) recently introduced in the USA for the treatment of adults with focal-onset seizures. In March 2021, the European Commission authorized its use for the adjunctive treatment of focal-onset seizures with or without secondary generalization (focal seizures with or without progression to bilateral tonic-clonic seizures, according to current ILAE terminology) in adults with epilepsy not adequately controlled despite the treatment with at least two ASMs. This review summarizes the mechanism of action, efficacy, and safety of Cenobamate. The authors provide their expert opinions on the use of this drug. The aim of this paper is to report on the Italian preliminary experience with the use of cenobamate, focusing on treatment goals, optimal dosing and titration schedules, strategies to minimize adverse effects, and identification of suitable candidates for treatment. There was agreement that slow titration may improve tolerability, and that clinically significant benefit can be achieved in many patients at relatively low doses. A favorable response to relatively low doses of cenobamate could be an early predictor of ultimate responsiveness. Overall, cenobamate is a welcome new treatment for adults with focal seizures resistant to conventional ASMs.

BACKGROUND: During COVID-19 lockdown, non-urgent medical procedures were suspended. Grade of urgency of electroencephalography (EEG) may vary according to the clinical indication, setting, and status of infection of SARS-CoV-2 virus. "Italian Society of Clinical Neurophysiology" (SINC), "Italian League Against Epilepsy" (LICE), and the "Italian Association of Neurophysiology Technologists" (AITN) aimed to provide clinical and technical recommendation for EEG indications and recording standards in this pandemic era. METHODS: Presidents of SINC, LICE, and AITN endorsed three members per each society to formulate recommendations: classification of the degree of urgency of EEG clinical indications, management and behavior of physicians and neurophysiology technologists, hygiene and personal protection standards, and use of technical equipment. RESULTS: Scientific societies endorsed a paper conveying the recommendation for EEG execution in accordance with clinical urgency, setting (inpatients/outpatients), status of SARS-CoV-2 virus infection (positive, negative and uncertain), and phase of governmental restrictions (phase 1 and 2). Briefly, in phase 1, EEG was recommended only for those acute/subacute neurological symptoms where EEG is necessary for diagnosis, prognosis, or therapy. Outpatient examinations should be avoided in phase 1, while they should be recommended in urgent cases in phase 2 when they could prevent an emergency room access. Reduction of staff contacts must be encouraged through rescheduling job shifts. The use of disposable electrodes and dedicated EEG devices for COVID-19-positive patients are recommended. CONCLUSIONS: During the different phases of COVID-19 pandemic, the EEG should be reserved for patients really benefiting from its execution in terms of diagnosis, treatment, prognosis, and avoidance of emergency room access.

During the Covid-19 pandemic, government restrictions limited health care to urgent needs. Neurophysiology centers had to suddenly reschedule their activities, with a lack of specific recommendations about electroencephalography (EEG) execution. During the pandemic phase 1, we launched an online survey to understand the flaws and strengths of the EEG management in Italy at the time of Covid-19 pandemic. A 45-item online survey (published from April 16 to 30, 2020), endorsed by the Italian Society of Clinical Neurophysiology (SINC), the Italian League Against epilepsy (LICE), and the Italian Association of Neurophysiology technologists (AITN), collected EEG management data (EEG’s number and type, indications, personnel and patients safety, devices’ sanification) during the Covid-19 pandemic. We received responses from 206 centers. The number of EEGs performed was reduced by 76 ± 20%, and several types of specific EEG (video-EEG, ambulatory-EEG, LTM, polysomnography) were reduced at a minimum. Half of the centers performed inpatient EEGs only for urgencies. Repetitive seizures, encephalitis, and non-convulsive status epilepticus were the most common indications. Covid-19-positive patients received less EEG than negative ones (p

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r2 = .78, P

Purpose The purpose of this study was to assess the priorities of patients with epilepsy and caring physicians and the correspondence between these priorities. Methods In this multicenter cross-sectional study, patients with epilepsy attending 21 Italian epilepsy centers and their caring physicians filled anonymously questionnaires on the needs and priorities in the management of the disease. Included were questions on patients' demographics, diagnosis, treatment, and outcome of epilepsy. The concordance between patients and their physicians was assessed on various aspects of the diagnosis and care of the disease. Patients' satisfaction with communication, services, and patient–doctor relationship was also assessed. Results Included were 432 women and 355 men aged 15 to 88 years (median: 41 years). Disease duration ranged from 6 months to 75 years. A structural/metabolic etiology predominated (52.7%), followed by a (presumed) genetic etiology (33.0%). Seizure remission was present in 56.5% of cases. Comorbidities requiring chronic treatment were present in 27.5%, and comorbidities affecting self-sufficiency in 9.5%. Psychiatric comorbidity was present in 35.0%. Patients' priorities included discovery of the cause (89.1%), use of right drug (98.7%), use of a drug without chronic side effects (94.0%), and a life without restrictions (90.4%). Physicians' priorities included choice of right drug (83.5%) and use of drugs without chronic side effects (86.8%). Priorities varied with patients' age, sex, education, and occupation. Patient–doctor relationships were at least good in most cases. The information imparted was considered unsatisfactory by 21–44% of cases on seizure circumstances and complications, side effects of drugs, limitations of daily activities, and management of physiologic or pathologic conditions. Patients declared overall satisfaction, except for appointments (21.5%) and emergencies (30.8%). Conclusion Patients and physicians' priorities in the management of epilepsy overlap only in part. Patients are satisfied with their caring physicians and less satisfied with communication and management of routine and emergency problems.

