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Despite the many therapeutic options for epilepsy available today, a third of patients still have poorly controlled epilepsy. Over the years, their transition through lines of treatment exposes them to increased risk of disease progression, mortality, morbidity, mental distress, and not least significantly impaired quality of life (QoL). The present review explores the multiple factors contributing to the impairment of health-related QoL in PWE-including both seizure-related and non seizure-related. The analysis aims to identify potential areas of intervention and strategies for a more holistic approach to epilepsy care and inform policy-makers and healthcare providers in their approach to this condition., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EBM has received consulting fees/and or honoraria from UCB, Angelini, GW Pharma. BS has received speaker honoraria or consultancy fees from Angelini Pharma, Desitin, Eisai, Precisis, Sanofi, and UCB-Pharma.RK has received speaker fee/honoraria from Angelini Pharma, Eisai, Finnish IBE chapter, Omamedical, GW Pharmaceuticals, Marinus, Orion, Sandoz, Takeda, UCB Pharma; consulting fees from Orion; grants from Angelini Pharma. She covers the role of Neurocenter Finland, EAN Epilepsy Scientific Panel management Group, EpiCARE ERN executive group.PK has served as a consultant, advisory board member or speaker for Abbott, Angelini, Aquestive, Arvelle Therapeutics, Aucta Pharmaceuticals, Dr. Reddy’s, Eisai, Neurelis, Neurona, Paladin, SK Life Science, Sunovion, UCB Pharma, UNEEG, UniQure, is a member of the Medical Advisory Board of Stratus and of the Scientific Advisory Board of OB Pharma, is the CEO of PrevEp, Inc, and has received research support from CURE/Department of Defense and from the NIH/SBIR. TR has received unrestricted grants from Angelini and UNEEG, consulting fees from Angelini, Bial, Biocodex, Eisai, Jazz/GW Pharma, Neuraxpharm, Sanofi, Takeda, UCB Pharma, Zogenix, payment and honoraria from Angelini, Bial, Eisai, Jazz/GW Pharma, UCB Pharma, UNEEG, Zogenix., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Status epilepticus (SE) is a neurological emergency characterized by high rates of short-term and long-term morbidity and mortality. Status epilepticus seems to be a marker of the severity of other underlying conditions rather than a determinant of death on its own. Careful diagnosis and acute treatment of complications and causes of death to SE or its underlying etiology will enable the differentiation of SE patients that would benefit from different levels of treatment intensity. All SE patients should be treated actively with first- and second-line drugs as early as possible. For cases in which seizures continue after second-line treatment, the current guidelines fail to offer possibilities other than the active path with general anesthesia and intensive care unit (ICU) care. However, the intensity of care should be evaluated before starting ICU care or in unclear cases with the time-limited trial at ICU. There are now multiple possibilities for specialty palliative SE care that include sequential and add-on use of second-line drugs and palliative sedation at the ward. If ICU care is prolonged, the patient's status needs to be constantly re-evaluated and communicated to the family. When patients exhibit multiple predictors of mortality and poor functional outcomes, they should be allowed to have a natural death in a peaceful environment without unnecessarily prolonged suffering. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.K. Declarations of interest: has received grants from the Academy of Finland, Saastamoinen Foundation, and Vaajasalo Foundation, speaker’s honoraria from Eisai, Omamedical, Orion, Sandoz, Sanofi, and UCB, and honoraria for membership of the advisory boards/consultation from Angelini Pharma, Eisai, Marinus Pharmaceuticals, Orion, and UCB.Z.A. Declarations of interest: has received consulting honoraria from the U.S. Department of State, the UN’s International Organization for Migration, The Association for Medical Education in Europe, ReInnovate Group, Orbital Learning Canada. A-M.K. Declarations of interest: nothing to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this neuropsychological study of a large cohort of patients with progressive myoclonus epilepsy type 1 (Unverricht-Lundborg disease, EPM1) was to characterize the cognitive function of EPM1 patients and to explore the association between the disability caused by the disease and cognitive performance., Method: Sixty-eight genetically verified EPM1 patients homozygous for the expansion mutation in the CSTB gene (37 males and 31 females aged 35 ± 11) participated in a neuropsychological assessment of intellectual ability, verbal memory, and