epilepsy yung-yang lin ( 林永煬 ), md, phd national yang-ming university taipei veterans general...

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