EPILEPSY AND COGNITIVE

DISORDERS
Jan S. Purba
Department of Neurology
RSCM/FK UI
 Definitions
Seizure: the clinical manifestation of an
abnormal, excessive excitation and
synchronization of a population of cortical
neurons

Epilepsy: recurrent seizures (two or more)

which are not provoked by systemic or acute
neurologic insults

American Epilepsy Society 2010 C-Slide 2

 Epilepsy Syndromes

Epilepsy

Partial Generalized

Idiopathic Symptomatic Idiopathic Symptomatic

American Epilepsy Society 2010 C-Slide 3

 Classification of seizure types
A. Partial seizure : The discharge begins locally, and often
remains localised, produce relatively simple symptoms
without loss of consciousness.
Simple partial seizure
Complex partial seizures
Partial seizures secondarily generalized
B. Generalized seizures : Involve the whole brain, including the
reticular system, thus producing abnormal electrical
activity throughout both hemispheres. Immediate loss of
consciousness.
Generalized tonic-clonic (grand mal) seizure
Absence (petit mal) seizures
Tonic seizures
Atonic seizures
Clonic and myoclonic seizures
Infantile spasms
 Epilepsy - Classification
Focal seizures account for 80%
of adult epilepsies
- Simple partial seizures
- Complex partial seizures
- Partial seizures secondarilly generalised

Generalised seizures
 Generalized seizures
(convulsive or non-convulsive)

Absences
Myoclonic seizures
Clonic seizures
Tonic seizures
Atonic seizures
 Epidemiology of
Seizures and Epilepsy
Seizures
Incidence: 80/100,000 per year
Lifetime incidence: 9%
(1/3 febrile convulsions)

Epilepsy
Incidence: 45/100,000 per year
Point prevalence: 0.5-1%
Cumulative lifetime incidence: 3%

American Epilepsy Society 2010 C-Slide 7

 Etiology of Seizures and Epilepsy
Infancy and childhood
Prenatal or birth injury
Inborn error of metabolism
Congenital malformation
Adolescence and young adult
Head trauma
Drug intoxication and withdrawal*
Older adult
Stroke
Brain tumor
Acute metabolic disturbances*
Neurodegenerative
C-Slide 8
American Epilepsy Society 2010
 Development of a seizure
Many structures and processes are involved in
the development of a seizure, including
neurons, ion channels, receptors, glia, and
inhibitory and excitatory synapses.
The AEDs are designed to modify these
processes so as to favor inhibition over
excitation and thereby stop or prevent seizure
activity (see the image below
 Pathophysiology

Still unknown
Some proposals:
Excitatory glutamatergic synapses
Excitatory amino acid neurotransmitter
(glutamate, aspartate)
Abnormal tissues tumor, AVM, dead area
Genetic factors
Role of substantia nigra and GABA
 Pathophysiology

Excitatory glutamategric synapses

And, excitatory amino acid neurotransmitter
(glutamate, aspartate)
These are for the neuronal excitation
In rodent models of acquired epilepsy and
in human temporal lobe epilepsy, there is
evidence for enhanced functional efficacy
of ionotropic N-methyl-D-aspartate (NMDA)
and metabotropic (Group I) receptors

Chapman AG. Glutatmate and Epilepsy. J Nutr. 2000 Apr; 130(4S Suppl): 1043S-5S
EpilepsyGlutamate

Diagram of the
various glutamate
receptor subtypes
and locations

From Takumi et al, 1998

B-Slide 12
 EpilepsyGABA
GABA site

Barbiturate site

Benzodiazepine
site

Steroid site

Picrotoxin site

Diagram of the GABAA receptor

From Olsen and Sapp, 1995 B-Slide 13
Dynamic target of seizure control in management of epilepsy is
achieving balance between factors that influence excitatory
postsynaptic potential (EPSP) and those that influence
inhibitory postsynaptic potential (IPSP).
 Cellular Mechanisms of
Seizure Generation
Excitation (too much)
Ionicinward Na+, Ca++ currents
Neurotransmitterglutamate, aspartate

Inhibition (too little)

Ionicinward CI-, outward K+ currents
NeurotransmitterGABA

B-Slide 15
Neuronal (Intrinsic) Factors Modifying
Neuronal Excitability
Ion channel type, number, and distribution

Biochemical modification of receptors

Activation of second-messenger systems

Modulation of gene expression

(e.g., for receptor proteins)

B-Slide 16
 Extra-Neuronal (Extrinsic) Factors
Modifying Neuronal Excitability
Changes in extracellular ion concentration

Remodeling of synapse location or

configuration by afferent input

Modulation of transmitter metabolism or

uptake by glial cells

B-Slide 17
 Hyperactive neurons: A Seizure
For various reasons (e.g. birth injury, TBI,
genetic misprogramming) a group of neurons
can become hyperactive
A bad connection
Over-firing neurons can activate their
neighbors, and, can then spread to the whole
brain (leading to loss of consciousness and
convulsion)
OUT