executive and psychomotor function. The clinical evaluation comprised administering (and video-recording) the unified myoclonus rating scale (UMRS) to assess the severity of each patient's myoclonus. Forty-six healthy volunteers (19 males and 27 females aged 32 ± 11) served as the control group for the neuropsychological tests., Results: The cognitive performance of the EPM1 patient group was impaired. Verbal Intelligence Quotient (VIQ) was below the average range (VIQ < 85) in 49% of the patients; further, Performance Intelligence Quotient (PIQ) was below average in 75% of the patients. The patients performed worse than the controls in both immediate and delayed story recall (p = 0.001); however, in the word list learning task, the patients performed only slightly worse than the controls. The one-hour delayed recall of the learned words was similar in both groups, and the percentage of retained words and story contents did not differ between the patients and controls. The patients were impaired in all of the executive function tests as well as in the psychomotor speed tests (p < 0.001 for all). Also, the patients' simple psychomotor speed in the tapping task was significantly slowed in comparison to controls (p < 0.001)., Conclusion: The patients had impaired performance in the majority of the cognitive measures; they showed the highest level of impairment in all the executive function tests and in the psychomotor speed tests. The measures of these cognitive domains are timed-therefore, it is clear that severe myoclonus limits patients' performance. In contrast, verbal memory, especially delayed recall, was the least affected cognitive domain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Juvenile myoclonic epilepsy (JME) is a common genetic generalized epilepsy syndrome. Adult patients with JME have shown a neuropsychological profile suggestive of subtle frontal dysfunction, but studies of cognitive functioning in the early phases of JME are rare. We analyzed the cognitive performance data of 18 patients who had undergone a neuropsychological assessment either at the time of JME diagnosis and before the initiation of an antiepileptic drug (AED) treatment (11 patients) or during the first 6 years after JME diagnosis (seven patients)., Methods: The cognitive performance of the18 patients with JME (mean age: 18.1, range: 15-33 years) and 18 healthy controls (mean age: 18.7, range: 15-25 years) was compared in a retrospective study. The assessed cognitive domains were visuomotor speed, attention, executive function, and verbal memory., Results: The patients with JME and the healthy controls did not differ in any of the assessed cognitive domains. The clinical variables did not correlate to cognitive performance. Furthermore, cognitive performance did not differ between the patients evaluated at the time of diagnosis and before the initiation of AEDs and the patients evaluated during the first 6 years after diagnosis and with an AED treatment., Conclusions: The cognitive performance of patients with new-onset JME was similar to healthy controls. We could not detect the frontal dysfunction that has been suggested to be associated with JME. Patients were in adolescence or early adulthood with a short duration of epilepsy, which may have contributed to the discovery of no cognitive impairments., Competing Interests: Declaration of competing interest R. Kälviäinen has received grants from the Academy of Finland and Saastamoinen Foundation, speaker's honoraria from Eisai, UCB, and Orion and honoraria for membership of the advisory boards of Eisai, Fennomedical, GW Pharmaceuticals, Sage Therapeutics, Takeda, and UCB. M. Raatikainen, L. Jutila and M. Äikiä have no potential conflicts of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to determine the incidence in Eastern Finland of the different stages of status epilepticus (SE): 1) at the early stage of SE (a prolonged seizure lasting over 5 min);, 2) refractory SE (RSE), and 3) super-refractory SE (SRSE)., Methods: Firstly, we conducted a retrospective study on the incidence and outcome of intensive care unit (ICU)-treated RSE and SRSE in the adult population (≥16 years) in Kuopio University Hospital (KUH)'s special care responsibility area (840,000 inhabitants). Secondly, we conducted a prospective study using the International League Against Epilepsy (ILAE)'s new definition for SE (prolonged seizures lasting over 5 min), in adult (≥16 years) patients in the KUH municipality district (North Savo, 248,000 inhabitants)., Results: The retrospective study on ICU-treated RSE and SRSE from 2010 to 2012 identified 75 patients with RSE, of whom 21% were treated as SRSE, resulting in an annual age-adjusted incidence of ICU-treated RSE of 3.0/100,000 (95% confidence interval [CI]: 2.4-3.8) and 0.6/100,000 (95% CI: 