Back to the Future: Endophenotypes of Idiopathic Generalized Epilepsy

Abstract

Prodromal Phase of Idiopathic Generalized Epilepsy: A Register-Based Case Control Study.

Gesche J, Rubboli G, Beier CP. Neurology 2024;103(8):e209921

Background and objectives: Idiopathic generalized epilepsy (IGE) is associated with distinct behavioral traits, symptoms of frontal lobe dysfunction, and psychiatric comorbidity. Whether psychiatric symptoms are part of the IGE endophenotype or secondary to the burden of chronic disease is unknown. In this study, we aimed at describing the sequence of appearance of psychiatric and epilepsy symptoms in patients with IGE. Methods: Inclusion criteria for this cohort study were diagnosis of IGE with age at diagnosis at 10–25 years. We created 2 mutually exclusive cohorts, 1 based on ICD-10 codes in Danish registers with a first IGE diagnosis from January 1, 2005, to December 31, 2018, and a second patient cohort treated at Odense University Hospital and the Danish Epilepsy Centre in the same period. Each case was matched with 10 age-matched, sex-matched, and geography-matched normal population controls from the Danish registers. We compared social status, health care utilization, and psychiatric diagnoses between the groups in the 5 years preceding epilepsy diagnosis, at diagnosis, and at the end of the study period using the Wilcoxon rank-sum test and confirmatory logistic regression models. Results: We identified 1009 patients for the register-based cohort (55.1% female; mean age at diagnosis [SD]: 15.9 [±3.8] years) and 402 patients for the hospital-based cohort (56.2% female; mean age at diagnosis [SD]: 18.3 [±7.4] years) and matched them to 10,090 and 4020 controls, respectively. IGE cohorts and controls did not differ at birth. In the 5 years before their IGE diagnosis, register patients had an increasing number of contacts with hospitals (mean visits [SD]: cases: 8.3 [±5.6], controls: 6.6 [±4.5]) and their general practitioners (mean visits [SD]: cases: 48.7 [±26.3], controls: 45.3 [±24.5]) and received more prescriptions for psychiatric medications (prescriptions: cases: 4.2%, controls: 2.5%, p = 0.003) compared with controls. Patients had a higher rate of psychiatric comorbidity (comorbidity: cases: 26.5%, controls: 17.8%, p < 0.0001) at the end of the study than controls. Data were similar in the hospital-based cohort. Discussion: Our data suggest a prodromal phase of IGE detectable approximately 5 years before the first seizure characterized by increased health care utilization and greater use of prescription medicine for psychiatric symptoms.

Commentary

Increasing evidence points to idiopathic/genetic generalized epilepsy (IGE) as a neurodevelopmental disorder affecting cortical-subcortical prefrontal networks with seizures as one of its manifestations. Associated co-morbidities are well described including aspects of psychiatric disorders, impulsivity, and cognitive impairment with associated psychosocial consequences. ¹ We still know very little about when these traits emerge in patients with IGE and whether they are due to the seizures or anti-seizure medication, as most published literature consists of cross-sectional studies after diagnosis.

The authors came up with an intuitive study design to answer this question, utilizing Danish national registries, enabling them to look in the past at “future patients with IGE.” ² Denmark has a universal publicly funded health system and national patient registries with details on hospital and outpatient visits for several decades. The authors previously showed that a cohort of patients with IGE compared to registry controls had higher rates of psychosocial and psychiatric issues. ³

They looked backwards from the index date of diagnosis of IGE at available morbidity and social status data. Overall, four different timepoints in the lifespan of the person with IGE were examined—birth, the 5 years before diagnosis, time of diagnosis (index date), and at the end of the study period.

Two cohorts of patients with an ICD-10 diagnosis of IGE between 2005 and 2018 at ages 10–25 years were extracted—one from Danish National Registries and one from a well-defined hospital-based cohort. Age and sex matched controls at a ratio of 10:1 were obtained from the registries and were without a diagnosis of IGE or anti-seizure medication (ASM) use within 10 years. Patients were mutually excluded from either cohort. Patients with mental retardation, disorders of psychological development and prior epilepsy or use of ASM were excluded for a purer cohort of newly diagnosed IGE. Developmental issues were controlled by looking at gestational age and Apgar scores at birth which were similar between cohort and controls.

There were 1009 patients in the registry cohort and 402 patients in the hospital cohort. Both were compared with controls from the registry on measures of psychiatric morbidity and healthcare utilization. The only time the hospital cohort was directly compared with their own registry data, was at the end of the study date for validation purposes, and which were similar.

Available socio-economic and healthcare utilization measures were compared between IGE and population controls, and included measures such as employment, household income, criminal charges, abortion rates, and general practioner (GP), hospital and psychiatric visits, and psychiatric medication use.

