Clinical manifestations

Presentation and course

Transient epileptic amnesia has been considered a syndrome of mesial temporal lobe epilepsy characterized by recurrent episodes of isolated memory impairment of epileptic cause (ictal or postictal) while other cognitive functions remain intact (27; 60; 59; 11; 14; 13; 07; 58; 23; 03; 30; 38; 19; 43).

Transient epileptic amnesia usually affects middle-aged or elderly subjects (older than 40 years; mean age of 57 years), men (60%) more than women, and the attacks often occur on waking. The amnesia itself has anterograde (inability to lay down memories during the episode) and retrograde (difficulty in retrieving memory from the past days or years) components. Anterograde amnesia may be partial in 44% of the patients.

Transient amnesia is the sole manifestation of the attacks in 34% of patients. Additionally, complex focal seizures occur in the other two thirds of patients whereas secondarily generalized tonic-clonic seizures are rare. In the report of Butler and colleagues, 46 of 50 patients reported at least one attack in which amnesia was the sole feature (11). There are other features seen during the attacks. Olfactory hallucinations are one of the most commonly reported features occurring in up to 42% of patients in one study (14); these are rare forms of epileptic hallucinations and typically suggest involvement of medial temporal lobe. Furthermore, it should be remembered that hippocampal seizures are often followed by prolonged postictal disturbances and that olfactory hallucinations are relatively less common than other seizure hallucinations; they are attributed to amygdala with tumors and hippocampal sclerosis as their main causes (42). In one study of 55 patients with transient epileptic amnesia, it was found that impairments in odor identification are common in patients and exceed changes that occur in normal aging (46). Olfactory hallucinations occur in approximately half of patients but do not always coincide with reduced sense of smell. Olfactory impairment and interictal memory problems both occur frequently but are not closely associated.

Additional symptoms reported include déjà vu, oroalimentary automatisms, autonomic changes, language impairment, or a brief period of unresponsiveness. However, it should be noted that patients with transient epileptic amnesia and prolonged attacks of amnesia may have additional seizures that are so mild and brief they are clinically undetected (40). Emotional lability is seen in a proportion of patients, manifested by intense emotional response, including tearfulness to relatively trivial triggers (05).

The duration of episodes of amnesia is usually less than an hour, most often lasting about 20 to 30 minutes (median duration is 30 to 60 minutes), though attacks lasting hours may occur (11; 14; 59).

The attacks are frequent, usually around 20 times each year in untreated patients, with a wide range between individuals (14).

Interictal memory manifestation. Patients with transient epileptic amnesia frequently report three varieties of persistent, interictal memory disturbance that are invisible to standard neuropsychological tests:

One study has also documented that patients with transient epileptic amnesia suffer from early picture recognition deficit, which could reflect either the early stages of the process that leads to accelerated long-term forgetting or a separable deficit of anterograde memory in transient epileptic amnesia (18). This study also found that that at least some patients with transient epileptic amnesia are prone to falsely recognizing new everyday visual information that they have not, in fact, seen previously (18).

Working diagnostic consensus criteria for transient epileptic amnesia. Criteria include: (1) a history of recurrent witnessed episodes of transient amnesia; (2) confirmation by a reliable witness that cognitive functions other than memory are intact during typical episodes; and (3) evidence for a diagnosis of epilepsy (60). This evidence is provided by either (a) wake or sleep EEG, (b) the co-occurrence of other seizure types, (c) a clear-cut response to antiseizure therapy, or (d) a combination of these factors.

Prognosis and complications

Transient epileptic amnesia is typically an epilepsy syndrome in which seizures are easily controlled with even small doses of antiepileptic drug monotherapy, though interictal memory disturbances might persist. The few cases that have been followed for a number of years indicate that once seizures are controlled, cognitive function does not progressively deteriorate (12; 59; 43), and patients typically report subjective improvement in cognitive symptoms. In some cases, the cognitive issues resolve completely (44). Cretin and colleagues reported a single case with relatively good cognitive and seizure outcome after a 67-year follow-up (16).

