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Introduction to Epilepsy and Related Brain Disorders

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DOI: 10.1007/978-3-319-20049-1_2

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Chapter 2
Introduction to Epilepsy and Related Brain
Disorders

Evangelia Giourou, Alkistis Stavropoulou-Deli, Aspasia Giannakopoulou,

George K. Kostopoulos, and Michalis Koutroumanidis

Abstract Epilepsy affecting 1 % of the world’s population and is the most common
serious disorder of the brain, greatly impacting on the quality of life of affected indi-
viduals, particularly those whose seizures are not fully controlled. Epilepsy has a
multifactorial origin and a multifaceted expression. It is caused by clusters of nerve
cells in the brain which sometimes signal abnormally, causing seizures. Anything that
disturbs the normal pattern of neuronal activity—from illness to brain damage to
abnormal brain development—can lead to seizures. Epilepsy may develop because of
an abnormality in brain wiring, an imbalance of nerve signaling chemicals called
neurotransmitters, changes in important features of brain cells called membrane
receptors and channels, or some combination of these and other factors.
Depending on the brain area affected and its physiological role, these distur-
bances of neuronal activity that occur during seizures may cause strange sensations,
emotions, and behaviors. They also sometimes cause convulsions, abnormal
movements, and loss of consciousness. In some people, seizures happen only occa-
sionally. Other people may experience hundreds of seizures a day. There are many
different forms of epilepsy, and symptoms vary greatly from one person to another.
About three-quarters of the individuals diagnosed with the epilepsies can control
their seizures with medicine or surgery. However, about 30 % will continue to expe-
rience seizures even with the best available treatment. In some cases, people experi-
ence a type of seizure that last so long that they can damage the brain and may be
life-threatening. Having a single seizure as the result of a high fever (called febrile
seizure) or head injury does not necessarily mean that a person has epilepsy. Only
when a person has had two or more seizures is he or she considered to have epilepsy.

E. Giourou • A. Stavropoulou-Deli • A. Giannakopoulou • G.K. Kostopoulos (*)

Neurophysiology Unit, Department of Physiology,
Medical School, University of Patras, Patras, Greece
e-mail: [email protected]
M. Koutroumanidis
Department of Clinical Neurophysiology and Epilepsy, Guy’s and St Thomas’
NHS Foundation Trust, London, UK
Department of Academic Neurosciences, Kings College London, London, UK

© Springer International Publishing Switzerland 2015 11

N.S. Voros, C.P. Antonopoulos (eds.), Cyberphysical Systems for Epilepsy
and Related Brain Disorders, DOI 10.1007/978-3-319-20049-1_2
12 E. Giourou et al.

A measurement of electrical activity in the brain and brain scans such as magnetic
resonance imaging or computed tomography are common diagnostic tests for
epilepsy.
Research efforts need to be stepped up to better understand pathophysiologic
mechanisms and to develop more effective therapies. Current understanding is on
the mechanisms underlying seizure expression and thus allow us only symptomatic
treatment (and still some seizures are or become with time drug resistant). To
develop a cure of epilepsy we have to understand epileptogenesis, the long process
which makes brain neurons vulnerable to hyperexcitability and abnormal synchro-
nization. Equally important is to raise awareness on the nature of epilepsy through
public education so that the lives of people with epilepsy are not adversely affected
by stigma, prejudice, and discrimination, neither face unjust restrictions in their
human rights, employment, marriage, and daily activities such as driving.
In this chapter we introduce the historical and current efforts to define and cate-
gorize epilepsy and we briefly describe the variety of its causes and our current
ideas on the mechanisms underlying the expression of its main types.

2.1 Introduction

This chapter aims to present a concise view of the major clinical and neuroscience
aspects of epilepsy for an academic but not necessarily medical audience. More
comprehensive accounts can be found in recent excellent reviews and books cover-
ing both clinical [1–5] and pathophysiological aspects [6, 7].
One can find descriptions of seizures since the beginning of recorded history, but
they were usually attributed to demonic possessions or other supernatural influence
[8, 9]. Babylonians astutely described many of the seizure types we recognize today
as tonic clonic seizures, absences, drop attacks, simple and complex partial seizures
and even focal motor (Jacksonian) or gelastic attacks. A writing from China’s
seventh to second century BC describes symptoms resembling both partial and gen-
eralized convulsions. All three Indian medical systems recognize epilepsy and a
compendium of the sixth century BC mentions loss of consciousness during par-
ticular seizures. The Babylonians and the other advanced Asiatic civilizations,
although apparently kin observers, were not motivated to search for underlying
mechanisms, being content with associating each seizure type with the invasion of
the body by a particular evil spirit. The concept of pathophysiology had to wait till
diseases were dissociated from the supernatural. Greeks imported all this medical
tradition by coining the verb ΕΠΙΛΑΜΒΑΝΕΙΝ (to seize someone) from which the
word epilepsy, while however questioning the nature of its causes and finally recog-
nized epilepsy as a disorder of the body rather than a sacred disease. This was
boldly asserted by Hippocrates in the fifth century BC—“AΛΛΑ ΓΑΡ ΑΙΤΙΟΣ Ο
ΕΓΚΕΦΑΛΟΣ ΤΟΥΤΟΥ ΤΟΥ ΠΑΘΕΟΣ … ΟΤΩ ΔΕ ΤΡOΠΩ ΚΑΙ ΕΞ ΟΙΗΣ
ΠΡΟΦAΣΙΟΣ ΓIΝΕΤΑΙ, ΕΓΩ ΦΡAΣΩ ΣAΦΑ” (Hippocrates Corpus 90, On the
sacred disease §§ 1–6, 21). Hippocrates was absolutely right on his first statement
that “the cause of epilepsy is in the brain”. But the second, that “he will proceed to
2 Introduction to Epilepsy and Related Brain Disorders 13

