Clinical manifestations

Presentation and course

Typically, the onset of this clinical syndrome is abrupt, and anterograde memory is profoundly impaired. Patients are disoriented to time and often to place but never to person. Particulars are forgotten even after repeated practice, resulting in ideational and motor perseveration. Patients may recognize their memory deficits and repeatedly ask orienting questions and also, "Why can't I remember?" (18). A much more mild reduction of retrograde episodic memory (inability to recall past events) may also be seen in transient global amnesia (168). Transient global amnesia occurs most frequently in the seventh decade of life. Taken across various studies, the mean age for an episode ranges from 61 to 67.3 years. Peak incidence of occurrence is around age 62 years (SD = 10 years). Demographically, 54% to 67% of patients with transient global amnesia are female (138). Women were found to have more frequent emotion-related precipitating events, whereas men were found to have precipitating events related to physical stressors. Women were also found to have increased hippocampal lesions (73). One study found no difference in age of episode for men and women. Regarding clinical presentation, migraine was a prevalent complaint for those within this population (180; 138). The Tynas and Panegyres study revealed a heightened reoccurrence rate (ie, 27%) within their sample than previously reported. The authors postulated a pathophysiological association between migraine and transient global amnesia through the presence of depression as a result of the shared presentation for those with reoccurring transient global amnesia. Participants with higher rates of reoccurrence are primarily female, with higher percentages of history of depression, overall shorter durations of transient global amnesia episodes, and a presence of abnormal hippocampal hyperintensities (138). In addition, Tynas and Panegyres found a significant increase in reports of a history of head injury for those with recurrence versus those with one episode (180). Hoyer and colleagues described a circadian rhythmicity in transient global amnesia attacks, marked by a morning peak and a secondary afternoon peak, independent of the age and sex of the patient (74).

In 1990, Hodges and Warlow developed diagnostic criteria for this clinical syndrome that have served as the basis for recognition of this condition (71).

Criteria include:

• Attacks must be witnessed • There must be anterograde amnesia during the attack • Cognitive impairment is limited to amnesia • No clouding of consciousness or loss of personal identity • No focal neurologic signs or symptoms • No epileptic features • Attack must resolve within 24 hours • No recent head injury or active epilepsy

Although focal neurologic deficits are part of the exclusionary criteria for transient global amnesia, the most common nonfocal symptoms include headache, nausea, and vomiting, each present in 10% of transient global amnesia cases immediately after an attack (71; 193; 180). Transient oculomotor abnormalities may also be present (190). No other major neurologic symptoms, signs, or overt seizure manifestations are present.

Although the standard accepted criteria state that deficits accrued during transient global amnesia resolve themselves within 24 hours, several studies following the resolution of acute-phase symptoms have mixed results (80; 181; 135; 168). There has been difficulty in differentiating transient global amnesia from transient epileptic amnesia (typically shorter duration with a higher rate of reoccurrence), especially because up to 9% of transient global amnesia episodes can last more than one hour (71; 10) and some transient epileptic amnesia cases can present with abnormal EEG findings (171). Short-duration transient global amnesia is not uncommon and is often described as “milder” or atypical transient global amnesia, marked by similar risk factor profiles, clinical features, and long-term prognosis as transient global amnesia episodes lasting more than 1 hour (155). Pantoni describes transient global amnesia as self-limiting, requiring no specific therapeutic intervention (141). Although transient global amnesia, itself, is not fatal and relatively benign, more life-threatening conditions like dissecting aortic aneurysm or tumor have been associated with this state (65; 49).

Neuropsychological assessment in the acute stage of a transient global amnesia attack reveals selective episodic memory impairment in the setting of otherwise largely intact cognitive functioning, including intact attention and working memory (84). More specifically, findings reveal striking anterograde amnesia for verbal and nonverbal information (80), thought to reflect deficient encoding in the earliest phase of transient global amnesia and deficient storage of new information in the later phase (151). A variable degree of retrograde amnesia may also be present and is typically temporally graded, such that more remote memories are spared (94; 70; 58). Work by Sandikci and colleagues examined semantic fluency performance in individuals with acute transient global amnesia and confirmed hippocampal diffusion-weighted MRI lesions (158). Patients with transient global amnesia had significantly poorer semantic fluency performances than healthy controls in the acute stage, with this difference then disappearing 24 hours after transient global amnesia. These patients also exhibited the expected pattern of pronounced anterograde amnesia.

Patients may also exhibit difficulties in temporally dating or sequencing remote memories (95). Jia and colleagues studied three patients with transient global amnesia using the Mini-Mental State Examination (MMSE), revised Wechsler Memory Scale (WMS-R), and MRI scans. As part of this study, patients were given a PET examination using (18)F-labeled deoxyglucose as the tracer at different periods during recovery. No obvious deficit or abnormality was found in MMSE performances or MRI scans in the three patients. However, memory testing revealed various degrees of dysfunction, and cerebral PET imaging revealed low metabolism in local areas related to memory in two of three patients. The authors concluded that in patients with transient global amnesia, cognitive function and cerebral metabolic levels are closely correlated with duration of symptoms (84).

