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Novel forms of forgetting in temporal lobe epilepsy

Adam Zeman1*, Chris Butler2, Nils Muhlert3, Fraser Milton4

1Cognitive Neurology Research Group, Peninsula Medical School, University

of Exeter, Exeter, UK

2Nuffield Department of Clinical Neurosciences (Clinical Neurology)

University of Oxford, Oxford, UK

3NMR Research Unit, Department of Neuroinflammation, Institute of

Neurology, University College, London, UK

4Department of Psychology, University of Exeter, Exeter, UK

*Corresponding author:

Professor of Cognitive and Behavioural Neurology, Peninsula Medical School, St Luke's Campus, Magdalen Road, Exeter EX1 2LU email: adam.zeman@pms.ac.uk

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Abstract

Transient Epileptic Amnesia (TEA) is a recently defined subtype of Temporal Lobe Epilepsy,

principally affecting people in middle age with a male predominance. Its key manifestation is the

occurrence of recurring episodes of transient amnesia, usually lasting less than an hour and often

occurring on waking. One third of patients have exclusively amnestic attacks, while in two thirds at

least some attacks are accompanied by other manifestations of epilepsy, especially olfactory

hallucinations. Several lines of evidence point to a seizure focus in the medial temporal lobes. TEA is

accompanied by a striking loss of autobiographical memories in two thirds of sufferers, accelerated

loss of memories which had been acquired successfully in around one half, and topographical

amnesia in around one third. This paper reviews the findings of the TIME project (The Impairment of

Memory in Epilepsy - http://sites.pcmd.ac.uk/time/tea.php ) in relation to TEA, accelerated long-

term forgetting and remote memory impairment.

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1 Introduction

Memory complaints are common in epilepsy generally, especially so among patients with temporal

lobe epilepsy (TLE), in whom the seizure focus lies within the brain region – the temporal lobe (TLs) –

most closely associated with memory formation and storage [1]. Much fruitful research has focused

on the memory deficits occurring in patients with intractable TLE, who often have structural

pathology in the TLs, such as mesial temporal sclerosis, and are likely to undergo intensive clinical,

neuropsychological, radiological and electroencephalographic assessment with a view to possible

epilepsy surgery [1]. This paper focuses on a different group of patients, whose TLE is usually

treatment responsive, but in whom problems with memory are an especially conspicuous clinical

feature. Such patients sometimes present with recurrent episodes of transient amnesia which prove

to be TL seizures, the syndrome of Transient Epileptic Amnesia (TEA) [2, 3]; others describe a striking

impairment in the ability to recollect important episodes from their past lives which they and their

relatives are sometimes confident were previously accessible, the phenomenon of ‘remote memory

impairment’ (RMI) [4]; a third set of patients complain of difficulty in retaining memories which they

are able to acquire initially, a phenomenon recently termed ‘accelerated long-term forgetting’ (ALF)

[5]. These memory difficulties are interrelated: around two thirds of patients with TEA complain of

RMI, and around half describe ALF [2]. But RMI and ALF also occur in association with more orthodox

presentations of TLE, in particular complex partial seizures, and they sometimes provide the clue to

the presence of subtle, underlying epilepsy in patients whose initial presentation is not, on the

surface, with epilepsy at all, but with disordered memory [4, 6, 7].

In the first part of this paper the senior author (AZ) introduces the historical background to the TIME

study (The Impairment of Memory in Epilepsy - http://sites.pcmd.ac.uk/time/tea.php ), a nationwide

UK study established to investigate TEA, ALF and RMI in 2003. In the second part, the study’s first

three research fellows describe the main findings of the study to date. We conclude by identifying

some important unanswered questions about this clinically important and theoretically intriguing

cluster of epilepsy-related memory disorders.

2 Transient Epileptic Amnesia

The hallmark of TEA is the occurrence of episodes of transient amnesia, during which other cognitive

functions are substantially intact, which prove to be due to epilepsy [3]. Not surprisingly the

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diagnosis of epilepsy in these cases is often delayed. More surprisingly, given the evidence we

marshal below, the existence of this form of epilepsy remains controversial.

Hughlings-Jackson provided an early case example, in the published diary of his physician patient, Dr

Z. Dr Z recorded an occasion on which he assessed, diagnosed and treated a child with pneumonia

following the onset of the characteristic aura of his seizures [8]. He subsequently realized that he

had no recollection of the consultation, but his notes revealed that he had conducted it competently

and the seizure had apparently gone unnoticed. The most natural interpretation is that his seizure

had disabled his anterograde memory, while sparing other cognitive functions. Subsequent single

case reports and small case series highlighted the occurrence of temporal lobe seizures of which the

sole or chief manifestation was transient amnesia [4]. Several terms were used to describe these

including pure amnestic seizures, ictal amnesia, epileptic amnesia, epileptic amnesic attacks,

epileptic transient amnesia and transient epileptic amnesia.

A large study of Transient Global Amnesia (TGA) corroborated the suggestion that TLE can present in

this way [9]. TGA classically causes prolonged (typically 4-6 hour) episodes of dense anterograde and

variable retrograde amnesia in middle aged people, often following physical or emotional stress.

Recurrence rates are under 10%/year. In Hodges’ extensive study of TGA, 8/114 patients satisfying

research criteria for a diagnosis of TGA went on to develop TLE. Their amnesic attacks were

distinguished from typical episodes of TGA by their brevity – less than an hour - and their tendency

to recur.

