NMDA receptor antibody encephalitis presenting as Transient Epileptic Amnesia.

Transient Epileptic Amnesia (TEA) is a subtype of temporal lobe epilepsy, typically presenting in a person's early 60s, and of unknown aetiology. Encephalitis caused by antibodies to NMDA receptors (NMDARE) has not previously been documented in TEA. We describe a 47-year-old male who satisfied criteria for TEA, but given his atypical symptoms, was also screened for autoimmune epilepsy. High levels of serum NMDAR antibodies were found, suggesting NMDARE. Immunosuppressive treatment gradually eliminated the NMDA receptor antibodies. Our case extends the clinical spectrum associated with neuronal cell-surface autoantibodies to include atypical cases of TEA.

Encoding-related brain activity and accelerated forgetting in transient epileptic amnesia.

The accelerated forgetting of newly learned information is common amongst patients with epilepsy and, in particular, in the syndrome of transient epileptic amnesia (TEA). However, the neural mechanisms underlying accelerated forgetting are poorly understood. It has been hypothesised that interictal epileptiform activity during longer retention intervals disrupts normally established memory traces. Here, we tested a distinct hypothesis-that accelerated forgetting relates to the abnormal encoding of memories. We studied a group of 15 patients with TEA together with matched, healthy control subjects. Despite normal performance on standard anterograde memory tasks, patients showed accelerated forgetting of a word list over one week. We used a subsequent memory paradigm to compare encoding-related brain activity in patients and controls. Participants studied a series of visually presented scenes whilst undergoing functional MRI scanning. Recognition memory for these scenes was then probed outside the scanner after delays of 45 min and of 4 days. Patients showed poorer memory for the scenes compared with controls. In the patients but not the controls, subsequently forgotten stimuli were associated with reduced hippocampal activation at encoding. Furthermore, patients demonstrated reduced deactivation of posteromedial cortex regions upon viewing subsequently remembered stimuli as compared to subsequently forgotten ones. These data suggest that abnormal encoding-related activity in key memory areas of the brain contributes to accelerated forgetting in TEA. We propose that abnormally encoded memory traces may be particularly vulnerable to interference from subsequently encountered material and hence be forgotten more rapidly. Our results shed light on the mechanisms underlying memory impairment in epilepsy, and offer support to the proposal that accelerated forgetting may be a useful marker of subtle dysfunction in memory-related brain systems.

Accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: Tests sensitive to presymptomatic changes in Alzheimer's disease could be valuable for clinical trials. Accelerated long-term forgetting-during which memory impairment becomes apparent over longer periods than usually assessed, despite normal performance on standard cognitive testing-has been identified in other temporal lobe disorders. We assessed whether accelerated long-term forgetting is a feature of presymptomatic autosomal dominant (familial) Alzheimer's disease, and whether there is an association between accelerated long-term forgetting and early subjective memory changes. METHODS: This was a cross-sectional study at the Dementia Research Centre, University College London (London, UK). Participants were recruited from a cohort of autosomal dominant Alzheimer's disease families already involved in research at University College London, and had to have a parent known to be affected by an autosomal dominant Alzheimer's disease mutation, and not report any current symptoms of cognitive decline. Accelerated long-term forgetting of three tasks (list, story, and figure recall) was assessed by comparing 7-day recall with initial learning and 30-min recall. 7-day recognition was also assessed. Subjective memory was assessed using the Everyday Memory Questionnaire. The primary outcome measure for each task was the proportion of material retained at 30 min that was recalled 7 days later (ie, 7-day recall divided by 30-min recall). We used linear regression to compare accelerated long-term forgetting scores between mutation carriers and non-carriers (adjusting for age, IQ, and test set) and, for mutation carriers, to assess whether there was an association between accelerated long-term forgetting and estimated years to symptom onset (EYO). Spearman's correlation was used to examine the association between accelerated long-term forgetting and subjective memory scores. FINDINGS: Between Feb 17, 2015 and March 30, 2016, we recruited 35 people. 21 participants were mutation carriers (mean EYO 7·2 years, SD 4·5). Across the three tasks, we detected no differences between carriers and non-carriers for initial learning or 30-min recall. The proportion of material recalled at 7 days was lower in carriers than non-carriers for list (estimated difference in mean for list recall -30·94 percentage points, 95% CI -45·16 to -16·73; p=0·0002), story (-20·10, -33·28 to -6·91; p=0·0048), and figure (-15·41, -26·88 to -3·93; p=0·012) recall. Accelerated long-term forgetting was greater in carriers nearer to their estimated age at onset (p≤0·01 for all three tests). Mutation carriers' 7-day recognition memory was also lower across all tasks (list [mean difference -5·80, 95% CI -9·96 to -2·47; p<0·01], story [-6·84, -10·94 to -3·37; p<0·01], and figure [-17·61, -27·68 to -7·72; p<0·01] recognition). Subjective memory scores were poorer in asymptomatic carriers compared with non-carriers (adjusted difference in means 7·88, 95% CI 1·36 to 14·41; p=0·016), and we found a correlation between accelerated long-term forgetting and subjective memory in mutation carriers. INTERPRETATION: Accelerated long-term forgetting is an early presymptomatic feature of autosomal dominant Alzheimer's disease, which appears to pre-date other amnestic deficits and might underpin subjective memory complaints in Alzheimer's disease. Accelerated long-term forgetting testing might be useful in presymptomatic Alzheimer's disease trials. FUNDING: MRC, NIHR, Alzheimer's Research UK, Dementias Platform UK, Dunhill Medical Trust, ERUK, Great Western Research, Health Foundation, Patrick Berthoud Trust.

