ACKNOWLEDGEMENTS AND DISCLOSURES

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Current Disclosures : In the early 90's and until 1994, I had limited paid presentations (approximately 20) for Welcome, Marion Merrel Dow, Sanofi, and Ciba-Geigy, probably in that order. In between 1992 to 1994, I had a project grant from Marion Merrell Dow to support a clinical and research fellow. From February 15, 2004 (after my NHS retirement), I have a consultancy with UCB Pharma.

HISTORICAL NOTE AND NOMENCLATURE
The first unequivocal documentation of absence status epilepticus with EEG was by Putman and Merritt (Putman and Merritt 1941) and Lennox (Lennox 1945). Prolonged episodes of nonconvulsive status epilepticus were described on many occasions before the EEG-era (Shorvon 1994; 1995).

Absence status epilepticus is the name proposed by the Commission on Classification and Terminology of the International League Against Epilepsy (Commission of Classification and Terminology of the International League Against Epilepsy 1981; 1989). Absence status is not synonymous with nonconvulsive status epilepticus. Nonconvulsive status epilepticus is a term that has been rightly discarded in the new ILAE diagnostic scheme, because it encompasses heterogeneous conditions, which may be focal, such as limbic status epilepticus, or generalised, such as absence status epilepticus (Engel 2001; Panayiotopoulos 2005a). Convulsive elements and particularly myoclonic jerks are common in generalised nonconvulsive status epilepticus as, for example, in eyelid or perioral status epilepticus. If the term “nonconvulsive” is used, the distinction between “focal nonconvulsive” and “generalised nonconvulsive” should be made for clinical and management purposes. Petit mal status and various other synonyms have also been used in the past. The ILAE diagnostic scheme used the name “continuous seizure type” instead of “status epilepticus” (Engel 2001).

Classification. Considering that absence status epilepticus is a prolonged absence seizure, it is reasonable to adopt for this condition a definition and classification similar to that recognized for epileptic seizures and syndromes manifested with absences (Commission of Classification and Terminology of the International League Against Epilepsy 1989; Panayiotopoulos 1997; Engel 2001; Panayiotopoulos 2005a).

Table 1. Classification of Absence Status Epilepticus

Typical absence status epilepticus

1. Idiopathic (typical) absence status epilepticus in order of prevalence:

• Simple absence status epilepticus (mainly in idiopathic generalized epilepsy with phantom absences and juvenile absence epilepsy)
• Perioral myoclonic absence status epilepticus (of perioral myoclonia with absences)
• Eyelid myoclonic absence status epilepticus (of eyelid myoclonia with absences)
• Myoclonic absence status epilepticus (of juvenile myoclonic epilepsy)
• Other types of simple or complex absence status epilepticus (fixation-off-sensitive idiopathic generalized epilepsy with mainly catamenial absence status epilepticus; photosensitive idiopathic generalized epilepsy with absences; other unrecognized or unclassified syndromes of idiopathic generalized epilepsy)

2. Cryptogenic or symptomatic (typical) absence status epilepticus of cryptogenic/symptomatic generalized epilepsy with typical absence seizures:

• fixation-off-sensitive cryptogenic/symptomatic generalized epilepsy with mainly catamenial absence status epilepticus
• frontal lobe typical absence status epilepticus

Cryptogenic or symptomatic (atypical) absence status epilepticus of:

1. Lennox-Gastaut syndrome
2. Other cryptogenic/symptomatic generalized epilepsies mainly of childhood

Situation-related absence status epilepticus due to:

1. Drugs such as major neuroleptics but mainly due to benzodiazepine withdrawal
2. Electrolyte and other metabolic disturbances
3. GABA-B agonist-induced absence status epilepticus in patients with epileptic seizures (Tiagabine or Vigabatrin)
4. Severe brain anoxia. Comatose or critically ill patients
   

Adapted from (Panayiotopoulos 2005a).

Absence seizures are broadly divided into: (a) typical absences of mainly idiopathic generalized epilepsy with generalized, greater than 2.5 Hz spike or polyspike-and-slow waves, and (b) atypical absences of symptomatic or cryptogenic epilepsies with slower, less than 2.5 Hz generalized discharges (Commission of Classification and Terminology of the International League Against Epilepsy 1981). Similarly, absence status epilepticus is divided into typical absence status epilepticus of mainly idiopathic generalized epilepsy|{diagram:asep1.bmp}{caption:Typical absence status epilepticus in idiopathic generalized epilepsy with phantom absences (1)}{label:Top: Video-EEG prior to diazepam. There was continuous spike and occasional polyspike and slow wave activity mainly at 3-Hz that lasted until the administration of diazepam. Note also slower or faster components and some topographic variability of the discharge. Bottom: Relative normalization of the EEG started within a minute from onset of diazepam administration. Note the fragmentation of the discharge and the reappearance of alpha rhythm.}| and atypical absence status epilepticus of symptomatic and cryptogenic generalized epilepsies.|{diagram:asep2.bmp}{caption:Atypical absence status in symptomatic generalized epilepsy}{label:Video-EEG from a 9-year-old girl who had severe mental and physical deficits due to birth related brain anoxia. Slow spike and slow wave activity is continuously recorded.}| Furthermore, to comply with seizure and syndrome classification, absence status epilepticus may be situation-related and caused by the introduction or withdrawal of certain drugs, intoxication, or electrolyte or metabolic disturbances. Symptomatic absence status may also be caused by severe brain anoxia or other brain damage.

