| Typical absence seizures C P Panayiotopoulos Date of submission: July 28, 1999 Date of update: November 26, 2000 Date of update: November 3, 2002 Date of update: April 26, 2004 Medline SEARCH DATE: April 11, 2004 |
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ACKNOWLEDGEMENTS AND DISCLOSURES Please disclose any financial or other conflicts of interest that might bias your contributions, or give rise to the perception of such bias. Relevant financial ties can include consultantships, memberships in speaker's bureaus, grants, research support, salaries, royalties, ownership, equity positions, stock options, or other financial arrangements wherein you stand to gain substantially from an increase of stock value or corporate revenues. Disclosures and acknowledgements will be linked to the author name(s) and will display along with appointments and affiliations. Disclosures, acknowledgements, and affiliations can be entered and updated via the "Update My Profile" link in the Online Submission System. Alternatively, you may send such information along with your updated manuscript. THUMBNAIL So that MedLink Corporation can highlight your clinical summary and your authorship on the MedLink Neurology home page and in our weekly email to subscribers, we ask that you provide here a brief overview of your subject (about 50 to 100 words) aimed at enticing readers to view this clinical summary. For updates, please include a sentence that refers to something new you have added. Refer to yourself in the 3rd person (eg, Dr. Doe of Superior Institution explains the basics…). For more information and examples of thumbnails, please see the Instructions to Authors, which can be downloaded from your "My Writing Assignments" page in the Online Submission System (http://www.medlinkoss.com). Current thumbnail: Typical absences (previously known as petit mal) are brief for seconds generalized epileptic seizures of abrupt onset and abrupt termination. They have 2 essential components: (1) clinically the impairment of consciousness (absence), and (2) EEG generalized 3 Hz to 4 Hz (less than 2.5 Hz) spike and slow wave discharges. Typical absences are a cluster of clinico-EEG manifestations that may be syndrome-related. Absences may be the only type of seizures as in childhood absence epilepsy or may be mild and non-predominant as in juvenile myoclonic epilepsy. Typical absences are fundamentally different and pharmacologically unique compared to any other type of seizures, which also makes their treatment different. Antiepileptic drugs effective for focal seizures may be deleterious for absence seizures. In this update, C P Panayiotopoulos MD PhD FRCP, Consultant Emeritus, Department of Clinical Neurophysiology and Epilepsies, St. Thomas ’ hospital, London details recent developments in the pathophysiology, genetics and pharmacological treatment of absence seizures and related epileptic syndromes.
Gibbs and colleagues described the clinico-EEG characteristics of absences (Gibbs et al 1935). The petit mal triad of Lennox ( Lennox 1945), which was misused and misunderstood, was clarified by the Commission of the International League Against Epilepsy with the differentiation of typical from atypical absences (Gastaut 1970). Both Penry and colleagues and Stefan and colleagues studied absences with video-EEG (Penry et al 1975; Stefan et al 1982). Panayiotopoulos and colleagues described syndrome-related characterization of typical absence seizures with video-EEG analysis (Panayiotopoulos et al 1989; Panayiotopoulos 1997). Terminology and clarifications. Typical absences are brief, generalized epileptic seizures of sudden onset and termination. They have 2 essential components: (1) clinically the impairment of consciousness (absence), and (2) EEG generalized 3 Hz to 4 Hz (less than 2.5 Hz) spike and slow wave discharges (Commission 1981). Typical absences are a cluster of clinico-EEG manifestations that may be syndrome-related. Impairment of consciousness may be severe, moderate, mild, or inconspicuous (the detection of which may require special cognitive testing). This is often associated with other symptoms, such as automatisms, autonomic disturbances, or regional (mouth or eyes) or widespread (head, limbs, and trunk) rhythmic or random myoclonia.|{video:tap3v.avi}{caption:Typical absence seizure in juvenile absence epilepsy}{label:This 14-year-old patient had severe impairment of consciousness, continuous rhythmic eyebrow myoclonia, and irrelevant and incomprehensible vocalizations in the middle of the discharge. All seizures stopped when small doses of lamotrigine were added to sodium valproate.}||{video:tap6v.avi}{caption:Typical absence seizure of symptomatic myoclonic absence epilepsy}{label:Typical absence seizure of a child with symptomatic myoclonic absence epilepsy, at age 15 months. Note the marked rhythmic myoclonic jerks during the discharge. There is sudden recovery with a cry. Prognosis was poor.}||{video:tap7v.avi}{caption:Typical absence seizure of idiopathic myoclonic absence epilepsy}{label:Note the rhythmic myoclonic jerks during the first 4 seconds of the discharge in this 7-year-old boy. He is unresponsive. There are automatisms after the end of the myoclonic jerks. The absence is terminated with somatosensory stimulation. Prognosis was excellent.}| The EEG discharge may be brief|{diagram:tap3.bmp}{caption:Phantom typical absence seizures}{label:Numbers annotate breath-counting. Note the delay in pronouncing number 39 after the EEG discharge of polyspike and slow wave.}| or long (lasting 30 seconds or more);|{diagram:tap2.bmp}{caption:Ictal EEG of typical absence seizure of childhood absence epilepsy}{label:Note the regular rhythm of the discharge, the constant spike and slow wave relation, and the abrupt onset. The opening phase is often variable and unreliable. The child remains unresponsive from the onset of the initial to the onset of the terminal phase of the discharge. However, she is able to understand the technologist during the terminal phase when the ictal discharge is waning out.}| it may be continuous|{diagram:tap1.bmp}{caption:Ictal EEG of classical typical absence seizure of childhood absence epilepsy}{label:Note the regular rhythm of the discharge, the constant spike and slow wave relation, the abrupt onset, and the termination.}| or fragmented;|{diagram:tap4.bmp}{caption:Juvenile myoclonic epilepsy with absences (1)}{label:From video-EEG of a 25-year-old woman with juvenile myoclonic epilepsy. Note the discharge fragmentation and the irregular intradischarge frequency. No apparent ictal clinical manifestations except some mild eyelid flickering or hesitations in pronouncing numbers (not shown). Also, note the independent focal spikes in the right frontal regions.