Epilepsy Flashcards
Epidemiology
- A common global neurological condition that is estimated to affect 65 million
people worldwide, with roughly 80% of them living in the developing world. - Third leading contributor to global burden of diseases. In 2012 epilepsy alone was
responsible for 20.6 million DALYs lost, which is comparable to DALY of breast
cancer in woman and lung cancer in men. - Age is highly correlated; early childhood peak of prevalence in 5-9 years of age,
and another peak in adults older than 60 years. - Zoonotic and vector-borne parasites (e.g., malaria) are important risk factors for
epilepsy, which are rampant in most resource-poor countries. This is an underlying
reason for prevalence of epilepsy in the developing world
Etiology
multifactorial
Seizure
and its kinds
An epileptic seizure is a transient
behavioral change that might be
objective signs or subjective symptoms
(such as loss of awareness, stiffening,
jerking, a sensation that rises from the
abdomen to the chest, a smell of burnt
rubber or deja vu), caused by abnormal
excessive and/or synchronous neuronal
activity in the brain.
* Genetic/Idiopathic epilepsy: Genetic
predisposition. Presents spontaneously.
Accounts for majority of cases (~60%).
* Acquired/Symptomatic epilepsy:
Known (or suspected) cause such as
head trauma, drug abuse, alcohol
addiction, brain tumors etc.
* Absence seizure (Petite mal): Less than
30s of generalized, 3 Hz EEG waves.
Motor signs absent. Restricted usually
to childhood
Epilepsy: a
disease of brain
hyperexcitability
Figure: Interictal abnormalities detected
using electroencephalography (EEG).
a | A moderate-amplitude left temporal spike in a
patient with focal left temporal lobe epilepsy.
b | A 2-second burst of bilateral, symmetric,
synchronous, high-amplitude, 4 Hz polyspike and
wave (a type of spike and wave discharge) in a patient
with genetic generalized epilepsy. The abbreviations
to the left refer to the location of EEG lead
Neuroimaging
- All patients with history of seizures are
advised to undertake MRI imaging of
their brain. Helps with diagnosis. - Figure: Coronal T1 inversion recovery (A)
and fluid-attenuated inversion recovery
(FLAIR) axial (B) and coronal (C)
magnetic resonance imaging (MRI)
showing left hippocampal atrophy
associated with changes in morphology
and internal structure and hyperintense
FLAIR signal (arrows). These are all
classic signs of hippocampal sclerosis –
most frequent pathological finding– on
MRI that were confirmed on
postoperative histopathology. Patient
with left mesial temporal-lobe epilepsy
and seizure-free after left
amygdalohippocampectom
Electrophysiological signatures
The core physiologic feature of epileptic seizures is hyperexcitability of CNS neurons.
* The hallmark of synchronous discharge of neurons in
the epileptic focus is the paroxysmal depolarization
shift (PDS), which is a large and sustained
depolarization of the neuron. During a PDS, the cell
membrane undergoes a high-voltage (approximately
10–15 mV) and long (100–200 ms) depolarization,
which is much longer than the normal EPSP (10–16
ms). The PDS corresponds to a spike on the EEG.
* During a seizure, the epileptic neurons undergo a
prolonged depolarization with continuous bursts of
action potentials without an intervening
repolarization. The behavioral correlate of this
prolonged depolarization is the tonic phase of the
seizure. An EEG recorded at this time on the surface
of the brain would demonstrate continuous spikes.
During the next stage, large inhibitory potentials
occur and alternate with recurrent rhythmic PDS. This
pattern coincides with the clonic stage of the seizure.
During this stage of the seizure, generalized spike-
and-wave discharges would be present on the EEG
Excitation-Inhibition Imbalance
- Aberrant “runaway” excitation of neurons
underlie the epileptic discharge during seizures. - Ascribed to an imbalance in glutamatergic
excitation and GABAergic inhibition (E-I
imbalance). - Many factors can influence this delicate balance,
including, 1) altered production or release of
neurotransmitters, 2) changes in brain circuits due
to developmental abnormalities or traumatic
insults, 3) genetic mutations. - Figure: A non-comprehensive list of epilepsy-
associated mutations found in genes which
functionally regulate every aspects of the
inhibitory system. The net effect of one or more
such mutations is reduced/impaired inhibition in
epileptic microcircuits that allows aberrant
excitation of excitatory neurons in them
Cellular and Molecular Causes
Right: Functions of epigenetic factors implicated in epilepsy.
Within the chromatin landscape (nucleosomes in blue wrapped in
DNA), epigenetic factors (red capsule) and potential mechanisms
underlying their involvement in the epilepsies are depicted.