In 1998 we reported 10 cases of TEA, reviewing a further 21 from the literature, using diagnostic

criteria which have since been adopted by others (Table 1) [10]. The clinical features were

consistent: TEA is a disorder of middle aged people, predominantly men, who present with

recurrent, brief episodes of transient anterograde and retrograde amnesia, often on waking (a useful

diagnostic clue). Patients sometimes ‘remember not being able to remember’ after the episode. The

majority had other seizure manifestations suggestive of TLE including olfactory hallucinations,

complex partial and secondarily generalised seizures, but in around one third of cases transient

amnesia was the sole manifestation. Neuroimaging was usually normal, but, when present,

epileptiform discharges on EEG pointed to an origin in the temporal lobes. The seizures almost

always remitted promptly on treatment. Sufferers were of high IQ, with a mean predicted value of

115. Interictal neuropsychological tests gave substantially normal results, but, despite this, the

majority of patients complained of a notable loss of recall for salient personal episodes which

persisted after successful treatment of the seizures.

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3 Remote memory impairment (RMI)

Seven of the 10 patients described in 1998 reported an ‘unusual and persistent impairment of

remote memory’. In five cases the impairment affected memories predating the clinical onset of TEA

by up to 30 years. We studied a single case from the series, RG, in detail, revealing marked reduction

in autobiographical – but not public event – memory extending over a quarter of a century [11].

Specifically the deficit involved an inability to evoke rich autobiographical memories for events that

RG knew had occurred and that he had been able to recollect before the onset of his epilepsy, one

year prior to study. Given that RG was able to retrieve some memories vividly, and that these had

previously been accessible to him, we interpreted his retrograde memory impairment in terms of a

degradation of previously established remote memories by subclinical epileptiform activity. Single

case studies by Kapur [12]and Luchelli and Spinnler [13] suggested that focal retrograde impairment

affecting memory for personal and/or public events could also occur in ‘orthodox’ TLE presenting

with non-amnestic seizures.

4 Accelerated long-term forgetting (ALF)

While the majority of patients with TEA reported difficulties in recollecting previously salient

memories from the remote past, some also complained of a subtly different memory problem,

difficulty in retrieving memories from the recent past (from around a day to a few weeks ago)

despite substantially normal performance on memory tests at standard retention intervals. Case 3

[10] is illustrative: this patient was able to function normally as a heating engineer, preparing

quotations for work over a matter of days, but found that over weeks his memory for recent jobs

faded irrevocably. Kapur [14], O’Connor [15], Luchelli [13] and Mayes [16] described similar

phenomena in single patients with other forms of TLE. Martin [17] and Blake [18], but not Giovagnoli

[19], found evidence for ‘accelerated long-term forgetting’ in group studies.

5 Key questions

The evidence marshalled so far, which summarises the state of knowledge before 2003, suggests

that TLE sometimes presents with amnestic seizures, and that patients with this presentation are at

a high risk of associated interictal memory disorders, RMI and ALF, which can occur in the face of

normal performance on standard memory tests. But the existence of TEA remained controversial,

and the data described so far left many questions unanswered: what causes TEA? What is its

prognosis? Why does it so often cause amnesia on awakening? Is RMI really a deficit of memory

storage, or might acquisition, consolidation or retrieval be at fault? Is it the result of epileptiform

activity in the memory system, as we hypothesised, or might subtle structural damage be

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responsible? Is ALF a disorder of memory consolidation, as its features suggest, and what is its

pathophysiology? The TIME study (The Impairment of Memory in Epilepsy) was established in 2003

to address these and related questions. The following sections review the progress made to date.

6 Promising areas of research and young investigators

6.1 Chris Butler

Clinical, neuropsychological and radiological features of Transient Epileptic Amnesia

Patient recruitment

With the help of the British Neurological Surveillance Unit

(http://www.theabn.org/AboutTheABN/BNSU.aspx), we recruited patients from around the United

Kingdom who met the criteria for TEA listed in Table 1 [10].

All patients underwent a clinical interview and a comprehensive battery of neuropsychological tests.

The available EEG data were collated and reviewed. Detailed magnetic resonance imaging (MRI) was

carried out including whole-brain, T1-weighted volumetric imaging. 24 healthy matched control

subjects also underwent neuropsychological testing and MRI.

6.2 Clinical Features of TEA

The clinical features of the patient cohort are summarized in table 2. A total of 50 patients (34

males) were recruited [2] .with a predominance of men. The mean age at the onset of amnesic

attacks was 62.1 years (range 44 to 77 years). The distribution of patients meeting each of the three

diagnostic criteria for TEA is shown in figure 1. The mean delay from symptom onset to the diagnosis

of TEA was 21 months. Other diagnoses previously received included transient global amnesia,

‘psychogenic’ attacks, transient ischaemic attacks, cardiac arrhythmia and dementia.

The amnesic attacks typically involved both loss of memory for recent events (retrograde amnesia)

and an inability to take on board new information (anterograde amnesia). Attack onset was sudden

and heralded by questions such as “Where am I?” “What are we doing here?” or “What day is it?”.

This questioning was typically repetitive but the anterograde amnesia was often incomplete, with

50% patients reporting at least partial recall of their attacks. Other cognitive domains, such as

language, perception and executive function were apparently preserved: witnesses reported

examples of patients being able to drive, play the piano, translate from French to English and play

golf during the amnesic period. The median duration of attacks was 30 minutes to 1 hour. The

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median frequency of recurrence was 12 attacks per year. A strong association of the amnesic

episodes with waking was observed: 74% patients had experienced attacks in this context. No other

consistent triggers or warning symptoms were identified. Amnesia was the sole feature of all attacks

in 28% patients, and 92% experienced at least one such episode. However, certain other features

sometimes preceded or accompanied the amnesia: olfactory or gustatory hallucinations (42%);

automatisms such as chewing, lip-smacking or fiddling with clothing (36%); and brief episodes of

unresponsiveness (24%). Two patients suffered temporally distinct generalised tonic-clonic seizures.