CLINICAL MANIFESTATIONS

Absence status epilepticus is a prolonged, generalized absence seizure, which is defined as lasting more than half an hour, but usually lasts for hours and even for days. It is associated with typically regular and symmetrical generalized discharges of 1 Hz to 4 Hz spike or multiple spike-and-slow wave complexes. Though the sharing symptom of absence status epilepticus is impairment of cognition, this is often associated with other clinical manifestations that may be syndrome-related. It should be emphasized that absence status epilepticus, like the brief absence seizure, is not one but many types of a prolonged, generalized, absence seizure (Andermann and Robb 1972; Commission of Classification and Terminology of the International League Against Epilepsy 1981; 1989; Guberman et al 1986; Dunne et al 1987; Rohr-Le Floch et al 1988; Shorvon 1995; Snead et al 1997; Agathonikou et al 1998; Panayiotopoulos 2005a)

Impairment of consciousness, memory, and higher cognitive functions.The cardinal symptom shared by all cases of absence status is the altered content of consciousness in a patient who is usually fully alert.|{video:asep9.avi}{caption:Absence status epilepticus}{label:Absence status epilepticus of late onset in idiopathic generalized epilepsies. This woman is unable to remember dates. She could not remember her date of birth or other significant dates from her life.}| Memory and higher cognitive intellectual functions such as abstract thinking, computation, and personal awareness are the main areas of disturbance (Andermann and Robb 1972; Guberman et al 1986; Agathonikou et al 1998; Panayiotopoulos 2005a). This varies from extremely mild to extremely severe with intermediate states of severity occurring more often. Mild impairment of consciousness manifests with slow reaction, behavior, and mental functioning.
Descriptions of this state as perceived by patients with idiopathic generalized epilepsies are well illustrative:

My mind slows down…able to understand but takes longer to formulate answers…I become slow but can communicate verbally with others…slow down in my behavior…muddling with words,…like in a trance…missing pieces of conversation

Moderate and severe impairment of consciousness manifest with varying degrees of confusion, global disorientation, and inappropriate behavior, and these are described by witnesses as follows:

Confused…cannot recognize people other than close relatives… disorientated in time and place… very quiet, disturbed, vague, uncooperative, confused,...markedly confused…goes into a dreamy state…able to formulate some answers to simple questions… puts trousers over pajamas...confused…makes coffee twice…fades away mentally and physically…disoriented in time and place (Agathonikou et al 1998).

Usually, the patient with absence status of idiopathic generalized epilepsy is alert, attentive, and cooperative. Verbal functioning is relatively well preserved, but is often slow with stereotypic and usually monosyllabic answers. Movement and coordination is intact. Although the patient may rarely become completely unresponsive, this author is not aware of any such case with idiopathic generalized epilepsy. It is surprising how often physicians are deceived by the general good appearance, alertness, and cooperation of the patient. Based on previous experiences, patients and relatives usually recognize the condition. However, medical intervention to stop the absence status and prevent an impending GTCS may not be offered because attending physicians may not appreciate this as an emergency. |{diagram:asep3.bmp}{caption:Typical absence status epilepticus in idiopathic generalized epilepsy with phantom absences (2)}{label:EEG (top) of absence status and "interictal video EEG" (bottom) with phantom absences of a woman who had her first absence status epilepticus followed by a generalized clonic-tonic seizure at age 56 years. Initially, we erroneously classified her as de novo absence status epilepticus instead of idiopathic generalized epilepsy with phantom absences. This mistake became apparent when interictal video-EEG demonstrated absences manifested with mild cognitive impairment and eyelid fluttering (bottom). In reviewing this video-EEG with the patient and her daughter, they recognized that these mild absences were occurring many years prior to the absence status epilepticus. Note the similarity between the EEG discharge of absence status epilepticus (top) and typical absence seizure (bottom).}| Basic testing of memory and higher cognitive functions are essential for diagnosis.

Behavioral abnormalities and experiential phenomena. Though the most common behavioral changes refer to daily activities disturbed by the impairment of consciousness, some patients become depressed, agitated, and occasionally, hostile. More commonly than usually appreciated are experiential and sensational phenomena such as: "sensation of viewing the word through a different medium,” “a feeling of not being in the same world as everyone else,” “uncontrollable rush of thoughts,” “a feeling of fear of losing control of my mind," "a feeling of closeness," "a funny feeling that I can not elaborate," "a strange feeling of not being myself," "edgy, worried, and uncomfortable,” "my character changes completely, I become extremely snappy…have a severe headache," or "weird" (Agathonikou et al 1998; Panayiotopoulos 2005a).

Myoclonic jerks. Segmental, usually eyelid or perioral and less often limb, myoclonic jerks frequently occur during typical absence status and vary in degree and severity. They are most likely to occur in syndromes manifesting with similar myoclonic phenomena during brief absences (Agathonikou et al 1998; Panayiotopoulos 2005a).


CLINICAL VIGNETTE
No information was provided by the author.

LOCALIZATION
By definition, absence status epilepticus is a prolonged, generalized absence seizure. "The first clinical changes indicate initial involvement of both hemispheres. Consciousness may be impaired and this impairment may be the first initial manifestation. Motor manifestations are bilateral. The ictal EEG patterns initially are bilateral, and presumably reflect neuronal discharge which is widespread in both hemispheres" (Commission on Classification and Terminology of the International League Against Epilepsy 1981). It is most likely due to an abnormal bilateral and synchronous oscillatory burst-firing of reciprocally connected neuronal populations located in the thalamus and in the neocortex (Snead et al 1997). Frontal lobe epileptogenic foci may generate absence seizures and absence status epilepticus (Ferrie et al 1995; Thomas et al 1999; Panayiotopoulos 2005b).

PATHOPHYSIOLOGY
The pathophysiology of absence status (typical or atypical) is unknown. It is likely that the generating mechanisms of absence seizures and absence status are the same because their clinico-EEG features show marked syndrome-related similarities (Agathonikou et al 1998). The difference is in the duration of the discharge, which may also perpetuate more severe cognitive impairment. Absence seizures last for only a few seconds, whereas absence status epilepticus is prolonged for hours and days, which indicates that the major deficit is inability of “seizure terminating” mechanisms. Therefore, the continuation of absence seizure may be due to a failure of brain systems, neurotransmitters, or neurophysiological circuits that usually interfere to terminate the abnormal discharge. It may also be possible that self-sustained feedback loops or other mechanisms perpetuate and sustain the absence seizure process (Snead et al 1997). In animal models of absence status epilepticus (genetic mutants, pentylenetetrazole), there is relatively scarce neuropathology that can be attributed directly to status epilepticus (Hosford 1999).

