review
Managing refractory seizures
in tuberous sclerosis complex
Tuberous sclerosis complex-related epilepsy is highly refractory and represents a challenge for
clinicians. Recently, some therapies have proved to be effective, acting not only on seizures but also
on the underlying mechanisms
Romina Moavero MD
Child Neurology and
Psychiatry Unit, Systems
Medicine Department,
Tor Vergata University
Hospital of Rome;
Child Neurology Unit,
Neuroscience and
Neurorehabilitation
Department, Bambino
Gesù Children’s Hospital,
Rome, Italy
Paolo Curatolo MD PhD
Child Neurology and
Psychiatry Unit, Systems
Medicine Department,
Tor Vergata University
Hospital of Rome, Italy
Tuberous sclerosis complex (TSC) is
a multisystem disease caused by the mutation
in one of the two tumour suppressor genes TSC1
and TSC2. 1 It affects about 1 in 6000 newborns, and
although it can affect multiple organs and systems
(brain, skin, heart, kidneys, lungs, liver, eyes),
neurological involvement is the cause of the major
mortality and morbidity, above all in the paediatric
age. 2 From a neuropathological point of view,
patients with TSC might present with cortical/
subcortical tubers, subependymal nodules,
subependymal giant cell astrocytomas and white
matter migration lines. 2 From a clinical point of
view, neurological manifestations include epilepsy
and its comorbidities, including cognitive disability,
autism spectrum disorders, attention deficit
hyperactivity disorder and other neuropsychiatric
disorders. 2
Epilepsy is a very common manifestation,
affecting up to 85% of subjects, and presenting in
the first years of life in two thirds of subjects. 3 Early
onset epilepsy can be in the form of infantile spasms
or focal seizures, which can coexist or evolve into
infantile spasms. The latter represent a significant
risk factor for later refractory epilepsy because
approximately 75% of patients with a history
of infantile spasms will present with refractory
seizures up to severe epileptic encephalopathies,
including focal refractory seizures and a Lennox-
Gastaut phenotype. 3
Epileptogenesis in TSC is a very long process,
starting far before birth. Indeed, the mutation of
TSC1/2 genes determines an overactivity of the
mTOR (mammalian target of rapamycin) pathway,
which is already evident during foetal life. 4 This
early mTOR overactivation determines alterations
of migration and orientation of neural cells, thus
leading to abnormal cortical lamination and
dendritic arborisation. 5 Abnormalities in this crucial
pathway also include the disruption of GABAergic
interneuron development as well as the regulation
of glutamatergic function, thus meaning an
imbalance between excitation and inhibition, which
is a clear predisposing factor to epileptic seizures. 6
The early dysregulation of the mTOR pathway,
causing altered migration and cell morphology,
causes the formation of tubers. These are the
hallmark of the pathology and can be already visible
during prenatal life with foetal magnetic resonance
imaging, and include different abnormal cells, such
as dysplastic neurons and giant cells. 5 Tubers are
dynamic lesions, and their continuous changes,
both in pre- and postnatal life, can contribute to the
establishment of extensive epileptogenic networks. 7
Tubers represent focal malformations of cortical
development and are characterised by loss of the
hexalaminar cortical architecture, presence of an
excessive number of astrocytes, and by dysmorphic
neurons and giant cells. 7 However, although tubers
are the most clear lesions, and for which there
is a documented link with epilepsy, many other
structural and microstructural lesions are evident
in 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 alterations
that might play a role in both epileptogenicity and
abnormal neurodevelopment. White matter also
appears to be extensively involved, with white
matter migration lines detectable on conventional
brain MRI as a result of abnormal migration. 2
However, normal appearing white matter can also
be involved by microstructural changes, which
are evident when diffusion tensor imaging is
performed, and can be linked to epileptogenesis. 8
Furthermore, white matter abnormalities appear
to be more evident in children with early onset and
refractory epilepsy, with persistent seizures seeming
to determine extensive connectivity alterations in
brain areas crucial for language, social development
and global cognitive functioning. 9
Management of tuberous sclerosis-related
seizures
Table 1 summarises treatment options for TSC-
related seizures.
hospitalpharmacyeurope.com | 2018 | Issue 90 | 29