Received: 8 June 2018 Revised: 21 August 2018 Accepted: 23 August 2018

DOI: 10.1002/ajmg.c.31652

RESEARCH REVIEW

Current concepts on epilepsy management in tuberous

sclerosis complex
Maria Paola Canevini1 | Katarzyna Kotulska-Jozwiak2 | Paolo Curatolo3 |
Francesca La Briola1 | Angela Peron1,4  ska2,5 | Jolanta Strzelecka5 |
| Monika Słowin
Aglaia Vignoli1 | Sergiusz Jóźwiak2,5

1
Child Neuropsychiatry Unit - Epilepsy Center,
San Paolo Hospital, Department of Health Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting
Sciences, Università degli Studi di Milano, approximately 1 in 6,000 people, and represents one of the most common genetic causes of
Milan, Italy
epilepsy.
2
Department of Neurology and Epileptology,
Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of
The Children's Memorial Health Institute,
Warsaw, Poland them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cogni-
3
Department of Pediatric Neuropsychiatry, Tor tive decline and neuropsychiatric problems including autism.
Vergata University, Rome, Italy Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique
4
Division of Medical Genetics, Department of opportunity to monitor EEG before the onset of clinical seizures, thus enabling early interven-
Pediatrics, University of Utah, Salt Lake tion in the process of epileptogenesis.
City, Utah
5
In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and pre-
Department of Pediatric Neurology, Warsaw
Medical University, Warsaw, Poland
sent recommendations of American and European experts in the field of epilepsy.

Correspondence
Aglaia Vignoli, Child Neuropsychiatry Unit - KEYWORDS
Epilepsy Center, San Paolo Hospital, epilepsy, seizures, tuberous sclerosis complex
Department of Health Sciences, Università
degli Studi di Milano, Via Di Rudinì 8, 20142
Milano, Italy.
Email: aglaia.vignoli@unimi.it
Funding information
EPIMARKER, Grant/Award Number:
STRATEGMED3/306306/4/2016 ;
FP7/2007-2013; EPISTOP, , Grant/Award
Number: grant agreement no. 602391; Polish
Ministerial funds for science ; Research and
Development, Grant/Award Number:
STRATEGMED3; EC Seventh Framework
Programme, Grant/Award Number: FP7

1 | INTRODUCTION
Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant
condition characterized by the development of multiple hamartomas.
The most frequently affected organs are the brain, kidneys, heart, liver,
and lungs, although other organs (i.e., pancreas, spleen, and thyroid
gland) may show signs of TSC as well. Recent studies indicate that the
incidence of TSC is at least 1 in 6,000 live births. However, the true
incidence seems to be underestimated, as some mosaic patients may
be difficult to diagnose (Jozwiak, Domanska-Pakieła, Kwiatkowski, &
Kotulska, 2005). Molecular studies have identified two genes that are
responsible for the manifestations of TSC: TSC1 (on chromosome
9q34) and TSC2 (on chromosome 16p13).
In addition to the typical lesions of TSC represented by hamarto-
mas, neurologic issues represent one of the most important clinical
problems. They consist of high risk of seizures, intellectual disability
(ID), autism spectrum disorder (ASD), and other behavioral disorders
(Henske, Jóźwiak, Kingswood, Sampson, & Thiele, 2016), and appear
in 85–90% of the patients with this condition. Among them, epilepsy
is the most common symptom, present in 80–90% of the patients and

Am J Med Genet. 2018;178C:299–308. wileyonlinelibrary.com/journal/ajmgc © 2018 Wiley Periodicals, Inc. 299

