Neurophysiology:
Studying and Interpretation

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Focal epileptic seizures


Focal epileptic seizures emanate from an epileptogenic focus anywhere within cortical and sometimes subcortical brain regions, leading to localisable and asymmetric semiology. Epileptogenic focus or zone refers to a specific network within a circumscribed brain area, from which seizures are initiated; it can range in size from small to large or be widely distributed within

Definition of epilepsy


one cerebral hemisphere. This also applies when focal seizures arise independently in either hemisphere because of regional epileptogenicity, as for example in rolandic epilepsy.


Focal seizures may remain entirely localised within the initial epileptogenic focus or propagate and spread to involve (a) networks in other localisations within the same and/or contralateral hemisphere and (b) widespread networks of larger parts of the brain that are involved in the initiation of generalised seizures (secondarily or focal-onset generalised seizures.


In practice, onset of focal seizures is determined by clinical and EEG manifestations (see page 22). Brain localization can be identified from (a) an insightful clinical history and (b) skilful assessment of interictal and ictal EEG changes. This is often easy but in other cases can prove very difficult. Furthermore, (a) clinical manifestations may be very subtle in the presence of marked EEG changes and vice versa; (b) the syptomatogenic zone may not be concordant with the epileptogenic zone; and (c) onset of ictogenesis may be from clinically silent localizations.


Let us consider benign childhood focal seizures, which are also a good example of regional epileptogenicity (see also Chapter 12).89


Interictal EEGs are disproportionally severe in relation to clinical manifestations


Epileptogenicity involves bilateral regional cortical areas which are bi-rolandic in rolandic epilepsy, bi-occipital in idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) and multifocal (bi-frontal, bi-parietal, bi-occipital and bi-temporal) in Panayiotopoulos syndrome (PS).


Ictal EEG always starts from a localized area of the corresponding region of epileptogenicity; this may be on the right on one occasion or on the left on another occasion in the same patient. Ictal clinical symptoms may appear shortly after the EEG onsets in rolandic and ICOE-G seizures or after a significant delay in PS. The symptomatogenic zone appears to correspond to the epileptogenic zone in rolandic epilepsy (sensorymotor symptomatology of the rolandic cortex) and the ICOE-G (occipital lobe symptomatology), while the autonomic clinical manifestations of PS are likely to be generated by variable and widely spread epileptogenic foci acting upon a temporarily hyperexcitable central autonomic network.


Ictal clinical symptoms may be subtle and entirely localized (elementary visual hallucinations of ICOE-G, hemifacial sensory-motor symptoms of rolandic epilepsy), or may spread to involve other brain regions within the same or contralateral hemisphere, occasionally initiating a secondarily GTCS. Symptomatic focal epileptic seizures may manifest with identical clinical semiology, as exemplified by the visual seizures of ICOE-G and other occipital epilepsies of structural cause.


Focal epileptic seizures and syndromes have been extensively reviewed with regard to clinical manifestations, diagnostic procedures and management in a two-volume issue of The educational kit on epilepsies. This publication includes numerous EEG and brain imaging illustrations as well as live video-EEG recordings of patients with focal seizures


The ILAE Core Group considers that:

(I). The anatomical substrates of a substantial number of focal seizure manifestations has now been sufficiently established to include this information in their description (see Table 2.3).

(II). As focal seizures represent dynamic events that usually involve propagation, and clinical manifestations can reflect discharges at the site of ictal onset, and/or sites of propagation, the organisation of focal seizures in their report takes into account the various patterns of ictal propagation (see Table 2.3).

(III). A number of factors will need to be investigated in order to develop more definitive criteria for distinguishing between different types of focal seizures. These include:

Factors that might distinguish between focal seizures due to discretely localized lesions, as occur with focal symptomatic epilepsy, and focal seizures due to more distributed network disturbances, as might occur with some focal idiopathic epilepsies (e.g. those responsible for the transverse dipole of the centrotemporal spikes of rolandic epilepsy), or even in IGEs.

Maturational factors.

Modes of precipitation, as in reflex seizures.

Pathology, i.e. focal seizures due to various malformations of cortical development may be different from each other and from those due to other lesions.

Pathophysiological mechanisms (see pathophysiology below).


The ILAE Core Group14 provides the following information for the focal seizures listed in Table 2.3 with regard to the factors influencing seizure-induced progressive disturbances in neuronal function and structure at the site of, and downstream from, ictal onset:

Focal onset (partial) seizures


A. Local

1. Neocortical

a. Without local spread

i. Focal clonic seizures are brief focal motor events that are distinguished from focal myoclonic seizures by their rhythmic repetition. Localization to the primary motor cortex is implied.

ii. Focal myoclonic seizures most likely consist of many types. These events, including multi focal myoclonus, will be discussed by the ILAE working group on myoclonus. There is no unanimity of opinion as to whether the myoclonic events in progressive myoclonic epilepsy, which have no EEG correlate, are epileptic. At least in Lafora disease, there is evidence to suggest a cortical site of initiation.

