Typical Absence Status in Adults: Diagnostic and Syndromic Considerations

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1 Epilepsia, 39(): 65-76, 998 Lippincoa Williams & Wilkins, Philadelphia 0 International League Against Epilepsy Typical Absence Status in Adults: Diagnostic and Syndromic Considerations A. Agathonikou, C. P. Panayiotopoulos, S. Giannakodimos, and M. Koutroumanidis Department of Clinical Neurophysiology and Epilepsies, St. Thomas Hospital, London, England Summary: Purpose: To study the electroclinical features of typical absence status (TAS) in adults with syndromes of idiopathic generalized epilepsies (IGEs). Methods: Twenty-one patients with one or more spells of TAS were identified among 36 consecutive adult patients with IGEs. All patients with TAS had comprehensive electroclinical investigations and EEG or video-eeg recorded absences. Results: TAS occurred in 4.4% of 86 patients who had IGEs with typical absences alone or in combination with other seizures presisting in adult life. The prevalence of TAS appeared to be syndrome related, ranging from as high as 57.% in perioral myoclonia with absences and 46.% in phantom absences with GTCS to as low as 6.7% in juvenile myoclonic epilepsy. A varying degree of impairment of cognition was the cardinal clinical symptom shared in all TAS, but corresponding syndromes of IGE were often betrayed by other symptoms such as eyelid or perioral myoclonia. In phantom absences with GTCS, TAS was more numerous (p S 0.05) and more frequently the first overt seizure type (p = 0.006) than in any other IGE. Only in the syndrome of eyelid myoclonia with absences, TAS was always situation related, mainly as a result of antiepileptic drug discontinuation. Conclusions: The clinical EEG semiology and prevalence of TAS appear to be syndrome related with the highest prevalence in the syndromes of perioral myoclonia with absences and phantom absences with GTCS (p = 0.004). Key Words: Typical absence status-nonconvulsive status epilepticus- Idiopathic generalized epilepsies-epileptic syndromes- Adults. Absence status is the commone3t form of nonconvulsive status epilepticus, ranging from 53 to 94% in different studies (-5). It is manifested with prolonged confusional states of varying severity and EEG continuous or repetitive generalized discharges of spikes, multiple spikes, and slow waves. Shorvon (6,7) proposed the following. classification of absence status: Typical (idiopathic) absence status epilepticus occurring in the syndromes of idiopathic generalized epilepsies (IGEs). The EEG discharges are of >.5 Hz. Atypical (cryptogenic and symptomatic) absence status epilepticus, mainly found in epilepsies, such as the Lennon-Gastaut syndrome. The EEG discharges are slow and <.5 Hz. De novo absence status epilepticus of late onset, arising de novo in adults without a history of previous epileptic seizures, mainly as the result of drug discontinuation. Accepted June 0, 998. Address correspondence and reprint requests to Dr. A. Agathonikou at Department of Clinical Neurophysiology and Epilepsies, St. Thornas Hospital, London SEl 7EH, England. 4. Absence status epilepticus occumng in other epileptic syndromes: progressive myoclonic epilepsies, electrical status epilepticus during slow sleep, Landau-Kleffner syndrome, metabolic or degenerative generalized epilepsies, electrographic gtatus. Although it is well documented in the literature (-6), absence status is frequently overlooked. It is erroneously considered as complex partial status or other conditions unrelated to epileptic seizures, such as dementia, psychogenic or other behavior disorder (,0, ). Furthermore, absence status is usually studied in a unitary fashion without consideration of epileptic syndromes. We previously showed that typical absences are not one symptom but a cluster of clinical EEG manifestations that are syndrome related (7-). This may also be the case in absence status, the manifestations of which and its relations to the various syndromes of IGEs are not known. This is a clinical, EEG, and video-eeg study of typical absence status (TAS) in with syndromes Of IGEs. 65

2 66 TYPICAL ABSENCE STATUS IN ADULTS METHODS AND PATIENTS Patient population The initial study population consisted of 40 consecutive patients, older than 6 years, who had definite epileptic seizures. They were evaluated from 989 to 994 in a new clinic for epileptic disorders at St. Thomas Hospital. This is a major general teaching hospital in London for patients of all ages in the National Health Service. The clinic for epilepsies was established by one of us (C.P.P.) in February 989, supported by a Special Trustees of St. Thomas grant for a prospective study on the syndromic classification of the first,000 patients with epilepsies. Referral pattern Most of the patients, mainly adolescents and adults, are referred from general practitioners, neurologists, pediatricians, other specialists, and the accident and emergency department of St. Thomas Hospital. Approximately 0% of the patients are tertiary referrals