YEBEH-05909; No of Pages 5

Epilepsy & Behavior xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Epilepsy & Behavior

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

Review

Common psychiatric comorbidities in epilepsy: How big of a problem

is it?
Jay A. Salpekar a,⁎, Marco Mula b,c
a
Kennedy Krieger Institute, Johns Hopkins University, USA
b
Institute of Medical and Biomedical Education, St George's University of London, United Kingdom
c
Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

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

Article history: Psychiatric illness and epilepsy commonly co-occur in adults and in children and adolescents. Theories of comor-
Received 23 July 2018 bidity are complex, but recurring associations between the conditions suggest overlap that is more than simple
Accepted 24 July 2018 co-occurrence. Common underlying pathophysiology may imply that epilepsy itself may constituently include
Available online xxxx
psychiatric symptoms. Conditions such as depression or cognitive difficulties commonly occur and in some
cases, are considered to be associated with specific epilepsy characteristics such as localization or seizure type.
Keywords:
Psychiatry
Regardless of etiologic attributions to psychiatric comorbidity, it is clear today that treatment for epilepsy
Epilepsy needs to target psychiatric illness. In many cases, quality-of-life improvements depend more upon addressing
Depression psychiatric symptoms than seizures themselves.
Cognitive © 2018 Elsevier Inc. All rights reserved.
Comorbidity
Behavior
Diagnosis

1. Introduction between psychiatric illness and epilepsy is abundantly present, espe-

cially for mood disorders and problems of cognition.
Psychiatric comorbidities have long been studied in the context of What remains unclear is how epilepsy-related characteristics may
epilepsy. A sizeable body of evidence supports the understanding that be etiologically associated with psychiatric comorbidity. While it has
psychiatric illness is overrepresented in epilepsy as compared with been long considered intuitive that the more severe the epilepsy, the
other chronic medical illnesses [1]. Even with the markedly altered more severe the comorbidity, this may not be completely accurate. It
functionality and lifestyle associated with conditions such as cancer, di- may be that specific seizure-related characteristics affect the presence
abetes, or asthma, the presence of psychiatric comorbidity in epilepsy or absence of comorbidity. Seizure frequency is commonly viewed as
appears to be more substantial [2]. Although opinions regarding the adversely affecting psychiatric state, as is the usage of multiple anticon-
best methods of diagnostic assessment may differ, comparable assess- vulsant medications, thus, adding to the potential risk of developing
ment tools clearly find that the overrepresentation of psychiatric illness psychiatric illness. However, neither context may represent the essence
is significant both in adults and in children [3,4]. of comorbidity in the truest sense.
Nevertheless, a persisting challenge is in measuring the presence of Ultimately, it may be that epilepsy is a broad spectrum illness with
comorbidity independent of possible confounding factors. Very few heterogeneity that includes psychiatric aspects. In that sense, thinking
studies assessing comorbidity are prospective in nature or have a popu- of comorbidity as the association of two etiologically unrelated condi-
lation-based approach. Additionally, the broad spectrum of illness tions would be inaccurate. Certain types of epilepsies could have psychi-
makes it difficult to isolate psychiatric symptoms from underlying med- atric, cognitive, or behavioral complications that are inherently
ical or neurologic illness. The population with epilepsy itself is heteroge- associated with a common underlying pathophysiology. With that ap-
neous, so overlap with heterogeneous and somewhat arbitrarily proach, comorbidity would not exist; instead, the associated behavioral
categorized psychiatric conditions may hinder a comprehensive diag- symptoms would be viewed simply as constituent parts of the epilepsy.
nostic approach. Still, even with these challenges, the connection Such a paradigm shift has marked implications in terms of treat-
ment. Despite the intrigue in thinking of comorbidity in this manner,
it is a modern approach, and as such, the evidence base for treatment
⁎ Corresponding author at: Neuropsychiatry in Epilepsy Program, Kennedy Krieger
Institute, Johns Hopkins University School of Medicine, 716 N. Broadway, Baltimore, MD
is underdeveloped. Treatment studies and clinical trials are not typically
21205, USA. conceptualized in this way. However, it seems clearer now that in order
E-mail address: Jsalpek1@jhmi.edu (J.A. Salpekar). to comprehensively treat epilepsy and to improve quality of life, both

https://doi.org/10.1016/j.yebeh.2018.07.023
1525-5050/© 2018 Elsevier Inc. All rights reserved.

