Time trends, frequency, characteristics and prognosis of short-duration transient global amnesia

Abstract

Background

Transient global amnesia (TGA) is characterised by a sudden onset of anterograde amnesia lasting up to 24 hours. One major differential for TGA is transient epileptic amnesia (TEA), which typically lasts<1h. However TGA can also be short in duration and little is known about the time-trends, characteristics and prognosis of TGA cases lasting<1h.

Methods

We compared the clinical features of TGA ascertained in two independent cohort studies in Oxfordshire, UK (Oxford cohort 1977-1987 vs. Oxford Vascular Study- OXVASC 2002-2018) to determine the time-trends of clinical features of TGA. Results were validated in another independent contemporary TGA cohort in Italy (Northern Umbria registry-NU 2002-2018). We compared the risk factors, clinical features and long-term prognosis (major cardiovascular events–MaCE, recurrent TGA and seizure/epilepsy) of patients presenting with episodes lasting <1h vs. those ≥1h.

Results

Overall 639 TGA patients were included (114 Oxford cohort, 100 OXVASC, 425 NU). Compared to the original Oxford cohort, there were more cases with TGA lasting <1 hour in OXVASC (n/% 32/32.0% vs. 9/8.8%), and in NU (11.8% vs 8.8% in Oxford cohort). In both OXVASC and NU, patient age, vascular risk factors and clinical features were largely comparable between those with TGA<1h vs. those lasting ≥1h. Moreover, there was no difference in the long-term risk of seizure/epilepsy or MaCE between TGA<1h vs. TGA≥1h.

Conclusions

Short-duration TGA episodes (<1h) are not uncommon and are more frequent now than in earlier studies. The clinical features and long-term prognosis of short-duration TGA did not differ from more typical episodes lasting≥1h.

Introduction

Transient global amnesia (TGA) is characterised by sudden onset of anterograde amnesia lasting up to 24 hours.[1,2] TGA was first reported in 1964 by Fisher and Adams,[3] and the current clinical diagnostic criteria for TGA were proposed by Hodges and Warlow in 1990.[2] However, little is known about the evolution of clinical features of TGA since then.

One diagnostic challenge of TGA is the exclusion of other potential causes of a transient amnestic syndrome, such as transient epileptic amnesia (TEA).[4] TEA is reported as being shorter than TGA, lasting typically less than 1 hour,[4–8] with higher rates of recurrence over time.[4] However, up to 30% of TGA cases also recur,[1] and some TGA cases can also present with electroencephalography (EEG) changes.[9] More importantly, TGA cases can potentially be of short duration with 9% of the TGA cases reported to be <1 hour in the original 1990 cohort report.[1,2] Diagnostic certainty about TGA vs. TEA will therefore partially depend on the frequency and prognosis of apparent short-duration TGA cases among patient presenting with a transient amnestic syndrome.

In the absence of any similar study, we aimed to determine if there has been any evolution of the clinical spectrum of TGA in routine clinical practice since the original report by comparing the clinical features of TGA ascertained in two independent cohort studies in Oxfordshire, UK (Hodges & Warlow 1977-1987 [1,2] vs. Oxford Vascular Study- OXVASC 2002-2018), and to validate the results in another independent contemporary TGA cohort in Italy (Northern Umbria TGA registry – NU). We also aimed to study the frequency, and prognosis of short-duration TGA.

Methods

Consecutive patients with first-in-study period suspected TGA were prospectively collected from OXVASC and from NU. Both studies received ethical approval (OXVASC: OREC A -05/Q1604/70; NU: CEAS-12976/18), and informed consent was provided. We also extracted data from the original TGA cohort reported by Hodges and Warlow (Oxford cohort).[2]

The original Oxford cohort consisted of 114 patients diagnosed with TGA either as part of the Oxfordshire Community Stroke Project (OCSP) or at the Department of Neurology in Oxford between 1977 and 1987. Patients were followed up for a mean duration of 34.8 months.[2]

The current Oxford cohort, OXVASC, is an ongoing population-based study of all incident and recurrent vascular events in a population of 92,728 individuals registered with 100 general practitioners (GPs) in 9 general practices in Oxfordshire, UK, which overlaps the general practice population of OCSP. The study methods have been reported previously.[10] As part of the study methods, all participating GPs were asked to refer any patient with suspected transient neurological attacks to the daily rapid-access TIA/stroke clinic. Daily searches of the local emergency department (ED) register and admissions to medical, stroke, or neurology wards were also performed to ascertain cases that were admitted. All cases were reviewed by the senior study neurologist (PMR) and only patients with a final diagnosis of TGA from 01/04/2002 till 31/10/2018 were included for the current study.