from outside the catchment area of the hospital or private patients. Clinical evaluation All patients are examined by the senior author (C.P.P.) alone or together with the clinical and research fellows of the department, who are all qualified neurologists or pediatricians trained in pediatric neurology. Patients, relatives, and witnesses are interragated through free-form interviews regarding clinical manifestations, major or minor seizures, circadian distribution, precipitating factors, possible causative factors, and family history. The clinical information is often supplemented with written accounts of the seizures and related factors and, when possible, with homemade videos of the clinical events. Patients with ICES and absences often have additional semistructured written or verbal interviews. More recently, all patients are requested to complete a detailed structured questionnaire. Scrutiny of old medical and EEG records is systematically sought. All patients have at least one follow-up per year. EEG evaluation All patients have at least one EEG or video-eeg, and if this is not conclusive, an EEG during sleep and awakening is performed. In view of our particular interest in IGE and typical absences (7-), all patients with IGEs also have serial video-eeg recordings and often video- EEG after partial sleep deprivation followed by 30 min recording on awakening, especially when prolonged routine video-eeg fails to record ictal phenomena. Cognitive impairment during 3- to 4-Hz spike-wave discharges is routinely tested by asking the patients to count their breaths during hyperventilation ( 8). Optional in- termittent photic stimulation is performed. Video-EEGs are appropriately tailored for patients with precipitating factors such as photosensitivity, fixation-off sensitivity, pattern sensitivity, reading, menstruation, awakening, and sleep. Brain imaging High-resolution magnetic resonance imaging (MRI) is obtained from all patients with partial and late-onset seizures, and it is often performed for patients with IGEs, particularly with seizures resistant to treatment, focal EEG, and seizure elements. Positron-emission tomography is often acquired for patients with intractable partial or cryptogenic/symptomatic generalized seizures. Diagnostic aim Our prospective aim for all patients is to establish a syndromic diagnosis according to strict clinical and video-eeg criteria (9,); when this is not possible, a seizure-symptom categorization is attempted (3). With this approach, we were able to show that some of the unclassified patients have a nonfortuitous clustering of clinical EEG features indicating that they belong to previously unrecognized by the International League Against Epilepsy (ILAE) epileptic syndromes () such as eyelid myoclonia with absences (4,5), perioral myoclonia with absences (6), IGE with phantom absences, generalized tonic-clonic seizures (GTCS), and often absence status (7). Data storage All data are stored in a database system called Epicare, which is specifically designed for patients with epileptic syndromes by Sanofi-Winthrop. Typical absence status Twenty-one of the first 40 consecutive patients older than 6 years fulfilled the criteria of TAS. This was clinically defined as a state lasting for >30 min, characterized by clouding of consciousness varying from mild torpor to deep stupor in the domain of IGEs. Inclusion criteria were (a) one or more spells of typical absence status; (b) clinical and EEG features consistent with the diagnosis of IGE (,3); (c) present age older than 6 years; and (d) normal neurologic state and intelligence. All patients with TAS had complete clinical and neurophysiologic investigations also including regular hematologic, biochemical, and antiepileptic drugs (AEDs) screening, routine EEG, video-eeg, and sleep EEG. TASs were documented in each patient with EEG or video-eeg ictal recordings. In all patients, the diagnosis of absence status was made on clinical grounds and confirmed with EEG or video-eeg in six (cases,, 7, 3, 8, and 0). Seventeen of the patients had normal CT or MRI. The information available for all patients with TAS Epilepsia, Vol. 39, NO, I:, 998

3 A. AGATHONIKOU ET AL. 67 was verified and supplemented for 0 of them through new free-form interviews with patients and witnesses. Patients were questioned specifically about TAS precipitants. Sleep deprivation, alcohol indulgence, and emotional stress were considered significant if they occurred in the preceding 4 h. Fatigue, relaxation, and photic stimuli were taken into account if they occurred simultaneous with the onset of TAS. AEDs were considered precipitants if their commencement coincided with increased frequency, severity, or the first episode of TAS. Discontinuation of AEDs was considered a precipitant if an episode of TAS occurred within a week. A precipitating factor was defined as consistent if it provoked more than one-half of the patient s episodes of TAS. Syndromic diagnosis was established according to strict clinical and video-eeg criteria (7-3). Four more adult