Accelerated Long-term Forgetting Research Articles

Longitudinal study of accelerated long-term forgetting in children with genetic generalized epilepsy: Evidence of ongoing deficits

Accelerated long-term forgetting (ALF) is a recently described memory disorder characterised by adequate recall after short, but not long delays. Currently, the prevailing conceptualisation of ALF is of a seizure related phenomenon. The main aim of this study was to assess whether ALF subsides as epilepsy severity and seizures abate in children with genetic generalized epilepsy (GGE). Eighteen children with GGE were compared over time to 29 healthy controls on a range of cognitive measures. The primary outcome was a modified version of the California Verbal Learning Test for Children with a long delay (seven day) recall component. At approximately two years follow up, ALF was apparent, although epilepsy severity subsided and seizures resolved in many children. This result contrasts with the dominant conceptualisation of ALF being a seizure related phenomenon. Moreover, at follow-up, worse recall at the long delay was related to greater epilepsy severity at baseline and earlier age of seizure onset, but not to being seizure free at follow-up. While at follow-up worse recall at the long delay related to the worse baseline recall at the long delay, this recall did not relate to scores obtained on standardised memory tests at baseline. Our study suggests that ALF may not be seizure related and identifies factors associated with risk of ALF in children with GGE.

Accelerated Long-Term Forgetting Is Not Epilepsy Specific: Evidence from Childhood Traumatic Brain Injury.

Accelerated long-term forgetting (ALF) is characterized by adequate recall after short, but not long delays. ALF is not detected by standardized neuropsychological memory tests. Currently, the prevailing conceptualization of ALF is of a temporal lobe seizure-related phenomenon. Nevertheless, Mayes and colleagues (2003) proposed that ALF may occur when any of the components of the brain network involved in long-term memory formation, or their interaction, is disrupted. This disruption does not have to be caused by temporal lobe seizures for ALF to occur. Here, we investigate this possibility in a group of school-age children who have sustained traumatic brain injury (TBI) (n = 28), as TBI typically disrupts the brain network that is important for long-term memory formation and recall. Healthy control children (n = 62) also participated. Contrary to the dominant conceptualization of ALF being a seizure-related phenomenon, children with TBI showed ALF. Sustaining a severe TBI and diffuse subcortical damage was related to ALF. Individually, 8 of the 13 children with severe TBI presented with ALF. ALF would remain undetected on standardized testing in six of these eight children. One child had the opposite pattern of dissociation, an impaired score on standardized testing, but an average long-term memory score. This is the first study, to our knowledge, to show ALF in patients with TBI, which has remained undiagnosed and untreated in this patient population. Our study also challenges the dominant hypothesis of ALF being a temporal lobe seizure-related phenomenon, and raises a possibility that short-term and long-term memory systems may be independent.

Accelerated Long Term Forgetting in patients with focal seizures: Incidence rate and contributing factors

Accelerated Long Term Forgetting (ALF) is usually defined as a memory impairment that is seen only at long delays (e.g., after days or weeks) and not at shorter delays (e.g., 30min) typically used in clinical settings. Research indicates that ALF occurs in some patients with epilepsy, but the incidence rates and underlying causes have not been established. In this study, we considered these issues. Forty-four patients with a history of focal seizures were tested at 30min and 7day delays for material from the Rey Auditory Verbal Learning Test (RAVLT) and Aggie Figures Test. Recently published norms from a matched group of 60 control subjects (Miller et al., 2015 ) were used to determine whether patients demonstrated ALF, impairment at 30min or intact memory performance. The incidence of ALF in the epilepsy patients (18%) was >3 times higher than normal on the RAVLT, but no different (7%) from the incidence in normal subjects on the Aggie Figures. A different, but again significantly high, proportion of patients (36%) showed shorter-term memory deficits on at least one task. ALF was found mainly in patients with temporal-lobe epilepsy, but also occurred in one patient with an extratemporal seizure focus. Presence of a hippocampal lesion was the main predicting factor of ALF. Many patients with a focal seizure disorder show memory deficits after longer delays that are not evident on standard assessment. The present study explored the factors associated with this ALF memory profile. These new findings will enhance clinical practice, particularly the management of patients with memory complaints.

Frequent sleep-related bitemporal focal seizures in transient epileptic amnesia syndrome: Evidence from ictal video-EEG.

