Highlights • We examined the prevalence of GAD antibodies in patients with cryptogenic epilepsy. • High titres of GAD antibodies (Ab) were found in 6 of 112 (5.4%) patients. • CSF analysis showed ...intrathecal GAD Ab and oligoclonal bands in all. • Immunotherapy (steroids, plasma exchange and IVIg) did not improve seizure control.
Abstract Longitudinal studies of newly diagnosed epilepsy in children and adults have identified prognostic factors that allow early identification of patients whose seizures are likely to remain ...uncontrolled with antiepileptic medication. Results from outcome studies may be subject to bias, depending on the setting (community versus clinic), design (retrospective versus prospective) and characteristics of the patient cohort studied (age, types of epilepsy, specific comorbidities). Nevertheless, factors such as early response to medication, underlying aetiology, and number of seizures prior to initiation of treatment have consistently been found to be predictive of seizure outcomes. Other variables such as age, electroencephalographic findings and the presence or absence of psychiatric co-morbidities have been correlated with outcomes in some analyses. This review has examined studies of seizure outcomes in adults and children with newly diagnosed epilepsy identifying the risk factors that are associated with subsequent refractory epilepsy.
Predictors of pharmacoresistant epilepsy Hitiris, Nikolas; Mohanraj, Rajiv; Norrie, John ...
Epilepsy research,
07/2007, Letnik:
75, Številka:
2
Journal Article
Recenzirano
Summary Outcome data were analysed from 780 patients newly diagnosed with epilepsy and followed up at a single centre over a 20-year period to investigate which clinical factors predicted ...pharmacoresistance. Patients were divided at the time of analysis into those whose seizures had been controlled for at least the last 12 months of follow up ( n = 462) and those whose epilepsy remained refractory ( n = 318). Numbers of pre-treatment seizures were greater in uncontrolled patients. Those reporting more than 10 seizures prior to initiation of therapy were more than twice as likely to develop refractory epilepsy. Univariate and multivariate logistic regression analyses demonstrated that pharmacoresistance was also associated with family history of epilepsy, previous febrile seizures, traumatic brain injury as the cause of the epilepsy, intermittent recreational drug use, and prior or current psychiatric comorbidity, particularly depression. Factors not predicting poorer outcome included gender, neurological deficit and mental retardation. The most interesting new finding was the correlation between psychiatric comorbidity and lack of response to antiepileptic drug therapy. The deleterious neurobiological processes that underpin depression, anxiety and psychosis may interact with those producing seizures to increase the extent of brain dysfunction and thereby the likelihood of developing pharmacoresistant epilepsy.
It is well established that abnormal thalamocortical systems play an important role in the generation and maintenance of primary generalised seizures. However, it is currently unknown which thalamic ...nuclei and how nuclear‐specific thalamocortical functional connectivity are differentially impacted in patients with medically refractory and non‐refractory idiopathic generalised epilepsy (IGE). In the present study, we performed structural and resting‐state functional magnetic resonance imaging (MRI) in patients with refractory and non‐refractory IGE, segmented the thalamus into constituent nuclear regions using a probabilistic MRI segmentation method and determined thalamocortical functional connectivity using seed‐to‐voxel connectivity analyses. We report significant volume reduction of the left and right anterior thalamic nuclei only in patients with refractory IGE. Compared to healthy controls, patients with refractory and non‐refractory IGE had significant alterations of functional connectivity between the centromedian nucleus and cortex, but only patients with refractory IGE had altered cortical connectivity with the ventral lateral nuclear group. Patients with refractory IGE had significantly increased functional connectivity between the left and right ventral lateral posterior nuclei and cortical regions compared to patients with non‐refractory IGE. Cortical effects were predominantly located in the frontal lobe. Atrophy of the anterior thalamic nuclei and resting‐state functional hyperconnectivity between ventral lateral nuclei and cerebral cortex may be imaging markers of pharmacoresistance in patients with IGE. These structural and functional abnormalities fit well with the known importance of thalamocortical systems in the generation and maintenance of primary generalised seizures, and the increasing recognition of the importance of limbic pathways in IGE.
We report that patients with idiopathic generalised epilepsy have different patterns of thalamic structural and functional connectivity alterations depending on whether they are refractory or not to anti‐seizure medication. Only refractory patients showed evidence of atrophy of the anterior (limbic) thalamic nuclei and increased functional connectivity between the ventral lateral posterior nuclei and cortex bilaterally.
