YEBEH-107266; No of Pages 4

Epilepsy & Behavior 111 (2020) 107266

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Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Brief Communication

Diagnostic gap in genetic epilepsies: A matter of age

Angel Aledo-Serrano a,⁎, Irene García-Morales a,b, Rafael Toledano a,c, Adolfo Jiménez-Huete a, Beatriz Parejo b,
Carla Anciones a, Ana Mingorance d, Primitivo Ramos e, Antonio Gil-Nagel a
a
Epilepsy Unit, Neurology Department, Hospital Ruber Internacional, Madrid, Spain
b
Epilepsy Unit, Neurology Department, Hospital Clínico San Carlos, Madrid, Spain
c
Epilepsy Unit, Neurology Department, Hospital Ramón y Cajal, Madrid, Spain
d
LouLou Foundation, London, United Kingdom
e
Social Assistance Agency, Government of Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Objective: This study aimed to evaluate the access to advanced diagnostic tests in patients with epilepsy and in-
Received 26 February 2020 tellectual disability, with special focus on genetics.
Revised 15 April 2020 Methods: Patients with epilepsy and intellectual disability evaluated between 2016 and 2018 at the Epilepsy Unit
Accepted 9 June 2020 of two hospitals in Madrid, Spain were included. The main inclusion criterion was an undetermined etiological
Available online xxxx
diagnosis after clinical assessment, neuroimaging, and electroencephalogram (EEG).
Results: Two hundred and five patients with epilepsy and intellectual disability were evaluated, with 124 fulfilling
Keywords:
Genetic testing
the inclusion criteria (mean age: 33.9 years). Regarding the etiological workup, advanced neuroimaging,
Intellectual disability prolonged video-EEG, and any type of genetic test had been performed in 58%, 41%, and 40%, respectively. An eti-
Precision medicine ological diagnosis was reached in 18.5%. The workup was considered incomplete in 67%. Variables that showed
Diagnostic barriers the strongest association with an incomplete diagnostic workup in the multivariate analysis were current age
Epilepsy genetic panel and seizure freedom.
Developmental and epileptic encephalopathies Conclusions: Despite the multiple implications of modern diagnostic techniques, especially genetic testing, there
is a large proportion of patients with epilepsy and intellectual disability who do not have access to them. Older
age and seizure freedom seem to be associated with the highest diagnostic gap.
© 2020 Elsevier Inc. All rights reserved.

1. Introduction targeted therapy, support prenatal diagnosis, provide information for

Epilepsy is one of the most common neurological disorders, both in
pediatric and adult populations. Historically, the etiology of a high pro-
portion of patients with epilepsy (up to 70%) has remained unknown,
being classically labeled as “idiopathic” or “cryptogenic” [1]. Over the
last years, there has been a breakthrough in diagnostic methods for
the etiological evaluation of patients with epilepsy, especially in the ge-
netic field. Genetic testing has a particularly high yield for children with
early life epilepsy and epilepsy associated with intellectual disability
(epileptic and developmental encephalopathies), where the diagnostic
rate can exceed 30%, approaching the outcome of neuroimaging and
surpassing that of metabolic testing [2].
The International League Against Epilepsy recommends genetic test-
ing to establish an etiology, prevent unnecessary tests, provide early
⁎ Corresponding author: Epilepsy Unit, Neurology Department, Hospital Ruber
Internacional, c/ La Masó, 38, 28034 Madrid, Spain.
E-mail address: aaledo@ruberinternacional.es (A. Aledo-Serrano).
prognosis, and allow parents to understand genetic implications for fu-
ture offspring [3]. For instance, some genetic mutations, which lead to
treatment implications, are those in SLC2A1 (treatment with ketogenic
diet), KCNQ2 or SCN2A (treatment with sodium channel blockers), or
POLG1 (avoidance of valproic acid) [4]. Even in mild epilepsies, the
knowledge of the genetic diagnosis has been associated with higher
quality of life [5].
However, these advances are relatively recent and have not reached
the entire population in the same manner. After an initial evaluation
during early childhood, most of the patients with epilepsy and intellec-
tual disability remain undiagnosed or are labeled as perinatal hypoxic–
ischemic encephalopathy (very often without definitive data
supporting it) and over the years, are relegated to symptomatic man-
agement, without further etiological investigations. This diagnostic bar-
rier seems to be more evident in adult patients, for whom genetic
testing was not yet available during their early childhood [6]. Neverthe-
less, there are to date limited studies focused on the diagnostic gap in
epilepsy and intellectual disability, both in pediatric and adult patients.