patients with absence status were excluded because three had borderline normal intelligence (cryptogenic generalized epilepsies), and one had a frontal lobe low-grade glioma. The mean follow-up period from entry to the epilepsy clinic was 5 years (range, 3-7 years; SD,.58 years). Statistical analysis The x test was used to examine associations between categoric variables or, where appropriate, Fisher s Exact test. To investigate differences in continuous variables between two groups, the Mann-Whitney test was used for nonnormally distributed variables, and the t test for normally distributed variables. RESULTS Prevalence The prevalence of TAS was 5.4% among 36 adult patients with IGE. However, TAS occurred only among 86 patients (prevalence, 4.4%) who had typical absences alone or in combination with other seizures persisting in adult life. Typical absence status: Sex, age at onset, frequency, duration, severity, clinical manifestations There were women and nine men with TAS. The mean age at the last follow-up was 44.5 years (range, -73 years; SD, 6.9 years). All were of normal neurologic state and intelligence, and most were successful in their occupations. The mean age of onset of typical absences, which could be determined in 3 patients, was 9 years (range, -0 years; SD, 4.5 years). All patients had GTCS at mean age of onset of 0.6 years (range, 5-56 years; SD,.3 years). In seven patients (cases,, 5, 6, 8, 9, and ), GTCSs were always preceded by TAS. The mean age of onset of TAS was 9.5 years (range, 9-56 years; SD, 4.8 years). The mean number of TAS episodes was 0.9 (range, -40; SD, ). The minimal duration of TAS ranged from 30 min to day (mean, 3.7 h) and the maximal duration varied from 30 min to 0 days (mean, 6.5 h) (Table ). The cardinal symptom of TAS was a mild to marked clouding of consciousness, with slow ideation, withdrawal, slowness of responses, confusion, and occasionally experiential phenomena (Table ). In five patients, during the same episodes of TAS, impairment of consciousness fluctuated between mild and marked clouding. In four other patients, there was a gradual deterioration of impairment of consciousness leading, in one of them, to somnolence. Verbal functioning was relatively preserved, varying from mild slowness and poverty of speech to stereotyped monosyllabic speech. Limb myoclonic jerks and perioral or eyelid myoclonia occurred in nine patients and were consistent symptoms in patients with the corresponding syndromes of juvenile myoclonic epilepsy (JME), perioral myoclonia with absences (PMA), and eyelid myoclonia with absences (EMA). Patients with the syndrome of phantom absences with GTCSs had impairment of consciousness without segmental or generalized myoclonus. The degree of amnesia for the TAS varied. All but one (case 7) of the patients were to some extent aware of their situation and of the impending GTCS. Patient 7 had total amnesia of an attack that lasted for days and was recorded on EEG. Simple gestural and ambulatory automatisms occurred in three patients (cases, 0, and ). Patient 0 had consistent diarrhea during the TAS, and patient four had pseudo-ataxic gait. Visual hallucinations with experiential phenomena were consistent clinical features in patient 5, who was previously detailed (8). In eight (38%) patients, TAS always ended with GTCS. Frequent or occasional termination with a GTCS occurred in another patients. Only patient 7 had a single episode of TAS that resolved without GTCS. In patients 7 and 8, the TAS could be heralded or punctuated by CTCS. In seven (33.3%) patients (cases,, 4, 5, 6, 6, and ), TAS was the first overt sign of an epileptic disorder. In the remaining 4 patients, the mean years of preexisting absences or GTCS was. years (range, 3-45 years; SD, 3.4 years). Precipitating factors A consistent precipitant was identified in only three patients. Patient 5 had nearly all episodes of TAS occurring during the first days of menstruation, and in patient 4, the two episodes of TAS occurred as a result of AEDs discontinuation. Sleep deprivation associated with alcohol indulgence precipitated the singular TAS of patient 0 (Table l). Epilepsia. Vol. 39, NO., 998

4 68 TYPICAL ABSENCE STATUS IN ADULTS TABLE. Clinical profile of the patients Duration of TAS Age at onset of seizures (yr) Sex! Number Min Max Motor features TAS to Pts age (yr) ABS GTCS TAS TASflife (h) (h) during TAS GTCS Precipitating factors Phantom absences and GTCS Fl73-30 F W Fl W4-8 6 W34-5 Perioral myoclonia with absences 7 Fl33 8 W W Fl5 0 0 Juvenile myoclonic epilepsy W69 7 Fl5 Eyelid myoclonia with absences 3 Fl Fl3 9 Juvenile absence epilepsy 5 Fl MI4 0 0 Absences with photosensitivity 7 Fl Unclassified T 8 W F F50 43 W >I0 0 A > Automatisms Pseudoataxia Rolling up of eyeballs Perioral myoclonus Perioral myoclonus Perioral myoclonus - MJ - Eyelid myoclonia, MJ Eyelid myoclonia MJ Few MJ Intermittent eyelid fluttering Automatisms, intermittent tonic spasms of the neck Automatisms Always usualy /4 l4 Yes Yes Always Once Once Always Yes No Always Always Once CZP withdrawal