Risk factors
Between recurrent and non-recurrent populations, age and gender did not differ significantly. Our findings for the events precipitating TGA were consistent with previous research.[1-4,14.25] Seventy-three per cent of TGA episodes were precipitated by an identifiable event, most commonly an emotional or physical stressor. Of the physical stressors, those that have previously been described as Valsalva-like manoeuvres, including coughing, vomiting, immersion in cold or hot water, and sexual intercourse did all occur in some patients. Of the emotional stressors, some occurred immediately prior to the episode, for instance, people watching a sporting grand final. Others were longer-term psychological stressors, present weeks or months prior to the episode, including home, family and workplace conflicts. With regards to these longer-term stressors, it has been suggested these increase susceptibility to TGA and its recurrence.[1,28]
Among our recurrent patient, stress, as a precipitating factor, had a greater frequency but this finding was not statistically significant. With regards to possible risk factors, a history of depression was significantly increased among those with recurrence.
Previous head injury was significantly increased in those with recurrence. Many cases were of mild head injuries, defined as losing consciousness for less than 30 minutes or feeling dazed without loss of consciousness, and in the absence of focal neurological deficits.[29] Sequelae of mild head injuries included migraine with or without aura. However, migraine itself was not found to be more prevalent among the recurrent group.
Migraine, through cortical spreading depression, is a proposed mechanism for the pathogenesis of TGA, as it seems to occur at higher frequencies in TGA patients compared to age-matched controls.[3] TGA may occur during migraine.[15,21,24,27] While the design of our study did not include controls, 35.5% of our cohort had history of migraine, and headache was associated with 21% of episodes. This differs greatly from the 6% general population estimate for migraine.[30] Nevertheless, as history of migraine was recorded in less than half of patients, it is unlikely an exclusive cause, even if it plays a role in the aetiology of TGA.
While other cardiovascular risk factors were present in the cohort, none were significantly associated with recurrence or a single episode. There was no control group in our study, but prevalence values from the Australian Bureau of Statistics’ for hypertension, type 1 and 2 diabetes mellitus, dyslipidaemia, transient ischaemic attack, stroke and ischaemic heart disease were all smaller than that found in our cohort, which suggests these are not risk factors for the development of TGA.[30] Earlier studies have found increased rates of these risk factors in TGA patients compared to controls,[5,31] others have not.[2,6] Recurrent patients have been observed to have increased incidence of atheroma and ischaemic heart disease, which may contribute to hippocampal vulnerability to an ischaemic insight.[4,20]
Family history
Incidence of TGA is low, so in cases where multiple family members are affected, it raises questions of whether there is a direct or indirect genetic component. Within our cohort, family history of TGA existed for five patients through a first degree relative, one patient through a cousin, and another patient through two first degree relatives and a cousin. This patient also had recurrent TGA; the other six had a single episode. The small sample size of patients with family history of TGA meant statistical analysis was not possible.
Family history of dementia was found to be significantly associated with recurrence of TGA (Table 2). It is established that family history of dementia increases the risk of developing dementia among APOE ε4 carriers.[32] However, whether this or another genetic factor plays a role in TGA is yet to be determined.
Recurrence
Within our patient population, 26 of 93 (28%) had a second episode of amnesia, though in only 15 of 93 (16%) was the documentation strong enough to conclusively support that the patient had two or more episodes of TGA within the study’s duration. The reason for this discrepancy is that, while patients and their family members could recall another episode of amnesia, few other characteristics were recorded in medical files and by the time they were re-interviewed, they had forgotten many of the details. TGA is a unique condition, in that the patient is rarely able to describe their symptoms, so it is important to take good notes on their cognitive deficits when they present to healthcare professionals. Otherwise a more precise figure for recurrence may never be reached.
DWI investigations
Another hypothesis for TGA pathogenesis relates to susceptibility of blood vessels around the CA-1 region of the hippocampus, based on observations of DWI lesions this area.[9,18] Our findings are not consistent with this hypothesis, with the 35 DWI spots observed located throughout the hippocampus, from head to tail.
All but one spot was detected within one week of TGA onset. We were not able to assess the minimum MRI latency for positive lesions, however infarctions on MRI within 24 hours may only have 82% sensitivity, creating a high frequency of false-negatives in this timeframe.[33-35] Repeat MRIs, when performed after one week, showed most lesions had disappeared, in keeping with previous findings. Sensitivity of DWI for acute infarctions after 24 hours ranges from 88-100%, and specificity is 86-100%.[36,37] False-positive causes of DWI lesions are rare, but include such non-ischaemic diagnoses as cerebral abscess, brain tumour, sudden onset isolated vertigo and loss of consciousness with seizure.[36,37]
Factors noted to increase incidence of positive DWIs include a history of smoking and systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mmHg.[34] In our patient population, 50% and 42% of the patients with positive DWI had a history of smoking or hypertension, respectively.
Nevertheless, among TGA patients with MRIs performed within 10 days from onset, 41% (25/61) had a visible, hyperintense lesion. False-negative DWIs may explain why some patients do not show areas of hyperintensity.
Posterior circulation infarctions are much likelier to give false-negative DWIs than an anterior circulation infarction.[35] Blood supply to the hippocampus is complicated as it is variable. In most the posterior cerebral artery (PCA), or a branch thereof, supplies the hippocampus. In some there are contributions from the anterior choroidal artery.[38] The anterior hippocampal artery, branching from the PCA, supplies the hippocampal head, whilst the middle and posterior hippocampal arteries supply the hippocampal body and tail, and have numerous anastomoses.[39] Therefore small infarctions in the body or tail of the hippocampus might not show DWI positivity because of these anastomoses.
It is also possible that, whatever the cause of TGA, it might not show a positive DWI.
Outcomes
Three patients from our TGA cohort later went on to develop dementia. One was a non-recurrent patient, who had an MRI performed outside of 10 days that was normal initially and later showed atrophy. The second patient had three episodes of TGA over 15 years, with normal MRIs, though all were performed outside of the 10-day window. The other patient had two episodes of TGA over 10 years, with hyperintense hippocampal lesions detected on DWI performed within one week, and atrophy appearing less than two months after the second episode.
Of the 24 patients with subjective memory impairment, only one showed signs of atrophy on imaging two months post-TGA. However, five other TGA patients, not reporting memory changes, had noticeable cortical atrophy on MRI, ranging in age from 59-78; two of the five had recurrent TGA and had scans performed 1 day to 2 months post-TGA.
Previous studies have suggested recurrence might be associated with longer-term changes to memory, ranging from verbal and non-verbal memory impairment to dementia.[12,13] We were unable to confirm this. Nevertheless, it is a concerning prospect if TGA is not benign, but rather a risk factor or early warning sign for dementia. It is also possible that, among the group of people who reported subjective memory impairment, anxiety from the experience of TGA may leave patients doubting their short-term memory capabilities.
In conclusion, our results suggest TGA is a heterogeneous syndrome, characterized by variable features in different patients. In our experience, depression and a history of previous head injury predicted recurrence. It is possible that encouraging primary prevention of head injury through education, managing depression and assisting patients in developing adequate coping mechanisms for stressors may decrease TGA and its recurrence.