Journal of

Personalized
Medicine

Review
State of the Art and Challenges in Epilepsy—
A Narrative Review
Aida Mihaela Manole 1,† , Carmen Adella Sirbu 2,3,† , Mihaela Raluca Mititelu 4,5, * , Octavian Vasiliu 6 ,
Lorenzo Lorusso 7 , Octavian Mihai Sirbu 2,8, * and Florentina Ionita Radu 9,10

1 Department of Neurology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital,
010242 Bucharest, Romania
2 Clinical Neurosciences Department, University of Medicine and Pharmacy “Carol Davila” Bucharest,
050474 Bucharest, Romania
3 Centre for Cognitive Research in Neuropsychiatric Pathology (Neuropsy-Cog), Department of Neurology,
Faculty of Medicine, “Victor Babes, ” University of Medicine and Pharmacy, 300041 Timis, oara, Romania
4 Nuclear Medicine Department, ‘Dr. Carol Davila’ Central Military Emergency University Hospital,
010242 Bucharest, Romania
5 Department No.8, University of Medicine and Pharmacy “Carol Davila” Bucharest,
050474 Bucharest, Romania
6 Department of Psychiatry, ‘Dr. Carol Davila’ Central Military Emergency University Hospital,
010242, Bucharest, Romania
7 Neurology Unit—Neuroscience Dept. A.S.S.T.Lecco, Merate Hospital, 23807 Merate, Italy
8 Department of Neurosurgery, ‘Dr. Carol Davila’ Central Military Emergency University Hospital,
010242 Bucharest, Romania
9 Department of Gastroenterology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital,
010825 Bucharest, Romania
10 Department of Gastroenterology, “Carol Davila” University of Medicine and Pharmacy,
020021 Bucharest, Romania
* Correspondence: raluca.mititelu@umfcd.ro (M.R.M.); octaviansirbu@gmail.com (O.M.S.)
† These authors contributed equally to this study.

Abstract: Epilepsy is a common condition worldwide, with approximately 50 million people suffering
from it. A single seizure does not mean epilepsy; almost 10% of the population can have a seizure
during their lifetime. In particular, there are many other central nervous system disorders other
Citation: Manole, A.M.; Sirbu, C.A.; than epilepsy in which seizures occur, either transiently or as a comorbid condition. The impact of
Mititelu, M.R.; Vasiliu, O.; Lorusso,
seizures and epilepsy is, therefore, widespread and easily underestimated. It is estimated that about
L.; Sirbu, O.M.; Ionita Radu, F. State
70% of patients with epilepsy could be seizure-free if correctly diagnosed and treated. However, for
of the Art and Challenges in
patients with epilepsy, quality of life is influenced not only by seizure control but also by antiepileptic
Epilepsy—A Narrative Review. J.
drug-adverse reactions, access to education, mood, employment, and transportation.
Pers. Med. 2023, 13, 623. https://
doi.org/10.3390/jpm13040623
Keywords: seizure; seizure-free; quality of life; epilepsy; education; drug-resistant; medically
Academic Editor: Chiara Villa intractable; pharmacoresistant; surgery; neurosurgery
Received: 23 February 2023
Revised: 18 March 2023
Accepted: 29 March 2023
Published: 1 April 2023 1. Introduction
Epilepsy is a heterogeneous disorder characterized by epileptic syndromes, diverse
etiologies, and variable prognosis. Epileptic seizures are quite common, affecting between
8 and 10% of the population throughout their lifetime and accounting for 1–2% of pre-
Copyright: © 2023 by the authors.
sentations to an emergency room, and about a quarter of these will be first seizure with a
Licensee MDPI, Basel, Switzerland.
different type (Table 1) [1,2].
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

J. Pers. Med. 2023, 13, 623. https://doi.org/10.3390/jpm13040623 https://www.mdpi.com/journal/jpm

J. Pers. Med. 2023, 13, 623 2 of 13

Table 1. The expanded version of the 2017 ILAE seizure-type classification.

Focal Onset Generalized Onset Unknown Onset

Aware Impaired Awareness
Motor
Motor Onset Tonic-clonic
Automatisms Clonic
Atonic Tonic
Clonic Myoclonic
Epileptic spasms Myoclonic-tonic-
Motor
Hyperkinetic clonic
Tonic-clonic
Myoclonic Myoclonic-atonic
Epileptic spasms
Tonic Atonic
Epileptic Spasms
Nonmotor
Nonmotor onset Nonmotor (absence)
Behavior arrest
Autonomic Typical
Behavior arrest Atypical
Cognitive Myoclonic
Emotional Eylied myoclonia
Sensory

Focal to bilateral tonic-clonic Unclassified

Caption: ILAE = International League Against Epilepsy.