explain clearly the mechanism and cause of seizures” is far from being true even
today. Of historical interest to medicine is also his proposal to search for abnormal
humors in the head of the epileptic goats—which seems to be the first ever proposal
to experiment with animal models of any disease.
The idea of the brain as a cause of epilepsy was well accepted in specific circles
even up to the second century AD when we see Galen and Aretaeus treating and
theorizing about epilepsy in the Latin era. Unfortunately it had little influence on the
public’s view of supernatural causes, which remained up to the middle ages (at least,
given the still lingering progress of our society to abolish the stigma of epilepsy).
The main holdup to progress in this field appears to have been the prohibition of
anatomical studies, which ended with the European Renaissance of the fourteenth to
seventeenth centuries, with Thomas Willis writing of convulsive disorders and the
advance of pathology in the nineteenth century. Two fundamental developments, the
concepts of animal electricity (from Galvani to Todd) and of functional localization
in the brain (i.e. motor cortex) lead to the study of “epileptiform” or “partial” and
“generalized” seizures. About this time Caton discovered EEG in animals and 52
years later Berger discovered human EEG. This led to confirmation of Todd’s hypoth-
esis that seizures are the result of electrical discharges by Lennox in 1935. In the
beginning of the twentieth century the road to basic mechanisms of epilepsy is paved
by the introduction of the neuron doctrine (Cajal), the role of synapses (Sherrington)
and their transmitters (Levy, Dale). In the second half of the twentieth century
research is accelerated by enormous methodological progress in both directions:
reductionistic i.e. discovery of ionic channels (Hodgkin and Huxley) and molecular
genetics and integrating i.e. structural and functional brain imaging, video-telemetry,
MEG, computer assisted analysis and multimodal data fusion. Every advance seems
to add to the enormous complexity of the nervous system and the probability that
multiple elusive genetic–molecular–metabolic mechanisms contribute to the wide
range of epilepsies. We seem to know enough at the micro- and macroscopic level but
not much at the mesoscopic one. This is probably why we know ictogenesis well
enough to have relatively efficient drugs to suppress seizures, but we know almost
nothing about epileptogenesis and how to prevent it.
Epilepsy, a chronic condition that is characterized by recurrent seizures, affects
people of any gender, age and geographic region. Approximately 1 % of the general
population in western societies suffers from some sort of epilepsy while up to 10 %
will have at least one seizure during their lifetimes [10].
The incidence and prevalence of epilepsy in the EU is estimated to be respec-
tively 3.3–7.8 per 1000 and 44/100.000 [11]. The total number of people affected
with epilepsy in EU is estimated to 2,64 million. The financial burden for EU
expressed in disability adjusted life years is 245,475 and in cost-of-illness 5221 €
per person and 13,800 in total [12]. However, besides the calculated financial bur-
den, there is also an enormous and uncalculated cost to the patients and their fami-
lies. Even today, epilepsy still remains a stigmatizing disease with many social
consequences. The term itself, which means that the control over one’s behavior is
lost and remains unchanged over three millennia [8], shows the awe experienced
by both the patient and the bystanders to a seizure. Epilepsy can alter patients’
everyday life causing impairments in quality of life [13] and psychological distress to
14 E. Giourou et al.

caregivers. One of the most stressful aspects of the disease is the unpredictability of
seizure occurrence [14]. A large number of epilepsy patients fail to remain seizure free
despite adequate treatment; there is no such thing as “cured” epilepsy since seizure
threshold remains reduced compared to that of an unaffected person [15].
Moreover, epileptic seizures can be lethal. Common causes of death include
accidents while Sudden Unexpected Death in Epilepsy Patients (SUDEP) is often
attributed to ictal cardiac arrhythmias [16].
Epilepsy is a chronic condition of multifactorial causes (from genetics to brain
trauma and from inflammation to tumor) and with a multifaceted expression (from
a mere brief loss of consciousness to focal or generalized convulsions) depending
on which brain area has developed a tendency for neuronal hyperexcitability and
hypersynchronization and what is the physiological role of this area.
In newly diagnosed patients with epilepsy, the initial treatment option is usually
choosing one of the available antiepileptic drugs (i.e. monotherapy) based on sei-
zure type, age, co-morbidities and other factors. Should this fail to control seizures,
an alternative drug can be selected or be additionally prescribed.
Antiepileptic drugs accomplish seizure reduction by suppressing neuronal intrin-
sic or synaptic excitation (usually mediated by the neurotransmitter glutamate) and
promoting synaptic inhibition (usually mediated by the neurotransmitter gamma-
amino-butyric acid or GABA). Mechanisms of action include blockage of voltage-
gated Na+ (e.g. carbamazepine) and Ca2+ channels, enhancement of GABA-mediated
inhibition (e.g. benzodiazepines) and interference with glutamatergic excitation
(e.g. felbamate). Some antiepileptics have multiple target systems (e.g. divalproate
influences Na+, Ca2+ and GABA), while some others’ mechanism of action remains
unknown (such as that of gabapentin) [17]. Unfortunately all available drugs treat
ictogenesis (the expression of seizures) rather than epileptogenesis (the long term
development of conditions leading to seizures). In that sense all treatment is symp-
tomatic rather than causal, i.e. we do not yet have a cure for epilepsy. This symp-
tomatic treatment is usually effective in about 70 % of the cases.
Surgery can be employed in selected cases of drug-resistant epilepsy or in the pres-
ence of structural lesions such as a brain tumor or hippocampal sclerosis. In certain
cases of uncontrolled seizures vagal nerve stimulation might also be considered [18].
Undoubtedly epilepsy and its multiple often long term neurobiological, cogni-
tive, psychological and social consequences require tailor-made and multitargeted
treatment.

2.2 Definitions

Epilepsy is defined as a neurological condition which is characterized by a predis-

position to generate recurrent epileptic seizures; it is not a single disease entity but
points toward multiple underlying neurological defects and structural or func-
tional changes in the brain. This is fundamentally considered to be independent of
readily identified, transient factors that can induce seizures in the normal brain.
2 Introduction to Epilepsy and Related Brain Disorders 15

The current definition of epilepsy requires at least two unprovoked seizures occurring
24 h apart [15].
The word seizure may refer to many sudden and severe events often including
psychogenic seizures, dissociative seizures, conversion seizures many of which can
often resemble epileptic seizures without being due to epilepsy [15].
Epileptic seizures are defined as events (behavioral expressions) of a paroxysmal
nature often accompanied by transient alteration in consciousness level and with
signs and symptoms due to abnormal, excessive or synchronized neuronal dis-
charges of the brain which can be widespread or localized [19].
Non epileptic seizures on the other hand are not caused by abnormal neuronal
discharges. They can be divided in two large groups; the organic non epileptic
seizures (i.e. atypical syncope and parasomnias) and the psychogenic non epileptic
seizures—NEPS (i.e. conversion symptoms and dissociative states). Typically, dur-
ing a NEPS paroxysmal event sustained forceful eye closure can be present while
eye closure in any form is uncommon during epileptic seizures [20].
There are currently several definitions employed to define the actual lesion or
zone which is responsible for or correlated to the origin of epileptic seizures, mostly
in terms of presurgical evaluation. The (actual and the larger ‘potential’)
Epileptogenic Zone is described as the total cortical area which is necessary and
sufficient to generate the seizures. The Epileptogenic Lesion refers to an abnormal
structural brain area which is presumed to be causal of epileptic seizures in the
symptomatic epilepsies and can be usually indentified by MRI. The Irritative Zone
is the cortical area which is capable of generating interictal discharges while the
Ictal Onset Zone is the cortical area from which ictal discharges arise. Both the
Irritative Zone and the Ictal Onset Zone can be identified by scalp or intracranial
EEG recordings. The Functional Deficit Zone is the cortical area with focal nonepi-
leptic dysfunction which is responsible for functional deficits identified by neuro-
logical medical examination. The Symptomatogenic Zone refers to the cortical area
which when activated by a seizure is responsible for producing the first clinical ictal
signs and symptoms [21, 22].
Diagnostics of epilepsy still rely on clinical features. EEG, video and brain imag-
ining such as MRI and CT are used for differential diagnostic purposes once a sus-
picion on a possible epileptic syndrome is made. Clinical manifestations depend on
several factors such as the type of epilepsy or the particular epilepsy syndrome, the
patient’s age, the area of the brain that generates seizures, and whether ictal dis-
charges remain localized or propagate to other brain areas.
Every person can suffer an epileptic seizure given the right trigger and circum-
stances [15]. Acute symptomatic seizures occur at the time of a systemic insult or in
close temporal association with a documented brain insult. Such precipitating events
include metabolic disturbances, trauma, fever, infection, intoxication and substance
withdrawal [23]. Alcohol withdrawal may precipitate seizures. Alcohol decreases
CNS excitability by facilitating GABA action and acting as an NMDA receptor antag-
onist. Chronic alcohol abuse results in a down regulation of GABA and an up regula-
tion of NMDA receptors and glutamate production. When withdrawal occurs, this
increased potential for excitation can result in seizures [24]. Metabolic disturbances
and trauma can further contribute to seizures in patients with alcohol abuse.
16 E. Giourou et al.