SummaryTwo patients who shared similar presenting clinical features of anterograde and retrograde autobiographical amnesia typical of transient epileptic amnesia (TEA) underwent prolonged video electroencephalogram (VEEG) monitoring and were found to have sleep‐activated epileptiform activity and frequent subclinical bitemporal seizures predominantly during sleep. Case 1 is a 59‐year‐old woman whose presenting complaint was memory impairment. Over 18 months, she had three distinct 8‐h‐long episodes of confusion and disorientation with persistent anterograde and retrograde autobiographical amnesia. VEEG recorded frequent interictal bitemporal sharp waves confined to sleep, and 14 subclinical seizures, also mostly during sleep. Case 2 is a 50‐year‐old woman with known focal epilepsy also presented with memory complaints. Over the course of 1 year, she had two discrete 2‐h‐long episodes of amnesia, with ongoing anterograde and retrograde autobiographical amnesia. VEEG recorded independent bitemporal sharp waves, and 14 subclinical seizures during sleep and drowsiness. Memory impairment improved in both patients with successful treatment of their seizures. Although the etiology of accelerated long‐term forgetting (ALF) and remote memory impairment (RMI) in transient epileptic amnesia (TEA) is unknown, these cases suggest frequent sleep‐related seizures may contribute, and they highlight the importance of video‐EEG monitoring.

Slow wave sleep and accelerated forgetting

We investigated whether the benefit of slow wave sleep (SWS) for memory consolidation typically observed in healthy individuals is disrupted in people with accelerated long-term forgetting (ALF) due to epilepsy. SWS is thought to play an active role in declarative memory in healthy individuals and, furthermore, electrographic epileptiform activity is often more prevalent during SWS than during wakefulness or other sleep stages. We studied the relationship between SWS and the benefit of sleep for memory retention using a word-pair associates task. In both the ALF and the healthy control groups, sleep conferred a memory benefit. However, the relationship between the amount of SWS and sleep-related memory benefits differed significantly between the groups. In healthy participants, the amount of SWS correlated positively with sleep-related memory benefits. In stark contrast, the more SWS, the smaller the sleep-related memory benefit in the ALF group. Therefore, contrary to its role in healthy people, SWS-associated brain activity appears to be deleterious for memory in patients with ALF.

Four-hour delayed memory recall for stories: Theoretical and clinical implications of measuring accelerated long-term forgetting

ABSTRACTIt has been noted that clinical neuropsychological assessment is “blind” to certain abnormalities of consolidation that occur beyond standard 30-min delay intervals. For example, normal forgetting at 30-min delays has been followed by enhanced forgetting at longer delays in temporal-lobe epilepsy, termed accelerated long-term forgetting (ALF). To evaluate whether ALF could be identified in the neuropsychological assessment of a small sample of examinees with head injuries or other neurological diagnoses (n = 42), a 4-hr delayed recall condition was added to the Logical Memory subtest of the Wechsler Memory Scale-Third Edition. A small percentage of examinees (5/42 or 11%), despite exhibiting unimpaired story recall immediately and after 30-min delays, showed increased forgetting when compared with the average retention of stories (M = 0.83, SD = 0.17) after a 4-hr delay. Three of these 5 examinees also had impaired scores on 20-min delayed recall of the California Verbal Learning Test-Second Edition (CVLT-II) and would have been identified as having memory impairment without an extended, 4-hr delayed recall. In fact, the highest correlation among memory indexes was between 4-hr delayed recall of stories and delayed recall of the CVLT-II word list (r = .59, p < .0001), suggesting different consolidation rates for relational and nonrelational material.

The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain – A detailed case report

We describe a patient in whom long-term, therapeutic infusion of the selective gamma-amino-butyric acid type B (GABAB) receptor agonist, baclofen, into the cerebrospinal fluid (CSF) gave rise to three distinct varieties of memory impairment: i) repeated, short periods of severe global amnesia, ii) accelerated long-term forgetting (ALF), evident over intervals of days and iii) a loss of established autobiographical memories. This pattern of impairment has been reported in patients with temporal lobe epilepsy (TLE), in particular the subtype of Transient Epileptic Amnesia (TEA). The amnesic episodes and accelerated forgetting remitted on withdrawal of baclofen, while the autobiographical amnesia (AbA) persisted. This exceptional case highlights the occurrence of ‘non-standard’ forms of human amnesia, reflecting the biological complexity of memory processes. It suggests a role for GABAB signalling in the modulation of human memory over multiple time-scales and hints at its involvement in ‘epileptic amnesia’.