Of note, personality and complex cognition, such as abstract thinking, problem solving, and language, are also preserved, although patients appear confused, tending to get lost once outside of familiar surroundings (176). Those with transient global amnesia are able to acquire new skills that do not heavily rely on episodic or working memory (52; 40). Impairment was found in prospective episodic memory (the ability to remember to perform an intended action at some point in the future (61). In 2011, Hainselin and colleagues found that although patients with transient global amnesia are well aware of personal deficiencies during an episode, they were unable to pinpoint the exact issues as they occurred. In the acute stage, self-awareness may be altered in this population, resulting in a lack of insight into their memory loss (61). A study employing pronoun use, as a proxy for attentional focus on self, showed that those with transient global amnesia use more pronouns and self-references than healthy controls. This aligns with previous studies noting heightened self-focus during the acute stages of transient global amnesia, which the authors postulated may relate to increased anxiety during this acute stage. This is related to the patient’s inability to utilize future projecting and action-oriented coping (eg, planning) during this stage. The authors suggest that the patient, therefore, employ a temporary self-focused attention as a method of “investing in self” and grounding that rejects the threat of dissociative amnesia when confronted with unfamiliar places or people (17).

There is literature that suggests the presence of precipitants in 33% to 89% of attacks (46; 193; 39). Physical exertion is the most common, followed by emotional stress and sudden temperature change; specific medical procedures may also be precipitating events in some cases (71; 122; 193; 19; 150; 39). Epinephrine and norepinephrine can cause vasoconstriction of the carotid arteries and impede blood flow to the hippocampus and medial temporal lobe, areas shown to be involved in transient global amnesia manifestation (157), in addition to the very large role of posterior hippocampal circulation, as later discussed.

In their review, Spiegel and colleagues highlighted a study comparing psychiatric disease in transient ischemic attack and transient global amnesia (168). Psychiatric disease was defined as having “a diagnosis of depression or anxiety disorder” or having received “treatment with specific drugs for at least 3 months.” Within this study, patients with transient global amnesia were significantly more likely to endorse psychiatric disease when compared to patients with transient ischemic attack. They also endorsed higher family history of psychiatric disease when compared with participants who experienced transient ischemic attack (168). In a longitudinal study by Noël and colleagues, participants were examined approximately 4 months and 1 year following a transient global amnesia episode (134). Those with higher scores on depression and anxiety scales showed worse performance on anterograde and retrograde memory tasks at a 4-month follow-up, respectively. Importantly, authors Hsieh, Chen, Ho, Yang, and Yang concluded that although highly associated with psychological distress, transient global amnesia episodes did not increase the long-term risk of depression at an 8-year follow-up (75).

Prognosis and complications

Prognosis is usually excellent. Patients usually make a good recovery from the event, except for amnesia during and around the event, which can last for around 24 hours, with little or no risk for cerebrovascular disease (56; 127; 47; 09; 67; 105). Gandolfo and colleagues followed 102 patients with transient global amnesia whose mean age was 62.8 years for a mean of 82 months (range of 12 to 241 months). There was no difference in the death rate between those with transient global amnesia and sex- and age-matched controls from the general population. Approximately 20% (19 of 102 cases) had recurrent attacks of transient global amnesia. Only four patients (4%) later developed a stroke (47). Mueller reported that within a mean period of observation of 5 years, a first recurrence was followed by one further amnesic attack in one fifth and by two or more attacks in one tenth of patients. Arena and colleagues followed 221 patients with transient global amnesia with a mean duration follow-up of 12 years (09). Results showed that, compared to the control group, there was no significant increase in the risk for cerebrovascular events, seizures, or cognitive impairment. There were no significant differences between survival rates for control patients and those with transient global amnesia when looking at the risk of cerebrovascular, seizure, or cognitive impairment occurrences in the years following a transient global amnesia episode. He and colleagues followed 73 patients with transient global amnesia and 73 controls who were matched for age and gender. It was concluded that eight patients had abnormal cerebral arteries during vascular assessment. However, overall data concluded that, consistent with other studies, patients with transient global amnesia did not have a high risk for cerebrovascular disease, nor did any risk for such events increase during the follow-up period. Compared to patients diagnosed with migraine or seizure, patients with transient global amnesia do not seem to face a heightened risk of stroke (113). Others have reported a lower rate of recurrence, 2.5% to 5% per year for at least 5 years after the first event (193; 95). The incidence of subsequent epilepsy is also low (67). Interestingly, it has been suggested that transient global amnesia represents a risk factor for mild cognitive impairment (23). A review highlighted that there could be both similar or an increased risk of dementia or epilepsy compared to healthy control groups (105). This indicates that more studies on the long-term risk in transient global amnesia may be needed. Romoli and colleagues concluded that the long-term prognosis of patients with transient global amnesia whose episode duration lasted less than one hour did not differ from patients whose episode lasted more than one hour (155). Of note, most episodes last several hours, and an episode lasting less than one hour is rare. Results were also consistent with previous studies in terms of cardiovascular risk. Patients with transient global amnesia, who are mostly middle-aged, often have vascular risk factors, such as hypertension, hyperlipidemia, diabetes, etc.

Varied recurrence rates from 2.9% to 25% for transient global amnesia have been reported (168; 05). In their study, Alessandro and colleagues found that only a minority of patients had a recurrence over a 2-year follow-up, with a recurrence rate of 8% (05). They found that patients reporting recurrent transient global amnesia had a greater history of migraine than transient global amnesia patients without recurrence. Similarly, another study found that increased risk for transient global amnesia recurrence is associated with having a personal or family history of migraine (125).

Clinical vignette

A 67-year-old teacher suddenly became amnestic after walking her dog. Her husband noted that she was oriented to person and knew the names of close friends; however, she was disoriented to time and place and seemed perplexed. She could follow complex commands but was unable to recall something she had been told 5 minutes before. The episode resolved after 10 hours, although she remained largely amnestic for the event. She had one instance of migraine without aura, but the episode of amnesia was not associated with headache. Her mother had a similar event after a traumatic experience. During and after the event, neurologic examination was normal. CT brain imaging, Doppler ultrasound of the extracranial cervical vessels, and EEG were all normal.