NU is a TGA registry including all patients diagnosed as TGA seen in the Hospital of Perugia between 2002 and 2018. In Italy, the public National Health System allows direct referral to the emergency department for any suspected TGA and as a result almost all suspected TGA cases were managed at ED or admitted as inpatients. All cases with suspected TGA were assessed by a neurologist as soon as possible and only patients with a definite diagnosis of TGA were included in the current study.

In both OXVASC and NU, patients with suspected TGA were assessed as soon as possible and the standard clinical diagnostic criteria for TGA was used.[2] Further investigations were left to the treating physician but patients routinely had brain imaging (CT or MRI) and EEG was performed in cases where TEA was suspected, with TEA diagnosed according to standardized criteria, including (i) a history of recurrent witnessed episodes of transient amnesia, (ii) normal cognitive function during the episode beside memory impairment, (iii) evidence for a diagnosis of epilepsy including concurrent onset of other clinical features of epilepsy, clear-cut response to anti-convulsant treatment, or epileptiform abnormalities on EEG[6].

In order to study the full spectrum of the disease and to represent routine clinical practice, all patients with confirmed TGA were included in the analysis and we did not limit the analyses only to those that had MRI and EEG performed. Demographic data, previous medical history including history of TGA, and clinical features of the presenting episode (e.g. trigger, duration of anterograde amnesia, duration of retrograde amnesia, accompanying symptoms) were collected from face-to-face interview, supplemented by review of medical records.

All patients were followed-up by a combination of face-to-face interview, telephone interview and administrative follow-up to identify any major cardiovascular events (MaCE), recurrent TGA, seizure/epilepsy or death. Major cardiovascular events (MaCE) included a composite outcome of nonfatal stroke, nonfatal acute coronary syndrome, or death from cardiovascular causes. In OXVASC, follow-ups were usually done at 1 month, 3 month, 6 month, 1 year, 5 year and 10 years and all patients presenting with stroke would also be prospectively identified by the ongoing daily ascertainment. [10] Stroke was defined as a new symptomatic neurologic deterioration lasting at least 24 hours that was not attributable to a non-stroke cause. Acute coronary syndrome included myocardial infarction (MI) with or without ST-segment elevation or unstable angina followed by urgent catheterisation. In OXVASC, all patients presenting with stroke or MI would also be prospectively identified by the ongoing daily ascertainment. [10]

Statistical analysis

Continuous variables are presented as means and standard deviation (SD) and categorical variables as number and percentage. Kaplan-Meier survival analyses were first used to present the time-course and risks of vascular events during follow-up, censored at death or 31/10/2018. We then calculated the annual rates of major cardiovascular event (MaCE), recurrent TGA and seizure/epilepsy using Poisson distribution.

We also compared the baseline characteristics and clinical features of TGA ascertained in the two independent cohort studies in Oxfordshire, UK (Oxford cohort [1,2] vs. OXVASC). We then compared the clinical feathers of TGA in two contemporary TGA cohorts (OXVASC, UK vs. NU, Italy). To characterise the clinical features and prognosis of short-duration TGA, we compared the demographic data, risk factors, clinical presentation and long-term risks of MaCE, recurrent TGA or seizure/epilepsy in patients with TGA lasting for <1h vs. those lasting for ≥1h in OXVASC and in NU respectively. All statistical analyses were carried out using SPSS 25.0.

Results

Overall, 639 TGA patients were included (114 Oxford cohort[2], 100 OXVASC, 425 NU). During the 16 years of OXVASC and NU, 9 patients were diagnosed with TEA and were thus excluded from the analyses. Overall, in OXVASC and NU combined, 345 patients (65.7%) underwent EEG, none of which displayed epileptic features.