Neuroimaging was clinically unremarkable in all but one patient, who had a meningioma abutting

the right temporal lobe. Clear, recurrent epileptiform abnormalities were present in 37% patients

(although only after sleep-deprivation in eight patients) and were consistently over temporal or

frontotemporal regions. Anticonvulsant monotherapy had abolished the attacks in 96% patients.

Even though the attacks responded well to treatment, persistent memory difficulties were common.

70% patients described a patchy loss of remote autobiographical memories. 44% reported problems

with “holding on to a memory for more than a few days”, suggesting the presence of accelerated

long-term forgetting. 36% had developed marked navigational difficulties.

6.3 Neuropsychological testing

Neuropsychological test results are shown in table 2. Patients and controls were well matched for

age and education. There were significant but small (<1 standard deviation) differences between the

groups on measures of anterograde memory. No differences were observed in measures of

language, visuospatial perception or executive function.

In order to investigate patients’ complaints of remote autobiographical memory loss, we

administered the Modified Autobiographical Memory Interview [2] which probes recollection of

personal facts and events from each decade of the patient’s life. This test demonstrated that

patients have impaired memory for events that occurred not only since the onset of their attacks,

but also extending back several decades (see section 8 for more details).

Finally, a subset of 24 patients who showed no deficit on the standard anterograde memory tests

were investigated for accelerated long-term forgetting. Subjects learned a list of words and a series

of meaningless designs until they achieved 90% accuracy at retrieval. They were then tested on this

material at delays of 30 minutes, 1 week and 3 weeks. Despite learning at a normal rate, patients

showed an accelerated rate of forgetting compared with controls, a difference that was particularly

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marked over the longer time intervals (figure 2). Importantly, the rate of long-term forgetting

correlated with patients’ subjective complaints of memory impairment, whereas performance on

standard memory tasks did not.

6.4 Brain imaging

As mentioned above, interictal neuroimaging rarely reveals clinically relevant abnormalities in TEA.

There is no imaging evidence of increased vascular disease in TEA patients compared with matched

healthy controls [20]. Nevertheless, across the whole group of patients in the TIME Project, we

identified subtle, bilateral hippocampal atrophy (~8% volume decrease compared with controls)

[21]. Recently, we have demonstrated additional gray matter atrophy bilaterally in the perirhinal and

orbitofrontal cortices, but in no other brain regions (Butler et al., submitted) The degree of medial

temporal lobe atrophy correlated with performance on standard tests of anterograde memory. This

relationship was identified using both manual volumetry and voxel-based morphometry. No brain

regions were found in which gray matter volume correlated with autobiographical memory or long-

term forgetting rate.

Perictal FDG-positron emission tomography (PET) was performed in one patient during a flurry of

amnestic seizures [22]. This revealed hypermetabolism in the left hippocampus, which had resolved

upon repeat scanning three months later.

6.5 Summary

We propose that TEA is a distinct but under-recognised syndrome of epilepsy characterised by

recurrent, brief amnestic attacks that begin in middle to old age, often occur upon wakening, and

are frequently associated with unusual memory deficits including accelerated long-term forgetting

and autobiographical amnesia. The clinical and neuroimaging features point towards a seizures focus

in the medial temporal lobes. As with many syndromes, TEA has debatable boundaries. A notable

example is the overlap with what Gallassi and colleagues have termed the Epileptic Amnesic

Syndrome (EAS) [6, 23]. Patients with EAS have late onset (mean age = 63 years) persistent memory

difficulties, often detectable on standard neuropsychological instruments, in association with subtle

temporal lobe seizures. In other patients (e.g.[7]), complaints of ALF and remote memory

impairment can precede the onset of amnesic seizures by several years. Further research is

necessary to clarify the relationship between TEA and other forms of late-onset temporal lobe

epilepsy. In the meantime, the concept serves to highlight this distinctive presentation of epilepsy,

and facilitate novel explorations of human memory function.

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7 Promising areas of research and young investigators

7.1 Nils Muhlert

The nature of accelerated long term forgetting (ALF)

Reports of memory complaints are extremely common in epilepsy clinics. Whilst these are often

corroborated by standard tests of memory, a substantial minority (24%) of those who complain

about their memories perform within normal limits on standard tests [24]. This discrepancy has

previously been ascribed to mood disorders (e.g. [25]). But ALF provides an alternative or additional

explanation [5]: forgetting may be normal at the 30 minute delays used in traditional tests of

memory yet increased over days or weeks . In a recent study, perceived memory loss was found to

correlate more strongly with forgetting over four weeks than with forgetting over 30 minutes [24].

The study of ALF may lead to improvements in the clinical detection of memory impairment, and

shed light on memory processes.

This brief review outlines the prevalence of ALF in epilepsy, the methods used to assess it and the

current evidence on the cognitive and neurobiological basis of ALF.

7.2 What is the prevalence of ALF in epilepsy?

ALF appears to be particularly widespread among people with TEA [2, 26, 27], affecting nearly half

(44%) of patients with this condition [2]. It has also been reported in people with TLE and, to a lesser

extent, those with idiopathic generalised epilepsies (IGE). In people with TLE, the majority of studies

have found evidence for ALF [18, 28, 29]. Whilst some have failed to do so [30, 31], this may be

explained by differences in the methodology used to assess ALF (discussed later). In a case-by-case

analysis Muhlert et al. found impaired retention over a three week delay in 30-55% of patients with

TLE, depending on the test used [29]. In people with IGE, Davidson et al. found some evidence for

ALF in children with IGE [32] while a study in adults found similar rates of forgetting in those with IGE

and healthy controls [29]. The existence of ALF in those with frontal lobe epilepsies has not been

assessed, although Blake et al. reported ALF in a heterogeneous sample of patients with partial

epilepsies originating from the left hemisphere [18]. The fact that ALF is seen in some forms of

epilepsy but not others suggests that psychosocial factors common to people with epilepsy, such as

worry about seizures, does not explain ALF.