There has been a long discussion on classification of the epilepsies which has
mainly been triggered by the recent technological advances both in imaging and
genetics. Diagnosing a specific electroclinical syndrome is not always possible
while the underlying cause might be of equal if not more value. Terminologies such
as idiopathic, symptomatic, cryptogenic and also partial, complex and simple are
not anymore used. A more descriptive approach has been recommended taking into
account the underlying aetiology while retaining electrophysical syndromes when
this is possible [25–28]. In parallel there is a growing appreciation of the fact that
classification schemes should be based on current pathophysiological explanations
but also serve to best distinguish conditions demanding different treatment and
often these two goals may be conflicting, while mutually dependent.

2.3 Classification

Epilepsy is not a single disease entity but it is rather consisted of a range of underly-
ing neurological disorders. The International League against Epilepsy—ILAE [25]
in response to concerns about the existing classification systems, proposed a multi-
axial diagnostic scheme which is summarized in Table 2.1. This diagnostic scheme
aimed in categorizing individuals according to a standardized terminology that
could be used by the vast majority of physicians in any relevant specialty while it
would be flexible enough to include the dynamic aspects of the disease.
Yet, a syndromic diagnosis is not always possible while presumed seizures types
and syndromes might alter as new information becomes available. Furthermore, a
classification system is used for a variety of purposes; epidemiological investiga-
tions, basic research, clinical aspects (e.g. screening patients before surgery) and
clinical trials. Thus a classification system should be able to address several different
needs of diverse areas. Therefore, in the light of new basic and clinical science
advances and led by the need to further simplify terminology used, a new classification has

Table 2.1 A proposed diagnostic scheme for people with epileptic seizures and epilepsy
Axis 1: Ictal phenomenology. Description of Ictal events using the Glossary of Descriptive
Ictal Terminology (Blume, 1991)
Axis 2: Seizure type. Specifying localization within the brain and precipitating stimuli for reflex
seizures using the List of Epileptic Seizures
Axis 3: Syndrome. Specifying possible syndrome from the List of Epilepsy Syndromes.
A syndromic diagnosis may not always be possible though
Axis 4: Aetiology. Defining when is possible genetic defects and pathologic underlying causes
for symptomatic focal epilepsies from the Classification of Diseases Frequently Associated with
Epileptic Seizures or Epilepsy Syndromes
Axis 5: Impairment. Classification of impairment. Optional additional diagnostic parameter
Modified from: Engel J. A proposed diagnostic scheme for people with epileptic seizures and with
epilepsy: report of the ILAE task force on classification and terminology, 2001 [25]
2 Introduction to Epilepsy and Related Brain Disorders 17

Table 2.2 Classification of seizures (2010)

Generalized seizures: Tonic-clonic; Absence (Typical, Atypical, Absence with special
features); Myoclonic (Myoclonic, Myoclonic atonic, Myoclonic tonic); Clonic; Tonic; Atonic
Focal seizures: according to severity (consciousness impairment, motor or autonomic
components, subjective sensory or psychic phenomena, evolving to bilateral, convulsive
seizures); according to site of origin according to sequence of clinical features
Unknown
Modified from: Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Bas W, Engel
J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer I. (2010) Revised
terminology and concepts for organisation of seizures and epilepsies: Report of the ILAE
Commission on Classification and Terminology 2005‐2009. Epilepsia;51:676‐685 [26]

Table 2.3 Electroclinical syndromes and other epilepsies (2010)

By age at onset
Neonatal period (Benign familiar neonatal epilepsy; Early myoclonic encephalopathy;
Ohtahara syndrome
Infancy (Epilepsy of infancy with migrating focal seizures; West syndrome; Myoclonic
epilepsy in infancy; Benign infantile epilepsy; Benign familiar infantile epilepsy; Dravet
syndrome; Myoclonic encephalopathy in nonprogressive disorders
Childhood (Febrile seizures plus; Panayiotopoulos syndrome; Epilepsy with myoclonic atonic
seizures; Benign epilepsy with centrotemporal spikes; Autosomal-dominant nocturnal frontal
lobe epilepsy; Late onset childhood occipital epilepsy; Epilepsy with myoclonic absences;
Lennox-Gastaut syndrome; Epileptic encephalopathy with continuous spike and wave during
sleep; Landau-Kleffner syndrome; Childhood absence epilepsy
Adolescence-Adult (Juvenile absence epilepsy; Juvenile myoclonic epilepsy; Epilepsy with
generalized tonic–clonic seizures alone; progressive myoclonus epilepsies; Autosomal
dominant epilepsy with auditory features; other familial temporal lobe epilepsies
Less specific age relationship (Familial focal epilepsy with variable foci; Reflex epilepsies)
Distinctive (MTLE with HS; Rasmussen syndrome; Gelastic seizures with hypothalamic
hamartoma; Hemiconvulsion-hemiplegia-epilepsy)
Epilepsies not fitting into any of the above are separated by the presence or not of a known
presumed cause (structural or metabolic) and by the primary mode of seizure onset (generalized
or focal)
By structural or metabolic causes
(Malformations of cortical development; Neurocutaneous syndromes; Tumor; Infection;
Trauma; Angioma; Perinatal insults; Stroke etc.
Of unknown cause
Conditions with epileptic seizures not diagnosed as epilepsy per se
Modified from: Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W,
Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer I. (2010)
Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE
Commission on Classification and Terminology 2005‐2009. Epilepsia;51:676‐685 [26]

arisen concerning mainly seizures classification but also introducing a simplification

of terminology used on epilepsies (Tables 2.2 and 2.3) [26].
18 E. Giourou et al.

