Bryan Schønecker

Student’s guide to
Epilepsy
Second Edition

Frydenskrig Forlag
Student’s guide to Epilepsy, Second Edition

Copyright © Bryan Schønecker 2014

All rights reserved

Published by Frydenskrig Forlag, Denmark

Cover and photos by Bryan Schønecker

Font: Georgia

ISBN-13: 978-87-997324-7-0 (EPUB)

ISBN-13: 978-87-997324-6-3 (PDF)

First Edition by Saxo Publish, Denmark, 2013

Other books by the author:

Student’s guide to Diabetes. 2013

Student’s guide to Animal Models. 2013

Student’s guide to Animal Stereotypies. 2013

The Bank Vole as Experimental Animal. 2013

Contents.
Preface 1

Abbreviations 2

Chapter 1 Fundamentals of epilepsy 3

Chapter 2 Historical perspective on epilepsy 5

Chapter 3 Classifying epilepsy 5

Chapter 4 Diagnosing epilepsy 8

Chapter 5 Epidemiology of epilepsy 9

Chapter 6 Complications of epilepsy 11

Chapter 7 Treatment of epilepsy 15

7.1 Treatment with drugs 15

7.2 Treatment by surgery 17

7.3 Treatment with diet 18

Chapter 8 Models of epilepsy 19

8.1 In vitro models 19

8.2 In vivo models 19

8.3 Genetic models 20

8.4 Models based on drugs/metals 22

8.5 Electrical stimulation models 24

8.6 Infection models 25

8.7 Lesion models 25

Chapter 9 Summing up on epilepsies and their models 27

References 28
Preface.
One of the subjects for my PhD dissertation was a new animal model of genetic
reflex seizures so I needed to also prepare a brief introduction to the epilepsies in
general. When I started to dig into the literature, I was at first confirmed in the
belief that scientists had indeed made significant progress in this field, simply
because the first many papers I read included a myriad of detailed informations in
addition to figures of brain waves during seizures, and the routinely use of complex
names for all types of different seizures and syndromes.

However, after a while the little details started to stand out, just as they usually do
after you have read enough papers on a given subject, and I had to adjust my
understanding. The epilepsies are basically still a mystery, and the main problem
for any researchers involved in studies of the brain is of course its immense
complexity. Anyway, I decided to try to get a little behind the usual headlines. The
result you are about to read now is more or less a direct copy of the introduction to
the epilepsies I presented in the above-mentioned dissertation [1].

My intention with this review is primarily to provide a compact and no-nonsense

aid for students of biology or medicine interested in achieving a factual overview of
the epilepsies. I also include a description of the literally countless and most diverse
models of seizures and the epilepsies as a service for those who might consider
doing some actual research and I provide plenty of references for those interested in
further studies.

This second edition of Student’s guide to Epilepsy only adds minor revisions to the
first edition. I hope you will enjoy the reading and that you afterwards will also feel
a little enlightened on the subject.

Bryan Schønecker.

Hareskovby, Denmark, April 2014.

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Abbreviations.
5-HT Serotonin (5-hydroxytryptamine)

AEDs Anti-epileptic drugs.

CNS Central nervous system (brain and spinal cord)

EEG Electroencephalograph.

ELmouse “Epilepsy” mouse. Named “ep” in 1959; “E1” in -64 and “EL” in -92 [2].

FSIQ Full-scale intelligence quotient.

GABA Gamma-aminobutyric acid.

GAD Glutamic acid decarboxylase (two isoforms: GAD65 and GAD67).

GEPR Genetically epilepsy-prone rats.

ILAE International league against epilepsy.

MRI Magnetic resonance imaging.

PET Positron-emission tomography.

SE Status epilepticus.

SSRI Selective serotonin re-uptake inhibitors.

SUDEP Sudden unexpected death in epilepsy.

TLE Temporal lobe epilepsy.

WHO World health organization.

2 
Chapter 1 - Fundamentals of epilepsy.
Epilepsy is basically any disorder characterised by uncontrolled excessive and
synchronous electrical discharges in various brain areas resulting in spontaneously
recurrent seizures which typically last from seconds to minutes [3].

Several authors consider epilepsy a heterogeneous group of disorders best

characterised as different syndromes (i.e. defined by types of seizures, onset ages,
eliciting causes if possible to access, complications, family history and other
variables), which is why the terms “the epilepsies” and “epilepsy” often are used
interchangeably (see e.g. [3-5]).

The part of the brain attracting the main interest as origin of seizures is the anterior
part of the forebrain (the cerebrum) which outermost portion (the cerebral cortex)
in one study were found to weigh approximately 82% of the total brain mass while
just containing 19% of the roughly 86 billion neurons in the total brain [6]. The
cerebrum is divided in two cerebral hemispheres, linked by a massive structure of
axons (the corpus callossum). Each hemisphere constitute a clear physical structure
which is further, more or less arbitrarily, divided in four lobes, named and
demarcated by the bones which overlie them. The frontal lobe is the foremost and
largest of the lobes and is bordered posteriorly by the central sulcus and inferiorly
by the lateral sulcus. It is positioned anterior to the parietal lobe and above/anterior
to the temporal lobe. The parietal and temporal lobes are separated by the lateral
sulcus and they both border the occipital lobe (no distinct boundaries) which is the
smallest of the four lobes and located in the posterior portion of the hemisphere [7].

The defining feature of the epilepsies is the “seizure” which to a casual bystander
can include unusual movements and inappropriate behaviours. Seizures are named
“convulsions” if they manifest as violent shakes of the body/limbs and “absence” or
”spell” if the person just stares indifferently without gross movements and reactions
to the surroundings. Other frequently used terms are e.g. “fit” and “attack” [3]. A
seizure might originate from a specific localization in any of the lobes (so-called
partial seizures) and later spread to include parts of the second hemisphere (i.e.
secondary generalized seizure) or start from multiple loci in both hemispheres (i.e.
primary generalized seizures).