7.3 How is ALF assessed in epilepsy?

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At present, the use of different tests by research groups complicates comparisons between studies.

In particular, the use of tests that are liable to ceiling effects and overlearning during acquisition or

to floor effects at long delays make it difficult to draw clear conclusions about the presence or

absence of ALF. Whilst experimental tests of memory have been designed to avoid such effects (e.g.

[28, 29]) a number of drawbacks prevent their use as standard clinical tools. For instance they lack

normative data, and require an additional appointment to assess very long-term memory. Use of

telephone assessments at delayed time points (e.g. [33]) may make clinical assessments of ALF more

cost-effective. There is need for a standardised set of measures supported by normative data to

facilitate the clinical diagnosis and theoretical investigation of ALF.

7.4 What is the cognitive basis of ALF?

As the clinical phenomenon of ALF involves apparently normal memory acquisition and retention at

short intervals, with impaired retention at longer delays, it is natural to suppose that it is due to a

disorder of memory consolidation or storage. This may be correct, but it remains possible that

memories are fragile from the outset in people with ALF. Learning is not always normal in patients

who show ALF (e.g.6, 10), and subtle abnormalities in encoding may become more apparent over

time. Yet if this were the main explanation for ALF, one would predict a direct relationship between

retention over short and long delays. Muhlert et al. [27] found no evidence for this: while retention

over 30 min was correlated with retention over 24 h in healthy controls, there was no correlation in

patients with TEA. This suggests a disruption of normal memory processing in the interval between

these time points.

7.5 What is the neurobiological basis of ALF?

The two most plausible explanations for ALF are clinical or subclinical epileptiform activity on the

one hand and structural brain damage on the other. The role of clinical seizures in ALF was

highlighted by the case of patient JT [15], who showed a ‘precipitous’ decrease in recall following

witnessed seizures. Further evidence came from a group study of people with TLE, in which those

who experienced frequent seizures (>4) over a four week delay showed greater forgetting over that

time [34]. However, a recent study found no association between seizures over a three week delay

and ALF in either TLE or IGE groups [29]. Similarly, ALF is seen in people with TEA who are typically

seizure-free (e.g. [2, 27]). Subclinical epileptiform activity could be relevant in such cases. Patients

with TLE with evidence of interictal discharges on EEG have been found to have worse recall after a

four week delay than those without interictal discharges [34]. There is an intriguing possibility that

subclinical epileptiform acitivity during sleep might lead to ALF. ALF is detectable over 24 hour

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delays in people with TEA [27]. Prior to treatment with medication, people with TEA often report

seizures upon awakening [2]. Residual epileptiform activity during sleep might disrupt the memory

consolidation processes that are thought to occur during sleep [35]. Further research, including EEG

recordings carried out during sleep and waking between acquisition and delayed memory testing, is

needed to explore this possibility.

A second potential explanation for ALF is structural brain damage. A number of studies have

demonstrated the existence of structural damage in patients who show ALF, including increased T2

relaxation times in the hippocampus [28], reduced hippocampal volume [21, 29], hypometabolism

in the medial temporal lobes [36], decreased hippocampal NAA/Creatine on MR spectroscopic

imaging (a marker of neuronal density and mitochondrial function) [36] and mesial temporal

sclerosis [29]. Furthermore, patients with TEA demonstrate abnormalities on tests of declarative

memory, which rely on an intact medial temporal lobe, but normal rates of forgetting on tests of

procedural memory, which rely on the integrity of the basal ganglia ([27]; [37]). Yet, no study has

demonstrated a significant correlation between ALF and structural brain damage, and so further

evidence is needed to establish a causative role.

7.6 Conclusion

In summary, ALF is relatively common in people with TEA and TLE and helps to explain the

discrepancy between memory complaints and the results of standard memory tests in these groups.

It is likely to play a less important role in IGE. The development of robust clinical tests for ALF will

help to define its clinical role and theoretical implications. Whilst its cause is not yet known future

investigation of the relationships between ALF, structural brain imaging and epileptiform activity in

wakefulness and sleep should prove informative.

Promising areas of research and young investigators

8.1 Fraser Milton

Remote memory impairments in TEA

The remote memory deficits of patients with TEA are clinically striking and have received increasing

attention in recent years. The following section will briefly describe the current evidence for

impairments of different types of remote memory information: autobiographical event memory,

personal semantic memory, and public semantic memory. We then consider whether TEA can be

considered a form of focal retrograde amnesia before discussing the implications of these findings

for theories of long-term memory.

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8.2 Autobiographical event memory

A number of recent group [2, 26, 38] and case studies [39, 40] provide evidence that TEA results in

deficits for autobiographical event memory. For instance, Butler et al. [2], who recruited 50 patients

diagnosed with TEA from across the UK as part of the TIME project, found that 70% of the patients

examined complained of autobiographical memory deficits. Using a modified version of the

Autobiographical Memory Interview (AMI [41]), Butler et al. found that the autobiographical

memory impairments extended back several decades. More recently, Milton et al. [38] tested 14

patients and 11 age and IQ matched controls using the Autobiographical Interview [42], which is

currently arguably the most sensitive test of autobiographical memory performance. This revealed

autobiographical memory deficits across the entire lifespan (see Figure 3). Additionally, these

impairments were present for all the different types of contextual information that were examined

(event, time, place, perceptual, and thought/emotion details).