https://doi.org/10.1016/j.yebeh.2020.107266
1525-5050/© 2020 Elsevier Inc. All rights reserved.
2 A. Aledo-Serrano et al. / Epilepsy & Behavior 111 (2020) 107266
The aim of this study was to evaluate the access to advanced diagnostic
tests in this population, with special focus on genetics.
2. Material and methods
Patients with epilepsy and intellectual disability evaluated between
March 2016 and December 2018 at the Epilepsy Unit of two tertiary care
hospitals (Hospital Ruber Internacional and Hospital Clinico San Carlos,
both in Madrid) were evaluated. Eligibility criterion was an undeter-
mined etiological diagnosis after clinical assessment, basic neuroimag-
ing, and routine electroencephalogram (EEG). Both hospitals
systematically identified all eligible patients.
Study data were obtained from the review of medical records. Re-
garding the subgroup of institutionalized patients, in some cases, the
data were completed in collaboration with the Medical Coordination
of Madrid Social Assistance Agency. Demographic and clinical variables,
as well as whether the diagnostic workup had been complete or incom-
plete, were analyzed. Uncontrolled epilepsy was defined as having one
or more seizures in the last 3 months. The diagnostic workup was con-
sidered complete when the etiological diagnosis was achieved or, in the
case of undiagnosed patients, the workup had included a sufficient eti-
ological evaluation, including genetic testing, according to investigator
assessment and current international recommendations [7,8]. This al-
ways included neuroimaging with epilepsy protocol, sometimes
prolonged EEG studies and on occasions, specific laboratory testing
(i.e., antibodies if an immunological origin was suspected). Study ap-
proval was obtained from the institutional review boards of both
hospitals.
Statistical analysis was performed with R 3.1.2 and the epicalc and
optimalcutpoints packages. The association between the diagnostic
workup group (incomplete vs complete) and the other variables was
analyzed with both univariate tests (Pearson's Chi-square test, Fisher's
exact test, Student's t test, or Mann–Whitney's test) and multivariable
logistic regression (likelihood ratio test). As a secondary analysis, a pre-
dictive model of complete vs incomplete workup according to age was
calculated with the area under the receiver operating characteristic
(ROC) curve (AUC) method.
3. Results
Two hundred and five patients with epilepsy and intellectual disabil-
ity were evaluated, with 124 fulfilling criteria for inclusion in the study
(66 males, 58 females), mean age of 33.9 years (range from 2 to 71
years; standard deviation, SD = 20.1); 39.5% were institutionalized.
The degree of intellectual disability was mild (32.3%), moderate
(20.2%), or severe (47.6%). Patients took a mean number of antiepileptic
drugs of 2.62 (SD = 1.3). Fifty-four percent of them have had at least
one seizure in the last 3 months.
Regarding the etiological workup, magnetic resonance imaging with
epilepsy protocol, prolonged video-EEG monitoring, and any type of ge-
netic testing had been performed in 58%, 41%, and 40%, respectively. Ge-
netic testing consisted of a single gene test in 21% of the cases, epilepsy
multigene panel in 11%, and array-CGH (Comparative Genomic Hybrid-
ization) in 6%; whole exome or trio-based exome sequencing was only
performed in 2% of the patients. An etiological diagnosis had been
reached in 18.5% of the cases. These diagnoses were all genetic, showing
different pathogenic single gene variants or copy number variants
(CNV): SCN1A in seven cases; TSC1, CDKL5, and InvDup15 in two
cases each; and UBE3A, KCNT1, SCN2A, KCNQ2, Del5p, GABRA1,
MECP2, POLG, and FMR1 one case each. After the evaluation of the
workup by the investigator team, it was considered complete in 33%
of the total and incomplete in 67%.
When comparing the two groups (complete vs incomplete etiologi-
cal workup; Table 1), there were statistically significant differences in
the univariate analysis in mean age (5.19 vs 34.5 years; p b 0.001), pro-
portion of institutionalized patients (4.9% vs 56.6%; p b 0.001),
proportion of patients with uncontrolled epilepsy (80.5% vs 41%; p b