Furthermore, we also do not know why and how an absence seizure or status may progress to a GTCS.|{diagram:asep7.bmp}{caption:Transformation from absence to a generalized tonic clonic seizure}{label:This is a rare illustration of the transformation of an absence to GTCS. It is from a video-EEG of a 23-year-old woman with idiopathic generalized epilepsy and absence seizures. Upon awakening she had numerous absence seizures with complete recovery in between, which is not absence status.}|

The etiology of absence status epilepticus is syndrome-related. It is genetically determined in idiopathic generalized epilepsy, it is symptomatic in atypical absence status epilepticus, and it is caused by drugs or electrolyte and metabolic disturbances in situation-related conditions. Absence status epilepticus, like absence seizures, may also be symptomatic from mainly frontal epileptogenic foci and constitutes a frequent seizure type of symptomatic generalized epilepsies (Ferrie et al 1995; Thomas et al 1999; Panayiotopoulos 2005b). Nonconvulsive status epilepticus of frontal origin is usually simple or complex partial status, rarely presenting with features as absence status epilepticus (Thomas et al 1999).

Absence status epilepticus does not appear to cause permanent neurologic damage from (Drislane 1999).

We know more about absence seizures than absence status (Panayiotopoulos 2005a). 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 neocortical pyramidal cells, the reticular thalamic 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: (A) stimulation of the medial thalamus induces a cortical generalized spike and wave discharges without leading to self-sustained activity and (B) thalamic neurons can intrinsically generate action potentials in both a tonic and a burst firing mode (Snead et al 1999; Manning et al 2003; Blumenfeld 2003). The relative importance of the cortex in the initiation and synchronization of the generalized spike and wave discharges is mainly documented by the finding that following thalamectomy, instigation of generalized spike and wave discharges persists although the thalamus is required to maintain rhythmicity once the generalized spike and wave discharges is established. More recently, in a rat model of absence, Meeren and colleagues (Meeren et al 2002) showed that during generalized spike and wave 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 generalized spike and wave discharges 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 an extremely fast 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 unbalance between inhibition and excitation, or 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 generalized spike and wave discharges of absence seizures. Ethosuximide exerts its antiabsence effect by either 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).

DIFFERENTIAL DIAGNOSIS
Absence status epilepticus should be differentiated according to the underlying epileptic syndrome.

Idiopathic (typical) absence status epilepticus. Idiopathic (typical) absence status epilepticus is easy to diagnose, providing that the associated syndrome of idiopathic generalized epilepsy with typical absences is correctly identified. This is often combined with myoclonic jerks and GTCS. With the possible exception of childhood absence epilepsy, all other syndromes of idiopathic generalized epilepsy with typical absences may manifest with typical absence status, either as a spontaneous expression of their natural course or provoked by external factors or inappropriate treatment maneuvers (Agathonikou et al 1998; Panayiotopoulos 2005a). In these conditions, the patient or relatives are well aware of the clinical manifestations of absence status epilepticus, which often heralds GTCS. The most common misdiagnosis is made because absences are not recognized or are misdiagnosed as complex partial seizures (Agathonikou et al 1998; Panayiotopoulos 2005a). A previous or a new EEG invariably shows generalized discharges in idiopathic generalized epilepsy. It may be normal or may show specific focal spikes in partial epilepsies, mainly temporal lobe epilepsy.

Impairment of consciousness and myoclonic jerks. Impairment of consciousness, memory, and higher cognitive function, as detailed in the clinical manifestations, may be the same irrespective of idiopathic generalized epilepsy syndrome. It is not the absence but the other associated clinical manifestations (ie, myoclonic jerks) that betray the underlying syndrome of idiopathic generalized epilepsy. These may be segmental (usually eyelid or perioral and less often limb) myoclonic jerks occurring during typical absence status. They are of varying degree and severity. They are most likely to occur in syndromes manifesting with similar myoclonic phenomena during brief absences. Thus, continuous and disturbing eyelid myoclonia is a consistent symptom of typical absence status in the syndrome of eyelid myoclonia with absences. Similarly, perioral myoclonia is the relevant clinical manifestation of absence status in perioral myoclonia with absences. Random myoclonic jerks of the limbs or eyelids may be seen in absence status epilepticus of juvenile absence epilepsy. In juvenile myoclonic epilepsy, absence status epilepticus is rare as opposed to the frequently occurring long series of myoclonic jerks and myoclonic status epilepticus prior to a generalized convulsion. It is possible that in juvenile myoclonic epilepsy, absence status epilepticus consists of a mixture of myoclonic jerks interspersed with absences. Absence or poverty of segmental or other jerks is rather characteristic of the syndrome of phantom absences. Only rarely, there may be some mild eyelid fluttering markedly different from that of the eyelid myoclonia. The relation of the typical absences and typical absence status epilepticus is epitomized as follows by the presented illustrative patient:

The absences [phantom absences] lasted a couple of seconds; the other state [absence status] was much longer, for 24 hours or more. They may be linked I suppose...I was doing silly things like making coffee without coffee, putting my pajamas over my clothes. I was able to answer the phone or the door and people would not understand that I was in that state. My husband knew and protected me. Once a physician was called but did not think that there was anything serious with me...there was nothing else abnormal, only in the mind...once, my daughter came while I was in that state. I remember that she was hungry. I could not help her. She did not realize that I was ill.

A 76-year-old woman is presented for 3 reasons:

1. She is a typical case of absence status documented with video-EEG.
2. She was unjustifiably misdiagnosed for 28 years as having complex partial seizures with secondary generalized tonic-clonic seizures, and she was inappropriately treated with primidone and sulthiame.
3. She demonstrates how a new syndrome can be recognized with our dual approach, which uses a retrospective and prospective collection of clinico-EEG data. The syndrome in her case is “phantom absences, generalized tonic-clonic seizures, and frequent absence status,” mainly of adult onset (Panayiotopoulos et al 1997b).