BACKGROUND The Internet has become one of the most important sources of health information, accessed daily by an ever-growing number of both patients and physicians, seeking medical advice and clinical guidance. A deeper insight into the current use of the Web as source of information on epilepsy would help in clarifying the individual attitude towards this medium by Internet users. OBJECTIVE We investigated views towards the Internet in a sample of Italian healthcare specialists involved in epilepsy field, to explore factors which explained the influence of information found on the internet. METHODS This study was a self-administered survey conducted in a group of members of the Italian Chapter of the International League Against Epilepsy (ILAE) in January 2018. RESULTS 184 questionnaires were analyzed. 97.8% of responders reported to seek online information on epilepsy. The Internet was most frequently searched to obtain new information (69.9%) or to confirm a diagnostic or therapeutic decision (37.3%). The influence of consulting the Internet on clinical practice was associated with registration to social network(s) (OR: 2.94; 95%CI: 1.28-6.76; p=0.011), higher frequency of Internet use (OR: 3.66; 95%CI: 1.56-9.21; p=0.006) and higher confidence in reliability of online information (OR: 2.61; 95%CI: 1.09-6.26; p=0.031). No association was found with age, sex, years in epilepsy practice or easiness to find online information. CONCLUSIONS Internet is frequently used among healthcare professionals involved in the epilepsy to obtain information about this disease. The attitude of being influenced by the Internet for diagnostic and/or therapeutic decisions in epilepsy is independent on age and years of experience in epilepsy, and probably reflects an individual approach towards the Web.

Introduction: After the European Medicines Agency (EMA) warning on the use of valproate (VPA) in female patients, we explored the antiepileptic drug (AED) prescribing attitudes of Italian epileptologists with regard to sex and VPA use in patients with epilepsy. Material and methods: A specifically designed 30-item questionnaire was distributed at the annual multicenter meeting of the Italian League Against Epilepsy (LICE), held in Rome on January 2018. One hundred and sixty-nine physicians answered the questionnaire. Results: In females, VPA was significantly less prescribed as first-choice AED in childhood absence epilepsy (22% females vs 64% males, p < 0.001), Dravet syndrome (54% vs 71%, p = 0.01), juvenile myoclonic epilepsy (JME) (2% vs 74%, p < 0.001), and undetermined epilepsy (0% vs 32%, p < 0.001). Ninety-six percent of the respondents inform teenage girls of the detrimental effects of intrauterine exposure to VPA; 74% recommend contraceptive measures when prescribing VPA. All the respondents stated that they were aware of the recommendations on VPA in female patients, and 64% claimed to have had difficulties in implementing them. Conclusions: The main challenges were represented by women with JME, who were seizure-free on VPA and failed to respond to levetiracetam and lamotrigine, and by little girls for whom VPA was considered the best choice. According to many Italian epileptologists, the decision to withdraw VPA should be shared with the patient.

Summary Objective Although many studies have attempted to describe treatment outcomes in patients with drug‐resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug‐resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. Methods This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug‐resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). Results A seizure‐free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a “treatment failure” as compared to the judgment of the investigator (46.7% vs 62.9%, P

Wikipedia is the most commonly accessed source of health information by both healthcare professionals and the lay public worldwide. We aimed to evaluate information-seeking behavior of Internet users searching the Italian Wikipedia for articles related to epilepsy and its treatment. Using Pageviews Analysis, we assessed the total and mean monthly views of articles from the Italian Wikipedia devoted to epilepsy, epileptic syndromes, seizure type, and antiepileptic drugs (AEDs) from January 1, 2015 to October 31, 2017. We compared the views of the article on epilepsy with those of articles focusing on Alzheimer's disease, migraine, multiple sclerosis, syncope, and stroke and adjusted all results for crude disease prevalence. With the only exception of the article on multiple sclerosis, the adjusted views for the Italian Wikipedia article on epilepsy were higher than those for the other neurological disorders. The most viewed articles on seizure type were devoted to tonic–clonic seizure, typical absence seizure, tonic convulsive seizures, and clonic convulsive seizures. The most frequently accessed articles on epilepsy syndromes were about temporal lobe epilepsy and Lennox–Gastaut syndrome. The most frequently viewed articles on AEDs were devoted to valproic acid, carbamazepine, and levetiracetam. Wikipedia searches seem to mirror patients' fears and worries about epilepsy more than its actual epidemiology. The ultimate reasons for searching online remain unknown. Epileptologists and epilepsy scientific societies should make greater efforts to work jointly with Wikipedia to convey more accurate and up-to-date information about epilepsy.

Objective To evaluate the efficacy and safety of adjunctive eslicarbazepine acetate (ESL) in patients with refractory partial-onset seizures. Methods This randomized, placebo-controlled, double-blind, parallel-group, phase III study was conducted at 173 centers in 19 countries, including the United States and Canada. Eligible patients were aged ≥16 years and had uncontrolled partial-onset seizures despite treatment with 1–2 antiepileptic drugs (AEDs). After an 8-week baseline period, patients were randomized to once-daily placebo (n = 226), ESL 800 mg (n = 216), or ESL 1,200 mg (n = 211). Following a 2-week titration period, patients received ESL 800 or 1,200 mg once-daily for 12 weeks. Seizure data were captured and documented using event-entry or daily entry diaries. Results Standardized seizure frequency (SSF) during the maintenance period (primary end point) was reduced with ESL 1,200 mg (p = 0.004), and there was a trend toward improvement with ESL 800 mg (p = 0.06), compared with placebo. When data for titration and maintenance periods were combined, ESL 800 mg (p = 0.001) and 1,200 mg (p

