1. Epilepsy Yung-Yang Lin (林永煬), MD, PhD National Yang-Ming University
Taipei Veterans General Hospital

2. Outline
Epidemiology
Diagnosis
Etiologies and Mechanisms
Treatment

3. Epidemiology

4. 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 )

5. Diagnosis

6. History of event
Medical history
Blood tests
Electroencephalography (EEG)
Simultaneous EEG and video recordings
Brain scanning (CT scan, MRI) - to discover if the patient has symptomatic epilepsy; a structural cause for their seizures
PET, SPECT, MRS
Magnetoencephalography (MEG)

10. Etiologies and Mechanisms

11. Aetiologies of epilepsy
Degenerative brain disorder 3.5%
Infection 2.5%
Neoplasm 4.1%
Idiopathic and cryptogenic
epilepsy 65.5%
Vascular injury 10.9%
Trauma 5.5%
Congenital causes 8.0%

12. Symptomatic seizures in different age groups10 20 30 40 50 60 70 80 90
100
0–4
5–14
15–24
25–44
45–64
65+
Others
Proportion of cases (%)
Degenerative
Cerebrovascular
Brain tumour
Trauma
Infection
Development
The major causes of new seizures are different in different patient age groups.
Seizures that occur in early life commonly result from injuries during birth, from metabolic disorders, as well as from other congenital problems

13. Seizure triggers
In rare cases patients may have one specific trigger that brings on a seizure, for example:
Flashing visual stimuli
Looking at a particular kind of pattern
Hearing a particular piece of music
Reading

14. Status epilepticus
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

15. Electrophysiological basis for epileptic seizures
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 cells
into a synchronous pattern of larger abnormal activity
(burst firing), there is transition from interictal to ictal activity
= SEIZURE

16. Imbalance between excitation and inhibition
Excess excitation
Lack of inhibition
epileptic seizures
epileptic seizures

17. Hippocampal sclerosis
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).

18. Neural circuits in hippocampal formation
input
output

20. 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.

21. Molecular mechanisms underlying epileptogenesis
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)

22. 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

23. TrkB signaling promotes epileptogenesis in kindling

24. Astrocytes and epileptiform activity
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

25. Dynamic cross-talk
PDS (paroxysmal depolarizing shift) : a brief(250ms) massive membrane depolarization with
an accompanying burst of AP. (best cellular marker of an epileptic event)

26. Treatment

27. Treatment of underlying causes
Trigger avoidance
Drug therapy
Surgery
Ketogenic diet
Vagus nerve stimulation
Deep brain stimulation
Complementary therapies

28. Medications and action mechanisms

29. Medication therapy Selection of antiepileptic drugs (AEDs) based on:
‘Standard’ vs ‘new’ drug
Spectrum of efficacy
Tolerability
Pharmacokinetics
Mode of action

30. Generations of AEDs New Standard Phenytoin (PHT), Pfizer
Benzodiazepines
Clonazepam (CZP)
Clobazam (CLB)
Barbiturates
Phenobarbital (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

31. Modes of action
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.

34. Likely outcomes in patients with newly diagnosed epilepsy
First drug
Success rate 50%
Failure rate 50%
Alternative monotherapy
Success rate 20%
Failure rate 30%
Dual therapy
Success rate 5%
Failure rate 25%

35. Focal resection – the seizure focus is localised and excised (in this case, by a frontal lobectomy)
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)

36. Vagus nerve stimulation

37. 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

38. Deep brain stimulation

39. 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