Pathophysiology of Epilepsy
Imad M Najm
Cleveland Clinic Epilepsy Center
Objectives:
1) To overview the natural history of seizures
and epilepsy
2) To provide an update on definition of terms
3) To discuss the mechanisms of first seizure
generation. Epileptogenesis and
Ictogenesis
Disclosures
• Speakers' bureau: Sunovion
• Research funding: National Institutes of Health
Natural History of Epilepsy
No
Seizures
First
AED
First
Seizure
Second
Seizure
Seizures are
controlled
47%
13%
Second
AED
Seizures
recur
More
AEDs
Seizures
continue
4%
Pharmacoresistant Epilepsy
36%
Update on Definition of Terms
•
•
•
•
•
•
Epilepsy
Unprovoked Seizure
Provoked Seizure
Epileptogenic abnormality
Epileptogenesis
Ictogenesis
“A seizure that is provoked by a
transient factor acting on an
otherwise normal brain to
temporarily lower the seizure
threshold does not count toward a
diagnosis of epilepsy”
At least two unprovoked (or reflex) seizures
occurring >24 hours apart
“The condition of recurrent reflex seizures, for
instance in response to photic stimuli, represents
provoked seizures that are defined as epilepsy.
Even though the seizures are provoked, the tendency
to respond repeatedly to such stimuli with seizures
meets the conceptual definition of epilepsy, in that
reflex epilepsies are associated with an enduring
abnormal predisposition to have such seizures”.
One unprovoked (or reflex) seizure and a probability of further
seizures similar to the general occurrence risk (at least 60%) after
2 unprovoked seizures over the next 10 years
“Its intent is to encompass circumstances for which
some practitioners and expert epileptologists manage
patients as if epilepsy is present after a single
unprovoked seizure, because of a very high risk of
recurrence. Such examples may include patients with a
single seizure occurring at least a month after a stroke
or a child with a single seizure conjoined with a
structural or remote symptomatic etiology and an
epileptiform electroencephalography (EEG) study”.
One unprovoked (or reflex) seizure and a probability of further
seizures similar to the general occurrence risk (at least 60%) after
2 unprovoked seizures over the next 10 years
“The term “unprovoked” implies absence of a
temporary or reversible factor lowering the
threshold and producing a seizure at that point in time.
Unprovoked is, however, an imprecise term because we
can never be sure that there was no provocative factor.
Conversely, identification of a provocative factor
does not necessarily contradict the presence of an
enduring epileptogenic abnormality”.
What are some of the “enduring
epileptogenic” abnormalities”?
There are the visible ones…
Epileptogenesis and Ictogenesis
• Epileptogenesis:
- The process(es) involved in transforming a “normal”
or “pro-epileptic” brain into a seizure-prone brain
- These mechanisms make epilepsy a progressive
disease
• Ictogenesis:
- Mechanisms involved in initiation of seizures:
distinct, transient occurrences caused by abnormal,
excessive, or synchronous neuronal activity in the
brain
Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by
the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE).
Epilepsia 2005;46:470-2.
1
The first seizure…
Seizures can be induced in any
“normal” animal
•
•
•
•
Kainic acid model
Pilocarpine model
Pentylenetetrazole (PTZ) model
Direct cortical stimulation model…
These are models of acute seizure
induction in otherwise normal brains:
These are PROVOKED seizures!
1
4
Marchi et al, 2007, Epilepsia
Can a single seizure occur in a
“normal” human brain?
1
21 y o RH male
IDDM
No FHx of epilepsy
No risk factors for epilepsy
Normal examination
Recent episodes of confusion
Blood glucose: 105
Rule out seizures
Episode of confusion
Blood glucose: 32
Severe hypoglycemia may induce a seizure in a
non epileptic human brain
Seizures can be induced/provoked
in a “normal” human brain
Triggers for the development of
seizures in the human brain
1.
2.
3.
4.
5.
Febrile illness in children
Trauma
CNS infections
Stroke
Other acute metabolic disturbances
These conditions may be associated
with provoked seizures in humans
A first seizure…
may be induced/provoked in
any brain
Multiple metabolic, endocrinologic,
endogenous/exogenous excitatory
conditions, electrical stimulations…
induce a seizure in a normal brain
Does epilepsy always develop after
one single provoked seizure?
NO
But the presence of a lesion and/or
EEG epileptic abnormality increases
the risk for recurrent seizures
Stroink H, Brouwer OF, Arts WF, et al. The first unprovoked, untreated seizure in childhood: a hospital
based study of the accuracy of the diagnosis, rate of recurrence, and long term outcome after recurrence.
Dutch study of epilepsy in childhood. J Neurol Neurosurg Psychiatry 1998;64:595–600.
Kim LG, Johnson TL, Marson AG, et al. Prediction of risk of seizure recurrence after a single seizure and
early epilepsy: further results from the MESS trial. Lancet Neurol 2006;5:317–322.
Does epilepsy develop in all
patients with pro-epileptic lesions?
No, only some patients with
potentially “epileptogenic
abnormalities” develop epilepsy
Examples: hemorrhagic infarcts,
severe head trauma…
21
If epilepsy is to develop…
Does it develop at the same age
in all patients with pro-epileptic
lesions?
NO…
22
Patients with FCD exhibit their first
seizure at different and variable ages
50
age of onset
40
30
20
10
0
1A
1B
2A
Pathology Classification
2B
Each Pair
Student's t
0.05
One way Analysis of Age of Onset By Pathology Classification, F<0.0001
2
Widdess-Walsh et al, Epilepsy Research
Is the presence of a lesion enough
for the generation of epilepsy?