3 
There are in principle four distinguishable components to a seizure and whether
they are present and, if so, their presentation are both important for the subsequent
diagnose.

The prodromal phase can last hours or sometimes days and is accompanied by
headache, irritability, insomnia, bad temper, depression, or increased activity [8]. It
should not be confused with the aura, which precedes the seizure by seconds or
minutes.

The aura signals the onset of a partial seizure and dependent on where in the brain
the seizure originates, patients will experience different “strange” sensations and
feelings which can persist for minutes/hours and sometimes be followed by a
generalized seizure [4]. Presence of an aura is therefore indicative of a partial
seizure. The feelings are often vague and the most common manifestations include
indescribable visceral symptoms, unpleasant smells, flushings, dizziness,
hallucinations, fear, etc [3, 4, 8].

Third phase is the seizure (ictus) itself and if it includes impairments of

consciousness the patient may have no recollection of the seizure where an aura is
remembered very well. More than 30 different types of seizures and 37 types of
epilepsy syndromes are named [9] and the most common types have been reviewed
by the International League Against Epilepsy (ILAE) in 1981 [10] and 1989 [11].

Citing from Dekker [8], the last phase, the post-ictal phase, “may be absent, brief or
may last several hours, and sometimes even days. There is usually a deep sleep
and waking up with headache, tiredness, irritability, vomiting, confusion,
muscular aches or ataxia. Transient paralysis of a part of the body, known as
Todd’s paresis may occur for a few hours or days. Altered speech or aphasia may
occur when the dominant hemisphere of the brain has been involved. Altered
behaviour and emotional outbursts may occur, and if these are interfered with,
violent behaviour is likely.”

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Chapter 2 - Historical perspective on epilepsy.
Epilepsy is one of the oldest conditions known to mankind. Two tablets, one in Neo-
Assyrian and the other in Neo-Babylonian cuneiform writings from around the
middle of the first millennium BC provided the first known description of
“prodromal symptoms, auras, descriptions of various types of seizure including
the tonic attack, absence attack, complex partial seizures (temporal lobe), the
Jacksonian attack, also post-ictal phenomena and inter-ictal emotional
disturbances. Provocative factors such as loss of sleep and emotion are mentioned.
Even noise-induced arousal would be of interest to the modern neurologist.” [12].

These surviving tablets are copies of an original whose exact date of origin is not
known with certainty, except that it probably is around the middle of the second
millennium BC [13]. Where the Babylonians apparently considered every attack the
result of a possession, Hippocrates (ca. 460 BC – ca. 370 BC) believed epilepsy to be
a disease of the brain, a view adopted by the Europeans only much later (17th - 18th
century) [14].

Chapter 3 - Classifying Epilepsy.

According to Reynolds and Rodin [15] there is still today a certain confusion
regarding the meaning of the words “epilepsies”, “attacks”, “seizures”, “fits”, and
“convulsions” leading to problems in first defining epilepsies, and second to the
fundamental nature of epilepsy.

This state of affairs is reflected in the fact that the most widely used classification
scheme for epileptic seizures was published by ILAE more than three decades ago
[10].

Seizures were classified as either localized (also named focal or partial seizures) or
generalized depending on whether the initial symptoms indicated that the seizures
originated from one location in the brain or, alternatively, resulted from
synchronous excessive discharges in both hemispheres.

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Localized seizures are then further subdivided into simple partial seizures
(consciousness is not affected), complex partial seizures (consciousness is affected –
not lost), and secondary generalized seizures, with a total of 25 further subdivisions.

In contrast to partial seizures, all generalized seizures involve partial or complete

loss of consciousness. Generalized seizures are further characterised in six groups
by ILAE, according to the effect they have on the patient.

• Absence seizures involve short periods (< 30 seconds) of impaired

consciousness, maybe with mild effects on the muscles and automatisms.

• Myoclonic seizures involves single or multiple sudden and brief contractions

in one limb, or bilateral.

• In Clonic seizures the muscles contract and relax rapidly without a sustained
tonus or tonic component.

• Tonic seizures involve immediate loss of consciousness and rigid, powerful

muscular contraction which is maintained, and lock the limbs in position.

• During a Tonic-clonic seizure consciousness is lost, the muscles stiffens (tonic

phase), breathing stops causing cyanosis and after a while clonic seizures
emerge and typically last for a couple of minutes.

• Atonic seizures (astatic seizures) involve a sudden loss of muscle tone, either
fragmentary or total and often causing a fall. For this reason atonic seizures
are also known as “drop seizures” and they are characterised by sudden onset
and loss of consciousness (seizure descriptions A-F after Dekker [8]).

The definition of seizures by ILAE lastly includes a category named “unclassified

epileptic seizures” where some types of neonatal seizures are placed [10].
Sometimes different seizure types is present in the same person and in such case
the classification is assumed to be based on the predominant type [16].

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ILAE also published the most widely used classification scheme for epilepsies and
epileptic syndromes back in 1989 [11] which basically presented two dichotomies:

• First dichotomy separates epilepsies and syndromes depending on whether

the seizures are localized (i.e. focal or partial seizures) or generalized.

• Second dichotomy addresses the presumed cause and separates idiopathic

seizures (“defined by age-related onset, clinical and
electroencephalographic characteristics, and a presumed genetic
aetiology”) from the symptomatic (“considered the consequence of a known
or suspected disorder of the central nervous system”) epilepsies and
syndromes. Both the partial and the generalized epilepsies contained an
additional group (the cryptogenic epilepsies), which have a hidden cause
suspected to be symptomatic.