Biological basis

Etiology and pathogenesis

The etiology is unknown. Suggested causes have included a transient ischemic attack (164; 56; 42; 185; 168), migraine (189; 71; 108; 168), epilepsy (44), vein thrombosis (166), central nervous system tumors (36), saline-contrast transthoracic echocardiography (182), transoesophageal echocardiography (26), drug intoxication (08) or other toxic and metabolic disturbances (120), circadian rhythmicity (74), possible stress induced with impact on the hippocampus (74), and hysteria (70). None of these proposed etiologies have gained full acceptance.

A transient ischemic attack that affects the hippocampi and associated mesial structures was thought to be a leading cause of transient global amnesia (164; 56; 104; 38), although many contest this view (50; 71; 123). Supporting evidence includes PET and SPECT studies that show hypoperfusion and hypometabolism in the hippocampi and associated mesial structures during an attack with resolution following the attack (169; 175; 107; 04; 11; 119). Wang and colleagues detected hyperintensities in the head, body, and caudate of CA1 and in the hippocampal tail on diffusion-weighted imaging during the acute phase after onset of transient global amnesia symptoms (184). The authors suggested that, due to the presence of microstructural sequelae, ischemic lesions in the hippocampus may be associated with transient global amnesia. However, patients with transient global amnesia do not present with an increased risk of subsequent stroke compared to individuals with transient ischemic attacks (105). Ogawa and colleagues suggested increased cytotoxicity in lesions found in the CA1 region of the hippocampus in patients with transient global amnesia, which led to cytotoxic edema in the lesion areas (136). Using ultra-high field 7 T MRI, hippocampal lesions, initially detected during the acute phase of transient global amnesia, did not show focal sequelae; this highlights the importance of diffusion-weighted imaging during the acute phase (139).

Matsui and colleagues observed a patient with pure transient global amnesia whose MRI demonstrated a small region of increased signal intensity in the right hippocampus on diffusion-weighted imaging (117). Functional changes in temporal lobe activity, particularly the temporolimbic circuits, during transient global amnesia have been reported (96; 187). Interestingly, sometimes the changes have been reported in the right (117), other times in the left, hippocampus (79), and sometimes bilaterally (107). He and colleagues have shown the hippocampal CA1 region and fornix column as areas involved in transient global amnesia (67). Guillery and colleagues reported the concomitant neuropsychological and PET assessment of two patients (57). Episodic disturbance was characterized by a storage disturbance for one case and an incapacity to learn episodic associations in the other, illustrating cognitive heterogeneity despite similar neurologic presentation. PET findings revealed mild but significant changes in the amygdala (right or left) and left posterior hippocampus, which could account for both the storage disturbance and the inability to associate episodic components. Utilizing MR imaging, Hodel and colleagues showed a decrease in structural connectivity and cortical thickness in regions of the limbic system in patients with transient global amnesia (69). Tiny hippocampal lesions have been associated with transient global amnesia (83). Takeuchi and colleagues studied the areas involved in episodes of transient global amnesia by calculation of cerebral blood flow (174). Technetium-99m L, L-ethyl cysteinate dimer single-photon emission tomography ((99m)Tc-ECD SPET) was performed during and after transient global amnesia attacks in eight patients. The (99m)Tc-ECD SPET images were anatomically standardized and grouped into 12 segments (callosomarginal, precentral, central, parietal, angular, temporal, posterior cerebral, pericallosal, lenticular nucleus, thalamus, hippocampus, and cerebellum). For the control, (99m)Tc-ECD SPET was performed on eight subjects and repeated within 1 month. The correlation between the first and second CBF values of each of the 12 segments was evaluated in the same way for patients with transient global amnesia. Excellent reproducibility between the two CBF values was found in all 12 segments of the control subjects. However, a significant correlation between intra-episodic and postepisodic CBF was not shown in the thalamus or angular segments of patients with transient global amnesia. The present study suggested that thalamus and angular regions are closely involved in the symptoms of transient global amnesia. Using brain perfusion SPECT, Lampl and colleagues found decreased perfusion in 16 cases during the acute stage. SPECT was normal 3 months later in 13 patients who had a first transient global amnesia episode. However, in three patients with recurrent transient global amnesia episodes, the brain perfusion remained abnormal after 1 year (97). Using neurite orientation dispersion and density imaging, Shimizu and colleagues found no structural or perfusion abnormalities in the hippocampus, indicating that transient global amnesia may not cause perfusion abnormalities within the hippocampus (163).

Possible explanations for the transient ischemic attack have included thromboembolic occlusion including paradoxical embolus through a patent foramen ovale (164; 92; 110), vasospasm, hemodynamic mechanisms (56; 193), and acute infarcts in the left mesial temporal lobe (55) and left cingulate gyrus (28). A case of acute amnesia resembling transient global amnesia after insertion of a coil into a posterior circulation aneurysm, suggesting an ischemia in the posterior circulation, has been reported (54). Cases of transient global amnesia have also been reported following the insertion of a coil for basilar tip aneurysm (66). There are also case reports that indicate transient global amnesia following radiofrequency catheter ablation of supraventricular tachycardia and following carotid artery stenting (102; 172). However, the hypothesis of arterial vasoconstriction as a pathogenic factor in transient global amnesia has been controversial (13). Some studies noted a high prevalence of vascular risk factors among patients with transient global amnesia, evidence that was said to support a vascular hypothesis and a possible thromboembolic basis. Arterial hypertension, cardiovascular disease, migraine headache (106), and thyroid disorders had been reported in patients with transient global amnesia (140; 159; 154). Winbeck and colleagues suggested that two different conditions could be distinguished in transient global amnesia. The etiology of transient global amnesia could be explained by an ischemic event due to arterial thromboembolic ischemia in one subgroup of patients (those with increased vascular risk factors) but due to venous ischemia in another subgroup (with Valsalva-like activities before symptom onset) (188; 110). Atrial fibrillation in patients with transient global amnesia could increase the risk of stroke (165).