iii. Inhibitory motor seizures are not a unique seizure type. The clinical manifestation merely represents the function of the involved cortex, just as focal motor seizures and unformed visual hallucinations reflect seizures in precentral gyrus and calcarine cortex.

iv. Focal sensory seizures with elementary (visual, somatosensory, vestibular, olfactory, gustatory or auditory) symptoms manifest themselves as a variety of sensory phenomena that can be produced by activation of primary sensory cortices.

v. Aphasic seizures can consist of inability to speak when Brocas area is principally involved, or more complex disturbances of speech production or reception when other language cortical areas are principally involved.


b. With local spread

i. Jacksonian march seizures refers to the clinical manifestations of the slow ephaptic propagation of epileptic discharge along the motor cortex, although similar progression can sometimes be seen in other primary cortical areas as well.

ii. Focal (asymmetrical) tonic seizures can be associated with seizure origin from practically anywhere in the neocortex. In their purest form, focal tonic seizures are seen in the explosive motor seizures of supplementary motor area origin.

iii. Focal sensory seizures with experiential symptoms are those with complex, usually formed, distorted and/or multimodal, sensory symptoms implying seizure initiation in association cortices, such as the temporo- parieto-occipital junction, with connections to multiple sensory areas.


2. Hippocampal and parahippocampal seizures almost always require local spread for clinical manifestation, which may involve insula, amygdala, hypothalamus and other limbic structures (Figure 2.1). Autonomic features such as a sensation of epigastric rising is common, as well as emotional experiences such as fear, dysmnesias, focal sensory seizures with olfactory or gustatory symptoms, and vague bilateral sensory phenomena such as tingling.

B. With ipsilateral propagation to:

1. Neocortical areas (includes hemiclonic seizures)

a. Same manifestations as A.1.a and A.1.b.

b. Hemiclonic seizures occur early in development before myelinisation of the corpus callosum and do not necessarily have localising value. They can alternately affect both hemispheres, as in Dravet syndrome and ischaemic encephalopathy, or only one hemisphere in the case of focal disturbances.



2. Limbic areas

a. Same manifestations as A.2.

b. Gelastic seizures are clearly unique ictal events when they are initiated in relation to structural abnormalities of the hypothalamus, which are usually hamartomas. The mechanism is unknown, but initiation, at least, is distinct from gelastic seizures arising from other areas, such as mesial temporal lobe and cingulate.


C. With contralateral spread to:

1. Neocortical areas (hyperkinetic seizures): also referred to by some as hypermotor seizures, involve bilateral forceful limb movements, sometimes with vocalisations. Frontal lobes are implicated in these behaviours.

2. Limbic areas: dyscognitive seizures with or without automatisms (psychomotor) are not exactly synonymous with the current term complex partial seizures, which were defined on the basis of impaired consciousness only and do not necessarily involve limbic areas. This new term, as well as the term psychomotor, conforms more to the original intent of the term complex partial seizures in the 1970 ILAE Classification of Epileptic Seizures. It is implied that mesial temporal limbic areas and their immediate connections are involved in the clinical manifestations, although seizures may have been initiated elsewhere.


D. Secondarily generalised

1. Tonicclonic seizures that are secondarily generalised probably consist of multiple types and may involve different pathophysiological mechanisms and anatomical substrates, at least initially , than GTCSs with generalised onset.

2. Absence seizures can rarely represent propagation from localised cortical areas, usually in the frontal lobe. There may be a continuum between these events and generalised atypical absences.

3. Although epileptic spasms can occur in infants with focal lesions, the mechanism by which these generalised events are generated is unknown.


Epidemiology


In population-based studies, focal seizures predominate with a median incidence of 30.4 cases/100,000 population/year compared with an incidence of generalised seizures of 19.6 cases/100,000 population/ year. Also, focal seizures predominate in prevalence studies 5560% (adults) and 3666% (children).


Clinical manifestations


The clinical manifestations of focal epileptic seizures are detailed in chapters 11, 12, 14 and 15, within focal epileptic syndromes and according to their site of origin and aetiology. It should also be noted that semiology, particularly at onset, is determined by localisation and not by cause.


Aetiology


This may be symptomatic (21.7% of all epilepsies), cryptogenic (21.8%) or idiopathic (9.1%) (Figure 1.5). In children it is much more common for focal epileptic seizures to be idiopathic than symptomatic.


In the elderly, nearly all newly identified epileptic seizures are focal from a symptomatic cause.


Pathophysiology


Focal epileptogenesis is a multistep process. An initial precipitating injury may predispose to the development of the first seizure. During the latent phase, structural and functional changes occur that may ultimately lead to spontaneously recurrent epileptic seizures in some patients over the course of days to years. At each step of the process, biological and age- or gender-specific factors, and genetic, epigenetic or comorbid conditions, may interfere and modify the course of epileptogenesis. Neocortical and limbic (mainly hippocampal) seizures have some important differences in their pathophysiology. This reflects anatomical, functional and phylogenetic disparities between them, as well as all other factors involved in ictogenesis from elements within the neurones, synapses, interconnections and their modifications by age, exogenous and endogenous influences and causes of disease. These are beyond the remit of this clinical book.