2.4 Etiology

The possible identification of specific brain abnormalities associated with epilepsy has
crucial implications in the treatment and prognosis of the disease. A broad category
of brain abnormalities stems from a strongly genetic/developmental component,
while other cases mainly originate from acquired insults (such as infection, trauma
and hypoxia). While still classified together with other acquired pathologies,
hippocampal sclerosis is considered to originate from a combination of genetic risk
factors and initiating insults (such as febrile seizures) [29].
Lesions such as tumors and severe trauma are in no way transient and reversible.
Seizures occurring in patients with a potential cause of epilepsy (such as a highly epi-
leptogenic oligodendroglioma) are not classified as acute symptomatic seizures [30].
Moreover, if the lesion generates an enduring predisposition for unprovoked seizures,
with a risk comparable to those who have had two unprovoked seizures, then the person
should be considered to have epilepsy despite having only one seizure [15].
Although there is an apparent variance in the power of potential seizure triggers,
a recognized epilepsy syndrome comes to blur the lines. Seizures in reflex epilep-
sies are triggered by sensory, motor or cognitive stimuli, such as bright lights, eating
and music. The pathophysiology of this syndrome involves the activation of hyper-
excitable diffuse cortical pathways, with different triggering points according to the
precipitating stimulus (f. ex. occipital triggering and propagation through cortico-
cortical pathways in photosensitivity [31].

2.4.1 Febrile Seizures

Febrile seizures (FS) encountered in children are a well-known example of provoked

seizures. Factors involved in their pathogenesis include genetic susceptibility
(reflected in a positive family history), inflammatory mechanisms (with a particular
significance of IL-1β) [32], mutations in the GABA-A receptors and participation of
sodium channels [33]. FS are benign and not to be confused with the distinct epilep-
tic syndrome of Generalizes Epilepsy with FS (GEFS+).

2.4.2 Developmental Brain Abnormalities

Abnormalities in neuronal cell migration and dysplasias of the neural ectoderm

occur in embryonic life and result in malformations of cortical development (such as
hemimesencephaly, heterotopias and lissencephaly) and epileptogenic neurocutaneous
syndromes (Tuberous Sclerosis Complex and Sturge-Weber syndrome), respectively.
A strong genetic component is involved in Tuberous Sclerosis (autosomal dominant
inheritance) as well as in vascular malformations such as cavernomas. Such lesions
mainly result in intractable seizures that require surgical intervention.
2 Introduction to Epilepsy and Related Brain Disorders 19

A variety of aggressors can disrupt the normal migration of neurons from the
periventricular germinal matrix to their final destination and disrupt cortical lamina-
tion, thus resulting in a failure of normal circuit formation. These include infectious
agents (such as rubella and the TORCH complex), toxins (e.g. alcohol) [34], while
genetic factors may also play a role. Histologically, a scattering of large anomalous
neurons is observed, associated with thickening and white matter “balloon cells”
(focal cortical dysplasia), a blurring of the cortical/white matter border (hemimega-
lencephaly), while heterotopic gray matter islands in the white matter are observed
in heterotopias. Lissencephaly and pachygyria are notable for disrupted gyri archi-
tecture [35].
In Tuberous Sclerosis, blurred cortical lamination results from masses of astro-
cytic cells and calcifications, while in Sturge-Weber cortical atrophy is the result of
overlying angiomas. This finding is also present in vascular malformations. Other
epileptogenic factors include the presence of hemosiderin from recurrent hemor-
rhages, especially in cavernomas [36].

2.4.3 Acquired Lesions

Epilepsies resulting from non-developmental abnormalities include post-traumatic

epilepsy (PTE), seizures originating after hypoxic brain injury (as in stroke and
perinatal insults) and tumor-associated epilepsy (TAE). Hippocampal sclerosis
(HS) and medial temporal lobe epilepsy (MTLE), classified as a distinctive constel-
lation, will also be mentioned here.
Although infectious and immunologic aetiologies are important in acquired epi-
lepsy, with the former playing an important role in the developing world (mainly in
the form of tuberculomas and cystic brain lesions due to neurocysticercosis) and the
latter in surgical constellations such as Rasmussen’s Syndrome [35], a systematic
review is beyond the scope of this chapter.

2.4.3.1 Brain Injury (Traumatic, Hypoxic/Ischemic)

Post traumatic epilepsy (PTE) is the most common cause of new-onset epilepsy in
young adults [37] and accounts for 20 % of structural epilepsy (5 % of all epilepsy
cases) [38]. Nevertheless, only a sub-group of brain trauma patients will develop
epilepsy. The latency from the time of the injury to the onset of epilepsy is extremely
variable (weeks to years) [39] while scalp EEG may be unable to detect initial epi-
leptiform activity [40]. Higher injury severity and the presence of an intracranial
hematoma are important risk factors for both early (in the first week after injury)
and late seizures [41]. Other risk factors for PTE include advanced patient age,
multiple concussions and seizures within 24 h post-injury [42].
Histopathological consequences of penetrating injuries include the formation of
an epileptogenic cortical scar, while non-penetrating trauma results in axonal
20 E. Giourou et al.

shearing, edema and ischemia in the gray–white matter junction [43]. Haemoglobin
breakdown products, resulting from haemorrhage, have been implicated in epilep-
togenesis [44].
Changes in molecular signaling involving gene induction and modifications of
neurotransmitter receptors and ion channels occur early after an injury. Axonal
sprouting and dendritic modifications (such as mossy fiber sprouting) happen later
on. A variety of mechanisms, including blood-brain barrier disturbances, inflamma-
tory responses and release of related cytokines have also been implied [43]. All of
the above changes result in an increased excitability that lowers seizure threshold.
Neuronal damage extends past an acute hypoxic insult and into the reperfusion
phase. Pathophysiological mechanisms include apoptosis, activation of inflamma-
tory mediators [45] as well as excessive extracellular glutamate excitotoxicity and
intracellular accumulation of calcium [46]. Astrocytes post-insult release signals
(such as thrombospondins) that increase excitatory synapse formation [47].
Apart from mechanisms leading to increased neuronal excitation, tissue necrosis
and liquefaction can result in the formation of isolated cortical foci. Animal models
of cortical isolation (“undercut” models) have shown a selective loss of GABAergic
interneuron [48], resulting in a limitation of inhibitory mechanisms, which also con-
tributes to epileptogenesis. It is worth noting that cortical isolation is present in both
acquired (PTE, hypoxic injury) and developmental structural epilepsies.