An underlying impairment of cerebral venous outflow has been suggested in some patients (30; 62). At times, the cerebral computerized tomography and single photon emission CT are abnormal; however, against a vascular hypothesis, patients with transient global amnesia tend to have fewer infarcts on cerebral CT than those with transient ischemic attacks (56). Prospective case-controlled studies have also cast significant doubt on the vascular hypothesis because stroke risk factors and vascular morbidity and mortality are no more common in patients with transient global amnesia than normal controls (56; 71; 193; 09). Thus, ischemia in the posterior cerebral artery is not the usual cause of transient global amnesia, although it can occasionally cause transient dysmnesia and other findings such as a visual field defect. Huber and colleagues performed diffusion-weighted imaging in 10 patients with typical transient global amnesia at an average delay of 18 hours between onset of symptoms and MRI. Cerebrovascular studies (electrocardiography, echocardiography, and extra/transcranial Doppler-sonographic and duplex-ultrasonic investigation) and EEG were normal in all patients. Diffusion-weighted MRI sequences were normal in all patients. Conventional T2-weighted MRI in three out of 10 patients showed microangiopathic subcortical changes and lacunar strokes of older origin. The authors conclude that transient global amnesia does not result from a vascular ischemic etiology in the majority of cases (77).

Bartsch and colleagues identified lesions in the hippocampus through the use of diffusion-weighted imaging, with the majority of lesions identified in the CA1 (cornu ammonis) region of the hippocampus (14; 15). In a sample of 41 patients, 29 exhibited lesions in the hippocampus within a time window of 48 hours after the onset of transient global amnesia. In a sample of 53 patients with established diagnostic criteria for transient global amnesia, all patients exhibited lesions in CA1, without evidence of further lesions outside the hippocampus. This area has been implicated as the functional correlate of amnesia, reflecting a transient disruption of the circuitry involved in the formation and retrieval of hippocampal-dependent memory (14; 15). Despite its likely involvement in the pathophysiology of transient global amnesia, the etiology of these episodes remains largely unknown (168; 184).

Given their transience, by definition, it is not surprising that a follow-up study 4 to 6 months after the event did not find evidence for residual structural lesions (14). Thin slice (3 mm or less) diffusion-weighted imaging on MRI between 24 and 84 hours after the onset of transient global amnesia allows for better detection rates of hyperintense lesions in the hippocampus (68). Furthermore, after a median duration of 6.5 years following the onset of transient global amnesia, no long-term memory deficits or structural abnormalities were found in patients with transient global amnesia when compared to healthy controls (147). Follow-up imaging in a group of 13 patients with transient global amnesia was unable to differentiate hippocampal T2-hyperintensities at sites of previously identified diffusion-weighted imaging hyperintensities between a healthy comparison sample and the patient group (139). Further research implicates a network approach towards understanding the neurophysiology involved in transient global amnesia. Using resting state fMRI with patients who were in the acute phase of transient global amnesia, Zidda and colleagues noted disruption of not only hippocampal structures but also prefrontal and parietal regions, which aligned with poor performance on recognition and delayed recall during brief neuropsychological assessments (192).

In another study, Kim and colleagues used resting-state fMRI to investigate brain networks in patients with transient global amnesia at multiple points after symptom onset (ie, 24 hours, 72 hours, and 3 months) (90). Within 24 hours, patients with transient global amnesia showed greater functional connectivity in the salience network and lower functional connectivity in the default mode network, with relatively preserved functional connectivity in the central executive network compared to healthy controls. Seventy-two hours after onset, patients with transient global amnesia continued to show decreased connectivity in the default mode network, but no alternations were shown in the salience network. Three months after onset, alterations in the default mode network and salient network were both normalized. These findings contrast with those of Zidda and colleagues, which found lower connectivity in the executive network during the acute phase (192). Kim and colleagues posit that this could be due to the inclusion of patients with a history of psychiatric illness, which is associated with lower functional connectivity of the central executive network (90). Further studies are warranted to investigate whether patients with transient global amnesia have true alternations in brain networks.

Functionally, episodic verbal memory deficits in the acute phase of transient global amnesia were correlated with lesions of the left hemisphere, whereas visuospatial memory deficits were associated with lesions of the right hemisphere. However, patients have demonstrated post-acute deficits in spatial orientation tasks that involved planning of novel routes with the potential for implementation of short-cuts (160). Additionally, patients with lesions in the CA1 field of the hippocampus can also experience significant impairments in autobiographical memory (16). Nonetheless, long-term neuropsychological impairments were not detected 4 to 6 months after the transient global amnesia episode for verbal and episodic memory. Moreover, despite this evidence of “double dissociation” of functioning in early symptom presentation, follow-up neuropsychological assessments reveal that patients do not exhibit long-term deficits in working and short-term memory in both verbal and nonverbal modalities (160). However, patients have demonstrated post-acute deficits in spatial orientation tasks that involved planning of novel routes with the potential for implementation of short-cuts (160). Additionally, patients with lesions in the CA1 field of the hippocampus can also experience significant impairments in autobiographical memory (16). Despite alterations in post-acute functionality, the literature does not support substantial long-term memory-related hippocampal impairment caused by transient global amnesia (147).