Compared to the original Oxford cohort, patients in OXVASC were older (mean/SD age 68.2/8.9 vs. 62.3/8.5 in the Oxford cohort, p=0.001; table 1), more likely to have diagnosed hypertension (n/% 45/48.0% vs. 25/21.9%, p<0.001; table 1) and less likely to be current smokers (5/5.0% vs. 17/14.9%, p=0.02; table 1). The baseline characteristics of OXVASC and NU were broadly similar, although patients in NU were younger and had a slightly higher prevalence of hypertension (table1). The frequency of treated hypertension however did not differ between OXVASC and NU (44/44.0% vs. 196/46.1% for NU, p=0.70; table 1).

Clinical characteristics of the TGA between the three cohorts are listed in table 1. As expected, abnormal neurological signs or autonomic features were similarly uncommon in all three cohorts (table 1). However, retrograde amnesia was documented marginally more frequent in OXVASC than in the Oxford cohort (47.0% vs. 35.1% for the original Oxford cohort, p=0.07; table 1), but was comparable between OXVASC and NU (47.0% vs. 47.3% for NU; table 1). There were significantly more cases with TGA anterograde amnesia lasting <1 hour in OXVASC than in the original Oxford cohort (32.0% vs. 8.8%, p<0.001; figure 1). Although TGA cases <1 hour were less commonly seen in NU than in OXVASC (11.8% vs. 32.0% for OXVASC, p<0.001; figure), they were still marginally more frequent than in the original Oxford cohort (11.8% vs 8.7%, p=0.23; figure). Of note, there was some evidence of digit preference with 34 (8.0%) of the NU patients reporting TGA episodes lasting for exactly 1 hour vs. 5 (5.0%) in OXVASC.

Figure 1. Frequency of anterograde memory deficit of different duration in the Oxford cohort vs. OXVASC vs. NU.

Table 2 compares the baseline risk factors and clinical features of patients with TGA <1h vs. those ≥1h in OXVASC and NU respectively (table 2). In OXVASC, patients with TGA<1h did not differ from those with TGA ≥1h in age, sex, vascular risk factors, clinical features or neurological examination at onset (table 2). The same was found in the NU cohort, although patients with TGA<1h had higher prevalence of dizziness reported than those with TGA≥1h in the NU cohort (table 2).

During follow-up of 3905 patient-years, there were 46 major cardiovascular events, 39 recurrent TGA and 6 seizure/epilepsy in OXVASC and in NU (table 3). In OXVASC, annual risk of any major cardiovascular event was 0.6% (95%CI 0.1-3.2) after a TGA episode lasting <1h vs. 1.6% (0.6-3.3) after a TGA episode ≥1h (p=0.35). Similarly, in NU, risks of any major cardiovascular event did not differ between those with episodes <1h vs. ≥1h (1.8% vs. 1.2% for ≥1h, p=0.42). Moreover, no differences in risks of recurrent TGA or seizure/ epilepsy were found between TGA<1h vs. TGA≥1h in OXVASC or in NU (table 3). Notably, risks of seizure/epilepsy were also much lower in OXVASC and NU than in the original Oxford cohort (Oxford cohort 2.5%, 95C% CI 1.1-4.7 vs. OXVASC 0.3%, 0.1-1.0 vs. NU 0.1%, 0.0-0.3; pOXVASC vs. Oxford=0.004, pOXVASC vs. NU=0.31).

Discussion

Using data from three independent cohorts of TGA patients, we showed for the first time that short-duration TGA episodes (i.e. <1h) are not uncommon and have become more recognised over the last four decades. Reassuringly, the clinical features and long-term prognosis of short-duration TGA did not differ from more typical episodes lasting ≥1h.

Our findings suggest that there have been an expansion in clinical phenotypes of TGA since the introduction of the diagnostic criteria in 1990, particularly in Oxfordshire, UK.[2] This is perhaps not surprising and has also been reported in other neurological diseases.[11,12] The apparently rising prevalence of “milder” or “atypical” cases is most likely related to increasing awareness and recognition of the disease by physicians. The design of this study allowed to compare the temporal trends of clinical features in two cohort studies from the same underlying population (Oxfordshire), and to then confirm the findings in a third independent study, accounting for regional variations. Although the prevalence of TGA<1h appeared to be lower in NU vs. OXVASC, possibly due to some digit preference in reporting in NU, it was still higher in NU than in the Oxford cohort [2], further supporting an expansion in TGA phenotype. Moreover, the benign long-term prognosis of TGA episodes in both NU and OXVASC cohorts corroborates that short-lasting TGA is getting increasingly more common but still benign.