Her first overt seizure occurred at age 30 years. She was moderately confused for 12 hours prior to a GTCS.|{diagram:asep1.bmp}{caption:Typical absence status epilepticus in idiopathic generalized epilepsy with phantom absences (1)}{label:Top: Video-EEG prior to diazepam. There was continuous spike and occasional polyspike and slow wave activity mainly at 3-Hz that lasted until the administration of diazepam. Note also slower or faster components and some topographic variability of the discharge. Bottom: Relative normalization of the EEG started within a minute from onset of diazepam administration. Note the fragmentation of the discharge and the reappearance of alpha rhythm.}||{video:asep9.avi}{caption:Absence status epilepticus}{label:Absence status epilepticus of late onset in idiopathic generalized epilepsies. This woman is unable to remember dates. She could not remember her date of birth or other significant dates from her life.}|Despite an EEG showing brief discharges of 3 Hz spike-and-slow waves|{diagram:asep6.bmp}{caption:Interictal EEG of idiopathic generalized epilepsy with phantom absences}{label:From interictal video-EEG. Brief generalized discharges of 3 Hz spike and slow waves lasting 2 to 3 seconds without apparent clinical manifestations. Similar abnormalities were recorded in 1972 and again in 1997. Note the similarity of the discharge with the ictal and immediately post-diazepam EEG. The only significant difference is duration, brief interictally, continuous for hours ictally.}|and no clinical evidence of brief complex partial seizures of temporal lobe symptomatology, she was misdiagnosed as having temporal lobe epilepsy and was treated with high doses of primidone and sulthiame until her referral to this author's clinic in 1990. Through the years, she had at least 30 episodes of absence status, lasting from 3 hours to 10 days and often progressing to GTCS. Also, questioning revealed that she frequently had brief episodes of 2 seconds to 5 seconds, wherein she experienced a lack of concentration (phantom absences) or of memory for a few seconds, which could be misinterpreted as normal variations in daily life. She was free of seizures for the previous 9 years on monotherapy with sodium valproate 1000 mg daily. Her last EEG in 1997 still showed some brief generalized discharges of 3 Hz spike-and-slow waves on overbreathing without clinical manifestations

Syndromic classification of this illustrative case. We initially categorized this woman amongst the unclassified cases suggesting that "she may be a case of late onset absence status, absences, and GTCS” (Panayiotopoulos et al 1992). Later, on the basis of another 12 similar cases, we concluded that she suffered from a previously unrecognized syndrome of idiopathic generalized epilepsy with phantom absences, GTCS with onset in adulthood, and frequent absence status epilepticus (Panayiotopoulos et al 1997b).

In some patients with idiopathic generalized epilepsy, there may be brief tonic spasms of facial muscles (Agathonikou et al 1998; Panayiotopoulos 2005a).|{diagram:asep4.bmp}{caption:Absence status epilepticus with repetitive discharges of unclassified generalized epilepsy}{label:Continuous recording from video-EEG of a 48-year-old woman with unclassified absences and GTCS from age 11 years. She realized from previous experiences that she was in absence status epilepticus when she felt “weird, like in a trance, missing pieces of conversation,” and she went to the hospital. Despite written instruction, no diazepam was administered. She was alert, attentive, cooperative, and well-behaved, but she seemed depressed. Movement and speech were normal. She was able to count with no errors except when the discharges between arrows occurred. During these discharges, eyes, and sometimes mouth, would tonically open with a slight retropulsion of the head. Video-EEG was recorded 7 hours from onset of symptoms, which ended with a generalized tonic clonic seizure one hour later.}|

Onset, duration, and evolution. Though of sudden onset, the severity of symptoms may be initially mild and inconspicuous. The patient or relatives, with the experience of previous episodes, recognize this state that may progress to more serious disturbances and probably a generalized convulsion. These initial symptoms may be mild slowness of thought and mental functioning, an increasing number of perioral or eyelid jerks interspersed with mild impairment of concentration, or just a familiar, habitual personal feeling heralding the status. Soon after this initial phase, half of the patients reach a more or less steady state that, mild or severe and with or without clinical manifestations other than impairment of consciousness, is stereotype for each patient. In another one-fourth of patients, the impairment of consciousness deteriorates with time. For the remaining one-fourth, severity shows marked fluctuations in the course of the absence status epilepticus. It is important to remember that more than half of the patients are aware of the situation when entering or during absence status epilepticus, which is of great practical significance regarding termination of this state and prevention of the impending GTCS by self-administration of appropriate medication.

Generalized tonic-clonic seizures associated with idiopathic typical absence status. Ending with a GTCS is probably the rule irrespective of syndrome (Andermann and Robb 1972; Guberman et al 1986; Agathonikou et al 1998; Panayiotopoulos 2005a). However, in only one-third of patients does absence status epilepticus end with GTCS when untreated. In the remaining patients, it may also terminate spontaneously without GTCS. It is exceptional for GTCS to precede or intersperse with typical absence status (Fagan and Lee 1990; Agathonikou et al 1998). It is also exceptional for more than one GTCS to occur following absence status epilepticus.

Duration and frequency. Idiopathic (typical) absence status epilepticus usually lasts for an average of 3 hours to 4 hours, rarely a minimum of half an hour, often exceeding 6 hours to 10 hours, and occasionally enduring for 2 days to 10 days. Frequency also varies from 1 in a lifetime to an average of 10 to 20 or catamenial. This depends on treatment strategies and syndromic classification (Agathonikou et al 1998).

Postictal state. Amnesia of the event is exceptional. The patient is usually aware of what happens during the absence status; some are able to write down their experiences, even when in status, and others have a patchy recollection of the events, usually missing the last part prior to GTCS. Following a GTCS, the patient feels tired, has a headache, and is confused for a varying duration of time

Age at onset and sex. It is rare for absence status epilepticus in idiopathic generalized epilepsy to start before the first decade. Other types of seizures such as absences, myoclonic jerks, and GTCS may predate the first occurrence of absence status epilepticus for many years. In the study of Agathonikou and colleagues, mean age at onset of absence status epilepticus was 29 years with a range of 9 years to 56 years (Agathonikou et al 1998). In 7 of 21 patients, absence status epilepticus was the first overt type of seizure; this was mainly the case in the syndrome of phantom absences with GTCS. Twelve of the 21 patients were women.

