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Slide 1: Version 21 A Monthly Publication presented by Professor Yasser Metwally May 2010 AGE DEPENDENT EPILEPTIC SYNDROMES [PART 3] The age of the patients has great influence on the ictal, clinical and EEG characteristics of the epileptic seizures disorders and it also determines the course and prognosis of epilepsy in general. This is particularly true in the first two decades of life, especially for infancy and early childhood. There are certain age- determined epileptological entities or epileptic conditions which appear to be monolithic, in spite of a wide variety of etiologies and probably also despite variations in the localization of cerebral involvement. The role of age in epileptic seizure disorder has been substantiated by experimental work and clinical electroencephalographic investigations. We find in age-determined epileptic conditions a) certain condition-related types of seizures, b) certain condition-related EEG patterns, and c) certain condition-related characteristics of course and prognosis. In the past, this aspect of epileptic seizure disorder had been neglected; too much emphasis was universally placed on locus and cause of the seizure. From the historical view- point, the description of infantile spasm and the discovery of a specific EEG pattern called hypsarrhythmia mark the first individualization of an age-determined polyetiological epileptic condition with certain clinical-electroencephalographic criteria. There is a long historical evolution of the very common condition known as febrile convulsions. the clinical picture of benign Rolandic epilepsy became clear due to the efforts of numerous authors. Neonatal convulsions, which are a particularly heterogeneous group, must also be listed in this context and the thought-provoking notion of primary generalized epilepsy also belongs in this category. PRIMARY GENERALIZED EPILEPSY Introduction The entire concept of a primary generalized epilepsy has its foundation in the EEG. Who would have thought that a simple petit mal absence with its rather subtle clinical symptomatology could be the result of massive generalized synchronous epileptic discharges? The first observation of the ictal EEG pattern of petit mal has been the starting point for numerous attempts to explain the phenomenon of primary generalized seizure discharges.
Slide 2: Terminology The term "primary generalized epilepsy" has been introduced by the International League against Epilepsy. This term deserves general acceptance. It implies that the clinical and electroencephalographic phenomena of the seizures occurring in this epileptic condition are generalized from the start. This term has superseded older terms such as "centrencephalic epilepsy", "cortico-reticular epilepsy", and "common generalized epilepsy". Its weakness lies in the fact that it seems to burn all bridges for a retreat if a truly focal cortical onset with extremely rapid generalization should ever be convincingly demonstrated in the future. Age and Prevalence The age depends on the type of seizure. Classical petit mal absences mostly start at age 4 to 6 yr; a special group starts at age 9 to 15 yr. Myoclonus and grand mal attacks usually start at age 11 to 14 yr. Improvement or full seizure control after age 20-25 yr is very common. A special manifestation is the petit mal absence status, which may occur in older children, adolescents, adults, and even the elderly. Primary generalized epilepsy is sometimes preceded by a period of febrile convulsions in infancy and early childhood. It is never preceded by severe conditions such as infantile spasms or the Lennox-Gastaut syndrome. Ictal Manifestations The petit mal absence was discussed in detail in the section dealing with types of seizures. The two different forms are 1) simple petit mal absences, starting at age 4 or shortly thereafter, with a large number of absences/day (sometimes exceeding 100/day); and 2) "juvenile" petit mal absences with an onset at age 9 up to 15 yr, more prolonged or mixed with more motor activity. Petit mal absences show a wide variety of mild to moderate motor accompaniment; rhythmical eye blinking in synchrony with the spike waves is the most common motor component. Retropulsion of the head is quite common ("retropulsive petit mal); adversive movements and some rhythmically repetitive oral motions may also occur. Children with petit mal absences often start having grand mal seizures in early adolescence. Figures range from 31 % to 54%. In most of these cases, the grand mal seizures do not pose a major problem and are readily brought under control. Grand mal attacks in patients with primary generalized epilepsy are very often preceded by sudden bilateral myoclonus. These myoclonic jerks may also occur as isolated events, especially in the morning hours after a night of insufficient sleep. Many patients with this combination of grand mal and myoclonus may never have experienced any petit mal absences earlier in childhood. This petit mal-free form is a special variant of primary generalized epilepsy which also shows slightly different inter-ictal bursts in the EEG. These bursts are relatively short and dominated by 4/sec or 4-5/sec spike wave complexes which are, contrary to the classical 3/sec or 3-4/sec spike waves, not readily activated by hyperventilation. Many of these patients are flicker-sensitive (photoconvulsive response) and positive family histories are more often obtained in this group. Myoclonus may also be associated with brief petit mal absences. Very