SummaryObjective To evaluate direct medical costs and their predictors in patients with refractory epilepsy enrolled into the SOPHIE study (Study of Outcomes of PHarmacoresistance In Epilepsy) in Italy. Methods Adults and children with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers and followed for 18 months. At entry, all subjects underwent a structured interview and a medical examination, and were asked to keep records of diagnostic examinations, laboratory tests, specialist consultations, treatments, hospital admissions, and day-hospital days during follow-up. Study visits included assessments every 6 months of seizure frequency, health-related quality of life (Quality of Life in Epilepsy Inventory 31), medication-related adverse events (Adverse Event Profile) and mood state (Beck Depression Inventory-II). Cost items were priced by applying Italian tariffs. Cost estimates were adjusted to 2013 values. Results Of 1,124 enrolled individuals, 1,040 completed follow-up. Average annual cost per patient was € 4,677. The highest cost was for antiepileptic drug (AED) treatment (50%), followed by hospital admissions (29% of overall costs). AED polytherapy, seizure frequency during follow-up, grade III pharmacoresistance, medical and psychiatric comorbidities, and occurrence of status epilepticus during follow-up were identified as significant predictors of higher costs. Age between 6 and 11 years, and genetic (idiopathic) generalized epilepsies were associated with the lowest costs. Costs showed prominent variation across centers, largely due to differences in the clinical characteristics of cohorts enrolled at each center and the prescribing of second-generation AEDs. Individual outliers associated with high costs related to hospital admissions had a major influence on costs in many centers. Significance Refractory epilepsy is associated with high costs that affect individuals and society. Costs differ across centers in relation to the characteristics of patients and the extent of use of more expensive, second-generation AEDs. Epilepsy-specific costs cannot be easily differentiated from costs related to comorbidities.

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Summary Purpose: To evaluate the relative contribution of demographic and epilepsy-related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health-related quality of life (HRQOL) in adults with pharmacoresistant epilepsy. Methods: Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory-II (BDI-II). Multivariate linear regression models were used to identify variables associated with QOLIE-31 total score and subscale scores. Key Findings: Of 933 enrolled individuals aged 16 years or older, 809 (87%) were able to complete the self-assessment instruments and were included in the analysis. Overall, 61% of the variance in QOLIE-31 scores was explained by the final model. The strongest predictors of HRQOL were AEP total scores (β = −0.451, p

Summary Purpose: To evaluate the adverse effects (AEs) of antiepileptic drugs (AEDs) in adults with refractory epilepsy and their relationship with number of coprescribed AEDs and AED load. Methods: Patients with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers. AEs were assessed through unstructured interview and the Adverse Event Profile (AEP) questionnaire. AED loads were calculated as the sum of prescribed daily dose (PDD)/defined daily dose (DDD) ratios for each coprescribed AED. Results: Of 809 patients enrolled, 709 had localization-related epilepsy and 627 were on polytherapy. AED loads increased with increasing number of AEDs in the treatment regimen, from 1.2 ± 0.5 for patients on monotherapy to 2.5 ± 1, 3.7 ± 1.1, and 4.7 ± 1.1 for those on two, three, and ≥4 AEDs, respectively. The number of spontaneously reported AEs correlated with the number of AEs identified by the AEP (r = 0.27, p

Objective Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) may involve extrahippocampal areas of structural and functional damage. The incidence and the features of this damage are still a matter of debate and vary depending on the method applied. Memory guided saccades (MGSs) with a memorization delay longer than 20 s can be used reliably to evaluate the parahippocampal cortex. Methods MGSs with 3 and 30 s memorization delays were recorded with the search coil technique in six patients affected by right MTLE-HS, and in 13 healthy controls. Results The patients were not able to reduce the MGSs residual amplitude error after the first saccade with a 30 s memorization delay. This finding was more evident with leftward saccades. Conclusions MGS abnormalities suggested the functional involvement of the right parahippocampal cortex in most of the patients with MTLE-HS, and this supports the clinical and anatomopathological heterogeneity of the disease. Significance MGSs can be used in patients with right MTLE-HS to detect a possible functional involvement of the ipsilateral parahippocampal cortex.

Summary: Purpose: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steadystate during a cycle of intake of combined hormonal contraceptive (HC) steroids. Methods: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4- to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay. Results: In all women, total and unbound VPA concentrations were higher during the HC-free interval than during HC intake (means ± SD: 425 ± 184 vs. 350 ± 145 μmol/L, respectively, for total VPA, p = 0.002, and 55 ± 37 vs. 39 ± 25 μmol/L, respectively, for unbound VPA, p = 0.005). Compared with the HC-free interval, HC intake was associated with a mean 21.5% increase in VPA total apparent oral clearance (from 8.0 ± 5.2 to 9.7 ± 6.4 ml/h/kg, p = 0.01) and a 45.2 % increase in VPA unbound apparent oral clearance (from 79 ± 81 to 115 ± 121 ml/h/kg, p = 0.029). Conclusions: The apparent oral clearance of total and unbound VPA increases during the HC intake period compared with the HC-free interval, probably due to induction of glucuronosyltransferase by ethinylestradiol. The magnitude of the change varies across individuals, being potentially clinically relevant in some cases. Serum VPA concentrations should be monitored when adding or discontinuing HC steroids, and possibly during the on‐off intervals of a HC cycle. Key Words: Valproic acid—Contraceptive steroids— Pharmacokinetics—Drug interaction—Epilepsy.

Summary: Purpose: The aim of this study was to evaluate the rate and features of obstructive sleep apnea (OSA) in adult epilepsy patients. Methods: Two hundred eighty-three adult epilepsy patients (137 men; mean age, 33 years; range, 18‐70 years) were prospectively screened for OSA by means of a structured interview. Those in whom OSA was clinically suspected were monitored for a full night by using a portable device (Polymesam), and OSA was diagnosed when they had an Apnea/Hypopnea Index greater than five. Results: Coexistence of OSA with epilepsy was found in 10.2% (15.4% of the male and 5.4% of the female) epilepsy patients investigated. The OSA was mild in 66.6%, moderate in 22.2%, and severe in 11.1% of the cases. The “epilepsy + OSA” patients were older, heavier, more frequently male, and sleepier (p < 0.05) than those with “epilepsy only.” Furthermore, they experienced their first seizure at an older age (p < 0.05). Conclusions: Systematic investigation reveals that OSA is frequent in epilepsy patients. The major risk factors for OSA in our epilepsy patients were the same as those typically found in the general population. Of the epilepsy-related factors, older age at onset of seizures appears to be significantly related to comorbidity with OSA (p < 0.05). The presence in epilepsy patients of these features should alert the clinician to the possibility of an underlying OSA. Key Words: Epilepsy—Obstructive sleep apnea.

