Our results for precipitating events leading to TGA were compatible with findings of others.[1-4,14,25] Most of our TGA episodes were precipitated by an identifiable event, most commonly an emotional or physical stressor involving Valsalva-like manoeuvres. Some emotional stressors occurred immediately before the attack; others were more longer-term, including home, family and workplace conflicts – it has been suggested that these increase susceptibility to TGA and its recurrence.[1,29] A history of depression and head injury were significantly increased among those with recurrence.
Approximately one-third of our cohort had a history of migraine; a much greater proportion than in the general population. Our data supports a pathophysiological association between migraine and TGA, probably through spreading depression.[15,21,24,27,28] Interestingly, one-fifth of our patients had attacks of TGA with headaches
Other studies have found increased rates of cerebrovascular risk factors in TGA patients;[5,30] a finding that has not been replicated.[2,6] Some observers have found increased incidence of ischaemic heart disease in recurrent TGA.[4,20] However, we did not observe any association with cerebrovascular risk factors.
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. The small sample size of patients with family history of TGA meant statistical analysis was not possible. The presence of TGA in families is not well studied. We have found a complex presentation of TGA in families which requires more investigation. Of note, a family history was found to be significantly associated with the occurrence of TGA, a finding not previously identified.
Family history of dementia was found to be associated with recurrence of TGA. The genetic predisposition of TGA is unknown; however, it is recognised that APOE e4 is a risk factor for dementia.[31] Therefore, we propose that the link between genetic factors operable in TGA and its relationship to dementia family history may be through an APOE e4-like mechanism.
Within our patient population, 28% had a second episode of amnesia, though in only 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, they could not remember other details. Recall bias might have influenced their recollection of the facts.
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 in 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 time frame.[32-34] 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%.[35,36]
Factors noted to increase incidence of positive DWIs include a history of smoking and systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mmHg.[33] 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.[34] 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.[37] 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.[38] Therefore, small infarctions in the body or tail of the hippocampus might not show DWI positivity because of these anastomoses.
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] Our data do not support that TGA is a risk factor for dementia. 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.