Savage and colleagues described a cohort of 10 patients with transient epileptic amnesia, which was first reported in 1998 and followed up at 2-time intervals, each 10 years apart (45). Information regarding clinical outcomes and subjective reports of memory functioning was gained via their records and clinical interview. 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. The authors concluded that there was no elevated risk of dementia, and although memory difficulties persist over time, the prognosis of transient epileptic amnesia appears generally benign (45).

Long-term follow up suggests that accelerated long-term forgetting can resolve, with improvements translating to recent autobiographical memory in some cases. It was also shown that control of seizures resulted in improvement in cognition, and a decline in performance was seen when seizures recurred (47).

Clinical vignette

The patient, a 54-year-old male, was first seen in the clinic in September 1991. He arrived saying "I'm having fugues, Doc," having been given a diagnosis of psychogenic amnesia elsewhere (28). After a "collapse" in February 1990, for which a good description was not available, his wife witnessed a second attack in May 1990. Shortly before they were going to bed, he bent down to pick up a cup of coffee and started to clench and unclench his hands transiently. He did not seem to understand what his wife said, and he moved into the kitchen where he looked around the room and "through" his wife for 1 or 2 minutes, seeming perplexed and confused, and then asked repetitive questions: "What day is it? ... What have I been doing? ... Why am I not at work? ... Where do I work?" His wife asked if he knew who or where he was, and he did. He "came round" one hour later, after which he went to bed and was fine in the morning. The next month, there was another attack when he was at the helm of a boat, sailing round the Isle of Man: suddenly, he demanded his fellow yachtsman tell him where they were, and he seemed very agitated, asking repetitive questions, until he came round an hour later. On this occasion, and during two further attacks at home lasting half an hour, there was no hand clenching nor any other evidence suggestive of epilepsy. As well as these symptoms, the patient complained of "gaps" in his memory, such as for a period when his wife was in hospital for a breast abscess in 1987; he also mentioned forgetfulness for appointments, everyday tasks, what he had read in the newspaper, and even for the location of familiar shops. On the other hand, it was noticeable that he remembered previous medical consultations with pernickety detail, and he never failed to attend medical appointments. There was a family history of possible epilepsy in a niece and of dementia in the patient's mother. A Cambridge graduate, he had worked as a partner in a small business for 20 years, but had lost his job in 1989 because of personality differences (not because of any memory problems). He had been seen previously by a neurologist and a psychiatrist in his local hospital where, after two routine EEGs, two CT scans, and cognitive testing, a tentative diagnosis of psychogenic amnesia had been made, and he had been treated with an antidepressant and a benzodiazepine.

Clinical assessment, investigations, and progress. An initial diagnosis of transient global amnesia was made based on the clinical history. Various investigations including EEG studies were organized, and a brief admission was arranged, which, for administrative reasons, did not take place for four months, during which the patient had a further four attacks that were identical to the previous ones. In the last of these attacks (although not in the others) clenching of the right hand was noted by his wife. Various psychological tests were carried out at the initial assessment. His verbal and full scale IQ were consistent with his educational accomplishments, although there did seem to be a relative decrement in performance IQ. Scores on the frontal lobe tests did not indicate any abnormality. The scores on the anterograde memory tests, however, were not as high as expected. After using published norms to convert these scores into "memory quotient" equivalents (with a population mean of 100 and SD of 15), an overall anterograde memory quotient of 98 to 0 was obtained, consistent with the population mean but 33 points below the patient's full scale IQ. A standard blood screen was normal, as were a chest radiograph, ECG, and MRI and a fluorodeoxyglucose PET (performed six months after cessation of the attacks). A standard EEG was normal, but two sleep EEGs showed frequent midtemporal sharp and slow wave complexes, arising independently in the right and left hemispheres. After a trial of carbamazepine, which produced adverse effects, he was started on phenytoin in February 1992, rising to a dose of 300 mg daily. No further attacks were recorded in the next 15 months, and there has been only one equivocal attack in the 21 months since this drug was commenced. Further neuropsychological testing was conducted after six months of treatment. Performance on the IQ, frontal, and anterograde memory tests was virtually identical to the (pretreatment) scores obtained a year earlier, although the verbal-performance IQ discrepancy had narrowed to 14 points. The anterograde memory quotient was unchanged; and the General memory quotient from the WMS-R scale gave a decrement of 23 points, relative to full scale IQ. On a retrograde memory test, requiring recall and recognition of pictures of famous news events, the patient performed at a superior level; his memory for facts about his past on a semistructured interview was also intact. He was hesitant, however, in recalling incidents from his childhood or early adult life, and his scores were at a "borderline" level according to published norms (28).