}| and it may be composed of single or multiple spikes,|{diagram:tap5.bmp}{caption:Juvenile absence epilepsy}{label:EEG sample from a video-EEG of a 50-year-old man with typical absence seizures since age 12. The patient manifests moderate impairment of consciousness during the discharge, which is dominated by multiple spikes.}| which may or may not be consistent with the slow wave. The intradischarge frequency may be relatively constant or may vary. Typical absences may be either spontaneous or precipitated by hyperventilation|{video:tap1v.avi}{caption:Typical seizure of childhood absence epilepsy (1)}{label:This 9-year-old girl’s seizure starts and ends abruptly. She stops counting and opens her eyes within 2 seconds of onset of the discharge. She is unresponsive. Note the marked automatisms and the lack of staring in her eyes. Seizures were controlled only when syrup was substituted by tablets of sodium valproate.}| or other specific modes of precipitation (eg, photic, pattern, video-games, thinking).|{diagram:tap6.bmp}{caption:Reflex typical absence seizures}{label:Typical absence seizures of a boy with photosensitivity and a girl with self-induced pattern-sensitive epilepsy.}| They may remit with age or be life-long, requiring continuous treatment. Thus, the clinico-EEG manifestations of typical absences are, by definition, wide-spread and often not as classical as in their archetype, childhood absence epilepsy. The term “typical” is not to characterize them as “classical”, but to differentiate them from “atypical” absence seizures. Atypical absences differ from typical absences in the following ways: • 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 such as atonic, tonic, and myoclonic seizures. • In atypical absences, onset and termination is not as abrupt as in typical absences, and changes in tone are more pronounced. • Ictal EEG of atypical absence is of slow, less than 2.5 Hz, spike-and-slow wave. The discharge is heterogeneous, often asymmetrical, and may include irregular spike wave and slow wave complexes and other paroxysmal activity. Background interictal EEG is usually abnormal.CLINICAL MANIFESTATIONS
The clinical manifestations of typical absence seizures vary significantly among patients (Penry et al 1975; Commission 1981; Stefan et al 1982; Panayiotopoulos et al 1989; 1995; Panayiotopoulos 1997; Panayiotopoulos et al 1997b; Capovilla et al 2001; Loiseau et al 2002; Panayiotopoulos 2002). Impairment of consciousness may be the only clinical symptom, but this is often combined with other manifestations. Absence with impairment of consciousness only. The hallmark of the absence attack is a sudden onset and interruption of ongoing activities, often with a blank stare.|{video:tap1v.avi}{caption:Typical seizure of childhood absence epilepsy (1)}{label:This 9-year-old girl’s seizure starts and ends abruptly. She stops counting and opens her eyes within 2 seconds of onset of the discharge. She is unresponsive. Note the marked automatisms and the lack of staring in her eyes. Seizures were controlled only when syrup was substituted by tablets of sodium valproate.}||{video:tap2v.avi}{caption:Typical seizure of childhood absence epilepsy (2)}{label:This 8-year-old boy suddenly stops counting and opens his eyes within 2 seconds of the onset of the discharge. Note the initial brief eyelid flickering followed by eyes and head deviating upwards and to the right. He is unresponsive.}||{video:tap3v.avi}{caption:Typical absence seizure in juvenile absence epilepsy}{label:This 14-year-old patient had severe impairment of consciousness, continuous rhythmic eyebrow myoclonia, and irrelevant and incomprehensible vocalizations in the middle of the discharge. All seizures stopped when small doses of lamotrigine were added to sodium valproate.}| 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. The attack lasts from a few seconds to (rarely) half a minute and terminates as rapidly as it commenced. Attacks are often aborted by auditory or sensory stimulation.|{video:tap7v.avi}{caption:Typical absence seizure of idiopathic myoclonic absence epilepsy}{label:Note the rhythmic myoclonic jerks during the first 4 seconds of the discharge in this 7-year-old boy. He is unresponsive. There are automatisms after the end of the myoclonic jerks. The absence is terminated with somatosensory stimulation. Prognosis was excellent.}| In less severe absences, the patient may not stop his or her activities, though reaction time and speech may slow down. In their mildest form, absences may be inconspicuous to the patient and imperceptible to the observer, as disclosed on video-EEG recordings with errors and delays during breath-counting or other cognitive testing during hyperventilation. Absence with clonic components. During the absence as above, clonic motor manifestations, rhythmic or arrhythmic and singular or repetitive, are particularly frequent at the onset. They may be continuous.|{video:tap3v.avi}{caption:Typical absence seizure in juvenile absence epilepsy}{label:This 14-year-old patient had severe impairment of consciousness, continuous rhythmic eyebrow myoclonia, and irrelevant and incomprehensible vocalizations in the middle of the discharge. All seizures stopped when small doses of lamotrigine were added to sodium valproate.}||{video:tap6v.avi}{caption:Typical absence seizure of symptomatic myoclonic absence epilepsy}{label:Typical absence seizure of a child with symptomatic myoclonic absence epilepsy, at age 15 months. Note the marked rhythmic myoclonic jerks during the discharge. There is sudden recovery with a cry. Prognosis was poor.}| They may also occur at any other stage of the seizure. The most common are clonic jerking of the eyelids, eye brows, and eyeballs, together or independently, as well as random or repetitive eye closures. Fast eyelid flickering is probably the most common ictal clinical manifestation, and may occur during brief generalized discharges 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. Absence with atonic components. Diminution of muscle tone is not unusual and may lead to 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 muscular contraction may affect the extensor or the flexor muscles symmetrically or asymmetrically. The 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 4 to 6 seconds after onset.|{video:tap1v.avi}{caption:Typical seizure of childhood absence epilepsy (1)}{label:This 9-year-old girl’s seizure starts and ends abruptly. She stops counting and opens her eyes within 2 seconds of onset of the discharge. She is unresponsive. Note the marked automatisms and the lack of staring in her eyes. Seizures were controlled only when syrup was substituted by tablets of sodium valproate.