A diversity of brain abnormalities may be found in a minority of patients with transient global amnesia. In a series of 130 cases, structural brain neuroimaging lesions were found in 10% of the cases; however, they were heterogeneous: nine patients had leptomeningeal cysts, two had falx meningiomas, one had a cerebellum hemangioma, and one had white matter parieto-temporal hyperintensities (01). A case of transient global amnesia associated with a unilateral infarction of the fornix was reported (59).

Interestingly, patients with transient global amnesia have fewer vascular risk factors than patients with transient ischemic attacks (109). Evidence is mixed as to whether a transient global amnesia episode increases the risk of subsequent stroke, with some studies finding no association (193; 48) and others noting an increased risk for ischemic stroke post-transient global amnesia episode (103). Of note, the preponderance of evidence is against transient global amnesia being on par with a transient ischemic attack as increasing subsequent stroke risk. It has also been shown that individuals with transient global amnesia have experienced higher acute blood pressure, higher cholesterol levels, and higher blood glucose levels than those with a transient ischemic attack (154). Comparing transient global amnesia and transient ischemic attack, it has been found that patients with a history of transient global amnesia more frequently also have a history of psychiatric conditions and alcohol use and less frequently a history of cardiac or peripheral artery disease (142; 75), although these studies may be outliers given other findings in the literature that would suggest otherwise.

In several case-controlled studies, patients with transient global amnesia have a significantly higher occurrence of migraine than normal and transient ischemic attack control subjects, suggesting that migraine may cause or predispose toward transient global amnesia (71; 193; 108; 148; 35). A meta-analysis by Liampas and colleagues focused on migraine in transient global amnesia and found a higher risk for transient global amnesia in migraine subjects versus non-migraine subjects (106). Additionally, subjects with transient global amnesia also appeared to have a higher risk of migraine versus those with transient ischemic attack. Also, a study described twin monozygotic brothers, both presenting episodes of transitory global amnesia observed only during episodes of migraine without aura; this clinical observation may suggest a common genetic trait in both conditions (112). Maggioni and colleagues’ work has been corroborated by many studies (162; 168). Also, patients have had episodes of transient global amnesia after typical attacks of basilar migraine (189; 149; 166; 21). Leao spreading depression in the hippocampus has been proposed as a mechanism by which migraine might cause hypoperfusion and hypometabolism in the mesial temporal lobes and thereby cause transient global amnesia (137; 53; 88; 126). However, only a quarter of patients with transient global amnesia have migraine (193; 09; 168), suggesting that migraine is not the only explanation. Also, transient global amnesia tends to be a singular event, whereas migraine is a recurrent disorder, further suggesting that this is not the entire explanation. Potential trigger factors, such as intense emotions or pain, have been identified in patients with transient global amnesia (193). It has been suggested that powerful sensory input may cause a migraine-related spreading depression in the hippocampus or a vasomotor response causing memory dysfunction. Nonetheless, transient global amnesia that occurs during a migraine attack is rare. The study by Donnet found six cases of transient global amnesia occurring during a migraine attack among 8,821 patients (37). Donnet’s work was supported by similar studies (143; 168).

As lesions on the hippocampus can also be found in epilepsy, seizure disorders have often been associated with the pathophysiology of transient global amnesia (128). However, the lack of altered awareness or cortical dysfunction other than amnesia and the rare findings of epileptiform activity on electroencephalography during attacks of transient global amnesia suggest that other neurologic disorders, such as epilepsy, are less likely to be causal of transient global amnesia (118). Additionally, it has been noted that transient epileptic amnesia mimics transient global amnesia and can be distinguished through atypical transient anterograde memory loss with epileptiform abnormalities during EEG monitoring (121). EEG findings reportedly revealed that all patients with epileptic amnesia experienced interictal epileptiform abnormalities, whereas patients with transient global amnesia demonstrated a significantly lower sensitivity for interictal epileptiform abnormalities. Furthermore, structural abnormalities were more frequent in patients with transient epileptic amnesia, whereas the only imaging alteration in patients with transient global amnesia was hippocampal hyperintensity (98).

Hodges and Warlow suggest a familial predisposition, in that 2% (2 of 114 cases) of their patients had a family history of transient global amnesia. They also point out that a number of other authors have reported a positive family history of transient global amnesia (72; 32). Consequently, a genetic predisposition has also been suggested (161; 34). Agosti and colleagues, however, did not find evidence of a genetic relationship (03). Consequently, a genetic predisposition has also been suggested (161; 34); however, Agosti and colleagues did not find evidence of such (03).

Potential risk factors for transient global amnesia are still controversial. Maalikjy Akkawi and colleagues selected 138 subjects; these included 48 patients with transient global amnesia, 42 age-matched patients with transient ischemic attack, and 48 controls (109). Patent foramen ovale was studied by contrast transcranial duplex sonography. Retrograde jugular venous flow was tested with air contrast ultrasound venography. This study found that patients with transient global amnesia and controls showed a lower prevalence for vascular risk factors than patients with transient ischemic attack. No statistical difference was found between the three groups with regard to patent foramen ovale. Air contrast ultrasound venography detected jugular valve incompetence in 72.9% of transient global amnesia participants, 35.7% of the transient ischemic attack group, and 39.5% of controls. It was concluded that patients with transient global amnesia have fewer vascular risk factors than those with transient ischemic attack. This study was supported by subsequent studies about amnesia (110; 62). Although jugular valve incompetence is commonly described (27; 116; 29; 62), its contributing role in its pathogenesis is not clearly understood. Agosti and colleagues argue that only in some cases is transient global amnesia associated with Valsalva-like maneuvers and emotional stress, supporting the venous blood congestion hypothesis; in other cases, a different vascular basis unrelated to venous congestion should be assumed (02; 81; 09). Tynas and Panegyres examined the precipitating events that lead to transient global amnesia, and their results were compatible with Agosti and colleagues (01; 180). Tynas and Panegyres conducted a longitudinal study examining 93 patients with transient global amnesia and found that transient global amnesia episodes were most commonly precipitated by an emotional or physical stressor involving Valsalva-like maneuvers, though no single risk factor was ubiquitous (180). No association was observed between transient global amnesia and cerebrovascular risk factors. However, one third of patients with transient global amnesia had a history of migraine (180). Similarly, He and colleagues examined a total of 73 patients with transient global amnesia and 73 age- and gender-matched controls; they found a significant difference in migraine history, but no significant differences were observed regarding the history of hypertension, diabetes, and other diseases (67). In young people, transient global amnesia has been reportedly associated with migraine and mild head injuries (eg, while playing football) (07; 179; 132; 168). A case of recurrent transient global amnesia associated with high altitude, and consequently reduced oxygen availability, has been reported (25; 115; 99); another case relates it to prolonged underwater swimming (82; 78); in another reported case, transient global amnesia is observed after prolonged and abnormal head posture (22); and, also, there are at least two case reports of marijuana-induced transient global amnesia (114; 167).