Please cite this article as: Salpekar JA, Mula M, Common psychiatric comorbidities in epilepsy: How big of a problem is it?, Epilepsy Behav (2018),
https://doi.org/10.1016/j.yebeh.2018.07.023
2 J.A. Salpekar, M. Mula / Epilepsy & Behavior xxx (2018) xxx–xxx

behavioral and seizure specific outcomes need to be addressed. Even 2.1.3. Psychoses
though this paradigm does not reflect the state of the evidence at this Psychoses and thought disorders are less frequent than mood and
time, the approach of identifying psychiatric symptoms independently anxiety disorders, but they represent serious complications affecting
is still meaningful as a first step in management. The evidence base prognosis, morbidity, and mortality in epilepsy. In general terms, epide-
does help us in that regard and will be reviewed in the following miological studies show that the prevalence of psychoses is 7 times
sections. higher than that of schizophreniform disorders in the general popula-
tion [18]. Psychotic symptoms in epilepsy are well recognized in a num-
ber of different clinical scenarios, from postictal psychoses [19] to
2. Common comorbidities in adults antiepileptic drug-related psychotic episodes [20] to chronic schizo-
phrenia-like disorders [21]. The prevalence of psychoses in epilepsy
2.1. Epidemiological aspects in adults with epilepsy seems again related to the severity of the seizure disorder but also to
the degree of pathology of the temporolimbic structures. Cross-sec-
2.1.1. Mood disorders tional, population-based studies in unselected samples show that the
Cross-sectional, population-based studies in adults with epilepsy are prevalence of nonorganic, nonaffective psychoses, including schizo-
showing a uniformly increased prevalence of depression, with preva- phrenia and related disorders, is around 4%–5% [9,22] but in selected
lence rates very similar to those of the general population only among samples, such as hospital case series, is even higher than that [23]. A sys-
seizure-free patients [5], while the prevalence is definitely higher than tematic review and meta-analysis of a published literature pointed out
that in unselected samples (between 17% and 22%) [6], and it is up to that patients with temporal lobe epilepsy present with the highest prev-
55% in patients with drug-resistant epilepsy [7]. In general terms, alence in the range of 7% [24]. In patients with temporal lobe epilepsy,
these figures partially reflect the severity of the underlying seizure dis- those with febrile seizures and hippocampal sclerosis are more likely
order not only in terms of psychosocial difficulties but also in terms of to develop psychoses than those with normal or minimal changes on
brain dysfunction. Cross-sectional studies are highly informative from Magnetic Resonance Imaging (MRI) [25]. Interestingly, both a family
a public health perspective, as they give an idea of the size of the prob- history of psychoses and a family history of epilepsy have been identi-
lem, but cohort studies can provide information on the temporal rela- fied as potential risk factors suggesting a strong neurobiological connec-
tionship between comorbid conditions. In fact, a number of studies are tion between epilepsy and psychoses [18]. As already discussed in the
now suggesting that the relationship between epilepsy and depression context of depression, psychoses have also shown a bidirectional rela-
is not necessarily unidirectional, and patients with depression are at in- tionship with epilepsy. A case–control study in Sweden shows that the
creased risk of developing epilepsy as well. Data from the UK General age-adjusted odds ratio for seizures is 2.5 in patients with any diagnosis
Practice Research Database show that the incidence-rate ratio of de- of psychosis even after controlling for antipsychotic drug treatment and
pression is significantly higher during the three years preceding the other potential confounding factors [9]. Two retrospective cohort stud-
onset of epilepsy [8]. A study from Sweden shows that the age-adjusted ies show that patients with schizophrenia have 2 to 3 times increased
odds ratio for the development of epilepsy is 2.5 for patients with a de- risk to develop epilepsy [26] with incidence rates of 7 per 1000 per-
pressive disorder [9], and these figures have been confirmed by at least son-year [27].
three other studies with an increased risk of up to 7 times in selected
cases [10–12]. All these data clearly suggest that either some patients 2.1.4. Cognitive problems
with depression develop epilepsy as part of the “natural course” of the Cognitive problems represent a significant burden for any neurolog-
depressive disorder or that depression is a premorbid phase of some ep- ical disorder. Despite the large amount of epidemiological studies in
ileptic syndromes. children with epilepsy, there are no population-based studies investi-
gating the neuropsychological status of people with adult-onset epi-
lepsy [28]. This obviously represents a serious omission in the
2.1.2. Anxiety disorders scientific literature as the issue of cognitive problems is not just for chil-
Data on anxiety disorders are less systematic than those on depres- dren and young people but also for adults. In fact, a subjective impair-
sion, and this is due to a number of reasons including the high preva- ment in cognitive functions is frequently reported by adult patients
lence of depression in epilepsy that can mask anxiety disorders, a and ranging between 44% and 59% [29]. Most importantly, 63% of pa-
common attitude among neurologists in considering anxiety as the nat- tients perceive that antiepileptic drugs prevent them from achieving
ural consequence of having unpredictable seizures and the potential goals in life rather than the epilepsy itself [30]. The problem of neuro-
misdiagnosis between panic attacks and seizure-based phenomena psychological deficits in adult-onset epilepsies is quite complex. Several
like ictal fear. As already discussed in the context of depression, the studies have clearly shown that subjective memory complaints do not
few available studies suggest a uniformly increased prevalence of all correlate with formal neuropsychological deficits but are rather due to
anxiety disorders [13]. Two US National surveys show that people other factors, especially anxiety and depression [31,32]. Antiepileptic
with self-reported epilepsy are two times more likely to report a diag- drugs have a different propensity for cognitive side effects, but a num-
nosis of anxiety disorder than those without [14,15]. These figures ber of different variables, which are both patient-related and epilepsy-
have been replicated by another cross-sectional, population-based related, have to be taken into account in adults [30].
study in unselected patients with epilepsy using standardized clinical Patients are often concerned that epilepsy may be responsible for ac-
interviews [16]. Although less established as compared with depression, celerated brain aging. Although population-based studies in this area
a few preliminary studies are suggesting a similar bidirectional relation- are lacking, it has been suggested that the potential cognitive decline
ship between epilepsy and anxiety disorders. A US study in veterans in aging patients with epilepsy is very slow, and the cognitive perfor-
older than 65 shows that a previous history of anxiety is significantly mance at the onset of the epilepsy is the most important variable [28,
more common in those who developed epilepsy as compared with con- 33]. It has been suggested that people with epilepsy may reach a clini-
trols [17]. A population-based, case–control study in Sweden shows that cally significant threshold of impairment late in life because they start
patients hospitalized for anxiety disorders are more than 2 times at in- at a lower baseline cognitive level than healthy subjects rather than be-
creased risk of developing unprovoked seizures [9]. Finally, a cohort cause of a true accelerated cognitive decline [33]. This would be further
study using data from the UK General Practice Research Database supported by studies in newly diagnosed adult patients with epilepsy
shows that the incidence for anxiety disorders is not only higher in peo- showing that they are cognitively compromised even at the onset of
ple with epilepsy as compared with controls but is also already in- the disorder and before starting antiepileptic drug treatment [34]. Fur-
creased three years prior to the diagnosis of epilepsy [8]. ther studies in this area are urgently needed.