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appearing mainly in the first 2 years of life. Seizure control is therefore
a critical issue in the clinical management of individuals with TSC.
The importance of epilepsy and ID in TSC was already recognized
by Vogt in 1908 in his first set of diagnostic criteria (Vogt's triad): epi-
lepsy, ID (formerly referred to as mental retardation), and adenoma
sebaceum (angiofibroma) (Vogt, 1908). Recent years have brought sig-
nificant progress in the diagnosis and treatment of epilepsy and its
comorbidities in TSC. Animal studies demonstrating the efficacy of
early or preventative treatment (Zeng, Xu, Gutmann, & Wong, 2008),
the increasing use of Electroencephalogram (EEG) as a biomarker of
ska-Pakieła et al., 2014), the first clinical pre-
epileptogenesis (Doman
ventative trials in infants and children younger than 2 years of age
(EPISTOP and PREVENT trials), and the approval of mTOR inhibitors
in the United States and in Europe as antiepileptic drugs (Curatolo
et al., 2016), are among the most important turning points in epilepsy
treatment in TSC.
2 | PATHOGENESIS OF EPILEPSY IN TSC
Genetic mutations in either TSC1 or TSC2 lead to overactivity of the
mammalian target of rapamycin (mTOR) pathway, an intracellular sig-
naling pathway involved in cell growth and proliferation, protein syn-
thesis, and metabolism (Curatolo, 2015). mTOR is a serine/threonine
kinase exerting its activity in response to nutrients and growth factors,
and plays a significant role in the regulation of synaptogenesis, axonal
polarization, and myelination (Curatolo, 2015). mTORC1 signaling is
activated early during brain development, and pathological neural net-
works with cellular, molecular, and functional abnormalities are
already present in the prenatal period (Prabowo et al., 2013). This
early hyperactivation of mTOR might lead to abnormalities of migra-
tion and orientation of neural cells, leading to abnormal cortical lami-
nation and dendritic arborization. The alteration of this crucial
pathway also includes the disruption of GABAergic interneuron devel-
opment as well as the regulation of the glutamatergic function via ino-
tropic glutamate receptors. This corresponds to an imbalance
between excitation and inhibition, which is an obvious predisposing
factor to epileptic seizures (Curatolo, 2015). From a neuropathologic
point of view, the early dysregulation of the mTOR pathway, causing
altered migration and cell morphology, leads to the formation of
tubers including different abnormal cells, such as dysplastic neurons
and giant cells. Tubers are the hallmark of TSC pathology, and can be
already visible on fetal magnetic resonance imaging (MRI) during prena-
tal life. They are dynamic lesions, and changes within tubers, through
pre- and postnatal life, may contribute to the establishment of exten-
sive epileptogenic networks (Curatolo, Moavero, Van Scheppingen, &
Aronica, 2018). Tubers represent focal malformations of cortical devel-
opment, and are characterized by loss of the hexalaminar cortical archi-
tecture, presence of an excessive number of astrocytes, and by
dysmorphic neurons and giant cells (Curatolo et al., 2018). Although
tubers are the most evident lesions, for which there is a documented
link with epilepsy, many other structural and microstructural lesions are
found in the TSC brains. In particular, mTOR alteration leads to focal
dyslamination and isolated giant cells even in the absence of major
structural abnormalities, resulting in global and focal network changes
CANEVINI ET AL.
that may play a role in both epileptogenicity and abnormal neurodeve-
lopment. White matter appears to be extensively involved too; in fact,
white matter migration lines are seen in over one third of TSC patients
at conventional brain MRI as a result of abnormal migration (Curatolo,
Moavero, & De Vries, 2015). However, also normal appearing white
matter can be interested by microstructural changes that are visible
when diffusion tensor imaging is performed, and can be linked to epi-
leptogenesis (Widjaja et al., 2010). Furthermore, white matter abnor-
malities appear to be more evident in children with early onset and
refractory epilepsy with persistent seizures seeming to determine
extensive connectivity alterations in areas of the brain that are crucial
for language, social development, and global intellectual functioning
(Moavero et al., 2016).
3 | N A T U R A L CO U R S E OF E P I L E P S Y I N TS C
The first large studies addressing epilepsy in TSC reported generalized
seizures—and specifically infantile spasms—as the most common type
of initial seizures, appearing between the fourth and the sixth month
of life (Gomez, 1988). In recent years, prenatal diagnosis of TSC has
been available in an increasing number of patients, resulting in the dis-
covery of 5–6% of TSC patients with neonatal presentation of epi-
lepsy, with the majority of them exhibiting large cortical dysplasias
brain MRI (Kotulska et al., 2014).
However, in current clinical practice epilepsy onset is mostly
diagnosed at the age of 3 months (Chu-Shore, Major, Camposano,
Muzykewicz, & Thiele, 2010). One of the main reasons is because
short-lasting subtle focal seizures, such as unilateral tonic or clonic
phenomena, localized to the face or limbs, may be easily overlooked
by caregivers. In fact, Whitney, Jan, Zak, and McCoy (2017) described
two infants with electroencephalographic seizures on video-EEG
(vEEG) and accompanying head and eyes deviation to one side and arm
extension lasting for 10–15 s, which had not been not recognized by
the parents.
Patients often manifest focal seizures from multiple independent
foci, either simultaneously or sequentially. If not diagnosed, focal sei-
zures become longer and generalized. Eventually, infantile spasms are
observed with concomitant hypsarrhythmia on EEG.
Focal onset seizures evolve into infantile spasms in approximately
one third of the patients with TSC. Infantile spasms in TSC can be flexor,
extensor, or mixed and can have lateralizing features such as head turn-
ing, tonic eye deviation, and asymmetric or unilateral involvement of the
extremities. In a group of 291 patients treated at Massachusetts General
Hospital in Boston, 37% had a history of infantile spasms. Infantile
spasms, age at seizure onset and refractory epilepsy each correlated with
poor cognitive outcome (p < .0001) (Chu-Shore et al., 2010).
Kaczorowska et al. (2011) documented a correlation between the
number of cortical tubers and age at epilepsy onset. Mean tuber count