The pathogenesis of transient global amnesia is unclear. Anterograde and retrograde memory defects in transient global amnesia may be due to an interruption in the transfer of data into and out of long-term storage (70). It has also been suggested that transient global amnesia is related to a functional disturbance in the brain episodic-memory network (146; 91).

Amnestic states are well known to correlate with damage to components of the limbic system, such as the hippocampi and other mesial temporal structures. Hodel and colleagues examined differences in cortical thickness and brain neural pathways or networks in patients with transient global amnesia and 18 age- and gender-matched controls (69). Findings suggest that patients with transient global amnesia had lower structural connectivity and cortical thickness in regions of the limbic system compared to neurologically healthy controls. SPECT and PET studies conducted during episodes of transient global amnesia show bilateral mesial temporal hypoperfusion, and PET studies indicate hypometabolism in the left temporal and bilateral parieto-occipital lobes as well as hypermetabolism in bilateral inferior frontal regions (169; 52; 191). In some patients, transient hyperperfusion of the medial temporal or occipito-cerebellar area has been found and is suggested to be related to changes in regional cerebral blood flow associated with different pathophysiological bases for transient global amnesia (144). Kim and colleagues reported the presence of significant hypoperfusion in six patients in the left hippocampus, left thalamus, and bilateral cerebellum, which was congruous with previous findings of hypoperfusion f the left hemisphere hippocampal and thalamic structures (89). Follow-up SPECT scans noted resolution of regional cerebral blood flow within the hippocampus and thalamus (89). The range of findings in SPECT studies is likely due to variable timings of scans following a transient global amnesia event and other patient-specific characteristics.

Strupp and colleagues published one of the earliest articles examining diffusion-weighted MRI findings in patients with transient global amnesia (170). Seven of the 10 patients examined (almost all of whom had experienced transient global amnesia within the preceding 48 hours) exhibited elevated signal intensities in the left hippocampus. Three of the seven also had concomitant findings in the right hippocampus. Increased hippocampal signal in the hippocampi on diffusion-weighted MRI likely corresponded to cellular edema in the temporal lobes and implicated the temporal lobe, particularly the dominant temporal lobe, in transient global amnesia. The authors suggest their findings support the spreading wave of depression of Leao as the mechanism of transient global amnesia, although they acknowledge that other etiologies cannot be excluded. Szabo and colleagues retrospectively examined 390 patients with isolated transient global amnesia and identified hippocampal DWI lesions in 272 (70.6%) of these patients (173). Their study suggests that DWI is useful in the diagnosis of transient global amnesia, particularly in patients with incomplete clinical information. However, although their findings also linked transient global amnesia to the hippocampus, the underlying mechanism of transient global amnesia remained unclear. Not all DWI studies consistently implicate the hippocampus. Higashida and colleagues found diffusion-weighted hyperintense lesions in the hippocampi of only 30% of their cohort of 79 patients (68). They also did not identify significant associations between DWI findings and either patient demographic or clinical characteristics. Their findings suggest that DWI lesions, although potentially related to mechanisms underlying transient global amnesia, are not particularly related to either the clinical manifestations of transient global amnesia or patient-related risk factors. Furthermore, some studies suggest that after transient global amnesia, there were no hippocampus cavities and no visible sequelae (139). These authors used ultra-high-field 7 T MRI, performed with the median of 4 months, to detect hippocampal lesions in 13 patients. Similarly, no hippocampal microstructural or perfusion abnormalities were visible after transient global amnesia (163). These results indicate no perfusion abnormalities or destructive damage involving baseline microstructures in the hippocampus due to transient global amnesia. Serial MRI exhibited persistent focal infarction of the fornix’s left column and of the body, without any hippocampal lesions (59). Overall, the brain MRI corroborates and confirms the clinical hypothesis of transient global amnesia, suggesting that imaging is a sufficient way of analyzing transient global amnesia (35).