Transient amnesic episodes lasting for <1h are challenging to diagnose and are often considered as a typical feature for TEA. However, we found that short-duration TGA (i.e. <1h) was much more common than TEA. In OXVASC and NU combined, 80 TGA were found to be <1 h vs. 3 of the 9 TEA cases. Moreover, we showed that TGA cases lasing <1h had similar risk factor profiles, clinical features and long-term prognosis compared to more typical TGA cases lasting ≥1h. Therefore short-duration TGAs should also be managed as typical TGAs, and clinicians can avoid over-requesting of additional diagnostic tests.

We also showed that the absolute risks of seizure after TGA in the two contemporary cohorts were very low and were much lower than in the original Oxford cohort. This finding has implications on management of these patients. In the UK, the Driver and Vehicle Licensing Agency (DVLA) requires appropriate investigations to exclude seizure after a brief episodes of amnesia (https://www.gov.uk/transport). However, our results highlight that, given the low risk of seizure, even in those with TGA episodes lasting <1h, routine MRI or EEG may not be justified even in those with episodes of short-duration. Moreover these more up-to-date risk estimates should also be taken into account for patient consultation and for future regulations/polices for driving after TGA.

The strength of our study includes that we were able to compare the temporal trends in studies from the same population (i.e. Oxfordshire) and to compare the results in a third larger independent cohort in Italy, accounting for any confounding by national differences. However, the study also has limitations. Firstly, although both cohorts attempted to be inclusive, there could still be cases missed. In OXVASC, those patients with typical TGA (i.e. lasting ≥1h) might not have been referred to the OXVASC study clinic as general practitioners might be more comfortable making the diagnosis themselves. Hence we may have overestimated the prevalence of TGA<1h in OXVASC. On the contrary, in Italy, patients were more likely to present to the emergency department directly. Patients with very brief episodes might decide not to go the hospital in the first place, particularly if they were alone when the episode occurred. Therefore the true prevalence of TGA<1h might be underestimated in the NU cohort. Secondly, we did not routinely perform brain MRI in all TGA patients hence we were not able to compare the prevalence of imaging findings in TGA cases <1h vs. those lasting ≥1h. However, it was reassuring that the risks of major cardiovascular events were low in both cohorts and therefore misdiagnosis of ischaemic events for TGA is unlikely. Thirdly, we did not routinely perform EEG. However, 66% of patients in OXVASC and NU combined had EEG, 59% of those with TGA<1h. No EEG revealed epileptiform abnormalities, and no differences were found between patients undergoing and those not receiving EEG. Although less than 5% of the patients received EEG during the TGA episode, the lack of epileptiform abnormalities in these patients at onset, together with the systematic ascertainment of any recurrent TGA-like symptoms and the very low risk of seizure/epilepsy during follow-up suggests that substantial misdiagnosis of TEA for TGA is also unlikely. Fourthly, we were only able to compare the clinical characteristics and outcomes of TGA<1h vs. TGA≥1h in the OXVASC and in the NU cohort as the equivalent data from the original Oxford cohort was not available. Fifthly, some patients may not have the whole TGA episode witnessed hence there could be underestimation of the true duration of some TGA episodes. However the way duration was recorded in the current study reflects routine clinical practice, where clinicians base their judgement on the reported duration from the witnessed episode. Finally, the TGA diagnosis in both OXVASC and NU was made after careful neurological ascertainment. Therefore our results may not be generalizable to settings where TGA is largely managed by non-neurology specialties.

In conclusion, we showed that short-duration TGA episodes (i.e. <1h) are not uncommon and have become more recognised in the last 4 decades. Reassuringly, the clinical features and long-term prognosis of short-duration TGA did not differ from more typical episodes lasting ≥1h and therefore they should still be managed in the same way as those otherwise typical TGAs.