Besides the localized and generalized epilepsies and syndromes, ILAE also operated
with a third category which contained epilepsies where it was undetermined
whether the seizures were localized or generalized (containing e.g. neonatal
seizures) and a fourth category called “Special syndromes” where the seizures are
provoked by special situations such as metabolic/toxic events (alcohol, drugs) or
e.g. fever as in febrile seizures [11]. Isolated events of status epilepticus (SE) fall
into this category and consist of prolonged seizure(s) lasting from 30 minutes (as
defined by ILAE [11]) up to as many as 20 days in one study [17].

Both classifications have been frequently debated (see e.g. [18-20]) and further
attempts to update the classifications were made in 2001 [21] and 2006 [22]. The
latest revision by ILAE is from 2010 [23] and basically substitutes a multitude of
older terms and concepts with new interpretations and terms. Old divisions have
been discarded, new proposed, and the reception by other experts in the field has
been somewhat mixed (see e.g. [24-26]). For a more exhaustive description of
seizures and epilepsy syndromes, I refer to Engel and Schwartskroin [27].

7 
Chapter 4 - Diagnosing epilepsy.
The main diagnostic tool is the use of an electroencephalograph (EEG) where
electrodes placed on the scalp each measures the actual summed electrical activity
from thousands of neurons [28]. Also magnetic resonance imaging (MRI) is
increasingly being used to search for any lesions which might explain the seizures in
patients otherwise classified with cryptogenic epilepsies [29].

Should the MRI turn out to be normal, other techniques such as positron-emission
tomography (PET scans), ictal single-photon emission tomography, proton
spectroscopy and [18F] fluorodeoxyglucose–positron-emission tomography (FDG-
PET scans) can alternatively be implemented [30].

Epilepsy is usually diagnosed after two or more unprovoked seizures more than 24
hours apart but can, in principle, be diagnose after “at least one” [31] unprovoked
seizure, provided available data suggest a more than 50% risk of a following seizure.
Since a positive diagnose can have serious consequences for the patient, it is
desirably to have a high degree of confidence to a diagnose, but it is not clear how
exactly to define epilepsy based on one sole seizure [32].

Considering the various epidemiologic estimates of epilepsy (see below), it is

important to realise that psychogenic non-epileptic attacks (which can resemble a
seizure but lack the characteristic electrical discharges, [33]) are commonly
misdiagnosed as epilepsy, just as EEGs can be over-interpreted and common
“staring spells” and shudder attacks in children can be mistaken for epilepsy [34].

In short – misdiagnoses are common (estimated to be 4.6-30% of the cases [35]),

and the average time to correct a faulty diagnose is 7-10 years [34].

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Chapter 5 - Epidemiology of epilepsy.
Epilepsy is the most common neurological disorder in childhood and the second
most common in adults [36]. It is estimated that 50 million people worldwide suffer
from epilepsies [37] and that roughly 80% of these reside in developing countries
[38].

The World health organization (WHO) estimates for developed countries a lifetime
prevalence of up to 10%; a prevalence in the range of 4-10 out of 1000, and an
incidence of 40-70 new cases annually per 100.000. The incidence in developing
countries is often twice as high because, as WHO puts it, “the higher risk of
experiencing conditions that can lead to permanent brain damage” [37]. If no
permanent remission occurred in the majority of people with epilepsy, a steady
annual incidence of 20-70 per 100.000 would result in a 2-5% prevalence instead of
the observed 0.4-1% which indicate that most patients are cured eventually (Blume,
[39], citing Bercovic et al. [40] and Sander and Sillanpaa [41]).

Most reviews present numbers within the WHO estimates and further points to
other differences related to regions, age and gender. In general, there seems to be a
higher incidence of epilepsy in developing countries as compared to developed
countries, unless cultural determined social stigmas could be thought to affect the
recorded prevalence negatively, as in the case of Asia [16]. Some of the presumed
causes for the higher incidence in developing countries are higher risk for
conditions such as neurocysticercosis, meningitis, malaria, pre- and perinatal
complications and malnutrition which all can lead to permanent brain damage,
resulting in epilepsy [42].

In developed countries incidence is relatively high among infants and young

children and several times higher among elderly than among adults (prevalence
increases with age). In developing countries, incidence is also high among infants
and young children, but the prevalence peaks in adolescence and early adulthood
[16]. Forsgren et al. (2005) estimated that the age-specific incidence rates in
Europe was 70/100.000 (age < 20), 30/100.000 (age 20-64) and 100/100.000 (age
> 65) and that 20-30% of those with seizures experience more than one seizure per
month [43].

9 
It would seem males are slightly more often affected by epilepsy than females,
although idiopathic generalized epilepsies are most common among females [44]. It
is still not clear if there is indeed a consistent significant difference, and if so, which
variables (e.g. physiology, exposure, cultural interactions with gender) would be
most explanatory [16]. Some studies show significance, others not, and dominance
could shift between age groups [43].

Regarding the epidemiology of seizure types (partial versus generalized) and their
presumed aetiologies (symptomatic/cryptogenic versus idiopathic), estimates vary
widely dependent on the studies, regions considered, and age of the patients. The
prevalence of partial and generalized seizures among people with epilepsy has been
reported to be 3-92% and 6-97%, respectively, with prevalence of
symptomatic/cryptogenic seizures in the range of 9-92% and 8-91% for idiopathic
epilepsies [16, 45-47]. SE is the most dreaded type of seizures due to high short-
term death rates (approx. 20%) and has an average incidence of at least
20/100.000 with a bimodal dispersion (highest in childhood and above age 60 -
reviewed in [48]).

10 
Chapter 6 - Complications of epilepsy.
People with epilepsy show a higher occurrence of anxiety-, mood- and attention
deficit hyperactivity disorders, but the causal relationship is at present
undetermined, as are the question whether a causal relationship exist at all, given
the bidirectional relation between these disorders and seizures disorders.
Furthermore, the comorbidity of these disorders with epilepsy has been ignored for
years as an “accepted” way to counteract pre-19th century lingering perceptions of
epilepsy as a mental disorder. These issues, as well as the hypothesis that epilepsy,
anxiety- and mood disorders share elements of the same pathogenic mechanisms
(decreased levels of serotonin (5-HT) in the central nervous system (CNS)) have
been reviewed by Kanner (2009) [49]. There seems to be a bidirectional relation
between mood disorders and epilepsy and Kanners review provide examples of how
a pre-existent mood and/or anxiety disorder can predict a worse response to anti-
epileptic drugs (AEDs) and anti-epilepsy surgery, as well as constitute a significant
risk factor for suicidality.