in children younger than 6 years of age was 23.58, and decreased to
14.73 in children older than 12 years, in contrast to a mean tuber
count of 7.5 in TSC patients without epilepsy.
Most patients with TSC develop multiple seizure types. Children
with TSC may have mixed seizures such as atypical absences, tonic
and tonic–clonic, myoclonic, or atonic seizures. In about 25–30% of
CANEVINI ET AL.
the patients, especially those with a history of infantile spasms, epi-
lepsy evolves into Lennox-Gastaut syndrome (Chu-Shore et al., 2010).
Of 248 TSC patients with epilepsy, 155 (62%) developed refractory
epilepsy (Chu-Shore et al., 2010), which is two times higher the num-
ber of drug resistant epilepsy in the general population with epilepsy.
Similarly, Jeong, Nakagawa, and Wong (2017) in their large Natural
History Database including 2,034 TSC patients, found a high inci-
dence of drug-resistant epilepsy, reaching 59.6% in children with focal
seizures.
4 | E V O L U T I O N O F E E G C H A R A C T ER I S T I C S
Early diagnosis of TSC in infants, even before the onset of clinical sei-
ska et al., 2018). The regular EEG
zures, is currently feasible (Słowin
surveillance recommended for these infants has allowed to define the
EEG features—mainly based on the distribution of interictal epilepti-
ska-Pakieła et al., 2014).
form discharges—and their intensity (Doman
Both typical and variant hypsarrhythmia have been reported in
children with TSC, while ictal EEG of epileptic spasms is often charac-
terized by fast rhythms, often preceded by focal or multifocal spikes
(Liu et al., 2012).
Ictal patterns of recorded focal seizures include flattening or low-
voltage fast activity evolving into rhythmic theta activity or rhythmic
theta-delta activity, and/or diphasic spike–wave discharges (Savini,
Mingarelli, Vignoli, et al., 2018). On the other hand, a characteristic inter-
ictal pattern is not recognized in TSC patients: focal or multifocal spikes,
spike-and-wave complexes, sharp waves, and sharp and slow-wave com-
plexes have been detected in the EEG of all TSC patients with epi-
lepsy. Jansen, van Huffelen, Bourez-Swart, and van Nieuwenhuizen
(2005) found that interictal activity is more frequently detected in
the fronto-temporal regions, and this finding is potentially important in
view of a surgical approach (Jansen et al., 2005). At follow-up, in seizure-
sustained patients, the incidence of epileptiform discharges in the initial
EEG recordings was higher (88.2%) than in the seizure-controlled group
(55.5%). This result suggests that initial EEG abnormalities may be related
to incurableness (Park, Lee, Son, Kim, & Woo, 2011).
5 | EPILEPSY AND ITS IMPACT ON
INTELLECTUAL DEVELOPMENT
About 50% of TSC patients exhibit ID, with an over-representation of
severe to profound ID (Curatolo, Moavero, & De Vries, 2015).
Cognitive impairment in TSC is thought to be a multifactorial con-
dition (Jansen et al., 2008). Studies in animal models have suggested a
biological basis for cognitive and behavioral deficits associated with
TSC, even in the absence of apparent cerebral lesions and seizures.
mTOR dysregulation may be the underlying pathogenic mechanism
(Goorden, van Woerden, van der Weerd, Cheadle, & Elgersma, 2007).
Many studies report genotype, number of tubers, tuber/brain
proportion, and epilepsy as risk factors for ID (Benova et al., in
press; Gipson & Johnston, 2017; Kaczorowska et al., 2011). With
regard to epilepsy, patients with ID tend to have early onset sei-
zures, take more antiepileptic drugs (AEDs), exhibit more seizure
301
types and with a higher frequency (Wang et al., 2017). It has been
recently demonstrated that early onset seizures are associated
with an increased risk of neurodevelopmental and cognitive prob-
lems, including ASD (Capal et al., 2017). It is also known that the
risk of ID increases significantly with prolonged duration of infan-
tile spasms (IS), gap between seizures onset and the start of treat-
ment, and poor control of subsequent seizures after IS.
Infants with spasms controlled with Vigabatrin (VGB) benefit from
clear long term cognitive and behavioral improvement, even when
focal seizures persist, suggesting that control of IS could be a key fac-
tor in cognitive outcome. Very early treatment after the onset of sei-
zures, or even before, can positively influence the final cognitive
outcome, even though not completely reversing cognitive impairment
(Cusmai, Moavero, Bombardieri, Vigevano, & Curatolo, 2011).
6 | C O R R E L A T I O N S O F E P I L E P S Y WI T H
GENETICS
TSC mouse models showing reduced expression of TSC1 exhibit aber-
rant neurons similar to those seen in TSC cortical tubers and present
with early onset spontaneous seizures with EEG abnormalities, dem-
onstrating that epilepsy in TSC is directly linked to mTOR hyperactiva-
tion (Meikle et al., 2007).
Although TSC is characterized by wide clinical variability,
genotype–phenotype correlations regarding epilepsy in humans have
emerged. Patients with a pathogenic variant in TSC2 exhibit epilepsy
more frequently than those with a pathogenic variant in TSC1, with a
median frequency from the major studies of 81% (range 65–97%) and
75% (range 58–91%), respectively (Curatolo, Moavero, Roberto, &
Graziola, 2015). Individuals with a pathogenic variant in TSC2 also
tend to present with seizures earlier than the other group, are more
likely to develop focal seizures, complex partial seizures, and infantile
spasms, whereas other types of seizures occur in equal frequency in
the two groups (Kothare et al., 2014).
van Eeghen, Nellist, van Eeghen, and Thiele (2013) showed that
certain but not all central TSC2 missense mutations (exons 23–33) are
associated with a lower risk of infantile spasms compared to missense
mutations in the proximal and terminal regions of the same gene.
Individuals with no mutation identified (NMI) exhibit epilepsy less
frequently (range 56–68%) and, when they do, seizures tend to occur
later in some of them compared to patients with a pathogenic variant
in TSC2, but may be as difficult to control as in the individuals with a
known mutation (Peron et al., 2018).
Despite emerging genotype–phenotype correlations, caution
should be taken when counseling patients for risk of epilepsy based
on the mutational status, as clinical variability and numerous excep-
tions are emerging.
7 | P RE S E I Z U R E ( P R E V E N T I V E )
T R E A T M E N T O F EP I LE P S Y
In recent years an increasing number of TSC patients is diagnosed pre-
natally or soon after birth, allowing subsequent clinical observations
302 CANEVINI ET AL.