}||{video:tap3v.avi}{caption:Typical absence seizure in juvenile absence epilepsy}{label:This 14-year-old patient had severe impairment of consciousness, continuous rhythmic eyebrow myoclonia, and irrelevant and incomprehensible vocalizations in the middle of the discharge. All seizures stopped when small doses of lamotrigine were added to sodium valproate.}| These are more or less coordinated, adapted (eupractic or dyspractic), involuntary movements that may be an unconscious continuation of the preservative automatisms, de novo automatisms, or both. They vary in location and character from seizure to seizure, the same patient having both simple and complex absences. Perioral automatisms such as lip licking, smacking, swallowing, or mute speech movements are the most common. Scratching, fumbling with the clothes, and other limb automatisms are also common. Automatisms can be evoked, and their pattern and distribution can be changed by passive movements, postural repositioning, or other ictal stimulations.|{video:tap7v.avi}{caption:Typical absence seizure of idiopathic myoclonic absence epilepsy}{label:Note the rhythmic myoclonic jerks during the first 4 seconds of the discharge in this 7-year-old boy. He is unresponsive. There are automatisms after the end of the myoclonic jerks. The absence is terminated with somatosensory stimulation. Prognosis was excellent.}| Absence with autonomic components. Autonomic components consist of pallor and, less frequently, flushing, sweating, dilatation of pupils, and incontinence of urine. Mixed forms of absence are the rule rather than the exception. Visual hallucinations. Exceptionally, patients may have visual hallucinations or visual illusions during the absence or absence status (Panayiotopoulos 1999).|{diagram:tap7.bmp}{caption:Typical absence seizures with visual illusions}{label:Despite severe impairment of consciousness, the child said after the absences that the shoes of his mother, who was in front of him, were different and covered with flowers.}| The ictal EEG is characteristic with usually regular and symmetrical generalized discharges of 3 Hz to 4 Hz spike wave and slow wave complexes.|{diagram:tap1.bmp}{caption:Ictal EEG of classical typical absence seizure of childhood absence epilepsy}{label:Note the regular rhythm of the discharge, the constant spike and slow wave relation, the abrupt onset, and the termination.}||{diagram:tap2.bmp}{caption:Ictal EEG of typical absence seizure of childhood absence epilepsy}{label:Note the regular rhythm of the discharge, the constant spike and slow wave relation, and the abrupt onset. The opening phase is often variable and unreliable. The child remains unresponsive from the onset of the initial to the onset of the terminal phase of the discharge. However, she is able to understand the technologist during the terminal phase when the ictal discharge is waning out.}| and may have multiple spike wave and slow wave complexes.|{diagram:tap5.bmp}{caption:Juvenile absence epilepsy}{label:EEG sample from a video-EEG of a 50-year-old man with typical absence seizures since age 12. The patient manifests moderate impairment of consciousness during the discharge, which is dominated by multiple spikes.}| The background interictal EEG is customarily normal, although some paroxysmal activity (such as spikes or spike wave and slow wave complexes) may occur. Focal abnormalities or other asymmetries are common.|{diagram:tap4.bmp}{caption:Juvenile myoclonic epilepsy with absences (1)}{label:From video-EEG of a 25-year-old woman with juvenile myoclonic epilepsy. Note the discharge fragmentation and the irregular intradischarge frequency. No apparent ictal clinical manifestations except some mild eyelid flickering or hesitations in pronouncing numbers (not shown). Also, note the independent focal spikes in the right frontal regions.}| Absences may be the only seizure type for a patient, particularly in childhood absence epilepsy. However, in other syndromes such as juvenile absence epilepsy, typical absences may be the predominant type amongst other coexistent seizures (eg, myoclonic jerks and generalized tonic-clonic seizures). They may be mild and nonpredominant with myoclonic jerks and generalized tonic-clonic seizures as the main seizure type, as in juvenile myoclonic epilepsy. Typical absence status epilepticus may occur in approximately one-third of patients. Contrary to the dominant view, typical absence seizures occur in approximately 10% of adults with epilepsies and are often combined with other types of generalized seizures (Panayiotopoulos et al 1995).LOCALIZATION The pathophysiological mechanisms of absence seizures have been studied in various animal models with generalized spike and wave discharges associated with behavioral arrest (Danober et al 1998; Futatsugi and Riviello 1998; Snead et al 1999; Crunelli and Leresche 2002; Manning et al 2003). It appears that the generalized spike and wave discharges are generated and sustained by highly synchronized abnormal oscillatory rhythms in thalamocortical networks that mainly involve the neocortical pyramidal cells, the reticular nucleus, and the relay nuclei of the thalamus. Neither the cortex nor the thalamus alone can sustain these discharges, indicating that both structures are involved in their generation. The involvement of thalamus as the generator of the generalized spike and wave discharges is documented by the following: (1) stimulation of the medial thalamus induces a cortical generalized spike and waves discharge without leading to self-sustained activity and (2) thalamic neurons can intrinsically generate action potentials in both a tonic and a burst-firing mode (Snead et al 1999; Blumenfeld 2003; Manning et al 2003). The relative importance of the cortex in the initiation and synchronization of the generalized spike and waves discharges is mainly documented by the finding that following thalamectomy, instigation of generalized spike and waves discharges persists even though the thalamus is required to maintain rhythmicity once the discharges are established. More recently, in a rat model of absence, Meeren and colleagues (Meeren et al 2002) showed that during generalized spike and waves discharges, cortical and thalamic interactions lag behind an initial burst of activity in the peri-oral region of the primary somatosensory cortex during the first 500 ms of discharge activity. These findings suggest that, in this animal model, a cortical focus is the dominant factor in initiating the paroxysmal oscillation within the corticothalamic loops and that the large-scale synchronization is mediated by ways of a rapid intracortical spread of seizure