1. Introduction
Coronavirus disease 2019 (COVID-19) caused by the
highly infectious caused by the highly infectious severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in Wuhan,
China in December 2019 with a rapid pandemic diffusion worldwide
(1). Of note, six coronavirus
species are recognized to cause human diseases and among these,
four viruses 229E, OC43, NL63 and HKUI are the most frequent and
known cause of common cold symptoms in immune-competent
individuals. The other two coronavirus strains, SARS-CoV and Middle
East respiratory syndrome-coronavirus (MERS-CoV) emerged in humans
at the beginning of the 21st century, likely originating in bats
(1-3).
Both these infections have a zoonotic origin and may present a more
severe course (2). Coronaviruses
belong to the Coronoviridae family that comprise viruses
which are characteristically identified by a ribonucleic acid core
surrounded by a protein-spiked envelope and by their structural
resemblance to a crown (4).
SARS-CoV-2 infection had a rapid diffusion in humans, resulting in
a global pandemic spread (5). The
period of incubation of the infection lasts ~5 days. The most
common presenting symptoms are fever, cough, malaise and fatigue
(6). In adults, neurological
complications of COVID-19 are frequently reported and mainly
include headache and dizziness. Some authors reported the incidence
of neurological manifestations to be as high as 36.4% (7), including acute cerebrovascular
diseases, impaired consciousness and skeletal muscle injury. Other
authors (8) have also reported
encephalopathy and delirium as possible manifestations. Among these
complications, the most frequently reported are cerebrovascular
accidents, Guillain-Barrè syndrome, acute transverse myelitis,
acute encephalitis, hyposmia and seizures (8). Anand et al (9) first published a case series of 7
patients who were epileptic. A following systematic review revealed
that epilepsy occurred in 0.7% of critical ill adult patients with
COVID-19(10).
Neurological manifestations in individuals affected
by COVID-19 have also been reported in children; however, there is
common evidence to indicate that the infection is less frequent and
less severe compared to that in adult patients. In fact, it has
been reported that only 5.6% of children affected by COVID-19
exhibit severe clinical symptoms (11). Among these affected children, only
7% had an associated diagnosis of neurologic complications, the
most frequent being febrile seizures (3.9%), non-febrile seizures
(2.3%) and encephalopathy (2.2%) (12-14).
Compared to adults, children appear to have a milder clinical
course, not only as regards respiratory symptoms, but also in the
incidence and severity of neurological complications, possibly due
to differences in immune response maturity, ACE2 receptor
expression and neurodevelopmental status.
The present review aimed to provide a summary of the
association between SARS-CoV-2 infection and seizures as possible
direct causal factors through infectious, inflammatory or vascular
noxious effects on the cerebral nervous system (CNS) or as indirect
events linked to the systemic complications caused by COVID-19.
SARS-CoV-2 infection on epileptic children and the risk of a
possible cerebral damage as basic pathway for subsequent epileptic
disorder is also discussed.
2. Literature search methods
The authors searched clinical trials, primary
research and reviews from online bibliographic databases (MEDLINE,
Embase, PubMed, Cochrane Central, Web of Sciences and Scopus)
selected from 2019 to October 2022. The key search terms derived
from the medical subject heading terms were pertaining to
‘COVID-19’, ‘SARS-CoV-2’ and ‘Neurologic manifestations’, and
‘neurological complication’ and ‘Epilepsy’ and ‘Seizures’, and
‘Febrile seizures’. The authors included case reports,
retrospective studies, prospective studies, systematic reviews and
meta-analyses, clinical guidelines and narrative reviews on
‘COVID-19 and Epilepsy’, COVID-19 and Seizures’, and ‘COVID-19 and
Neurologic complications’. The literature research was restricted
to studies published in the English language. Relevant studies were
manually examined and included in the current reference list. After
removing duplicate records, the main research results were
included. The authors reviewed all the articles and discussed each
article. A formal quality assessment of the included studies was
not performed due to the narrative nature of the review and the
heterogeneity of the selected studies. This constitutes a
limitation of the present study.