Epileptic activity in Alzheimer's disease: causes and clinical relevance.

Epileptic activity is frequently associated with Alzheimer's disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer's disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer's disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer's disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer's disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer's disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid ß and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer's disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

On the nose: Olfactory disturbances in patients with transient epileptic amnesia.

OBJECTIVE: While olfactory hallucinations are relatively rare in epilepsy, a high prevalence (up to 42%) has been reported in one form - Transient Epileptic Amnesia (TEA). TEA is characterized by recurring amnestic seizures and is commonly associated with persistent interictal memory deficits. Despite reports of changes in smell, olfactory ability has not been objectively assessed in this group. The aim of this study was to measure olfactory ability in patients with TEA and explore whether olfactory symptoms relate to other clinical variables. METHODS: Fifty-five participants with TEA were recruited from The Impairment of Memory in Epilepsy project database. The presence of olfactory symptoms was obtained via case notes and clinical interview. Participants completed questionnaires to evaluate their olfaction and memory function subjectively. Olfactory ability was measured using the University of Pennsylvania Smell Identification Test (UPSIT). TEA participants' performance was compared to 50 matched healthy control participants. A subset of TEA participants (n=26) also completed a battery of memory tests including standard neuropsychological measures, and assessment of accelerated long-term forgetting and autobiographical memory. RESULTS: Olfactory hallucinations were reported in 55% of patients with TEA. A significant reduction in smell identification (UPSIT) was found between patients with TEA and healthy controls (p<0.001). Epilepsy variables, including history of olfactory hallucinations, were not predictive of olfactory ability. Patients reported ongoing memory difficulties and performed below normative values on objective tests. While no correlation was found between objective measures of memory and olfactory performance, subjective complaints of route finding difficulty was associated with UPSIT score. CONCLUSIONS: Impairments in odor identification are common in patients with TEA and exceed changes that occur in normal aging. Olfactory hallucinations occurs in approximately half of patients with TEA, but do not always coincide with reduced sense of smell. Olfactory impairment and interictal memory problems both occur frequently in TEA but are not closely associated.

Transient Epileptic Amnesia over twenty years: Long-term follow-up of a case series with three detailed reports.

PURPOSE: Transient Epileptic Amnesia (TEA) is a form of adult onset temporal lobe epilepsy characterised by ictal amnesia. The amnesic seizures are often accompanied by interical memory disturbance, involving autobiographical amnesia and accelerated long-term forgetting. Short-term follow-up studies suggest a relatively stable cognitive profile once treated, but recent case reports raise concerns regarding the risk of developing Alzheimer's disease (AD). The current study reports clinical and cognitive outcome in TEA patients over a 20-year period. METHODS: A cohort of ten TEA patients first reported in 1998 were followed up at two time intervals, each 10 years apart. Information regarding clinical outcomes and subjective reports of memory functioning was gained via GP records and clinical interview. Objective memory function was determined at each time point via a comprehensive neuropsychological assessment, where possible. RESULTS: Information was obtained for nine of the original 10 participants. Over the 20-year period, 4 participants died, with no indication of dementia prior to death. One participant was diagnosed with Vascular Dementia. Seizures were generally well controlled. Subjective reports of memory varied, including no concerns, stable memory difficulties, and worsening memory. Neuropsychological assessment at 10 years showed stable performances across most measures. At the 20-year follow up, there was no evidence of a general cognitive decline. Participants showed stability on some measures, with reductions on others. Performance was not consistent with AD. CONCLUSIONS: No elevated risk of dementia was evident from this TEA series. Although memory difficulties persist over time, the prognosis of TEA appears generally benign.

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.

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.

Imagining the present: amnesia may impair descriptions of the present as well as of the future and the past.