Evidence from patient R.G. [11], mentioned earlier, is consistent with the idea that these

autobiographical memory deficits in TEA reflect a storage problem. Specifically, R.G.’s performance

did not benefit from salient verbal and visual cues indicating that the memory loss appears to be

permanent. However, a recent case study showed that a patient with TEA recovered previously lost,

personally significant, memories following episodes of déjà vu [43] raising the possibility that the

deficits may, at least partially, be due to a retrieval deficit. In this regard, it is notable that previous

group studies investigating autobiographical event memory in TEA have focused on recall tasks (e.g.,

[2, 38]). Future work should, therefore, assess performance using a recognition test (such as by

interleaving personal photos seldom viewed with lure photos) perhaps along the lines of that

adopted by Manes et al. [11]. Such a study could work by asking participants to provide information

for all the photos recognised about “who” is shown in the photo, “where” the event took place, and

“when” the event took place. The idea here is that if there is a retrieval problem, then the extra

retrieval support offered by cueing the memory should result in an improvement in performance. In

contrast, a storage problem would result in no improvement as the memories are no longer there to

be retrieved. This appears a particularly important issue to explore because if extra retrieval support

does have a beneficial impact then this could help ameliorate the memory difficulties in TEA.

One explanation often given for the autobiographical memory deficits in TEA is that clinical

or subclinical activity propagates from the MTL to neocortical regions of the autobiographical

memory network and this disrupts the memory trace (e.g., [4, 38]; for related accounts, see [44,

45]). A recent imaging study from our group (Milton et al, submitted) provides evidence relevant to

this theory. Specifically, we showed a decrease in activation in the MTL and, in particular, the right

posterior parahippocampal gyrus (pPHG), for patients compared to controls when recollecting

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memories from their past. Furthermore, there was reduced effective connectivity between this right

pPHG region and the right middle temporal gyrus which is a key part of the autobiographical

memory network.

8.3 Personal semantic memory

Butler et al. [2], using the modified version of the AMI, found that deficits for personal semantic

memory stretched back several decades. Similarly, Milton et al. [38] found that patients had an

overall impairment for personal semantic information, although when examining different life

periods separately (childhood, teenage, young adult, middle age, and recent events) deficits only

reached significance for the middle age time period. These results indicate that the personal

semantic memory deficits may be less temporally extensive than the autobiographical event

memory impairments detected by Milton et al. [38]. An alternative explanation, however, for the

more restricted deficits is that the personal semantic tests used by Butler et al. [2] and Milton et al.

[38] may be less sensitive measures than the Autobiographical Interview used by Milton et al. [38] to

investigate autobiographical event memory. Indeed, in both studies performance was close to

ceiling for both patients and controls meaning that it is possible that relatively subtle deficits in

other time periods were not detected. It would, therefore, be valuable to further investigate

personal semantic memory using a more difficult and sensitive test to assess whether the personal

semantic memory deficits in TEA extend across the lifespan or whether they are indeed more

restricted than the autobiographical event memory deficits.

8.4 Public Semantic memory

Milton et al. [38] provided the first systematic examination of public semantic memory performance

in TEA. Significant deficits were apparent on the Dead-Or-Alive test [46] and these deficits were most

marked for recent rather than remote memories. No overall impairments emerged on a Famous

Events test, although, as for the Dead-or-Alive test, when examining the different time periods

separately, deficits were found for recent events. No impairments were found either on a test of

Famous Faces or on a New Words Acquisition test. One reasonable question is why an overall deficit

was found for the Dead-or-Alive test but not for the other three tests? One potential explanation is

that the Dead-or-Alive test appears to have a greater episodic component than the other tests used.

This would be consistent with the idea that the episodic and semantic memory systems are closely

intertwined [47]. For instance, autobiographical significance has been shown to modulate

performance on a semantic test of famous people in healthy participants [48]. It could, therefore, be

that the overall deficit in the Dead-or-Alive test is the result of patients benefiting less than controls

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from episodic information about the person to supplement their semantic information. In future

work, it would be of interest to examine whether any neural differences between patients and

controls when retrieving public semantic information overlap with those found for autobiographical

event memory recollection. If the explanation we offer is correct, then one might expect

considerable similarity in the neural deficits.

8.5 Is TEA a form of focal retrograde amnesia?

Previous work has consistently demonstrated that the memory deficits in TEA constitute a form of

focal retrograde memory as the term is generally understood – an inability to retrieve memories that

have been successfully acquired in the past, in the absence of any deficit on standard tests of

anterograde memory (e.g., [2, 26, 38]). Furthermore, Hornberger et al. [7] have provided evidence

that focal retrograde amnesia can even be a prodromal symptom of TEA. Nevertheless, a careful

inspection of the autobiographical memory data (see Figure 1) collected by Milton et al. [38]

suggests that this conclusion may not be as straightforward as it first appears. Specifically, whilst

performance was preserved on a series of standard anterograde memory tests, patients’

autobiographical memory was significantly impaired the most recent time period. Critically, the

events recalled in this time period for all the patients occurred after the onset of their TEA, and in

most cases after the onset of successful treatment. Whilst this impairment may not be surprising for

a subset of these patients (5/14) who complain of accelerated long-term forgetting, it is notable that

all patients performed at least 1 standard deviation below the mean performance of the control

group. This pattern of results therefore suggests that some form of anterograde memory deficit may

be a general feature of TEA. Examining the time course of this apparent deficit using a prospective

design could provide considerable theoretical insight into the nature of this problem. One possibility

is that patients with TEA do, in fact, have a mild encoding deficit that cannot be detected using

standard tests but which may emerge when a more sensitive measure such as the Autobiographical

Interview is used. In this case, one would expect the impairment to be apparent immediately after

the event. Alternatively, initial encoding may be preserved but there may be a problem with early

consolidation processes resulting in accelerated long-term forgetting over the course of days or

weeks. This possibility would imply that accelerated long-term forgetting is more prevalent in TEA

than has commonly been acknowledged. Finally, performance may be preserved several weeks after

the event but the deficits emerge over a longer duration (e.g., months) than has previously been

examined. If any of these possibilities are the case, then it would provide some explanation for why

subjective reports of memory problems in epilepsy often do not correlate with objective measures

on standard neuropsychological tests (e.g., [49]).