Precipitating factors. These are also syndrome- and treatment-related. Inappropriate use or discontinuation of antiabsence medication is the most common precipitant of idiopathic absence status epilepticus. Sleep deprivation, stress, and excess of alcohol consumption, alone or usually combined, are common precipitating factors. Some patients may have catamenial precipitation. In others, this mainly starts on awakening. Lights precipitate absence status epilepticus in eyelid myoclonia with absences, a mainly photosensitive type of epilepsy.

Cryptogenic or symptomatic (atypical) absence status epilepticus. Cryptogenic or symptomatic (atypical) absence status epilepticus is clinically characterized by fluctuating impairment of consciousness, often with other ictal symptoms such as repeated serial tonic or atonic seizures and segmental or generalized jerks. The ictal EEG pattern is of slow, less than 2.5 Hz spike and slow wave generalized activity (Commission of Classification and Terminology of the International League Against Epilepsy 1981; 1989; Aicardi 1994; Shorvon 1994; 1995). Both the clinical patterns and the EEG abnormalities are more variable than of the typical absence status epilepticus.

The main distinction of atypical from typical absence status is that it occurs mainly in children with symptomatic or cryptogenic generalized epilepsies who also have a plethora of other types of frequent seizures such as atypical absences, tonic and atonic seizures, myoclonic jerks, and GTCS. Most of them also have moderate or severe learning and physical handicaps. In addition, interictal EEG is often abnormal with slow background and frequent brief or long runs of slow generalized spike-and-slow waves, paroxysmal fast activity, and paroxysms of polyspikes. It is often difficult to define the boundaries, onset, and termination of atypical absence status epilepticus because these children frequently have alterations of behavior and alertness as well as long interictal slow spike-and-slow wave discharges.|{diagram:asep2.bmp}{caption:Atypical absence status in symptomatic generalized epilepsy}{label:Video-EEG from a 9-year-old girl who had severe mental and physical deficits due to birth related brain anoxia. Slow spike and slow wave activity is continuously recorded. Despite video-EEG monitoring, it was difficult to detect overt clinical manifestations. The girl was probably less communicative and quieter during the discharge, which ended when she was alerted by the pain from inserting the drug infusion tube.}|As Aicardi stated, “No doubt, Lennox-Gastaut syndrome is commonly associated with distinct episodes of absence status, but in this condition all transitions may be found between distinct episodes of absence status and prolonged bad periods during which paroxysmal EEG activity is permanent and mental efficiency is fluctuating, at times, only in certain specific tasks” (Aicardi 1994). Atypical absence status epilepticus occurs in more than two-thirds of patients with Lennox-Gastaut syndrome. It may last days, weeks, or months and is highly resistant to treatment. "The EEG often becomes hypsarrhythmic and these status-like seizures constitute a reversible aggravation of the interictal symptomatology."

Additional discriminating features of atypical absence status epilepticus are:

• Onset and offset are gradual.
• The level of consciousness and other coexistent seizures tend to fluctuate, sometimes for weeks, with little distinction between ictal and interictal phases.
• Initiation or termination with a GTCS is exceptional.
• Incontinence is common (Shorvon 1994; 1995).

Situation-related absence status epilepticus. De novo absence status epilepticus is often misdiagnosed as a psychotic state or dementia. EEG is probably mandatory in adults on neuroleptic drugs or withdrawal of diazepines who present with a confusional state.

Drugs or electrolyte and metabolic disturbances. De novo absence status epilepticus is coined for this condition if it appears in adults, mainly middle age women, without antecedent history of epileptic seizures (Thomas et al 1992; Thomas and Andermann 1994; Thomas 1999). Most of the patients have a history of psychiatric disorders, and the main cause of absence status epilepticus is withdrawal of benzodiazepines. Thomas and colleagues reported absence status epilepticus in 11 middle-aged patients (10 female, 1 male; mean: 58.6 years) without a history of seizures (Thomas et al 1992). Absence status epilepticus coincided with benzodiazepine withdrawal in 8 cases. Cofactors included excessive use of mainly psychotropic drugs, hypocalcemia, hyponatremia, and chronic alcoholism. CT demonstrated mild cerebral atrophy in 6 cases. There was no recurrence, even without chronic antiepileptic treatment. The impairment of consciousness was mild, more often moderate, and rarely reached severe states of the patient becoming bedridden, stuporous, and incontinent. Half of the patients also had mainly facial myoclonic jerks, and one-third had automatisms. One-fourth of patients had GTCS either prior to or during the absence status epilepticus. The EEG pattern varied with continuous or more often short, repetitive recurrent bursts of generalized 0.5 Hz to 4 Hz spike- or polyspike-and-slow waves.

Typical absence status manifested as prolonged confusional state with continuous 3 Hz spike-and-slow waves is also well documented after metrizamide myelography in nonepileptic patients (Vollmer et al 1985; Obeid et al 1988). The clinical and EEG features are easily reversible with diazepam intravenously.

Antiepileptic medication. There is an increasing number of reports of absence status epilepticus induced by certain antiepileptic drugs introduced for the treatment of "epilepsy". Vigabatrin and tiagabine are notable examples (Panayiotopoulos et al 1997a; Ettinger et al 1999; Knake et al 1999; Panayiotopoulos 2005a). They even induce "de novo" absence status in patients with partial seizures. Despite their pro-absence effect, these drugs are used for the treatment of idiopathic generalized epilepsy, because the official bodies are casual in appropriately informing physicians regarding treatment and other respects of "epilepsies" (Panayiotopoulos 2005a). The treatment of "epilepsy" is different in partial from generalized epilepsies.