Old dogs with new tricks: Detecting accelerated long-term forgetting by extending traditional measures

Accelerated long-term forgetting (ALF) is a condition in which normal memory performance is displayed after short delays, but significant memory loss is detected when memory is tested after several days or weeks. This condition has been reported in patients with epilepsy, but there are few normative scores available for its detection in clinical practice. In the present study, we assessed 60 healthy control subjects 18–60years of age on three memory measures [Rey Auditory Verbal Learning (RAVLT), Logical Memory (LM), and Aggie Figures] at delays of 30min and 7days. With these normative values, we determined cutoff scores to look for ALF and then categorized the performance of 15 patients with focal epilepsy on the same tasks. Seven of the patients showed ALF, and, in four of these, no other memory deficits (i.e., deficits at 30min on at least one task) were detected. Of the several demographic and epilepsy factors examined, only higher estimated IQ and older age predicted ALF (and only on one task: RAVLT). The findings provide a useful set of data to be applied in the clinic and some insight into the factors that influence retention within the first week.

Accelerated long-term forgetting can become apparent within 3-8 hours of wakefulness in patients with transient epileptic amnesia.

Objective: Accelerated long-term forgetting (ALF) is typically defined as a memory disorder in which information that is learned and retained normally over standard intervals (∼30 min) is forgotten at an abnormally rapid rate thereafter. ALF has been reported, in particular, among patients with transient epileptic amnesia (TEA). Previous work in TEA has revealed ALF 24 hr - 1 week after initial memory acquisition. It is unclear, however, if ALF observed 24 hr after acquisition reflects (a) an impairment of sleep consolidation processes taking place during the first night’s sleep, or (b) an impairment of daytime consolidation processes taking place during the day of acquisition. Here we focus on the daytime-forgetting hypothesis of ALF in TEA by tracking in detail the time course of ALF over the day of acquisition, as well as over 24 hr and 1 week. Method: Eleven TEA patients who showed ALF at 1 week and 16 matched controls learned 4 categorical word lists on the morning of the day of acquisition. We subsequently probed word-list retention 30 min, 3 hr, and 8 hr postacquisition (i.e., over the day of acquisition), as well as 24-hr and 1-week post acquisition. Results: ALF became apparent in the TEA group over the course of the day of acquisition 3–8 hr after learning. No further forgetting was observed over the first night in either group. Conclusions: The results of this study show that ALF in TEA can result from a deficit in memory consolidation occurring within hours of learning without a requirement for intervening sleep.

The impact of epileptiform abnormalities and hippocampal lesions on retention of recent autobiographical experiences: Adding insult to injury?

Accelerated long term forgetting (ALF), whereby information is rapidly lost over days or weeks has been noted in patients with epileptic conditions. The present study sought to determine which clinical factors underlie such consolidation failure for recent autobiographical experiences in patients with focal epilepsy. We enrolled 21 patients with temporal lobe epilepsy (TLE), with and without hippocampal lesions (TLE(+)=12; TLE(−)=9, respectively), 11 patients with extratemporal epilepsy (ETE) and 29 controls (NC). Recall and recognition were tested at different delays (i.e., 30min, 24h and 4 days). During the study interval, most of the patients underwent concurrent ambulatory EEG monitoring. Analyses of variance indicated Group×Delay interval interactions for recall. The TLE(+) group showed significant decline in recall by 24h delay. On recognition Group by Delay interval was not detected but main effect for Group revealed that the ETE group demonstrated ALF on recognition questions over the interval between 24h and 4 days. Regression analyses confirmed that a hippocampal lesion was particularly disruptive to consolidation over the first 24h, and that seizures were associated with memory decline over longer delays. Our findings show that the retention of autobiographical experiences involves multiple mechanisms, which operate over different timeframes.

