epilepsy yung-yang lin ( 林永煬 ), md, phd national yang-ming university taipei veterans general...
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Epilepsy
Yung-Yang Lin (林永煬 ), MD, PhDNational Yang-Ming UniversityTaipei Veterans General Hospital
Epidemiology
Diagnosis
Etiologies and Mechanisms
Treatment
Outline
Epidemiology
The incidence is around 50/100 000/year.
Prevalence of active epilepsy is in the range of 5-10/1000.
Age-specific incidence rates: a decrease in younger age groups and an increase in persons above 60 years
Overall prognosis for seizure control is good and over 70% will enter remission.
Increased risk of premature death particularly in patients with chronic epilepsy (Sudden unexpected death )
Diagnosis
History of eventMedical historyBlood tests Electroencephalography (EEG)Simultaneous EEG and video recordingsBrain scanning (CT scan, MRI) - to discover if
the patient has symptomatic epilepsy; a structural cause for their seizures
PET, SPECT, MRS Magnetoencephalography (MEG)
Etiologies and Mechanisms
Vascular injury 10.9%
Idiopathic and
cryptogenic epilepsy
65.5%
Neoplasm 4.1%
Trauma 5.5%
Congenital causes 8.0%
Infection 2.5%
Degenerative brain disorder 3.5%
0102030405060708090
100
0–4 5–14 15–24 25–44 45–64 65+
Others
Pro
po
rtio
n o
f ca
ses
(%)
Degenerative
Cerebrovascular
Brain tumour
Trauma
Infection
Development
In rare cases patients may have one specific trigger that brings on a seizure, for example:
Reading
Looking at a particular kind of pattern
Flashing visual stimuli
Hearing a particular
piece of music
In the majority of cases an epileptic seizure ends of its own accord
Status epilepticus is a condition characterized by an epileptic seizure that is so frequently repeated or prolonged as to create a fixed and lasting condition
It is a medical emergency that requires prompt and appropriate treatment
An abnormal synchronous and sustained activity (overexcitation) in a group of nerve cells
This group of nerve cells = epileptogenic focus
Abnormal interictal activity
When this focus recruits surrounding, normal nerve cellsinto a synchronous pattern of larger abnormal activity
(burst firing), there is transition from interictal to ictal activity
= SEIZURE
Excess excitation
epileptic seizures
Lack of inhibition
epileptic seizures
(1) Extensive neuronal loss and gliosis in the areas of CA1 and the hilus but also in other hippocampal regions to varying degrees.
(2) Synaptic reorganization, although not necessarily limited to the mossy fibers of the dentate gyrus.
(3) Dispersion of the dentate granule cells.
(4) Extrahippocampal pathology (i.e.neuronal loss in the neighboring entorhinal cortex and amygdala).
Hippocampal sclerosis
Neural circuits in hippocampal formation
inputoutput
Hilar neuronal loss and mossy fiber sprouting
Sprouting is classically seen as a response to the loss of neuronal targets: the loss of mossy cells and somatostatin-positive interneurons in the hilus lead to mossy fiber sprouting in the inner and outer molecular
layers.
Mossy fibers in humans with MTLE and in animal MTLE models: form excitatory recurrent circuits through collaterals synapsing onto granule cell and interneuron dendrites in the supragranular layer and onto new subgranular dendrites in the hilus.
NMDA receptor activation
Group I mGluR activation in CA3 pyramidal neurons
TrkB signaling
Cross-talk between neurons and astrocytes (synchronous epileptiform activity in CA1 pyramidal neurons)
Molecular mechanisms underlying epileptogenesis
Activation of NMDA receptors (at postsynaptic sites on dendritic spines)
Ca2+ influx
CaMKII and calcineurin activation
CaMKII calcineurin
GluR1 of AMPA receptors internalization of GABAA receptor
[Ca2+]i GABA-mediated synaptic inhibition
Ca2+-dependent gene expression KCC2
Mossy fiber sprouting
Epileptogenesis
TrkB signaling promotes epileptogenesis in kindling
Astrogliosis – abnormal shape and increased numbers of astrocytes – is a prominent feature of Ammon’s horn sclerosis.
Glu released from neurons can activate mGluR on astrocytes.
Glu released from an astrocyte is sufficient to trigger a PDS (paroxysmal depolarizing shift) in neighboring neuron.
A novel mechanism for the synchronization of neuronal firing
Positive feedback model
PDS (paroxysmal depolarizing shift) : a brief(250ms) massive membrane depolarization with an accompanying burst of AP. (best cellular marker of an epileptic event)
Dynamic cross-talk
Treatment
Treatment of underlying causesTrigger avoidanceDrug therapySurgeryKetogenic dietVagus nerve stimulationDeep brain stimulationComplementary therapies
Medications and action mechanisms
Selection of antiepileptic drugs (AEDs) based on: ‘Standard’ vs ‘new’ drugSpectrum of efficacyTolerabilityPharmacokineticsMode of action
BenzodiazepinesClonazepam (CZP)Clobazam (CLB)
BarbituratesPhenobarbital (PB)Primidone (PRM)
Ethosuximide (ESM), Pfizer
Sodium valproate (VPA), Sanofi Synthelabo (Depakine)
Carbamazepine (CBZ), Novartis(Tegretol)
Phenytoin (PHT), Pfizer (Dilantin)
Standard
Zonisamide (ZNS), Athena
Oxcarbazepine (OCBZ), Novartis(Trileptal)
Tiagabine (TGB), Sanofi Synthelabo(Gabatril)
Topiramate (TPM), Janssen-Cilag(Topamax)
Gabapentin (GBP), Pfizer(Neurontin)
Lamotrigine (LTG), GSK(Lamictal)
Vigabatrin (VGB), Aventis(Sabril)
Felbamate (FBM), Carter-Wallace
New
Decreased excitation – via blockade of sodium channels, interaction with voltage-sensitive calcium channels or blockade of glutamate receptors.
Increased inhibition – via an increase in the concentration of GABA in the synaptic cleft.
First drug
Success rate 50% Failure rate 50%
Alternative monotherapy
Success rate 20% Failure rate 30%
Dual therapy
Success rate 5% Failure rate 25%
1. Sub-dural grid used to localise the site of seizure onset
2. Frontal lobectomy of non-dominant hemisphere (red area indicates the extent of resection)
Vagus nerve stimulation
Alteration of norepinephrine release by projections of solitary tract to the locus coeruleus
Elevated levels of inhibitory GABA related to
vagal stimulation
Inhibition of aberrant cortical activity by reticular system activation
Vagus nerve stimulation
Deep brain stimulation
Probably mimics that of high frequency DBS for movement disorders
Neurons adjacent to stimulating electrodes
appear to undergo long term inactivation following stimulation, leading to interruption of pathologic network activity
Deep brain stimulation