Biological basis

Etiology and pathogenesis

The pathophysiological basis of transient epileptic amnesia remains largely unknown though emotional and/or dysimmune factors may have a potential influence (19). Clinical, EEG, and brain imaging findings indicate that transient epileptic amnesia is a focal mesial temporal lobe epilepsy syndrome of middle-aged and elderly patients with additional pathology in connected brain regions. The unusual interictal memory deficits of transient epileptic amnesia remain unexplained by structural pathology and may reflect physiological disruption of memory networks by subclinical epileptiform activity and/or seizures (09). Neurometabolic data support a dysfunction of a hippocampal-neocortical network sustaining episodic memory (38).

The attacks of transient epileptic amnesia are either ictal or postictal manifestations. It has been postulated that transient epileptic amnesia results from recurrent focal seizures arising from mesial temporal lobe structures with resultant impaired memory function caused by an enduring postictal state (50; 56).

In most cases of transient epileptic amnesia, no clear cause for the epilepsy is identified, although focal brain structural lesions, always in the temporal region, have been reported in a small minority of transient epileptic amnesia cases (13; 23; 59; 30). There is no evidence of an increased prevalence of recognized risk factors for epilepsy, such as birth injury, febrile seizures, head injury, intracranial infection, or family history of epilepsy. Frequent occurrence of depression and association with autoimmune disorders, along with older age of onset, raises interesting questions regarding putative pathophysiologic mechanisms (38). A case with atypical symptoms of transient epileptic amnesia showed high levels of serum NMDAR antibodies (48). As a group, there is often presence of bilateral hippocampal volume loss, but whether this is a cause or an effect of repetitive seizures is not clear (10). There was no increased rate of cerebrovascular risk factors noted in patients with transient epileptic amnesia (13).

Ictal and interictal memory disturbances are thought to be related to dysfunction of medial temporal lobe and interconnected networks of entorhinal, perirhinal, and parahippocampal cortices.

Autobiographical amnesia maybe caused by repeated seizures in the temporal lobe resulting in the progressive "erasure" of memories. Alternatively, autobiographical memory loss may result from subtle changes in the temporal lobe, giving rise to temporal lobe epilepsy and memory problems. As with accelerated long-term forgetting, it is unlikely that antiepileptic drugs or problems with mood cause autobiographical memory loss in people with transient epileptic amnesia.

The neural mechanisms underlying accelerated forgetting are poorly understood. It has been hypothesized that interictal epileptiform activity during longer retention intervals disrupts normally established memory traces. Atherton and colleagues tested a distinct hypothesis that accelerated forgetting relates to the abnormal encoding of memories (04). The study compared a group of 15 patients with transient epileptic amnesia together with matched, healthy control subjects. Participants studied a series of visually presented scenes while undergoing functional MRI scanning. Recognition memory for these scenes was then probed outside the scanner after delays of 45 minutes and 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 transient epileptic amnesia. The authors proposed that abnormally encoded memory traces may be particularly vulnerable to interference from subsequently encountered material and, hence, be forgotten more rapidly (04).