3. Pathogenesis of neurological
complications
In individuals affected by COVID-19, several
hypotheses have been proposed to elucidate the neurological
effects; however, numerous questions remain unanswered. As detailed
in the study by Palabiyik et al (15), neurological implications associated
with COVID-19 could stem from four probable pathways: i) Systemic
inflammatory reactions instigated by the viral infection, either
during its acute phase or in cases involving multisystem
inflammatory syndrome (MIS-C); ii) vascular and prothrombotic
influences of the viral infection; iii) an immune-driven
parainfectious or post-infectious autoimmune reaction arising from
the viral presence; iv) a direct neurotropic or neuroinvasive
action of the virus via the olfactory route. SARS-CoV-2 is
acknowledged for its neurotropic capability, akin to other
respiratory pathogens, such as influenza, respiratory syncytial
virus, human herpesvirus-6 and -7, echovirus and coxsackievirus
(16). The respiratory system is
initially targeted by COVID-19, subsequently progressing through
three distinct stages: In the first stage, the virus adheres to
epithelial cells within the respiratory tract, initiating primary
replication; in this phase, most infected individuals can manage
the virus, resulting in mild clinical presentations. In the second
stage, the infection may extend into the lower airways, affecting
alveolar epithelial cells, leading to pulmonary viral replication,
inflammation, and pneumonia. The third stage is marked by rapid
viral replication in the lungs, inducing cellular death (apoptosis)
and vascular leakage, accompanied by the release of proinflammatory
proteins (4,17,18).
It has been suggested that SARS-CoV-2 binding to
pulmonary epithelial cells can initiate a systemic inflammatory
response syndrome, increasing the levels of interleukin (IL)-2,
IL-6, IL-7, IL-10, IL-12 and IL-15, alongside factors such as
Granulocyte-macrophage colony-stimulating factor, interferon
gamma-induced protein-19, macrophage chemoattractant protein-1 and
TNF-α, producing an intense pro-inflammatory state similar to that
observed in acute respiratory distress syndrome (ARDS) and MIS-C,
among other neurological and systemic complications (4,17-22).
As regards neurological effects, SARS-CoV-2 infections are
considered to elevate cytokine production, referred to as a
‘cytokine storm’, which is deemed to cause increased permeability
and the partial breakdown of the blood-brain barrier (BBB),
allowing peripheral cytokines to infiltrate the CNS. This can, in
turn, exacerbate or provoke neuroinflammation and impair neuronal
function (23-25).
CNS manifestations observed in patients with COVID-19 may also be
attributed to ‘endotheliopathy’, either due to the direct invasion
of endothelial cells in the BBB vasculature or as a result of an
immune-mediated cascade causing swelling or inflammation of these
cells, ultimately leading to neurological involvement (16). Almqvist et al (26) noted that common neurological
symptoms of COVID-19 include fatigue, headaches and disturbances in
smell/taste, urging clinicians to monitor at least five major
categories of neurological complications associated with COVID-19:
i) Cerebrovascular conditions, such as ischemic stroke and
macro/micro-hemorrhages; ii) encephalopathies; iii)
para-/post-infectious immune-mediated complications, such as
Guillain-Barré syndrome and acute disseminated encephalomyelitis;
iv) (meningo-)encephalitis, potentially accompanied by seizures;
and v) neuropsychiatric issues, including psychosis and mood
disorders. They suggested that some of these complications may lead
to lasting disabilities. They also suggested that genetic
susceptibility factors may contribute to the development of
neurological complications following SARS-CoV-2 infection, although
further studies are required to clarify this role (26).
4. Seizures, epilepsy and COVID-19
infection
SARS-CoV-2 infection, as a potential direct or
indirect contributor to seizures and epilepsy, is a subject
infrequently explored in the literature, and the role of COVID-19
in worsening seizures among epileptic individuals is insufficiently
addressed. The most widely accepted theories regarding
SARS-CoV-2-associated seizures include the direct viral invasion of
neurons, immune-mediated harm, or a combination of both mechanisms
(23,27). The documented likelihood of
unprovoked seizures among population-based cohorts of survivors of
CNS infections from developed nations ranges between 6.8 and 8.3%,
with significantly higher rates in underprivileged regions.