Functional neuroimaging studies using SPECT and PET, performed during or immediately after the period of amnesia, have shown unilateral or bilateral alterations in perfusion and metabolism, respectively, in the thalamic regions, basal ganglia, and various areas of the neocortex (169; 52; 40; 31; 45; 89). Eustache and colleagues, in a PET study performed during the period of transient global amnesia, showed no change in the hippocampi but did show reduced cerebral blood flow and metabolism in the frontal and temporal cortices (especially inferior temporal cortex), with a mild reduction in cerebral blood flow and normal metabolism in the occipital cortex (40). This suggests that, at least in some patients, neocortical involvement may predominate in the pathogenesis of transient global amnesia. This study has also been interpreted as lending support to the hypothesis that transient global amnesia is due to the spreading wave of depression of Leao (101; 63; 183). Jovin and colleagues performed follow-up SPECT studies in a patient with transient global amnesia during the episode, 24 hours after the episode, and 3 months after the episode. The initial study showed bilateral mesial temporal lobe hypoperfusion that partially resolved after 24 hours and returned to normal at 3 months. Resolution of the SPECT scan abnormalities correlated well with resolution of memory loss (86; 81; 89). The authors suggest that a process causing decreased local metabolism, such as cortical spreading depression, constitutes the primary pathophysiologic mechanism in this case. Jimenez-Caballero and colleagues reported on a transcranial Doppler study on a female patient during the acute phase of the amnesia, which showed no evidence of hemodynamic alterations or significant asymmetries (85). Repeating the test after clinical recovery offered values similar to those of the previous study. The authors concluded that the basis of this process would not be related to ischemia but instead to a mechanism enabling spreading neurogenic depression that is similar to that which takes place during a migraine attack (76; 178). Several case studies have identified cerebellar abnormalities, primarily in the vermis, in transient global amnesia using DWI (124) and SPECT (190). These findings, although preliminary, suggest that cerebellar dysfunction may also play a role in the development of transient global amnesia.

Tikhonova and colleagues analyzed 27 patients with transitory global amnesia in the acute and late (from 7 days) periods and 31 patients with dyscirculatory encephalopathy and subjective memory impairments (control group) (177). EEG data and assessment of the P300 cognitive-evoked potential wave established differences in the nature of beta1 activity between these groups. The extent of beta1 activity on the EEG showed different relationships with the latent period of the P300 wave. In the control group, there were increases in beta1 activity with increases in the latent period, but beta1 activity in transient global amnesia decreased with increases in the latent period. These changes were most marked in the frontocentral areas. The authors believe that these patterns of changes in EEG and cognitive-evoked potentials provide evidence of the functional nature of transient global amnesia syndrome, which is not related to any damaged brain structure. Quinette and colleagues also corroborate the work of Tikhonova and colleagues (151). More recently, Park and colleagues conducted an EEG network analysis study and found that compared with the latent phase, the acute phase of transient global amnesia was associated with an impaired network of efficiency in the theta band between the anterior and posterior brain areas (145). These results suggest that transient global amnesia deteriorates network efficiency of the theta frequency band and might be related to a desynchronization between the anterior and posterior brain areas. Imperatori and colleagues analyzed 16 patients with acute transitory global amnesia and 16 neurologically healthy controls (78). Analyzing EEG power spectra differences, patients with transient global amnesia showed a decrease of theta power localized in the temporal lobe and frontal lobe and a decrease of EEG beta power in the bilateral precuneus and bilateral postcentral gyrus compared to healthy controls. The authors believe these patterns reflect impairment of both episodic and autobiographical memory, which affects patients with transient global amnesia during the acute phase. Taken together, these results support transient functional impairments in the acute phase.

A fascinating observation by Merriam and colleagues may hint at the molecular mechanisms underlying transient global amnesia. They have suggested that transient global amnesia triggered by intense emotion is likely linked to the benzodiazepine system, as benzodiazepine-induced amnesia in humans causes profound impairment of anterograde memory yet spares retrograde memory. Also, benzodiazepine receptors are linked to GABA(A) receptors and occur in high density in the human hippocampus, an area known to be affected in transient global amnesia (120). Danek and colleagues have suggested an association between transient global amnesia and endogenous benzodiazepines (33). Melo and colleagues also linked transient global amnesia with a disturbance in various neurotransmitter systems. They noted that intense effort, emotion, or stress in a patient prone to migraine headaches may alter the activity of unstable serotonergic systems, which may lead to transient global amnesia by two possible mechanisms: (1) vasospasm of vessels supplying memory related areas or (2) an inhibitory effect on hippocampal cortex (similar to the spreading wave of depression of Leao) (118).

Epidemiology

Onset is usually after 50 years of age, and the mean age of onset is approximately 60 years of age (193). In most studies, either no difference in incidence between sexes (71; 118) or a slight female predominance is noted (47; 193). The overall incidence has been estimated to be between 3.4 and 10.4 per 100,000 per annum (71; 93; 100; 20; 24). However, when examining individuals aged 50 years or older, incidence increases to between 23.5 to 32 per 100,000 per year (95). It has been suggested that transient global amnesia incidence has increased as a result of psychosocial strain associated with the global COVID-19 pandemic (133; 186), although this requires further investigation. At least one third of attacks have an identifiable physical or psychological precipitant (95). Most attacks are singular; the rate of recurrence is 2.5% to 5% per year for at least 5 years after the first event (193). Oliveira and colleagues found that female sex, history of depression, shorter duration episode, and hippocampal hyperintensity on MRI were associated with transient global amnesia recurrence; however, only a history of depression was predictive of a greater risk of recurrence (138). Tynas and Panegyres identified depression, as well as a history of head injury and a family history of dementia, as predictive of recurrence (180). Earlier age and personal and family history of migraine may also be predictive (125).

