Keywords

A number of factors have been described in close temporal association with (i.e. immediately before) the onset of an attack of TGA and hence may be designated as precipitating factors, as opposed to those with a more distant temporal association which may be designated predisposing factors (Chap. 7). Miller Fisher identified such precipitating factors in 26/85 TGA episodes (30.6%) [1], whilst Rösler et al. identified precipitants in 58% of their 72 TGA patients based on administration of a standardised questionnaire [2]. In their review of cases reported in the literature, Quinette et al. noted precipitating factors in 462 of 881 cases (= 52.4%) and in their own series in 131 of 147 episodes (= 89.1%) [3]. Cejas et al. identified triggering factors in 41/79 (51.9%) of their TGA patients who agreed to complete a questionnaire [4], and in a retrospective survey of 389 patients, Hoyer et al. identified a precipitating factor in 266 (68.4%) [5]. Morris et al. found a similar percentage of cases with identifiable triggers in single-episode (28.8%) and recurrent (35.0%) TGA [6].

8.1 Emotional Stress

In his report on a series of 85 episodes of TGA, Miller Fisher found that highly emotional experiences were found to be the most common recognised precipitating event (8/26) [1]. Hodges and Warlow noted an emotionally stressful event in the 24 h before an episode of TGA in 14% of their prospective sample, examples including receiving bad news, witnessing an accident or being involved in an argument [7]. Emotional arousal was also noted as a precipitating factor for TGA by Merriam and colleagues [8, 9] who emphasised the differentiation of TGA from the forms of transient psychological amnesia (Sect. 3.3) which may also follow stressful experiences. Quinette et al. noted that emotionally charged events may be a precipitant of TGA, reported in 28% of cases in their literature survey and in 29% of their personally observed cases [3]. Emotional stress may be a predisposing factor for as well as precipitating event to TGA (Sect. 7.10).

The specific emotional stress may take many various forms, including the experience of a burglary [10], a disturbing dream [11] or an emotionally charged psychotherapy session [12]. A similar explanation might account for TGA following general anaesthesia in an anxious patient undergoing otolaryngological surgery [13].

Quinette et al. reported that TGA in women was mainly associated with an emotional precipitating event (cf. men, physical precipitating event) [3]. In a retrospective study of a cohort of 389 TGA patients, Hoyer et al. examined gender-related differences in stressful precipitating events and confirmed that emotional triggers were more often experienced by women (37.2% vs. 22.8%) [5]. Noh and Kang reported “extreme stress” occurring in 64.6% of their cohort of TGA patients, most of whom (114/128 = 89%) were women [14].

8.2 Physical Effort

Many forms of physical exercise have been described as precipitating factors for TGA, including cycling (e.g. [15, 16]; see also Case Studies 2.1 and 7.1), swimming (e.g. [17], and [18], case 2), skiing ([19]; also Case Study 7.1), gardening/digging (e.g. [4, 20]), sawing wood, after extreme exercise (e.g. [21]) and after medical procedures involving an exercise testing procedure such as the bicycle ergometer or treadmill [22, 23]. Other recorded effortful activities include defecation in constipated patients, coughing, vomiting and repeated yawning [4].

Hodges reported exercise as a precipitant in 18% of patients in the Oxford TGA study ([24], p.19). Quinette et al. noted physical effort as a precipitant of TGA in 31% of cases in their literature survey and in 25% of their personally observed cases [3]. Hoyer et al. found physical stressors were more common in men than women (41.1% vs. 30.7%) [5]. Hence, physical triggers of TGA are more often experienced by men and emotional triggers more often by women.

8.3 Water Contact or Temperature Change

Fisher and Adams “first case” (see Sect. 1.1) was associated with a swim in cold water [25]. In a report on a series of 85 episodes of TGA, Fisher found that bathing in cold water (specifically the Atlantic Ocean) was found to be a common recognised precipitating event (3/26) [1]. Other examples have also been reported (e.g. Case Studies 2.1 and 6.1). Quinette et al. reported water contact or temperature change (which could include hot baths) in 14% of patients in their literature review and in 11% of their own series [3]. Martin coined the term “amnesia by the seaside” for TGA cases associated with cold water immersion [26]. Tubridy et al. also used the term [27], even when there was no cold water immersion, merely a walk by the seaside ([28], p.11–6).

An episode of transient amnesia in a volunteer undergoing experimental repeated cold water (20 °C) immersion has been reported as TGA [29], but the details are not convincing for this diagnosis, specifically the development of “altered affect … whimpering, anxious delirium-like state” for 20 min. It was also atypical in the subject’s age (23).

Temperature change might also possibly contribute to or explain TGA cases associated with skiing ([19]; Case Study 7.1), high altitude [30,31,32], transoceanic flight [33], paragliding [34], infusion of cryopreserved cells [35] and whole-body cryotherapy (brief exposure to very cold and dry air) [36]. A study from relatively high altitude (Davos, Switzerland) found TGA cases peaked in the winter, suggesting that low temperature might be either a predisposing factor or a trigger for TGA, but no relation was found with atmospheric pressure, wind or humidity [37].