Seizures related to COVID-19 may emerge as a consequence of
encephalopathy or due to severe infection-related complications,
and as noted by Al-Ramadan et al (28), they may sometimes be the initial
indication of COVID-19. Vollono et al (29) documented the case of a 78-year-old
female patient with COVID-19, hypertension, and well-controlled
post-encephalitic epilepsy who, following a 2-year seizure-free
interval, exhibited a focal seizure as her first sign of
epilepsy.
In their study, Román et al (30) emphasized that amidst various
COVID-19-related complications, isolated cases of seizures,
encephalopathy, meningitis, encephalitis and myelitis have been
observed. Mithani et al (31) detailed the cases of three
critically ill adult patients with COVID-19 undergoing EEG
monitoring who experienced new-onset seizures and encephalopathy up
to 3.5 weeks following symptom onset. CNS infections, as
highlighted by Vezzani et al (27), are among the leading risk factors
for developing epilepsy. In pediatric studies, COVID-19-related
seizures or epilepsy are seldom mentioned. It is well-established
that children and adolescents appear less susceptible to
SARS-CoV-2, and the disease trajectory in this population is
generally milder than that in adults. The mechanisms underlying
seizure onset in children appear to differ from those in adults,
with a greater role attributed to systemic inflammatory responses
and multisystem inflammatory syndrome rather than direct viral
invasion.
Common causes of seizure-inducing disorders,
epilepsy and severe neurological complications are rarely reported
in children. This rarity may be attributed to the recent emergence
of the infection and the longer time required to observe systemic
and neurological disorders stemming from COVID-19 that could later
manifest as epilepsy or other conditions. Some researchers have
suggested that children with pre-existing severe health conditions
are more prone to experiencing severe complications. The study by
Tiruneh (32) stated that the
clinical symptoms of COVID-19 in children are non-specific and
difficult to define. The majority of affected children present mild
symptoms without fever or pneumonia, with favorable outcomes.
According to the author, only a small proportion of infected
children experience severe complications. Underlying health issues,
such as chronic pulmonary or cardiovascular conditions,
immunosuppression and obesity, may increase the severity of the
course of the disease (32). Other
factors contributing to clinical severity include seizures, kidney
or liver disease, endocrine disorders and being <1 year of age
(32).
In a previous systemic review and meta-analysis
involving 3,707 patients, only 1% of children were found to have
definitive neurological complications, most of which were linked to
pre-existing severe conditions. Among these cases, 25 children
experienced encephalopathy, 12 had seizures and 17 exhibited
meningeal involvement, all exhibiting signs indicative of MIS-C or
Kawasaki-like syndrome (33).
MIS-C represents a severe complication of SARS-CoV-2 in children,
also referred to as Pediatric inflammatory multisystem syndrome
temporally associated with SARS-CoV-2 (PIMS-TS). Common MIS-C
symptoms include fever, gastrointestinal issues, rash and
conjunctivitis; however, in severe cases, cardiac symptoms may
necessitate intensive care (34).
Neurological features and laboratory analyses of
patients with MIS-C suggest a post-infectious immune response,
similar to COVID-19-related autoimmune meningoencephalitis reported
in adults (35). Yilmaz Ciftdogan
et al (36), in a review of
614 children with COVID-19 and MIS-C, noted that 17 (2.8%) had
seizures. The clinical presentation of MIS-C shares a number of
features with incomplete Kawasaki disease and toxic shock syndrome,
requiring careful differential diagnosis. However, as Hogan et
al (37) stated in a large
cohort study, seizures and epilepsy are rarely reported in mild
COVID-19 cases, although they may appear in more severe instances
at later stages in the progression of the disease.
In a prospective observational cohort study of 651
children and young individuals <19 years of age admitted to 138
hospitals in the UK, Wales, and Scotland, Swann et al
(38) identified three distinct
clinical phenotypes: The most common was a respiratory illness
cluster involving upper and lower respiratory symptoms; the second
was a systemic muco-cutaneous-enteric illness cluster; and the
third was a rarer neurologic cluster characterized by seizures and
confusion. These findings align with the general observation that
seizures and epilepsy associated with COVID-19 are uncommon.