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8.6 Implications for theories of long-term memory.

We have already presented evidence consistent with the idea that TEA is a medial temporal lobe

(MTL) syndrome (e.g., [21, 22]). Consequently, the remote memory impairments in TEA have

implications for current theories of remote memory. The standard consolidation model posits that

the MTL, and in particular the hippocampus, has a time limited role in episodic memory (e.g., [50]).

The MTL, at first, is critical for the storage of new memories, but, over time, these memories

become independent of the MTL and are represented in the neocortex alone. In contrast, multiple

trace theory argues that the MTL is essential for episodic memories throughout the lifespan [51].

Each time a memory is retrieved a new trace is laid down leading to the formation of multiple traces

in the MTL. Both theories predict that the MTL has a time limited role for semantic memory. In this

regard, the finding of a temporally graded deficit on public semantic memory tests [38] would be

compatible with both the standard consolidation model and multiple trace theory. On the other,

hand, the finding of autobiographical event memory deficits extending across the lifespan appears

more in line with the assumptions of multiple trace theory. Nevertheless, the standard consolidation

model could potentially explain these results if it posits that the deficits are due to clinical or

subclinical activation from the MTL disrupting the memory trace along the lines suggested in Section

8.2.

9 Questions for future research

The work summarised in this paper has established that recurrent episodes of transient amnesia can

be caused by TLE in the syndrome of Transient Epileptic Amnesia. These are often accompanied by

two non-standard forms of memory impairment, accelerated long-term forgetting and remote

memory impairment, which can occur in the face of normal performance on standard memory tests.

While these interictal deficits are especially common in TEA, they are also seen in patients with

forms of TLE other than TEA [4]. The work of the young investigators summarised above has

advanced our knowledge of TEA, ALF and RMI considerably, but there are many unanswered

questions for future research. The following are particularly important:

TEA: what causes the syndrome to develop in middle age? What is the long term prognosis

of the syndrome? What is its underlying neuropathology?

ALF: is it, as it appears to be, a disorder of memory consolidation, or is there a subtle

impairment of memory acquisition? Is it due to a disorder of physiology (eg epileptiform

discharges during sleep or wakefulness) or to a disorder of structure? Does it respond, to

some degree, to antiepileptic treatment?

16

RMI: is the apparent loss of memories in some patients with RMI due to a disorder of

memory storage, or is there an impairment of memory retrieval? As for ALF, Is RMI due to a

disorder of physiology (eg epileptiform discharges during sleep or wakefulness) or to a

disorder of structure?

17

Box 1: TEA – an illustrative case report

A 58-year-old carpet fitter experienced 28 episodes of transient amnesia over 18 months. All occurred

upon waking in the night and lasted about 20 minutes. He repetitively questioned his wife, but was

responsive and coherent throughout. During one attack he was unable to recall the death of his

brother a few days earlier. Routine EEG and MRI were normal. Lamotrigine abolished the attacks but

they briefly returned, with associated olfactory hallucinations, during a period of non-compliance,

and ceased again when he restarted the medication. At interview, he described rapid forgetting of

recently acquired memories, patchy loss of salient autobiographical memories from the past 30

years, such as his wife’s abdominal surgery and the wedding of his son, and significant new

difficulties navigating around his local area.

18

FIGURE LEGENDS

Figure 1

Venn diagram showing the distribution of patients meeting the diagnostic criteria for TEA

employed by Butler et al [2].

Figure 2

Recall performance of patients with TEA trained to a 90% criterion on a 15 word list at 30

minutes, 1 week and 3 weeks. ‘Patients’ are the TEA group as a whole; ‘ALF+’ 12 patients

with TEA who complained subjectively of ALF; ‘ALF-‘ 12 patients who did not complain

subjectively of ALF [2].

Figure 3

Mean number of details recalled for events from five life periods by patients with TEA

compared to control participants [38].

19

Table 1: Diagnostic Criteria for Transient Epileptic Amnesia

1. A history of recurrent witnessed episodes of transient amnesia

2. Cognitive functions other than memory judged to be intact during typical episodes by

a reliable witness

3. Evidence for a diagnosis of epilepsy based on one or more of the following:

a. epileptiform abnormalities on electroencephalography

b. the concurrent onset of other clinical features of epilepsy (e.g. lip-smacking,

olfactory hallucinations)

c. a clear-cut response to anticonvulsant therapy

20

Table 2: Core clinical features of Transient Epileptic Amnesia

Demographics age at onset (y) 62.1 (range 44 to 77)

sex distribution m=34; f=16

Amnestic attack

characteristics

number of attacks median = 10

(IQR 6 to 30)

frequency (attacks per year) median = 12

(IQR 5 to 20)

attack duration median = 30-60min (range

<1min to days)

cessation of attacks on AED 96%

some attacks on waking 74%

partial amnesia for attack 56%

repetitive questioning 50%

olfactory hallucinations 42%

motor automatisms 36%

brief unresponsiveness 24%

Interictal memory c/o autobiographical memory loss 70%

c/o accelerated forgetting 44%

c/o topographical memory loss 36%

Investigations interictal epileptiform EEG abnormalities 37%

structural lesion on MRI 2%

21

Table 3: Demographic and neuropsychological profile of TEA patients and controls

Raw scores are shown with the maximum possible score for each test given in parentheses in the left-hand

column

AF subgroup = subgroup of TEA patients selected for accelerated forgetting tests and matched pairwise with controls.