As the ILAE Task Force emphasised:
Hypersynchronous ictal onsets most commonly occur in hippocampus while low voltage fast ictal onsets, most commonly occur in the neocortex. These electrophysiological features clearly reflect different pathophysiological mechanisms of seizure initiation, which may not be absolutely correlated with location, and there may be other ictal onset patterns indicative of other initiating mechanisms that have not yet been well described. Also there are differences in neurophysiological properties and anatomical connections unique to specific areas of cortex, e.g. those that cause brief and clustered seizures with little or no post ictal disturbances and nocturnal predilection typical of some frontal areas, compared with longer, less frequent events with profound post ictal disturbances in other areas, and those that cause fast distant propagation from some areas and localised, slower propagation in others.


Diagnostic procedures


EEG and neuroimaging remain the cornerstones of investigation in the focal epilepsies, as detailed in chapter 7 and in the discussion of the individual focal epileptic syndromes. In view of the high incidence of symptomatic epilepsies, a high resolution structural MRI scan on a scanner with a field strength of at least 1.5 Tesla should now be considered standard practice. Other appropriate tests have been described in page 4 and these include molecular testing when genetic focal epilepsies are suspected (Chapter 14). More elaborate diagnostic procedures including functional neuroimaging, advanced MRI technologies, invasive EEG and magnetoencephalography are used to investigate patients with focal epileptic seizures that may benefit from neurosurgical interventions (page 222).


Prognosis


This largely depends on aetiology and syndromic diagnosis. It varies from purely benign and age-limited (see examples in chapter 12) to very severe and progressive (Chapter 15).



Definition of epilepsy


In 2005, a Task Force of the International League Against Epilepsy (ILAE) formulated conceptual definitions of seizure and epilepsy.


The two unprovoked seizure definition of epilepsy has served us well, but it is inadequate in some clinical circumstances. A patient might present with a single unprovoked seizure after a remote brain insult, such as a stroke, central nervous system infection, or trauma. A patient with such brain insults has a risk of a second unprovoked seizure that is comparable to the risk for further seizures after two unprovoked seizures. When two individuals with a history of at least one unprovoked seizure have the same high risk for having another, an argument can be made that both have epilepsy. Under limits of the current definition, another patient might have photosensitive epilepsy, yet not be considered to have epilepsy because the seizures are provoked by lights. Another might be free of seizures and seizure medications for 50 years, yet still have epilepsy. In order to bring the practical (operational) clinical definition of epilepsy into concordance with how epileptologists think about epilepsy, the ILAE Task Force recommends broadening the definition of epilepsy


Epilepsy has traditionally been referred to as a disorder or a family of disorders, rather than a disease, to emphasize that it is comprised of many different diseases and conditions. The term disorder implies a functional disturbance, not necessarily lasting; whereas, the term disease may (but not always) convey a more lasting derangement of normal function. The term disorder is poorly understood by the public and minimizes the serious nature of epilepsy. The ILAE and the International Bureau for Epilepsy (IBE) have recently agreed that epilepsy is best considered to be a disease.


High recurrence risk


Such reserch may include patients with a single seizure occurring at least a month after a stroke (Hesdorffer et al. 2009) or a child with a single seizure conjoined with a structural or remote symptomatic etiology and an epileptiform electroencephalography (EEG) study. Another example is a patient in whom diagnosis of a specific epilepsy syndrome associated with persistent threshold alteration can be made after the occurrence of a single seizure. A first seizure might present as status epilepticus, but this does not in itself imply epilepsy. Recurrence risks are not known for the majority of individual cases. However, if a treating physician is aware that the lesion has generated an enduring predisposition for unprovoked seizures with a risk comparable to those who have had two unprovoked seizures (which we all agree is epilepsy), then that person too should be considered to have epilepsy. Choosing a specific threshold risk number might be excessively precise, but for general comparison, this risk is about 6090% after two unprovoked seizures.


It is important to note that a single seizure plus a lesion or a single seizure plus epileptiform EEG spikes does not automatically satisfy criteria for this operational definition of epilepsy, because data may vary among different studies and specific clinical circumstances. In the Dutch Epilepsy Study,10 children with epileptiform EEG patterns after their first seizure had a 2-year risk for recurrence of 71%, but in the study by Shinnar et al., children with a first idiopathic seizure and abnormal EEG patterns had recurrence risk of 56% at 3 years. No formula can be applied for additive risks, since data are lacking on how such risks combine; such cases will have to be decided by individualized considerations. Recurrence risk is a function of time, such that the longer the time since the last seizure, the lower the risk.


Implications for treatment


Diagnosing epilepsy after a single unprovoked seizure when there is high risk for recurrence may or may not lead to a decision to initiate treatment. The proposed practical definition may provide support to a physician who wishes to treat a patient with high recurrence risk after a single unprovoked seizure. However, a treatment decision is distinct from a diagnosis, and should be individualized depending upon the desires of the patient, the individual risk-benefit ratio and the available options. The physician should weigh the possible avoidance of a second seizure with associated risks against the risk for drug-related side effects and costs for the patients.


