Epilepsy & Behavior 117 (2021) 107869

Contents lists available at ScienceDirect

Epilepsy & Behavior

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

Review

Behavioral comorbidities of epilepsy and neuroinflammation: Evidence

from experimental and clinical studies
Elena M. Suleymanova
Institute of Higher Nervous Activity and Neurophysiology of RAS, 117485 Butlerova 5A, Moscow, Russia

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

Article history: Currently, a significant amount of data is accumulated showing that neuroinflammation is one of the key
Received 13 January 2021 processes in the development of brain pathology in trauma, neurodegenerative diseases, and epilepsy.
Revised 14 February 2021 Various brain insults, such as prolonged seizure activity, trigger the activation of microglia and astrocytes
Accepted 14 February 2021
in the brain. These cells, in turn, begin to synthesize pro-inflammatory cytokines. The inflammatory
response to the insult causes a cascade of processes leading to a wide range of pathological effects,
including changes in neuronal excitability, long-term plastic changes, astrocyte dysfunction, impaired
Keywords:
blood–brain barrier (BBB) permeability, and neurodegeneration. These effects may ultimately contribute
Epilepsy
Comorbidity
to the development of chronic spontaneous seizures. On the other hand, neuroinflammation contributes
Neuropsychiatric disorders to the pathogenesis of a number of neuropsychiatric disorders. Therefore, neuroinflammation can be a
Neuroinflammation link between epilepsy and its comorbidities, such as mood and anxiety disorders and memory impair-
ment. The mechanisms behind these behavioral and cognitive impairments remain not fully understood.
In this paper, clinical evidence of an important role of neuroinflammation in epilepsy and potentially
comorbid neurological disorders is reviewed, as well as possible mechanisms of its involvement in the
pathogenesis of these conditions obtained from experimental data.
Ó 2021 Elsevier Inc. All rights reserved.

1. Introduction also plays an important role in the pathogenesis of a wide range

Epilepsy is one of the most common neurological disorders,
which affects large populations of people across the world. Even
though new epilepsy treatments are constantly developed and
improved with time, the problem of a decrease in the quality of life
still remains relevant. Mood and anxiety disorders, as well as other
neuropsychiatric conditions, are common comorbidities of epi-
lepsy and even further worsen the condition of patients with epi-
lepsy, reduce the quality of life, and can interfere with treatment
compliance [1–3]. Since behavioral comorbidities can seriously
affect the prognosis of a patient with epilepsy, investigation into
possible mechanisms of these disorders and search for the new
therapeutic targets draw significant attention. Moreover, the possi-
ble common mechanisms underlying epilepsy and its comorbidi-
ties can be of great interest from the fundamental research point
of view, because understanding these mechanisms would provide
more insights into how the brain functions in the state of altered
excitability associated with epilepsy. It is known that inflammation
is involved in the mechanisms underlying increased excitability
and epileptogenesis [4,5]. On the other hand, neuroinflammation
E-mail address: suleymanova.em@ihna.ru
of neurological conditions including anxiety and depression, psy-
chiatric disorders, and cognitive impairments [6–9].
In this paper, clinical evidence of the involvement of neuroin-
flammation in epilepsy and potentially comorbid neurological dis-
orders and experimental data on possible mechanisms of its
involvement in the pathogenesis of these conditions are reviewed.
2. Epilepsy and neuropsychiatric comorbidities
Comorbid depression in patients with epilepsy was reported for
over decades. Depressive disorders are the most common neu-
ropsychiatric comorbidities in patients with epilepsy [10]. It is gen-
erally accepted that the risk of depression in patients with epilepsy
is much higher than in general population: studies report up to 80%
of patients with epilepsy with subjective feeling of depression [10],
and in various populations, depression is reported in 20%–40% of
cases and up to 77.5% in patients with pharmacoresistant temporal
lobe epilepsy (TLE) [11–13]. Depression also seems to be more
prevalent in epilepsy compared to other chronic conditions [11].
Another common comorbidity in epilepsy is anxiety, which is
the second most prevalent comorbid disorder after depression
[12]. Anxiety significantly worsens the quality of life of patients