2.4.3.2 Hippocampal Sclerosis (HS)

HS is present in at least 30 % of all epilepsy cases, according to both surgical [49]

and post-mortem [50] series. HS is mainly associated with mesial temporal lobe
epilepsy (MTLE) and reported in 50–70 % of patients with TLE and MTLE [51].
Whether HS is the cause or a consequence of seizures remains a highly contro-
versial subject. Although status epilepticus has been proved to cause neuronal
death, whether brief seizures amount to a similarly deleterious effect is still debated.
Studies supporting the claim that the type of precipitating injury, seizure frequency
and severity influence HS abound [52]. On the other hand, it has been proposed that
hippocampal abnormalities in TLE play a pathogenetic role. Further support to this
claim comes from imaging studies, showing that the degree of hippocampal atrophy
is not correlated with the duration and severity of seizures [53]. Also, patients with
multiple or poorly controlled seizures, as well as patients in a distinct subgroup of
TLE, do not always display hippocampal sclerosis and neuronal loss. Finally, it has
also been suggested that the pathologic alterations observed in sclerotic hippocampi
can result from an abnormal cell migration during brain development [54].
Histopathologically, two areas of the hippocampus are mainly affected in HS:
Ammon’s horn and the dentate gyrus. In Ammon’s horn, there is a marked neuronal
depletion and astrocytic proliferation. These astrocytes display increased expres-
sion of glutamatergic receptors and are more capable of generating action potential-
like responses in vitro compared to normal astrocytes [55]. In the dentate gyrus, loss
and dispersion of granule cells, growth of new fiber systems (mossy fiber sprouting),
2 Introduction to Epilepsy and Related Brain Disorders 21

loss of inhibitory interneurons and upregulation of inhibitory neurotransmission

(perhaps in an attempt to curb increased excitation) are observed. In contrast to
these changes, the subiculum (which is the main output region of the hippocampus)
remains intact [56]. Nevertheless, it has been reported to contribute to epileptogen-
esis by initiating spontaneous interictal discharges [57].
ILAE classifies HS in three distinct categories, based on the regions (CA1 or
CA4) involved in neural cell loss and gliosis. These categories differ in epilepsy
history and prognosis of postsurgical seizure control [54].

2.4.3.3 Tumor-Associated Epilepsy (TAE)

Epilepsy is far more common in brain tumor patients than in the general population.
Compared to high-grade tumors and cerebral metastases, low-grade gliomas are
linked to a higher risk of seizures. Although the longer survival rate of patients with
low-grade tumors, as well as molecular differences of each tumor category, could
contribute to these findings, slow growing tumors might deafferentate cortical areas
and thus create highly epileptogenic foci, as opposed to high-grade tumors that
could induce epilepsy mainly through rapid tissue disruption and necrosis [58].
The most common seizure types in TAE are generalized tonic-clonic and complex
partial seizures.
Evidence from both animal models [59, 60] and patients with TAE [61, 62] point
towards the fact that crucial changes occur in the peritumoural region and not the
immediate tumor invasion zone. These include glial cell swelling and damage
resulting from hypoxia, acidosis [63] and altered expression of glutamate receptors
in reactive astrocytes.
Numerous studies have shown that a frontal location of the tumor (and thus close
to the premotor and motor cortex) is associated with a higher probability of associated
epilepsy [64, 65]. Propagation of abnormal signals and/or a disruption of electrical
activity transmitted to the primary motor cortex could be a logical explanation for the
higher incidence of epilepsy when a tumor is located closer to the premotor cortex. In
addition, the limbic and temporal lobe, the primary somatosensory cortex (S-I) and
the opercula and insula regions of the secondary somatosensory area (S-II) also have
a low threshold for producing seizures [65]. Notable exceptions include medial
sphenoid wing meningiomas (where incidence of seizures is low) and seizure-like
phenomena associated with posterior temporal-inferior occipital lesions [66].

2.4.4 Seizure Precipitants and Modulators

2.4.4.1 Sleep Deprivation

There is a controversy regarding seizures occurring after sleep deprivation. EEG

recordings after sleep deprivation in epilepsy patients have been widely used, while
sleep deprivation is known to activate epileptiform discharges independently of the
22 E. Giourou et al.

activating effects of sleep [67]. However, seizures occurring after sleep deprivation
are not classified as provoked by ILAE [15] and epilepsy specialists [68], since
recurrence is far more likely than for patients with a provoked seizure. Further con-
founding to this issue, sleep deprivation is causing severe stress, a known seizure
promoting factor, so it is hard to say whether epilepsy aggravation upon sleep depri-
vation is a direct effect (Chap. 3 will elaborate on the complex relationship between
sleep and epilepsy).

2.4.4.2 Stress and Epilepsy

Seizures, particularly infantile spasms, have been linked to a stress-related elevation

of CRH, which is responsible for the cascade leading to the production of adrenal
steroids (such as cortisol). CRH has been found to act proconvulsively on seizure-
prone brain regions such as the limbic system [69], by enhancing the actions of
glutamate and suppressing afterhyperpolarisation [70]. Glucocorticoids limit the
production of CRH as part of a negative feedback loop. Nevertheless, they activate
CRH gene expression in the amygdala (a potential proconvulsive action) while
adrenal-derived neuropeptides have both pro- and anticonvulsive properties [71].
Adrenocorticotropic hormone (ACTH) is released from the pituitary in response to
hypothalamic CRH and has been proved to be anticonvulsive. ACTH also sup-
presses CRH, while inducing steroid synthesis, and thus is superior to oral steroids
in the treatment of infantile spasms [72]. Under the influence of CRH, β-endorphin
is released in an attempt of stress-level reduction. It acts as an endogenous opioid
(μ-receptors), inhibiting the release of GABA and increasing dopamine levels [73]
hence its excitatory effect.

2.4.4.3 Epilepsy and Reproductive Hormones

While men are reported to be more susceptible to epilepsy [74], sex-specific seizure
propensity differs in various epilepsy syndromes. Sex-related differences are mainly
thought to be the consequence of estrogen, progestin and androgens, which are also
responsible for sexual brain dimorphism and behaviour patterns [75].
Ten to seventy percent of female patients with epilepsy has a greater propensity
to seize in specific phases of their menstrual cycle, a “clustering” termed catamenial
epilepsy, and observed in premenstrual and preovulatory periods, where the estro-
gen/progesterone ratio is high. Progesterone has antiepileptic properties, mediated
by the GABAergic neurosteroid allopregnanolone, while it also has receptors in the
limbic system. Estrogen, on the other hand, is primarily proconvulsive, by directly
affecting glutamate receptor subtypes and increasing the density of hippocampal
dendritic spines and excitatory synapses in animal models. Nevertheless, it has also
been reported to increase neuropeptide Y concentration, with a possible antiepileptic
effect [76].
2 Introduction to Epilepsy and Related Brain Disorders 23

2.5 Pathophysiology of Seizures and Epilepsy

Medicine is both art and science. The Hippocratic art of healing becomes a medical
science to the extent that we succeed to identify which physiological function is
changed in each disease and by what mechanism. Decades of neurological and neu-
rosurgical observations have made numerous such links between the expression of
seizures (loss of motor control, consciousness etc.) and the normal function of the
particular brain areas which appear to initiate epileptic discharges and/or show
lesions in each patient. In the process epileptology has become the greatest school for
neuroscience, i.e. the description of the motor homunculus (for motor control), cor-
relates of consciousness etc. More recently basic research in epileptology has eluci-
dated many mechanisms underlying the expression of seizures at the macroscopic
(brain imaging) and microscopic levels, especially in the ionic channels and neu-
rotransmitter systems involved in the expression of seizures. Knowledge at the meso-
scopic level (brain circuits) is seriously lagging behind. The most crucial question of
mechanisms underlying epileptogenesis is still unanswered, although strides are cur-
rently made in this direction by molecular genetics and neuroplasticity research.