Cl- Na+

Cl- Na+
GABAA receptor Glutamate/AMPA
receptor

Inhibition Excitation
IN
 Brain Function Differs with Location
Different areas of the brain have different
functions
Brainstem: primitive structures: concerned
with breathing, eating, sexual activity,
emotion
Neocortex: Newer part of the brain:
Complex reasoning, sensation, movement
Regions separated by folds (sulci) and
hemispheres (right vs. left), and lobes
Brain Function Differs with Location
 Neurotransmitters for epilepsy
GABA as the major inhibitory transmitter of the
brain
diversity of glutamate receptors,
evidence is accumulating that glia may play active
roles in brain function and in epilepsy: their role
in potassium homeostasis has been known since
1970s, in transmitter re-uptake since the mid
1970s, and in releasing glutamate and other
gliotransmitters onto neurons since the mid
1990s
Gamma-aminobutyric acid (GABA)-A receptor
mediates chloride (Cl-) influx, leading to
hyperpolarization of cell and inhibition
Schematic representation of N-methyl-D-
aspartate (NMDA) receptor.
 EpilepsyGlutamate
The brains major excitatory neurotransmitter
Two groups of glutamate receptors
Ionotropicfast synaptic transmission
NMDA, AMPA, kainate
Gated Ca++ and Gated Na+ channels
Metabotropicslow synaptic transmission
Quisqualate
Regulation of second messengers (cAMP and Inositol)
Modulation of synaptic activity
Modulation of glutamate receptors
Glycine, polyamine sites, Zinc, redox site

B-Slide 25
 Epilepsy and Brain Disorders

The Lancet 2012 380, 1180-1192DOI: (10.1016/S0140-6736(12)61455-X)

 Definition
Cognitive function is defined as higher brain function,
that is, the capacity of the brain to programme
adaptive behaviour, solve problems, memorise
information and focus attention
Epilepsy is a chronic neurological condition
characterised by recurrent unprovoked seizures.
Cognitive impairment often develops as a symptom
secondary to the disorder
The most frequently reported cognitive problems
associated with epilepsy are memory impairment,
mental slowing and attentional deficits.
 Does Epilepsy Impact Memory?
This is a hot area of discussion, with
disagreement amongst the experts
Prolonged seizures lasting longer than an hour
(status epilepticus) can immediately damage the
brain
Small seizures (e.g. continuous right hand
twitching)no impact on cognition
Large seizures (complex partial seizures)if
poorly controlled FREQUENT for years may
impact SOME people, however, others have NO
complaints
 Cognitive Impairment in Epilepsy
Neurocognitive impairment is frequent in epilepsy
patients.
Causes are multiple, and may be influenced by several
factors including the epilepsy syndrome.
Most cognitive complaints in adult patients are mental
slowness, memory difficulties and attention deficits.
In children, cognitive problems are more diffuse,
responsible for language troubles, learning difficulties,
poor academic outcome, behavior problems and finally
unfortunate socio-professional prognosis.
 Definition: mental processes
This includes *attention, *remembering,
*producing and understanding language,
*solving problems, and *making decisions
Also can include *emotional problems like
depression and anxiety (which will be covered
at future lectures), *attention problems
likeattention-deficit disorder (ADD)
Brain area, Epilepsy and cognition
Both frontal and temporal lobe epilepsy were
associated with deficits in the short-term
memory and speed/attention domains
Case studies of children have described the
onset of frontal-lobe seizures accompanied by
behavioral, cognitive, and motor impairments
that were reversed when seizure control was
obtained with pharmacotherapy
(Boone et al 1988; Jambaque and Dulac, 1989)
What Seizure Related Factors May Affect
Cognition in Epilepsy?

Age
Seizure at Etiology
Syndrome Onset

Anti-epileptic
Seizure medication
Burden Epileptiform
(Duration, Activity
Frequency,
Status)