0.4-1.0) for SRSE. In the prospective study of early stage SE (seizures lasting over 5 min), we identified 151 consecutive episodes during the 9-month study period in 2015, corresponding to an annual age-adjusted incidence of 81.1/100,000 (95% CI: 75.8-87.0). In this study, 11 seizure episodes became refractory, resulting in an age-adjusted incidence of RSE of 6.0/100,000 (95% CI: 3.4-10.4), of which seven were treated in the ICU [3.8/100,000 (95% CI: 1.8-7.8)], four were treated palliatively [2.2/100,000 (95% CI: 0.82-5.7)], and two evolved to SRSE [1.1/100,000 (95% CI: 0.3-4.3)]., Conclusions: The new ILAE 2015 definition of SE resulted in a four-fold increase in incidence of SE compared to the earlier 30-min definition reported earlier in Europe. In the epidemiology of RSE, the incidence of ICU-treated RSE, palliatively treated RSE, and SRSE needs to be separated. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Prolonged seizures and status epilepticus (SE) are relevant problems in palliative care. Timely recognition and effective early treatment with first- and second-line antiepileptic drugs (AEDs) may prevent unnecessary hospitalizations. Seizures should be recognized and addressed like any other symptom that causes discomfort or reduces quality of life. Use of alternative AED administration routes (buccal, intranasal, or subcutaneous) may offer possibilities for effective and individualized AED therapy, even during the last days of life. In hospice or home care, however, also intravenous treatment is possible via vascular access devices for long-term use. Aggressive unlimited intensive care unit (ICU) treatment of refractory SE in palliative patients is mostly not indicated. At worst, intensive care can be futile and possibly harmful: death in the ICU is often preceded by long and aggressive treatments. Metastatic cancer, old age, high severity of acute illness, overall frailty, poor functional status before hospital admission, and the presence of severe comorbidities all increase the probability of poor outcome of intensive care. When several of these factors are present, consideration of withholding intensive care may be in the patient's best interests. Anticipated outcomes influence patients' preferences. A majority of patients with a limited life expectancy because of an incurable disease would not want aggressive treatment, if the anticipated outcome was survival but with severe functional impairment. Doctors' perceptions about their patients' wishes are often incorrect, and therefore, advance care planning including seizure management should be done early in the course of the disease. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures"., (Copyright © 2019. Published by Elsevier Inc.)

Background: A generalized tonic-clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper., Methods: Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs)., Results: (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs., Conclusion: Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy., Method: From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed., Results: Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs., Conclusions: Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic interactions with other drugs, especially if exposed to carbamazepine, but these interactions can be controlled via rational drug choices and with prediction of the possible drug-to-drug interactions. Patients on dihydropyridine calcium-channel blockers, statins, warfarin, and risperidone face the highest risk of interactions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24h or more after the onset of anesthetic therapy. We defined the incidence and outcome of SRSE in adults in Finland., Methods: We analyzed retrospectively the Finnish Intensive Care Consortium database in order to identify adult patients with SRSE treated in ICUs in Finland during a three-year period (2010-2012). The database consists of admissions to all 20 Finnish hospitals treating refractory SE (RSE) with general anesthesia in the intensive care unit (ICU). We included consecutive adult (16 years or older) patients with RSE and identified those who had SRSE. Patients with postanoxic etiologies were excluded., Results: All five university hospitals and 10/15 of the central hospitals participated. The adult referral population of the study hospitals is 3.9 million, representing 91% of the total adult population of Finland. We identified 395 patients with ICU-treated RSE, 87 (22%) of whom were classified as having SRSE. This corresponds to an annual incidence of SRSE of 0.7/100,000 (95% confidence interval [CI]: 0.6-0.9). The one-year mortality rates were 36% (95% CI: 26-46%) for patients with SRSE and 22% (95% CI: 17-27%) for patients with RSE. Mortality was highest (63%) in patients