2. Definition and Terminology

Epileptic seizure has been defined by the International League Against Epilepsy (ILAE)
as the transient occurrence of signs and/or symptoms as a result of abnormal, excessive, or
synchronous neuronal brain activity [3]. The definition of epilepsy has undergone some
changes, so since 2014, the ILAE has proposed the inclusion of one of the following [4]:
1. At least two unprovoked (or reflex) seizures occurring more than 24 h apart;
2. An unprovoked (or reflex) seizure and the likelihood of subsequent seizures similar
to the overall risk of recurrence (at least 60%—accompanied by clinical, electrical-
electroencephalogram (EEG), or neuroimaging changes) after two unprovoked seizures
occurring within the next 10 years;
3. Diagnosis of epilepsy syndrome [5].

3. Etiology
While some causes of seizures (Table 2) can affect children of any age, others have a
predilection for certain age groups. In newborns, for example, most of them are symptoms
of an identifiable etiology, such as neonatal encephalopathy, a metabolic disorder, or a
systemic infection of the central nervous system. In older infants and young children,
febrile seizures are the most common, age-dependent cause [5]. A structural etiology
is determined when an abnormality is seen on neuroimaging and when the signs and
symptoms of seizures, in combination with electroencephalogram (EEG) data, suggest this
abnormality is the probable cause of the seizures. If the clinical and EEG data are discordant
with the localization of the visible anatomical abnormality, then the imaging modification
is not relevant to the patient’s epilepsy. The structural difference may be genetic, acquired,
or both.
J. Pers. Med. 2023, 13, 623 3 of 13

Table 2. The causes of seizures and epilepsy.

Genetic Structural Metabolic Immune Infectious

o Stroke
o Tumor o Rasmussen
o Mitochondrial
o Childhood absence o Neurodegenerative encephalitis o Neurocysticercosis
disease
epilepsy diseases, Alzheimer o Anti-NMDA Human
o Hyperthermia
o Juvenile absence o Vascular receptor immunodeficiency
o Hyperglicemya
epilepsy, and malformation encephalitis virus (HIV)
o Hypocalcemia
juvenile myoclonic o Head trauma o Autoimunne o Cytomegalovirus
o Hyponatremia
epilepsy o Neural encephalitis o cerebral
o Hepatic
o Dravet syndrome development o Anti–leucine-rich, toxoplasmosis
encefalopahty
lesions, cortical glioma inactivated 1 o Tuberculosis
o Uremic
dysplasia, (anti-LGI1)
encefalopathy
hippocampal encephalitis
sclerosis
Caption: categories of etiology according to the International League Against Epilepsy (ILAE).

4. Clinical Aspects
Seizures in younger children are significantly different from those in older children
and adults (Table 3). Those older than 6 years tend to have seizures similar to adults, while
younger children have fewer complex behaviors, especially focal seizures with impaired
consciousness [6].

Table 3. The most common syndromes in children.

- Occurs between 3 and 12 months.

West Syndrome - Consists of the triad: epileptic spasms, hypsarrhythmia, and psychomotor retardation.
- It may also be a precursor to Lennox–Gastaut syndrome [7].
- Onset in the first 18 months of life, which may be with focal seizures, some with secondary
bilateralization, usually triggered by fever or hyperthermia.
- Absence-type, myoclonic, focal, and reflex seizures may also occur in preschoolers on
Dravet Syndrome
photostimulation or hyperventilation.
- Initially, intellectual capacity is not affected, but over time, as the number of seizures
increases, cognitive impairment can be severe [8].
- can be simple or complex
- Simple febrile seizures are usually generalized, last less than 15 min, and do not recur over a
24-h period.
Febrile seizure
- Complex seizures also occur after the age of 6 years, accompanied by fever or not, and may be
the basis of Dravet syndrome, myoclonic–atonic epilepsy, and hippocampal sclerosis; they are
focal, prolonged, and may recur over 24 h.
- Is a type of self-limiting epilepsy, presenting with focal seizures with the clonic or tonic
activity of a part of the face or tongue and oral paresthesia.
Benign rolandic epilepsy - Focal seizures are more frequent in young children, and progression to bilateralization is
frequent during sleep and may be associated with a post-critical deficit, Todd’s palsy.
- Psychomotor development in this situation is normal [9].
- The onset is sudden and lasts 20–30 s and can occur up to 50 times a day, and can be
Typical absence seizure complicated in 40% of cases by generalized tonic–clonic seizures.
- It may be associated with palpebral myoclonus and may be triggered by hyperventilation [8].
- Includes the triad: generalized, tonic, atonic, myoclonic, and atypical absence seizures,
peak-wave complex EEG interictal changes, and psychomotor retardation.
- Nocturnal tonic events are characteristic of this syndrome but are difficult to recognize
Lennaux– Gastaut
without video-electroencephalogram monitoring.
syndrome
- Negative prognostic factors are psychomotor retardation preceding seizures, history of
epileptic spasms, the onset of symptoms before the age of 3 years, increased seizure frequency,
and recurrence of non-convulsive status epilepticus [10].
- Is the most common form of genetic epilepsy.
Juvenile Myoclonic - Patients usually present with a generalized tonic–clonic seizure, often caused by sleep
Epilepsy deprivation, alcohol ingestion, stress, or intermittent light stimulation, although on a
thorough history, most patients have had morning myoclonus [11].
J. Pers. Med. 2023, 13, 623 4 of 13