The aim of this study was twofold: 1 - to identify a psychological profile of patients with psychogenic nonepileptic seizures (PNESs) that is possibly distinct from that of subjects affected by epileptic seizures (ESs) alone; 2 - to detect the possible differences between the clinical features and psychological profile of patients affected by PNESs alone and those of subjects in whom PNESs are associated with epileptic seizures (ES/PNES patients). We assessed the psychological profiles of 2 different groups of subjects. The first group was of 38 patients who had all developed PNESs after epileptic seizures (ES\PNES, group 1). The second group was of 31 patients with PNESs alone (PNES, group 2). We compared the psychological findings of each of these 2 groups with those of 2 control groups, composed of patients who matched groups 1 and 2 for sex, age, and educational level, but who were affected only by ESs (groups 1C and 2C). Finally, we considered possible differences between the ictal symptoms and signs of PNESs occurring in ES/PNES and in PNES patients. Both the ES/PNES group and the PNES group revealed higher percentages of Somatoform Disorders and Cluster B Personality Disorders (DSM-III-R diagnoses) than the ES patients in the control groups. The scores obtained on the Psychophysiological Distress Scale of the Cognitive Behavioural Assessment Battery (CBA) followed the same pattern. Among PNES ictal phenomena, autonomic symptoms and signs were significantly more frequent in the PNES than in the ES/PNES group. The occurrence of PNESs mimicking generalised tonic-clonic ESs (GTC-PNESs) was significantly associated with a low academic level. The results of this study suggest that the patients with PNESs alone and those affected by PNESs and ESs share the same psychological profile, which is different from that of patients with ESs alone. However, some differences between ES/PNES and PNES patients were found in the clinical semiology of their PNESs. Our findings could have implications for the diagnosis and for the treatment of patients with PNESs.

To assess the extent of off-label prescribing of antiepileptic drugs (AEDs) and associated variables in a large population of patients with pharmacoresistant epilepsy. Descriptive analysis of data recorded from consecutively enrolled patients with pharmacoresistant epilepsy attending 11 tertiary referral centers in Italy. Off-label use was stratified by therapeutic indication, dose, and age. Multivariate logistic regression was used to identify variables associated with off-label prescription. Of a total of 1,124 patients enrolled between November 2006 and August 2007, 53 % (101/191) of children and 31 % (287/933) of adults were receiving at least one off-label AED prescription. Among adults, off-label use was related primarily to indication and was highest for clobazam (100 %) and ethosuximide (40 %), followed by lamotrigine (25 %), and vigabatrin (25 %). In children, clobazam (100 %), lamotrigine (79 %), vigabatrin (55 %), ethosuximide (46 %), and levetiracetam (43 %) were most frequently used off-label, with indication or age being the main causes depending on the specific AED. Logistic regression analysis indicated that higher rates of off-label use were associated with a polytherapy regimen (odds ratio [OR] 2.50, 95 % confidence interval [95 % CI], 1.55–4.03), pediatric age (2.49, 1.66–3.76), having failed ≥3 AEDs (2.16, 1.04–4.48), a diagnosis of generalized epilepsy with structural/metabolic or unknown etiology (2.97, 1.25–7.04), and increasing seizure frequency (1.07, 1.01–1.14). Off-label prescribing of AEDs is common among patients with pharmacoresistant epilepsy and is influenced by demographic and disease-related characteristics. Studies are needed to improve the quality of evidence guiding epilepsy treatment, and to evaluate the risks and benefits of off-label prescribing in epilepsy.

Objective: To identify the genetic cause of a complex syndrome characterized by autophagic vacuolar myopathy (AVM), hypertrophic cardiomyopathy, pigmentary retinal degeneration, and epilepsy. Methods: Clinical, pathologic, and genetic study. Results: Two brothers presented with visual failure, seizures, and prominent cardiac involvement, but only mild cognitive impairment and no motor deterioration after 40 years of disease duration. Muscle biopsy revealed the presence of widespread alterations suggestive of AVM with autophagic vacuoles with sarcolemmal features. Through combined homozygosity mapping and exome sequencing, we identified a novel p.Gly165Glu mutation in CLN3 . Conclusions: This study expands the clinical phenotype of CLN3 disease. Genetic testing for CLN3 should be considered in AVM with autophagic vacuoles with sarcolemmal features.

Two hundred and seventy epilepsy patients referred to the Epilepsy Centre of the C. Mondino Institute of Neurology and 230 healthy subjects comparable for age, sex and education completed a sleep questionnaire of 112 multiple choice questions including those that concern sleep hygiene practice. The percentage of subjects with habitually inappropriate sleep hygiene habits was significantly higher in controls than in epilepsy patients for 7 out of the 9 sleep hygiene practices considered (P at chi square less than 0.05). No significant relationship between kind and/or severity of epilepsy and the degree of sleep hygiene practice was found. The data show that sleep hygiene practice is more adequate in epilepsy than in control subjects. It is possible that the appropriate sleep hygiene practice of epilepsy patients derives from the fact that they habitually refrain from a lot of practices which possibly aggravate both the course of epilepsy and seizure-related complications.