•PERMIT is the largest pooled analysis of perampanel (PER) clinical practice data•A post-hoc analysis was done of 156 patients from PERMIT with myoclonic seizures•12-month responder and seizure ...freedom rates were 89.5% and 68.8%, respectively•Adverse events occurred in 46.8% of patients and led to discontinuation of 14.0%•These real-world findings support the use of PER for myoclonic seizures
Purpose: To investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study.
Methods: PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs.
Results: 156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency interquartile range, 1.7 1.0–10.0; mean standard deviation prior antiseizure medications, 2.9 2.6). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months.
Conclusion: PER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice.
Genetic factors contribute to the aetiology of epilepsy in >50% of cases, and information on the use of antiseizure medications in people with specific aetiologies will help guide treatment ...decisions. The PERMIT Extension study pooled data from two real-world studies (PERMIT and PROVE) to investigate the effectiveness and safety/tolerability of perampanel (PER) when used to treat people with focal and generalised epilepsy in everyday clinical practice. This post-hoc analysis of PERMIT Extension explored the use of PER when used to treat individuals presumed to have epilepsy with a genetic aetiology. Assessments included retention rate (evaluated at 3, 6 and 12 months), effectiveness (responder and seizure freedom rates; evaluated at 3, 6, 12 months and the last visit last observation carried forward) and tolerability (adverse events AEs). Of the 6822 people with epilepsy included in PERMIT Extension, 1012 were presumed to have a genetic aetiology. The most common genetic aetiologies were idiopathic generalised epilepsy (IGE; 58.2%), tuberous sclerosis (1.1%), Dravet syndrome (0.8%) and genetic epilepsy with febrile seizures plus (GEFS+; 0.5%). Retention rates at 3, 6 and 12 months in the total genetic aetiology population were 89.3%, 79.7% and 65.9%, respectively. In the total genetic aetiology population, responder rates at 12 months and the last visit were 74.8% and 68.3%, respectively, and corresponding seizure freedom rates were 48.9% and 46.5%, respectively. For the specific aetiology subgroups, responder rates at 12 months and the last visit were, respectively: 90.4% and 84.4% (IGE), 100% and 57.1% (tuberous sclerosis), 100% and 71.4% (Dravet syndrome), and 33.3% and 20.0% (GEFS+). Corresponding seizure freedom rates were, respectively: 73.1% and 64.6% (IGE), 33.3% and 22.2% (tuberous sclerosis), 20.0% and 28.6% (Dravet syndrome), and 0% and 0% (GEFS+). The incidence of AEs was 46.5% for the total genetic aetiology population, 48.8% for IGE, 27.3% for tuberous sclerosis, 62.5% for Dravet syndrome, and 20% for GEFS+. Tolerability findings were consistent with PER’s known safety profile. PER was effective and generally well tolerated when used in individuals with a presumed genetic epilepsy aetiology in clinical practice. PER was effective across a wide range of genetic aetiologies.
•Perampanel was evaluated in people with epilepsy with different genetic aetiologies.•At 12 months, 75% of participants responded to treatment and 49% were seizure free.•Perampanel was effective across a wide range of genetic aetiologies.•Perampanel was generally well tolerated with no new or unexpected adverse events.
•22 % people with intellectual disability (PwID) have epilepsy, 70 % pharmaco-resistant.•Brivaracetam (BRV) was licenced in 2016 for pharmaco-resistant seizures.•This study compares effectiveness & ...side-effects of BRV in PwID to those without ID.•This is the 1st study on BRV comparing ID cohorts with differing severity & non-ID.•Efficacy, tolerability & side-effects are similar across ID severity & non-ID groups.
In England, nearly a quarter of people with intellectual disability (PwID) have epilepsy. Though 70 % of PwID have pharmaco-resistant seizures only 10 % are prescribed anti-seizure medication (ASMs) licenced for pharmaco-resistance. Brivaracetam (BRV) licenced in 2016 has had nine post-marketing studies involving PwID. These studies are limited either by lack of controls or not looking at outcomes based on differing levels of ID severity. This study looks at evidence comparing effectiveness and side-effects in PwID to those without ID prescribed Brivaracetam (BRV).