prolonged absence-like stages, attacks of petit mal- like stupor, or petit mal automatisms have been termed "Petit mal status", whereas the modern terminology recommends the term "absence status." These states will be discussed in the section on status epilepticus. While all of the ictal manifestations of primary generalized epilepsy tend to occur in children and adolescents, the absence status not only occurs in elderlies but may even have its onset in old age. Figure 1. The 3 c/s spike/wave discharge with frontal dominance EEG Most of the relevant EEG findings have been described in detail in the chapter on abnormal paroxysmal EEG patterns. May it suffice to reiterate that the 3/sec or 3-4 c/s spike wave pattern is the EEG correlate of the classical petit mal absence and also occurs, often abundantly, in the interval, sometimes in drowsiness and sleep. These generalized bursts, with or without clinical absence, are readily triggered by hyperventilation and may materialize after a few deep breaths in untreated patients. Intermittent photic stimulation may occasionally trigger petit mal absences with 3/sec spike waves; more often, it is associated with generalized polyspikes of frontal accentuation, with or without clinical myoclonic jerking, most often at frequencies of 14-18 flashes/sec. As was pointed out above, photosensitivity is more often noted in patients with 4/sec or 4-5/sec spike wave bursts and a history of grand mal and/or myoclonus.
Slide 3: The phenomenon of myoclonus is almost invariably linked with polyspike discharges as far as patients with primary generalized epilepsy are concerned. Polyspikes also contaminate the spike wave sequences in children with massive myoclonus as a variant of petit mal. In the majority of patients with primary generalized epilepsy, the EEG frequency spectrum appears to be normal aside from the generalized paroxysmal bursts, the so called background activity. A remarkable exception is the occurrence of prolonged stretches of rhythmical high voltage 3/sec waves in occipital leads with moderate spread into the vicinity; these bursts occur in a significant number of children with petit mal absences. this rhythm is found in 55% of the patients with petit mal absences and persists in 60% of the cases following seizure control. Hyperventilation almost invariably activates this rhythm. In some cases, a very small spike component is discernible between the large rhythmical delta waves. The rhythmical posterior activity may be enhanced under treatment with ethosuximide (Zarontin), while the 3/sec spike wave complex disappears. Children with petit mal absences and rhythmical occipital delta trains fall into a special epileptological category. The occipital rhythmical slow activity is a very favorable prognostic sign. The sleep records of patients with primary generalized epilepsy show frequent bursts of spikes, polyspikes, and spike waves; with common association between the K complex and the frontal midline maximum of the spike discharges. This maximum over the frontal midline is almost invariably present, not only in sleep but also in the waking state. This indicates that arousal plays an important role in the generation of these discharges. REM sleep is associated with an attenuation or total suppression of bilateral synchronous paroxysmal bursts. In exceptional cases, the maximum of the 3/sec spike wave bursts lies in the vertex region rather than in frontal midline; these children also show Rolandic spikes. It goes without saying that genetic factors are particularly important in the field of primary generalized epilepsy. Generalized synchronous seizure discharges follow an autosomal-dominant pattern of genetic transmission, with variable penetrance regardless of presence or absence of seizures with an unusual characteristic of a very low penetrance at birth which rises to nearly complete penetrance (close to 50%) for age 4.5 to 16.5 years" with a gradual decline to almost no penetrance at age 40 yr. These figures are in excellent agreement with the incidence of generalized synchronous seizure discharges of the 3-4/sec spike-wave type as well as the clinical seizure manifestations of primary generalized epilepsy. The Presence of Focal Spikes in Patients with Primary Generalized Epilepsy A certain type of focal spikes in childhood ("benign Rolandic spikes") may be occasionally present in children who, suffer from petit mal absences, especially after suppression of the absences and the spike waves with medication. This view would shed more light on the demonstration of genetic factors in children with midtemporal spikes. Concluding Remarks The challenging problem of primary generalized epilepsy remains unsolved. Genetic predisposition and age (chiefly 4-20 yr) are significant factors. It is a specifically human disorder; for this reason, animal models can provide only partial insight into pathogenetic mechanisms. In the human, the generalized synchronous seizure discharge originates from the interhemispheric frontal portion bilaterally. Arousing stimuli play a crucial role in the detonation of these discharges. In some patients, however, the mechanism of photosensitivity is paramount . BENIGN ROLANDIC EPILEPSY Introduction In children with spikes over the central region and/or adjacent midtemporal and parietal areas, a benign and readily controllable type of epileptic seizure disorder with focal motor seizures and/or grand mal is the rule. An increasing number of reports over the past 40 yr gives testimony to growing awareness of this special form of childhood epilepsy. This