Epidemiology

Incidence and prevalence are unknown though it appears that transient epileptic amnesia is rare. There are around 150 cases reported in the literature. In 2003 to 2005, only 32 patients were recruited via the British Neurological Surveillance Unit (11). However, transient epileptic amnesia is often misdiagnosed or underrecognized. Three cases (4%) of transient epileptic amnesia were found in a cohort of 76 consecutive patients with mild cognitive impairment (17), and 15 of 83 patients had an abrupt onset of amnesic disorder (29).

Differential diagnosis

Transient epileptic amnesia should not be difficult to diagnose for patients who also have coexistent attacks typical of temporal lobe seizures. In the absence of such brief seizures or if their presence is not detectable, the diagnosis of transient epileptic amnesia may be confused with transient global amnesia, psychogenic amnesia, and other causes of acute amnesia (27; 12; 07; 59; 52; 29; 02).

The main differential diagnostic criteria of transient global amnesia are:

In a real-life differential diagnosis between transient epileptic and global amnesia, Lanzone and colleagues retrospectively collected clinical data of 83 patients with an abrupt onset of amnesic disorder, initially interpreted as transient global amnesia (29). Clinical features, neurophysiological, and neuroimaging data were analyzed and compared in the two groups of transient epileptic amnesia (15 patients) versus transient global amnesia. From a clinical point of view, recurrence (p< .001) and atypical symptoms such as confusion or language disorder appear to be key elements in favor of transient epileptic amnesia (80% of patients with transient epileptic amnesia versus 7.8% of patients with transient global amnesia; p< .001). Duration of the episodes did not significantly differ between the two groups. The analysis of routine EEG results evidenced low sensitivity for interictal epileptiform abnormalities (52.3%), with no conclusive data in distinguishing the two groups. On the contrary, 24-hour EEG showed interictal epileptiform abnormalities in all patients with epilepsy, mostly during sleep, suggesting an essential diagnostic role of long EEG recording for transient epileptic amnesia. Finally, structural abnormalities were more frequent in patients with transient epileptic amnesia (26.6%) (29).

The main differential diagnostic criteria of psychogenic seizures are:

Confusing conditions

Transient epileptic amnesia should not be difficult to diagnose for patients who also have coexistent attacks typical of temporal lobe seizures. In the absence of such brief seizures or if their presence is not detectable, the diagnosis of transient epileptic amnesia may be confused with transient global amnesia, psychogenic amnesia, and other causes of acute amnesia (27; 12; 07; 59; 52; 29; 02).

The main differential diagnostic criteria of transient global amnesia are:

In a real-life differential diagnosis between transient epileptic and global amnesia, Lanzone and colleagues retrospectively collected clinical data of 83 patients with an abrupt onset of amnesic disorder, initially interpreted as transient global amnesia (29). Clinical features, neurophysiological, and neuroimaging data were analyzed and compared in the two groups of transient epileptic amnesia (15 patients) versus transient global amnesia. From a clinical point of view, recurrence (p< .001) and atypical symptoms such as confusion or language disorder appear to be key elements in favor of transient epileptic amnesia (80% of patients with transient epileptic amnesia versus 7.8% of patients with transient global amnesia; p< .001). Duration of the episodes did not significantly differ between the two groups. The analysis of routine EEG results evidenced low sensitivity for interictal epileptiform abnormalities (52.3%), with no conclusive data in distinguishing the two groups. On the contrary, 24-hour EEG showed interictal epileptiform abnormalities in all patients with epilepsy, mostly during sleep, suggesting an essential diagnostic role of long EEG recording for transient epileptic amnesia. Finally, structural abnormalities were more frequent in patients with transient epileptic amnesia (26.6%) (29).

The main differential diagnostic criteria of psychogenic seizures are:

Rarely, transient epileptic amnesia can be confused with transient ischemic attacks (TIA). These attacks typically happen in older patients, often with risk of cerebrovascular disease, and they are associated with focal neurologic deficits related to vasculature affected. Memory impairment is typically seen with completed strokes.

