People with epilepsy and intellectual disability: More than a sum of two conditions.

BACKGROUND: Around 25% of people with Intellectual Disability (PwID) have comorbid epilepsy with seizures in up to two-thirds being drug-resistant. Little is known of the general characteristics and prescribing practices to this population. AIM: Describe and compare characteristics of two cohorts of PwID and epilepsy in two different countries to inform clinical practice better. METHOD: An explorative, retrospective, case-note review in a specialist ID community service in England and in an expert center for PwID and epilepsy in the Netherlands was conducted. Information on ID severity, medical/behavioral/psychiatric/neurodevelopmental/genetic comorbidities, psychotropic, and antiepileptic drugs (AEDs) for each cohort was collected. FINDINGS: The English cohort consisted of 167 people (98 males; age range 18-73 years; mild/moderate ID- 35%) and the Dutch cohort of 189 people (111 males; age range 18-85 years; mild/moderate ID - 51%). The two cohorts were comparable in their baseline characteristics. The Dutch had higher rates of physical comorbidity, but less mental or behavioral disorders and were more likely to be on anti-psychotic medication. The mean dosages between three most common AEDs prescribed were similar. The most frequently prescribed drug in both centers is valproate. Three-quarters of the Dutch were on three or more AEDs compared to a third in the English cohort. CONCLUSIONS: Structured description of the characteristics, differences, and commonalities of PwID, treatment, and services of both countries is presented. This is the first real-world study to reveal unique characteristics of managing epilepsy for a complex ID population. In particular, it highlights the considerable comorbid psychiatric burden and psychotropic prescribing.

Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability.

OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.

Mood, anxiety, and perceived quality of life in adults with epilepsy and intellectual disability.

OBJECTIVE: Depression and anxiety symptoms are common among patients with epilepsy, but are relatively under-researched in patients with both epilepsy and intellectual disability (ID). The aim was to investigate whether epilepsy and ID characteristics are associated with mood, anxiety, and quality of life. MATERIALS AND METHODS: Adult patients with epilepsy and ID who rely on tertiary epilepsy care were included (N = 189). Mood, anxiety, and quality of life were assessed by standardized questionnaires. Epilepsy and ID characteristics were retrieved from patient charts or determined by psychometric instruments. RESULTS: Elevated levels of depressive and anxiety symptoms were present in 21.7% and 12.7%, respectively. Anxiety was significantly associated with a focal epilepsy type and ID domain discrepancy (substantial difference between two domains of adaptive behavior), but was negatively related to seizure frequency and drug load of mood-stabilizing antiepileptic drugs. Depressive symptoms were not significantly related to epilepsy characteristics, but a severe ID and ID domain discrepancy was associated with more depressive symptoms. Quality of life was significantly worse in those with multiple seizure types and ID domain discrepancy. CONCLUSION: Whereas anxiety and quality of life are associated with individual epilepsy characteristics, this could not be confirmed for depressive symptoms in patients with epilepsy and ID, despite its high prevalence.

Challenging behavior in adults with epilepsy and intellectual disability: An analysis of epilepsy characteristics.

PURPOSE: The study aimed to describe the frequency and severity of self-injurious, stereotyped, and aggressive/destructive behavior in adults with both epilepsy and intellectual disability (ID) who reside at a tertiary epilepsy center and to investigate the associations between challenging behavior and epilepsy and ID characteristics. METHOD: The frequency and severity of self-injurious, (motoric) stereotyped, and aggressive/destructive behavior among 189 patients was assessed using the Behavior Problem Inventory. Comparisons were made with an adult reference population with ID, based on gender, to determine whether the behavior was clinically deviant. Epilepsy characteristics, including age at onset, epilepsy type, seizure types, seizure frequency, and use of antiepileptic drugs (AEDs), were retrieved from patient files. The level of ID was classified using the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) and an ID domain discrepancy was allocated if there was a substantial difference between two domains of adaptive behavior within a subject. RESULTS: Self-injurious behavior was present in 35% of subjects, stereotyped behavior in 60%, and aggressive/destructive behavior in 63%. The behavior exceeded clinical norms in 7%, 18%, and 12%, respectively. Aggression was the behavior evaluated most often as being problematic, despite its reported frequency being the lowest. When adjusting for level of ID and use of psychotropic medication, logistic regression analyses showed that self-injurious behavior was significantly associated with a lower number of AEDs (odds ratio (OR) = 0.4); that stereotyped behavior was significantly associated with a higher number of seizure types (OR = 1.4) and a lower number of AEDs (OR = 0.4); and that aggression was significantly associated with the presence of an ID domain discrepancy (OR = 3.1). CONCLUSION: Challenging behavior is a serious issue among adults with epilepsy and ID. Although some of the epilepsy and ID characteristics seemed to contribute independently to these types of challenging behavior, the effects of epilepsy-related characteristics are modest when compared with ID.