activity (Meeren et al 2002). Both inhibitory and excitatory neurotransmissions are involved in the genesis and control of absence seizures. This may be the result of an excessive cortical excitability due to an imbalance between inhibition and excitation or of excessive thalamic oscillations due to abnormal intrinsic neuronal properties under the control of inhibitory GABAergic mechanisms. It is likely that the generation of absences is due to a predominance of inhibitory activity, in contrast to generalized or focal convulsive seizures where an excess of excitatory activity is present (Manning et al 2003). The basic intrinsic neuronal mechanisms involve low-threshold (T-type) calcium currents elicited by activating the low threshold calcium channels. These channels are present in high densities in thalamic neurons and trigger regenerative burst firing that drive normal and pathologic thalamocortical rhythms, including the spike wave discharges of absence seizures. Ethosuximide exerts its anti-absence effect either by reducing thalamic low-threshold calcium currents probably through a direct channel-blocking action that is voltage dependent (Coulter 1997) or through a potent inhibitory effect in the peri-oral region of the primary somatosensory cortex (Manning et al 2003). Of neurotransmitters, GABA-B receptors play the most prominent role by eliciting long-standing hyperpolarization required to drive low threshold calcium channels for the initiation of sustained burst firing. GABA-B agonists, such as baclofen aggravate, and GABA-B antagonists suppress typical absences. GABAergic drugs (such as vigabatrin and tiagabine) are pro-absence substances; they interfere with the degradation of, and the re-uptake of, GABA (Panayiotopoulos 2001; Manning et al 2003). The only exception of GABAergic activation inhibiting absences is that of the reticular thalamic nucleus, with exclusively GABA-A receptors; it functions as a pacemaker to synchronize thalamocortical oscillations (Gibbs et al 1996; Hosford et al 1999). Enhanced activation of GABA-A receptors in this nucleus decreases the pacemaking capacity of these cells, therefore decreasing the likelihood of generating absence seizures. Functional imaging with positron emission tomography demonstrates normal cerebral glucose metabolism and benzodiazepine receptor density in absence epilepsies with diffuse hypermetabolism during 3 Hz spike and wave discharges (Ryvlin and Mauguiere 1998; Duncan 1999). There is no evidence of any interictal overall abnormality of opioid receptors in idiopathic generalized epilepsy, but typical absences have been found to displace 11C-diprenorphine from the association areas of the neocortex. In contrast, binding of 11C-flumazenil to central benzodiazepine receptors has been shown to be unaffected by serial absences ( Duncan 1999). Ictal single photon emission computed tomography shows an overall increase in the cerebral blood flow (Yeni et al 2000) and may be useful in detecting secondarily generalized cases (Iannetti et al 2001). Microdysgenesis and other cerebral structural changes were reported in some patients with childhood absence epilepsy and juvenile absence epilepsy from autopsy (Meencke 1995) and MRI (Woermann et al 1998) studies. These results were not replicated in a more recent blinded study (Opeskin et al 2000). Microdysgenesis may be inconceivable for a benign, age-dependent and age-limited epileptic syndrome such as childhood absence epilepsy, though the current ion channel hypothesis for the pathogenesis of idiopathic generalized epilepsy does not preclude microscopic or ultramicroscopic abnormalities. Idiopathic generalized epilepsies with typical absences are genetically determined, as indicated by the high incidence of similar disorders among families. However, the precise mode of inheritance and the genes involved remain largely unidentified (Crunelli and Leresche 2002). Currently, various chromosomal loci have been identified for idiopathic generalized epilepsies with absences. Linkage to chromosome 1 was found in families with absences starting in childhood and later developing myoclonic jerks and generalized tonic-clonic seizures as in juvenile myoclonic epilepsy (Delgado-Escueta et al 1999). Linkage analysis of a 5-generation family in which affected patients had childhood absences and generalized tonic-clonic seizures provided evidence for a locus on chromosome 8q24 (Fong et al 1998; Delgado-Escueta et al 1999). The candidate region for this locus, designated ECA 1, has been refined, but a gene has yet to be identified (Sugimoto et al 2000). There is also evidence suggesting that mutations in genes encoding GABA receptors or brain expressed voltage-dependent calcium channels may underlie absence seizures of childhood onset. Furthermore, available evidence suggests that mutations in genes encoding GABA receptors (Feucht et al 1999; Marini et al 2003) or brain expressed voltage-dependent calcium channels (Chen et al 2003) may underlie CAE. Feucht and colleagues (Feucht et al 1999) found a significant association between a polymorphism in GABRB 3 in chromosome 15q11 and in 50 families with childhood absence epilepsy. Marini and colleagues (Marini et al 2003) found GABA-A receptor gamma2 subunit (GABRG2) gene mutations on chromosome 5 in a large family with childhood absence epilepsy and febrile seizures (including febrile seizures plus and other seizure phenotypes). This gene mutation segregated with febrile seizures and childhood absence epilepsy and also occurred in individuals with the other phenotypes. The clinical and molecular data suggested that the GABA-A receptor subunit mutation alone could account for the febrile seizure phenotype but that an interaction of this gene with another gene or genes was required for the childhood absence phenotype in this family. Linkage analysis for a putative second gene contributing to the childhood absence phenotype suggested possible loci on chromosome 10, chromosome 13, chromosome 14, and chromosome 15 (Marini et al 2003). Chen and colleagues (Chen et al 2003) found 68 variations, including 12 missense mutations in the calcium channel CACNA1H gene in CAE patients. The identified missense mutations occurred in the highly conserved residues of the T-type calcium channel gene (Chen et al 2003). However, another study of 33 nuclear families, each with 2 or more individuals with childhood absence epilepsy, provided conclusive evidence that genes encoding GABA-A and GABA-B receptors, voltage-dependent calcium channels, and the ECA1 region on chromosome 8q do not account independently for the childhood absence trait in a majority of the families (Robinson et al 2002). Genetic heterogeneity of the spike wave phenotype in animal models of absences favors a similar, and probably much wider, genetic heterogeneity in humans (Snead et al 1999; Crunelli and Leresche 2002; Manning et al 2003).