To be clear, the diagnosis of epilepsy and a decision to treat are two related but different issues. Many epileptologists treat for a time after an acute symptomatic seizure (for example, with Herpes encephalitis), with no implication of epilepsy. In contrast, patients with mild seizures, with seizures at very long intervals, or those declining therapy might go untreated even when a diagnosis of epilepsy is beyond dispute.


Unprovoked seizures separated in time


The time span between two unprovoked seizures that together qualify as epilepsy is subject to ambiguity. Seizures clustering within 24 h confer approximately the same risk for later seizures as does a single seizure. The Task Force retained the current thinking that unprovoked seizures clustering in a 24 h period be considered to be a single unprovoked seizure for purposes of predicting recurrence risk.


Some authorities consider epilepsy to be present, but in remission, after 5 years of seizure freedom. However, the definition of epilepsy does not specify an outer time limit for occurrence of the second unprovoked seizure to mark the onset of epilepsy. Therefore, epilepsy could be considered present if an unprovoked seizure occurred at age 1 and at age 80, a condition sometimes referred to as oligoepilepsy. The Task Force acknowledges that, in such circumstances, the causes of the seizures occurring at the two time points might be different, and if so then epilepsy would not be present. Otherwise, the Task Force did not agree on a specific interval of time between seizures that would reset the clock for counting an event as a second seizure.


The Task Force therefore adopted the phrase resolved., when epilepsy is resolved, it implies that the person no longer has epilepsy, although it does not guarantee that it will not return.


What time intervals and circumstances should characterize resolved epilepsy? Recurrence risk depends on the type of epilepsy, age, syndrome, etiology, treatment, and many other factors. Juvenile myoclonic epilepsy is known to be subject to an elevated risk of seizures for several decades, but remissions do still occur. Structural brain lesions, such as malformations of cortical development, may elevate risk of seizures long term. Seizures may recur at variable intervals after remission due to removal of an epileptogenic lesion, such as a cavernous malformation.


Epilepsy previously has been defined as at least two unprovoked seizures >24 h apart. The revised practical definition implies that epilepsy also can be considered to be present after one unprovoked seizure in individuals who have other factors that are associated with a high likelihood of a persistently lowered seizure threshold and therefore a high recurrence risk. Such risk should be equivalent to the recurrence risk of a third seizure in those with two unprovoked seizures, approximately at least 60%. The latter risk level occurs with remote structural lesions, such as stroke, CNS infection, certain types of traumatic brain injury, diagnosis of a specific epilepsy syndrome, or in some circumstances with the presence of other risk factors. Those with recurrent reflex seizures, for example, photosensitive seizures, are also considered to have epilepsy. This definition of epilepsy brings the term in concordance with common use by most epileptologists. Epilepsy is not necessarily life-long, and is considered to be resolved if a person has been seizure-free for the last 10 years, with at least the last 5 year off antiseizure medicines, or when that person has passed the age of an age-dependent epilepsy syndrome. The new definition is more complicated than is the old definition.


Medical history


The medical history should include:

-details of the paroxysmal events (not only the most dramatic ones) as they have been experienced by the patient and witnesses
-the circumstances under which the paroxysmal events occurred
-timing and circadian distribution
-position (standing, sitting or lying)
-leisure or occupation (at rest or during exercise)
-possible triggering, precipitating or facilitating factors
-personal and family medical history.


Laboratory diagnostic procedures


The EEG, the most significant investigative procedure in the diagnosis of epilepsies, is often misunderstood, undermined and misused. Brain imaging, another top diagnostic procedure, provides in vivo visualisation of structural causes of epilepsy such as hippocampal sclerosis, malformations of brain development and tumours, as well as other brain diseases. Blood, urine have an important role in the evaluation of the child with epilepsy.
Genetic testing has become available for a growing
number of hereditary disorders associated with
epileptic seizures.


Three important steps to take in order to make a correct specific diagnosis, which will determine prognosis and management:

1. First step: are the paroxysmal events epileptic
seizures?
2. Second step: what type of epileptic seizures?
3. Third step: what is their cause and what is the
epileptic syndrome or disease?


First step: are the paroxysmal events epileptic seizures?


NEPEs that have been misdiagnosed as epileptic seizures affect as many as 2030% of patients diagnosed with epilepsy; these patients have often received treatment for epilepsy for many years or have been admitted to tertiary care epilepsy units. The problem is complicated by the fact that approximately 30% of patients with genuine epileptic seizures also suffer from non-epileptic, mainly psycho genic seizures.


Second step: what type of epileptic seizures?


Minor seizures are more important than major ones for diagnostic procedures, correct diagnosis and appropriate management strategies.
Approximately three-quarters (74%) of patients with newly identified unprovoked seizures (mainly GTCSs) had experienced multiple seizure episodes before their first medical contact.18 Yet, studies on the prognosis and treatment of the first seizure mainly refer to a GTCS, although this may not be the first seizure in the patients life.