Focal epilepsy can develop at any time of life, and the etiology varies according to age,
as does the semiology vary according to location as well:
Temporal lobe epilepsy is one of the most typical regions. Many patients present with
aura, which may include „deja vu,” „jamais vu,” and „butterflies in the stomach”—epigastric
aura, fear, dyscognitive phenomena, or olfactory symptoms [12]. The aura is usually fol-
lowed by impaired/maintenance of consciousness but with the appearance of oromandibu-
lar or brachial automatisms or even dystonic postures. Symptomatology associated with the
nondominant lobe may include nausea and vomiting. The seizure lasts between 60 and 90 s
and is followed by a state of confusion which predominates in patients with dominant-lobe
damage [13]. If the focus is in the lateral area of the temporal lobe, perisylvian, the eloquent
areas, Wernicke’s area, or primary and secondary auditory cortex are affected, leading to
an aphasia-type language disorder or auditory aura. Localization at the temporo-occipital
junction may associate with vertigo symptoms or visual aura. The aura may progress to a
capped gaze followed rapidly by bilateralization [14].
Frontal lobe epilepsy is the second-most-frequent location. Compared to the previous
one, seizures are predominantly motor, of shorter duration, and have a nocturnal onset.
The postictal period is characterized by a rapid return of awareness and may occasionally
be associated with a motor deficit. Regarding semiology, it is divided into the primary
motor area, somatomotor area, orbitofrontal, dorsolateral, and opercular regions. Most
of them are associated with predominantly motor phenomena, but those in the posterior,
opercular zone can easily be mistaken for temporal lobe epilepsies through gaze capping,
automatism, and head and eyeball versa. Asymmetric tonic seizures, which are described
as tonic flexion of one arm and extension of the other, with or without tonic involvement of
the lower limbs, are associated with activation of the Brodmann area [15,16].
Parietal and occipital lobe epilepsy. In this case, this type of localization is much rarer
than the others. The occipital region is associated with elementary visual hallucinations,
unlike the temporal lobe, where complex visual hallucinations occur [17]. Parietal lobe
epilepsy may present with a somatosensory aura, which may be unilateral or bilateral. Both
types can spread rapidly and may mimic/associate semiological elements [18].

5. Diagnostic of Epilepsy
First of all, the diagnosis of epilepsy is a clinical one, and the other additional tests
are supportive. For an accurate diagnostic, there are some paraclinical tests illustrated in
Table 4. The first thing to consider in correctly diagnosing epilepsy is to determine whether
a paroxysmal clinical event is actually an epileptic seizure or another pathology. For the
differential diagnosis, we must consider all the causes of episodes of altered consciousness,
altered mental status, motor or sensory manifestations, and seizures, which are common in
other epilepsies. For epileptologists, it is often easy to recognize different forms of epilepsy
when they are able to obtain a clear history of events. However, at the same time, even the
most experienced epileptologists have great difficulty in reaching an unequivocal diagnosis
for various reasons, such as atypical seizure presentations, inadequate or incomplete
historical data, or overlapping symptomatic manifestations.

Table 4. Paraclinical examinations in epilepsy.