2.5.1 Basic Neurophysiology

GABA is the major inhibitory neurotransmitter in the brain. GABAA receptors

coupled to chloride are involved to the hyperpolarizing of membranes which
enables the inhibition of neuronal activity. The chloride mediated hyperpolarizing
current counterbalances the excitatory input’s depolarizing currents and needs to
be overcome for an action potential to fire. As data of animal models suggest, the
acute GABAA receptor blockade will produce epileptic activity while in addition
the GABAA receptors are the targets of many anticonvulsant medications which are
currently in use. Benzodiazepines and topiramate increase the rate of chloride
channels opening while barbiturates increase the duration that these channels
remain open thus decreasing excitability. GABAB receptors show a similar action
through a different mechanism. GABAB receptors couple to potassium channels
and form a current with longer duration of action compared to the GABAA receptor
activation [77].
Glutamate on the other hand, is a major excitatory neurotransmitter in the brain,
mediated by three main receptors: N-methyl-D-aspartic acid (NMDA), alpha-amino-
3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainite and metabotropic.
Selective NMDA receptor agonists show proconvulsant action while antagonists of
the AMP/kainite and NMDA receptors have antiepileptic properties [78].
Glia cells and gap junctions between neuron cells facilitate voltage spread.
GABA regulates the release and reuptake of neurotransmitters and transporters located
both on glia and neurons. Furthermore, glia regulates the extracellular potassium
concentration, which is correlated to neuronal excitability and epilepsy [79].
24 E. Giourou et al.

Two main types of ion channels exist. The ligand-gated channels which are
activated by GABA, glutamate and acetylcholine, mediate cell communication at
the synapse while the voltage-gated channels mediate the action potential and the
axonal conduction of electrical signals. During resting state, the latter are closed
and they open with the local membrane potential changes. Abnormalities of these
channels lead to a disruption of membrane’s depolarization and repolarization that
is necessary for the action potential. Several studies have suggested that channelo-
pathies can be the underlying cause of certain epileptic syndromes. Generalized
Epilepsy with Febrile Seizures Plus (GEFS+) is linked to missense mutations in
sodium (NaV1.1) channels, while complete loss-of-function mutations in NaV1.1
cause Severe Myoclonic Epilepsy of Infancy. Benign Neonatal Infantile Seizures is
also caused by mutations in sodium (NaV1.2) channels [80]. Potassium channelo-
pathies have been implicated in Sudden Unexplained Death in Epilepsy (SUDEP,
Kv1.1) [81], while monogenic idiopathic generalized epilepsies (IGE) have been
associated with mutations in GABAA receptor genes [82]. Absence epilepsies have
also been linked to GABAA [83], GABAB [84] as well as voltage-gated calcium
channel dysfunction [85].
Neuromodulators (such as neuropeptides and neurosteroids) are endogenous
factors that influence the balance between excitation and inhibition in the brain.
Neuropeptides regulate GABAergic and glutamatergic neurotransmission, as well
as the monoaminergic system. Neurosteroids are locally synthesized from choles-
terol and circulating steroid hormones, and mostly target membrane receptors.
Many neuropeptides have been identified as endogenous antiepileptics. However,
only one is currently in use as a treatment (ACTH). Other anticonvulsant neuropep-
tides include neuropeptide Y, which increases neocortical GABAergic neurotrans-
mission and hippocampal dopamine, and somatostatin (expressed, most importantly,
in GABA-ergic, inhibitory hippocampal hilar interneurons) [86].
The list of proconvulsant neuropeptides includes, among others, corticotropin-
releasing hormone (CRH), β-endorphin and arginine-vasopressin peptide (AVP).
While the former two are implicated in stress-related mechanisms, high levels of
AVP have been associated with febrile seizures, given that this peptide in lower
levels also acts as an endogenous antipyretic [87].

2.5.2 Hypersynchrony, Hyperexcitation and Epileptogenesis

Current research converges on the notion that seizures erupt when two fundamental
measures of neuronal activity, excitability and synchronization, surpass certain nor-
mal level and that epileptogenesis is based on an aberrant exploitation of the most
fundamental property of our brain, neuronal plasticity, the very one that enables us
to develop, adopt to the environment and learn.
The early Penfield and Jasper’s hypothesis on generalized seizures introduced the
idea of seizures correlating to synchronous brain activity characterized by decreased
inhibition and enhanced excitation leading to the transient hypersynchronous activity
2 Introduction to Epilepsy and Related Brain Disorders 25

a b
NORMAL

excitation
inhibition B C

ition
inhib
D
ation B
excit A

HYPEREXCITABLE

Fig. 2.1 (a) Simplified view of excitability changes towards an epileptiform activity. (b)
Comparison of a normal neuronal discharge (upper) to an epileptiform one (lower). A = excitatory
postsynaptic potential, B = sodium channel mediated action potential, C = inhibitory postsynaptic
potential. Blockage of C leads to delayed and persistent expression of NMDA receptor channels
mediated Ca++ spikes and paroxysmal depolarization shift (D)

of electrical epileptiform discharges [88]. The hallmarks of epilepsy which refer to

hypersynchrony and hyperexcitation, still remain. Yet, synchronization in epilepsy is
complex and it strongly depends on how ‘synchrony’ is defined, on the signals being
measured (i.e. neuronal spikes or field potentials) and the spatial scale [89].
There is a variety of possible causes of hyperexitability. They can be intrinsic to
neurons, like changes of types, numbers and opening times of voltage gated ion
channels for Na+ or Ca2+, which may occur post-translationally, through 2nd mes-
sengers or through modulation of gene expression. They can also be extrinsic, like
changes of local ion concentrations i.e. in [K+], and in extracellular space or modula-
tion of transmitter metabolism or uptake by glial cells. Finally they can be synaptic,
like increased excitatory post synaptic potentials (usually mediated by glutamate)
and/or decreased inhibitory potentials (usually mediated by GABA), alterations in
expression of transmembrane gated ionotropic channels, remodeling of synapse
location or configuration, changes in gap-junction synaptic function etc. Simply put,
it is a matter of balance tipped in favor of excitation in specific neurons (Fig. 2.1).
Synchronization can be increased in an equally large number of different ways
like: recurrent excitation of neighbouring neurons, rhythms offering a narrow time
window of higher opportunity to fire, gap junctions and rebound from synchronous
inhibition.
Neuronal populations synchrony caused by an excitation/inhibition imbalance
along with alterations in neural communication are key elements of epileptogenesis,
while glia cells, through their extracellular modulation of environment, also play a
role to it.
Hyperexcitability, i.e. burst of action potentials and paroxysmal depolarization
shifts coupled with hypersynchronization of neighboring neurons may lead to
seizure local initiation. Activation of connected neurons with concomitant loss of
surround inhibition can lead to seizure propagation to other brain areas.
26 E. Giourou et al.