Third step: what is their cause and what is the epileptic syndrome or disease?


Important features of a syndrome include:

-the type of seizures, their localisation and frequency
-the chronological sequence of the events
-circadian distribution
-precipitating factors
-age at onset
-mode of inheritance
-physical and mental symptoms and signs
-response to treatment
-prognosis.


A syndromic diagnosis of epilepsies is now a basic recommendation of good clinical practice.



Generalised seizures


Generalised tonic seizures are convulsive attacks of sustained muscular contractions only, without clonic components.
They usually last a few seconds (>2 s to 10 s) but sometimes minutes and thus they are of longer duration than myoclonic jerks (under a tenth of a second) and epileptic spasms (0.22 s).


The tonic seizures differ from the tonic convulsions of GTCS, which occur in continuity with the subsequent clonic convulsions. In addition, the mechanism responsible is probably different to that of the tonic phase of GTCS. Prevalence is high, because generalised tonic seizures frequently occur in a variety of common epileptic syndromes affecting neonates, infants and children. Aetiology: The aetiology of generalised tonic seizures is mainly symptomatic.


Clinical manifestations


Tonic seizures usually have an abrupt onset, may be symmetrical or asymmetrical, and may be inconspicuous or violent. Concurrent autonomic manifestations including apnoea may be prominent. Consciousness is impaired. Focal and asymmetric signs of head or eye deviation may occur.


In LennoxGastaut syndrome, tonic seizures occur more often during slow non-rapid eye movement (REM) sleep (hundreds of times in some patients) than in states of wakefulness; they do not occur during REM sleep. Tonic seizures are descriptively classified as: Axial tonic seizures affect the facial, neck, trunk, paraspinal, respiratory and abdominal muscles, either alone or in combination.


Symptoms include raising the head from a pillow, elevation of the eyebrows, opening of the eyes, upward deviation of the eyeballs, opening of the mouth and stretching of the lips to a fixed smile. An epileptic cry is common at the onset of attacks.Axorhizomelic tonic seizures are axial seizures that also involve the proximal (rhizomelic) muscles of the upper and less often the lower limbs.


Elevation and abduction or adduction of the upper limbs and shoulders occur together with the other symptoms of axial tonic seizures. Global tonic seizures are axorhizomelic seizures that also involve the distal part of the limbs. The arms are forced upwards, abducted and semiflexed with clenched fists. The lower limbs are forced into triple flexion at the hip, knee and ankle or into extension. Global tonic seizures often cause forceful falls and injuries. Tonic seizures are precipitated/facilitated by sleep. Startle-induced tonic seizures may be of focal origin.


Aetiology


The aetiology of generalised tonic seizures is mainly symptomatic. Tonic seizures are the most common type of seizure (80100%) in Lennox-Gastaut syndrome. They are exceptional or do not occur in epilepsy with myoclonicastatic seizures or IGE.


Diagnostic tests


Interictal EEG is grossly abnormal with frequent runs of fast rhythms and spikes mainly in non-REM sleep and also slow spikewave discharges. Ictal EEG comprises low-voltage accelerating fast paroxysmal activity that may be: (a) very rapid (20 5 Hz) and progressively increasing in amplitude from low to 50100 μV; and (b) rhythmic discharge 44 A Clinical Guide to Epileptic Syndromes and their Treatment of around 10 Hz similar to that of the tonic phase of GTCS.


Generalised tonic seizures


Generalised tonic seizures usually correlate with the burst component of the burst-suppression pattern. Brain imaging and other tests are necessary, because most tonic seizures are symptomatic.


Differential diagnosis


Generalised tonic seizures should be differentiated from epileptic spasms, myoclonic attacks, other seizures manifesting with combined tonic, clonic and other symptoms, and focal tonic seizures. Conditions that may mimic tonic seizures include hyperekplexia, dystonia and repetitive sleep starts in neurologically impaired patients, and benign nonepileptic myoclonus in infancy.


Management


Treatment with any AED is often disappointing (see Lennox-Gastaut syndrome). Callosotomy may be the last resort.


Generalised clonic seizures


Generalised clonic seizures, by definition, manifest with bilateral rhythmic clonic convulsions only. Their duration varies from minutes to hours but each clonic event lasts < 100 ms at a rate of 13 Hz (Figure 12.3). The generalised clonic seizures differ from the clonic convulsions of GTCS, which occur in continuity with the preceding tonic convulsions.


They also differ from other types of seizure that manifest with tonic components mixed with myoclonus (e.g. Eyelid myoclonia) or absence (e.g. myoclonic absence seizures in which the myoclonic component is rhythmic at 2.54.5 Hz, is clonic rather than myoclonic and has a tonic component). The mechanisms responsible for generalised clonic seizures (rhythmic excitatory discharges) are probably different from those in the clonic phase of GTCS (phasing in of seizuresuppressing mechanisms). Clonic seizures should also be distinguished from myoclonic seizures; clonic seizures are rhythmic at 15 Hz, whereas myoclonic seizures are singular or irregular recurrent events. Thus, the ILAE defines clonic seizures as rhythmic myoclonus at a frequency of about 23 Hz.11


According to the ILAE Task Force,14 generalised clonic seizures are: fast rhythmic events (12 Hz), associated, or not, with impaired consciousness and proposes that their mechanisms are different from those of the clonic phase of GTCS. In the latter, the clonic phase represents the phasing in of seizuresuppressing mechanisms, whereas in clonic seizures, the repetitive discharges appear to be due primarily to rhythmic excitatory discharges.