February 6, 2006 32
 Which Comes First ?
Epilepsy or cognitive impairment

Some people with epilepsy had difficulty

academically BEFORE their first seizure
Psychiatric, behavioral, and academic
problems commonly precede seizures in
children AND adults
This may suggest an underlying abnormality
leading to BOTH problems: problems with
thinking AND epilepsy
Symptoms Correlated to Location
Every brain is unique and everyones seizures
are different, depending on where the
seizures are coming from For example :
Occipital lobe/visual area cause perception of
color/shapes/hallucination
Temporal lobe/emotional areas/memory
cause emotions like fear, dj vu
Taste center causes metal taste, etc.
 Cognitive Impairment in Epilepsy
Memory problems are a core symptom of
amnestic mild cognitive impairment (MCI), but
are also one of the chief complaints of patients
with temporal lobe epilepsy (TLE).
Even worse, quality of life is negatively influenced
by memory impairment.
This superficial analogy is not only a possible link
between TLE and MCI but can serve as starting
point from which researchers in each field may
add innovative aspects to their respective
research areas
 Memory is Complicated
There are several different types of memory
(remembering names vs. reading a map vs. completing
a puzzle)
Memory also changes naturally as one ages
(Remembering details from childhoodbut where are
those darn keys ?!)
how do you know whether it is the epilepsy causing
the problem??
Age vs. Epilepsy
Medications vs. Epilepsy
Underlying brain disease vs. Epilepsy
 Memory and Temporal Lobe
Temporal lobe epilepsy may be more likely to
cause long term problems in memory
This is based on the anatomy of the temporal
lobe, including the hippocampus and
amygdalaimportant in memory

Temporal Lobe
 After a Seizure
A single seizure DOES NOT permanently
impair intellectual or behavioral abilities.
Postictal Period: After a seizure, most people
have a period of poor memory, concentration,
and tiredness.
This generally lasts several minutes to hours.
You may have difficulty remembering things
during this period
Seizure Medication and Cognition
ALL antiepileptic medications have the
potential to have the detrimental side effect
of slowing cognition
This is by nature of the medication: stopping
brain over-activity like during a seizure
The newer medications generally have less
side effects than the older medications
Some seizure medications even have cognitive
ENHANCING side-effects
 Some antiepileptic drugs stabilize inactive
configuration of sodium (Na+) channel, preventing
high-frequency neuronal firing
 EpilepsyGABA
GABA site

Barbiturate site

Benzodiazepine
site

Steroid site

Picrotoxin site

Diagram of the GABAA receptor

From Olsen and Sapp, 1995 B-Slide 41
Effects of Antiepileptic Drugs (AEDs)
on Cognition
Can cause adverse cognitive side effects.
Newer AEDs typically have more favorable cognitive
side effect profile but may still have some cognitive
side effects
Of the newer AEDs, greater concern is for effect of
topiramate (TPM, Topamax)
Side effects are typically dose dependent and greater
when treated with more than one drug (polytherapy)

February 6, 2006 42
 Older Medications and Cognition
The most significant thinking side-effects have
been shown to be from Phenobarbital and
Phenytoin (Dilantin)
These effects can be related to the DOSE, and
typically are REVERSIBLE when the medication is
stopped
Some of these side-effects may wear off with
time, as has been shown with carbamazepine
(Tegretol) 1-month into treatment
Valproic acid (Depakote) may have minimal
cognitive side-effects.
Dynamic target of seizure control in management of epilepsy is
achieving balance between factors that influence excitatory
postsynaptic potential (EPSP) and those that influence
inhibitory postsynaptic potential (IPSP).
 Positive Effects on Cognition
Some medications have been shown to improve
cognitive testing in patients:
Tegretol has been shown to IMPROVE memory in
some patients (though may be more likely to
cause problems)
In one study, 72% of patients on Clobazam have
reported improvement in thinking
Positive effects also reported with Lamotrigine,
Levetiracetam (Keppra), Topamax (!), and others
 Dose Size
Some of the thinking side-effects are present
at bigger doses, but not lower doses
Some or all of the effect might wear off with
time
These side-effects might be minimalized by
increasing the dose slowly
 Multiple Medications?
The side-effects of different medications may
add-up
4 medications added together may be more
likely to cause cognitive side-effects than any
of these medications alone (intractable
epilepsy)
 Anti-epileptic drugs
Drugs that act on sodium channels are
associated with the fewest cognitive side-
effects, whereas the risk is greatest in those
with GABAergic action
Anti-glutamatergic drugs are associated more
with positive effects on learning and memory,
especially those that work on the N -methyl-d-
aspartic acid (NMDA) receptor
 Mechanism of Action Antiepilepsy
drugs
Reducing electrical excitability of cell membranes,
possibly through inhibition of sodium channel.

Enhancing GABA-mediated synaptic inhibition.

This may be achieved by an enhanced pre- or
post- synaptic action of GABA, by inhibiting
GABA-transaminase, or by drugs with direct
GABA-agonist properties.
Brain Function Differs with Location
 CONCLUSION
Cognition is how we think, and can be affected
by many things, including *age, *poor sleep,
*depression, and importantly *seizures and
*seizure medication, etc.
Some seizure types are more likely to cause
problems with thinking.
Older seizure medications may be more likely
to cause greater problems with thinking.
 References

BOOKS:
Living Well with Epilepsy and other seizure Disorders: An Expert Explains
What You Really Need to Know; by Carl Bazil, MD, PhD; 2004.
Epilepsy; by Orrin Devinsky, MD; 2008.

ARTICLES:
Eddy C, Rickards H, Cavanna A. (2011) The cognitive impact of antiepileptic
drugs. Ther Adv Neurol Disord 4(6): 385-407