before epilepsy onset. Serial EEG follow-up of young infants with TSC epileptiform discharges on EEG significantly reduces the risk of sei-
is currently recommended by European (Curatolo et al., 2012), Ameri- zure development and ID (Jóźwiak et al., 2011). In this group, only
can (Wu et al., 2016), and Australian experts (Chung et al., 2017). 14% of the children developed infantile spasms, and there were no
In the majority of TSC infants, the first clinical seizures are notice- cases of severe ID at the age of 24 months. Moreover, drug resistant
able at the age of 3–5 months. With a traditional approach to epilepsy epilepsy was observed in 7% of these children versus 42% in chil-
treatment (treatment started as soon as clinical seizures appear) neu- dren receiving Vigabatrin 7 days after the onset of clinical seizures
rodevelopmental delay and drug-resistant epilepsy at the age of (Jóźwiak et al., 2011).
24 months are observed in 48% and 42% of TSC children, depending Based on these findings, two randomized clinical studies aimed at
on the studies (Chu-Shore et al., 2010; Jóźwiak et al., 2011). comparing the results of the treatment with Vigabatrin introduced
It is now widely accepted that clinical seizures are preceded by a before and after the onset of clinical seizures are ongoing: EPISTOP
latent period of epileptogenesis (Pitkanen & Lukasiuk, 2011). Two pro- (www.epistop.eu) launched in 2013 in Europe, and PREVeNT (https://
spective observational studies of TSC infants starting before the onset clinicaltrials.gov/ct2/show/NCT02849457) started in 2016 in the
of clinical seizures have identified abnormal EEG as a predictive bio- United States. EPISTOP also comprises a comprehensive analysis of
ska-
marker of imminent clinical seizures in infants with TSC (Doman molecular, clinical, neuroimaging, and electrophysiological biomarkers
Pakieła et al., 2014; Wu et al., 2016). Epileptiform discharges preceded of epileptogenesis in addition to the clinical study. The results of this
 ska-Pakieła et al., 2014,
clinical seizures by 1 day to 1.9 months (Doman project are expected by the end of 2018.