with SRSE aged over 75 years., Conclusions: Approximately 20% of patients with RSE treated in Finnish ICUs progressed to having SRSE. The incidence of SRSE, 0.7/100,000, is about 5-10% of the incidence of SE. The mortality of patients with SRSE, 36%, was comparable to earlier studies and twofold higher than the mortality of patients with RSE. This article is part of a Special Issue entitled "Status Epilepticus"., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Most seizure emergencies occur outside of the hospital, and there is a need for treatment interventions that can be administered quickly and safely by nonclinical caregivers. Intranasal benzodiazepine administration does not require intravenous access and offers rapid seizure cessation. Intranasal midazolam is faster at aborting seizure activity than rectal diazepam and quicker to administer than intravenous diazepam. Although time to seizure cessation varies from study to study, intranasal midazolam is efficacious when administered not only by emergency department personnel but also by paramedics and caregivers in out-of-hospital and home settings. Absorption of midazolam intranasal formulations appears to be relatively rapid compared to diazepam formulations. Its shorter elimination half-life may also be beneficial in that patients may more quickly return to normal function because of rapid offset of effect. On the other hand, the faster rate of elimination of midazolam may expose patients to a higher rate of seizure recurrence compared with diazepam. Two diazepam formulations and one midazolam formulation are being currently developed for intranasal use. This article is part of a Special Issue entitled "Status Epilepticus"., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Acute EEG is vastly underutilized in acute neurological settings. The most common reason for this is simply the fact that acute EEG is not available when needed or getting EEG is delayed as it requires trained technicians and equipment to be properly recorded. We have recently described a handy disposable forehead EEG electrode set that is suitable for acute emergency EEG recordings. The specific objective in this study was to assess the forehead electrode's utility when the clinical demand was to exclude SE., Patients and Methods: One hundred consecutive acute neurological patients (53 women, 47 men, age: 18-90 years) with unexplained altered mental state were studied with acute emergency EEG to rule out SE. Electroencephalographic recordings were obtained simultaneously with forehead EEG electrode and routine 10-20 system full-head scalp electrodes to clarify the clinical usefulness of forehead EEG electrode in this setting. Electroencephalographic recordings were interpreted blindly by three experienced clinical neurophysiologists first only based on forehead EEG and then by full-head EEG., Results: Ninety-six out of the 100 patients did not show EEG evidence of SE. There was 100% agreement with forehead and routine EEG. Four out of the 100 patients showed EEG evidence of SE in routine EEG, with 50% agreement between different electrode types. The forehead EEG missed two cases because the EEG findings supporting SE were restricted to the posterior parts of the brain., Major Conclusions: With a forehead EEG set, the sensitivity of detecting NCSE was 50%. There were no false positive cases yielding a specificity of 100%. Patients with AMS can benefit from forehead EEG recording in prehospital, hospital, and ICU settings. Since EEG recording can be started within a few minutes with the forehead EEG set, it will significantly reduce the delay in treatment of SE. This article is part of a Special Issue entitled "Status Epilepticus"., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To ensure the development of new effective treatments in medicine, clinical trials (CTs) need to be conducted. The study was aimed at assessing knowledge of and attitudes toward clinical drug trials among patients with epilepsy, along with factors that motivate them to participate in CTs. Use of this information could improve recruitment for future trials and enhance their quality., Methods: A 45-item questionnaire on the views of patients with epilepsy about CTs was developed. It included statements that the respondents assessed on a Likert scale from 1 ('strongly disagree') to 5 ('strongly agree'). The questionnaire was mailed to a random sample (n=1875) of members of the Finnish Epilepsy Association aged at least 18 years. In all, 342 questionnaires were returned, and 325 were accepted after exclusion., Results: The analysis indicates that the general attitudes of patients with epilepsy toward CTs are positive. Most of the patients with epilepsy saw participation in clinical trials as indispensable to new treatments becoming available. Retired