Among adult patients with COVID-19, various seizure
types have been reported, including new-onset focal seizures,
serial seizures and status epilepticus (39). In the majority of cases, these
seizures are multifactorial in origin, with affected individuals
often having prior vascular issues or other comorbidities such as
diabetes, obesity, kidney disease, multiorgan failure and metabolic
imbalances (39). In children, the
mechanisms leading to new-onset seizures related to COVID-19 remain
poorly understood and are likely diverse. These seizures may result
from viral encephalitis directly affecting the CNS, metabolic or
respiratory dysfunction, or complications associated with COVID-19.
Children with underlying health problems, immunosuppression, or
poor general health are more prone to developing neurological
complications, including seizures. MIS-C, one of the most severe
COVID-19-related complications, frequently presents with seizures
(36).
5. Seizures and COVID-19 in
children/adolescents
Following a search of the literature, in children,
eight clinical reports of SARS-CoV-2-related seizures were
identified (Table I). In the UK,
during the period from April 2, 2020, to February 1, 2021, 52 cases
out of 1,334 children and adolescents were hospitalized with
COVID-19, indicating an estimated prevalence of 3.8 (95% CI
2.9-4.9) cases per 100 pediatric patients. These children had a
median age of 9 years (range, 10-17 years); 22 (42%) were girls,
and 30 (58%) were boys (40).
Children exhibiting neurological symptoms were categorized into two
groups: 27 (52%) in the COVID-19 neurology group and 25 (48%) in
the PIMS-TS neurology group. In the first group, diagnoses included
status epilepticus in 7 children, encephalitis in 5 children,
Guillain-Barré syndrome in 5 children, acute demyelinating syndrome
in 3 children, chorea in 2 children, psychosis in 2 children,
isolated encephalopathy in 2 children and transient ischemic attack
in 1 child. The PIMS-TS group predominantly displayed features,
such as encephalopathy in 22 children, the involvement of the
peripheral nervous system in 10 children, behavioral changes in 9
children and hallucinations during presentation in 6 children. Of
the PIMS-TS group, 20 out of 25 children were admitted to intensive
care units, compared to 6 out of 27 children in the neurology
group. No seizures were explicitly reported within the PIMS-TS
group (40). In another study,
between April 2020 and March 2021, a cohort of 237 children with a
median age of 3.2 years, who tested positive for SARS-CoV-2 via
molecular swabs, was recruited from an Italian tertiary pediatric
center (41). Neurological
symptoms were noted in 32 (13.5%) children, while 205 (86.5%)
children exhibited no neurological involvement. Among those without
neurological symptoms, respiratory issues (59.5%) and
gastrointestinal complaints (25.3%) were most common. In the group
with neurological impairments, the following symptoms were
observed: Headache (65.6%), altered consciousness (18.8%),
anosmia/ageusia (12.5%), seizures (6.3%) and vertigo (6.3%), with
combined symptoms in 7 (21.9%). In this cohort, 5 (2.1%) children
had a prior history of epilepsy, which included symptomatic
epilepsy (1 arachnoid cyst and 1 astrocytoma), genetic generalized
epilepsy, developmental epileptic encephalopathy and epilepsy
linked to fragile X syndrome. All these seizures were well-managed.
However, new-onset seizures occurred in a 5-year-old girl with a
history of ischemic stroke and jejunal atresia who was admitted to
the emergency department with a focal-onset motor seizure. Her EEG
revealed left frontotemporal epileptiform abnormalities (41). In their study, Garazzino et
al (42) described, in April
2020, 168 children, the majority of whom were hospitalized, with an
average age of 5 years, along with 5 neonates. The most prevalent
symptoms were fever (82.1%), cough (48.8%), rhinitis (26.8%) and
gastrointestinal issues (18.4%). Among these children, 5 (2.5%)
children experienced seizures: 2 were febrile and 3 were
non-febrile. Among children with non-febrile seizures, 3 children
had a known history of epilepsy. Of the 2 children with febrile
seizures, 1 child had a prior history of febrile seizures, and the
other was experiencing their first episode (42). In another study, out of a group of
175 children (age range, 0-18 years) admitted to the emergency
department with acute SARS-CoV-2 infection, 11 children were
hospitalized due to seizures (43). Among these, 9 children presented
with tonic-clonic seizures, 1 child had a focal tonic seizure, and
1 child, a 5-month-old infant, exhibited bilateral symmetrical
tonic-clonic seizures. Five children had convulsive status
epilepticus; none had a prior history of status epilepticus, and
only 1 child had no prior history of seizures. Of these, 7 children
had a pre-existing neurological condition, 5 children had epileptic
seizures, 1 child had a single unprovoked seizure three years prior
and 1 child had intellectual disability (43). In another study, from October to
December 2021, 6,287 children and adolescents were admitted to 42
hospitals in the Tshwane District, South Africa, with COVID-19, 99%
of whom were affected by the Omicron variant. Detailed clinical
data were available for 139 out of 183 (76%) hospitalized children.