Pooled case note data for patients prescribed BRV (2016–2022) at 12 UK NHS Trusts were analysed. Demographics, starting and maximum dose, side-effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher’s exact and logistic regression methods were employed.
37 PwID (mild 17 M/P 20) were compared to 102 without ID. Mean start and maximum dose was lower for PwID than non-ID. Mean maximum dose reduced slightly with ID severity. No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in BRV’s efficacy i.e. >50 % seizure reduction or tolerability. Mental and behavioural side-effects were more prevalent for PwID (27.0 % ID, 17.6 % no ID) but not significantly higher (P = 0.441) or associated with ID severity (p = 0.255).
This is the first study on BRV, which compares ID cohorts with differing severity and non-ID. Efficacy, tolerability and side-effects reported are similar across differing ID severity to those with no ID.
Abstract Cryptogenic new onset refractory status epilepticus (NORSE) syndrome has been described in both adults and children, and is often associated with poor outcome. A variety of terms have been ...used in the literature to refer to this syndrome. The condition may be triggered by as yet unidentified infections or an immunological mechanism. We present a series of 5 patients with NORSE syndrome treated at 2 neuroscience centres in the North of England, in whom early use of immunotherapy appears to be associated with good neurological outcomes. Methods Case note review of the index case and four other patients was undertaken to obtain details of clinical presentation, imaging and CSF findings, infectious/inflammatory tests, management of seizures, immunotherapy and outcome. Results Case 1 was a 26 year old male with a prodrome of headache and vomiting. He developed refractory multifocal and generalised seizures, which required admission to intensive care unit and administration of general anaesthetic. Seizures recurred on withdrawal of barbiturate anaesthetic until day 29. MR imaging, CSF examination and serological tests for viral and autoimmune aetiologies were normal apart from positive anti-TPO antibodies: the patient had previously treated hyperthyroidism. He was initially treated with aciclovir and antibacterials. IV steroids were administered day 12 and IV immunoglobulin day 18. He made a good recovery being discharged home 2 months after admission. Seizures recurred on withdrawal of steroid therapy, and required longer term immunosuppressant treatment with azathioprine. Clinical features and investigations of the four other patients were similar. Two were given early immunotherapy with steroids and intravenous immunoglobulins and survived with few deficits. One patient who was not given immunotherapy died from complications associated with prolonged ICU stay. Outcome was not known for the fourth patient as she was repatriated to her home country in thiopentone coma. Conclusion In our experience, early immunotherapy has been associated with good outcomes in NORSE. Multicentre collaboration is required to establish the diagnostic criteria and appropriate management of patients presenting with NORSE.
•Levetiracetam (LEV) is a 1st line anti-seizure medication (ASM) in the UK.•There is no high-quality evidence comparing PwID to those without ID prescribed LEV.•Concerns exist regarding LEV's ...behavioural & psychological side-effects in PwID.•This is the largest study of PwID trialled on LEV & compared to non-ID controls.•Findings largely support prescribing of LEV for PwID as a first line ASM.
People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM) to PwID is driven by trials excluding them. Levetiracetam (LEV) is a first-line ASM in the UK. Concerns exist regarding LEV's behavioural and psychological adverse effects, particularly in PwID. There is no high-quality evidence comparing effectiveness and adverse effects in PwID to those without, prescribed LEV.
Pooled casenote data for patients prescribed LEV (2000–2020) at 18 UK NHS Trusts were analysed. Demographics, starting and maximum dose, adverse effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed.
173 PwID (mild 53 M/P 120) were compared to 200 without ID. Mean start and maximum dose were similar across all groups. PwID (Mild & M/P) were less likely to withdraw from treatment (P = 0.036). No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in LEV's efficacy i.e. >50 % seizure reduction. Significant association emerged between ID severity and psychiatric adverse effects (P = 0.035). More irritability (14.2 %) and aggression (10.8 %) were reported in M/P PwID.
PwID and epilepsy have high rates of premature mortality, comorbidities, treatment resistance and polypharmacy but remain poorly researched for ASM use. This is the largest studied cohort of PwID trialled on LEV compared to general population controls. Findings support prescribing of LEV for PwID as a first-line ASM.
Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to ...neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function.
PDF