Test Result
Electroencephalogram (EEG)
EEG helps us to complete the diagnosis of epilepsy, choose
Focal spikes or sharp waves with associated slowing of the
appropriate therapy, monitor response to treatment, and
electrical activity in the area of the spikes.
determine candidates for antiepileptic drug withdrawal and
surgical localization.
J. Pers. Med. 2023, 13, 623 5 of 13

Table 4. Cont.

Test Result
Video-electroencephalogram (EEG) long-term monitoring
(LTM)
Video-EEG recording is useful and indicated in patients with Capturing seizure activity simultaneously on video recording
suspected psychogenic seizures, for epilepsy classification, and and EEG; increased EEG sampling may reveal evidence of
especially in those with pharmacoresistant focal epilepsy, interictal abnormalities (spikes and sharp waves), which may
possible candidates for epilepsy surgery. It is also helpful in make the diagnosis of focal seizures more likely.
intensive care units in the evaluation of encephalopathies and
non-convulsive status epilepticus.
CT head
Usually ordered in emergencies in patients presenting with a
first seizure episode (37). It is useful for identifying acute causes Structural lesions
of seizures but is less sensitive to smaller abnormalities often
seen on MRI.
MRI brain
Neuroimaging helps us to identify the underlying etiology of
focal or generalized seizures and the location of the
epileptogenic area and to determine the surgical location in
focal pharmacoresistant epilepsies [19].
Structural injuries (mesial
The optimal MRI technique for patients with focal seizures is 3
temporal sclerosis, neoplastic lesions, vascular malformations,
Tesla studies with coronal, axial, and sagittal T1, T2, and FLAIR
and developmental lesions).
sections [20]. The epilepsy protocol should also include a 3D T1
with a volumetric acquisition, which allows better assessment of
cortical dysplasia or discrete focal lesions [21]. FLAIR has a 97%
accuracy in detecting abnormalities, especially temporal
sclerosis [22,23].
PET scan
Part of the surgical evaluation of treatment drug-resistant focal Ictal-hypermetabolic; interictal-hypometabolic
epilepsy.
Laboratory test Extreme hypoglycemia or hyperglycemia can cause provoked
- Blood glucose focal seizures.
- Toxicology screen
- FBC
- Electrolyte panel
- Lumbar puncture is indicated when CNS infection or an
immune etiology is suspected.
Genetic testing
Genetic testing is increasingly available for a number of
inherited syndromes but has variable clinical utility depending
on the clinical and genetic heterogeneity of a syndrome [24,25].

Thus, the misdiagnosis of epilepsy is a huge medical problem with a significant

impact on the patient. Many disorders can mimic epileptic seizures (Table 5), but this
is also possible the other way around; some seizures can mimic symptoms of other dis-
eases. This can happen in patients with non-epileptic disorders who may be misdiagnosed
and automatically mismedicated. Also, patients with epileptic seizures may be misdiag-
nosed as migraine, encephalitis, or other paroxysmal non-epileptic events and are likely
to be mismanaged with treatments that cannot help them and also deprived of specific
therapies [26].
J. Pers. Med. 2023, 13, 623 6 of 13

Table 5. Epilepsy mimics.

Condition Differentiating Signs/Symptoms

Vasovagal syncope usually has prodromal sensations of dizziness, nausea, and
diaphoresis, often caused by the change of position, physical exertion, Valsalva
maneuvers, and strong emotional impact. The loss of consciousness is short-lived;
Syncope if it persists, convulsive movements may occur, and confusion may arise between
the diagnosis of syncope and epileptic seizure. Post-critical confusion and urinary
incontinence are rare in this situation. Cardiogenic syncope is usually the result of
bradyarrhythmia or tachyarrhythmia disorders [27].
The clinical features depend on the duration of the ischemia, the territory of the
vasculature affected, and the anatomical location. Transient ischemic attacks
typically last from a few minutes to an hour, usually. Cerebrovascular disease is
Cerebrovascular disease usually associated with negative signs such as muscle weakness, aphasia, and
decreased visual acuity. Epileptic seizures are associated with positive signs in the
ictal period but post ictally may have negative signs, confusing with stroke, in
which situations-imaging and video-EEG clarify.
May have clinical similarities similar to an epileptic seizure, such as visual,
Migraine sensory, or dyscognitive phenomena. However, the mechanism is different, and it
is quite rare for an epileptic seizure to follow a migraine.
Dyskinesias, paroxysmal dystonia, or tremor can mimic a focal epileptic seizure.
Movement disorders Normal EEG during these movements and carefully studied semiology
differentiate the two pathologies.
Another easily confusing category is REM sleep disorders, parasomnias.
Non-REM parasomnias involve confused behavior with or without vocalization
Sleep disorders and sleepwalking. Patients with REM sleep disorders often behave violently,
dreaming that they are being attacked or chased, with the risk of injury during
these episodes. Polysomnography is required to confirm the diagnosis.
Usually occurs in people older than 50 years.
Transient global amnesia
Sudden onset of amnesia that lasts for several hours. Patients maintain alertness
but are confused and ask questions repeatedly.
PNES can be distinguished by spontaneous closing and opening of the eyes,
associated with volitional head movements of „yes-yes” or „no-no” and
Psychogenic non-epileptic seizures (PNES)
prominent thrusting of the pelvis [28]. Correct diagnosis is usually based on the
semiology of the event and the absence of an epileptiform EEG correlate.