Wu et al., 2016). Both American and European experts therefore rec-

ommend serial EEG monitoring in TSC infants and implementation of
8 | P O S T - S E I Z U R E T R E A T M EN T OF
antiepileptic treatment when electroencephalographic seizures appear,
E P I L EP S Y
even in the absence of clinical symptoms (Curatolo et al., 2012; Wu
et al., 2016). Vigabatrin is recommended as a first-line drug in infantile
Despite recent advances in preventative treatment, treatment of exist-
spasms and focal seizures in infants with TSC (Curatolo et al., 2012).
ing epilepsy associated with TSC remains a major challenge. No consen-
The European recommendations for surveillance and treatment of
sus regarding the most effective AED has been reached yet, with the
infants with TSC are shown in Figure 1.
exception of Vigabatrin (VGB) for IS, representing the first-line therapy
Regular EEG surveillance with vEEG carried out every 4–6 weeks
(Pellock et al., 2010). Visual field constriction caused by VGB should be
in infants with TSC enables early recognition of initial subtle focal sei-
taken into consideration; however, the balance between positive and
zures that are frequently overlooked by caregivers (Whitney et al., negative effects—catastrophic sequelae of infantile spasms against the
2017). Such approach and the early treatment of seizures reduce the good response to VGB—supports this treatment choice. In order to
risk of ID to 61%, as opposed to 100% in children receiving delayed minimize side effects, some authors proposed a supplementation with
treatment (Cusmai et al., 2011). However, treatment introduced after taurine (Jammoul et al., 2009), but the efficacy of such approach has
the onset of clinical seizures is still associated with 32% of severe not been confirmed on long-term follow up yet.
forms of Tuberous Sclerosis Associated Neuropsychiatric Disorders In our experience, higher doses of VGB (100–150 mg/kg/day) are
(TAND) in the first 2 years of life (Cusmai et al., 2011). effective in children younger than 2 years. Treatment lasting longer
As shown in animal models, interventions applied prior to the than 6 months is now recommended, after Humphrey et al. (2006)
onset of clinical epilepsy can prevent or delay the development of sei- reported that a 6-month treatment was effective, but seizures reap-
zures (Zeng et al., 2008; Zhu et al., 2018). The time between early peared in their patients after discontinuation. Recently, Schmid
diagnosis of TSC and seizure onset offers the ideal therapeutic win- et al. demonstrated that higher doses of Vigabatrin (>100 mg/kg/day)
dow for preventative strategies in infants (Jozwiak & Kotulska, 2014). are associated with lower risk of infantile spams relapse in children
An open, prospective study of 14 TSC infants demonstrated that anti- with TSC (Schmid et al., 2017).
epileptogenic treatment with Vigabatrin introduced before the onset Second line treatment consists of corticosteroids/hormonal ther-
of clinical or electroencephalographic seizures but after multifocal apy, if hypsarrhythmia is present, and Topiramate (TPM) if no hypsar-
rhythmia but focal/multifocal abnormalities are present (Curatolo
et al., 2012).
months of life
TSC infants <6