Many physicians are unfamiliar with the syndromic classification of absence epilepsies. Eyelid myoclonia with absences is the most straightforward diagnosis because it is betrayed by the characteristic, easily recognizable eyelid myoclonia. Equally simple to diagnose is the syndrome of myoclonic absence epilepsy with characteristically rhythmic myoclonic jerks, mainly of the upper extremities. Perioral myoclonia (marked perioral jerking) with absences is often erroneously diagnosed as motor partial epilepsy in adults and as childhood absence epilepsy in children. The onset of generalized tonic-clonic seizures before or at the same age as typical absences, the brief duration of absences, the EEG irregularities, and the occurrence of absence status are useful clinical indicators in favor of perioral myoclonia with absences and against childhood or juvenile absence epilepsy. Juvenile myoclonic epilepsy should not be difficult to diagnose if fully developed by the mid-teens. Myoclonic jerks on awakening are the hallmark of the disease. However, one-third of the patients also have absences that are often simple (with no automatisms or localized limb jerks). Impairment of consciousness is usually mild, and the EEG discharges are often fragmented and brief and have multiple spikes. In adolescents, it may be difficult to differentiate juvenile absence epilepsy from juvenile myoclonic epilepsy. However, in juvenile absence epilepsy, absences are more frequent and there is severe impairment of consciousness, whereas in juvenile myoclonic epilepsy, absences are often so mild that they are not easily discernible. Childhood and juvenile absence epilepsy are the most pure syndromes of typical absence seizures. In childhood absence epilepsy, absences are the primary, the most disturbing, and the most characteristic seizure-type. Childhood absence epilepsy is manifested only with age-related typical absences. There are no myoclonic jerks, generalized tonic-clonic seizures, or photosensitivity. The impairment of consciousness is more severe than in any other syndrome, and the EEG discharge is harmonious with no polyspikes or fragmentations. Juvenile absence epilepsy is the only syndrome wherein the ictal manifestations of absence seizures show similar clinical and EEG similarities to those of childhood absence epilepsy. However, in juvenile absence epilepsy they are milder and less frequent. Furthermore, juvenile absence epilepsy often manifests with infrequent generalized tonic-clonic seizures and sporadic, infrequent myoclonic jerks. Symptomatic absences mainly originating from frontal lobe pathology are detailed in the next section of the diagnostic workup. Typical absence seizures of idiopathic generalized epilepsies are also easy to differentiate from atypical absences that occur only in the context of mainly severe symptomatic or cryptogenic epilepsies in children with learning difficulties who also suffer from frequent seizures of other types, such as atonic, tonic, and myoclonic seizures. Although the differential diagnosis of typical absence seizures should be straightforward, they are frequently misdiagnosed as complex partial seizures, especially in adults (Panayiotopoulos et al 1995; 1997b; 2002). A typical absence seizure can be reproduced by the hyperventilation test, whereas a complex partial seizure cannot. In this author’s experience, this test is never undertaken by physicians for adult patients. Further, typical absence seizures occur daily, are shorter than 30 seconds, are frequently associated with bilateral facial myoclonic jerks or eyelid fluttering, are of sudden onset and termination, are not associated with complex behavioral automatisms or complex hallucinations or illusions, and there are no postictal manifestations. Table 1. Differential Diagnosis of Typical Absences from Complex Partial Seizures
Typical absences are easily induced by hyperventilation in more than 90% of the patients. They are best studied with video EEG. Ideally, all children with absence seizures should have video-EEG recordings in an untreated state, as this may reveal features favoring a specific epileptic syndrome and may, therefore, determine long-term prognosis and management. If this is not possible, the clinical manifestations of the seizures should be documented with camcorders by the parents or the treating physicians. The absences are videotaped while the patient is holding hands in front of him or her and counting his or her breaths while overbreathing for 3 minutes. Breath-counting during hyperventilation (wherein the patient is asked to count his or her deep breaths) is an important, often neglected, method to detect impairment of consciousness during the discharge. Practical, easy to perform, and clinically relevant, this method may reflect impaired performance in daily life. Frequently, the patients are able to recall numbers or phrases told to them during the spike wave and slow wave discharge, whereas these may be associated with serious errors in breath-counting (Panayiotopoulos et al 1995). Despite its practicality, breath-counting is rarely performed in EEG examinations of these patients; unfortunately, absences are often not apparent without this procedure. The significance of breath-counting may be appreciated by reviewing the video clips of this chapter with the volume off. Sleep EEG patterns are normal. Generalized discharges of polyspike waves and slow waves are more likely to increase, but a reduction is also observed during sleep. The discharges are shorter and usually devoid of discernible clinical manifestations, even in those patients who have numerous clinical seizures with motor manifestations during the alert state.SYNDROMES AND DISEASES IN WHICH THE SEIZURE TYPE OCCURS An epileptic syndrome, by definition, requires the nonfortuitous clustering of many symptoms and signs. The Commission has recognized 4 epileptic syndromes with typical absences: (1) childhood absence epilepsy, (2) juvenile absence epilepsy, (3) juvenile myoclonic epilepsy, and (4) myoclonic absence epilepsy (Commission 1989) and similar is the view of the new diagnostic scheme of the ILAE Task Force (Engel 2001). There may be more epileptic syndromes with typical absences, such as eyelid myoclonia with absences (Jeavons syndrome), perioral myoclonia with absences, stimulus-sensitive absence epilepsies, idiopathic generalized epilepsy with phantom absences, and others awaiting further studies and confirmation. Examples of these are provided in the video clips and