6. Evolution, Complication, and Prognostic

In general, prognosis refers to the likelihood of not having a seizure after starting
the treatment. Most people have a good prognosis for complete seizure control and
eventual discontinuation of antiepileptic medication, but epilepsy syndromes have different
treatment responses and outcomes. Prognostic factors include etiology, EEG pathology
changes, seizure type and number, and therapeutic response. Early feedback to treatment is
an important long-term positive predictor, while a history of a large number of seizures at
diagnosis, intellectual disability, and symptomatic etiology are negative predictors. Patients
with epilepsy have a higher mortality risk than the general population [29].
Attention is paid to reducing seizure frequency, and severity, and to treatment man-
agement. However, quality of life is also determined by other factors: impact of diagnosis,
adverse effects of medication, driving, education, employment, and independence.
Patients with this pathology have a higher risk of psychiatric diseases, including
depression, anxiety, and attention-deficit disorders. Despite the implications of life quality,
depression in epilepsy is under-detected and underdiagnosed. In this category, we can add
cognitive impairment, a common problem. It depends on several factors: seizure frequency,
type of treatment, early onset, interictal discharges, educational level, and polypharmacy. It
can manifest differently depending on the area or areas affected, such as memory disorder,
J. Pers. Med. 2023, 13, 623 7 of 13

executive dysfunction, slowed psychomotor speed, sustained attention-deficit disorder,

visual-spatial disorder, and anomic aphasia.
Another complication can be an increased risk of injury, which is attributable to
seizures due to falls. Additional risk factors are epilepsy not under therapeutic control,
seizures with altered consciousness, and therapeutic neglect. Sequelae can lead to shoulder
dislocation, vertebral fractures, and in more severe cases, subdural hematoma [30].
The most often cause of death straight associated with epilepsy is SUDEP, sudden
unexpected death in epilepsy, in which autopsy reveals no other anatomical or toxicological
explanation. A couple of risk factors have been identified: the presence of generalized
tonic–clonic seizures, >3 generalized tonic–clonic seizures per year, and uncontrolled, phar-
macoresistant epilepsy. The majority of patients, around 70%-80%, are well-controlled
therapeutically. Pharmacoresistant epilepsy is, according to the ILAE, failure of two tol-
erated antiepileptic drugs, appropriately chosen and used, either as monotherapy or in
combination [31]. One of the neurological emergencies is status epilepticus, which is associ-
ated with a higher probability of mortality and morbidity. It is not a single entity; it has a
number of different aspects, forms, and a wide range of etiologies. Currently, the accepted
definition is either a seizure lasting at least 5 min or two or more seizures with incomplete
recovery of consciousness. In contrast, non-convulsive status epilepticus is defined as status
epilepticus without prominent motor symptoms lasting more than 10 min [32]. Refractory
status epilepticus refers to the clinical and electroencephalographic persistence of seizures af-
ter initiation of line 1 benzodiazepine and line 2 treatment. Super refractory status epilepticus
is defined by a prolonged frequency of seizures 24 h after initiation of anesthetic treatment.
Suportting the factors described above, some studies have shown an increased incidence
of seizures directly proportional to environmental factors such as ambient temperature,
methane (CH4), and nitric oxide (NO). Moreover, the average daily number of hospital
visits was significantly high in January and February than in other months of the year.
Some seizures may be caused by an underlying etiology, such as cerebral hemorrhages,
and the risk of their occurrence depends on variations in temperature and atmospheric
humidity [33].