Prevalence: Isolated generalised clonic seizures (without the preceding tonic phase of GTCS, or the clonic-absence or clonic/tonic complex) are rare. They are reported in neonates and infants (but are often of focal onset), progressive myoclonic epilepsies (but may be myoclonic jerks with rhythmic or pseudorhythmic occurrence) and hemiconvulsions (which are not generalised seizures).


Clinical manifestations


Clonic seizures may cause: t repetitive rhythmic flexion and extension t repetitive rhythmic contraction and relaxation of the affected muscles. In neonates and infants, generalised clonic seizures may appear as more or less rhythmically repeated, bilateral clonic contractions, distributed more or less regularly throughout the entire body and associated with loss of consciousness and massive autonomic symptoms and signs.


Clonic seizures are associated with the loss, or severe impairment, of consciousness. Exceptionally, bilateral clonic convulsions of the upper extremities may occur without clouding of consciousness; however, in these cases, there are no EEG generalised spikewave discharges and the seizures originate in the supplementary motor area. Also, some children with benign myoclonic epilepsy of infancy may have generalised clonic seizures exclusively during sleep or on awakening, which are prolonged (up to 1520 min) and can cause cyanosis without loss of consciousness.


Aetiology


The aetiology is usually symptomatic. Generalised clonic seizures alone are not specific to any syndrome.


Diagnostic tests


Interictal EEG can range from normal to grossly abnormal.


Ictal EEG: Each clonic convulsion corresponds to a generalised discharge of spike and multiple spikes or, more rarely, a mixture of rapid rhythms and slow waves.


Brain imaging and other tests are needed to detect the underlying pathology.


Differential diagnosis


The main problem is to differentiate clonic seizures from myoclonic seizures and from seizures manifesting with clonic convulsions in continuity or together with tonic, absence and myoclonic manifestations. In early childhood and the epileptic encephalopathies, GTCS may appear only as generalised clonic convulsions, in which the preceding tonic phase is brief and inconspicuous.


Management


Pure generalised clonic seizures probably require AEDs that are suitable for generalised seizures. Phenobarbital may be preferred in neonates.


Myoclonus


There is no generally accepted, precise definition of myoclonus and there is a long-standing source of confusion and debate about the term and concept of epileptic and non-epileptic myoclonus.


Myoclonus is a descriptive term for heterogeneous phenomena such as sudden brief jerk caused by involuntary muscle activity, quick muscle regular or irregular jerks, a sudden brief, shock-like uscle contraction arising from the central nervous system, and abrupt, jerky, involuntary movements unassociated with loss of consciousness.


Myoclonus is probably best defined as sudden jerks typically lasting 1050 ms, with the duration of movements rarely longer than 100 ms. The ILAE definition for myoclonus 2,14 is: Myoclonic (adj.); myoclonus (noun): sudden, brief (<100 ms), involuntary, single or multiple contraction(s) of muscles(s) or muscle groups of variable topography (axial, proximal limb, distal).


Description of myoclonus


Myoclonic jerks are shock-like, irregular and often arrhythmic, undirectional, clonic, twitching movements that are singular or occur in irregular clusters. They are of variable amplitude, force, location, dura tion, precipitating factors and circadian distribution.


Myoclonic jerks may be:

- focal, segmental, multifocal or generalised

- mild, causing minor and inconspicuous flickering, or massive with traumatic falls rhythmic, arrhythmic or oscillatory (often resembling a very fast tremor)

- spontaneous, reflex (photic, acoustic, somatosensory, reading) or action (movement or intention to move) induced

- related to sleep, awakening or alert stages

- brief bursts or repetitive and continuous for hours and sometimes for days.


Classification of myoclonus


Myoclonus may be:


- a normal (physiological) phenomenon such as hiccups (singultus) or hypnagogic jerks (sleep starts)

- an abnormal (epileptic or non-epileptic) symptom

- of a wide range of different disorders with regard to aetiology, semiology, nosology, pathophysiology and prognosis. The two main classification systems of myoclonus are based on aetiology (Table 2.5) and physiology.


Epileptic myoclonus


There are various definitions of what epileptic myoclonus


is: myoclonus is termed epileptic when it occurs in combination with cortical epilepti form dis charges. In some cases, the latter may be demonstrated only by the technique of back-averaging or myoclonus is epileptic, when generated in the cortex, and non-epileptic, when generated in subcortical structures.


Others prefer indirect definitions such as epileptic myoclonus is the presence of myoclonus in the setting of epilepsy or myoclonic seizures are epileptic seizures in which the motor as well as the main manifestation is myoclonus.