• Kainic acid-induced hippocampal sclerosis
leads to chronic/recurrent spontaneous
seizures
• Pilocarpine-induced hippocampal lesions
lead to chronic/recurrent spontaneous
seizures
• Radiation-induced cortical dysplasia in
utero leads to spontaneous seizures
Not all animals with lesions become
spontaneously epileptic
Animals with pro-epileptic lesions
(enduring epileptogenic
abnormalities) have a lower
threshold for the development of
acute seizures (second hit) and
later on may easily develop
spontaneous seizures (epilepsy)
Rats with cortical dysplasia have lower threshold for
spontaneous and PTZ induced seizures
10% of dysplastic rats exhibit
spontaneous seizures
70% of animals exhibit status after
subthreshold dose of PTZ
2
6
Kunieda et al, 2002
Oghlakian et al, 2009
Epileptogenesis in more prevalent after
TBI in animals with preexisting
pathology (CD)
Nemes et al, 2016
Epilepsy is defined as the occurrence of
TWO or more unprovoked “epileptic”
seizures, or…
One unprovoked (or reflex) seizure and a
probability of further seizures similar to the
general occurrence risk (at least 60%)
What does it take to
transform a non epileptic
brain/lesion into an epileptic
one?
A possible second hit history in
patients with pharmacoresistant FCD
145 patients
• Febrile seizures: 17 (12%)
• CNS infection 11 (7%)
• Head trauma 31 (21%)
• Family history 36 (25%)
• Perinatal adverse events 48 (33%)
Widdess-Walsh et al, 2005
29
Dysplastic (but not yet epileptic) cortex
expresses pro-growth and anti-apoptotic
genes
Increased Excitatory
receptors genes
Increased anti-apoptotic
genes
Increased dendrite/axon
outgrowth genes
Hiremath et al, Epileptic Disorders, 2009
Congenitally abnormal hippocampus develop
sprouting following one single generalized
seizure
Nothing!!!
Timm’s staining
Control after PTZ GTC
Sprouting
CD after PTZ GTC
O’Dwyer et al, 2014 (Submitted)
Synaptogenesis increases after a second hit
in animals with cortical dysplasia
Nemes et al, Submitted
What about human
pathology?
Synaptogenesis in FCD type II
Ying et al, 2014
Synaptogenesis in FCD type II is
epilepsy duration dependent
New synapse formation is proportional
to epilepsy duration
Ying et al, 2014
Other factors may play a role in the expression
of epilepsy in some but not all patients with
“pro-epileptic” (Enduring epileptogenic)
abnormalities
Familial
Single “Major”
Gene
Multiple “Minor”
Genes
Sporadic
Mesial TLE
Neocortical epilepsy
due to FCD, tumor…
Environmental
Factors
(“second hit effect”)
Courtesy
of Jocelyn Bautista, MD (Modified)
3
What happens after a
single seizure? A “second”
hit?
NORMAL BRAIN
NOTHING
BRAIN with PROEPILEPTIC
LESION
EPILEPTOGENESIS:
NEW CONNECTIONS
NEW SYNAPSES
OTHER CHANGES…
Can epileptogenesis be
prevented?
3
Prevention of Epileptogenesis
• Clinically:
- No AED has been shown to work as an
antiepileptogenic agent
• Animal models:
- Levetiracetam delayed the expression of
spontaneous seizures in the kindling model
of epilepsy development
Pitkanen, Epilepsia 2010
Seizure/Normal brain
Pretreatment with levetiracetam
prevents the development of
sprouting following second hits
(PTZ induced seizures in rats
with cortical dysplasia
100µm
Seizure/CD/No Levetiracetam
Seizure/CD/Levetiracetam Pre Rx
O’Dwyer et al, Unpublished Data
What are the molecular
mechanisms of epileptogenicity
(ictogenesis)?
Excitatory mechanisms of ictogenesis
Normal
Normal
Astrocytes
Meldrum et al, Journal of Nutrition;130:1007S-15S, 2000.
Astrocyte
Failure of glial function:
Decrease in K+ clearance
Decrease in glutamate
clearance
Increase in Ca++ channels
Epileptic
Epileptic
Increase in Na+ channels
Mutation in Na+ channels
NR1
Ca++
channel
Nat Med 2005;11:919-20,
NR2 B
NR1
SV2
A
Na+ channel
NMDA
receptor
Glutamate
SV2
A
Non-NMDA
receptor Increase in AMPA receptors
Change in Presynaptic composition??
Presynapse
Increase in NMDA
receptors
Change in the subunit
composition
Postsynapse
Change in the subunit
composition
Inhibitory mechanisms of
ictogenesis:
Decrease in GABAergic
inhibition
Low glutamic acid
decarboxylase levels in
kindled
rats and in excised
GABAergic
interneuron
human epileptic tissue (2)
GABA-T
Reduced GABA levels in
CSF (1)
GABA
receptor
Reduced GABA receptors
in human brain tissue (2)
EPILEPTOGENESIS
:
ICTOGENESIS:
Increase in Excitatory mechanisms
Decrease in inhibitory mechanisms
Failure in glial buffering
Other systemic changes (electrolytes)
NEW CONNECTIONS
NEW SYNAPSES
SECOND HIT
Upregulation of progrowth, excitatory
receptors and antiapoptotic genes
Modified from: Najm et al, 2013 (Epilepsia)
Pathophysiology of Epilepsy
No
Seizures
EPILEPTOGENESIS
Starts
First
Seizure
Second
Seizure
Seizures are
controlled
47%
EPILEPTOGENESIS
Continues
EPILEPTOGENESIS
Continues
13%
Seizures
recur
4%
Pharmacoresistant Epilepsy
Seizures
continue
36%