https://doi.org/10.1016/j.yebeh.2021.107869
1525-5050/Ó 2021 Elsevier Inc. All rights reserved.
E.M. Suleymanova
with epilepsy as well; furthermore, mixed depression/anxiety dis-
orders aggravate the drop in the quality of life of these patients
even more [2].
Patients with epilepsy are also known to carry higher risks of
other types of neuropsychiatric disorders such as personality disor-
ders, interictal dysphoric syndrome, and psychosis [14]. These dis-
orders are less frequent than mood disorders and anxiety: the
overall prevalence is 6%, and the prevalence in patients with TLE
is 7% [15].
In addition, patients with epilepsy often show a persistent
decrease in cognitive function, including memory, attention, and
language deficits [9,16,17].
3. Inflammation in epilepsy
An increase in serum levels of pro-inflammatory cytokines in
patients with epilepsy is well established [18,19]. Blood serum
and cerebrospinal fluid (CSF) levels of cytokines are reported to
be increased in patients with epilepsy both postictally [20] and
interictally [21]. The levels of interleukin-1 beta (IL-1b),
interleukin-6 (IL-6), interferon gamma (IFN-c), and interleukin
17A (IL-17A) are elevated in patients with epilepsy; and the postic-
tal CSF level of IL-17A is higher in comparison with its interictal
level [22]. In patients with TLE, CSF and plasma concentrations of
IL-6 are increased postictally in comparison with baseline levels,
while the IL-1b level does not significantly change [23,24]. In CSF
and serum of patients with different types of seizures, IL-6 levels
increase postictally, and moreover, IL-6 levels correlate with sever-
ity of seizures. The IL-6 level dramatically increases after recurrent
generalized tonic–clonic seizures; and after single tonic–clonic or
prolonged partial seizures, it increases to a lesser extent [25]. Inter-
ictal levels of cytokines are reported to be similar in temporal and
extratemporal lobe epilepsy [21,26]. At the same time, a study on a
cohort of over 1200 patients with epilepsy has shown that interic-
tal levels of interleukins IL-6, IL-8, IL-17a, and the interleukin-1
receptor antagonist IL-1Ra depend on the severity of seizures: IL-
6 is the most ‘‘universal” and correlates with all studied severity
scaling systems in temporal, extratemporal, and idiopatic types
of epilepsy, IL-1Ra is a biomarker of seizure severity in temporal
and extratemporal epilepsy, and IL-8 and IL-17a correlate with sei-
zure frequency in all types of epilepsy [26].
The studies of cytokine expression in surgically removed human
epileptic tissue show upregulation of multiple genes related to
neuroinflammation [27–29]. The comparison of IL-6 and IL-1b pro-
tein levels in the neocortex of patients with TLE with postmortem
controls with no preexisting neurological conditions shows a sig-
nificant increase in these proteins levels in the patients with epi-
lepsy [30]. The increased levels of cytokines in resected brain
tissues of patients with TLE are region-specific: the highest levels
of IL-6, IL-1b, and macrophage inflammatory protein 1a (MIP-1a)
are found in the temporal cortex; the highest levels of IL-17A, IL-
2, and IL-4 are detected in the hippocampus [31].
In the resected olfactory bulbs of patients with chronic intract-
able frontal lobe epilepsy, who underwent surgical removal of the
orbito-frontal area, a significant increase in gene expression of pro-
inflammatory cytokines (IL-1b, IL-6 and tumor necrosis factor a
TNFa) is found, i.e., an increase in expression of genes involved
in inflammation can also be observed in structures not directly
involved in epileptic process, which could probably contribute to
cognitive and olfactory dysfunction among patients with intract-
able epilepsy [32].
It is interesting that in patients with intractable TLE who under-
went surgery and became seizure free, the plasma levels of pro-
inflammatory cytokines IL-1b and IL-6, TNFa, CCL3/MIP-1a signif-
2
Epilepsy & Behavior 117 (2021) 107869
icantly decline in comparison with the levels before surgery
[19,31].
Therefore, there is a large body of evidence showing that
inflammatory processes take place in the epileptic brain and are
directly associated with seizures.
Studies on experimental models provide more insights into how
neuroinflammation is involved in pathologic processes taking
place in the epileptic brain. Animal experiments allow more
detailed research of the central immune response to seizure in
absence of many factors such as treatment with antiepileptic
drugs, so the results of multiple studies provided a large body of
data about time course and mechanisms of neuroinflammatory
response to epileptic activity [4]. Various experimental brain
insults result in an increase in levels and gene expression of pro-
inflammatory cytokines and their receptors. For example,
enhanced gene expression and elevated levels of cytokines were
found in the brain in the experimental status epilepticus [33,34].
Early and lasting upregulation of IL-1R1 receptors that mediate
the IL-1 effect on neuronal excitability occurs in neurons shortly
after the induction of status epilepticus; in astrocytes it is transient
and detected in a few hours after seizures [35,36].