Demographic data was similar between each cohort and their controls, and in most economic measures including employment. The rate of employment was 75% in the registry and 38% in the hospital cohort likely reflecting a more refractory epilepsy population in the tertiary center. There was no difference in rates of abortion and criminal charges between cohorts and normal controls. The authors make a statement that out of home placement was higher in IGE compared to controls, that is foster or kinship care, but absolute numbers were low 4.9% registry cohort versus 3.1% in controls—95% of patients with IGE were not in out of home placement, and in most socio-economic measures, IGE and controls were very similar.

While we want to understand the landscape of IGE, and help those patients with co-morbid difficulties, we should also recognize that patients with IGE are not so very different from any of us, and we should aim to reduce any lingering stigma. For example, the finding in this study that criminality is no different between IGE and normal controls debunks old extreme views that used to link criminality genetically with epilepsy. ⁴

The authors looked at available data on healthcare utilization and psychiatric comorbidity from registries before and up to the index diagnosis in both the registry and hospital cohort.

Results that reached statistical significance by univariate analysis included an increased number of GP visits in the registry but not hospital cohort (26.3% registry vs 24.5% controls). There was an increased number of total hospital visits in the registry cohort (5.6% registry vs 4.5% controls).

Psychiatric prescription data from the Danish National Prescription Registry included total psychiatric medication prescriptions and were divided into antipsychotics, anxiolytics, and antidepressants.

There was increased total psychiatric prescriptions in the registry but not the hospital cohort, and there was increased use of anxiolytics in both registry and hospital cohorts and antidepressants in the registry cohort.

There was no difference in psychiatric visits or at least one psychiatric diagnosis leading up to index diagnosis but there was an upward linear trend.

The authors then looked at healthcare utilization and psychiatric comorbidity at the index diagnosis and at the end of study period. There was an increased number of total GP and somatic visits, and of patients with at least one psychiatric diagnosis. There was increased total psychiatric prescriptions in both cohorts. There was no overall increase in psychiatric visits, and no difference in psychoactive substance abuse or personality disorders.

The authors also looked at the parents of the index cases and found higher rates of interactions with authorities, but it is unclear if this was due to parents or the patients with IGE. Parents had a lower affiliation with the labor force but other measures such as household income were similar.

The findings broadly match those of previous cross-sectional studies but now provide additional longitudinal knowledge of IGE co-morbidity. ⁵ Taking a glass half full approach it is important to consider that not all patients with IGE have co-morbidities, and we can counsel our patients that they can still lead successful and productive lives.

Denmark and other countries with well-established population registries are well placed at looking back into the past. Registries reflect a more real-world population than a specialist center cohort, minimizing selection bias, and readily provide large numbers of controls. However, there are lots of questions and potential confounders that cannot be answered by this study. One can only look at data measured in the registry, hence in this study was confined to data on healthcare visits, prescriptions, and civic data. The actual reason for the GP or hospital visit is not contained in the register, so it is speculative if this is epilepsy related or not, although the authors argue that a higher rate of psychiatric medication use support a neuropsychiatric reason for at least some consultations. Healthcare and education free in Denmark and >90% of patients were of Danish origin, so the data reflects well the Danish population but limits generalizability to other regions.

The Hospital cohort was well characterized by clinical phenotyping, including EEG but the registry cohort coding likely did contain some patients not fulfilling a more rigorous clinical syndrome definition of IGE. ⁶ Despite these limitations, this is the best data that we have to date. The cost and time it would take to obtain this data in a prospective format would be exorbitant and take decades. By validating the well phenotyped hospital cohort with the registry, and comparing analysis of the registry and hospital cohort, they showed that the registry cohort broadly represented the IGE population without confounding from other neurological disorders (which would otherwise be the case in a pure registry cohort with limited phenotyping).

The authors picked an arbitrary 5-year time point prior to diagnosis but perhaps endophenotypic features start even earlier and this could be explored in future studies. Most of the 5-year prodrome period was in childhood (ie 5 years before onset of the epilepsy at 10 or 15 years of age) so some societal measures are harder to ascertain in this age group ie abortion as a measure of impulsivity. The actual date of seizure onset is often before the date of diagnosis where seizures, particularly non-motor, could have already started in the “prodrome” period.

How can we use the information from this article? The study helps us understand the endophenotype of IGE, and discussing the origin of these comorbidities will help patients understand their condition. Teasing out the sequence of symptoms of a syndrome is typically by careful clinical history taking, and this should still be the preferred first line method in our individual patients. However, there may be circumstances where history is limited or unreliable due to recall bias. For validity among larger groups without bias, similarly designed studies could be insightful into evolution of clinical epilepsy syndromes over time.

Further analysis of the registries after the index diagnosis at future timepoints would also help us understand the lifetime course of IGE, without the need for a large scale prospective projects such as the Framingham Heart Study, albeit with data limited to that contained in the registry. This could control for use of behavior-modifying medications such as levetiracetam from registry prescription data – there was an increase in psychiatric morbidity between the index diagnosis and end of the study in which this cannot be separated.

Sequels to this study would be welcomed and data on IGE endophenotypes replicated in other countries with registry resources as well as combining with insights from collaborative groups, such as the Biology of Juvenile Myoclonic Epilepsy (BIOJUME) Consortium. ⁷