7. Healthcare of people with Epilepsy

There are different types of epilepsy involving the frequency and severity of seizures.
By their nature, they are often unpredictable and sporadic. The purpose is to keep the equi-
librium between restrictions planned to keep health and safety during the ictal period with
sustaining a full and active lifestyle during seizure freedom. Quality of life is determined
not only by seizure control but also by side effects of medication, relationships, school
education, employment, and transport. Well-being not only includes illness-therapeutic
control but also mental state, lifestyle elements such as employment, and resources. A
secondary reaction is the major impact as a financial cost to society. In the USA, the total
spending on this disease reached 12.5 billion dollars, of which 85% is the not directly
related expenses. For these people, these costs are also countable in days lost from work
and school, unemployment, social isolation, poor social life, and minimal emotional and
financial support [34].
One of the major issues is the high incidence of psychiatric disorders. Meta-analyses of
population-based studies indicate a cumulative lifetime prevalence of 23% for depression
and 20% for anxiety. In addition, they have been shown to be twice as likely to have suicidal
thoughts and up to 3 times more likely to die by suicide compared to the general popula-
tion [35,36]. Unfortunately, depression can occur at any time of life or age and can precede
the onset of seizures. Furthermore, the severity of depression is directly proportional to an
increased likelihood of uncontrolled seizures and has been correlated with lower adherence
to antiepileptic drugs [37]. Even though the implications are potentially serious in terms of
quality of life, depression in epilepsy is underdiagnosed. One reason for this may be the
difficulty in differentiating between its symptoms: fatigue, insomnia, and cognitive decline,
from the side effects of antiepileptic therapy. In this context, research has shown that in
J. Pers. Med. 2023, 13, 623 8 of 13

terms of cognitive impairment, older-generation antiepileptics (carbamazepine, valproate)

are clearly inferior to newer ones (lamotrigine and levetiracetam). Topiramate has the
greatest negative effects on cognition. In order to prevent or keep these disorders under
control, health professionals can perform neuropsychological testing. This can pinpoint
areas of deficiency for the patient, and then we can develop strategies to overcome them
(i.e., treatment optimization, memory exercises: meditation, crosswords, puzzles, Sudoku,
chess). Another problem is regarding the family members, who may also attribute these
signs to a “normal” response to seizure-induced limitations and, therefore, will not inquire
about any investigation. Recognition can be improved by the use of screening tools for
depression that have been validated in these cases [38]. The choice of antiepileptic therapy
can also have an impact on mental status, for better or worse. One expert recommendation
in this regard includes the use of an antiepileptic with mood-stabilizing properties, such as
lamotrigine or valproate, as well as avoiding drugs with emotional side-effect-increasing
properties. Lamotrigine has been shown in two randomized, double-blind trials to improve
emotional status after 7 to 8 weeks of treatment [39,40]. Another issue with emotional
impact is driving. In a survey of people with epilepsy, driving was rated as the main con-
cern that impacts the quality of life. The ability to drive can influence work performance,
preserve relationships, and live independently. It is not difficult to conceive that a seizure
with loss of consciousness while driving could have catastrophic effects [41]. Seizures with
impaired consciousness can lead to burns, drowning, and motor vehicle accidents. Most
related incidents are of low to moderate severity and generally include lacerations, frac-
tures, dental injuries, contusions, and burns. Serious injuries such as subdural hematomas
or death by drowning occur, but rarely [42].
One of the most important strategies to reduce the risk of injury is to improve seizure
control. Risk strategies for prevention must be personalized to the direct factors closely
associated with epilepsy, such as seizure characteristics, recurrence, timing (sleep versus
wake), and other triggers. It is also important to consider data appropriate to the patient
profile, such as age, cultural and social norms of the patient, and family. Too many measures
for prevention may determine the lack of involvement in healthy habits, which reduces
their social life and may inhibit the patient from achieving autonomy. A few strategies have
been selected to reduce the risk of seizure-related injury:
• Wear a helmet when cycling or horseback riding;
• No unsupervised swimming;
• It is advisable to use the shower, not the bathtub;
• Water temperature control of the hot water heater to reduce the risk of scalding;
• Use a microwave oven, not a stove;
• Avoid locking the toilet or bedroom door;
• The height of the bed should be small in order to avoid possible post-crash injuries;
• It is preferable to use an epilepsy safety pillow (made to reduce the risk of suffocation
if sitting face down);
• Be careful of high stairs;
• Beware of driving rules for patients with epilepsy;
• Administration of medication according to the scheme-continuum.
An important problem for this kind of patient is the shift from childhood to adult-
hood. Transition involves multiple medical resources to provide for the young adult’s
psychosocial, educational, and therapeutic needs. At a minimum, this involves the coordi-
nation between health professionals to ensure proper continuity of treatment management
and ensuring the transfer of the necessary information about the patient. To the extent
possible, they should achieve some skills in different types of areas of self-care so that
they are prepared to increase their empowerment regarding their healthcare needs. In
children with inherited metabolic disease, the elementary healthcare provider is commonly
either a pediatric neurologist or a metabolic pediatrician. While in the changeover from
pediatric to adult neurologist, the biggest issue may be exaggerated patient and/or fam-
ily anxiety, which is entirely resolved with proper coordination, the transition between
J. Pers. Med. 2023, 13, 623 9 of 13