WCST = Wisconsin Card Sort Test 64

HAD = Hospital Anxiety and Depression scale

All patients (n=50) Controls

(n=24)

mean (SD) mean (SD)

Age (years) 68.3 (8.6) 67.7 (8.1)

Education (years) 12.2 (2.9) 12.5 (3.1)

Full scale IQ 118.3 (12.8) 120.0 (14.4)

Episodic memory

Story recall immediate (25) 14.0 (4.3) 15.9 (3.8)

Story recall delayed (25) 11.7 (5.0)* 14.7 (3.8)

Rey figure delayed recall (36) 15.0 (6.5)* 18.6 (6.1)

Word recognition (50) 46.1 (4.7)* 48.3 (1.9)

Face recognition (50) 40.7 (5.4)*** 45.1 (2.9)

Semantic memory

Graded faces (60)† 40.0 (9.6) 44.0 (7.6)

Graded naming (30) 21.4 (5.1) 23.5 (4.2)

Visuospatial perception

Rey figure copy (36) 34.5 (3.1) 35.5 (1.1)

Executive function

Letter fluency (words/3min) 42.5 (13.9) 43.8 (11.4)

Category fluency (words/min) 19.3 (5.9) 22.0 (4.4)

WCST categories completed 2.8 (1.3) 3.4 (1.4)

22

† for each face: one point for providing identifying information; * = p<0.05, *** = p<0.001

Reference List

[1] Zeman A, Jones-Gotman M, Kapur N. Epilepsy and Memory. 2012. Oxford, Oxford University

Press.

[2] Butler CR, Graham KS, Hodges JR, Kapur N, Wardlaw JM, Zeman AZ. The syndrome of

transient epileptic amnesia. Ann Neurol 2007;61:587-98.

[3] Zeman A, Butler C. Transient epileptic amnesia. Curr Opin Neurol 2010;23:610-6.

[4] Butler CR, Zeman AZ. Recent insights into the impairment of memory in epilepsy: transient epileptic amnesia, accelerated long-term forgetting and remote memory impairment. Brain 2008;131:2243-63.

[5] Muhlert N, Zeman A. The enigma of long-term forgetting. Seizure 2012;21:77-8.

[6] Gallassi R. Epileptic amnesic syndrome: an update and further considerations. Epilepsia 2006;47 Suppl 2:103-5.

[7] Hornberger M, Mohamed A, Miller L, Watson J, Thayer Z, Hodges JR. Focal retrograde amnesia: Extending the clinical syndrome of transient epileptic amnesia. J Clin Neurosci 2010;17:1319-21.

[8] Hughlings Jackson J. On a particular variety of epilepsy (intellectual aura), one case with symptoms of organic brain disease. Brain 1888:179-207.

[9] Hodges JR. Transient Amnesia. London: WB Saunders; 1991.

[10] Zeman AZ, Boniface SJ, Hodges JR. Transient epileptic amnesia: a description of the clinical and neuropsychological features in 10 cases and a review of the literature. J Neurol Neurosurg Psychiatry 1998;64:435-43.

[11] Manes F, Hodges JR, Graham KS, Zeman A. Focal autobiographical amnesia in association with transient epileptic amnesia. Brain 2001;124:499-509.

[12] Kapur N, Young A, Bateman D, Kennedy P. Focal retrograde amnesia: a long term clinical and neuropsychological follow-up. Cortex 1989;25:387-402.

[13] Lucchell F, Spinnler H. Ephemeral new traces and evaporated remote engrams: a form of neocortical temporal lobe amnesia? A preliminary case report. Neurocase 1998;4:447-59.

[14] Kapur N., Millar J, Colbourn C, Abbott P, Kennedy P, Docherty T. Very long-term amnesia in association with temporal lobe epilepsy: evidence for multiple-stage consolidation processes. Brain Cogn 1997;35:58-70.

[15] O'Connor M, Sieggreen MA, Ahern G, Schomer D, Mesulam M. Accelerated forgetting in association with temporal lobe epilepsy and paraneoplastic encephalitis. Brain Cogn 1997;35:71-84.

23

[16] Mayes AR, Isaac CL, Holdstock JS, Cariga P, Gummer A, Roberts N. Long-term amnesia: a review and detailed illustrative case study. Cortex 2003;39:567-603.

[17] Martin RC, Loring DW, Meador KJ, Lee Gp, Thrash N, Arena JG. Impaired long-term retention despite normal verbal learning in patients with temporal lobe dysfunction. Neuropsychology 1991;5:3-12.

[18] Blake RV, Wroe SJ, Breen EK, McCarthy RA. Accelerated forgetting in patients with epilepsy: evidence for an impairment in memory consolidation. Brain 2000;123 Pt 3:472-83.

[19] Giovagnoli AR, Casazza M, Avanzini G. Visual learning on a selective reminding procedure and delayed recall in patients with temporal lobe epilepsy. Epilepsia 1995;36:704-11.

[20] Butler CR, Zeman A. The causes and consequences of transient epileptic amnesia. Behav Neurol 2011;24:299-305.

[21] Butler CR, Bhaduri A, Acosta-Cabronero J, Nestor PJ, Kapur N, Graham KS et al. Transient epileptic amnesia: regional brain atrophy and its relationship to memory deficits. Brain 2009;132:357-68.

[22] Butler CR, Zeman A. A case of transient epileptic amnesia with radiological localization. Nat Clin Pract Neurol 2008;4:516-21.

[23] Gallassi R, Morreale A, Di Sarro R, Lugaresi E. Epileptic amnesic syndrome. Epilepsia 1992;33 Suppl 6:S21-S25.