SLEEP AND MEMORY CONSOLIDATION IN TEA

Accelerated long-term forgetting (ALF), which is common in transient epileptic amnesia (TEA), is a form of memory impairment in which learning and initial retention of information appear normal but subsequent forgetting is excessively rapid. A deficit in sleep-dependent memory consolidation has been proposed as an explanation for ALF. If this proposal were correct, then sleep would not benefit memory retention in people with ALF as much as in healthy people, and ALF might only be apparent when the retention interval contains sleep. To test this theory, we compared memory retention over a night of sleep and a day of wakefulness. We found, contrary to the hypothesis, that sleep benefits memory retention in TEA patients with ALF and that this benefit is no smaller in magnitude than that seen in healthy controls. Indeed, patients performed significantly more poorly than the controls only in the wake condition and not the sleep condition. These results indicate that ALF is not caused by disruption of sleep-dependent memory consolidation. Instead, ALF may be due to an encoding abnormality that goes undetected on behavioural assessments of learning, or by a deficit in memory consolidation processes that are not sleep-dependent.

Sleep-dependent memory consolidation and accelerated forgetting

Accelerated long-term forgetting (ALF) is a form of memory impairment in which learning and initial retention of information appear normal but subsequent forgetting is excessively rapid. ALF is most commonly associated with epilepsy and, in particular, a form of late-onset epilepsy called transient epileptic amnesia (TEA). ALF provides a novel opportunity to investigate post-encoding memory processes, such as consolidation. Sleep is implicated in the consolidation of memory in healthy people and a deficit in sleep-dependent memory consolidation has been proposed as an explanation for ALF. If this proposal were correct, then sleep would not benefit memory retention in people with ALF as much as in healthy people, and ALF might only be apparent when the retention interval contains sleep. To test this theory, we compared performance on a sleep-sensitive memory task over a night of sleep and a day of wakefulness. We found, contrary to the hypothesis, that sleep benefits memory retention in TEA patients with ALF and that this benefit is no smaller in magnitude than that seen in healthy controls. Indeed, the patients performed significantly more poorly than the controls only in the wake condition and not the sleep condition. Patients were matched to controls on learning rate, initial retention, and the effect of time of day on cognitive performance. These results indicate that ALF is not caused by a disruption of sleep-dependent memory consolidation. Instead, ALF may be due to an encoding abnormality that goes undetected on behavioural assessments of learning, or by a deficit in memory consolidation processes that are not sleep-dependent.

Accelerated long-term forgetting of verbal information in unilateral temporal lobe epilepsy: Is it related to structural hippocampal abnormalities and/or incomplete learning?

The factors contributing to accelerated long-term forgetting (ALF) are not yet clear. In this study, a 12-item word list was presented repeatedly to 23 patients with temporal lobe epilepsy (TLE) and 27 control participants (NC) until it was recalled completely on two consecutive trials or until 12 trials were undertaken. Compared to NCs, patients with hippocampal lesions and those who failed to learn the list showed ALF by one day post learning, but the alternative patient groups also showed ALF when tested after seven days. Overall, our findings suggest that in patients with TLE neither a preserved hippocampus nor intact learning protects against ALF.

Can temporal lobe epilepsy surgery ameliorate accelerated long-term forgetting?

Accelerated long-term forgetting (ALF) is a relatively newly identified phenomenon in neuropsychology which has been associated with temporal lobe epilepsy (TLE). ALF is characterised by intact acquisition and retention of memories over delays of minutes and hours, but abnormally fast forgetting over delays of 24h or more. The causes of ALF are unknown; however disruption of “slow” consolidation processes through seizure activity in the temporal lobes is proposed as a possible explanation. We looked to establish whether seizure control following epilepsy surgery ameliorated ALF in patients with TLE. Parallel sets of verbal and visual stimuli were administered comparing seven TLE patients and 25 healthy controls, matched on key demographic characteristics. Free recall and recognition were assessed at both pre-surgery/time 1 and post-surgery/time 2 at delays of 25 or 45s, 30min and one week. The TLE group retained significantly less verbally and visually learned material between 30min and one week at the pre-surgery assessment than the control group. Comparison of the groups at post-surgery assessment indicated evidence of improved retention in the TLE group for both visual and verbal material, despite reduced initial registration on the verbal sub-tests. Exploratory analysis of individuals indicated heterogeneity in the patient group with regards to the presence/absence of ALF and post-surgical improvement in ALF. The findings offer some support to the theory that ALF is associated with uncontrolled seizures and that elimination of seizures via epilepsy surgery may improve retention by providing a stable environment for “slow” consolidation to occur. However, our results suggest that this is unlikely to be the sole cause and that “slow” consolidation may normally depend also on the integrity of structures within the neocortex or medial temporal lobes. Further investigation of these apparent heterogeneous groups may be informative in further defining the nature and causes of ALF.