0.001), and female gender (63.4% vs 38.6%, p = 0.016). The variables
that showed the strongest association with complete/incomplete diag-
nostic workup in multivariable multiple regression analysis were cur-
rent age (p b 0.001) and proportion of patients with controlled/
uncontrolled epilepsy (p = 0.048), with older age and seizure freedom
being associated with incomplete workup. In a predictive model of com-
plete vs incomplete workup according to age, an optimal cutoff of 27
years was found (AUC = 0.921, sensitivity = 0.819, specificity =
0.902; Fig. 1).
4. Discussion
Despite the multiple implications of the modern diagnostic tech-
niques, especially in the field of genetics, in the management of epilepsy
associated with intellectual disability, there is a large proportion of pa-
tients (about two-thirds according to our data) who do not have access
to them. In our study, older age and seizure freedom are associated with
the highest diagnostic gap.
Nowadays, the value of diagnosing a genetic epilepsy goes beyond
just obtaining a diagnosis. It can lead to better understanding of the
prognosis, anticipatory guidance for patients and families, and ulti-
mately, improved outcomes. Even when genetic etiology does not
alter management, parents often have a strong interest in genetic test-
ing, and the discovery of a genetic etiology might assist with family
planning and counseling [9]. Dravet syndrome is a good example of
how genetic diagnosis can improve disease management. The finding
of a pathogenic SCN1A mutation will lead to the avoidance of contrain-
dicated sodium channel blockers and help choose the most effective an-
tiepileptic (antiseizure) medications for the condition. Moreover, there
are also precision treatments on the horizon for this group of patients
including small molecules targeting the Nav 1.1 channel, antisense oli-
gonucleotides, and viral vector therapies, which could have the poten-
tial to modify the course of the disease [10]. Dravet syndrome is not
the only condition with disease-modifying treatments in advanced pre-
clinical stages, as there are ongoing programs to develop antisense oli-
gonucleotides for SCN2A and KCNT1 encephalopathy, gene therapy for
CDKL5 deficiency disorder, and specific ion channel modulators for
KCNQ2 and SCN8A, among other efforts [11]. In a recent study where in-
vestigators performed an epilepsy gene panel after the first unprovoked
seizure in patients under 5 years old, the diagnostic yield was 24.4%, and
a precision medicine treatment could be applied in around 6% [4]. In the
near future, the proportion of genetic epilepsy diagnosis with a preci-
sion medicine treatment option is likely to increase, with only 6 genetic
etiologies accounting for 50% of the diagnostic cases and having preci-
sion medicine programs in development [12].
Although our study reflects a real-world scenario, one of the main
limitations is the lack of standardized genetic testing pathway in this co-
hort. Therefore, there is a need for standardized genetic testing in pa-
tients with epilepsy of any age. In the past few years, the approach for
suspected genetic epilepsies has changed over time, mainly due to the
development of new genetic techniques and genes or CNV descriptions
[3,7,8,11]. For instance, in a recent collaborative large-scale research, a
similar target population was investigated for the search of CNVs in un-
explained cases, showing that a specifically adapted workflow enables
identification of new pathogenic autosomal CNVs in 10.9% of patients
[13].
Very few studies have focused on the diagnostic barriers for patients
with epilepsy and intellectual disability. In a survey carried on in the
United States, clinicians felt it was more difficult to get epilepsy genetic
testing for patients with Medicaid insurance compared with commer-
cial insurance. Increased availability of testing was associated with less
complex testing, in-house testing, and no preauthorization require-
ments [14]. Access to genetic testing in the US is also likely to increase
with the recent availability of a company-sponsored program that offers
free genetic testing to all patients with epilepsy age 8 and younger.
 A. Aledo-Serrano et al. / Epilepsy & Behavior 111 (2020) 107266 3