Sleep deprivation, alcohol, relaxation, fatigue Alcohol Alcohol, relaxation, fatigue Once VPA withdrawal, VGB once, fatigue Sleep deprivation and alcohol once, febrile illness once Stress Sleep deprivation and alcohol Alcohol, stress Once VGB and pregnancy Once sleep deprivation and awakening, once ESM withdrawal Once withdrawal ESM, once withdrawal PRM Menstruation Sleep deprivation, alcohol, stress Once ESM withdrawal, once alcohol and sleep deprivation, strtss Italics indicate probable, nonconsistent precipitants. -, unknown; ABS, absences; GTCS, generalized tonic-clonic seizures; TAS, typical absence status; MJ, myoclonic jerks; CZP, clonazepam; VPA, sodium valproate; VGB, vigabatrin; ESM, ethosuximide; PRM, primidone. AEDs discontinuation was the precipitant for single episodes of TAS in patients,6, 3, and 0. Introduction of vigabatrin (VGB) caused the worst-ever episode of absence status and GTCS in patient 6 (9), and one of two episodes of TAS in patient. Other precipitants for single episodes of TAS, and probable, nonconsistent precipitants are listed in Table. In six patients (cases I, 7, 6, 7, 8, and 0) with recurrent or singular TAS, no precipitants were identified. Misdiagnosis In only four (9%) patients, TAS was recognized by the treating physicians. In seven patients, TAS was misdiagnosed as depression (three patients), complex partial status (two patients), and postictal confusion (two patients). In the remaining 0 patients, TAS was ignored. The syndromic classification and the prevalence of absence status in idiopathic generalized epilepsies with absences The syndromic classification and the prevalence of typical absence status among 86 adult patients with IGE with absences were as follows (Table ). Phantom absences with GTCS Thirteen ( 5. %) patients had phantom absences and GTCSs (7). Six (46.%) of them also experienced TAS with moderate impairment of cognition. of the patients had regional or generalized myoclonus during TAS. The mean age at onset of TAS was 33.8 years (SD, 6.4; range, 5-56 years). The episodes of TAS were more numerous (mean, 9.5 per life; median, 5; range, -40) than in other IGEs (mean, 7.4 per life; median, 4; Epilepsia, Vol. 39, No., 998

5 A. AGATHONIKOU ET AL. 69 TABLE. Severity of impairment of consciousness and descriptions of the absence status Marked clouding. Goes into a dreamy state. Able to answer questions only in a vague manner. Dresses herself in a peculiar way (trousers over pajamas) Marked clouding. Confused, cannot recognize people other than close relatives, disorientated in time and place, quiet 3 Mild clouding. Slow-down in his behavior, cannot communicate well (muddle of words). Describes a feeling of closeness, as in a very hot summer evening. When he feels it, he goes out for a walk, which may prevent the GTCS. His secretary could recognize this situation and predict the fit 4 Mild and gradually marked clouding. Confused, makes coffee twice, fades away mentally and physically, unable to control her limbs. Disorientated in place and time 5 Mild clouding. Sensation of viewing the world through a different medium and 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, my heart will beat faster, and I feel hotter. This may go on for several hours until a fit occurs 6 Mild clouding. My mind slows down. Able to understand, but it takes much longer to formulate answers. Objects in the central visual field seem to vibrate at times 7 Fluctuating mild to marked clouding. She was feeling drunk. Came to hospital on her own. At times unable to understand basic commands. Continuous perioral myoclonus. Terminated in GTCS 8 Mild clouding. Lip twitching so intense that I could not drink my coffee. I was able to talk with people. This continued for the whole day, and a GTCS occurred 9 Marked clouding. Describes a funny feeling and was unable to elaborate events. Lip twitching. He did not remember conversations. Terminated h later with GTCS 0 Mild cloudmg. Dizziness. Could not communicate properly. Describes a strange feeling of not being herself Gradually marked clouding. Prolonged episodes in which I begin to feel edgy, worry and uncomfortable. This becomes gradually more and more intense, I am jerking. I withdraw to a safe plae for the fit Mild clouding. Feels muzzy headed, strange, slow, not myself for a whole day before a GTCS 3 Fluctuating mild clouding. I was unable to look after myself, drowsy and off-work for a few days. My eyes were continuously jerking 4 Mild clouding. I became slow but could communicate verbally with other people. My eyes were fluttering, and I had a slight spasm in my neck 5 Fluctuating mild to marked clouding. For to h before a GTCS, my character changes completely, I become extremely snappy, have a severe headache and frequent jerks, mainly in the arms 6 Gradually marked clouding. Felt tired, had great difficulty in concentration. I could hear what the other people were saying, but I had to struggle to find the meaning. Subsequently he became vacant, staring ahead, and had a GTCS 7 Mild to marked clouding. I felt that I