Nonhyperammonemic, reversible mental deterioration with brain pseudoatrophy in epilepsy children on valproate (VPA)1-4 is rare but potentially underestimated. VPA may trigger a not-otherwise clinically expressed mitochondrial disease.5 We describe a child who developed severe but reversible behavioral and cognitive dysfunctions with brain pseudoatrophy while receiving VPA. The child carried the rare, known6 heteroplasmic C8393T-Pro→Ser mutation in the MTATP8 gene. A 4-year-old, right-handed, Caucasian boy had an isolated febrile seizure. Since starting primary school, he showed mild learning difficulty. At age 8 years 1 month, an episode of loss of consciousness was suspected to be of epileptic origin. The CT showed normal patterns. Awake EEG documented focal and diffuse interictal epileptiform abnormalities (IEAs) on normal background activity. After the VPA (18 mg/kg/day), he showed increasing irritability and learning difficulties. At age 9 years 4 months, neurologic examination was normal. Awake EEG was unmodified (figure, B [a]). Whole-night sleep EEG showed marked activation of IEAs, with continuous spike-and-wave activity lasting up to 3 minutes for about 50% of the slow wave sleep (figure, B [a′]). Gradual VPA increase up to 27 mg/kg/day (serum levels within therapeutic range) coincided with further worsening of school performance and cognitive function. Figure. (A) MRI. Axial T2- and sagittal …

Unusual late-onset complications of brain irradiation, characterized by reversible neurologic focal signs, seizures, and MRI alterations, have recently been reported and classified as stroke-like migraine attacks after radiation therapy (SMART)(1) and peri-ictal pseudoprogression (PIPG).(2.)

To evaluate the relative contribution of demographic and epilepsy-related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health-related quality of life (HRQOL) in adults with pharmacoresistant epilepsy.Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory-II (BDI-II). Multivariate linear regression models were used to identify variables associated with QOLIE-31 total score and subscale scores.Of 933 enrolled individuals aged 16 years or older, 809 (87%) were able to complete the self-assessment instruments and were included in the analysis. Overall, 61% of the variance in QOLIE-31 scores was explained by the final model. The strongest predictors of HRQOL were AEP total scores (β = -0.451, p0.001) and BDI-II scores (β = -0.398, p0.001). These factors were also the strongest predictors of scores in each of the seven QOLIE-31 subscales. Other predictors of HRQOL were age (β = -0.060, p = 0.008), lack of a driving license (β = -0.053, p = 0.018), pharmacoresistance grade, with higher HRQOL in individuals who had failed only one AED (β = 0.066, p = 0.004), and location of the enrolling center. Epilepsy-related variables (seizure frequency, occurrence of tonic-clonic seizures, age of epilepsy onset, disease duration) and number of AEDs had no significant predictive value on HRQOL. The AEP total score was the strongest negative predictor of HRQOL in the subgroup of 362 patients without depressive symptoms (BDI-II score10), but even in this subgroup the BDI-II score was retained as a significant predictor.In individuals with pharmacoresistant epilepsy, AEs of medication and depressive symptoms are far more important determinants of HRQOL than seizures themselves. When seizure freedom cannot be achieved, addressing depressive comorbidity and reducing the burden of AED toxicity is likely to be far more beneficial than interventions aimed at reducing the frequency of seizures.

Subjective and objective measures of daytime sleepiness and psychomotor function were determined in normal control subjects and in epileptic patients on chronic monotherapy with phenobarbital or valproate (n = 10 in each group). All patients had primary generalized epilepsy with a normal resting EEG and were seizure-free for at least 1 year. After nocturnal polysomnographic recording, each subject was evaluated at 2 h intervals between 10:00 and 16:00 h by using multiple sleep latency tests (MSLT), a visual analogue rating scale for alertness (VARS), an anxiety scale (STAI-X1) and a battery of psychomotor tests. Nocturnal sleep parameters before daytime assessment were comparable in the 3 groups. At MSLT, patients on phenobarbital showed a shorter mean sleep latency (9.0 +/- 1.7 min) compared with the valproate group (12.5 +/- 1.3 min) and controls (12.9 +/- 1.2 min), though within-group variability was considerable. Compared with controls, patients on phenobarbital showed longer motor movement times, impaired attention (cancellation test, CT), reduced processing speed (digit-symbol substitution, DSS) and a trend towards lower critical flicker fusion threshold. Patients on valproate showed some impairment in attention and a trend towards longer motor movement time. In patients, no correlation was found between assessed parameters and serum drug concentrations, which were 19.3 +/- 1.7 micrograms/ml for phenobarbital and 85.7 +/- 4.7 micrograms/ml for valproic acid.

Epileptic phenomena are usually not considered a possible cause of prolonged hallucinatory states such as Charles Bonnet syndrome (CBS). A 65-year-old woman with previous right hemorrhagic strokes developed complex visual hallucinations (CVHs), featuring CBS, and delayed palinopsic phenomena, along with new neurological signs and worsening of existing deficits. Video/EEG/polygraphy monitoring revealed the presence of right-sided periodic lateralized epileptiform discharges of the “plus” type (PLEDs plus) and documented a focal seizure in close relation to a delayed palinopsia episode. Adjustment of antiepileptic drug treatment led to remission of the CVHs with simultaneous disappearance of PLEDs plus and epileptic seizures and return to previous neurological status. We discuss the role of continuous (PLEDs plus) and intermittent (focal seizures) epileptic activities in this episodic form of CBS, considering current theories on the genesis of CVHs. EEG assessment is recommended if CBS develops in a patient with unexplained worsening of existing neurological signs.