4. Inflammation in psychiatric disorders
At present, more and more evidence of the involvement of
inflammatory pathways in the development of various neuropsy-
chiatric diseases is accumulated. Conditions associated with
inflammatory response, such as stroke, tumors, and brain trauma
are long known to induce symptoms overlapping with neuropsy-
chiatric disorders, and more recently, neuroinflammatory abnor-
malities were discovered in patients with neuropsychiatric
disorders [8]. Interestingly, medical conditions associated with
chronic inflammatory and immunological abnormalities, including
diabetes, malignancies, rheumatoid arthritis, and multiple sclero-
sis, are the risk factors for depression and bipolar disorder [8,37].
For example, elevated levels of inflammatory cytokines correlate
with self-assessed levels of anxiety and depression in patients with
type 2 diabetes [38]. Overexpression of pro-inflammatory cytoki-
nes, such as IL-6, is found in patients with obesity; and obesity
has a strong association with depression [39,40]. Therefore, inflam-
mation clearly links neuropsychiatric and metabolic conditions.
While inflammation-associated disorders increase the risk of
psychiatric disorders, these neurological conditions, in turn, are
associated with peripheral and central inflammation. There are
multiple reports of increased serum levels of inflammatory cytoki-
nes, such as IL-1b, IL-6, and TNF-a, in patients with depressive dis-
order [41–44]. Increased cytokine levels can be reversed by
antidepressant treatment [43].
Cytokine levels can have a predictive value for the severity of
the condition and response to treatment. In adolescents, plasma
levels of cytokines IL-6 and IFN-c positively correlate with self-
assessed symptoms of anxiety and depression [45]. Studies of cyto-
kine levels in the CSF of patients with depression have shown ele-
vated levels of pro-inflammatory cytokines IL-1b, IL-6 and TNFa
[46]; moreover, the increased level of IL-6 is associated with a
higher risk of suicide attempts [47]. Cerebrospinal fluid levels of
pro-inflammatory cytokines correlate with the severity of clinical
manifestations of depression [48]. Increased levels of TNF-a, IL-6,
and IL-1b in patients diagnosed with major depressive disorder
or anxiety disorders can predict the lack of response to treatment
with fluoxetine [49,50].
Therefore, there is a large body of clinical data providing evi-
dence of the involvement of inflammation in the pathogenesis of
psychiatric disorders. This link between inflammation and
psychiatric disorders is bidirectional: elevated expression of
E.M. Suleymanova
pro-inflammatory cytokines associated with various conditions
and metabolic syndromes increases the risk of the development
of neuropsychiatric conditions.
In patients, it is usually difficult to distinguish the endogenous
mood disorders and the result of stress from chronic pain, disabil-
ity, and social stigma. For example, in patients with juvenile idio-
pathic arthritis, anxiety and depressive symptoms are associated
with pain and disability, but not with the peripheral levels of
pro-inflammatory cytokines [51]. The mechanisms underlying
the role of neuroinflammation in the pathogenesis of these disor-
ders are still unclear and require further clinical and experimental
studies.
5. Neuroinflammation in the epileptic brain
How does neuroinflammation develop in the epileptic brain?
Many recent findings suggest that nervous and immune systems
are not autonomous, but mutually affect each other [52]. Neuroin-
flammatory mediators take part in various signaling pathways and
can have a significant neuromodulatory effect. The activation of
cytokine receptors in neurons rapidly alters their excitability via
modifications of ion channels, presynaptic changes in neurotrans-
mission, and activation of many signaling pathways. Proinflama-
tory mediators also can modulate neuronal excitability via
mediating inflammation-related interactions between glia and
neurons that play a role in reducing the seizure threshold [52].
For example, IL-1b can induce phosphorylation of the NR2B sub-
unit of the NMDA receptor thus facilitating NMDA-mediated Ca2
+ influx into neurons [53].
5.1. The role of cell death
Experimental data from rodent models show that seizures can
induce high levels of pro-inflammatory cytokines in the brain
regions involved in the generation and propagation of epileptic
activity [36]. Focal seizures induced by kainic acid activate micro-
glial cells and induce an increase in the IL-1b level 24 hours after
seizures [54]. In the lithium-pilocarpine model of status epilepti-
cus, an increase in the pro-inflammatory cytokine gene expression
occurs in the regions that are most prone to neurodegeneration:
IL1-b, NF-jB, and cyclooxygenase-2 expression is found in degen-
erating neurons during status epilepticus; however, it is absent in
the latent period despite continuing neurodegeration [55]. Severe
seizures during status epilepticus are known to induce massive cell
death via necrosis [56], which is accompanied by a dramatic
change in ion balance in the tissue; but in addition severe seizures
induce neuroinflammation with rapid increase in the level of pro-