was drifting away, became slow in my answers, but I was able to understand and respond. An hour later, she was unable to remember the conversation that she had 8 Fluctuating mild to marked clouding. Many hours before a fit, I am disturbed, vague, uncooperative. My speech is slow and slurred. His physician wrote: He had a GTCS, which had been preceded by some very strange disorientated behavior with a few jerks. For a number of days, he was going in and out of a state of consciousness that the patient believes was an epileptic state 9 Fluctuating mild to marked clouding. I&ecome slightly slow. I am there one second and not the next. This lasts for at least 30 min before a fit 0 Marked clouding I feel confused, like in a trance. I miss pieces of conversation. The patient usually wanders about without having later any recollection of the event Marked clouding and gradually somnolence. Initially he feels vague and detached and complains of dizziness. Gradually, he gets more and more confused, walks around purposelessly, replies yes to any question, and fumbles his clothes. He finally becomes unconscious, lies limp and then rigid for 5 min without clonic convulsions range, -30; p G 0.05). Furthermore, TAS was significantly more often the first overt epileptic manifestation in patients with phantom absences and GTCS (83.3%) than in those with other IGEs (3.3%; p = 0.006). In patients and, video-eeg during TAS showed continuous generalized spike and slow-wave complexes at -3 Hz, identical to that of the phantom absences and interictal generalized discharges (Fig. ). In both patients, the status was rapidly terminated by intravenous administration of diazepam (DZP). Perioral myoclonia with absences Seven (8. %) patients had the syndrome of perioral myoclonia with absences (6). They all had absences with perioral myoclonia and infrequent GTCSs. Four (57.%) of them and probably another two also experienced TAS. In two of the four patients, perioral myoclonia was more apparent than the associated impairment of cognition. EEG during the TAS in patient 7 showed continuous generalized polyspikes and slow-wave com- plexes at.5-4 Hz accompanied by perioral twitching (Fig. ). The amplitude and number of polyspikes varied significantly between the complexes. The structure of the complexes was identical to the absence ictal or interictal discharges of previous EEGs. This episode was terminated by a GTCS, but was followed by recurrence of TAS within h. Juvenile myoclonic epilepsy Thirty (34.9%) patients had the classic clinical EEG features of JME with typical absences (30). They all had myoclonic jerks on awakening, and all but two had GTCSs. Only two (6.7%) patients experienced TAS. One of them had minor myoclonic jerks during the TAS. Eyelid myoclonia with absences Eleven (.8%) women had frequent eyelid myoclonia with absences, photosensitivity, and the characteristic eye-closure seizures of eyelid myoclonia and EEG discharges (4,5). All but one had GTCS and five random Epilepsin. Vol. 39, No., 998

6 70 TYPICAL ABSENCE STATUS IN ADULTS Typlcal ebaence etatuo In phantom ebeanrer wlth QTCS Typlcal rbranca rtetur kparloral myoclonla wlth ebrancor FIG.. Upper: Video-EEG of patient during absence status. Note that the discharge is continuous and rhythmic with generalized 3-Hz spike and slow-wave activity. Lower: EEG of patient 7 during absence status. Note that the discharge is continuous and consists of irregular.5- to 4-HZ multiple spike and slow waves. The electrical differences between these two cases are apparent. myoclonic jerks. Two (8.%) patients experienced TAS, which was manifested with severe eyelid myoclonia and mild impairment of cognition. Both of them had two episodes of TAS per life, which were always situation related. Three of four episodes of TAS were precipitated by AEDs discontinuation and the other by sleep deprivation and awakening. In patient 3, routine video- EEG after partial sleep deprivation showed on awakening repetitive (every 4 s) generalized discharges of polyspikes and slow waves, associated with eyelid myoclonic absences lasting for 3-9 s (Fig. ). She was able to count aloud, with a few mistakes, intermittently during the normal intervals. This episode lasted for 30 min and resolved spontaneously. FIG.. Eyelid myoclonia with absences. Video-EEG recording of patient 3 during absence status. There are continuous repetitive discharges of multiple spikes and slow waves associated with eyelid myoclonia and impairment of consciousness. Epilepsia, Vol. 39, No., 998