Summary Purpose: Reproductive dysfunction in epilepsy is attributed to the seizures themselves and also to antiepileptic drugs (AEDs), which affect steroid production, binding, and metabolism. In turn, neuroactive steroids may influence neuronal excitability. A previous study in this cohort of consecutive women with epilepsy showed that patients with more frequent seizures had higher cortisol and lower dehydroepiandrosterone sulfate levels than those with rare or absent seizures. The present study was aimed at evaluating, in these same women, the possible relationship between some clinical parameters, seizure frequency, AED therapies, and sex hormone levels. Methods: Estradiol (E2), progesterone (Pg), sex hormone-binding globulin (SHBG), and free estrogen index (FEI) were measured during the luteal phase in 113 consecutive females, 16–47 years old, with different epilepsy syndromes on enzyme-inducing AED (EIAED) and/or non–enzyme-inducing AED (NEIAED) treatments, and in 30 age-matched healthy women. Hormonal data were correlated with clinical parameters (age, epilepsy syndrome, disease onset, and duration), seizure frequency assessed on the basis of a seizure frequency score (SFS), and AED therapies. Results: E2, Pg, and FEI were lower, whereas SHBG levels were higher in the epilepsy patients than in the controls. However, sex steroid and SHBG levels were not different between groups of patients categorized according to SFS. Therapies with EIAEDs accounted for changes in E2 levels and FEI. Conclusions: Despite globally decreased sex steroid levels in serum, actual hormone titers were not significantly correlated with SFS in consecutive epilepsy women; rather, these hormonal changes were explained by AED treatments, mainly when EIAED polytherapies were given.

Sleep paralysis (SP) is a common parasomnia. The diagnostic criteria for SP, as reported in the International Classification of Sleep Disorders, are essentially clinical, as electroencephalography (EEG)-polysomnography (PSG) is not mandatory. We describe a subject whose sleep-related events fulfilled the diagnostic criteria for SP, even though her visual hallucinations were elementary, repetitive and stereotyped, thus differing from those usually reported by patients with SP. Video/EEG-PSG documented the focal epileptic nature of the SP-like episodes.

Summary: Purpose: Hormonal changes occur in epilepsy because of seizures themselves and of antiepileptic drug (AED) effects on steroid production, binding, and metabolism. Conversely, steroids may influence neuron activity and excitability by acting as neuroactive steroids. This cross-sectional observational study aimed to evaluating cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in female epilepsy patients with different disease severity, as assessed by a seizure frequency score (SFS). Methods: Morning serum levels of cortisol and DHEAS were assayed in 113 consecutive women, aged 16 to 47 years, with varied epilepsy syndromes, receiving mono- or polytherapy with enzyme-inducing and/or noninducing antiepileptic drugs (AEDs). Hormonal data were correlated with clinical parameters (age, body mass index, epilepsy syndrome, disease onset and duration, SFS, AED therapy, and AED serum levels) and compared with those of 30 age-matched healthy women. Results: In epilepsy patients, cortisol levels and cortisol-to-DHEAS ratios (C/Dr) were significantly higher, whereas DHEAS levels were significantly lower than those in controls. Patients with more frequent seizures showed higher cortisol and C/Dr values and lower DHEAS levels than did those with rarer or absent seizures during the previous 6 months. SFS mainly explained the increase of cortisol levels and C/Dr in patients with more active disease. Changes in DHEAS levels correlated with SFS and epilepsy syndrome, as well as with AED treatments and ages. Conclusions: Women with more frequent seizures had alterations of their adrenal steroids characterized by an increase of cortisol and a decrease of DHEAS levels. Such hormonal changes might be relevant in seizure control and in patient health.

Some surveys indicate that elderly nursing home residents are extensively prescribed antiepileptic drugs (AEDs). Few studies have evaluated the prevalence of seizure-related diagnoses as a risk factor for AED administration in nursing homes. To assess the prevalence of AED use and of epileptic seizures in the elderly nursing home residents in our country, we considered age and gender data, functional status (measured by the Barthel's Index), drugs currently administered on a scheduled basis, clinical diagnoses from the patient's chart including possible history of epileptic seizures, of all subjects aged 60 years and over living in 21 federated nursing homes in the province of Pavia, Northern Italy. Data relating to 2.001 subjects (77.5 % females) were collected over a 4-month period (September-December 2000). Eighty-seven of the 2.001 residents (4.3%; 5.3% of all the males and 4.0% of all the females) were taking AEDs and 58 (3.5% of all the males and 2.7% of all the females), all of them under treatment with at least one AED, had epileptic seizures in their history. Both these subgroups had a mean modified Barthel's Index score significantly lower than that of the population as a whole. Phenobarbitone was the most frequently prescribed AED, and the penetration of newer AEDs was minimal. Subjects in early old age (60-74 years) were more likely than older subjects to take an AED. Logistic regression indicated a significant association between seizures reports, a younger age and a history of cerebrovascular events, alcohol abuse and meningiomas. The prevalence of AED use in this study was lower than that found by previous U.S. studies: nevertheless, our data confirm male gender and early old age as factors associated with AED taking in elderly nursing home residents. In our series AED users showed a lower level of autonomy. Taken together, our data suggest that an earlier institutionalization of seizure subjects could be facilitated by the clustering of various conditions, such as seizures, cerebrovascular events, other clinical disorders and a possibly inappropriate anticonvulsant treatment.

Summary: Purpose: To investigate the risk of illnesses in a cohort of patients with epilepsy and in matched nonepilepsy controls, by type and complications. Methods: A total of 951 children and adults with idiopathic, cryptogenic, or remote symptomatic epilepsy and 904 matched controls seen in secondary and tertiary centers in eight European countries (England, Estonia, Germany, Italy, the Netherlands, Portugal, Russia, Slovenia) were followed prospectively for 17,484 and 17,206 person-months and asked to report any spontaneous complaint requiring medical attention (illness), its type and complications (hospitalization, absence from work or school, medical action). Risk assessment was done by actuarial methods, relative risks (RR), and 95% confidence intervals (CIs). Results: During the study period 644 patients (68%) and 504 controls (56%) reported an illness (p < 0.0001); 30% were seizure related. The cumulative probability of illness at 12 and 24 months was 49 and 86% in the cases and 39 and 75% in the controls (p < 0.0001). The largest differences regarded disorders affecting the nervous system (NS) (RR, 3.3; 95% CI, 2.3–4.2) and ear, nose, and throat (ENT) (RR, 1.3; 95% CI, 1.0–1.6). In patients with epilepsy, an NS illness was more likely to be followed by hospital admission, work absence, or medical intervention. All risks were significantly reduced after excluding seizure-related events. Conclusions: Patients with epilepsy are at higher risk of NS and ENT illnesses and complications than the general population. However, the risk of illness is significantly reduced when seizure-related events are excluded.