Epilepsy in children is also associated with highly increased risk for a social detour
in later life, although striking regional differences have been shown. A review of
nine papers on the subject showed that adults with a history of epilepsy and of
normal intelligence from Canada, Finland and England obtained significantly lower
levels of education compared with matched controls and 2-4 times higher rates of
unemployment, disability pensions, dependency of others for care, behavioural
problems, psychiatric difficulties, etc. In contrast, adults from Japan diagnosed
with epilepsy as children and of normal intelligence fared approximately as well as
matched controls where those with metal retardations (roughly a third of the
reviewed study groups) resembled the european studies where virtually all with
mental handicaps ended up with only a rudimentary education, unemployed, and
living alone [50].

SE is a frequent complication in both frontal lobe partial seizures and the childhood
epilepsies (the Lennox-Gastaut syndrome and myoclonic-astatic seizures) [11]. It
has been known for about 100 years that prolonged seizures can damage the brain,
especially those of SE. The damages include neuronal losses in the CA1, CA2 and

11 
CA3 pyramidal cell layer of the hippocampus, the dentate hilus, and the amygdala
accompanied by gliosis (proliferation of glial cells) [51].

Whether repeated seizures of shorter duration also damage the brain is more
controversial [52] since it is often difficult to differentiate the effect of an
underlying brain injury triggering seizures from the effect of the seizures itself, and
also because pre-epilepsy informations of relevance seldom is available when
people after years with epilepsy are investigated for brain alterations [53]. However,
hippocampal sclerosis (a condition where neuronal losses is seen in both the hilus
of the dentate gyrus and the C1 and C3 regions accompanied by gliosis [54]) is
reported in roughly 2/3 of patients with temporal lobe epilepsy (TLE), and neuronal
loss in CA1, CA3 and the hilus of the dentate gyrus in more than 90% of cases [52].
Sclerotic hippocampi in patients with TLE show extensive cell loss, gliosis, axonal
sprouting and deviant expression in both neurons and glial cells of many genes
encoding ion channels and receptors (reviewed in [55]). Although studies in
humans are sparse, some suggest that patients with TLE have decreased
neurogenesis in hippocampus, further suggesting that the deficits in hippocampal-
dependent memory and learning and depressive behaviour observed in these
patients are linked somehow to this decreased neurogenesis (reviewed in [56]).

The developing brain has a higher incidence of seizures than the developed but
shows more resistance towards seizure-induced brain damages. Most neonatal
seizures, i.e. seizures developing within the first 28 days post-natal, are
symptomatic and caused by a traumatic event such as lack of oxygen (hypoxia),
insufficient blood supply (ischemia), intracerebral hemorrhages, metabolic
disturbances, etc. Neonatal seizures constitute a risk factor for later childhood
epilepsy, particularly refractory (i.e. drug-resistant) epilepsy, increased morbidity
and mortality and the aetiology behind the seizures are believed to have major
influence on the prognosis (reviewed in [57]).

Research in animal models has shown how neonatal seizures can alter the
development of the brain, impair cognition, increase anxiety, and alter behaviour,
but the evidence for brain damage obtained so far in studies of human neonates are
much weaker [57]. However, a recent study of 77 newborns at risk for hypoxic-
ischemic brain injury showed that at age four years the 11 children which had

12 
experienced severe seizures after birth scored dramatically lower in a full-scale
intelligence quotient (FSIQ) test than the 52 children without a history of seizures
(mean FSIQ: 67 versus 97). The 14 children with mild/moderate seizures fell in
between with a mean FSIQ of 83. The results were adjusted for the extent of brain
injury and although the study could not differentiate between effects of the seizures
and the potential adverse effects of treatment with AEDs, the authors concluded
that neonatal seizures are indeed associated with deficiencies in
neurodevelopmental outcome independently of the degree of hypoxic-ischemic-
induced brain injury [58].

The compromise between staying safe and leading as “normal” a life as possible can
also be problematic for people with epilepsy. For instance, driving a car can have
obvious and serious consequences in case of a seizure, and perhaps common
applications in the home need to be fitted with “dead-man switches”, irons replaced
with new models only capable of heating when held in the appropriate position, etc.
(see websites such as e.g. Epilepsy.com for an overview of potential problems and
solutions [59]). The mere knowledge of perhaps being susceptible to incapacitating
seizures would naturally place some limitations on both work- and social life, and
recreational hobbies such as swimming suddenly becomes something to reconsider.
In fact, the risk of dying from drowning was in one review 15-19 times higher among
people with epilepsy than as seen in the general population [60]. Also the risk of
suicide is roughly three times higher among people with epilepsy compared to the
general populations [61], as are their general mortality, independently of age [62].

The reason for the apparent increase in seizure-unrelated mortalities and

comorbidities are not clear and it has been suggested that the burden of increased
psychological stress due to the possibilities of having unpredictable seizures could
lead to pathophysiological changes causing increased mortality and morbidity [63].
A feling of stigmatization is presumably also a widespread problem across cultures
since half (51%) of the respondents in a study involving 5.211 Europeans felt
stigmatized by their epilepsy and 18% felt highly stigmatized (i.e. “other people
were uncomfortable with them, treated them as inferior, and preferred to avoid
them”) [64]. The feeling of stigma was somewhat lower in a middle-eastern study

13 
(3.847 respondents living in Iran, the Gulf, and Near East regions [65]) where a
third reported a feeling of stigma and 15% felt highly stigmatized [65].