7 A. AGATHONIKOU ET AL. 7 Juvenile absence epilepsy Ten (.6%) patients had juvenile absence epilepsy. All had severe and frequent typical absences, and all but one experienced GTCS. Two (0%) had TAS manifested with moderate impairment of cognition. Myoclonic jerks occurred in one of them during TAS. IGE with specific modes of precipitation Four (4.6%) patients had absences and GTCS with specific modes of precipitation, mainly flickering lights. Only one patient had a single episode of TAS without apparent precipitants. Unclassified patients with IGE and typical absences Typical absence status occurred in four (36.4%) of (.8%) patients with unclassified forms of IGE with absences. Patient 8, a solicitor, came to the hospital in a mild confusional state for a routine EEG. He wandered around the hospital, unable to find his way to the EEG department, which he knew well from previous visits. The technician thought he was strange and slow. The EEG showed a normal background activity intermingled with pseudorhythmic brief (-.O s) generalized discharges of multiple spikes and slow waves with a repetition rate at per 5 s (Fig. 3). The repetitive complexes were not associated with any regional or generalized myoclonic jerks. He had a GTCS 0 min after the end of the EEG. Follow-up and response to treatment Patients were followed up for an average of 5. years (range, 3-7 years). All but three (85.7%) were free of TAS for > years, and 4 (66.6%) patients were free of all types of seizures during the last year of follow-up (Table 3). Sixteen patients were taking valproate (VPA) in the last year of follow-up. Eleven (68.7%) of them were seizure free. DISCUSSION All patients had IGE () with typical absences confirmed with EEG or video-eeg and GTCS. All had normal mental and neurologic status, and 7 had brain imaging, which also was normal. Only six patients had EEG confirmation of TAS, but there should be no doubt for the diagnosis of the other 5. Several stereotyped and prolonged episodes of altered consciousness, often with eyelid, perioral, or limb jerks and usually terminating with a GTCS are probably pathognomonic of TAS for patients with definite IGE with typical absences (0). Epilepsia, Vol. 39, No., 998

8 7 TYPICAL ABSENCE STATUS IN ADULTS TABLE 3. Antiepileptic drugs, treatment profile, and outcome AEDs on AEDs last Outcome last year Patients referral Other used AEDs follow-up of follow-up PRM Nil PHT PHT Nil PHT, VPA CBZ PHT VPA, PHT CBZ PHT, PB VGB, CLB CBZ ESM, PRM CBZ VPA, PHT VPA PHT, CBZ VPA PHT, PB, ESM CBZ SUL, PB, PHT VPA, LTG VGB PB, PHT VPA PHT, PRM ESM PHT, PB VPA VPA VPA, CZP VPA, CLB PHT? LTG VPAI VPA, LTG. Poor compliance VPA, CZP VPA?, PHT, LTG VPA, Poor compliance PHT, PB, CZP, rectal DZP VPA, CLB, AZM. Poor compliance VPA, CZP VPA, ESM, PRM VPA, CBZ, CLB LTG VPAI VPA, CBZ, PHT VPA? PB, PHT, ESM, CZP VPA Single GTCS Frequent TAS Infrequent TAS and absences Infrequent absences Absences Infrequent MJ, and absences Convulsive status VPA, valproate; PHT, phenytoin; PB, phenobarbitone; ESM, ethosuximide; PRM, primidone; VGB, vigabatrin; CZP, clonazepam; CLB, clobazam; AZM, acetazolamide; LTG, lamotrigine; SUL, sulthiame, DZP, diazepam;?, increase of daily dose; MJ, myoclonic jerk. All the patients of this study shared the following characteristics: (a) history of other types of primarily generalized seizures; (b) EEG consistent with IGE; (c) EEG confirmation of typical absences; (d) frequent termination of TAS with GTCS; (e) usually moderate or no amnesia of the attack, in contrast to complex partial status (6); (0 relative preservation of verbal functioning, in contrast to complex partial status (7); (g) recovery from the attacks that do not culminate in a GTCS without postictal confusion, in contrast to complex partial status (3); (h) no cycling between unresponsiveness and partial responsiveness, which mainly occurs in complex partial status (3); (i) lack of complex partial seizures; and (i) normal neuroimaging. Furthermore, in rare cases with hallucinations and experiential phenomena ( 0,8), the intellectual impairment is mild in relation to the severity of the psychic symptoms. For example, patient 5 was able to write his thoughts and feelings and the sequence of ictal events as the attack progressed. This patient with vivid visual hallucinations and experimental phenomena is exceptional and was detailed elsewhere (8) because of the differential diagnosis from complex partial status. The first EEG-recorded classic case of typical absence status was reported by Putnam and Merritt in 94 (8) in a 3-year-old man (case ). Ever since, there have been numerous publications on absence status, grouping together patients with typical, atypical, de novo absence status and complex partial status epilepticus [see for review Shorvon (6,7)]. The syndromic prevalence of TAS may be deduced from reports of individual syndromes (3-44), but a comparative study of TAS in syndromes of IGEs has not been reported. Typical absence status occurred in 4.4% of our adult patients with IGE and typical absences. This is compatible with previous reports varying from 38% (40), 33% (44), to 0% (8). However, our study indicates that TAS is syndrome related, with the highest prevalence in perioral myoclonia with absences (57.%) and phantom ab sences with GTCS (46.