tein and gene expression of pro-inflammatory cytokines [36]. Neu-
roinflammation triggered by the initial impact may lead to further
neurodegeneration, which is known to progress during a long time
after the initial damage [57,58]. It is interesting though that neu-
roinflammation apparently can lead to increased excitability and
cause epileptogenesis even in the absence of prominent neuronal
death [59]. At the same time, neuroinflammation is clearly
involved in the neuronal death. Pro-inflammatory IL-1b is known
to be involved in the processes leading to neuronal injury in vari-
ous degenerative diseases presumably via regulation of glutamate
release and NMDA receptors activation resulting in enhancement
of NMDA-mediated [Ca2+]i current [53,60,61].
5.2. The role of glia activation
Neuron-glia interactions are complicated and underlie normal
functioning of the nervous system. Glial cells regulate water and
ion balance, modulate neurotransmitter release and synaptic plas-
3
Epilepsy & Behavior 117 (2021) 107869
ticity, and regulate the local blood flow and the brain–blood barrier
(BBB) function [62]. The increased excitation of neurons in the
epileptic brain induces the activation of microglia and astrocytes,
which in turn synthesize inflammatory cytokines [62–64]. The
activation of astrocytes and microglia was reported in both human
and experimental TLE [65–67]. Astrocytes in the epileptic brain
undergo both morphological and functional alterations [64], and
the disruption of astrocytic function is possibly one of the patho-
logic mechanisms underlying changes in the neuronal activity
and promoting epileptogenesis [68]. Reactive astrocytes in the
epileptic brain play a role in the change of neuronal excitability
via various mechanisms including the impaired regulation of
extracellular K+ concentrations and glutamate reuptake [62].
Microglia, the resident immune cells in the brain, are very sensitive
to the brain damage and disease, including such pathologic pro-
cesses as epileptic activity, and rapidly acquires the so-called acti-
vated state [69]. Activated microglial cells can affect neuronal
excitability via an increase in Na+ current density [70]. Activated
microglia give the critical input into the neuroinflammatory
response to brain insults by rapidly secreting a wide range of
pro-inflammatory cytokines and chemokines. Microglia are acti-
vated earlier than astrocytes, and in turn, induce astrocyte activa-
tion [71]. In vitro studies of the effect of the endotoxin
lipopolysaccharide (LPS) administration showed that neuroinflam-
mation in the neuron/astrocyte/microglial cortical network modu-
lated neuronal activity inducing prolonged bursting ‘‘seizure-like”
activity [72].
5.3. Blood–brain barrier dysfunction
Epileptic activity, especially during prolonged severe seizures
such as status epilepticus (SE), causes at least transient disruption
of the blood–brain barrier (BBB). This was shown both in patients
with TLE and experimental models [73–76]. The BBB damage
occurs almost immediately after the onset of SE and is observed
to some extent during the chronic period after SE. The use of con-
trast agents or serum albumin as a marker showed that BBB break-
down can be detected minutes after the onset of seizures [77].
Magnetic resonance imaging (MRI) studies of the rat brain after
SE show that BBB leakage is observed as early as 2 h after the onset
of seizures and is still present 6 weeks after SE [78,79].
Blood–brain barrier leakage and disruption of neurovascular
interactions lead to neuronal hypersynchronization and epilepti-
form activity caused by serum albumin uptake by astrocytes and
subsequent downregulation of inward-rectifying potassium (Kir
4.1) channels in astrocytes, which results in reduced buffering
and accumulation of extracellular potassium [80]. As a result of
the initial BBB damage, a positive feedback loop is formed: epilep-
tic activity induces barrier leakage leading to more seizures,
thereby promoting epilepsy progression [81]. Neuroinflammation
is one of the mechanisms contributing to the formation of this pos-
itive feedback loop. The BBB disruption leads to infiltration of
immune cells from systemic blood flow to the cerebral tissues.
However, the migration of blood leucocytes to the brain parench-
yma is reported to be insignificant and does not correlate with
acute and chronic seizures [82]. At the same time, monocyte infil-
tration, activation of microglia and perivascular macrophages are
increased in the hippocampus of both patients with TLE and rats
with post-SE spontaneous seizures, and the number of activated
perivascular macrophages positively correlates with the BBB
breakdown [77].
Therefore, the growing body of data shows that seizures induce
a complex of pathologic events including the rapid activation of
microglia and subsequent activation of astrocytes, the release of
a wide range of pro-inflammatory cytokines, which alter neuronal
excitability directly via neuronal receptors and indirectly via
E.M. Suleymanova
changes in water and ion balance and neurotransmitter release.
Neuronal death and BBB damage, on the one hand, are caused by