respondents and persons who had developed epilepsy when young had inadequate knowledge of general issues related to CTs. Level of education and number of antiepileptic medications (AEDs) were significant predictors for failure to understand the nature and purpose of clinical research - i.e., for therapeutic misconception (TM). Additionally, strong correlation was found between TM and respondents' willingness to participate in clinical trials., Conclusions: The new treatments are often studied in patients with a high risk of TM and impaired comprehension of general procedures associated with CTs. Clinically, it may be worthwhile for the investigators to be able to recognize vulnerable individuals and pay special attention to the information provided on the purposes and methods of the trial, to contribute to high-quality AED studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Children exposed to valproate monotherapy in utero were evaluated with respect to neurological functioning, behavior, and additional educational needs, and the results were compared with those for age- and gender-matched controls exposed to carbamazepine and children with no prenatal exposure to antiepileptic drugs. We identified from the community-based pregnancy registry of Kuopio University Hospital area (1989-2000) all first-born and school-aged children exposed to valproate (N=13). Neurological and neuropsychological assessments were made clinically, and behavioral problems were assessed with the Conners' Teacher Rating Scale (CTRS). Eight children (62%) exposed to valproate and two (15%) each in the carbamazepine-exposed and nonexposed groups (P=0.022) required educational support. Minor dysmorphic features were noted in eight children (62%) exposed to valproate and in three children (23%) each in the carbamazepine-exposed and nonexposed groups. On CTRS, children exposed to valproate received higher scores, indicating behavioral problems. In our small but population-based study, all children exposed to valproate had minor, and some of them major, cognitive or neurological problems. This difference is clearly observed when assessing each child individually, but the many confounding factors explaining at least part of this difference are difficult to control and avoid in clinical practice. Larger studies with a prospective design are needed to confirm these findings.

The long-term effects of tiagabine monotherapy on cognition and mood were evaluated in adult patients with chronic partial epilepsy in a 48-week, open-label extension period that followed an 8-week, double-blind, titration study. Cognitive function was evaluated using neuropsychological evaluations that measured learning and memory, general intellectual ability, attention and mental speed, and reaction speed. Mood was assessed using a Finnish modification of the Profile of Mood States. Of the 34 patients who entered the open-label extension period, 18 successfully continued long-term monotherapy and underwent neuropsychological evaluation at 48 weeks of tiagabine monotherapy. The mean daily dose of tiagabine monotherapy at the end of open-label treatment was 19.7 mg/day (range, 5-35 mg/day). Tiagabine monotherapy did not adversely affect cognitive function. No significant changes in mood were observed. The median number of seizures was 2 (range, 0-71), and 8 patients (44%) were seizure-free during the 48 weeks of open-label tiagabine treatment. The results of this small open-label extension study indicate that patients with chronic partial epilepsy who were successfully converted to long-term tiagabine monotherapy demonstrated no adverse effects on cognitive function or mood.

The objective of this study was to evaluate verbal memory in newly diagnosed and chronic left temporal lobe epilepsy (LTLE). Verbal memory performance of 39 newly diagnosed, previously untreated adult patients with LTLE and 16 patients with chronic LTLE, as well as 46 healthy controls, was analyzed. The patients with newly diagnosed and chronic LTLE had impaired verbal memory performance compared with normal controls. Memory performance was more affected in chronic LTLE. However, preliminary data from 5-year follow-up of 20 newly diagnosed LTLE patients did not show any deterioration in verbal memory performance. The memory impairment was not associated with the etiology of epilepsy or the hippocampal volumes, but was associated with early onset of epilepsy in LTLE and with secondarily generalized seizure type in newly diagnosed LTLE. The results of this study show that verbal memory is impaired not only in chronic LTLE but also in newly diagnosed, untreated LTLE. This suggests that the memory problems observed in patients with chronic LTLE cannot be attributed solely to medication effects or the chronic effects of recurrent seizures.