detailed elsewhere by Panayiotopoulos (Panayiotopoulos 1997; 2002). Childhood absence epilepsy. Previously known as pyknolepsy, childhood absence epilepsy is the archetypal syndrome of typical absence seizures (Loiseau et al 2002; Panayiotopoulos 2002). This is an idiopathic generalized epilepsy with frequent (tens or hundreds per day), severe (complete unresponsiveness), brief (4 to 30 seconds but usually around 10 seconds) typical absence seizures that occur in otherwise normal children. Typical age of onset is before 10 years, with a peak at 5 years of age. Remission occurs in more than 90% of the children before the age of 12 years. Clinically, there is abrupt and severe impairment of consciousness. The eyes spontaneously open, and overbreathing, speech, and other voluntary activity stop within the first 3 seconds of the discharge. Automatisms are frequent. The eyes stare or move slowly; random eyelid blinking (usually not sustained) may occur. The background EEG is normal with frequent rhythmic posterior delta activity. Ictal discharges consist of generalized high amplitude 2.5 Hz to 4 Hz spike wave and double (maximum 3) spike waves and slow waves.|{video:tap1v.avi}{caption:Typical seizure of childhood absence epilepsy (1)}{label:This 9-year-old girl’s seizure starts and ends abruptly. She stops counting and opens her eyes within 2 seconds of onset of the discharge. She is unresponsive. Note the marked automatisms and the lack of staring in her eyes. Seizures were controlled only when syrup was substituted by tablets of sodium valproate.}||{video:tap2v.avi}{caption:Typical seizure of childhood absence epilepsy (2)}{label:This 8-year-old boy suddenly stops counting and opens his eyes within 2 seconds of the onset of the discharge. Note the initial brief eyelid flickering followed by eyes and head deviating upwards and to the right. He is unresponsive.}||{diagram:tap1.bmp}{caption:Ictal EEG of classical typical absence seizure of childhood absence epilepsy}{label:Note the regular rhythm of the discharge, the constant spike and slow wave relation, the abrupt onset, and the termination.}||{diagram:tap2.bmp}{caption:Ictal EEG of typical absence seizure of childhood absence epilepsy}{label:Note the regular rhythm of the discharge, the constant spike and slow wave relation, and the abrupt onset. The opening phase is often variable and unreliable. The child remains unresponsive from the onset of the initial to the onset of the terminal phase of the discharge. However, she is able to understand the technologist during the terminal phase when the ictal discharge is waning out.}| Exclusion criteria for childhood absence epilepsy. The following 5 seizure activities may be incompatible with childhood absence epilepsy: (1) Other than typical absence, generalized seizures such as generalized tonic-clonic seizures, or myoclonic jerks prior to or during the active stage of absences. (2) Eyelid myoclonia, perioral myoclonus, rhythmic massive limb jerking, and single or arrhythmic myoclonic jerks of the head, trunk, or limbs.|{video:tap3v.avi}{caption:Typical absence seizure in juvenile absence epilepsy}{label:This 14-year-old patient had severe impairment of consciousness, continuous rhythmic eyebrow myoclonia, and irrelevant and incomprehensible vocalizations in the middle of the discharge. All seizures stopped when small doses of lamotrigine were added to sodium valproate.}||{video:tap6v.avi}{caption:Typical absence seizure of symptomatic myoclonic absence epilepsy}{label:Typical absence seizure of a child with symptomatic myoclonic absence epilepsy, at age 15 months. Note the marked rhythmic myoclonic jerks during the discharge. There is sudden recovery with a cry. Prognosis was poor.}| However, mild myoclonic elements of the eyes, eyebrows, and eyelids may be featured particularly in the first 3 seconds of the absence seizure. (3) Mild or no impairment of consciousness during the 3 Hz to 4 Hz discharges. (4) Brief EEG discharges of less than 4 seconds.|{diagram:tap4.bmp}{caption:Juvenile myoclonic epilepsy with absences (1)}{label:From video-EEG of a 25-year-old woman with juvenile myoclonic epilepsy. Note the discharge fragmentation and the irregular intradischarge frequency. No apparent ictal clinical manifestations except some mild eyelid flickering or hesitations in pronouncing numbers (not shown). Also, note the independent focal spikes in the right frontal regions.}| (5) Visual (photic) and other sensory precipitation. Juvenile absence epilepsy. Juvenile absence epilepsy is an idiopathic generalized epilepsy mainly characterized by typical absences that are similar to, but probably not as severe as, childhood absence epilepsy (Panayiotopoulos 1997; 2002). Random and infrequent myoclonic jerks as well as infrequent generalized tonic-clonic seizures occur in most of the patients. Age at onset is between 7 and 16 years with a peak at 10 to 12 years. Juvenile absence epilepsy is a lifelong disorder, but absences tend to become less severe with age. The ictal EEG shows generalized, spike or multiple spike-and-slow waves at 2.5 Hz to 4 Hz.|{diagram:tap5.bmp}{caption:Juvenile absence epilepsy}{label:EEG sample from a video-EEG of a 50-year-old man with typical absence seizures since age 12. The patient manifests moderate impairment of consciousness during the discharge, which is dominated by multiple spikes.}| Exclusion criteria for juvenile absence epilepsy. Mild impairment of consciousness, brief ictal discharges (less than 4 seconds), eyelid or perioral myoclonus, rhythmic limb jerking, and single or arrhythmic myoclonic jerks during the absence ictus are incompatible with juvenile absence epilepsy. Visual, photo-sensitive, and other sensory precipitation of absences may be against the diagnosis of juvenile absence epilepsy. Myoclonic absence epilepsy. Myoclonic absence epilepsy is a rare generalized cryptogenic or symptomatic absence epilepsy. Severe bilateral rhythmical clonic jerks, often associated with a tonic contraction, occur during the absence.|{video:tap6v.avi}{caption:Typical absence seizure of symptomatic myoclonic absence epilepsy}{label:Typical absence seizure of a child with symptomatic myoclonic absence epilepsy, at age 15 months. Note the marked rhythmic myoclonic jerks during the discharge. There is sudden recovery with a cry. Prognosis was poor.}||{diagram:tap10.bmp}{caption:Myoclonic absence epilepsy}{label:EEG sample from video-EEG at age 15 months.}| Awareness of the jerks may be maintained. Seizures occur many times a day. Other types of seizures are rare. Age of onset is around 7 years, and there is a male preponderance. Prognosis is not good because of resistance to therapy, mental deterioration, and possible evolution to other types of epilepsy such as Lennox-Gastaut syndrome. An idiopathic form of myoclonic absence epilepsy may exist.