Evaluation of perampanel in patients with intellectual disability and epilepsy.

INTRODUCTION: Initial registration studies of perampanel (PMP), an AMPA receptor antagonist, have now been followed up by 'clinical' studies that confirmed its efficacy and safety in patients with refractory epilepsy. Publications on the use of PMP among patients with intellectual disability (ID) are still limited. This study extends our knowledge with respect to the relevance of PMP for patients with both ID and epilepsy, and furthermore specifies the behavioral side effects of PMP in this specific population. METHODS: Retrospective evaluation of medical records at 3, 6 and 12months of follow-up after the initial start of PMP. RESULTS: 62 patients were included. 21 patients (33.9%) were female. All patients had complete data of 6months follow-up and we were able to review 42 patients with a 1-year follow-up. Level of ID varied from borderline to profound, and mild ID was most common (43.5%). The mean maximum daily dosage of PMP was 5.6mg (range 1-12mg). Retention rates for PMP were 87.1% and 67.7% after three and six months. A trend indicated a longer mean retention time in patients with a more severe ID (borderline-mild-moderate ID: 205days, severe-profound ID: 275days). Seizure reduction was achieved in 53.2%. 36 patients (58.1%) experienced adverse effects, 80.6% of those within 3months. 45.2% of the patients experienced somatic adverse effects. Most common were fatigue & sleep problems, motor problems & unsteadiness, and gastrointestinal problems. Behavioral adverse effects were present in 40.3%. Most common were aggression, agitated behavior, disruptive behavior, and mood symptoms. Reasons for discontinuation of PMP were lack of efficacy in 14.8%, intolerable adverse effects in 44.4%, and a combination of both in 40.7%. Altogether, 24.2% (15/62) of the patients achieved seizure reduction without experiencing adverse effects, though none reached seizure freedom. CONCLUSIONS: The use of PMP might lead to an effective seizure reduction without adverse effects in a minority of patients with both epilepsy and ID. Pre-existing behavioral problems or polypharmacy do not predict the occurrence of additional behavioral adverse effects, implying that these patients need not be excluded from the introduction of PMP when clinically indicated. Patients should, ideally, be monitored at a multidisciplinary clinic.

A systematic review of neuropsychiatric comorbidities in patients with both epilepsy and intellectual disability.

Epilepsy is a neurological condition that is particularly common in people with intellectual disability (ID). The care for people with both epilepsy and ID is often complicated by the presence of neuropsychiatric disorders, defined as psychiatric symptoms, psychiatric disorders, and behavioral problems. The aim of this study was to investigate associations between epilepsy or epilepsy-related factors and neuropsychiatric comorbidities in patients with ID and between ID and neuropsychiatric comorbidities in patients with epilepsy. We performed a systematic review of the literature, published between January 1995 and January 2015 and retrieved from PubMed/Medline, PsycINFO, and ERIC and assessed the risk of bias using the SIGN-50 methodology. Forty-two studies were identified, fifteen of which were assessed as having a low or acceptable risk-of-bias evaluation. Neuropsychiatric comorbidities were examined in relation to epilepsy in nine studies; in relation to epilepsy-related factors, such as seizure activity, seizure type, and medication in four studies; and in relation to the presence and degree of ID in five studies. We conclude that the presence of epilepsy only was not a clear determinant of neuropsychiatric comorbidity in patients with ID, although a tendency towards negative mood symptoms was identified. Epilepsy-related factors indicating a more severe form of epilepsy were associated with neuropsychiatric comorbidity as was the presence of ID as compared to those without ID in patients with epilepsy, although this should be validated in future research. A large proportion of the studies in this area is associated with a substantial risk of bias. There is a need for high quality studies using standardized methods to enable clear conclusions to be drawn that might assist in improving the quality of care for this population.

Accuracy of WISC-III and WAIS-IV short forms in patients with neurological disorders.

The assessment of intellectual abilities is intensive, time-consuming, and might be considered burdensome for patients. We examined psychometric qualities of short forms (SFs) of the Wechsler Intelligence Scales for Children (WISC-third edition) and for adults (WAIS-fourth edition), in children (n = 986; Mage = 10.9) and adults (n = 324; Mage = 40.9) with neurological disorders. SF estimates were compared with Full Scale IQ (FSIQ), obtained by a complete administration, for the entire sample and for the subgroups FSIQ < 80 and FSIQ ≥ 80. The FSIQ was correctly identified within ± 7 points in 86% of children and 87% of adults. There were, however, some differences regarding the optimal SF subtest combination between subgroups. Although clinical inferences should not be made, SFs may be useful in research settings to obtain a global estimate of intelligence, and in clinical settings to screen periodically for possible intellectual deterioration.