form of childhood epilepsy is occasionally listed among the primary generalized epilepsies despite its prominent focal features in the ictal and electroencephalographic semiology. Such a classification certainly appears to be provocative. There are indeed certain relationships between benign Rolandic epilepsy and primary generalized epilepsies and conversion from one form to the other may occur. There is certainly good reason to separate benign Rolandic epilepsies from the bulk of focal (partial) epileptic seizure disorders which will be presented somewhat later. Age and Prevalence Benign Rolandic epilepsy occurs at age 3 to 12 yr. The majority of these children are in the range from 6 to 10 yr. Disappearance of the seizures during adolescence (or even prior to puberty) is the rule. The seizures may occasionally recur much later in life, probably due to seizurefacilitating factors such as severe illness or toxic-metabolic factors. The sex distribution shows that boys are more often affected. The prevalence is not quite clear and might be somewhere between 5 and 10% in a population of epileptics below age 15 yr. Ictal Manifestations The seizures, regardless of focal or grand mal character, tend to occur during nocturnal sleep, mostly during the last hour of sleep or in the first 2 hr. About 80% of the attacks occur in sleep and, of the remaining 20%, about 10% take place shortly after awakening. (Note the similarities with primary generalized epilepsy.) Nocturnal seizures may awaken the child afterward. Preservation of consciousness and hence the ability to
Slide 4: describe the experienced seizure was found in 58%; this indicates the predominance of focal seizures. Grand mal (tonic-clonic) seizures were noted in 26%. The seizures are hardly ever seen by the physician, even by the epileptologist who sees sizeable numbers of these children. One therefore depends heavily on descriptions by the patient Or his family; nocturnal video- tape or biotelemetry recordings are quite helpful. Focal seizures often involve the face. The midtemporal spike localization has been thought to be related to paroxysmal activity in the very closely located lower portion of the motor strip (facio-laryngo-pharyngeal muscles). Hemifacial twitching is definitely more common than clonic motions in the contralateral arm; least common is clonic activity in the leg. In some cases, the entire half of the body participates, but a typical Jacksonian march does not seem to occur. Speech arrest is quite common (39% of the seizures). This is apparently an ictal anarthria with preserved internal speech. Oropharyngeal involvement is very often reported, with sounds described as "guttural," "gargling," "throaty," "wheezing," or "as if going to vomit." Feelings of suffocation are reported as coming from the mouth but not from the chest. These patients also have focal seizures which are not Rolandic, with blindness, vertigo, and torsion of the body as ictal signs. This underscores the complexity of the underlying neurophysiological mechanisms. EEG Spiking over central-midtemporal area in children is of limited epileptogenicity. It is reasonable to presume that 50-70% of these children have seizures and the remaining 50-30% are seizure-free. These latter patients are referred to the EEG laboratory because of a variety of symptoms such as behavior disorder, headaches, and other complaints or derivations. The spatial distribution of the spike activity requires an appropriate number of electrodes; the International Electrode System is particularly suitable. Otherwise, the Rolandic cortex may lie between a frontal and a parietal electrode and strictly local spiking may escape detection, especially when the midtemporal region is not explored ideally. In my personal experience, a central maximum of spike discharge is slightly more often noted than a midtemporal maximum. The spikes themselves are large and may be either spikes in the strict Figure 2. Trains of spikes/sharp waves recorded in a sense or sharp waves (see chapter on abnormal paroxysmal patterns). quasirhythmical pattern in a child with benign Rolandic epilepsy. Spiking is usually enhanced in light nonREM sleep, during which the discharges may become extremely abundant. Their random character may give way to quasirhythmical or periodical spiking at intervals of less than 1 see; previously unilateral spikes become bilateral synchronous or asynchronous. In many children, Rolandic spikes are found in the sleep portion only. REM sleep restores the unilateral character of the spiking. Bilateral parieto-occipital 4/sec spike wave-like discharges of moderate voltage is occasionally seen in the waking patient. The rest of the tracing is usually normal in these patients and the frequency spectrum corresponds to age. Central mu rhythm is sometimes present and there is reason to presume that central spikes of childhood may be gradually replaced by mu rhythm, at least in some of the patients. There is indubitable evidence that, in a limited number of patients, the central spike activity can be blocked by contralateral fist clenching or, even better, by alternate clenching and opening of the fist. This provides further evidence for the functional character of the spikes. In a small number of cases, the spike activity shows a consistent maximum over the vertex or over the centroparietal midline region, which may be the sole region of spiking, so that omission of midline leads would result in missing the abnormality. Some of these patients show focal motor or sensory ictal activity of leg predominance