|{video:tap7v.avi}{caption:Typical absence seizure of idiopathic myoclonic absence epilepsy}{label:Note the rhythmic myoclonic jerks during the first 4 seconds of the discharge in this 7-year-old boy. He is unresponsive. There are automatisms after the end of the myoclonic jerks. The absence is terminated with somatosensory stimulation. Prognosis was excellent.}| Eyelid myoclonia with absences (Jeavons syndrome). Eyelid myoclonia with absences is an idiopathic generalized epilepsy manifested with frequent (pyknoleptic) seizures. Eyelid myoclonia consists of marked, rhythmic, and fast jerks of the eyelids and is often associated with jerky upward deviation of the eyeballs and retropulsion of the head. The seizures are brief (3 to 6 seconds) and occur mainly after eye closure. Onset is usually in early childhood. All patients are highly photosensitive in childhood, but this declines with age. Infrequent generalized tonic-clonic seizures are inevitable in the long term, and they are likely to occur after sleep deprivation, fatigue, and alcohol indulgence. Myoclonic jerks of the limbs may occur but are infrequent and random. Eyelid myoclonia with absences may be resistant to treatment and life-long. The EEG ictal manifestations consist mainly of generalized polyspikes and slow waves at 3 Hz to 6 Hz, though these are more likely to occur after eye closure in an illuminated room. Total darkness abolishes the abnormalities related to eye closure. Photoparoxysmal responses are recorded from all untreated young patients. Juvenile myoclonic epilepsy. Juvenile myoclonic epilepsy is a genetically determined, common idiopathic generalized epilepsy. Prevalence is 5% to 11% among adult and adolescent patients with other epilepsies, and both sexes are equally affected. Juvenile myoclonic epilepsy is characterized by myoclonic jerks on awakening, generalized tonic-clonic seizures, and typical absences in more than one-third of the patients. The seizures have an age-related onset with absences first appearing either in childhood or adolescence, followed by myoclonic jerks and generalized tonic-clonic seizures in the middle teens. Seizure-precipitating factors like sleep deprivation and fatigue, alcohol, photosensitivity, and mental and psychological arousal are prominent. All seizures are probably life-long, although absences may become less severe with age; jerks and generalized tonic-clonic seizures commonly improve after the fourth decade of life. Typical absences are not the predominant type of absence, and they are usually highly mild and simple (with no automatisms or localized limb jerks), and impairment of consciousness is subtle. Generalized discharges of 3 Hz to 6 Hz spike waves have an unstable intradischarge frequency with fragmentations and multiple spikes.|{diagram:tap4.bmp}{caption:Juvenile myoclonic epilepsy with absences (1)}{label:From video-EEG of a 25-year-old woman with juvenile myoclonic epilepsy. Note the discharge fragmentation and the irregular intradischarge frequency. No apparent ictal clinical manifestations except some mild eyelid flickering or hesitations in pronouncing numbers (not shown). Also, note the independent focal spikes in the right frontal regions.}||{diagram:tap9.bmp}{caption:Juvenile myoclonic epilepsy with absences (2)}{label:EEG sample of a video-EEG from a 15-year-old girl who was erroneously assessed as having a first generalized tonic-clonic seizures. An experienced technician assessed that she also had absences and myoclonic jerks of juvenile myoclonic epilepsy. Absences were confirmed with this video-EEG. Numbers annotate breath-counting.}| The following are possible syndromes with typical absence seizures (Panayiotopoulos 1997): Perioral myoclonia with absences. This is an idiopathic generalized epilepsy with onset in childhood or early adolescence. Rhythmic myoclonus of the perioral facial or masticatory muscles occurs during the absence, together with a variable impairment of consciousness. The absences are frequent and may be brief. Absence status is common. Generalized tonic-clonic seizures, usually infrequent, always occur either early or many years after the onset of absences. Clusters of absences or absence status usually precede generalized tonic-clonic seizures. Absences and generalized tonic-clonic seizures may be resistant to medication, unremitting, and possibly life-long. Other patients may have a mild but long-standing course. Ictal EEG shows high-amplitude generalized discharges of typical but often irregular, rhythmic multiple spike waves and slow waves at 3 Hz to 4 Hz. There is no photosensitivity. The syndrome of phantom absences and generalized tonic-clonic seizures. “Phantom absences” denote typical absences that are so mild that they are inconspicuous to the patient and imperceptible to the observer. They are disclosed by video-EEG recording and breath-counting or other cognitive testing during hyperventilation with brief (usually 3 to 4 seconds) 3 Hz to 4 Hz spike or multiple spike wave and slow wave discharges. The absences are simple, occasionally with eyelid blinking. They may be clinically unrecognized, but they usually manifest in adult life with generalized tonic-clonic seizures, and often with absence status epilepticus (Panayiotopoulos et al 1997). Typical absences with specific modes of precipitation (reflex absences). Absences with specific modes of precipitation (eg, photic, pattern, video games, thinking, reading, fixation-off) have been recently reviewed (Duncan and Panayiotopoulos 1995).|{diagram:tap6.bmp}{caption:Reflex typical absence seizures}{label:Typical absence seizures of a boy with photosensitivity and a girl with self-induced pattern-sensitive epilepsy.}| Photosensitivity is estimated to occur in approximately one-fifth of patients with onset of absences in childhood or adolescence, and it is associated with a bad prognosis. The most well-defined syndrome with photosensitivity is eyelid myoclonia with absences. Absences with single myoclonic jerks during the absence ictus. Typical absences with single, often violent jerks of the head, body, or limbs during the absences ictus may appear in early childhood and continue in adult life- often with other types of generalized seizures. They are frequently difficult to treat and may be associated with a bad prognosis. Symptomatic and cryptogenic absences. Although typical absences are considered the paradigm seizure type of idiopathic generalized epilepsy, they may occasionally be symptomatic, arising as a consequence of a known disorder of the central nervous system (Ferrie et al 1995a).