neurology
Managing refractory seizures
in tuberous sclerosis complex
TSC-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
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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