Reported symptoms included fever (47%), coughing (40%), vomiting
(24%), difficulty breathing (23%), diarrhea (20%) and convulsions
(20%). The majority of children (92%) were treated in standard care
wards, with 31 (25%) requiring oxygen therapy. A total of 7
children (6%) were ventilated, and 4 children, all with severe
comorbidities, succumbed (44).
Data from the New York-Presbyterian Morgan Stanley Children's
Hospital, involving 82 children aged 5 days to 18 years
hospitalized between March and June, 2020, revealed that 35 (43%)
children developed neurological symptoms, including headache in 12
(12.4%) children, fatigue or malaise in 9 (25%) children, an
altered mental state in 8 (23%) children, weakness in 5 (14%)
children and seizures in 4 (11%) children (45). Ludvigsson (46) reported on 3 children who were
positive for COVID-19 with seizures: A 3-month-old with prolonged
convulsions, a 21-month-old with 15-20 min of continuous seizures,
and a 14-year-old who experienced a 30-60-min seizure followed by
an unusual aggressive episode. Cadet et al (47) retrospectively analyzed a series of
febrile seizures in children with COVID-19. Among 8,854 children
aged 0-5 years across 34 healthcare facilities, 44 (0.5%) children
experienced febrile seizures, of which 30 (68.2%) children were
classified as simple and 14 (31.8%) children as complex. None of
these children had a prior history of epilepsy or seizures. In
total, 3 children (6.8%) exhibited status epilepticus. In that
study, no deaths were reported among children diagnosed with
epilepsy (47). Additionally,
other post-infectious inflammatory complications, such as recurrent
otitis media, have been reported in pediatric patients following
COVID-19, supporting the hypothesis of a broader inflammatory
impact of the infection even beyond the neurological system.
 | Table ISeizures in children with SARS-CoV-2
infection identified in the literature. |
Table I
Seizures in children with SARS-CoV-2
infection identified in the literature.
| Author(s) | Period of
recruitment | No. of
children | Seizures (%) | (Refs.) |
|---|
| Ray et
al | April,
2020-February, 2021 | 51/1,334 | 7 SE (13.7%) | (40) |
| Riva et
al | April, 2020-March,
2021 | 237 | 5 (6.3%) | (41) |
| Garazzino et
al | April, 2020 | 168 | 5 (2.5%) | (42) |
| Kurd et
al | March-December,
2020 | 175 | 11 (6%) | (43) |
| Cloete et
al | October-December,
2021 | 139 | 14 (20%) | (44) |
| Lin et
al | March-June,
2020 | 82 | 4 (11%) | (45) |
| Ludvigsson | - | - | 3 | (46) |
| Cadet et
al | - | 8,854 | 44 (0.5%); 30 FSS
(68%); 14 FSC (31.8%) | (47) |
6. Epilepsy and COVID-19 in
children/adolescents
In the study by Yoo et al (48) regarding the influence of COVID-19
infection on adult patients with epilepsy, the researchers
addressed two key points: i) Whether individuals with epilepsy are
more likely to contract COVID-19; and ii) whether epileptic
patients with COVID-19 are at an increased risk of developing
severe complications compared to those without epilepsy. Among the
212,678 participants, 3,919 (1.8%) had a history of epilepsy.
Following a detailed statistical analysis, the authors of that
study concluded that epilepsy was not associated with increased
vulnerability to COVID-19 infection, nor was there elevated
mortality linked to the infection. However, that study underscored
a higher likelihood of severe complications from COVID-19 in
patients with epilepsy (48).