Initial predisposing
Latent period chronic Disease
insult

genes
0 10 20 30 40 50 60

Febrile spasms Epileptic

Perinatal injury
Neuronal plasticity
Seizures EPILEPSY

Genetic
substrate Developmental Disorder
Neo - neurogenesis
Reorganization
Changed synaptic weights
Changed AED targets
Lower levels of AED
EPILEPTOGENESIS

Fig. 2.2 Putative mechanisms of epileptogenesis

Epileptogenesis is a dynamic process which progresses until the manifestation of

the first clinical seizure. Changes on neuronal interconnectivity and excitability are
present [5], either in relation to a genetic susceptibility to seizures [90] or to an
identifiable structural brain lesion [25].
One feature that facilitates seizures in the cortex is the existence of positive feed-
back loops between the pyramidal neurons which enable them to excite each other.
Therefore, the connection structure of the neuronal network (rather than the density
of existing neurons) seems to be of high importance to epileptogenesis [91, 92].
The fact that there is a wide diversity of seizure types, apparent causes and the
variety of epileptic syndromes phenomenology [93] does not make it possible for a
single pathophysiologic mechanism to underlie it all.
Epileptogenesis consists of a variety of intracellular, intrinsic membrane and
extracellular mechanisms with neuronal plasticity and glia offering adaptation to
environmental changes [94]. Therefore, the existence of a small group of neurons
being responsible for epileptic discharges which then spread throughout the rest of
the brain is also unlikely.
Epileptogenesis is considered to take several years in three stages (Fig. 2.2) and
mainly unexplored remains the 2nd one: the latent period. If the initial insult is not
countered several modification in the brain are escalated leading to epileptogenesis
and expression of the first spontaneous seizures. Things may stabilize there or
worsen in which case chronic epilepsy is established. Pharmacoresistance may
develop either because antiepileptic drugs cannot cope with the new hypersynchro-
nous and complex networks which newly emerge or because their membrane targets
have changed or because mechanisms develop which decrease their brain levels.
The putative mechanisms of epileptogenesis as they emerge from research in
several animal models have been recently reviewed [85, 95–101]. In retrospect,
probably the most influential animal model has been that of kindling induced epilepsy
2 Introduction to Epilepsy and Related Brain Disorders 27

in rodents [102]. An example of significant relevance between animal and human

studies is the observation that hippocampus is the brain area most vulnerable to
epileptogenesis and specifically its anterior part (in humans—ventral in rodents a
distinction based on still unresolved underlying mechanisms (see [103, 104].
Epilepsy syndromes can be broadly separated in two categories: generalized and
focal epilepsies. Focal onset seizures and generalized onset seizures differ in terms of
the main mechanisms involved. While in both types of seizures cellular excitability
is increased, the mechanisms of synchronization differ.

2.5.3 Pathophysiology of Focal Epilepsy

Pyramidal neurons receive a large amount of excitatory input in contrast to the rela-
tively less inhibitory one. Yet, with inhibitory synapses being on the soma and close
to axon hillock, inhibition is able to counterbalance the large amount of excitation
received through ‘gating it out’, an effect known as the ‘inhibition veto’ [105].
A paradoxical action of inhibitory interneurons, being active during seizure
onset, suggests this as the basis of a cellular correlate to the large scale discharges
that are recorded in EEG. A period of intense activation of interneurons is followed
by recurrent discharges of principal excitatory cells which had been ‘silenced’ dur-
ing the inhibitory activation. These fast oscillations are important markers of the
seizure onset zone. Possible mechanisms of this action is firstly the extracellular
increase of potassium concentration which will cause depolarization of membranes
and as a result the increase of excitatory neurons discharges and secondly the intra-
cellular increase of chloride within the principal excitatory neuron which results to
the impairment of inhibition and thus an excitation/inhibition imbalance. It has been
shown that the reversed chloride gradient is correlated to GABA having an excit-
atory effect on neurons [106].
There are suggestions that the seizure onset zone is organized in microdomains
which present synchronous high frequency firing in the form of ‘microseizures’
[107]. The merging of these cortical microdomains is proposed as the mechanism
underlying the ictal transmission and the emergence of the macroseizure [89].
At the time that a seizure initiates, an early ictal desynchronization is noted.
As the seizure progresses, this is followed by an increasing large scale synchroniza-
tion [108, 109]. A possible explanation of this phenomenon is the ‘inhibition veto’
induced by the area ahead of the ictal waveform [105].
Long lasting repetitive seizures, as seen in status epilepticus, lead to a progres-
sive and permanent modification of cortical neuronal networks thus repetitive sei-
zures will lead to spontaneous recurrent seizures. This might also be true in the
cases of acquired epileptogenesis for example after brain damage. The degeneration
of GABAergic interneurons and the spouting of new glutamatergic circuits both
leading to increased excitation is a consistent finding in both animal models and
human tissue studies. This diminished inhibition permits the recurrent excitation
and multisynaptic network activation while the remaining GABAergic inhibition
28 E. Giourou et al.

prevents it from happening continually [110]. Repetitive seizures cause neuronal

damage which strongly depends on the seizure severity as this is recorded by elec-
trographic recordings. Neuronal death and synaptic regeneration appear to be
important mechanisms to epileptogenesis.
Beyond the cell level though, epileptic seizures are also “multi- scale network
phenomena”. Networks can be represented as a graph made of nodes and links
between them. Small worlds as they have been described by Watts and Strogatz
[111], have many local links and a few of long-range connections. This characteris-
tic allows them to locally process information and at the same time coordinate this
local activity by long range connections, therefore balancing ‘segregation’ and
‘integration’ which are crucial for information processing. A network’s topography
(i.e. how the nodes are connected or in regard to epileptic seizures in the brain, cor-
tex topography) will influence the dynamics that take place on the network.
Spatial scale’s impact of synchronization can be seen in the high frequency inter-
ictal discharges. Populations of neurons synchronize their action potential firing
which manifests as high-frequency oscillations with spectral peaks correlating to
the inter-spike frequency of individual neurons at the 200–300 Hz. Also, in chronic
epilepsy, the presence of interictal high frequency oscillations (i.e. fast ripples)
which have a much higher firing frequency than the maximum firing rate of the
pyramidal neuron, suggests the emergence of a network phenomenon generated by
out-of-phase neuronal populations [89].
Finally, synchronization reaches its maximum close to seizure termination. It has
been suggested that synchronization’s enhancement or disruption promotes the seizure
termination, proposing that once all of the available neural correlates are integrated
within the synchronous paroxysmal activity, the seizure terminates because of the
emergence of an extended ‘hypoexcitable area’. A synchronized neural bursting can
be terminated either by the decreased excitatory transmission caused by the mas-
sively increased membrane conductance [112] or by the synchronized inhibition;
inhibition can be synchronized by synchronized excitation due to the interconnec-
tivity between inhibitory interneurons and their connections to the principal excit-
atory cells [113]. On top of that, extracellular environmental changes can further
contribute to seizure termination [114].