TSC infants >6 and

TSC  children > 12
and <24 months of
life
<12 months of life

vEEG vEEG vEEG

recordings recordings recordings Although not widely accepted, according to the European experts in
every 4 every 6 every 3
weeks weeks months TSC Vigabatrin is the recommended treatment also for focal seizures
before age 1 year due to its high efficacy in this specific group of patients
(Curatolo et al., 2012). In order to control drop attacks and tonic seizures,
especially in patients with Lennox-Gastaut Syndrome, Rufinamide should
be considered as a useful option (Curatolo et al., 2012). Clobazam has
•antiepileptic treament 
clinical seizures •vigabatrin as a first line drug for infantile spasms and focal seizures been noted to be safe and effective in treating refractory epilepsy in

electroencephalographic seizures
•antiepileptogenic treatment TSC (69% had >50% seizure reduction) (Jennesson, van Eeghen,
•vigabatrin as a first line drug 
Caruso, Paolini, & Thiele, 2013). Other AEDs reported to be effective in
FIGURE 1 Schematic of the European recommendations for patients with TSC were TPM (64% had >50% reduction in seizures)
surveillance and treatment of infants with TSC (Franz, Tudor, & Leonard, 2000), Lamotrigine (LTG, 37% had >50%
CANEVINI ET AL.
reduction in seizures) (Franz et al., 2001), and Levetiracetam (LEV, 40%
had >50% reduction in seizures) (Collins, Tudor, Leonard, Chuck, &
Franz, 2006).
With regard to seizure control, it has been reported that 35.6% of
patients from a large group of 160 had their seizures controlled: by
monotherapy in 56% and by polytherapy in 32% (Vignoli et al., 2013).
The most effective AEDs appeared to be Carbamazepine (CBZ) and
Valproic acid (VPA) (Vignoli et al., 2013). Overwater et al. (2015) used
several different AEDs, such as VPA, LEV, and VGB, with VPA being
the most frequently prescribed first treatment. This was also the most
frequently used drug in infants presenting with focal seizures. Similar
data have been obtained in a Swedish study where VPA, CBZ, LTG,
LEV, and TPM were the most commonly prescribed drugs (Welin
et al., 2017). Recently, also Lacosamide appeared to be an effective
and safe treatment of refractory focal onset seizures in TSC (Geffrey,
Belt, Paolini, & Thiele, 2015).
9 | SURGICAL TREATMENT
Surgical therapy for epilepsy in TSC was advocated as far back as
1966 (Perot, Weir, & Rasmussen, 1966) based on the hypothesis that
a single tuber might well be responsible for epileptogenesis.
As in all epilepsies, surgery in TSC should be considered early in
patients with drug resistant epilepsy (DRE) despite treatment with
two AEDs (Kwan et al., 2010). Non-invasive recordings together with
MRI might be sufficiently informative when there is a clear anatomo-
electroclinical correlation. Invasive recordings should be considered
whenever the correlation between MRI and EEG data is not clear
(Curatolo et al., 2012).
The presence of multiple tubers, multiple interictal foci, bilateral
seizures, or epileptic spasms (Chipaux et al., 2017) should not prevent
from initiating presurgical evaluation, since a single epileptogenic tuber
can be found responsible of the most impairing seizures (Curatolo
et al., 2012).
Risk factors associated with seizure recurrence after surgery are
poorly understood, and we still need to learn when a tuber will
become epileptogenic. Therefore, the perspective of future seizure
recurrence should be weighted against that of a temporary relief of
epilepsy during a critical period of neurodevelopment (Curatolo &
Moavero, 2010).
Controversy exists about the contribution of tubers, perituberal
cortex and the underlying genetic abnormality to epileptogenesis.
Kannan, Vogrin, Bailey, Maixner, and Harvey (2016) provided support
for a central role of the tuberal core in seizure initiation and propaga-
tion. Other studies report that electrical activity (complete removal of
areas with High Frequency Oscillations and fast ripple at ictal onset) is
the most relevant data in order to obtain a good outcome, regardless
of the MRI findings (Fujiwara et al., 2016).
Some studies support the hypothesis that a greater extent of re-
section (i.e., more than just the tuber) is associated with a higher proba-
bility of seizure freedom (Fallah et al., 2015), and that epileptogenic
regions are mostly characterized by “Focal Cortical Dysplasia (FCD)-like”
changes outside cortical tubers (Jahodova et al., 2014). Therefore, FCD
seems to be an important hallmark. Malformations of the cerebral cortex
303
meeting the criteria for FCD type IIb were a frequent finding and an indi-
cation for early epilepsy surgery also in a series of patients with neonatal
onset of epilepsy in TSC (Kotulska et al., 2014).
However, surgery in TSC is not always effective. Literature data
report a highly variable rate of seizure freedom (25–90%) (Fallah
et al., 2013; Jansen, van Huffelen, Algra, & van Nieuwenhuizen,
2007; Madhavan et al., 2007; Moavero, Cerminara, & Curatolo,
2010; Weiner et al., 2006; Wu et al., 2010), but in general the litera-
ture suggests that resective surgery may be beneficial in a selected
population of TSC patients with drug-resistant epilepsy. Individuals
with the forme fruste have been reported to have an excellent surgi-
cal outcome (Teutonico et al., 2008).
Finally, cost effectiveness is another parameter that should be
kept in mind when evaluating possible surgery or other treatment
options. For instance, Fallah, Wang, Lewis, Baca, and Mathern (2016)
showed that resective epilepsy surgery resulted as the most cost-
effective treatment option in TSC children with DRE after the intro-
duction of a third AED but before vagus nerve stimulation, and the
authors concluded that the most cost-effective treatment should be
chosen based on available resources.
Epilepsy surgery in TSC remains challenging and should be
driven by a sound presurgical hypothesis based on MRI, Video-EEG
recordings, and invasive recordings when needed, keeping in mind
surgery goals.
10 | VAGUS NERVE STIMULATION
Vagus Nerve Stimulation (VNS) is a therapeutic option that should be
taken into account when resective surgical intervention is not feasible
in patients with drug resistant epilepsies (Marras et al., 2013).
Lagae et al. (2015) studied the efficacy of VNS therapy in a group
of patients with highly drug-resistant childhood epilepsy: the only fac-
tors that made a difference in the outcome were age at implantation
and duration of epilepsy. In the youngest group, 7/9 were responders
(77%), including three of the four seizure-free patients: the three
seizure-free children had TSC. In a retrospective series of 11 patients,
Zamponi, Petrelli, Passamonti, Moavero, and Curatolo (2010) found
that the patients who had received implantation during childhood
exhibited a better improvement in cognitive and seizure outcome
(significantly improved in 72% of the patients).
Major and Thiele (2008) performed a retrospective study of
16 adults and children with TSC and intractable epilepsy who received
VNS, with a longer follow-up (average: 4 years). Eighty-two percent
experienced at least a 50% reduction in seizure burden, and improved
function was observed in five individuals (31%), but no patients
resulted seizure free. In a series of 11 individuals with drug resistant
epilepsy and TSC, Elliott et al. (2009) reported that nine of them (82%)