but, more often, the ictal symptoms do not correspond with the spike localization. Clinical Signs of Nonictal Character Neurological deficits are not compatible with benign Rolandic epilepsy. This condition is based on dysfunction rather than structural pathology. It is worthwhile, however, to search carefully for a true intracranial lesion. Arteriovenous malformation occasionally may be the cause of the discharges and associated seizure. Central, midtemporal, or parietal spikes or spikes over the midline may also occur in children with evidence of cerebral palsy, in mostly diplegic, quadriplegic, or choreoathetoid forms. In these children, Rolandic spikes have a different connotation and do not herald a good prognosis for the seizure disorder. The reader will find more extensive discussion in the section on cerebral palsy. Behavior disorders are very common in children with true Rolandic spikes; they may range from hyperkinetic behavior and signs of minimal cerebral dysfunction to severe anxiety neurosis. Various types of headaches may occur. The intelligence is normal in true benign Rolandic epilepsy.
Slide 5: Course The seizures are easily controlled with routine anticonvulsive treatment. Treatment may even be withheld unless seizures repeat themselves. Freedom from seizures in adolescence is the rule. The return of a single major convulsion may occasionally occur under the influence of infections, stress, or toxic substances. These cases show no resurgence of the central spike focus, which renders the EEG diagnosis very difficult. The presence of central mu rhythm may serve as a hint that the patient has had central spikes in the past, but such conclusions can be made only with reservations. Etiological Considerations This form of epilepsy is due to dysfunction rather than pathology. A genetic basis is the most logical thought. Problem of Differential Diagnosis Benign Rolandic epilepsy must be differentiated from: 1. 2. 3. Children with Rolandic spikes and no seizures whatsoever (these children are certainly not epileptics; about 30 to 50% of the children with Rolandic spikes have no overt clinical seizures). Children with Rolandic spikes and a history of antecedent brain damage or cerebral palsy. Children who have typical psychomotor seizures and evidence of temporal lobe epilepsy which may gradually progress in severity; these children may have atypical spike localization (central, midtemporal), while the classical anterior temporal sharp wave focus does not materialize before adolescence. Children with midtemporal spikes, marked tendency to generalization and spike wave formation, clinically with aphasia, probably a temporary inflammatory condition which gradually subsides. Children with frequent focal motor seizures which become progressively worse: "malignant" Rolandic epilepsy of childhood. Children with centroparietal spikes elicited by tactile stimulation of corresponding cutaneous areas of the body (see under benign parietal epilepsy). The differentiation of these conditions rests on a careful combined clinical-electroencephalographic assessment of each case. The EEG shows considerable slowing. There is evidence of constant muscle activity, but no authentic cerebral spikes are demonstrable. Spike Foci Outside the Rolandic Region in Children. Occipital spike foci are usually found between the ages of 2 to 5 yr. These children show no neurological or ophthalmological deficit; about 40% of them have clinical seizures, mostly grand mal, with good prognosis. Frontal spike foci in children are associated with epileptogenicity, with about 80% having overt seizures, and a guarded prognosis. Multiple spike foci (two or more areas of independent spiking) are also highly epileptogenic; the prognosis is guarded and probably fairly good if Rolandic spikes predominate. Considerations of Basic Mechanisms True benign Rolandic epilepsy is likely to be based on temporary paroxysmal hyperirritability of the motor cortex, which naturally has a lower threshold of epileptic excitability. This is merely a working hypothesis in need of further substantiating evidence. "Malignant" Rolandic Epilepsy Cases of progressively worsening focal motor seizures and prolonged episodes of epilepsia partialis continua are quite rare but probably constitute a special epileptological entity. Motor deficits and mental decline are associated with the seizure disorder. Their etiology is poorly defined; chronic localized encephalitis may be one of the causes (Rasmussen syndrome). Hemispherectomy seems to be the only effective treatment; limited cortical excisions or lobectomics are ineffective. The EEG shows endless sequences of ictal spike discharges during focal motor attacks but becomes uninformative in states of epilepsia partialis continua, which probably originate from deep structures or possibly from lamina V of the motor cortex without participation of the superficial layers. Benign Parietal Epilepsy The vast majority of these patients were children between the ages of 4 and 8 yr.The occurrence of spikes over the parietal region (parasagittal zone) following contralateral tactile stimuli characteristic of this condition. The paroxysmal response to tactile stimuli was found to be enhanced in nonREM sleep. Only 20% of children had clinical seizures; the remaining children were referred because of behavior problems. Children with Midtemporal Spikes, Progressive Aphasia and Seizures This syndrome of childhood epilepsy with progressive aphasia has stimulated much interest over the past 40 yr and may be regarded as an 4. 5. 6.