2.5.4 Pathophysiology of Generalized Epilepsy

Generalized seizures can be classified as atonic, tonic, clonic, tonic-clonic, myoclonic,

or absence seizures on the basis of clinical symptoms and EEG abnormalities.
Typical absence seizures and the interactions of the thalamocortical circuitry have
been used as examples to understand the pathophysiological mechanisms underlying
generalized seizures.
Especially the mechanisms underlying the conspicuous EEG rhythm of 3/s
generalized spike and wave discharges (GSWD) and the transient “loss of con-
sciousness” characterizing these seizures have been investigated for over eight
2 Introduction to Epilepsy and Related Brain Disorders 29

Fig. 2.3 (a) The historical development of ideas regarding the generation of synchronous activity
in generalized absence epilepsy (modified from [120] see text therein). (b) The prevalent today
prototype of epilepsy circuits (from [121])

decades because—although relatively benign—they are thought to constitute a

unique electrographic and behavioral marker of the genetic predisposition to most
types of epilepsy [115–117]. Interestingly, the subject is still controversial since
both its classification terms, idiopathic and primary generalized, are recently pro-
posed to be abandoned. The question of the neuronal mechanisms underlying the
generation of GSWD and the concomitant “loss of consciousness” will be more
properly dealt with in the next chapter (Chap. 3), since it relates to some mecha-
nisms of sleep [118, 119]. Regarding the second term, all seizures, even those asso-
ciated with what have historically been thought of as ‘primary generalized’
epilepsies, are considered now to originate in local microcircuits and then propagate
from that initial ictogenic zone [7]. The matter goes beyond semantics and is of
crucial practical importance to the clinic where the pharmacology of seizures known
as generalized is quite distinct from that of focal epilepsies. The long history of
conceptual developments as for the mechanisms by which rhythmical GSWD
appear so very synchronous all over the brain (in titles in Fig. 2.3a) can be found in
[6, 115, 117, 118, 120].
According to the prototype epileptic circuit (Fig. 2.3b) there is always a focus
from where generalized seizures start. This neocortical focus develops in mutual
influence with the thalamocortical neurons of its sector and initiates activity in
GABAergic neurons of reticular thalamic nucleus. The interaction of thalamocortical
and reticular neurons sets the pace of the oscillatory neuronal activity, while seizures
spread through cerebral networks and subsequent involvement of the newly recruited
cortex in cortico-thalamo-cortical reverberations, resulting in a globally synchronous
EEG rhythm. According to this general prototype, locally-lead (mostly frontally)
GSWD and absences have been referred to as “frontal absences” and thought to rep-
resent fast secondary generalization by a frontal focus [122]. They correspond to
those with apparently localized onset of the ILAE guidance [26].
30 E. Giourou et al.

Fig. 2.4 Comparison of topographic features of the first SWD in a sustained 3/s GSWD (red
arrows), singular interictal focal SWD (in blue frame) and “lead in” or pre-generalization focal
SWD (modified from [124])

To better understand the nature of focal SWDs (FSWDs) in relation to GSWD in

idiopathic generalized epilepsy Koutroumanidis and colleagues [123, 124] studied
video-EEG recordings of children with typical childhood absence epilepsy. In par-
ticular they studied their behavior during the different phases of sleep microstruc-
ture and the topographic relation of the FSWDs to the EEG leading areas of the
absences in each child. They found significant concordance (80 %) between the
interictal FSWD (in blue frame in Fig. 2.4) and the “lead-in” or pre-generalization-
FSWD (indicated by blue arrows in Fig. 2.4) in waveform, topography, in onset and
propagation patterns as well in their affiliation to CAP-B periods. On the contrary
the first generalized spike of the sustained 3/s GSWD (indicated by red arrows in
Fig. 2.4) showed limited variability and only 8.2 % concordance with the focal SWD
and the focal (pre-generalisation) SWD, while appearing in proximity to CAP-A and
sleep transition periods. In general, focal SWDs were frontal or occipital, while the
generalized mostly fronto-temporal or temporal (Fig. 2.4 right). These studies con-
cluded that focal “lead in” or pre-generalization SWD are not likely the determi-
nants of GSWD. They may reflect a system of multifocal non-localizing electrically
unstable cortical areas that under the facilitatory influence of exogenous or endog-
enous factors like sleep instability can foster a corticothalamic response strong
enough to generate 3 Hz GSWD in long preset networks—of autonomous onset
location—that are conditionally sustainable and potentially ictal. FSWD can be
viewed as incomplete forms of the GSWD; together they define the EEG identity of
idiopathic “generalized” epileptogenesis. It is worth exploring the relationship
between the characteristics of the focal as well as the generalized EEG signs and the
2 Introduction to Epilepsy and Related Brain Disorders 31

variation in behavioral deficits in different absence seizures. Such electroclinical

investigation may reveal what is lost in particular absence seizures [123, 124].
The recognition of focal onset generalized epilepsies does not take the magic
away from the spectacular synchronization of GSWD and the associated behavioral
changes of IGE. On the contrary it kindles interest on the brain mechanisms which
have prepared (probably through long epileptogenesis) specific brain-wide circuits
to be ready to respond to cortical hyperexcitability in this so well organized way.
These considerations are in line with increasing acceptance of epilepsy as a network
disease. Epileptic activity is increasingly considered as the dysfunction of a neuro-
nal networks, a multi-entrance circuits rather than a single pinpoint source [125].
Gloor’s 1968 paper on corticoreticular epilepsy (see Fig. 2.3a) had a pioneering
influence in this direction [126]. Brain networks are neither orderly nor random;
they are very complex and non-linear; but both of the latter are quantifiable. Recent
observations suggest that networks acquire larger path lengths and clustering coef-
ficients near the beginning of the seizure and that become more small-world during
seizure propagation and more random at seizure termination, when there is also
increased coupling. Contradiction in data exist, but the total evidence converges to
the suggestion of a refinement of the traditional idea that seizures are hypersynchro-
nous events [127]. In parallel or perhaps in consequence to the network aspects of
epilepsy there is a very interesting fermentation about the concept of “system epi-
lepsies” [128–130] to describe some types of epilepsy that depend on the dysfunc-
tion of specific functional neural systems.
Typical absence seizures and the interactions of the thalamocortical circuitry are
examples used to understand the pathophysiological mechanisms underlying gener-
alized seizures. The thalamocortical circuitry consists of the pyramidal neurons of
the neocortex, the thalamic relay nucleus and the thalamic nucleus reticularis and it
generates the sleep spindles observed during NREM sleep. The thalamocortical
systems thus appears as the primary hub of neural processes common to sleep and
generalized epilepsy and possibly underlying their mutual relationships.

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