%; p = 0.004). PMA is a newly described syndrome, not yet recognized by the ILAE (), manifested with typical absences with ictal rhythmic perioral jerking and onset in childhood or early adolescence (6). Absences persist in adult life, often with infrequent GTCS. Perioral muscle twitching is consistently reported during TAS. With the ILAE classification (), some of these patients would have been classified as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE). Phantom absences with GTCS and often absence status (7) may also be an unrecognized syndrome of IGE in adults, manifested with mild typical absences that are inconspicuous to the patient and imperceptible to the observer (phantom absences), infrequent mainly lateonset GTCS, and often typical absence status. Mild to moderate impairment of consciousness is the cardinal symptom of TAS, which is significantly more numerous (p S 0.05) and more frequently the first overt seizure type (p = 0.006) than in any other IGE. Janz et al. (39) reported that 7.4% of 53 patients with nonpyknoleptic absences (mean age of onset of absences, 3.3 years; range,4-30 years) had TAS. It is possible that some of these patients with TAS and mild absences that may easily escape notice by the patient and the doctor belong to this group of phantom absences with GTCS. Epilepsia, VoI. 39, No., 998

9 A. AGATHONIKOU ET AL. 73 Similar cases may be found in reports of patients with TAS as the major presenting symptom, infrequent GTCS and EEG sub-clinical generalized spike-wave discharges (45). It may be difficult to differentiate TAS of this form of IGE from de novo absence status of late onset, which is a situation-related nonconvulsive generalized status epilepticus with low risk of recurrence, affecting mostly middle-aged or elderly women without epileptic antecedents (46,47). GTCS may occur during the de novo absence status, but neither initiating nor terminating the status, as in TAS (6,7,46). Phantom absences may have been overlooked in some cases of de novo absence status mainly associated with recurrence and no detectable precipitating factors. Patient had her first TAS at age 56 years. Six months later, a second episode was due to abrupt clonazepam discontinuation. A diagnosis of de novo absence status could be justifiable. However, routine video-eeg after her first TAS documented mild absences, which her daughter retrospectively recognized began many years before the onset of TAS. In EMA (4,5), another IGE syndrome not yet recognized by the ILAE (), seizures consist of eyelid myoclonia often associated with absences. They are characteristically precipitated by eye-closure and lights and persist in adult life. In two of our patients who developed TAS, eyelid myoclonia was the most characteristic symptom associated with mild impairment of consciousness. TAS in EMA was always situation related, mainly as a result of AEDs discontinuation. TAS in EMA was previously reported (4), consisting, as in patient 3, of frequent repetitive brief, eyelid myoclonic seizures. In all relevant reports of TAS, myoclonic jerking of the eyelids and perioral muscles is considered a common ictal manifestation (-7,9-6). In our series, eyelid or perioral myoclonia occurred exclusively in TAS of patients with EMA or PMA, and they are probably pathognomonic for these syndromes. In JAE, TAS is relatively infrequent (0%), which is somewhat at variance with other reports of a higher prevalence. This should be attributed to different diagnostic criteria for JAE. Janz et al. (39) reported TAS in 7.4% of patients with nonpyknoleptic absences versus 3% with pyknoleptic absences of earlier onset. Wolf and Inoue (40), in their study on the therapeutic response of 9 adult and adolescent patients with absence seizures, reported that 87 (38%) had TAS. Reutens and Berkovic (43) reported TAS in 9% of patients with absences alone or in combination with GTCS, and onset of IGE between the ages of 8 and 0 years. The prevalence of TAS was 6% and % in patients with a peak onset of absences in childhood varying from to 7 years (36) and -5 years (38), respectively. In our study, only six (8.6%) of patients with TAS had onset of absences before age 0 years. of them had the electroclinical features of CAE (7,9). Loiseau et al. (4), with similar classification criteria for CAE and JAE as ours, did not find a single case of TAS in 5 cases of CAE and only two (3.%) of 6 patients with JAE had TAS. In JME, typical absence status occurred in 6.7% of patients, characterized by mild to moderate impairment of cognition associated with myoclonic jerks in one of them and inevitably leading to GTCS. The low prevalence of TAS in JME is consistent with previous reports on patients with JME (3-35,43). Predominant myoclonic status, which is more frequent in JME, was not included in this study. However, patients with JME may have long-lasting clusters of myoclonic jerks interspersed with absences (30,48). Andermann and Robb (lo), Roger et al. (ll), and Rohr-Le Floch et al. () described a wide spectrum of altered consciousness during absence status. Fincham et al. (49) reported a woman aged years who could have EEG continuous spike-wave at Hz associated with subtle perceptive and expressive impairment uncovered only with the dichotic listening test. In our study, mild to moderate clouding of consciousness was the