The aim of this study was to evaluate the rate and features of obstructive sleep apnea (OSA) in adult epilepsy patients.Two hundred eighty-three adult epilepsy patients (137 men; mean age, 33 years; range, 18-70 years) were prospectively screened for OSA by means of a structured interview. Those in whom OSA was clinically suspected were monitored for a full night by using a portable device (Polymesam), and OSA was diagnosed when they had an Apnea/Hypopnea Index greater than five.Coexistence of OSA with epilepsy was found in 10.2% (15.4% of the male and 5.4% of the female) epilepsy patients investigated. The OSA was mild in 66.6%, moderate in 22.2%, and severe in 11.1% of the cases. The "epilepsy + OSA" patients were older, heavier, more frequently male, and sleepier (p0.05) than those with "epilepsy only." Furthermore, they experienced their first seizure at an older age (p0.05).Systematic investigation reveals that OSA is frequent in epilepsy patients. The major risk factors for OSA in our epilepsy patients were the same as those typically found in the general population. Of the epilepsy-related factors, older age at onset of seizures appears to be significantly related to comorbidity with OSA (p0.05). The presence in epilepsy patients of these features should alert the clinician to the possibility of an underlying OSA.

We describe a 43-year-old neurologically intact patient who reported episodes of diplopia and oscillopsia associated with a right-beating nystagmus and a skew deviation. These symptoms and signs were related to a left posterior epileptic EEG discharge. We suggest that these ocular motor signs derived from an ictal activation of the vestibular cortex, which in turn activated descending projections to the vestibular nuclei, leading to both a dynamic (right-bearing nystagmus) and a static (skew deviation) vestibular imbalance.

The effects of topiramate in 15 patients with drug refractory partial epilepsy or Lennox-Gastaut syndrome were assessed in an open, add-on prospective study. After a follow-up of 14–21 months, six patients are still on topiramate (mean dosage 583 mg/day, range 400–800 mg/day), and nine have discontinued treatment because of adverse events (n=6), inefficacy (n=2) or poor compliance (n=1). Nine patients (69%) continued to have a ≥50% reduction in seizure frequency during the last two months of treatment, and one has been seizure-free for the last 19 months. The most common adverse events were somnolence, weight loss, mental slowing, fatigue, ataxia and irritability. Most of these events were reversible, but withdrawal of treatment was required in six cases as a result of ataxia (two patients), somnolence, metabolic acidosis, irritability or psychotic symptoms (one patient each). It is concluded that topiramate is a valuable agent for the long-term management of refractory epilepsy.

Summary: Purpose: The present study was aimed at evaluating electrocardiographic (ECG) changes associated with partial epileptic seizures without seizure activity secondarily generalized. Methods: We assessed heart rate (HR) changes occurring during 100 partial epileptic seizures, as recorded by ambulatory EEG-ECG in 50 outpatients. Consecutive R-R intervals were measured for the 30 s immediately preceding the onset and for the first 10-s period of discharge. In addition, HR was sampled at 10-s intervals during EEG paroxysmal discharge and for 1 min after the end of discharge. Results: The highest and lowest respective HR peaks achieved during these seizures were 186 and 44 beats/min. Analysis of the R-R intervals during the first 10-s period of EEG discharge showed a significant early HR increase in 49% of the seizures; the corresponding figure for an early HR reduction was 25.5%. Eighty percent of the seizures showing an early HR decrease were of temporal lobe origin. No severe cardiac arrhythmias were noted during the seizures. Conclusions: Our data suggest that an early HR decrease is more probable in temporal lobe seizures than in seizures of other origin. An accurate HR measurement, focused on discharge onset, may provide both a reliable way of evaluating the possible effect of partial seizures on HR and valuable information about the cerebral sites involved in the control of cardiac rhythm.

Male epileptic patients frequently complain of sexual dysfunction, particularly impotence and loss of libido. Epilepsy itself, antiepileptic drugs (AEDs), and psychosocial factors are believed to contribute to impaired sexuality. We studied luteinizing hormone (LH) pulsatile secretion, gonadotropin, and prolactin (PRL) responses to LH-releasing hormone (LHRH) and thyrotropin-releasing hormone (TRH) in 37 adult male epileptic patients receiving AED monotherapy who were seizure-free and had normal EEGs. Sexuality was assessed by psychological interview. Impotence was diagnosed in 8 patients (in 2 combined with loss of sexual desire). The occurrence of hyposexuality (approximately 20%) was independent of epilepsy syndrome or AED. No change in total testosterone (T) level was observed. Free T (fT) and dihydrotestosterone (DHT) levels were lower and sex hormone binding globulin (SHBG) levels were higher in epileptic subjects than in healthy controls, but a statistically significant difference was not observed between hypo- and normosexual patients. In impotent epileptic patients, estradiol (E2) levels were significantly increased as compared with those of patients with preserved sexuality and of healthy controls. The unbalanced relation between androgen and E2 levels was emphasized by decreased T/E2, fT/E2, and DHT/E2 ratios obtained in hyposexual epileptic patients. In this group, LHRH induced blunted LH peaks. No changes were noted in LH pulsatility features. These findings of higher E2 levels and of decreased LH response to LHRH administration in some epileptic patients with impaired sexuality, may suggest they have subclinical hypogonadotropic hypogonadism.