experienced at least a 67% reduction in seizure burden. Finally, a
cost-utility analysis found VNS implantation to be more expensive
and less effective than alternative strategies, and suggested that it
should not be prioritized (Fallah et al., 2016).
In conclusion, literature data support the suggestion to use VNS
only as a third line therapy (Curatolo et al., 2012).
304
11 | KETOGENIC DIET
Ketogenic diet (KD) has been reported as effective in small series of
TSC patients (Coppola et al., 2006; Kossoff, Thiele, Pfeifer, McGrogan, &
Freeman, 2005; Larson, Pfeifer, & Thiele, 2012; Park et al., 2017).
Martinez, Pyzik, and Kossoff (2007) demonstrated that children with
TSC are more likely to have seizure recurrence if KD is weaned, and
that they may benefit from being on KD for longer than 2 years if
seizure freedom has been achieved.
Hypotheses regarding the possible specific mechanism involved
in seizure control with KD in TSC patients have been reported.
Tuberin is phosphorylated by AMP-activated kinase (AMPK) in
response to certain stresses, such as energy starvation (Inoki, Zhu, &
Guan, 2003). KD may thus represent a form of cellular stress involving
the AMPK pathway, as preclinical data (cited previously) show a
change in the brain's energy state during the KD. Interestingly, inhibi-
tion of one component of this pathway with rapamycin prevents the
development of epilepsy in mice harboring a TSC1 mutation (Zeng
et al., 2008). Whether the KD exerts a similar mechanism in this con-
dition remains to be clarified (Hartman, 2008). Liskiewicz et al. (2016)
demonstrated that prolonged feeding with ketogenic diet in the Eker
rat (Tsc2+/−) promotes the growth of renal tumors by recruiting
ERK1/2 and mTOR, which are associated with accumulation of oleic
acid and overproduction of growth hormone. However, the ketogenic
diet did not show any modifications in growth of TSC-related tumors
in a case series of five TSC patients (Chu-Shore & Thiele, 2010).
Based on the recent literature, KD should be considered in those
patients with epilepsy that is difficult to treat (Kossoff et al., 2005;
Park et al., 2017).
12 | MARIJUANA DERIVATIVES
Cannabidiol (CBD) is one of the non-psychoactive components of the
cannabis plant. In recent years, the use of CBD has been challenged in
intractable epilepsy, especially in early onset epileptic encephalopathies.
However, the pharmacologic mechanisms have not been fully understood
yet (Reddy & Golub, 2016). Hess et al. (2016) have recently studied the
efficacy, safety, and tolerability of CBD in patients with TSC and drug-
resistant epilepsy, finding that median reduction in seizure frequency was
48.8%, and approximately 50% of the patients demonstrated a >50%
reduction in seizures. The response was maintained during the 12-month
follow-up. These findings suggest that CBD is a potential antiseizure
medication for intractable epilepsy in TSC, and randomized controlled tri-
als are needed to confirm these data.
1 3 | EP I LE P S Y T RE A T M E NT I N TS C W I T H
MTOR INHIBITORS
mTOR inhibitors (e.g., Everolimus and Sirolimus) are immunosuppres-
sants that inhibit the mTOR kinase, which is hyperactivated in TSC
patients.
Muncy, Butler, and Koenig (2009) reported for the first time on a
10-year-old girl treated with rapamycine for frequent seizures, who
CANEVINI ET AL.
obtained good response. Subsequent larger studies exploring the ben-
eficial role of mTOR inhibitors in epilepsy treatment in TSC came from
the observation of patients treated with this medication because of
growing subependymal giant cell astrocytomas (SEGAs) (Kotulska
et al., 2013; Krueger et al., 2013; Perek-Polnik, Jozwiak, Jurkiewicz,
Perek, & Kotulska, 2012).
Experimental trails and clinical observations confirmed that inhibi-
tion of the mTOR pathway is an attractive therapeutic option, and
that it may modify the process of epileptogenesis (Curatolo, 2015;
Krueger et al., 2013; Sadowski, Kotulska-Jóźwiak, & Jóźwiak, 2015;
Samueli et al., 2016; Stafstrom, Staedtke, & Comi, 2017). The largest
prospective, randomized, multicenter, placebo-controlled study aiming
at assessing the effect of Everolimus on seizure frequency in TSC
patients with drug-resistant epilepsy (EXIST-3) documented a positive
antiepileptic effect of Everolimus as additional antiepileptic therapy
with tolerable safety profile (French et al., 2016). The reduction of
≥50% in seizure frequency was significantly higher in patients treated
with Everolimus compared to the placebo group. Furthermore, a posi-
tive effect of Everolimus was observed in a variety of seizure types
(French et al., 2016).
Recently, Krueger et al. (2016) reported the long-term results
of their prospective, open-label, non-randomized study of Everoli-
mus in drug-resistant epilepsy in TSC. The authors documented a
sustained reduction in seizure frequency in the group of children
<6 years (Krueger et al., 2016). This effect has been confirmed in
the long-term follow-up of the EXIST3 trial as well (Curatolo, Franz,
Lawson, et al., 2018).
Based on these results, both the European Medicinal Agency
(EMA) in Europe and Federal Drug Administration (FDA) in the
U.S. approved Everolimus, in 2017 and April 2018 respectively, as an
adjunctive therapy in partial-onset seizures in TSC patients aged 2 years
and older. The recommended therapeutic drug monitoring is to target
Everolimus plasma concentrations within a range of 5–7 ng/mL initially
and 5–15 ng/mL in the event of an inadequate clinical response (Franz
et al., 2018). Starting doses depend on age and concomitant use of
CYP3A4/P-glycoprotein inducers/inhibitors.
1 4 | C O N C L U S I O N S A N D F U T U RE
PERSPECTIVES
Despite significant improvements in understanding TSC, epilepsy
treatment in individuals affected by this condition remains chal-
lenging. As 71% of the patients develop epilepsy in the first
24 months of life (Jóźwiak et al., 2011) contributing significantly to
neurocognitive delay, a matter of utmost importance is early recog-
nition of seizures and prompted treatment. Recent European rec-
ommendations of repeated pre-seizure video-EEG screening and
subsequent preventative treatment in those who result to be at
high risk for epilepsy have been considered by an increasing num-
ber of centers as routine procedures. Moreover, the use mTOR
inhibitors as an initial AED is now considered by some investiga-
tors, facilitating future studies.
CANEVINI ET AL.
ACKNOWLEDGMENTS
The work was partly financed by the EC Seventh Framework Programme
(FP7/2007-2013; EPISTOP, grant agreement no. 602391) (SJ, KKJ, MS,
PC), the Polish Ministerial funds for science (years 2013–2019) for the
implementation of international co-financed project (SJ, KKJ, MS) and
the grant EPIMARKER of the Polish National Center for Research and
Development No STRATEGMED3/306306/4/2016 (SJ, KKJ, MS, JS).
ORCID
Angela Peron https://orcid.org/0000-0002-1769-6548
Aglaia Vignoli https://orcid.org/0000-0003-4638-4663
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AUTHOR BIOGRAPHIES
M. P. CANEVINI is an Associate Professor of
Child Neurology and Psychiatry at the Uni-
versità degli Studi di Milano, Italy. She is the
head of the Child Neuropsychiatric Unit and
Epilepsy Center and the director of the TSC
Clinic at San Paolo University Hospital in
Milan, Italy. Her main research interests focus
on epilepsy and rare diseases associated with epilepsy.
308 CANEVINI ET AL.