most prominent clinical feature of TAS. There was no correlation between the severity of impairment of consciousness during brief typical absence seizures and TAS. Thus, patients with phantom absences may have more severe clouding of cognition than do patients with JAE, who have profound absences. Gastaut and Tassinari (50) reported that only 40% of 48 patients with absence status had the classic continuous spike-wave pattern. However, 30% of these patients had discontinuous patterns consisting of frequent spikewave bursts. Ohtahara et al. (5) proposed subclassification of TAS into petit ma status in cases with frcquent bursts of spike-wave corresponding to a series of absence attacks, and spike-wave stupor in cases in which the spike-wave discharges are uninterrupted, corresponding to a prolonged absence seizure. Ictal EEGs obtained in our study during TAS showed a continuous pattern in three (cases,, and 7) and discontinuous in the other three patients (cases 3, 8, and 0). The repetitive generalized discharges of patients 3 and 0 were so frequently repeated and so prolonged as to create a fixed and lasting condition, which fulfills the criteria of nonconvulsive status epilepticus (350). However, the clinical EEG characteristics of patient 3 with EMA and frequent serial eyelid myoclonic absences (Fig. ) were different from patient 0 with discontinuous pattern but persistent, nonfluctuating mild confusion intermixed with intermittent brief tonic seizures (Fig. 4). Patient 8 had a discontinuous EEG pattern consisting of pseudoperiodic brief discharges associated with nonfluctuating confusion, which again fulfills the clinical criteria of Epilepsia, Vol. 39, No.. 998

10 74 TYPICAL ABSENCE STATUS IN ADULTS FP-F4 F4-C4 C4-P4 P4-0 C3-P3 P3-0 FIG. 4. Video-EEG of patient 0 during absence status. There are continuous, repetitive, and polymorphic generalized discharges of spike/multiple spike and slow waves or generalized paroxysmal fast activity. The patient was mildly confused. Motor ictal symptoms occurred only during the paroxysmal fast activity (arrows) and consisted of tonic eyes and mouth opening with backward head deviation. Onset of typical absence status (TAS) was 7 h before this recording and ended with a generalized tonic-clonic seizure (GTCS) h later. TAS (Fig. 3). A similar case also was reported (0). It is apparent from previous studies and our report that TAS cannot be considered a uniform tondition with specific clinical EEG features. Typical absence status may begin at any time but rarely before age 0 years (0,3). In most of our patients, onset was after the second decade and could occur many years after the onset of absences, or as the first overt seizure type, such as in the majority of patients with phantom absences with GTCS. Although typical absences in IGEs predominate in frequency and severity in childhood and adolescence, it is unknown why TAS mainly occurs in adulthood. The mechanisms responsible for the relatively early drop out of the spike component from the spike-wave complexes and the smooth decline in frequency probably prevent the prolongation of the discharge. Conversely, this phenomenon is not common in typical absences in adults, suggesting a failure of the inhibitory mechanisms of spike-wave discharges as the brain matures (0). However, this does not explain that typical absences in adults are of shorter duration than in children (8,0,,44). The extreme examples of TAS associated with pseudoperiodic brief spike-wave complexes [Andermann and Robb (lo), and our patient 8 may favor different pathophysiologic mechanisms of TAS and absence seizures. Gastaut et al. (5) reported psychomotor slowing in 36% of adults with IGE and persisting absences, almost all of them women, which did not affect job performance. Michelucci et al. (44) reported that frequent absences and repeated TAS in adults seem to predispose to mental slowing. Rabinowicz et al. (53) found that serum neuron-specific enolase, a marker of brain injury and acute seizures, was increased during TAS in a 40-yearold woman with IGE. Moreover, the ensuing GTCS may be associated with severe injury. Therefore, irrespective of whether syndromes of IGE are distinct entities that we support or a biological continuum (54), TAS is a common and undiagnosed condition in IGE, which requires appropriate attention and treatment. It is easy to diagnose on clinical grounds, and patients are aware of it, often helplessly retreating to a safe place to have the major GTCS. This is the first comparative study of the syndromic classification of TAS in adults with IGEs. TAS is a heterogeneous seizure type occurring in all idiopathic absence syndromes in adults. It is suggested that the clinical EEG semiology of TAS is syndrome related, with the highest prevalence in the syndromes of perioral myoclonia with absences and phantom absences with GTCS. Acknowledgment: The Epilepsy Research Foundation is acknowledged for supporting our studies on the epilepsies. Epilepsia, Vol. 39, NO., 998

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