Article abstract-Four of five members of a family complained of repeated attacks of hemiplegic migraine, migraine with aura of different types, or migraine without aura. The hemiplegia always outlasted the headache and was often accompanied by altered consciousness, aphasia, and, in one patient, coma; in this latter patient, the ictal EEG, recorded during two attacks, showed delta activity in the hemisphere contralateral to the hemiplegia. At least 2 months after their latest attacks, three patients showed dyscalculia, attentional disturbances, and impaired long-term verbal memory on neuropsychologic assessment. There were no cognitive disturbances in the unaffected relative. The severity of cognitive impairment appears to be correlated with migraine history. We attempt to classify these cases according to the criteria of the International Headache Society.NEUROLOGY 1995;45: 33-37

Sex steroid peripheral pattern, pulsatile luteinizing hormone (LH) secretion, gonadotropin and prolactin responses to LH-releasing hormone (LHRH) and thyrotropin-releasing hormone (TRH) were studied in 35 male epileptics treated with phenobarbital (PB), carbamazepine (CBZ), or phenytoin (PHT), and in age-matched healthy males. Idiopathic generalized epilepsy (IGE) was diagnosed in 12 cases and partial epilepsy (PE) in 23 cases. Patients were seizure-free and did not show EEG abnormalities at repeated controls in the last 5 years, so that interfering effects of seizures were possibly excluded. The aim of the study was to evaluate both the role of epileptic syndromes and of anti-epileptic drugs on the endocrine function. Changes in sex hormone binding globulin, total and free testosterone, dihydrotestosterone and delta 4-androstenedione were found to be independent of the epileptic syndrome type. The LH response to LHRH was lower in PB-treated PE than in IGE subjects on the same drug regimen. An impairment of LH pulsatility with respect to controls was found in PE but not in IGE patients taking PB. Among antiepileptic drugs, PHT is associated with higher sex hormone binding globulin and estradiol and lower free testosterone and dihydrotestosterone levels. PB and CBZ, but not PHT, blunt the LH response to exogenous LHRH in PE. Prolactin responses to TRH were consistently enhanced in PE subjects treated with CBZ or PHT.

The kinetics of oxcarbazepine (OXC) and its active metabolite 10-hydroxy-carbazepine (10-OH-CZ) after a single oral OXC dose (600 mg) were compared in healthy control subjects and in epileptic patients treated with phenobarbitone or sodium valproate (n = 8 in each group). In all groups, serum 10-OH-CZ concentrations were much higher than those of the parent drug. In patients on valproate, the kinetics of OXC and 10-OH-CZ did not differ significantly from those observed in controls. In patients on phenobarbitone, AUC values of both OXC and 10-OH-CZ were lower than in controls (2.9 +/- 0.4 vs 5.1 +/- 0.7 microg ml(-1) h and 89 +/- 7 vs 119 +/- 10 microg ml(-1) h respectively, means +/- s.e. mean, P < 0.05), whereas 10-OH-CZ half-lives were only marginally shorter (17 +/- 1 h vs 20 +/- 2 h, NS). These data indicate that the biotransformation of OXC and 10-OH-CZ may be accelerated by concomitant treatment with phenobarbitone but that the magnitude of this effect is unlikely to be of great clinical significance.

A multiparametric investigation of daytime sleepiness was carried out in 10 patients with a generalized epilepsy treated by phenobarbital, 10 with a cryptogenic partial epilepsy treated by carbamazepine and 10 healthy controls. After a standard ambulatory night-time polysomnography, an objective and subjective estimate of daytime sleepiness was made in each subject by means of the Multiple Sleep Latency Test (MSLT) and visual analogue rating scale (VARS), respectively. Furthermore, a parallel assessment of mood and cognitive tasks involving attention and psychomotor speed was also carried out. The data show that patients on chronic treatment with phenobarbital have a greater daytime sleep tendency and they show a worse score at the digit symbol substitution test, than patients on carbamazepine and healthy controls.

Twenty-five patients with epilepsy (mostly with partial seizures) who had responded favourably to a short-term trial of add-on vigabatrin entered maintenance treatment. After 52 to 78 months, 15 patients continue to take the drug with good therapeutic response. Median monthly seizure frequency during the last 2 months on vigabatrin in all patients, including drop-outs, was 3.5 (range 0-74) as compared with 10 (range 3-98) during an initial placebo period (p0.01). Drop-outs were caused by adverse events in 2 cases (ataxia and psychotic symptoms respectively), seizure breakthrough in 4 cases and reasons unrelated to treatment in 4 patients. In most patients, side effects were absent or mild, the most frequent complaint being weight gain. It is concluded that the antiepileptic efficacy and good clinical tolerability of vigabatrin are generally maintained during long-term treatment for up to 6 years.

A multiparametric investigation of daytime sleepiness was performed in 18 healthy young university students. After undergoing a standard polysomnographic recording at home the night before, all subjects were evaluated by Multiple sleep latency test (MSLT) at 10.00, 12.00, 14.00, 16.00, 18.00. Subjective sleepiness (by using Visual Analogue Rating Scale) and performance tasks (Cancellation Test, Digit Symbol Substitution, Choice Reaction Time, Critical Flicker Fusion Threshold) were also assessed at the same times. Mean daily sleep latency was found to be about 10 minutes, with several individual values in the borderline range (greater than 5 less than 10 minutes). Subjects did not rate themselves as excessively sleepy and there was no correlation between subjective and objective estimates of sleepiness. No consistent correlation was found between subjective-objective sleepiness and results of performance tests. Anxiety trait (Spielberg State Anxiety Trait) did not correlate with sleepiness, but higher anxiety scores were significantly associated with poor performance. These results confirm the occurrence of fairly marked objective drowsiness in healthy young subjects which, however, was not associated with subjective sleepiness and did not adversely affect performance on a variety of tests of CNS function.