De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity.

Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984 A > G (p.(N995S)))-encoding the BK channel-that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.2984 A > G (p.(N995S)) variant markedly increased the macroscopic potassium current by increasing both the channel open probability and channel open dwell time. The c.2984 A > G (p.(N995S)) variant did not affect the calcium sensitivity of the channel. We also identified three other variants of unknown significance (c.1554 G > T (p.(K518N)), c.1967A > C (p.(E656A)), and c.3476 A > G (p.(N1159S))) in three separate patients with divergent epileptic phenotypes. However, these variants did not affect the BK potassium current, and are therefore unlikely to be disease-causing. These results demonstrate that BK channel variants can cause epilepsy without paroxysmal dyskinesia. The underlying molecular mechanism can be increased activation of the BK channel by increased sensitivity to the voltage-dependent activation without affecting the sensitivity to the calcium-dependent activation. Our data suggest that the BK channel may represent a drug target for the treatment of epilepsy. Our data highlight the importance of functional electrophysiological studies of BK channel variants in distinguishing whether a genomic variant of unknown significance is a disease-causing variant or a benign variant.

Psychogenic nonepileptic seizures in adults with epilepsy and intellectual disability: A neglected area.

PURPOSE: To describe the main characteristics of psychogenic nonepileptic seizures (PNES) in adults with epilepsy and intellectual disability (ID), and to analyse the differences regarding psychosocial functioning, epilepsy severity and ID between patients with PNES and a control group without PNES. METHODS: Medical records of adults with ID and epilepsy living at an epilepsy care facility (N = 240) were screened for PNES and evaluated by a neurologist. A control group consisting of patients with epilepsy and ID, without PNES, was matched according to age, sex and level of ID. Characteristics of PNES and epilepsy were provided by the subject's nursing staff or retrieved from patient charts, psychosocial data were collected by standardised questionnaires and level of ID was individually assessed using psychometric instruments. RESULTS: The point prevalence of PNES was 7.1%. The patients with PNES (n = 15) were most often female and had a mild or moderate level of ID. Compared to controls, they showed more depressive symptoms, experienced more negative life events and had more often an ID discrepancy (ID profile with one domain particularly more impaired than another). Stress-related triggers were recognised in a large majority by the nursing staff. CONCLUSION: PNES appears to be a relatively rare diagnostic entity among inpatients with both epilepsy and ID. However, the complexity of diagnosing PNES in this population, and the similarities in stress-related triggers for PNES in patients with and without ID, suggest that PNES may be underdiagnosed in the ID population. Diagnostic challenges of PNES and, as subcategory, reinforced behavioural patterns are discussed.

Vitamin D supplementation in children with epilepsy and intellectual disability.

BACKGROUND: Children with epilepsy and intellectual disability have an increased risk of vitamin D deficiency. In this patient group, it is neither clear which factors are associated with the level of 25-hydroxyvitamin D nor what the therapeutic results are when Dutch guidelines are followed. METHODS: This retrospective study included 30 patients who, in October 2012, were residents of the children's wards of a tertiary epilepsy center in The Netherlands (Kempenhaeghe). From November 2012 onward they received cholecalciferol supplementation in doses that met or exceeded Dutch guidelines. At baseline, after 6, and 15 months, serum 25-hydroxyvitamin D concentration was measured. RESULTS: At baseline, the vitamin D status in 11 (36.7%) residents was found to be deficient, in 10 (33.3%) to be insufficient and in 9 (30.0%) sufficient. Supplementation dose, diet, body mass index, intellectual disability, and mobility were significantly associated with baseline 25-hydroxyvitamin D concentrations. The mean 25-hydroxyvitamin D concentration increased significantly from 57.40 ± 22.00 nmol/L at baseline to 89.47 ± 26.77 nmol/L after 15 months (P < 0.001). In spite of supplementation ranging from 400 to 1200 IU/day, 64% of the residents in the deficient category and 30% of those with an insufficient level at baseline failed to attain a sufficient vitamin D status after 15 months. CONCLUSIONS: Not all residents reached a sufficient vitamin D status after supplementation at least equal to the amount recommended by the Dutch guidelines. In a high-risk population, such as our residents, we advise monitoring 25-hydroxyvitamin D concentrations, adjusting supplementation accordingly and following patients to ensure they reach sufficiency.