Recent evidence suggests that in some patients with amnesia the capacity to imagine the future is impaired in parallel with the capacity to remember the past. This paper asks whether descriptions of the present may be similarly affected. We recruited 7 patients with amnesic syndromes of varying aetiologies who were matched for age, sex and education with 7 control participants. Patients showed no deficits on subjective measures of visual imagery. They were impaired by comparison with controls on measures of imagination and future thinking. However there was an even more marked impairment on tasks requiring them to give descriptions of their current experience. Potential explanations include effects of amnesia on narrative construction or on the texture of experience itself, and the confounding influence of cognitive impairments outside the memory domain. We conclude that tasks requiring descriptions of current experience provide a valuable control condition in studies examining the relationship between memory and imagination.

The neural basis of autobiographical memory deficits in transient epileptic amnesia.

Transient epileptic amnesia (TEA) is a recently recognized form of temporal lobe epilepsy which is often associated with persistent interictal impairment of autobiographical memory. We used fMRI to investigate the neural basis of this deficit. Eleven patients with TEA, who had no significant deficits on standard tests of anterograde memory, and 17 age and IQ matched healthy controls retrieved memories from across the lifespan. Both groups engaged the autobiographical memory network, but activation in patients was less extensive than in controls. Direct comparison revealed hypoactivation of regions in the right hemisphere. Specifically, patients showed reduced activation of the posterior parahippocampal gyrus (pPHG), especially for mid-life and recent memories, with decreased engagement of the right temporoparietal junction and the cerebellum. In addition, we found reduced effective connectivity in patients between the right pPHG and the right middle temporal gyrus. Our results are consistent with other evidence that TEA is a syndrome of medial temporal lobe epilepsy and indicate that it affects the function and connectivity of regions within the autobiographical memory network.

Remote memory deficits in transient epileptic amnesia.

Transient epileptic amnesia is a form of temporal lobe epilepsy in which sufferers often complain of irretrievable loss of remote memories. We used a broad range of memory tests to clarify the extent and nature of the remote memory deficits in patients with transient epileptic amnesia. Performance on standard tests of anterograde memory was normal. In contrast, there was a severe impairment of memory for autobiographical events extending across the entire lifespan, providing evidence for the occurrence of 'focal retrograde amnesia' in transient epileptic amnesia. There was a milder impairment of personal semantic memory, most pronounced for midlife years. There were limited deficits of public semantic memory for recent decades. These results may reflect subtle structural pathology in the medial temporal lobes or the effects of the propagation of epileptiform activity through the network of brain regions responsible for long-term memory, or a combination of these two mechanisms.

Loss of imagery phenomenology with intact visuo-spatial task performance: a case of 'blind imagination'.

The capacity for imagery, enabling us to visualise absent items and events, is a ubiquitous feature of our experience. This paper describes the case of a patient, MX, who abruptly lost the ability to generate visual images. He rated himself as experiencing almost no imagery on standard questionnaires, yet performed normally on standard tests of perception, visual imagery and visual memory. These unexpected findings were explored using functional MRI scanning (fMRI). Activation patterns while viewing famous faces were not significantly different between MX and controls, including expected activity in the fusiform gyrus. However, during attempted imagery, activation in MX's brain was significantly reduced in a network of posterior regions while activity in frontal regions was increased compared to controls. These findings are interpreted as suggesting that MX adopted a different cognitive strategy from controls when performing the imagery task. Evidence from experimental tasks thought to rely on mental imagery, such as the Brooks' matrices and mental rotation, support this interpretation. Taken together, these results indicate that successful performance in visual imagery and visual memory tasks can be dissociated from the phenomenal experience of visual imagery.

The syndrome of transient epileptic amnesia.

OBJECTIVE: Transient amnesia can be the principal manifestation of epilepsy. This diagnosis, however, is seldom suspected by clinicians and remains controversial. The amnestic attacks are often associated with persistent memory complaints. This study was designed to provide the first description of transient epileptic amnesia in a substantial series of patients. METHODS: Fifty patients were recruited over 18 months using the following diagnostic criteria: (1) recurrent, witnessed episodes of amnesia; (2) other cognitive functions intact during attacks; and (3) compelling evidence of epilepsy. We assessed clinical features and performed neuropsychological evaluation in cases and 24 matched control subjects. RESULTS: Transient epileptic amnesia develops in later life (mean onset, 62 years). Amnestic episodes are frequent (median, 12/year), brief (median duration, 30-60 minutes), and often occur on waking (37/50 cases). Epilepsy was the initial specialist diagnosis in only 12 of 50 cases. Attacks ceased on anticonvulsant medication in 44 of 47 treated patients. A total of 40 of 50 cases described persistent memory difficulties. Despite normal performance on standard memory tests, patients exhibited accelerated forgetting of verbal and visual material over 3 weeks by comparison with matched control subjects (p < 0.001). They also showed loss of autobiographical memories for events extending back over 40 years (p < 0.05). INTERPRETATION: We propose that transient epileptic amnesia is a distinctive epilepsy syndrome, typically misdiagnosed at presentation and associated with accelerated long-term forgetting and autobiographical amnesia. The syndrome is of clinical and theoretic importance.