The most common cause of direct seizure-related deaths, particularly among people
with refractory epilepsies, is the so-called sudden unexpected death in epilepsy
(SUDEP), which is defined as an unexpected, nontraumatic death with no obvious
toxicological or anatomical cause. SUPED is most usually not witnessed, occurs for
the most parts at home during night and frequently shows circumstantial evidence
of a preceding seizure. The most important risk factor seems to be poorly controlled
seizures but others have been suggested, e.g. cardiac and respiratory dysfunctions
in combination with other risk factors.

Incidences of SUDEP in the general population of people with epilepsy ranges

between 0.1-2/1000 person years but can reach 6-9/1000 person years among
candidates for antiepileptic surgery (reviewed in ref. [66]).

14 
Chapter 7 - Treatment of epilepsy.
The process by which normal brain tissue becomes capable of generating
spontaneous seizures is termed epileptogenesis and is generally perceived as to
include both the initial development of seizure-prone tissue as well as its later
expansion as the disease progresses [28].

The available indications concerning the nature of human epileptogenesis are

mostly derived from studies of animal models and are believed to involve at first
immediate releases of primarily glutamate (the main excitatory neurotransmitter in
the brain [67]), ion channel activations, and sometimes cell injuries and –deaths.

The following hours/days post-injury are characterised by inflammatory events, up-

regulated gene transcriptions, neuron deaths, and possibly decreased synaptic
transmission. The following weeks/months are characterised by circuit
reorganisation such as axonal sproutings, gliosis, and neurogenesis, resulting in an
increased tendency towards synchronous neuronal activities.

If it was possible to predict whether a person would develop epilepsy following a

potential epileptogenic insult, proper intervention during the epileptogenic events
might improve the prognosis. However, there are no established biomarkers
available for therapeutic intervention prior to the onset of seizures, although a few
studies have shown promise (reviewed by Jacobs et al. [28]).

7.1 - Treatment with drugs.

AEDs are used in early onset epilepsy with the primary purpose of controlling
seizures, but also due to recognition of the potential adverse effect of ongoing
seizures on normal brain development. At present, 24 different AEDs (e.g.
lamotrigine, phenobarbital, phenotoin and valproate) have been approved for use in
USA and Europe, and additional agents are available for acute treatment of SE [68].
The therapeutic approach has basically not changed since 1989 [69] and involve an
individual assessment of presumed aetiology and seizure types. As example,
symptomatic epilepsy with generalized tonic–clonic seizures carry a high-risk for
recurrence where some benign partial epilepsies do not necessary require treatment
[68]. Further decisions involve whether to initiate monotherapy, administer
15 
multiple drugs, or perhaps consider other types of treatment (e.g. diet, surgery).
Despite the number of available AEDs has greatly increased since 1989 (13 new
AEDs licensed 1989-2009), none have shown strikingly superiority to the others, or
to the first generation AEDs such as phenytoin which appeared in 1938 and
phenobarbital which was widely used by 1912 [69, 70].

A possible explanation to this state of affairs could be that the simple models (e.g.
the maximal electroshock model) used to identify and develop these newer AEDs
were validated using first generation AEDs, whereas more laborious models (e.g.
the kindling model of TLE) due to logistic considerations are first used later in the
drug development process [71].

However, it should be mentioned that several studies point to the adverse effect of
some AEDs (especially sodium valproate) in terms of increased numbers of birth
defects and interference with both foetal and later brain development which is why
caution is advised when administered to women of childbearing age (see e.g.
reviews by Cross [72] and Meador et al. [73]). Although factors such as possible pre-
existent brain injuries, age, comorbidities, effect of seizures and design of studies do
complicate the interpretations of results, AEDs have been associated with adverse
cognitive effects in patients (sedation, problems with memory and attention),
impaired balance (resulting in falls and bone fractures) and increased risk of
atherosclerosis and suicide [74-78].

The before-mentioned study involving 5.211 adult europeans with epilepsy, and of
which 96% were receiving AED treatment, also showed that 88% reported at least
one side-effect from the AED of which tiredness (58%), memory problems (50%),
difficulties in concentration (48%), sleepiness (45%), difficulties in thinking clearly
(40% and nervousness/agitation (36%) were the most common [64]. The study
involving 3.847 people from the middle-eastern regions (98% on AED medication)
showed overall similar results with nervousness (58%), headache (53%) and
tiredness/behaviour problems (e.g. agitation) (both 50%) as the most commonly
reported side effects from AED treatment [65].

16 
Nevertheless, the prognosis for epilepsy is overall good with full remission within
five years of diagnosis for the majority of the patients [79]. It is furthermore broadly
recognised that some epileptic syndromes have an excellent outcome independent
of AED treatment [80], but in 20-30% of the cases, dependent of the type of
epilepsy, seizures cannot be controlled [68].

7.2 - Treatment by surgery.

There is a general consensus among epileptologists that a patient which does not
achieve seizure-freedom after treatment with 2-3 different AEDs at proper doses is
suffering from a refractory epilepsy and surgery could be an option for those
patients qualifying as “good surgical candidates” (i.e. patients with a clearly defined
epileptogenic area which it is possible to surgically remove with minimal
subsequent morbidity) [81].

The exact location, however, can be difficult to pinpoint, even with invasive EEG
recordings, so surgery is basically a compromise between achieving seizure-relief
while at the same time minimizing the resection (removal) of normal tissue [82].

The most frequent type of surgery is resection procedures such as anterotemporal

lobectomies to control focal epilepsies (approx. 75% of the operations) where e.g.
hemispherectomy (approx. 5% of the operations) is used in children with severe
seizures originating from multiple foci accompanied by arrest of cognitive and
motor development. Other types of surgery could be disconnection procedures such
as part- or complete resection of the corpus callosum which connect the two
hemispheres (especially used to control drop-seizures in patients diagnosed with
the Lennox-Gastaut syndrome); stimulation procedures such as electrical
stimulation of the vagal nerve by a “pace-maker” device [81], and e.g. deep brain
stimulation using implanted electrodes [83].