I propose the following definition of epileptic myoclonus, which is in compliance with the current ILAE definition of an epileptic seizure: Epileptic myoclonus is a transient (<100 ms) involuntary single or multiple muscle jerk due to abnormal excessive or synchronous neuronal activity in the brain.


Myoclonic seizures are briefer than tonic seizures and epileptic spasms (Figure 2.7). According to the recent ILAE report:



The distinction between myoclonic seizures and clonic seizures is not clear. Classically, clonic seizures are rapid rhythmically-recurrent events, whereas myoclonic seizures are single, or irregularly recurrent events. The prototype of generalized myoclonic seizures are those occurring with JME.


These are typically bilateral and symmetrical, but localized reflex myoclonus can also occur. The slowly rhythmic events of subacute sclerosing panencephalitis (SSPE) used to be considered epileptic myoclonus but are more accurately epileptic spasms, those with biPEDs (bilaterally ynchronous periodic laterilizing epileptiform discharges) in comatose patients also are not necessarily epileptic, and their cause is usually not clearly defined.


Differential diagnosis between myoclonic and clonic seizures can be difficult because a single jerk can be a fragment of a clonic seizure. Working groups will be convened to specifically evaluate myoclonic epileptic phenomena, including negative myoclonus and atonic seizures, compare them with non-epileptic myoclonic phenomena, and develop uniform criteria and terminology for these diagnoses.


The epileptic myoclonus may be:

- generalised such as myoclonic jerks in JME (Figure 2.8)

- segmental such as eyelid myoclonia in Jeavons syndrome

- focal such as epilepsia partialis continua (EPC) of Kozhevnikov or jaw myoclonus of idiopathic reading epilepsy

- the only manifestation of an epileptic seizure, as in the above examples

- one component of an epileptic attack combining in continuity with another type of seizure such as myoclonicatonic seizures, myoclonic absence seizures, myoclonic tonicclonic seizures.



Epileptic myoclonus is commonly accompanied by generalised EEG discharges of mainly polyspikes, as in the generalised epilepsies. However, the ictal EEG may show focal abnormalities only (idiopathic reading epilepsy) or be entirely normal, requiring documentation with jerk-locked back-averaging techniques.


The cause of epileptic myoclonus may be idiopathic, cryptogenic or symptomatic.


Epileptic negative myoclonus


Mostmyoclonic jerks are caused by abrupt muscle contraction (positive myoclonus), but similar jerks are sometimes caused by sudden cessation of muscle contraction associated with a silent period in the ongoing EMG activity (negative myoclonus).


Epileptic negative myoclonus, focal or generalised, is a motor symptom characterised by abrupt and brief (<500 ms) stoppage of muscular activity, not preceded by any enhancement of EMG activity.


Negative myoclonus of cortical origin may be associated with an EEG spike or spikewave complex.


Patients may manifest with positive and negative myoclonus in various proportions, either independently or in combination.


When both forms of myoclonus occur in combination, the abrupt increase in muscle discharge (positive myoclonus) often precedes the onset of the silent period (negative myoclonus), but occasionally follows its offset.



Typical absence seizures


Typical absences (previously known as petit mal) are brief (lasting seconds) generalised epileptic seizures of abrupt onset and abrupt termination. They have two essential components:


1. a clinical component manifesting with impairment of consciousness (absence)


2. an EEG component manifesting with generalised spikeslow-wave discharges of 3 or 4 Hz (>2.5 Hz).


Typical absences are predominantly spontaneous, although they are precipitated by hyperventilation in around 90% of untreated patients. Other specific modes of precipitation include photic, video games and thinking (reflex absences).


The ictal EEG consists of generalized discharges with repetitive and rhythmic 3 or 4 Hz single or multiple spikeslow-wave complexes. These generalised spikewave discharges (GSWD) may be brief (sometimes <3 s) or long (≥30 s), and continuous or fragmented. The intra discharge frequency of the spikewave may be relatively constant or may vary.


Clinical manifestations


The clinical manifestations of typical absence seizures vary significantly between patients. Impairment of consciousness may be the only clinical symptom, but it is often combined with other manifestations.

Typical absences are categorised as:


simple absences with impairment of consciousness only


complex absences when impairment of consciousness combines with other ictal motor manifestations.


Complex absences are far more frequent than simple absences in children. Simple absences are more common in adults. The same patient may have both simple and complex absences.


Absence with impairment of consciousness only:


The classic descriptions refer to absence seizures with severe impairment of consciousness, such as CAE and JAE:


The hallmark of severe absence seizures is a sudden onset and interruption of ongoing activities, often with a blank stare. If the patient is speaking, speech is slowed or interrupted; if walking, he or she stands transfixed. Usually the patient will be unresponsive when spoken to. Attacks are often aborted by auditory or sensory stimulation.


In less severe absences, the patient may not stop his or her activities, although reaction time and speech may slow down.


In their mildest form, absences may be inconspicuous to the patient and imperceptible to the observer (phantom absences), as disclosed by video-EEG recordings showing errors and delays during breath counting or other cognitive tests during hyperventilation.