Slide 6: epileptological entity unless the discovery of a consistently present pathogenic agent such as a virus turns this condition into a specific disease entity. This condition is found in children around ages 4 to 6 yr. Speech becomes less intelligible and eventually is limited to a few words. Myoclonic jerking and other forms of brief seizures (akinetic, etc.) are reported. The EEG shows marked spiking, mainly over the left midtemporal region, but there are numerous generalized spike wave- like bursts, first 3-4/sec and later in the 1.5-3/sec range, suggestive of a LennoxGastaut syndrome. Cortical biopsy may show inflammatory changes and gliosis with mildly appearance of the meninges over left temporal region. In the course of years, the speech function starts to improve, the seizure frequency diminishes, and the EEG abnormalities gradually vanish. Considerations of "Functional" Versus "Autochthonous" Seizure Discharges The presentation of age-determined epileptic conditions clearly shows benign and vicious forms. It was mentioned before that generalized synchronous spikes and spike waves in primary generalized epilepsy and focal spikes in benign Rolandic epilepsy can be easily suppressed for a limited period with small doses of iv diazepam, whereas many cases of chronic epileptogenic foci are not touched by such small amounts. This dichotomy of responses of human epileptogenic EEG discharges reminds us of a similar dichotomy which has been widely discussed among neurophysiologists and basic science workers in the field of epileptology. Are we dealing with basically normal neurons which fire excessively due to hypersynchronous synaptic input? Such an epileptogenic focus would consist of a hyperexcitable "neuronal aggregate". On the other hand, one could view the epileptogenic focus as composed of intrinsically abnormal neurons. There is accumulating evidence that epileptic seizure disorders based upon neuronal hyperexcitability do exist. The key areas of predisposition to epileptic neuronal hyperexcitability may be summarized as follows. 1. Frontal lobe-supplementary motor area in interhemispheric fissure: Presumed trigger: arousing stimuli in a state of reduced vigilance. Generalization: very common and very pronounced, exemplified by 3/sec spike waves, with or without petit mal absence (perhaps via cingulate and thalamocortical connections). 2. Occipital lobe Trigger: flickering light and other visual stimuli. Generalization: common, exemplified by polyspikes with or without myoclonus, occasionally by spike waves with or without petit mal absence, via occipito-frontocentral connections and/or geniculatethalamocortical fiber systems. 3. Rolandic region Trigger: unclear; possibly sensorimotor idling. Generalization: is not quite as common; seizures, if occurring, are most often of focal motor character. Hyperexcitability of all three key areas may occasionally exist in certain patients with primary generalized epilepsy. Such cases epitomize the significance of predisposition (i.e., genetic factors). The hyperexcitability of the sensory- parietal cortex with local spike responses to contralateral tactile stimuli seems to be a related phenomenon. References 1. Metwally, MYM: Textbook of neurimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publishing, version 11.2a April 2010 2. Issues in brainmapping...Generalized epilepsies [Click to download in PDF format] The author, Professor Yasser Metwally Professor of clinical neurology, Ain Shams university, Cairo, Egypt. www.yassermetwally.com A new version of this publication is uploaded in my web site every month Follow the following link to download the current version: http://brainmapping.yassermetwally.com/map.pdf © Yasser Metwally, all rights reserved