In general, serious post-operative complications are rare (2%); the mortality is

comparable to that in the general population and estimates of long-term seizure-
freedom after resection surgery range from 36-100% (reviewed in [84]).

17 
7.3 - Treatment with diet.
Besides various AEDs and surgical procedures, an alternative treatment is a
ketogenic diet based on the notion of mitigating seizures through the choice of an
appropriate diet. Variants of ketogenic diets have now has been used to treat
epileptic patients for close to a century [85]. The diets basically involve relatively
high amounts of fats, adequate levels of proteins, and low amounts of
carbohydrates, intended to mimic the conditions of fasting (the earliest recorded
treatment for epilepsy mentioned in the Hippocratic collection – see Wheless for
review of its history [86]), including the production of ketosis [87]. The ketogenic
diet has in several studies been shown to reduce the occurrences of seizures in
patients with refractory epilepsies, and although several potential mechanisms of
actions have been proposed, it is still not known why exactly the diet works so well
(see e.g. [85, 87-90]).

18 
Chapter 8 - Models of epilepsy.
According to the most recent attempt to provide a comprehensive guide to the
various models of epilepsy [91], researchers have a wide array of both in vitro and
in vivo models to choose from. The following sub-chapters aim at presenting what
can only be considered a glimpse of this multitude.

8.1 - In vitro models.

In vitro model preparations range in size from intact whole-brain models (e.g.
isolated guinea pig brains to study epileptogenesis in the temporal lobe [92]) over
200-600 micrometer thick brain slices, obtainable from any species with a complex
brain [93, 94], dissociated cell-cultures [95], individual neurons dissociated from
the brains of human and animals, and even further (neuron fragments, single-
channel patch-preparations) [96].

Regarding in vitro samples of human brain tissue it is important to note that they
exclusively are prepared using abnormal (i.e. epileptic) samples resected for
therapeutical reasons, and as such they will typically have different backgrounds in
terms of treatment with AEDs. Furthermore, such samples will typically also have a
history of resistancy towards pharmacotherapy, given that surgery has been chosen
as treatment [97].

8.2 - In vivo models.

Seizures and epilepsies have previously been described in species as phylogenetic

diverse as the fruit fly (Drosophila melanogaster) [98], the roundworm
(Caenorhabditis elegans) [99], the zebrafish (Danio rerio) [100] and the horse
(Equus ferus caballus) [101]. Also rodents such as deer mice (Peromyscus
maniculatus) [102-104], American meadow voles (Microtus pennsylvanicus) [105],
and gerbils (Meriones unguiculatus) [106-108] have been shown to develop
genetically influenced reflex seizures in captivity (reflex seizures can be generalized
or partial and are triggered by specific intrinsic/extrinsic stimuli. Around 5-6% of
people with epilepsy suffer from reflex seizures [109]).

19 
Mild handling or placement in a novel environment typically triggers seizures in
meadow voles and gerbils whereas seizures in deer mice most usually are provoked
by audiogenic stimulation (e.g. jingling bells). In contrast to both deer mice [102]
and gerbils [107] where reflex seizures to my knowledge only have been described
in animals bred in colonies, wild-caught meadow voles can also develop reflex
seizures [105]. According to Bronson and de la Rosa, the discoverers of the meadow
vole model, this special feature would make meadow voles suited for studies in the
population genetics of seizure susceptibility and the natural variation in both
genetic and neurological control of seizure-proneness [105]. However, I have not
been able to find any follow-up studies to Bronson and de la Rosa’s paper, and
papers focussing on seizures in deer mice are sparse compared to papers focussing
on seizures in Mongolian gerbils. My own contribution to this field is a new model
for genetic reflex seizures - Danish bank voles (Clethrionomys glareolus) - in which
seizures could be elicited in captive born voles (albeit not the wild caught) by
placing them in a cold jar [110].

8.3 - Genetic models.

Genetic reflex epilepsies are represented by several models, e.g. photogenic seizures
in Guinea baboons (Papio papio) ([111], but see also [112]), audiogenic seizures in
different strains of mice and rats [113, 114], and both types of triggered seizures in
Fayoumi chickens (Gallus gallus fayoumi) [115]. The before-mentioned deer mice,
American meadow voles, gerbils, and bank voles also develop genetic reflex seizures
and other models of idiopathic epilepsies would be e.g. the genetically epilepsy-
prone rats (GEPR-3 and GEPR-9) which are two often used strains susceptible to
audiogenic seizures but differing in the degree of seizure disposition and expression
in response to various stimuli [116]. Both seizure-experienced and seizure-naive
GEPRs show abnormally low CNS concentrations of 5-HT and norepinephrine
[117].

Drugs which further decrease these levels function as proconvulsants, whereas

drugs such as the selective serotonin re-uptake inhibitor (SSRI) fluoxetine (a 5-HT
agonist) function as anticonvulsants (reviewed in Dailey et al. [117]). Several studies
have in fact shown that SSRIs have anticonvulsant effects in GEPRs (see [118-120]).
20 
However, the exact site(s) at which 5-HT influence seizure-proneness is unknown
and e.g. neither depletions nor increments of 5-HT in the substantia nigra (a part of
the brain which is heavily serotonergic innervated and have been shown to
modulate seizures in the rat) showed an effect on any aspect of audiogenic seizures
in GEPRs [121]. There have also been some indications that citalopram (another
SSRI) can reduce seizures in both depressed [122] and non-depressed [123] patients
with epilepsy (albeit it should be mentioned that an earlier study found no effect
[124]). Treatment with citalopram also reduced audiogenic seizures in DBA/2J
mice [125], kindled seizures in cats [126], and handling-induced seizures in the
“epilepsy” (EL) mouse [127].