Please cite this article as: Salpekar JA, Mula M, Common psychiatric comorbidities in epilepsy: How big of a problem is it?, Epilepsy Behav (2018),
https://doi.org/10.1016/j.yebeh.2018.07.023
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2.2. Psychiatric comorbidities as a poor prognostic marker in adults with side effects while at the same time, serving as a valuable treatment op-
epilepsy tion is still present.

The amount of epidemiological data on psychiatric comorbidities of 3.2. Childhood absence epilepsy (CAE)
epilepsy has increased the attention of clinicians and researchers on the
potential impact of comorbidities on the prognosis of epilepsy and the Childhood absence epilepsy is characterized by interruptions in con-
identification of potential biomarkers [35]. As already discussed, the dif- sciousness though with little other visible semiology. Inattention is ob-
ferent prevalence rates in different populations with epilepsy, namely vious not only during seizures themselves but also has long been
seizure-free patients and patients with drug-resistant epilepsy, seem observed in these children in between absence episodes. One study of
to suggest that the presence of psychiatric comorbidities partially re- CAE comorbidity found that 25% had subtle cognitive deficits, 43%
flects the severity of the seizure disorder. In adults with epilepsy, linguistic difficulties, and 61% had a psychiatric illness, primarily
there is now enough literature supporting the hypothesis that psychiat- Attention-Deficit Hyperactivity Disorder (ADHD) [50]. Differentiation
ric comorbidities represent also a poor prognostic marker. of CAE from the inattentive subtype of ADHD may be difficult [51].
It has been established a long time ago that depression is a better in- For many years, CAE was considered a benign form of epilepsy, hav-
dicator of quality of life than seizure frequency itself [36]. It is now be- ing little sequelae beyond the distraction associated with the discrete
coming evident that depression is also associated with poor response events. However, if this was the case, then comorbidities of attention
to antiepileptic drug treatment [37,38], poor outcome after epilepsy or executive function deficits in children with epilepsy would not be
surgery [39,40], increased seizure severity [41], increased risk of injury markedly overrepresented as compared with the typical pediatric pop-
[42], and premature mortality [43]. Future studies need to clarify ulation. Instead, the cognitive deficits associated with CAE may be sim-
whether early identification and prompt treatment of psychiatric co- ilar to those associated with ADHD in children without epilepsy [52].
morbidities can have an impact on the prognosis of the epilepsy or Childhood absence epilepsy has increasingly become viewed as a dis-
whether they just represent indicators of poor prognosis. ease with persisting cognitive problems, well beyond the time scale of
individual absence episodes [53].
3. Comorbidities in pediatrics The idea that attention and cognitive problems are so prominent in
CAE suggests physiologic overlap of cognition and the mechanisms
Psychiatric comorbidity has historically been less well studied in that underlie absence seizures. An intriguing study recently done with
children than in adults. However, recent high-quality population stud- functional magnetic resonance imaging (fMRI) suggests that connectiv-
ies offer detailed information regarding the amount of medical and psy- ity in attention, salience, and default mode networks is altered in CAE
chiatric comorbidity in pediatric epilepsy. A recent study of a Norwegian [54]. The consideration is that these network abnormalities persist be-
patient registry showed that 78.3% of the pediatric epilepsy population yond discrete seizure episodes and may explain the problems of execu-
had comorbid medical, neurologic, or psychiatric illness as compared tive function commonly seen in CAE. Network abnormalities in epilepsy
with 30.3% of the general pediatric population [44]. Developmental or as well as in psychiatric disorders in general may explain a great deal of
psychiatric disorders were present in 42.9% of children with epilepsy the overlap not only with CAE but also with other epilepsies. Childhood
and higher if the epilepsy was deemed complicated. Although the diag- absence epilepsy is not just associated with attention or cognitive prob-