Magnetic resonance volumetry reveals focal brain atrophy in transient epileptic amnesia

Transient epileptic amnesia (TEA) is a recently described epilepsy syndrome characterized by recurrent episodes of isolated memory loss. It is associated with two unusual forms of interictal memory impairment: accelerated long-term forgetting (ALF) and autobiographical amnesia. We investigated the neural basis of TEA using manual volumetry and automated multi-atlas-based segmentation of whole-brain magnetic resonance imaging data from 40 patients with TEA and 20 healthy controls. Both methods confirmed the presence of subtle, bilateral hippocampal atrophy. Additional atrophy was revealed in perirhinal and orbitofrontal cortices. The volumes of these regions correlated with anterograde memory performance. No structural correlates were found for ALF or autobiographical amnesia. The results support the hypothesis that TEA is a focal medial temporal lobe epilepsy syndrome but reveal additional pathology in connected brain regions. The unusual interictal memory deficits of TEA remain unexplained by structural pathology and may reflect physiological disruption of memory networks by subclinical epileptiform activity.

Accelerated long-term forgetting in transient epileptic amnesia: An acquisition or consolidation deficit?

Accelerated Long-term Forgetting (ALF) is the rapid loss of newly acquired memories over days to weeks despite normal retention at standard (~30min) intervals. It has recently been described in association with epilepsy, particularly the syndrome of Transient Epileptic Amnesia (TEA). The cognitive mechanisms underlying ALF remain uncertain, but disruption either of memory acquisition or consolidation processes has been postulated. To arbitrate between these accounts, we reanalysed data from an existing word-list recall data set to investigate whether ALF can be observed for words learned under precisely matched conditions in TEA patients and controls. We reanalysed the data of 24 patients with TEA and 24 matched healthy controls who learnt a 15-item word list to a learning criterion of 90% with a minimum of five learning trials. Free recall of the words was probed at delays of 30min and 1 week and 3 weeks after learning. In addition, a ‘yes–no’ recognition test was conducted after the 3-week free recall. Forgetting rates across the first 30min delay and the subsequent 1 week and 3 week delay were compared between patients and controls. To ensure that learning conditions were closely matched between patients and control participants, we excluded exceptionally fast (NTEA=1, Ncontrols=4) and slow (NTEA=6, Ncontrols=2) learners. Furthermore, we analysed only words that were presented five or six times during learning and retrieved successfully on four or five occasions during learning. Recall performance on the last learning trial and 30min after acquisition were indistinguishable between TEA patients and controls. Over the delay interval of 30min to 1 week, however, accelerated forgetting of this newly learned verbal material was observed in TEA patients. This severe forgetting is also reflected in the three-week recognition test, where TEA patients performed significantly worse than controls. Moreover, whereas recall on the last learning trial correlated significantly with the 30min delayed recall in both groups, recall on the last learning trial correlated significantly with 1 week and 3 week delayed recall only in the controls. In both groups, the three-week free recall performance correlated with the three-week recognition test. Patients with TEA demonstrate ALF even for verbal material that is learned under precisely matched conditions. These results are consistent with the hypothesis that ALF represents a disruption of memory consolidation rather than an acquisition deficit.

Detecting the onset of accelerated long-term forgetting: Evidence from temporal lobe epilepsy

Accelerated long-term forgetting (ALF) refers to a slowly developing anterograde amnesia in which material is retained normally over short delays but then forgotten at an abnormally fast rate over days to weeks. Such long-term memory impairment is not detected by standard clinical tests. This study analysed ALF in a temporal lobe epileptic, RY. Key issues addressed were: (i) the timeframe of ALF onset; (ii) whether disruption of memory consolidation during sleep is a necessary requirement for precipitating ALF; (iii) the effectiveness of repeated recall in limiting the impact of ALF. RY's memory for novel word-pairings was compared with that of matched controls using cued-recall and forced choice recognition (FCR) tests at multiple delays (5, 30, 55, 240min). To investigate the impact of repeated recall some pairings were recalled at all intervals, and all material (repeatedly and non-repeatedly recalled) was tested again after a 24h delay. RY's initial learning and performance at 30min were normal, but by 55min both his cued-recall performance and the subjective quality of his recognition memory were significantly impaired. This suggests disruption of secondary consolidation processes occurring relatively soon after learning. It also raises the possibility of developing a standard test to diagnose ALF within a single clinical session rather than requiring multiple visits. Since RY remained awake it appears that disruption of memory consolidation during sleep is not a necessary condition for him to experience ALF. Repeated recall at multiple time-points within the first 4h sustained normal recall performance to 24h, indicating repeated recall could form the basis for a protective strategy.