EL mice show a genetic disposition to develop seizures and although spontaneous

seizures have never been observed in EL mice, seizures are easily triggered by mild
handling, such as lifting it by its tail when changing cages, or tossing it up in the air
[128-130]. The proneness to triggered seizures in EL mice is apparently strongly
dependent on genetic interaction with in particularly age and gender [130] and also
significantly influenced by early stressors, as exemplified by increased susceptibility
of pups raised by both parents instead of only the mother [131]. Since EL mice fed a
ketogenic diet from age 30 days showed a four weeks delay in triggered seizure
onset compared to EL mice fed [presumably] ordinary chow, they have also been
suggested as a suitable genetic seizure model for further investigations of the
antiepileptogenic mechanisms of the ketogenic diet [132].

Although different types of seizure-prone models have been created successfully

through laborious selective breedings (e.g. the GAERS [133] and WAG/Rij [134] rat
models of genetic absence epilepsy), the most widely used procedure to create
models of seizures is to administer systemic injections of chemical convulsants
[135].

21 
8.4 - Models based on drugs/metals.

Such convulsants can be Gamma-aminobutyric acid (GABA)-related (e.g.

bicuculline, picrotoxin, various glutamic acid decarboxylase (GAD)-inhibitors and
beta-carbolines), excitatory amino acids (“EAAs”), such as kainic acid (see ref. [136]
for a closer description of kainate-induced SE) and N-methyl-D-aspartic acid
(“NMDA”), drugs which interact with the cholinergic system, such as pilocarpine
(see ref. [137] for a closer description of pilocarpine-induced SE), and low doses of
weapon-grade organophosphorus compounds, such as the extremely toxic
nervegasses tabun, sarin, and VX [135].

Other (unrelated) types of drugs have also been associated with seizures, e.g.
caffeine, aminophylline, strychnine, and insulin (hypoglycaemia-induced seizures)
[135]. Systemic injections of these drugs, and also inhalants such as flurothyl,
produce acute seizures which typically are primarily or secondarily generalized,
with some features being age specific [135].

The convulsant drugs mentioned above can also be injected directly into sensitive
brain regions to produce acute or chronic partial seizure models, with possible
secondarily generalization using only minute quantities of the drug. Also antibiotics
such as penicillins, tetanus toxin (see ref. [138] for a closer description of the
tetanus-model) and various metals such as cobalt, iron, zinc, nickel, and alumina
gel can be used to generate partial seizures [135].

Alumina gel injected into the sensorimotor cortex regions of a monkey reliably
produce partial motor seizures which are extremely similar in several variables to
those seen in human patients suffering from partial motor seizures. If the alumina
gel is injected into the temporal lobe, the result is complex partial and secondarily
generalized seizures with many similarities to the seizures observed in patients with
TLE [139]. In contrast to treatment with the above mentioned metals where the
seizures arise quickly and disappears after some weeks [135], alumina gel
injections, dependent on the actual injection site, result in seizures after 2-8 weeks
which can continue in variable frequencies for years (1/month – 10-20/day) [139].

Models of generalized typical absence seizures can be produced by treating a

normal mouse or rat with a single low dose of either pentylenetetrazole (PTZ) (the

22 
“PTZ-model”; repeated low doses of PTZ are used to induce SE [135]), or single
doses of “THIP” (4,5,6,7 tetrahydroxyisoxazolo (4,5,c) pyridine 3-ol), γ-
Hydroxybutyric acid (“GHB”) or, better, the prodrug of GHB which is γ-
butyrolactone (“GBL”) [140]. Atypical absence seizures, for which there is no
genetic model, can be produced by a single injection with the cholesterol
biosynthesis inhibitor AY-9944 (the “AY-model”), either alone or in combination
with a previous pre-weaning injection of the antimitotic neurotoxin
methylazoxymethanol (“MAM”), i.e. the “MAM-AY model” [140].

SUDEP has been modelled in DBA/2J mice where respiratory arrest can follow
audiogenic seizures and result in death [141]. Also a well-characterised sheep-model
of bicuculline-induced SE has been suggested to model SUDEP since roughly a
third of the experimental animals died shortly after seizure onset accompanied by
pronounced hypoventilation [142, 143]. Also the phenomenon of “Sudden Death
Syndrome” in broilers has recently been suggested as a model of SUDEP [144], as
have sudden deaths without apparent causes among captive Hamadryas baboons
(Papio hamadryas) with epilepsy [145] .

TLE is the most common form of drug-refractory epilepsy (affecting 20% of people
with epilepsy) and is most usually mimicked by the “pilocarpine model” [137, 146].
A single injection of pilocarpine into a rodent will initially produce limbic seizures
followed by SE lasting 6-12 hours, leaving the animal in a comatose condition with
abnormal activity in hippocampal and cortical neurons (acute phase). After that
follows a ”silent” or ”latent” period where hippocampal damage resembling
hippocampal sclerosis in human TLE occurs, and finally recurrent spontaneous
seizures emerge. Co-administration of lithium has been shown to enhance the effect
of pilocarbine in rats, whereas no such effect is seen in mice [147]. Other SE models
based on injections with kainic acid have frequently been used to model TLE (see
e.g. [148]).

Also, a close structural and functional analogue to kainic acid (domoic acid -
reviewed in [149]) can induce seizures which an incident of human mass poisoning
after ingestion of contaminated mussels showed in 1987 [150]. Four persons
subsequently died following a period of impaired consciousness and seizures, and
their neuronal damages were similar to kainic- and pilocarpine-induced SE

23 
damages in rats, thus showing the relevance of these models for SE [51]. Domoic
acid was subsequently isolated from diatoms (common marine microalgae), and
several later incidents with mass poisonings among marine mammals/birds have
been recognised. Poisoned sea-lions would show seizures, and subsequent autopsies
showed selective cellular vacuolation and necrosis in the hippocampal CA1, CA3
and CA4 sub-fields (reviewed in [36]), resembling SE-induced lesions in humans
[51].