noses were not verifiable beyond the initial medical record notation, the lems but may involve mood complications as well [55]. The widespread
sample size of over one million is notable and reinforces the notion that networks subsuming generalized epilepsy may intuitively explain co-
psychiatric comorbidity is significant in the larger population of persons morbidities present, even in a pediatric population [56].
with epilepsy.
Sizeable comorbidity has also been found in a large-scale retrospec- 3.3. Mood disorder and anxiety
tive study of newly diagnosed epilepsy. Administrative review of over
six million records found 7654 children with newly diagnosed epilepsy. Mood disorder and anxiety often co-occur in children and adoles-
Neurobehavioral comorbidities were present in 60% of these children as cents without epilepsy. Co-occurrence of mood and anxiety disorders
compared with 23% without epilepsy [45]. These recent studies comple- and epilepsy is likely to be as common in children as it is in adults, al-
ment existing information in the adult population and affirm that comor- though large-scale prospective studies addressing this comorbidity
bidity is markedly present in children as well as in adults. Furthermore, have not been done [57]. Some studies in selected populations suggest
in children, the comorbidity may be more readily measurable and thus, co-occurrences of 5–40%, though samples are heterogeneous and as-
stimulate valuable insight into theories of pathophysiologic overlap. sessment tools are variable [58–61]. Depression is underreported in
children in general, and the same may be true in pediatric epilepsy
3.1. Behavioral side effects of anticonvulsants [62,63]. Many with depressive symptoms do not seek mental health
treatment for reasons of stigma or lack of clinician availability [64]. Clin-
A common question, especially in children, is whether anticonvulsants ically, quality-of-life measures have highlighted the adverse effect of de-
cause behavioral or cognitive side effects. Cognitive side effects may be pression in pediatric epilepsy. Similar to adults, the presence of
more noticeable in children because of academic emphases and measur- depression has a marked effect upon quality of life and upon recovery
able trajectories of cognitive development. Much literature in epilepsy has postsurgery [65,66].
been devoted to potential side effects of anticonvulsant drugs, and despite The association of depression or anxiety with specific seizure types
the difficulty in isolating etiologies, some medicines have been neverthe- or localization is less well established. However, two small studies sug-
less identified as more likely associated with behavioral issues [46]. gest that depression is more often present in children with temporal
Behavioral side effects may be reported with any anticonvulsant, but lobe seizure localization [67,68]. This finding is consistent with litera-
depression and fatigue have commonly been associated with phenobar- ture associating depressive phenomena with temporal lobe pathology
bital [47]. A recent retrospective review suggests that levetiracetam and in persons without epilepsy [69].
valproate have behavioral side effects more often than other anticonvul-
sants, particularly if hyperactivity is noted at baseline [48]. 3.4. ADHD
It must also be noted that anticonvulsant drugs often have positive
effects upon behavior, particularly in the context of mood disorders, Attention-deficit hyperactivity disorder has proven to be very com-
and have proven effective either as primary or adjunct treatments mon in children with epilepsy. Reports estimate that 30% of children
[49]. The conundrum of anticonvulsants yielding behavioral or cognitive with epilepsy may meet criteria for ADHD, with some reports

Please cite this article as: Salpekar JA, Mula M, Common psychiatric comorbidities in epilepsy: How big of a problem is it?, Epilepsy Behav (2018),
https://doi.org/10.1016/j.yebeh.2018.07.023
4 J.A. Salpekar, M. Mula / Epilepsy & Behavior xxx (2018) xxx–xxx

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Please cite this article as: Salpekar JA, Mula M, Common psychiatric comorbidities in epilepsy: How big of a problem is it?, Epilepsy Behav (2018),
https://doi.org/10.1016/j.yebeh.2018.07.023