Absence status epilepticus in comatose or critically ill patients. Comatose, mainly after severe brain anoxia, or critically ill patients may have EEG features of absence status with continuous generalized spike and wave complexes at 1 Hz to 3 Hz. When clinically possible to determine, this may be associated with additional impairment of consciousness and segmental facial, trunk, or limb jerking. These features are usually associated with a fatal outcome. Prognosis does not appear to improve with treatment.

DIAGNOSTIC WORKUP

In idiopathic (typical) absence status epilepticus, all patients by definition are of normal physical and mental state and have normal brain imaging. Ictal EEG confirms the diagnosis with continuous, greater than 2.5 Hz generalized spike-and-slow wave complexes.|{diagram:asep1.bmp}{caption:Typical absence status epilepticus in idiopathic generalized epilepsy with phantom absences}{label:Top: Video-EEG prior to diazepam. There was continuous spike and occasional polyspike and slow wave activity mainly at 3-Hz that lasted until the administration of diazepam. Note also slower or faster components and some topographic variability of the discharge. The patient was fully alert, attentive, and cooperative. Movements and speech were normal. There were no abnormal ictal symptoms other than severe global memory deficit and global diminution of content of consciousness. She was unable to remember her name, how many children she had, date, and location. She could not perform simple calculations but could repeat up to 5 numbers given to her. She could read text correctly, and she wrote her address correctly, although she could not remember it on verbal questioning. She did not know where she was, but given the choice between various locations, she correctly recognized that she was in the hospital. Bottom: Relative normalization of the EEG started within a minute from onset of diazepam administration and the patient was able to say the correct date, her address, the name of the hospital and that she had one child and her name. Note in EEG the fragmentation of the discharge and the reappearance of alpha rhythm. She continued having problems with calculations and there were still some memory disturbances even after the intravenous administration of another 5 mg of diazepam and 400 mg of sodium valproate. However, she was sufficiently well to be allowed to leave hospital with her husband and she recovered completely at home.|{diagram:asep3.bmp}{caption:Typical absence status epilepticus in idiopathic generalized epilepsy with phantom absences (2)}{label:EEG (top) of absence status and "interictal video EEG" (bottom) with phantom absences of a woman who had her first absence status epilepticus followed by a generalized clonic-tonic seizure at age 56 years. Initially, we erroneously classified her as de novo absence status epilepticus instead of idiopathic generalized epilepsy with phantom absences. This mistake became apparent when interictal video-EEG demonstrated absences manifested with mild cognitive impairment and eyelid fluttering (bottom). In reviewing this video-EEG with the patient and her daughter, they recognized that these mild absences were occurring many years prior to the absence status epilepticus. Note the similarity between the EEG discharge of absence status epilepticus (top) and typical absence seizure (bottom).}| Ictal EEG during the absence status may consist of repetitive discharges of multiple spikes and slow waves.|{diagram:asep4.bmp}{caption:Absence status epilepticus with repetitive discharges of unclassified generalized epilepsy}{label:Continuous recording from video-EEG of a 48-year-old woman with unclassified absences and GTCS from age 11 years. She realized from previous experiences that she was in absence status epilepticus when she felt “weird, like in a trance, missing pieces of conversation,” and she went to the hospital. Despite written instruction, no diazepam was administered. She was alert, attentive, cooperative, and well-behaved, but she seemed depressed. Movement and speech were normal. She was able to count with no errors except when the discharges between arrows occurred. During these discharges, eyes, and sometimes mouth, would tonically open with a slight retropulsion of the head. Video-EEG was recorded 7 hours from onset of symptoms, which ended with a generalized tonic clonic seizure one hour later.}|Interictal EEG of idiopathic generalized epilepsy usually shows brief discharges with similar characteristics as those of the ictal EEG.|{diagram:asep6.bmp}{caption:Interictal EEG of idiopathic generalized epilepsy with phantom absences}{label:From interictal video-EEG. Brief generalized discharges of 3 Hz spike and slow waves lasting 2 to 3 seconds without apparent clinical manifestations. Similar abnormalities were recorded in 1972 and again in 1997. Note the similarity of the discharge with the ictal and immediately post-diazepam EEG. The only significant difference is duration, brief interictally, continuous for hours ictally.}|

In symptomatic absence status epilepticus, video-EEG may be essential for diagnosis. Also, a high resolution MRI or positron emission tomography may be needed because of the possibility of a distinct epileptogenic focus amicable to surgery.

PROGNOSIS AND COMPLICATIONS

Prognosis depends on the type of absence status epilepticus and syndrome. It may occur only once in a lifetime (situation related); it may be infrequent or preventive (as in most cases of idiopathic generalized epilepsy with typical absences); it may be frequent and intractable (which is often the case with symptomatic generalized epilepsies and atypical absences); or it may be associated with death due to the underlying severe medical condition (as in absence status epilepticus of severe brain anoxia).

Absence status epilepticus often terminates spontaneously or with a generalized tonic-clonic seizure. In most cases of idiopathic absence status epilepticus, the patient is aware of this condition and the risk of ending with GTCS. The role of self-administered drugs for its termination should be addressed.