Associated or underlying disorders

Transient epileptic amnesia is considered a distinct subtype of medial temporal lobe epilepsy. The pathophysiological basis suggests involvement of hippocampus and neocortical structures, with resultant impairment in anterograde and retrograde memory. Imaging and EEG features are concordant with the same.

Diagnostic workup

EEG is the most useful diagnostic procedure, particularly if the recording is obtained during the amnestic attack.

There are very few reported EEGs taken during these episodes (07; 59), with some documenting that the transient epileptic amnesia is an epileptic seizure or nonconvulsive status epilepticus itself (32; 36; 55) while other recordings are consistent with postictal events (54; 20; 41; 33; 11).

Illustrative cases of postictal amnesic attacks. One patient had an amnesic episode while undergoing EEG. A brief (less than one minute) burst of left temporal spikes, during which the patient was unresponsive to speech, was followed by normalization of the EEG and a 10-minute period of amnesia characterized by repetitive questioning about recent events (11). The video-EEG recording of an attack of another patient showed that the amnesic state was characterized by a normal EEG tracing followed by electroclinical complex focal seizures (54). In another patient with medically-resistant transient epileptic amnesia, prolonged postictal slowing in the mesial temporal structures was evident on invasive EEG five hours after the occurrence of a brief focal seizure, supporting the theory of a Todd phenomenon as the underlying pathophysiological mechanism in transient epileptic amnesia (50; 56).

Illustrative cases of ictal amnesic attacks. In one woman, a prolonged amnestic state was caused by complex focal status epilepticus with bilateral mesiotemporal lobe involvement, confirmed by EEG with nasopharyngeal electrodes. An MRI scan obtained shortly after recovery from the amnesia showed reversible focal abnormalities consisting of increased signal intensity on T2-weighted scan in the mesiotemporal lobe (32).

In another woman, EEG during a prolonged amnesic episode showed diffuse bursts of delta activity prominent in the frontal areas, subcontinuous polymorphic delta activity more evident in the temporal areas and more often on the left side, and paroxysms of spikes and spike and wave complexes in the left temporal or temporofrontal areas and, asynchronously and more rarely, in the right temporal areas. In the occipital areas, a quite stable alpha rhythm was generally preserved, superimposed on the slow activity. During the recording, an ictal discharge was observed as well. This was apparently subclinical because no further changes in behavior and consciousness were observed. The discharge began with diffuse, fast, low-amplitude activity followed by small spikes originating from the right temporo-central areas and successively by a recruiting rhythm in the right hemisphere spreading to the left side. The ictal discharge lasted about 50 seconds and was followed by a return to the preictal picture, without postictal flattening and with preserved occipital alpha (36). The patient also had clinical evidence of overt complex focal seizures with automatisms. In another patient with transient epileptic amnesia, the ictal EEG during an amnesic episode documented nonconvulsive status epilepticus (07). The discharge beginning with diffuse, fast, low-amplitude activity was followed by small spikes on the right temporocentral areas and successively progressed to a recruiting rhythm on the right hemisphere spreading to the left side (07).

Illustrative case of ictal EEG of clinically inconspicuous seizure. A 79-year-old patient had an episode of anterograde amnesia that lasted 90 minutes. An EEG, performed after the episode, showed bilateral temporal electrographic seizures. A standard EEG performed three hours after the episode showed a right temporal electrographic seizure with a recruiting pattern of about 25-second duration, immediately followed by a left temporal electrographic seizure of shorter duration (about 15 seconds); the patient was not tested by the technician, but there were no obvious clinical symptoms (40).

When ictal EEG recording is not possible, interictal EEG during sleep often reveals unilateral (32% left sided; 12% right sided) or bilateral (56%) spikes or sharp waves in the temporal regions (14; 59). An otherwise healthy man had four to five late-onset episodes of transient amnesia, mainly on wakening (42). These were initially diagnosed as transient global amnesia. A routine EEG and brain MRI were also normal. Treatment with lamotrigine 50 mg daily resulted in freedom of attacks. It has been suggested that confinement of epileptic discharge to the nondominant temporal lobe can lead to partial preservation of consciousness during seizure attacks that produce transient amnesia (15).