There are limited studies available exploring why epileptic
children may have a greater predisposition to COVID-19. Parihar
et al (49) suggested that
epileptic children who administered immunosuppressive treatments,
including steroids, adrenocorticotropic hormone and other
medications for underlying conditions, may exhibit an increased
susceptibility to COVID-19. Furthermore, psychological stress
commonly observed in individuals with COVID-19 may lower immune
defenses in epileptic children, potentially increasing the risk of
infection (50). Currently, there
is no direct evidence to indicate that COVID-19 itself increases
seizure frequency in children with pre-existing epilepsy. However,
in certain epileptic syndromes or children with febrile seizures,
fever, a common early symptom of COVID-19, may act as a significant
trigger for initiating or worsening seizures. This is particularly
true in cases such as severe myoclonic epilepsy of infancy (Dravet
syndrome), characterized by seizures beginning at 6-8 months of
age, typically associated with fever at either high or low
temperatures. Clinical features include severe myoclonic seizures,
multiple seizure types, prolonged episodes of status epilepticus,
often prompted by fever (51).
Additionally, poor sleep reported in children with COVID-19 may
precipitate seizures in generalized epilepsy syndromes, such as
juvenile myoclonic epilepsy (49).
The potential of COVID-19 to exacerbate epileptic seizures is
highlighted in the study by Brisca et al (52), which detailed 2 children with
pre-existing epilepsy who, following prolonged seizure-free
intervals, experienced seizure recurrence during COVID-19. One case
involved a 5-year-old girl with a history of perinatal ischemic
stroke complicated by focal epilepsy, well-controlled with
levetiracetam. Following 4 years being seizure-free, she developed
focal motor status epilepticus, resolved with intravenous
midazolam. The second case involved an 11-year-old girl with
fragile X syndrome and recurrent status epilepticus linked to
febrile episodes. Following 6 years of being seizure-free on
levetiracetam, she experienced prolonged focal seizures triggered
by a febrile episode lasting 2 days. Both girls tested positive for
COVID-19 through polymerase chain reaction testing. Children with
chronic comorbidities are at an increased risk of developing severe
COVID-19 outcomes. In their study, Farrar et al (53) examined 544 children, 330 (60.7%)
hospitalized for COVID-19-related illnesses, while the remaining
were admitted for unrelated care (n=201, 36.9%) or for social or
infection control reasons (n=13, 2.4%). Among the COVID-19-related
hospitalizations, 70.3% (n=232) were classified as non-severe
cases, while 29.7% (n=98) were severe. In the group of children
with existing morbid conditions, 142 (43.0%) were hospitalized,
including 79 (23.9%) with non-complex conditions and 63 (19.1%)
with complex conditions. Neurological and neurodevelopmental
disorders were the most prevalent among comorbidities, affecting 46
children (13.9%), including epilepsy (n=20), chronic
encephalopathies (19, with 8 cases of cerebral palsy), and
chromosomal/genetic disorders (n=9, including trisomy 21). That
study concluded that severe outcomes occurred across all age
groups, regardless of comorbidities, although neurological and
pulmonary disorders and dependency on medical technology were
associated with higher risks of severe COVID-19 complications
(53).
The reasons why children with epilepsy experience
more severe COVID-19 outcomes remain unclear. As noted by Berg and
Jobst (54), children who are at
higher risk of developing neuro-COVID conditions often have
pre-existing neurological issues, with epilepsy being the most
common. In neuro-COVID cases, epilepsy was present in 16% of
patients compared to 3% in non-neuro-COVID cases. One explanation
for the more severe disease course in epileptic patients may
involve interactions between seizure medications and other factors,
including the presence of additional neurological and
non-neurological complications. Pre-existing epilepsy is often
considered a clinical risk factor during COVID-19 infection. As
previously reported by LaRovere et al (14), children who were most vulnerable to
neuro-COVID during hospitalization were those with pre-existing
neurological conditions, particularly epilepsy. This highlights the
importance of early identification and close clinical monitoring in
children with epilepsy affected by COVID-19, particularly for the
prevention of severe disease courses and long-term
consequences.