MANAGEMENT

Absence status epilepticus of any cause is treated with intravenous diazepam, other benzodiazepines, or sodium valproate, but this may be available only in hospitalized patients (Wheless 2003; Panayiotopoulos 2005a).|{diagram:asep1.bmp}{caption:Typical absence status epilepticus in idiopathic generalized epilepsy with phantom absences}{label:Top: Video-EEG prior to diazepam. There was continuous spike and occasional polyspike and slow wave activity mainly at 3-Hz that lasted until the administration of diazepam. Note also slower or faster components and some topographic variability of the discharge. The patient was fully alert, attentive, and cooperative. Movements and speech were normal. There were no abnormal ictal symptoms other than severe global memory deficit and global diminution of content of consciousness. She was unable to remember her name, how many children she had, date, and location. She could not perform simple calculations but could repeat up to 5 numbers given to her. She could read text correctly and she rightly wrote her address though she could not remember it on verbal questioning. She did not know where she was but given the choice between various locations she correctly recognized that she was in the hospital. Bottom: Relative normalization of the EEG started within a minute from onset of diazepam administration and the patient was able to say the correct date, her address, the name of the hospital and that she had one child and her name. Note in EEG the fragmentation of the discharge and the reappearance of alpha rhythm. She continued having problems with calculations and there were still some memory disturbances even after the intravenous administration of another 5 mg of diazepam and 400 mg of sodium valproate. However, she was sufficiently well to be allowed to leave hospital with her husband and she recovered completely at home.}||{video:asep13.avi}{caption:Absence status epilepticus of late onset in idiopathic generalized epilepsy: response to treatment}{label:Sample from video-EEG of a patient immediately after the first intravenous diazepam of 5 mg was administered from 16:33:38 to 16:34:50 . EEG shows relative normalization, the patient has significant improvement but complete recovery did not occur until the next day.}|Rectal preparations of benzodiazepines as soon as the first symptoms of absence status epilepticus appear may stop it, but often this is not applicable (Panayiotopoulos 2005a). Some patients may prevent GTCS with sodium valproate (usually double of the daily dose) at the onset of absence status. A practical therapeutic option is buccal application of midazolam, which may stop absence status epilepticus and prevent the development of GTCS (Scott et al 1999). Ten milligrams of midazolam solved in a 2 ml peppermint (otherwise it smells and tastes terribly) should be swirled in the mouth for 4 to 5 min and then spat out. Midazolam is not yet licensed for this type of treatment.

Absence status epilepticus is syndrome and seizure related. Appropriate treatment of the responsible syndrome will also prevent absence status (Panayiotopoulos 2005a).

Sodium valproate and ethosuximide are the established antiepileptic drugs licenced as monotherapy for absence seizures (Posner et al 2003; Panayiotopoulos 2005a). Sodium valproate controls absences in 75% of patients, GTCS in 70%, and myoclonic jerks in 75%, but because of adverse reactions may be undesirable for women. Ethosuximide controls 70% of absences but has no effect on GTCS.

If patients with IGE are unwilling to receive treatment with sodium valproate, newer antiepileptic drugs levetiracetam, lamotrigine and topiramate are effective therapeutic drug agents (Table 2) (Panayiotopoulos 2005a). Levetiracetam, because of its efficacy in all seizures, photosensitivity and safer adverse reactions profile appears to be the most promising substitute for valproate (Krauss et al 2003; Kasteleijn-Nolst Trene and Hirsch 2003; Gallagher et al 2004; Panayiotopoulos 2005a). Lamotrigine is effective in absences and GTCS but often exaggerates myoclonic jerks (Carrazana and Wheeler 2001). Topiramate is effective in generalised tonic clonic seizures but it is associated with significant adverse reactions both in children and adults.

Table 2. Efficacy and safety of new antiepileptic drugs in idiopathic generalized epilepsy and photosensitivity in comparison with valproate

Modified from Panayiotopoulos (2005) with the permission of Bladon Medical Publishing.

Choice between these antiepileptic drugs depends on other than absences associated generalized seizures (myoclonic jerks and GTCS) and adverse reactions. Combination of 2 antiepileptic drugs may be needed for resistant cases. Minute doses of lamotrigine added to sodium valproate have a dramatic beneficial pharmacodynamic effect; small doses are also mandated because of increased adverse effects (Panayiotopoulos 2005a). Levetiracetam alone or in combination with lamotrigine or other antiabsence antiepileptic drugs may prove a potent efficacious option if sodium valproate is unwanted (Panayiotopoulos 2005a).

Clonazepam, particularly in absences with myoclonic components or idiopathic generalized epilepsy with myoclonic jerks is a useful adjunctive drug. Acetazolamide may be also be used as an add-on drug (Panayiotopoulos 2005a).

Contraindicated drugs. Contraindicated drugs in syndromes with absence seizures, which make seizures worse and may induce status epilepticus are: carbamazepine, gabapentin, oxcarbazepine, phenytoin, phenobarbitone, vigabatrin, tiagabine irrespective of cause and severity (Panayiotopoulos 2005a). In particular, vigabatrin and tiagabine, which are GABA agonists, may induce absence seizures and absence status epilepticus.

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ILAE

ILAE Copyright Notice

ABBREVIATIONS

CT:computed tomography
GTCS:generalized tonic-clonic seizures
MRI:magnetic resonance imaging

SYNONYMS

Petit mal status

SUBTOPICS

Absence status epilepticus in comatose or critically ill patients
Cryptogenic or symptomatic (atypical) absence status epilepticus
Drug or electrolyte and metabolic disturbances
Generalized tonic-clonic seizures associated with idiopathic absence status
Idiopathic (typical) absence status epilepticus
Impairment of consciousness and myoclonic jerks
Situation-related absence status epilepticus

MAJOR KEYWORD DESCRIPTORS

atypical absences
cryptogenic epilepsies
excitatory neurotransmissions
frontal lobe epileptogenic foci
generalized absence seizure
idiopathic generalized epilepsy
impairment of cognition
impairment of consciousness
impairment of memory
inhibitory neurotransmissions
photosensitivity
spike-and-slow waves
symptomatic epilepsies
tonic-clonic seizures
typical absences

MINOR KEYWORD DESCRIPTORS

altered state of consciousness
behavioral abnormalities
confusion
epilepsy
jerks

AGE OF PRESENTATION

0-01 month
01-23 months
02-05 years
06-12 years
13-18 years
19-44 years
45-64 years
65+ years

AGE OF TYPICAL PRESENTATION

01-23 months
02-05 years
06-12 years
13-18 years
19-44 years
45-64 years

GLOSSARY - ILLUSTRATION  CAPTIONS

Figure 1
Title: Typical absence status epilepticus in idiopathic generalized epilepsy with phantom absences

Legend: Sample from video-EEG of illustrated clinical vignette. The recording started at 16:10 and the first intravenous diazepam of 5 mg was administered between 16:33:38 to 16:34:50.