Table 1
Comparison between patient groups with complete or incomplete diagnostic workup.

Variable Complete workup Incomplete workup p-Value (univariate) p-Value (multivariable)

Age (mean [SD]) 5.19 (0.8) 34.5 (4.7) b0.001 b0.001

Gender (%) Male 13 (56.5) 53 (52.5) 0.016 0.178
Female 10 (43.5) 48 (47.5)
Institutionalization (%) Yes 2 (4.9) 47 (56.6) b0.001 0.231
No 39 (95.1) 36 (43.4)
Intellectual disability (%) Mild 18 (43.9) 22 (26.5) 0.081 0.478
Moderate–severe 23 (56.1) 61 (73.5)
Number of AED (median [IQR]) 2 (1.3) 3 (2.4) 0.087 0.912
Controlled epilepsy (%) Yes 8 (19.5) 49 (59) b0.001 0.048
No 33 (80.5) 34 (41)

SD: standard deviation; AED: antiepileptic drugs; IQR: interquartile range.

These results are not comparable with ours, since the socioeconomic
context and healthcare are very different in Spain and in the US. In ad-
dition, their survey was only focused on pediatric population, while
adult populations face additional barriers.
In our study, age was the strongest predictor of access to genetic
testing. In a recent study performed in Canada, investigators assessed
the diagnostic yield of a multigene panel in adults with epilepsy and in-
tellectual disability, identifying the etiology in 22% [15]. This rate is sim-
ilar to what others have reported for pediatric populations and support
the need to facilitate access to genetic testing for adult patients. In a sur-
vey carried out in Spain, a Delphi consensus with the participation of na-
tional experts already identified a high proportion of undiagnosed
Dravet syndrome in adults when compared with children (60% vs 20%,
respectively [16]). However, to our knowledge, no previous studies
have focused on the diagnostic gap in both pediatric and adult popula-
tions with epilepsy and intellectual disability.
The limited access of adult patients to genetic testing is likely multi-
factorial. Patients who are currently adults did not have access to ge-
netic testing when they were children, or only access to single gene
testing through Sanger, which yielded much lower diagnostic rates. In
addition to not having had access to genetic testing as children, many
adults continue to have limited access to comprehensive genetic testing
today. It is possible that caregiver and clinician's motivation to advocate
for a diagnosis is higher for younger patients, limiting the opportunities
for those who are no longer of pediatric age. The fact that all epileptic
and developmental encephalopathies have their onset in childhood
also leads to a research attention focus on pediatric populations. There-
fore, adult patients face a diagnostic (and therapeutic) gap, without the
benefits of these advances. Importantly, without studies in adults living
with these conditions, the question whether their outcomes could be al-
tered with the diagnosis will remain unanswered [17]. In our study,
controlled epilepsy and institutionalization were also associated with
poor access to genetic testing. Although these differences could simply
reflect a trend towards reduced seizure frequency and institutionaliza-
tion with age, this fact has been separately analyzed in other surveys,
with most of them pointing to the stigma of intellectual disability and
institutionalization, as well as the lack of awareness, advocacy, and fam-
ily hope in this population [6].
Nevertheless, the diagnostic yield of multigene panels in adults
with epilepsy and intellectual disability is comparable with that in
children, with important implications for prognosis, therapeutic
management, and family counseling. Therefore, efforts must be
done to better identify and document this population, and to iden-
tify and find solutions for the barriers that create the diagnostic
gap.
Declaration of competing interest
None.
Acknowledgments
This research received fundings from Gmp and INCE Foundations,
Madrid. It was implemented in collaboration with the Social Assistance
Agency of the Government of Madrid.

Fig. 1. Density graph of the predictive model for optimal cutoff (prediction of complete/incomplete workup according to age).
4 A. Aledo-Serrano et al. / Epilepsy & Behavior 111 (2020) 107266
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