Epigenetics-related epilepsies are often accompanied by a range of
comorbidities, including intellectual disability
Reactive Gliosis
and Seizures
- Various CNS insults such as stroke, infection, trauma, tumors and
hypoxia can cause blood–brain barrier (BBB) damage. - The resulting increased BBB permeability promotes
extravasation of peripheral immune cells (macrophages,
monocytes, B cells and T cells) and chemokines into the brain,
where, along with direct CNS insult, they induce reactive gliosis. - Reactive gliosis refers to morphological (hypertrophy of the cell
bodies and processes) and physiological changes (changes in
the expression and functions of many glial proteins) in glial cells
in response to various CNS injuries. - Reactive glia release extracellular matrix (ECM)-remodeling
enzymes such as matrix metalloproteinases (MMPs),
neurotrophic factors such as brain-derived neurotrophic factor
(BDNF), growth factors such as transforming growth factor-β
(TGFβ) and immunomodulators such as cytokines. These
modulate the expression and function of receptors, transporters,
enzymes and other molecules regulating excitatory and
inhibitory neurotransmission. - Consequently, network hyperexcitability and seizures occur
owing to impairment in K + , Cl − and glutamate buffering and
imbalance in excitatory and inhibitory neurotransmissio
Fallout of
Epilepsy
- Focal cortical seizures trigger
spreading depression (also
called spreading depolarization). - Spreading depression is
characterized by slow,
propagating wave of cellular
depolarization and is associated
with epilepsy, migraine, stroke,
and traumatic brain injury. - This has been proposed to be
an innate anti-seizure
mechanism.
Ref: 10.1038/s41467-021-22464-x
Ref: 10.1101/455519
Gliomas and Seizures
- Gliomas (type of brain tumor that originates from
glial cells) are commonly associated with epilepsy;
the two conditions share common pathogenic
mechanisms and influence each other. - Excessive glutamate release and activation of
glutamate receptors promote glioma growth, and
neuronal epileptic activity. - GABAergic signaling is antiproliferative, whereas
chloride accumulation is required for mitosis and
migration of tumor cells and is responsible for
epileptogenic GABAergic depolarizing activity in
immature neurons (impaired KCC2). - The molecular target of rapamycin (mTOR)
signaling pathway and epigenetic abnormalities
are also involved in epileptogenesis and tumor
growth. - As a result of the shared pathogenic mechanisms,
antiepileptic drugs can have antitumor effects, and
antitumor therapy can control seizures. - Single drug therapies targeting the shared
mechanisms are now being assessed for combined
seizure and tumor control.
DOI: 10.1038/nrneurol.2016.26
Inhibitory - Repression of Na+
–K+
–Cl− transporter NKCC1, which normally transports Cl−
, Na+
and K+ into immature neurons. - activation of K–Cl transporter 2 (KCC2), co-transport efflux of K+ and Cl-
- intracellular Cl− is maintained at low levels.
Aberrant expression of
KCC2 and/or NKCC1 leads
to accumulation of
intracellular Cl−
, which
contributes both to tumor
growth and epileptic activity
GABA levels are higher in tissue around gliomas, but GABAergic synaptic density
on nearby pyramidal cells is reduced and GABA-mediated inhibition is impaired.
Current Therapeutics
Current approved antiepileptic drugs (AEDs) act by…
* …enhancing GABAergic inhibitory function, either
by modulating the post-synaptic GABAa Rs
(barbiturates and benzodiazepines) or by acting on
synaptic GABA availability by preventing its
metabolic breakdown (Vigabatrin).
* …modulating channel functions, either by
inhibiting NMDA-Rs (Felbamate) or other Na+
channels (Lamotrigine), or by modulating
neurotransmitter release (Levetiracetam).
* stabilizing resting membrane potential
(Oxcarbazepine) and repetitive neuronal discharge
(Carbamazepine).
* …other mechanisms as well.
Activation of GABA synapses in young neurons produces
depolarization instead of the characteristic hyperpolarization,
because of a relatively high concentration of intracellular
chloride ions ([Cl − ] i ). The intracellular accumulation of
chloride seems to be generated by a delay in the expression
of the chloride exporter KCC2.
Although many adult epilepsy patients respond well to
conventional AEDs—particularly those that potentiate
GABAa Rs—these drugs are largely ineffective in controlling
neonatal epilepsy and may actually potentiate seizures in this
patient population. Consequently, it is critical that we pursue
novel AEDs for epilepsy treatment, especially for newborns
and young children.