A possible complication of febrile childhood seizures is SE and this complication

has been modelled using rat- or mice pups exposed to streams of heated air. The
hyperthermia-induced seizures which readily follows may be used to further explore
the association between childhood febrile SE and later development of hippocampal
dysfunction and TLE [151].

8.5 - Electrical stimulation models.

As Gastaut stated in 1962 ”there are as many types of SE as there are types of
epileptic seizures” (cited from [152]) and there are indeed numerous models of SE,
some of which are triggered by drugs as described above, and others using electrical
stimulation (e.g. repeated trains of stimuli delivered through electrodes implanted
into the perforant path or the hippocampus [153]) and/or taking advantage of
“kindling”, a phenomenon named by Goddard (et al.) [154] who discovered it in
1967 [155].

Kindling refers to a process by which a focally employed, usually electrical and

brief, subconvulsant stimulus triggers afterdischarges in neurons near the
electrodes which, over a period of daily stimulations, results in permanent lowered
susceptibility towards both triggered and spontaneous seizures. Kindling initially
models partial seizures, but as the process progresses, kindling models complex
partial seizures with secondary generalization. Fully kindled animals are to be
considered epileptic and the procedure has been shown highly robust and able to
produce seizures in species as different as amphibians and primates. It is also
possible to kindle animals using a variety of drugs by either direct intracerebral
injections, or, more commonly, using systemic injections in subconvulsant doses.

24 
Since these drugs have distinct and different modes of action, the robustness of the
kindling procedure supports the view that seizures themselves play a significant
part in the epileptogenesis, and also that kindling “is a neurobiological
phenomenon of plasticity and should be regarded as more than a chronic model of
epileptogenesis”. Kindling using one drug/mode also renders the model more
susceptible to triggering by other drugs/modes (reviewed in [156-158]).

8.6 - Infection models.

Models of epilepsies induced by infections (infection by the tapeworm Taenia

solium is worldwide one of the most common causes for epilepsy [159]) could e.g.
be mice infected by the tapeworm Taenia crassiceps to model human
neurocysticercosis, and mice, rats or rabbits infected with herpes simplex type 1
virus can be used to model encephalitis-induced seizures in humans. The
limitations in these models reside in the association between high incidence of
seizures and high mortality for the exposed animals and, of course, the problem
with infected researchers/caretakers due to shredded material from the animals.
Virus-infected brain slices are also used to study mechanisms of viral actions
(reviewed in [160]).

8.7 - Lesion models.

Severe traumatic brain injuries are estimated to confer a 29-fold increase in the risk
of developing epilepsy and are, further, estimated to account for approximately 20%
of the symptomatic epilepsies in the general population (reviewed in [161] and see
also [162]).

Traumatic brain injuries (TBI) have be modelled in various ways, (e.g. by direct
application of metals in the brain) and a widely used model is now the “Lateral
fluid-percussion brain injury model” (reviewed in [162]). In the study by Pitkänen
et al. a 5 mm wide hole is drilled in the skull of a rat without damaging the dura. A
fluid-percussion device then delivers a pulse of approximately 3 atm onto the dura
and the results, besides a 30-40% acute mortality, included a 43-50% development

25 
of spontaneous seizures during the 11 months follow-up and the replication of “the
entire epileptogenic process in humans after TBI” [162].

Where the Lateral fluid-percussion model mimics a cerebral concussion, the

“Partially isolated cortical islands model” is intended to mimic penetrating cortical
injuries. In this model, originally used on cats and monkeys and later modified to be
used in rodents, a bend spatula is inserted through a hole in the skull and then
rotated 180 degrees to undercut a targeted portion of the cortex [163]. Overt
seizures are not a feature in vivo but evoked and occasional spontaneous
epileptiform discharges will reliably be generated in brain slices obtained between
10 days and “at least 2 years” after the operation. The subsequent mortality is low
and usually connected to the anaesthesia [163].

Yet other models intend to mimic post-stroke epileptogenesis and epilepsy by

temporary occlusion of arteries (the “Middle cerebral artery/common carotid
artery occlusion model” [164]). Also, neuronal migration disorders (structural
malformations in the brain often associated with refractary epilepsy) have been
modelled by freezing small points of cortical area of newborn rodents to induce
malformations (the “Cortical freeze lesion model” [165]).

26 
Chapter 9 - Summing up on epilepsies and their models.
Clearly there is still quite some confusion, uncertainty and lack of factual knowledge
regarding the basic concepts of epilepsy (e.g. defining terminology and
classifications), epidemiology (huge variations in inter/intra regional estimates),
causalities (human epileptogenesis), and to a lesser extent comorbidities and
complications of the epilepsies.

The reasons for this state of affairs might to some extent be related to less public
(and thereby funding) attention compared to other fields such as research in
diabetes, cancer, and circulatory dysfunctions, but most certainly also to the basic
fact that the very target organ for these epilepsies are immensely complex.
Compared to what researchers have gathered of information and qualified
“guestimates” addressing the function and structure of the brain, regulation of
blood glucose can only be described as a miniscule collection of possible
interactions, and still the basic causalities behind diabetes remain obscure despite
6-7 decades of increasingly intense research.

The basic problem of brain complexity aside, it should also be safe to assume that
no free person of sound body and mind will ever contemplate the possible benefits
of venturing into experiments aiming at exploring epileptogenesis, refining
resection procedures and the like. Present day ethical climate also happens to
effectively prevent such experiments on healthy volunteers.

Consequently, researchers have to use a wide array of models, ranging from intact
non-human animals, over experimentally modified non-human animals, to various
tissue samples, and to the occasional human resected epileptic brain tissue. The
number of available models for the epilepsies is so high that I have been quite
unable to find any publications even attempting to estimate the number of available
and emerging models.

27 
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