Download Slide 1 - The Neurology Report

Future Therapies: How We
Will Treat, Prevent, and Cure
Epilepsy in the Year 2025
Pawan V. Rawal, MD, MHA
University of Alabama at Birmingham School of Medicine,
Birmingham, Alabama
A REPORT FROM THE 67TH ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY (AES 2013)
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Anti-Inflammatory Therapy

An increasing body of evidence suggests that
inflammation and immune reactions are associated
with epilepsy.

Over the past decade, researchers have focused on
the function of glial cells and other non-neuronal
components, the blood-brain barrier, and leukocytes
to investigate the role of inflammation in initiating
and maintaining epilepsy.

The search for new drug targets is leading to a fresh
appreciation of immune and inflammatory pathways
in the pathogenesis of epilepsy.
Vezzani A. Epilepsy Curr. 2005;5:1; Choi J et al. J Neuroinflammation. 2009;6:38.
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Anti-Inflammatory Therapy

Experimental seizures and epileptogenic brain
injuries induce long-lasting brain inflammation that
precedes the development of epilepsy itself.

Interleukin-6 levels are elevated in the plasma and
cerebrospinal fluid of epilepsy patients who have had
recent tonic-clonic seizures.

Perivascular lymphocytes, along with increased
expression of interleukin-1 and tumor necrosis
factor-, provide further evidence of a role for
inflammation. Likewise, inflammatory mediators
have been detected in surgically resected brain
tissues from patients with refractory epilepsy.
Vezzani A. Epilepsy Curr. 2005;5:1; Vezzani A et al. Nat Rev Neurol. 2011;7:31
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Anti-Inflammatory Therapy

Data on the efficacy of immunomodulatory agents
such as IVIG and prednisone in individuals with
epilepsy are mixed and modest at best.

Experimental data supporting a role for antiinflammatory treatment in epilepsy are more robust.
For example, acute and chronic seizure suppression
was attained in mice using specific blockers of TLR4.
The same study demonstrated that blockage of the
TLR4 pathway delays the onset of seizures.

Other evidence suggests a positive feedback cycle
between brain inflammation and epileptogenesis.
Mikati MA et al. Epilepsy Behav. 2010;17:90; Maroso M et al. Nat Med. 2010;16:413; Xu D et al. Front Cell
Neurosci. 2013;7:195.
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Cell Therapy

Epileptiform discharges occur more often when
interneuron inhibition is compromised.10

Inhibitory interneurons make up about 20% of brain
cells. The ability of interneurons to interfere with
seizure propagation (“inhibitory restraint”) has been
demonstrated in vivo in humans.11

Drugs that mimic the effects of gamma-aminobutyric
acid (GABA) can modulate postsynaptic receptors;
others can block GABA reuptake.

Cell therapy potentially could increase inhibition by
incorporating new GABAergic interneurons.
Trevelyan AJ, Schevon CA. Neuropharmacology. 2013;69:45; Schevon CA et al. Nat Commun. 2012;3:1060
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Cell Therapy

The promise of cell therapy starts with generating an
interneuron cell line with desirable qualities, such as
reliable expression of GABA, migration in the host
brain, mature firing properties, and integration into
the host circuitry.

Embryonic medial ganglionic eminence (MGE)
possesses the unique ability to migrate long
distances after implantation into the brain.

Functional integration of MGE cells, resulting in
inhibition of principal neurons and seizure
suppression, has also been demonstrated in an
animal model.
Wichterle H et al. Nat Neurosci. 1999;2:461; Alvarez-Dolado M et al. J Neurosci. 2006;26:7380
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Cell Therapy

Several human embryonic stem (hES) cell lines
currently being studied for epilepsy therapy include:
» Sox1-expressing embryonic stem cells (ESCs)
» Nkx2.1-expressing ESCs
» Induced pluripotent stem cells from patients with Dravet
syndrome.

Intravenously transplanted hES cells have
suppressed spontaneous recurrent seizure
formation, and transplanted hES cells have been
differentiated into GABA-immunoreactive
interneurons in the damaged hippocampi of adult
rats with pilocarpine-induced status epilepticus.
Chu K et al. Brain Res. 2004;1023:213
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Cell Therapy

Potential problems identified during in vitro studies
of human stem cells include slowed differentiation
and functional maturation.

The development of teratocarcinomas from
undifferentiated human stem cells also is possible.

Human pluripotent, stem cell-derived, threedimensional, organoid culture systems known as
cerebral organoids recently have been considered to
be potential MGE donors that may possess
different—and perhaps superior—qualities than
those of existing human stem cell lines.
Lancaster MA et al. Nature. 2013;501:373
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Optogenetic Therapy

Optogenetics is a control technology that uses light
to express light-sensitive proteins in cells for fast,
selective control of specific neuron excitability.

Optogenetic techniques that
use selective manipulation of
neurons address the inability
of current therapy to target
aberrant cells and circuits,
while leaving others unaltered.

Optogenetics holds promise for treating various
neurobehavioral disorders, including epilepsy.
Bentley JN et al. Neurosurg Focus. 2013;34:E4; Kos A et al. Mol Neurobiol. 2013;47:172; Fiala A et al. Curr Biol.
2010;20:R897.
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Optogenetic Therapy

Optogenetic activity can inhibit
focal cortical epileptiform and
network activities.

Seizure termination can be
achieved either via inhibition
of excitatory cells or excitation
of inhibitory cells.

Inhibition of only a portion of excitatory cells at the
focus is sufficient for seizure termination.

Optogenetics has the potential to be a versatile
control technology that could allow manipulation of
normal and abnormal neuronal activity.
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Neurostimulation Devices

Neurostimulation devices
provide stimulation
regardless of the occurrence
of seizures or brain activity.

Examples include vagus
nerve stimulation for epilepsy
and deep-brain stimulation
for anterior thalamus
syndromes.

A second category of devices, known as responsive
stimulation, employs an implantable microprocessor
that delivers programmable stimulation in response
to seizure activity.
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Seizure Forecasting Devices

The usefulness and safety of a seizure advisory system
in humans were recently reported.

Fifteen patients underwent implantation of an seizure
advisory system consisting of a hand-held device that
received and analyzed EEG signals recorded directly
from the surface of the brain; the device then
provided a visual and audible signal showing the
likelihood of a seizure occurring in the minutes or
hours ahead.

Although no significant changes in seizure activity
were detected, the feasibility of long-term ambulatory
EEG and seizure prediction was demonstrated.
Cook MJ et al. Lancet Neurol. 2013;12:563
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