epileptic activity, and on the other hand, lead to its further propa-
gation via activation of neuroinflammatory processes. In their turn,
released pro-inflammatory cytokines can further affect BBB perme-
ability by activating receptors on astrocytes and endothelial cells
[83] and also enhance the microglial activation, which also can
have an effect on epileptogenesis not just via immune response
and cytokine release but also via nonimmune mechanisms: there
is evidence that elevated mTOR signaling in microglia and micro-
glial activation without any substantial pro-inflammatory cytokine
release is sufficient for epileptogenesis [84].
6. Neuroinflammation and behavior
It is well established that systemic inflammation induced by
injection of LPS or other pro-inflammatory agents causes anxious
and depressive-like behavior in rodents [85,86]. A systemic
increase in the levels of pro-inflammatory factors, such as IL-1b
and TNF-a cytokines, induces behavioral impairments (‘‘sickness
behavior”) including decreased motor activity, decreased food
and water intake, social withdrawal, impaired sleep, and cognitive
behavior [8,87]. Administration of LPS also induces a decrease in
cognitive function in rodents [88,89].
Depression models in rodents are associated with an increase in
pro-inflammatory cytokine levels [90]. Forced swimming induces
an increase in the levels of pro-inflammatory cytokines IL-1b, IL-
6, and markers of microglia activation in rodents with stress-
induced anhedonia [91]. Stress in a learned helplessness paradigm
leads to activation of microglia in rats, which can be suppressed by
the administration of antidepressants [92]. On the other hand, ani-
mal models of conditions associated with inflammation are charac-
terized by depressive-like behavior. It is known that ‘‘sickness
behavior” induced by systemic inflammation is reversible, but after
it is resolved, the depressive-like behavior remains [87]. Repeated
LPS exposure during 4 months induces chronic depressive-like
behavior in mice with behavioral and hippocampal alterations sim-
ilar to the major depressive disorder, and has been proposed as an
inflammatory model of depression [93,94]. Central administration
of LPS can induce an increase in TNF-a, IL-6, and nitric oxide syn-
thase expression in the hippocampus and cause the development
of depressive-like behavior in mice [95].
The role of neuroinflammation in anxiety disorders is less stud-
ied; however there is evidence that the inflammatory system can
be involved in the pathogenesis of anxiety [96]. Anxiety-like
behavior induced by repeated mild traumatic brain injury is asso-
ciated with inflammatory changes in the brain regions involved in
spatial memory and anxiety [97]. In obesity-related anxiety in
mice, central TNF-a blockade reduces anxiety-like behavior [98].
Studies of the relationship between inflammation and depres-
sion show that inflammation disrupts serotoninergic transmission
on several levels, which could induce depressive-like behavior
[90]. Pro-inflammatory cytokines are able to affect tryptophan
metabolism, which is crucial for serotonin synthesis, and as a con-
sequence, disrupt serotoninergic transmission [90,95]. The devel-
opment of depressive-like behavior induced by inflammation is
mediated by indoleamine 2,3-dioxygenase activation, which leads
to enhanced catabolizing of tryptophan along the kynurenine path-
way [99]. It seems that similar mechanisms involving the immune-
kynurenine pathway and serotonin and melatonin deficiency could
underlie the development of anxiety disorders as well [96].
Lipopolysaccharide-induced anxiety- and depressive-like behavior
might be mediated by the microglia activation and the production
of inflammatory cytokines and increase in the glutamatergic trans-
4
Epilepsy & Behavior 117 (2021) 107869
mission in the basolateral amygdala, and this effect can be reversed
by fluoxetine [100].
7. Conclusion
To summarize, a lot of data show that neuroinflammation
accompanies various kinds of brain disorders including epilepsy
and behavioral and mood disorders. It is well established that neu-
robehavioral disorders appear in patients with epilepsy much more
often than in general population, and depressive-like and anxious
behavior is common in animal models of chronic epilepsy. The
mechanisms underlying these comorbidities are yet to be under-
stood. In the brain pathology, an initial insult triggers a cascade
of various processes that can mutually enhance each other and, if
processes maintaining the homeostasis fail, lead to the develop-
ment of a novel functional state of the brain with increased
excitability. At present, accumulated data suggest that neuroin-
flammation plays one of the central roles in the development
and maintaining of this state. Neuroinflammation is also clearly
involved in the pathogenesis of neurobehavioral disorders and
could be a link between these conditions and altered excitability
in the epileptic brain.
Conflict of interest
I have no conflict of interest to declare.
Declaration of interests
None.
Acknowledgements
This work was supported by the Russian Foundation for Basic
Research, project no. 20-015-00468.
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