Accelerated long-term forgetting in temporal lobe epilepsy: Verbal, nonverbal and autobiographical memory

Patients with temporal lobe epilepsy (TLE) often present with memory complaints despite performing within normal limits on standard memory tests. One possible explanation for this phenomenon is accelerated long-term forgetting (ALF). The present study investigated material‐specific ALF in patients with unilateral TLE and also examined whether ALF could be demonstrated on a novel, standardized anterograde autobiographical memory (ABM) task. Fourteen patients with TLE and 17 controls were administered verbal, nonverbal and ABM event memory tasks. The participants were tested for immediate recall, recall and recognition at 30‐minute delay, and recall and recognition after four weeks. The extent of ALF was calculated based on the percentage decay of memory from the 30‐minute delay trial to the four-week delay trial. Patients with left TLE showed significantly greater ALF for verbal material and a trend towards greater forgetting of ABM. Patients with right TLE showed a non-significant trend towards greater ALF for nonverbal material. Patients with unilateral hippocampal abnormalities showed greater ALF compared to patients without hippocampal abnormalities. Patients with seizures that generalize had more global memory deficits and greater ALF. We conclude that patients with unilateral TLE show material‐specific ALF, which appears to be more pronounced with an abnormal hippocampus or seizures that secondarily generalize.

Accelerated long-term forgetting (ALF) and transient epileptic amnesia (TEA): Two cases of epilepsy‐related memory disorder

Temporal lobe epilepsy (TLE) has long been associated with memory impairment. Recently, two specific forms of memory complaint in this population have been identified: accelerated long-term forgetting (ALF) and transient epileptic amnesia (TEA). This paper presents neuropsychological data (standard neuropsychological tests and experimental measures) on two patients who presented in the epilepsy clinic with seemingly similar subjective reports of profound memory difficulties. This paper illustrates the differences between TEA and ALF. Our focus was on measuring long-term forgetting utilizing a novel visual and verbal test protocol, with responses elicited via verbal prompts over the telephone at intervals up to 30days. Whereas patient SK had neuropsychological test evidence of problems with learning plus ALF at short and long intervals without clinical evidence of TEA, patient EB had clinically convincing TEA without neuropsychological test evidence of ALF. In particular, SK showed accelerated forgetting while EB did not. This detailed case work develops our understanding of ALF measurement and demonstrates that ALF and TEA can be dissociated.

Accelerated long-term forgetting in temporal lobe but not idiopathic generalised epilepsy

Temporal lobe epilepsy (TLE) has been associated with the phenomenon of accelerated long-term forgetting (ALF), in which memories are retained normally over short delays but are then lost at an accelerated rate over days or weeks. The causes of ALF, and whether it represents a consolidation deficit distinct from the one associated with forgetting over short delays, remain unclear. In addition, methodological issues have made results of some previous studies difficult to interpret. This study used improved methodology to investigate the role of seizure activity in ALF. Forgetting was assessed in participants with TLE (who have involvement of temporal lobe structures) and idiopathic generalised epilepsy (IGE; in which seizures occur in the absence of identified structural pathology in the temporal lobes). Learning of novel stimuli was matched between patients with TLE, patients with IGE and healthy controls matched for age and IQ. Results indicated that the TLE group showed accelerated forgetting between 30-min and three-weeks, but not between 40-s and 30-min. In contrast, rates of forgetting did not differ between patients with IGE and controls. We conclude that (1) ALF can be demonstrated in TLE in the absence of methodological confounds; (2) ALF is unlikely to be related to the experience of epilepsy that does not involve the temporal lobes; (3) neither seizures during the three-week delay nor polytherapy was associated with ALF.