8.4 Sexual Activity

Amnesia is one of the recognised acute neurological consequences of sexual activity, as is headache, but whether these are separate or pathophysiologically related conditions is not currently known [38].

Sexual activity was noted as a precipitating factor for TGA in 2/17 patients reported by Fisher and Adams [25], and in a later report on a series of 85 episodes of TGA, Fisher found it to be the second most common recognised precipitating event for TGA (7/26) [1]. Hodges and Warlow reported sexual intercourse to be the precipitant of TGA in 3% of their cases [7]. Quinette et al. reported sexual intercourse as a precipitant in 12% of patients in their literature review and in 9% of their own series [3].

In addition, many individual possible reports of “coital” or “post-coital” amnesia have also been presented (e.g. [39,40,41,42,43,44,45,46,47,48,49,50,51].; see also Case Study 4.1 and Case Study 8.1). These include examples of recurrent episodes of amnesia after intercourse [52,53,54].

Case Study 8.1: Sexual Activity as a Precipitating Factor of TGA

A previously healthy 61-year-old man had an episode of memory loss. Somewhat abashed, he reported that about 7 weeks earlier he and his wife had been making love at 5 o’clock in the morning, “not something we usually do”. He then got up and was found in the kitchen some minutes later by his wife. She reported that he was repeatedly asking “where am I?”. Questioned by her, he had forgotten the names of his medications for high blood pressure and the fact that his son had recently passed his driving test. However, these functions returned after a period of about 4 h and did not recur. His general practitioner made a provisional diagnosis of transient ischaemic attack (TIA). The patient was commenced on aspirin, non-urgent structural brain imaging was arranged and referral made to the neurology clinic (adapted from [45]).

Monzani et al. reported on 10 patients (all male; age range 41–64 years) with transient amnesia related to sexual activity, which comprised 18% of all acute global amnesia patients observed during the study period; of these ten, one had a subarachnoid haemorrhage whilst all the others were diagnosed as TGA [55].

Episodes of TGA reported in association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, sildenafil (Viagra) and tadalafil, and with the intracavernosal injection of alprostadil (Caverject) (Sect. 3.4.2 and Table 3.8), may also be precipitated by sexual activity rather than being an acute adverse drug effect.

Concurrence of sex-related TGA and primary headache associated with sexual activity (PHSA), whose features differ from migraine, has been reported on occasion [56,57,58]. This may suggest the possibility either of shared pathophysiological mechanisms, perhaps related to activation of pathways within the trigeminocervical complex [58] or a concurrence of two disorders with a shared trigger [57].

8.5 Pain

In a report on a series of 85 episodes of TGA, pain was found to be one of the most common recognised precipitating events (6/26) [1]. Examples may include abdominal pain [25], dental extraction [59], trigeminal ganglion stimulation ([1], in 2/26), pain from a pilonidal sinus ([24], p.18) and myocardial infarction, although TGA after painless MI has also been reported (Sect. 3.1.6). TGA associated with other painful medical procedures is also well described (Sect. 8.8). Quinette et al. noted acute pain as a precipitant of TGA in 2% of cases in their literature survey and in 3% of their personally observed cases [3].

Migraine headache is a not infrequent accompaniment of TGA episodes, possibly as a precipitant (Sect. 8.6), as well as being a predisposing factor (Sect. 7.9) and a symptomatic cause of amnesia which enters the differential diagnosis of TGA (Sect. 3.4.1). Whether the pain associated with migraine headache per se may be considered a precipitant of TGA, rather than the migraine pathophysiology, does not seem to be commented upon in the literature.

The absence of case reports of TGA related to events acknowledged to be associated with severe pain such as parturition or cluster headache might be taken to argue against pain per se as a precipitant. Nephrolithiasis or ureteral colic is a rarely reported association with TGA [1, 60]. Fisher and Adams ([25], p.40) reported “One woman was in the throes of rather severe ureteral colic (this patient thought two of her previous attacks had also been precipitated by pain)”. Another possible association of TGA and kidney stone was confounded by use of multiple doses of opioid and non-opioid analgesia [61].

8.6 Migraine

Migraine has already been discussed in the context of the differential diagnosis of TGA (Sect. 3.4.1) and as a possible predisposing factor for TGA (Sect. 7.9). It may also be a precipitating factor.

TGA occurring during a migraine attack has been reported by many authors (e.g. [62,63,64,65,66,67,68]. However, this is probably a very rare occurrence. A large retrospective analysis from a centre in France identified six cases of TGA occurring (hence, according to the paper’s title, “triggered”) by a migraine attack amongst a cohort of 8821 new patients seen over an 11-year period [69]. Other mechanisms might also be envisaged, for example forceful vomiting in the context of a migraine attack might be associated with the Valsalva manoeuvre (Sect. 8.9).

Many of the familial examples of TGA (Sect. 7.8) had TGA episodes which reportedly occurred at the same time as a migraine (see Table 7.3).