K. KOTULSKA is the professor and head of the
Department of Neurology at The Children's
Memorial Health Institute, Warsaw, Poland.
She is also a representative of Poland in the
Board of Member States for European Refer-
ence Networks. She is certified in neurology
and neuropediatrics. Dr Kotulska's clinical
and basic research focuses mainly on diseases of the developing
nervous system. In 2009, Dr Kotulska received the L'Oreal-
UNESCO award for Women in Science in Poland.
P. Curatolo is Full Professor of Child Neurol-
ogy and Psychiatry at Tor Vergata University
of Rome, Italy. His main research interest is in
the neurological and neuropsychiatric mani-
festations of individuals with Tuberous Scle-
rosis Complex. Other areas of interest include
developmental disorders and epilepsy.
F. La Briola is a pediatric neurologist and epi-
leptologist at the San Paolo University Hospital
in Milan, Italy. She is part of the TSC Clinic and
of the Rett Clinic. He main clinical focus is pedi-
atric epilepsy and rare diseases requiring a mul-
tidisciplinary approach, especially TSC, Rett
syndrome, and Neurofibromatosis Type I.
A. Peron is a clinical geneticist and post-
doctoral fellow at the University of Milan (Italy)
and an adjunct assistant professor at the Univer-
sity of Utah. She serves as the geneticist of the
pediatric and adult TSC clinic of San Paolo Uni-
versity Hospital in Milan, and her research inter-
ests focus on individuals with TSC and No
Mutation Identified, and genotype–phenotype correlations. Her other
research interests include dysmorphology, intellectual disability, genet-
ics of epilepsy and autism spectrum disorder, and genomic medicine.
epilepsy and epileptogenesis in a genetic model of epilepsy—
tuberous sclerosis complex and mTOR dependent epilepsy.
J. Strzelecka is a certified neurologist and
neuropediatrician working in the Neurology
Department of the Medical University of
Warsaw. She is the head of EEG Department
and a licensed electroencephalographer and a
leader of the EEG work package in the pro-
ject EPIMARKER of the Polish National Cen-
tre for Research and Development focused on EEG evolution in
TSC patients.
A. Vignoli is a Senior Assistant Professor in
Child Neurology and Psychiatry at the
Department of Health Sciences, University of
Milan, Italy. She has published widely on sei-
zures, treatment, and behavioral outcomes in
children with epilepsy. Her research has
focused on children with epilepsy and rare
diseases, in particular with drug resistant seizures.
S. Jozwiak is a pediatric neurologist and epi-
leptologist and the head of the Department
of Child Neurology at Medical University in
Warsaw. His research focuses mainly on neu-
rocutaneous disorders and epilepsy, espe-
cially infantile spasms. For almost 30 years,
he has led a special program for tuberous
sclerosis patients and worked out practical guidelines for TSC
management. In 2009, Prof Jóźwiak received the prestigious Man-
uel Gomez Award. Currently, he is a coordinator of the large-scale
European Commission Project EPISTOP evaluating clinical and
molecular biomarkers of epileptogenesis in a genetic model of
epilepsy—tuberous sclerosis complex.

M. Slowinska is a pre-doctoral fellow and a

resident doctor of pediatric neurology in the
Department of Child Neurology in Warsaw,
How to cite this article: Canevini MP, Kotulska-Jozwiak K,
Poland. Her research is mostly focused on
Curatolo P, et al. Current concepts on epilepsy management in
early diagnosis and management of tuberous
tuberous sclerosis complex. Am J Med Genet Part C. 2018;
sclerosis complex. She works within EPISTOP
178C:299–308. https://doi.org/10.1002/ajmg.c.31652
and EPIMARKER projects that are focused on