Top: Video-EEG prior to diazepam. There was continuous spike and occasional polyspike and slow wave activity mainly at 3 Hz that lasted until the administration of diazepam. Note also slower or faster components and some topographic variability of the discharge. The patient was fully alert, attentive, cooperative, well behaving and in good mood. Movements and speech were normal. There were no abnormal ictal symptoms such as segmental or generalized motor ictal symptoms other than severe global memory deficit and global diminution of content of consciousness. She was unable to remember her name, how many children she had, date and location. She could not perform simple calculations such as subtracting 7 out of 20 but could repeat up to 5 numbers given to her. She could read text correctly and she rightly wrote her address though she could not remember it on verbal questioning. She did not know where she was but given the choice between various locations she correctly recognized that she was in the hospital.

Figure 2
Title: Atypical absence status in symptomatic generalized epilepsy

Legend: Video-EEG from a 10 years old girl who had severe mental and physical deficits due to birth related brain anoxia. Slow spike and slow wave activity is continuously recorded. Despite video-EEG monitoring, it was difficult to detect overt clinical manifestations. The girl was probably less communicative and quieter during the discharge, which ended when she was alerted by the pain from inserting the drug infusion tube.

Figure 3
Title: Typical absence status epilepticus in idiopathic generalized epilepsy with phantom absences

Legend: EEG (top) of absence status (aged 56 years) and 'interictal video EEG' (aged 61 years) with phantom absences (bottom) of a woman who had her first ever absence status epilepticus followed by a GTCS at age 56 years. Initially, we erroneously classified her as de novo absence status epilepticus instead of idiopathic generalized epilepsy with phantom absences. This became apparent when interictal video-EEG demonstrated absences manifested with mild cognitive impairment and eyelid fluttering (bottom). In reviewing this video- EEG with the patient and her daughter, they recognized that these mild absences were occurring many years prior to the absence status epilepticus, which, therefore, was not de novo. She has three nephews, each from a different sister, with infrequent, spontaneous or provoked, generalized tonic-clonic seizures of mainly late onset.

Note the similarity between the EEG discharge of absence status epilepticus (top) and typical absence seizure (bottom).

Figure 4
Title: Absence status epilepticus with repetitive discharges of unclassified generalized epilepsy

Legend: Continuous recording from video-EEG of a 48 years old woman with unclassified absences and generalized tonic-clonic seizures from age 11 years. She realized from previous experiences that she was in absence status epilepticus 'feels weird, like in a trance, missing pieces of conversation' and came to hospital. Despite written instructions no diazepam was administered. She was alerted, attentive, cooperative, well behaving but seemed depressed. Movement and speech were normal. Higher brain function were not appropriately tested. However, she was fully aware who and where she is of the people in the department. She was able to count with no errors except when the discharges between arrows occurred. During these discharges eyes, sometimes also mouth, would tonically open with a slight retropulsion of the head. This was subtle and could not be considered as abnormal without EEG confirmation. Video-EEG was recorded 7 hours from onset of symptoms that ended with a generalized tonic-clonic seizure one hour later that we erroneously failed to prevent.

Note that contrary to patient of fig 1 with continuous rather monomorphic spike and slow wave complexes, the discharges here are repetitive with normal rhythms in between.

Figure 5
Title: Absence status epilepticus in a comatose patient

Figure 6
Title:Interictal EEG of idiopathic generalized epilepsy with phantom absences

Legend: From interictal video-EEG of patient in fig 1 in 1993. Brief generalized discharges of 3 Hz spike and slow waves lasting 2-3 seconds without apparent clinical manifestations. Similar abnormalities were recorded in 1972 and again in 1997. Note the similarity of the discharge with the ictal and immediately post-diazepam EEG. The only significant difference is duration, brief interictally, continuous for hours ictally.

Figure 7
Title:Transformation from absence to a generalized tonic-clonic seizure

Legend: This is a rare illustration of the transformation of an absence to GTCS. It is from a video-EEG of a 23 years old woman with IGE and absence seizures. On awakening she had numerous absence seizures with complete recovery in between, which is not absence status.

Video-Clips
Video clip 1

Title:Absence status epilepticus of late onset in IGE
Legend for video clip 1. From video-EEG of illustrative case (clinical vignette) in 1991. See also legend of fig 1. She is unable to make simple calculations but she able to correctly write down her address, which she could not remember on verbal questioning.

Video clip 2

Title:Absence status epilepticus of late onset in IGE
Legend for video clip 2. Same patient of clinical vignette. She is unable to remember dates. Also, she could not remember her date of birth and other significant dates from her life.

Video clip 3

Legend for video clip 3. Interview with the daughter of patient in fig 3. The patient is mute and deaf but of normal intelligence and social life.

Legend for video clip 4. Sample from an interview in 1997 with the patient of the clinical vignette.

Legend for video clip 5. Another sample from an interview in 1997 with the patient of the clinical vignette.

Video clip 6

Title:Absence status epilepticus of late onset in IGE: Response to treatment
Legend for video clip 6. Sample from video EEG of the patient of the clinical vignette immediately after the first intravenous diazepam of 5 mg was administered between 16:33:38 to 16:34:50. EEG shows relative normalization, the patient has significant improvement but complete recovery did not occur until the next day.

PERMUTED TOPIC, SYNONYMS, VARIANTS
Absence status epilepticus
status epilepticus, Absence
epilepticus, Absence status
mal status, Petit
status, Petit mal

RELATED TOPICS
Atypical absence seizures
Childhood absence epilepsy
Drug-induced seizures
Epilepsy
Epilepsy with myoclonic absences
Eyelid myoclonia with and without absences
Juvenile absence epilepsy
Myoclonic absences
Myoclonic status
Typical absence seizures

DIFFERENTIAL DIAGNOSIS
idiopathic (typical) absence status epilepticus
complex partial seizures
syndrome of phantom absences
Lennox-Gastaut syndrome
psychotic state or dementia
drug withdrawal
alcohol withdrawal
hypoglycemia
hypocalcemia
uremia
comatose
severe brain anoxia