Absence with clonic or myoclonic components:


During the absence clonic motor manifestations, rhythmic or arrhythmic and singular or repetitive, are particularly frequent at the onset. They may also occur at any other stage of the seizure.


Fast flickering of the eyelids is probably the most common ictal clinical manifestation, and may occur during brief GSWD without discernible impairment of consciousness. Myoclonias at the corner of the mouth and jerking of the jaw are less common.


Myoclonic jerks of the head, body and limbs may be singular or rhythmical and repetitive, and they may be mild or violent. In some patients with absence seizures, single myoclonic jerks of the head and, less often, of the limbs may occur during the progression of ictus.


Absence with atonic components:


Diminution of muscle tone is usual when absences are severe. This manifests with drooping of the head and, occasionally, slumping of the trunk, dropping of the arms and relaxation of the grip. Rarely, tone is sufficiently diminished to cause falls.


Absence with tonic components:


Tonic seizures alone do not occur in IGEs.


However, tonic muscular contractions are common concomitant manifestations during typical absence seizures. They mainly affect facial and neck muscles symmetrically or asymmetrically. The eyes and head may be drawn backwards (retropulsion) or to one side, and the trunk may arch.


Absence with automatisms:


Automatisms are common in typical absences when consciousness is sufficiently impaired, and they are more likely to occur 46 s after the onset of GSWD. They do not occur in mild absence seizures irrespective of duration, as, for example, in absence status epilepticus. Automatisms of typical absence seizures are simple and void of behavioural changes. They vary in location and character from seizure to seizure. Perioral automatisms, such as lip licking, smacking, swallowing or mute speech movements, are the most common. Scratching, fumbling with clothes and other limb automatisms are also common.


Absence with autonomic components:


Autonomic components consist of pallor and, less frequently, flushing, sweating, dilatation of the pupils and urinary incontinence.


Absences with focal motor components, hallucinations and other manifestations of neocortical or limbic symptomatology:


During a typical absence seizure, patients frequently manifest with concomitant focal motor components (tonic or clonic) imitating focal motor seizures. Hallucinations and other manifestations such as concurrent epigastric sensations may occur; these are, in particular, more apparent during absence status epilepticus.


Electroencephalography


The ictal EEG is characteristic with regular and symmetrical 3 or 4 Hz GSWD. The intra discharge spikewave frequency varies from onset to termination. It is usually faster and unstable in the opening phase (first 1 s), becomes more regular and stable in the initial phase (first 3 s), and slows down towards the terminal phase (last 3 s). The intra discharge relationship between spike/poly spike and slow wave frequently varies. The GSWD are often of higher amplitude in the anterior regions. Duration of the discharges commonly varies from 3 s to 30 s.
The background inter-ictal EEG is usually normal. Paroxysmal activity (such as spikes or spikewave complexes) may occur.


Diagnosing absences and differential diagnosis


The brief duration of absence seizures, with abrupt onset and abrupt termination of ictal symptoms, daily frequency and almost invariable provocation by hyperventilation, makes the diagnosis easy.
The differential diagnosis of typical absence seizures with severe impairment of consciousness in children is relatively straightforward. The absences may be missed if mild or void of myoclonic components. Automatisms, such as lip smacking or licking, swallowing, fumbling or aimless walking, are common and should not be taken as evidence of complex partial (focal) seizures, which require entirely different management.


The EEG or, ideally, video-EEG can confirm the diagnosis of typical absence seizures in more than 90% of untreated patients, mainly during hyperventilation.
If not, the diagnosis of absences should be questioned.
The differentiation of typical absences from complex focal seizures may be more difficult when the motor components of the absence are asymmetrical and in adults in whom absences are often misdiagnosed as temporal lobe seizures


Atypical absence seizures


Atypical absences are generalised epileptic seizures of inconspicuous start and termination with the
following:


clinical symptoms of mild-to-severe impairment of consciousness (absence), often significant changes in tone with hypotonia and atonia, mild tonic or autonomic alterations


EEG discharges of slow spikewave (12.5 Hz), which are often irregular and heterogeneous and may be mixed with fast rhythms. They also invade limbic areas.


Their duration, determined by EEG changes rather than clinical manifestations, ranges from 510 s to minutes. A patient may have few or numerous atypical absences each day.


Atypical absences occur only in the context of mainly severe symptomatic or cryptogenic epilepsies of children with learning difficulties, who also suffer from frequent seizures of other types. They are common in LennoxGastaut syndrome, epileptic encephalopathy with continuous spike and waves during sleep, and epilepsy with myoclonicastatic seizures.


The differentiation of typical from atypical absence seizures patients with atypical absences usually have learning disabilities and also suffer from frequent seizures of other types, such as atonic, tonic and myoclonic seizures in atypical absences, onset and termination are not as abrupt as in typical absences, and changes in tone are more pronounced the ictal EEG of atypical absence has slow (<2.5 Hz) GSWD. These are heterogeneous, often asymmetrical, and may include irregular spikewave complexes and other paroxysmal activity. Background inter-ictal EEG is usually abnormal.