Routine awake EEG is usually normal or shows minor nonspecific abnormalities (14; 59). Prolonged sleep EEG recording is usually revealing epileptiform abnormalities (29; 43).

Brain MRI is usually normal (38) or shows evidence of bilateral atrophic changes mainly involving the hippocampi (10; 09). In the latter study, 40 patients with transient epileptic amnesia and 20 healthy controls were investigated using manual volumetry and automated multi-atlas-based segmentation of whole-brain MRI data. 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 memory performance. No structural correlates were found for accelerated long-term forgetting or autobiographical amnesia (09). The volumes of these regions correlated with memory performance. No structural correlates were found for accelerated long-term forgetting or autobiographical amnesia (09). It is interesting to note that one of the studies actually showed no atrophy of hippocampi but instead showed calcifications in CA1 regions of hippocampus (08).

In one patient, the fluid-attenuated inversion-recovery MRI scan revealed high signal in the left hippocampus. Dramatic and circumscribed hypermetabolism in the left medial temporal lobe was evident on the PET scan. After one month, during which the patient had no intervening acute episodes, the PET abnormalities had resolved (12). This patient went on to develop left-sided hippocampal atrophy (59).

There have been few case reports of isolated amygdala enlargements in patients with transient epileptic amnesia; in two of those cases, amygdala enlargement improved with antiepileptic therapy (26; 53; 31; 01). A systematic case review of patients with temporal lobe epilepsy with amygdala enlargement found that patients had later age of onset, higher frequency of complex partial seizures compared to generalized convulsive seizures, and a better response to medications (06).

18F-FDG-PET is usually normal but may complement MRI with its ability to rule out neurodegenerative disease when suspected, potentially identify other patterns of hypometabolism suggestive of transient epileptic amnesia, and monitor for metabolic response to antiepileptic medication (43). In the few cases with abnormal FDG-PET, abnormalities are limited to focal hypometabolism involving the frontal or temporal regions, or both. In a report, 18F-FDG-PET showed positive correlations between left mesial temporal metabolism levels and anterograde and retrograde memory scores (38).

The detection of “accelerated long-term forgetting” requires specific memory testing because patients commonly perform within the normal range in the standard neuropsychological memory tests that assess the retention of new memory after delays of 30 to 40 minutes (22). In one study, it was found that accelerated long-term forgetting became apparent within 3 to 8 hours after learning, suggesting possible defects in memory consolidation process (21).

Management

Once a definite diagnosis of transient epileptic amnesia has been established, the physician can reassure the patient with a good prognosis with appropriate antiepileptic drug monotherapy. Though the antiepileptic drug treatment is empirical, the expert view is to prescribe rather small doses either with lamotrigine or levetiracetam, also considering the age of the patient and possible comorbidities (11; 51; 59; 38; 43). With antiepileptic drug therapy, seizure-freedom is achieved in 96% (11) to 73% of patients (38). However, despite control of the seizures, interictal memory problems remain, though without progression to deterioration (11; 58; 59; 38; 49). A patient with transient epileptic amnesia and a left temporal seizure focus developed isolated compulsive versifying, producing multiple rhyming poems, following seizure cessation induced by lamotrigine (57).

Exceptionally, a few patients do not respond to antiepileptic drugs but see good results with neurosurgical intervention (50; 56).

Outcomes

Long-term follow-up in different case series of patients has demonstrated that transient epileptic amnesia is largely a treatment-responsive syndrome with seizures amenable to antiepileptic drugs though interictal memory deficits might remain.

Special considerations

Pregnancy

Though complications are rare, see precautions listed in the article titled Pregnancy and epilepsy for care of pregnant women with transient epileptic amnesia.

Elderly

For elderly people, it is important to consider their safety and comorbidities. It is possible that with advancing age, there may be other comorbidities, which contribute to persistent cognitive complaints rather than seizures and which may need additional evaluation.