Prevention

Unless attacks recur, prophylactic treatment is not recommended; prevention management is best done within multidisciplinary teams to provide supportive treatment (129). That being said, a higher prevalence of both personal and family history of migraine is associated with recurrence (125). Prophylactic anti-migraine treatment is considered in such patients, particularly those with a history of recurrent episodes of transient global amnesia. For those with recurrent attacks, identifying and treating associated neurologic disorders or head trauma may rule out the diagnosis of transient global amnesia (130). Transient global amnesia has a recurrence rate that ranges between 2.9% and 23.8%, with a nonsignificant increase in risk of cerebrovascular events or seizures (09; 156). Individuals who experience a first episode of transient global amnesia before the age of 60 years have a higher risk for recurrence (125). Patients with recurrent transient global amnesia and risk factors for cerebral ischemia, such as hypertension and smoking, may be best treated by attending to these factors. Only in cases with a clearly defined etiology, such as epilepsy, ischemic events, or brain tumor, should patients be specifically treated for these disorders.

Differential diagnosis

Associated or underlying disorders

The differential diagnosis for transient global amnesia is broad; it includes transient ischemic attack, stroke, posttraumatic amnesia due to head injury, epilepsy, migraine, dementia, Wernicke encephalopathy, substance or alcohol intoxication, hypoglycemia, and various causes of acute confusional states or delirium. Concurrent presentations should be considered as cases of transient global amnesia secondary to acute hippocampal stroke have been reported in patients positive for COVID-19 (153). There are reports of transient global amnesia occurring after medical procedures, such as coil embolization for posterior circulation cerebral aneurysms, which should be considered in the differential diagnosis (66). In addition, psychogenic amnesia, also known as dissociative amnesia (06), and functional or hysterical amnesia are considered in the differential diagnosis of transient global amnesia. Clinical history and examination will often clarify the diagnosis.

Transient epileptic amnesia symptomatically differentiates itself from transient global amnesia through the presence of oral automatisms, a duration of less than 1 hour, the ability to recall having retrograde amnesia, and an abnormal EEG during the period between events (ie, interictal phase) (168). Lanzone and colleagues showed that the presence of interictal epileptiform abnormalities captured during 24-hour ambulatory EEG helped distinguish between transient epileptic amnesia and transient global amnesia (98). Twenty-four-hour ambulatory EEG was more sensitive in differentiating transient epileptic amnesia than standard EEG. Given that transient epileptic amnesia manifests as a clinical presentation of epilepsy, it is more likely to recur than transient global amnesia (152).

An acute confusional state or delirium differs from transient global amnesia in that the former is characterized by more global impairment of attention and awareness, with additional disturbances in cognition, including memory deficits and impairments in language or perception (06). In dementia, recurrent confusional episodes with memory impairment are common, but memory does not return to normal between attacks.

Transient global amnesia may be mistaken for psychogenic amnesia, as both may be preceded by emotional stress (71). Unlike patients with transient global amnesia, patients with psychogenic or dissociative amnesia have salient retrograde amnesia with loss of personal identity, whereas anterograde memory is generally spared (64). The pattern of retrograde amnesia varies among patients, such that it may extend over an identifiable time period or may be material-specific. Episodes of psychogenic amnesia may last from days to months, and after recovery, recall for events during the episode is often preserved (18; 64). Memory often returns abruptly (as opposed to the gradual return following transient global amnesia). Also, patients with psychogenic amnesia do not appear distressed about their condition. Patients with psychogenic amnesia tend to be younger than those with transient global amnesia, they often have a history of psychiatric disorders (such as depression or personality disorder), and there is often an identifiable stress-inducing precipitating event (70; 95; 99).

Diagnostic workup

Initial workups should begin with a search for potential inciting events such as vigorous exercise, intense psychological stressors, or water contact or temperature change (eg, hot shower or cold swim), with vigorous exercise being the most common precipitating event (87; 168; 148). Reports of other inciting events, with onset weeks before transient global amnesia, include anxiety secondary to conflict at home or work, health problems, and financial stressors (148). In a study by Kim and colleagues, 96% of patients (N=50) visiting the emergency department and receiving a diagnosis of transient global amnesia reported precipitating events, such as pain, emotional stress, or physical distress, before the onset of amnestic symptoms (90). A neurologic examination should consider differentials of transient epileptic amnesia and transient ischemic amnesia. Brain imaging is recommended for cases with altered neurologic status given the possibility for transient global amnesia being associated with acute ischemic strokes or brain tumor. MRI with diffusion-weighted imaging is recommended to rule out stroke and potentially identify hippocampal lesions that may be associated with transient global amnesia, though this largely remains a diagnosis of exclusion (168; 129; 130). However, detection of diffusion-weighted hyperintense lesions significantly decreases after 84 hours of transient global amnesia onset (68).

Electroencephalography, although not routinely recommended or utilized, is of use to assess status following altered consciousness, impairment in ability to perform tasks, or features that are suggestive of repetitive or seizure-like events (98; 130). Twenty-four-hour ambulatory studies may aid in the differential between transient global amnesia and transient epileptic amnesia (98). Interictal EEG findings in transient epileptic amnesia typically fall within one of the following three categories: unilateral or bilateral temporal sharp waves, nonspecific focal waves, or normal EEG, with ictal findings only being found in rare cases (131). However, transient epileptic amnesia has a higher recurrence rate than transient global amnesia and is more likely to respond favorably to antiepileptic drugs (168; 12).

Management

No specific treatment is available for an episode of transient global amnesia. Following the attack, a discussion with the patient regarding the overall good prognosis does much to alleviate anxiety. Indeed, a study by Maffei and colleagues tried to understand male self-administration of a Caverject injection for erectile dysfunction, suggesting a correlation between intracavernous injection and neurologic phenomenon (111). No specific etiology for transient global amnesia was evident. Faust and Nemes proposed a way to understand and manage transient global amnesia with classic features; a minimalist approach should be taken, including ensuring patient safety, avoiding overtesting inappropriate medication and medical interventions, and reassuring the patients and their families (41).