|{diagram:tap11.bmp}{caption:Symptomatic absence epilepsy}{label:EEG samples from video-EEG of a 33-year-old woman with typical absence seizures due to a frontal lobe glioma.}| Symptomatic and cryptogenic absences may be focal or diffuse, traumatic, metabolic, or inflammatory. In most cases an etiological link is not proven, and it is likely that they are coincidental. The mesial surfaces of the frontal lobe are most likely to generate typical absences. “Brief blank spells” with 3 Hz spike wave EEG paroxysms mainly due to subependymal heterotopia have been reported (Raymond et al 1995). It is apparent from the above description of syndromes with typical absences that most of them are life-long and manifest with myoclonic jerks and generalized tonic-clonic seizures.PROGNOSIS AND COMPLICATIONS The prognosis and complications are syndrome-related. Childhood absence epilepsy is a relatively benign syndrome of children, which usually remits within 2 to 5 years from onset. In all other syndromes, there is probably a life-long liability to absences, myoclonic jerks, and generalized tonic-clonic seizures. Response to appropriate treatment is often excellent, but 10% to 20% of the patients may not achieve control of seizures. MANAGEMENT The assessment of the drug treatment of absences and related IGE epileptic syndromes is problematic because it is based mainly on class 2 and class 3 evidence and commonly is void of randomized controlled trials (Faught 2003; Posner et al 2003). Despite significant uncertainties, the following outlines the best guidelines based on extensive review of the literature regarding old AEDs as well as observational and open studies, case reports, and postmarketing experience on the new AEDs (Panayiotopoulos 2001; 2002). Monotherapy if typical absences are the only type of seizures. Treatment is mainly with sodium valproate or ethosuximide, which are of equal efficacy controlling absences in around 75% of patients. Lamotrigine monotherapy is less effective with nearly half of the patients becoming seizure free (Coppola et al 2004). If monotherapy fails or unacceptable adverse reactions appear, replacement of one by the other is the alternative. Adding small doses of lamotrigine to sodium valproate may be the best combination in resistant cases. Monotherapy in syndromes of idiopathic generalized epilepsy with typical absence seizures and other types of generalized seizures such as myoclonic jerks, generalized tonic-clonic seizures, or both. Established first-line monotherapy is with sodium valproate which controls absence seizures in around 75%, generalized tonic-clonic seizures in 70% and myoclonic jerks in 75% (Panayiotopoulos 2001). A major problem is that sodium valproate is undesirable in women because of teratogenic effects, weight gain, and polycystic ovarian syndrome. The adverse effects of valproate and its lack of efficacy in 25% of patients have prompted the search for alternatives among newer AEDs; however, these have not been licensed for monotherapy. Levetiracetam appears to be more promising because it is highly effective in controlling generalized tonic-clonic seizures, myoclonic jerks, absences, and photosensitivity (Panayiotopoulos 2002; Krauss et al 2003; Manning et al 2003). Lamotrigine is effective in controlling generalized tonic-cloinc seizures and absence seizures, but it exaggerates myoclonic jerks. Topiramate is effective in generalized tonic-clonic seizures but with a weak anti-absence (Cross 2002) and anti-myoclonic action. Efficacy and adverse reactions have to be carefully balanced in these cases because treatment is often life-long. Levetiracetam has a relatively safe profile. Skin rash is a problem with lamotrigine. Topiramate often has serious cognitive and other adverse reactions. Monotherapy should not be abandoned before making sure that maximum tolerated dose has been achieved if smaller doses have failed. If monotherapy fails or unacceptable adverse reactions appear, then replacement of one by the other is the alternative. Polytherapy in syndromes of idiopathic generalized epilepsy with typical absence seizures and other types of generalized seizures such as myoclonic jerks, generalized tonic-clonic seizures, or both. For monotherapy failures, the combination of sodium valproate with small doses of lamotrigine appears to be the most effective. Small, minute doses of lamotrigine added to adequate doses of sodium valproate may have a dramatic beneficial effect in more than half of the patients. In resistant cases and particularly those with persistent myoclonic jerks, the best add-on drug is clonazepam that in small doses (0.5 mg to 2 mg) prior to sleep may have a dramatic beneficial effect. Ethosuximide should be added only for uncontrolled absence seizures. Contraindicated drugs. Carbamazepine, vigabatrin, and tiagabine are contraindicated in the treatment of absence seizures, irrespective of cause and severity. This is based on clinical and experimental evidence. In particular, the GABA agonists vigabatrin and tiagabine are used to induce, not to treat, absence seizures and absence status epilepticus (Panayiotopoulos 2002; Manning et al 2003). The error of prescribing these drugs in the treatment of absence seizures may be of the same magnitude as prescribing a gluten-rich diet in the treatment of celiac disease. Similarly, phenytoin, phenobarbitone, and gabapentin should not be used in the treatment of absence seizures, because they are ineffective (Panayiotopoulos 2002; Manning et al 2003). Withdrawing antiepileptic medication. Withdrawal of the medication is dependent on the syndrome. In the pure form of childhood absence epilepsy, drug therapy can be gradually withdrawn (within 3 to 6 months) after 2 to 3 seizure-free years. 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Ictal and interictal SPECT findings in childhood absence epilepsy. Seizure 2000;9(4):265-9. ILAE. ABBREVIATIONS SYNONYMS SUBTOPICS MAJOR KEYWORD DESCRIPTORS MINOR KEYWORD DESCRIPTORS AGE OF PRESENTATION AGE OF TYPICAL PRESENTATION ILLUSTRATION CAPTIONS Video clip 2 Video clip 3 Title: Typical absence seizure of symptomatic myoclonic absence epilepsy Video clip 5 Figures Fig 2. Title: Ictal EEG of typical absence seizure of childhood absence epilepsy Fig 3. Title: Phantom typical absence seizures Fig 4. Title: Juvenile absence epilepsy Fig 5. Title: Reflex typical absence seizures Fig 6. Title: Typical absence seizures with visual illusions Fig 7. Title: Juvenile myoclonic epilepsy with absences Fig 8. Title: Myoclonic absence epilepsy Fig 9. Title: Symptomatic absence epilepsy PERMUTED TOPIC, SYNONYMS, VARIANTS RELATED TOPICS DIFFERENTIAL DIAGNOSIS
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