metabolic medicine specialists is usually difficult due to a deficit of adult specialists in

this domain [43]. EuroNASH: European Audit of Seizure management in Hospitals and
the European Study of Burden and Care in Epilepsy (ESBACE) will provide guidance for
better management and use of investigations in people with seizures [44]. These things
combined draw our attention to the needs of these patients and the care we need to take
in managing both the underlying disease and adjacent ones, which may or may not be
secondary to treatment.

8. Treatment of Epilepsy—Principles of the Current Status

The major determinants in the selection of antiepileptic therapy are the types of seizure
and epilepsy. Classification of seizures into focal and generalized help us in choosing the
appropriate treatment. However, in children, it has specific age-dependent characteristics,
with seizure types and syndromes involving therapies rarely used in adults. There are some
syndromes, such as Lennox–Gastaut, where seizure frequency is very high and requires
polytherapy, but there are also childhood epilepsies with benign character, centrotemporal
and occipital spike epilepsy, where long-term medication is not required.
The decision to initiate an antiepileptic lean on whether the diagnosis of epilepsy is con-
firmed. Aspects that help raise the risk of recurrence implicate the presence of an abnormal
clinical examination, imaging abnormalities, nocturnal seizures, and abnormal EEG.
Two types of seizures in children, epileptic spasms and typical absence seizures, have
unique treatment options. Factors that help in choosing the right antiepileptic depend on:
• Epilepsy characteristics: seizure type, seizure frequency, specific epilepsy syndrome;
• Patient characteristics: gender, age, comorbidities, pregnancy, allergies, current and
previous medication;
• Drug characteristics: efficacy, adverse reactions, drug interactions, half-life, titration,
risk of teratogenicity, interaction with oral contraceptives, liquid/solid form;
• Socio-economic characteristics: cost, availability, personal choice.
Results of the meta-analysis demonstrated that for focal seizures, lamotrigine and lev-
etiracetam were considerably superior to carbamazepine, which was better than phenytoin
and phenobarbital. Regarding generalized seizures, valproic acid was superior to topira-
mate, carbamazepine, phenytoin, and phenobarbital. In newly diagnosed focal epilepsies,
carbamazepine and lamotrigine were superior, and levetiracetam and perampanel had
some advantages in treatment-refractory epilepsies [45].

9. Drug-Resistant Epilepsy
Epilepsy is considered drug resistant if at least two appropriately chosen and used
antiseizure medications have failed to control seizures [46].
Various anticonvulsant drugs are available for the treatment of focal epilepsy with
seizures refractory to a first or alternative monotherapy. Anticonvulsant drugs that are cur-
rently used in clinical practice as adjunctive treatments include lamotrigine, oxcarbazepine,
levetiracetam, pregabalin, clobazam, zonisamide, eslicarbazepine acetate, brivaracetam,
gabapentin, lacosamide, topiramate, valproate, vigabatrin, and perampanel [47].
In cases with idiopathic generalized epilepsy, approximately 35% of them will require
adjuvant therapy. In some studies, perampanel has been demonstrated to reduce seizure
frequency by 76.5%. Other antiepileptics such as Lamotrigine, Levetiracetam, and Topira-
mate have shown efficacy in first generalized tonic–clonic seizures not controlled by a first
or additional monotherapy [48].
There are situations where monotherapy cannot succeed, and the addition of a second
antiepileptic is necessary. The choice of an adjuvant is difficult because issues of efficacy,
tolerability, pharmacokinetic properties, drug interactions, and frequency of administration
must be taken into consideration. Therefore, in order to have an ideal and rational poly-
therapy, some criteria should be met: synergistic effects (their mixed effectiveness should
be higher than the sum of the efficacy of each individual anticonvulsant drug) and infra-
additive toxicity (their summed toxicity should be lower than the individual one). Preferred
J. Pers. Med. 2023, 13, 623 10 of 13