[24] Witt JA, Glockner C, Helmstaedter C. Extended retention intervals can help to bridge the gap between subjective and objective memory impairment. Seizure 2012;21:134-40.

[25] Corcoran R, Thompson P. Epilepsy and poor memory: who complains and what do they mean? Br J Clin Psychol 1993;32 ( Pt 2):199-208.

[26] Manes F, Graham KS, Zeman A, de Lujan CM, Hodges JR. Autobiographical amnesia and accelerated forgetting in transient epileptic amnesia. J Neurol Neurosurg Psychiatry 2005;76:1387-91.

[27] Muhlert N, Milton F, Butler CR, Kapur N, Zeman AZ. Accelerated forgetting of real-life events in Transient Epileptic Amnesia. Neuropsychologia 2010;48:3235-44.

[28] Wilkinson H, Holdstock JS, Baker G, Herbert A, Clague F, Downes JJ. Long-term accelerated forgetting of verbal and non-verbal information in temporal lobe epilepsy. Cortex 2012;48:317-32.

[29] Muhlert N, Grunewald RA, Hunkin NM, Reuber M, Howell S, Reynders H et al. Accelerated long-term forgetting in temporal lobe but not idiopathic generalised epilepsy. Neuropsychologia 2011;49:2417-26.

[30] Bell BD, Fine J, Dow C, Seidenberg M, Hermann BP. Temporal lobe epilepsy and the selective reminding test: the conventional 30-minute delay suffices. Psychol Assess 2005;17:103-9.

[31] Bell BD. WMS-III Logical Memory performance after a two-week delay in temporal lobe epilepsy and control groups. J Clin Exp Neuropsychol 2006;28:1435-43.

24

[32] Davidson M, Dorris L, O'Regan M, Zuberi SM. Memory consolidation and accelerated forgetting in children with idiopathic generalized epilepsy. Epilepsy Behav 2007;11:394-400.

[33] Kemp S, Illman NA, Moulin CJ, Baddeley AD. Accelerated long-term forgetting (ALF) and transient epileptic amnesia (TEA): Two cases of epilepsy-related memory disorder. Epilepsy Behav 2012;24:382-8.

[34] Mameniskiene R, Jatuzis D, Kaubrys G, Budrys V. The decay of memory between delayed and long-term recall in patients with temporal lobe epilepsy. Epilepsy Behav 2006;8:278-88.

[35] Stickgold R. Sleep-dependent memory consolidation. Nature 2005;437:1272-8.

[36] Tramoni E, Felician O, Barbeau EJ, Guedj E, Guye M, Bartolomei F et al. Long-term consolidation of declarative memory: insight from temporal lobe epilepsy. Brain 2011;134:816-31.

[37] Deak MC, Stickgold R, Pietras AC, Nelson AP, Bubrick EJ. The role of sleep in forgetting in temporal lobe epilepsy: a pilot study. Epilepsy Behav 2011;21:462-6.

[38] Milton F, Muhlert N, Pindus DM, Butler CR, Kapur N, Graham KS et al. Remote memory deficits in transient epileptic amnesia. Brain 2010;133:1368-79.

[39] Illman NA, Rathbone CJ, Kemp S, Moulin CJ. Autobiographical memory and the self in a case of transient epileptic amnesia. Epilepsy Behav 2011;21:36-41.

[40] Ioannidis P, Balamoutsos G, Karabela O, Kosmidis MH, Karacostas D. Transient epileptic amnesia in a memory clinic setting: a report of three cases. Epilepsy Behav 2011;20:414-7.

[41] Kopelman MD, Wilson BA, Baddeley AD. The autobiographical memory interview: a new assessment of autobiographical and personal semantic memory in amnesic patients. J Clin Exp Neuropsychol 1989;11:724-44.

[42] Levine B, Svoboda E, Hay JF, Winocur G, Moscovitch M. Aging and autobiographical memory: dissociating episodic from semantic retrieval. Psychol Aging 2002;17:677-89.

[43] Milton F, Butler CR, Zeman AZ. Transient epileptic amnesia: deja vu heralding recovery of lost memories. J Neurol Neurosurg Psychiatry 2011;82:1178-9.

[44] Gallassi R, Morreale A, Lorusso S, Pazzaglia P, Lugaresi E. Epilepsy presenting as memory disturbances. Epilepsia 1988;29:624-9.

[45] Mendes MH. Transient epileptic amnesia: an under-diagnosed phenomenon? Three more cases. Seizure 2002;11:238-42.

[46] Kapur N, Ellison D, Smith MP, McLellan D, Burrrows EH. Focal retrograde amnesia following bilateral temporal lobe pathology. Brain 1992;115:73-85.

[47] Levine B, Turner GR, Tisserand D, Hevenor SJ, Graham SJ, McIntosh AR. The functional neuroanatomy of episodic and semantic autobiographical remembering: a prospective functional MRI study. J Cogn Neurosci 2004;16:1633-46.

[48] Westmacott R, Moscovitch M. The contribution of autobiographical significance to semantic memory. Mem Cognit 2003;31:761-74.

25

[49] Corcoran R, Thompson P. Memory failure in epilepsy: retrospective reports and prospective recordings. Seizure 1992;1:37-42.

[50] Squire LR, Bayley PJ. The neuroscience of remote memory. Curr Opin Neurobiol 2007;17:185-96.

[51] Moscovitch M, Rosenbaum RS, Gilboa A, Addis DR, Westmacott R, Grady C et al. Functional neuroanatomy of remote episodic, semantic and spatial memory: a unified account based on multiple trace theory. J Anat 2005;207:35-66.

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Figure 1.

27

Figure 2.

28

0

10

20

30

40

50

60

70

80

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Child Youth Young Adult Middle Age Recent

Time period

Nu

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Controls

Figure 3.