7. New-onset epilepsy and COVID-19
Several theories have been proposed regarding the
development of neurological symptoms and new-onset epilepsy
associated with COVID-19 infection; however, the exact pathogenic
mechanism remains uncertain. One hypothesis suggests that the virus
reaches the central nervous system either directly via neural
pathways or indirectly through the ACE2 receptor, resulting in
brain damage that may lead to epilepsy. COVID-19 infection induces
a significant elevation of proinflammatory cytokines in the nervous
system. This ‘cytokine storm’ can disrupt the BBB, increase
concentrations of glutamate and aspartate, reduce gamma amino
butyric acid levels and impair ion channel functions, thereby
enhancing excitability and triggering epileptic seizures (55,56).
Vezzani et al (27)
proposed that viral infections may impact brain parenchyma through
two distinct mechanisms once the virus penetrates the brain: The
first involves the direct viral infection of neurons, causing
neuronal destruction and death, accompanied by the release of
pro-inflammatory cytokines and cellular byproducts acting as danger
signals. The second mechanism involves these pro-inflammatory
cytokines and danger signals activating innate immunity, which
eventually leads to adaptive immune responses and subsequent
immunopathology or tissue damage (27). In the study by Lu et al
(57), which included 304
participants, 108 of whom were severely affected, none had a
documented history of epilepsy, acute symptomatic seizures or
status epilepticus. Among children, there is no concrete evidence
to indicate a connection between COVID-19 infection and the onset
of epilepsy. However, given the potential for inflammatory injury
to the CNS, prospective studies are warranted to monitor long-term
neurological outcomes in pediatric populations. The potential for
COVID-19 to create conditions conducive to epilepsy development has
not been demonstrated, as the clinical progression of COVID-19 in
children is typically milder compared to that observed in
adults.
8. Treatment of seizures and epilepsy
Children experiencing seizures related to COVID-19
and those with pre-existing epilepsy affected by COVID-19 infection
should receive the standard and appropriate treatment for these
conditions. It is important to highlight that certain combinations
of anti-epileptic medications and COVID-19 treatments (e.g., the
combination of eslicarbazepine/lacosamide with
atazanavir/lopinavir/ritonavir) have been reported to result in
severe complications in adult patients (58-61).
Vaccination against SARS-CoV-2 is strongly advised for healthy
children to prevent the spread of the infection. Research has shown
that COVID-19 vaccination does not increase seizure frequency in
the majority of epileptic patients, and no significant interactions
between antiepileptic medications and COVID-19 vaccines have been
documented. In children predisposed to febrile seizures, the fever
induced by the vaccine may potentially trigger seizures; however,
the likelihood of this occurrence is extremely low (59). Particular attention should be paid
to the management of pediatric patients with epilepsy in
resource-limited settings, where access to diagnostic tools and
therapeutic interventions may be reduced during pandemic peaks.
Strategies to ensure continuity of care and seizure control are
essential.
9. Conclusions and future perspectives
According to the data obtained from the literature,
the incidence of seizures in children occurring during the
infection is extremely low. Seizures may be caused by direct
invasion or immune-mediated mechanisms or both conditions in
association. More often, chronic underlying diseases, such as
pulmonary disorders, cardiovascular diseases, immunosuppressive
illnesses, or complications such as MIS-c, obesity and seizures per
se, may be the secondary cause of the onset of seizures and in same
case, may constitute the cerebral environment for the subsequent
development of epilepsy. The incidence of epilepsy as a direct
consequence of COVID-19 infection is not yet known (60-62).
The present review aimed to fill part of the existing knowledge
gaps by summarizing the available clinical reports and highlighting
the importance of the early diagnosis and management of seizures in
children with COVID-19 infection.
Future prospective studies are warranted to better
clarify the associations between SARS-CoV-2 infection and the
possible development of epilepsy during childhood. Clinicians
should be aware of the need for long-term neurological monitoring,
particularly in children with pre-existing comorbidities or severe
disease presentations. Further studies and clinical experiences are
required to address this critical issue.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
GC, PP, RF and AM conceptualized the study. LLV was
involved in the literature search. CP, GN, SS and OA were involved
in the investigative aspects of the review (analyzing the data from
the literature). GC and AM were involved in the writing and
preparation of the original draft of the manuscript. OA, CP and RP
were involved in the writing, reviewing and editing of the
manuscript. PP and RF supervised the study. All authors have read
and agreed to the published version of the manuscript. Data
authentication is not applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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