combinations are those that have different mechanisms of action or that have multiple
mechanisms of action [49]. For generalized epilepsies, the combination with the maximal
evidence for synergistic potency is valproic acid and lamotrigine. Patients who have not
reacted to the top-tolerated dose of lamotrigine or valproic acid may have seizure control
by combining them. In some patients with Dravet syndrome, Lennox–Gastaut syndrome,
cannabidiol can be used, an enzyme-inhibiting drug that can boost serum concentrations of
the active metabolite of clobazam [50].
Other options for patients with pharmacoresistant epilepsy include surgery, the use
of neurostimulation (vagus nerve stimulation (VNS), responsive neurostimulation (RNS),
deep-brain stimulation (DBS)), and modern minimally invasive techniques, laser interstitial
thermal therapy (LITT), and stereotactic radiosurgery.
Candidates with focal epilepsy for resective surgery can be divided into:
• Mesial temporal lobe epilepsy or neocortical epilepsy;
• Lesional epilepsy due to focal structural pathology (low-grade glioma, cavernous
malformation);
• Nonlesional focal epilepsy.
Patients with drug-resistant focal epilepsy require pre-surgical evaluation to properly
determine and define the epileptogenic area to be removed, subsequently to have a chance
to be seizure-free. For this purpose, a history is taken with the semiology of epileptic
seizures, frequency, and duration in order to better understand their location and epilepsy
subtype. An important marker is video-EEG monitoring to observe interictal, ictal changes,
and correspondence between symptoms and location of seizure onset. In some situations,
antiepileptic treatment is reduced to increase the possibility of seizure recording and make
sure that the patient is having only one type of seizure [51,52].
High-resolution brain imaging with epilepsy protocol is necessary to detect potential
abnormal structures that may be the cause of epileptic seizures. Neuropsychological testing
is necessary to detect any pre-surgical deficits that may be correlated with the seizure-onset
area and to predict possible postoperative deficits. Positron emission tomography (PET)
has proven to be useful, especially in cases with negative MRI; there may be areas of
hypometabolism that can confirm the epileptogenic site [53]. Once these investigations are
completed, and there is a reliable correlation between the symptoms and their outcome,
surgery can be performed. Otherwise, when in doubt, investigations should continue with
intracranial EEG monitoring. Intracranial EEG is also necessary when the seizure-onset
zone is close to the eloquent cortex.
Neurostimulation therapy may help patients with drug-resistant epilepsy who present
contraindications for epilepsy surgery or have epileptogenic regions close to the eloquent areas.
In general, a significant amount of epilepsy exploration endeavors have been centered
on the development of treatments and surgical interventions, but few clinical trials have
evaluated medical services, and etiologies, and there has been less evaluation of the process
of care and affiliated outcomes and costs.
It is well known that air pollution is also an important negative factor in exacerbating
neurological pathologies, epilepsy being no exception. That is why we need to create new
strategies and mechanisms to reduce its negative effects on the nervous system and mental
health [54,55].

10. Conclusions
Informing patients about all aspects of this pathology, such as triggers of seizures,
adverse reactions of treatment, and possible risks to which they are susceptible, can be
considered an important step in the management and, implicitly, in easier integration into
society. When doing so, it is important to consider the wider population, as those without
specialist care are likely to have poorer outcomes, which could be improved if outpatient
care were more accessible. These things combined draw our attention to the needs of these
patients and the care we need to take in managing both the underlying disease and adjacent
ones, which may or may not be secondary to treatment.
J. Pers. Med. 2023, 13, 623 11 of 13

Author Contributions: Conceptualization, C.A.S. and A.M.M.; methodology, A.M.M., C.A.S., O.V.
and O.M.S.; software, A.M.M., C.A.S., M.R.M. and L.L.; validation, M.R.M., O.V., L.L. and F.I.R.;
formal analysis, M.R.M., O.V., L.L. and O.M.S.; investigation, A.M.M. and C.A.S.; resources, O.V.,
L.L., O.M.S. and F.I.R.; data curation, M.R.M., O.M.S. and F.I.R.; writing—original draft preparation,
A.M.M. and C.A.S.; writing—review and editing, A.M.M. and C.A.S.; visualization, O.M.S. and F.I.R.;
supervision, A.M.M. and C.A.S.; project administration, C.A.S. and A.M.M. All authors have read
and agreed to the published version of the manuscript.
Funding: Publication of this paper was supported by the University of Medicine and Pharmacy Carol
Davila through the in-stitutional program Publish not Perish.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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