8.7 Brain Infections

Brain infections are included amongst the symptomatic causes of amnesia (Sect. 3.5.2; Table 3.2) and may enter the differential diagnosis of TGA. Cases labelled diagnostically as “TGA” have on occasion been reported in association with infective disorders of the brain, including herpes simplex encephalitis [70, 71], neurosyphilis [72] and Epstein–Barr virus encephalitis [73], although Daniel states that these latter authors “clearly described a case of transient epileptic amnesia” ([74], p.205).

8.8 Medical Procedures and Therapies

Onset of TGA concurrent with the performance of various medical procedures has been described. Of these, angiography (cerebral, coronary) appears to be the most frequently described (see Sect. 3.1.5; Table 3.6).

Angiography was recognised as a possible precipitating event for transient amnesia even before the TGA nomenclature was coined ([75]; see Sect. 1.2). A retrospective analysis of over 20,000 angiographic procedures undertaken at one hospital over a period of 7.5 years identified 9 cases of TGA (= 0.04%), which followed either cerebral angiography (5 in 4360 = 0.11%) or cardiac angiography (4 in 8817 = 0.05%) but no cases following peripheral angiography were identified (0 in 7659), indicating the infrequency of the association of TGA with angiography [76]. Even cardiologists with extensive (>25 years) experience of cardiac angiography, encompassing many thousands of procedures, may not encounter a case of TGA (Dr WL Morrison, personal communication, Liverpool Heart and Chest Hospital, 24/12/16).

Various other medical procedures have sometimes been associated with the onset of TGA (Table 8.1). For example, upper gastrointestinal endoscopic procedures have on occasion been followed by TGA (e.g. [85, 87, 89, 90]), as has transoesophageal echocardiography [82, 83]. Possible explanations might include the emotional stress of instrumentation, associated pain, autonomic activation from passing the scope and medication use (scopolamine in [85], although TGA is also recorded following endoscopy without medication [87]). No account of TGA after colonoscopy has been identified.

Table 8.1 Reports of medical procedures associated with onset of TGA (see text for caveats)
Full size table

A review by Jeong et al. published in 2018 found 89 patients with medical procedure-related TGA described in 49 articles. The most common procedure was angiography (cerebral > coronary) followed by general anaesthesia, although with only nine cases the latter could simply be chance. Neurological procedures were more common than cardiac, anaesthetic, gastrointestinal and pulmonary procedures. The authors concluded that Valsalva-associated activities, emotional stress with anxiety and acute pain were predisposing (sic) conditions in these cases [90]. Hoyer et al. recorded TGA following a medical procedure in 2.1% of their cohort of 389 patients [5].

All these accounts of TGA associated with medical procedures are rare, considering the frequency with which the various procedures are undertaken, so could be chance concurrence rather than causal association. Moreover, medical procedures are often accompanied by patient emotional stress (e.g. psychotherapy [12]), particularly anxiety (Sect. 8.1) and pain (Sect. 8.5), which might also be contributory factors in the cases observed.

8.9 Valsalva Manoeuvre

Bedside spirometry (forced vital capacity), one of the medical procedures reported on occasion to precipitate an episode of TGA [22, 95, 96] (Sect. 8.8), requires breath holding before forced expiration, effectively the performance of a Valsalva manoeuvre. This manoeuvre has sometimes been implicated in a number of other situations associated with TGA onset, including physical exercise, sexual activity, cold water immersion and response to pain. It has also been considered relevant to the retrograde internal jugular vein blood flow due to jugular vein valve incompetence (Sect. 4.3.3.2) which is pertinent to one of the hypotheses of TGA pathogenesis (Sect. 9.2.2).

However, attempts to reproduce the typical clinical and neuroradiological findings of TGA by voluntary Valsalva manoeuvre have failed. Patients with a previous episode of TGA were subjected to a controlled Valsalva manoeuvre, at least 3 months post-event, and suffered no recurrence of either typical symptoms or MR-DWI findings of TGA [99]. Jeong et al. noted that more than half of their patients (n = 8) with incidental MR-DWI hippocampal hyperintensities had performed Valsalva manoeuvre-associated activities but this was also true of their TGA group (n = 16) [100].

Valsalva manoeuvre may thus be an associated, rather a precipitating, factor in some episodes of TGA.

8.10 Other Possible Precipitating Factors

TGA cases associated with medication use have been reported on occasion (Table 3.8). These drugs might possibly be considered as precipitating factors, but the paucity of reports and the variety of drugs suggest no one specific class of drugs as being particularly culpable. Emerging pharmacovigilance data suggest COVID-19 vaccines may be an exception.

There have been occasional reports of TGA occurring at high altitude [30,31,32] suggesting a possible role for cerebral hypoxia, although physical effort and temperature change may be contributory (and/or confounding) factors in these cases.

8.11 Summary and Recommendations

Many possible precipitating factors for TGA have been examined. Some consistent observations have been made, but no factor seems to be necessary and/or sufficient to induce TGA. This has prompted various aetiological theories for TGA which are reviewed and elaborated upon in the next chapter.