Clinical manifestations

Presentation and course

Typically, the onset of this clinical syndrome is abrupt, and anterograde memory is profoundly impaired. Patients are disoriented in time and often in place but never to person. Particulars are forgotten even after repeated practice, resulting in ideational and motor perseveration. Patients recognize their memory deficits and repeatedly ask orienting questions and also, "Why can't I remember?" (15). A much more mild reduction of retrograde episodic memory (inability to recall past events) may also be seen in transient global amnesia (141). Transient global amnesia occurs most frequently in the seventh decade of life. Taken across various studies, the mean age of an episode ranges from 61 to 67.3 years. Peak incidence of occurrence is around age 62 years (SD = 10 years). A total of 54% to 67% of patients with transient global amnesia are female.

In 1990, Hodges and Warlow developed diagnostic criteria for this clinical syndrome that have served as the basis for recognition of this condition (61).

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 (61; 160). Transient oculomotor abnormalities may also be present (158). 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 (67; 150; 116; 141). Pantoni describes transient global amnesia as self-limiting, requiring no specific therapeutic intervention (121). Although transient global amnesia itself is not fatal, more life-threatening conditions like dissecting aortic aneurysm or tumor have been associated with this state (59; 43).

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 (73). More specifically, findings reveal striking anterograde amnesia for verbal and nonverbal information (67), thought to reflect deficient encoding in the earliest phase of transient global amnesia and deficient storage of new information in the later phase (130). A variable degree of retrograde amnesia may also be present and is typically temporally graded, such that more remote memories are spared (84; 60; 52).

Patients may also exhibit difficulties in temporally dating or sequencing remote memories (85). Jia and colleagues studied 3 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 3 patients. However, memory testing revealed various degrees of dysfunction, and cerebral PET imaging revealed low metabolism in local areas related to memory in 2 of 3 patients. The authors concluded that in patients with transient global amnesia, cognitive function and cerebral metabolic levels are closely correlated with duration of symptoms (73).

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 (146). Those with transient global amnesia are able to acquire new skills that do not heavily rely on episodic or working memory (46; 36). Impairment was found in prospective episodic memory (the ability to remember to perform an intended action at some point in the future (Hainselin et al 2011). In 2012, 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.

There is literature that suggests the presence of precipitants in 33% to 89% of attacks (41; 160; 35). 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 (61; 107; 160; 16; 129; 35). 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 (132).

In their review, Spiegel and colleagues highlighted a study comparing psychiatric disease in transient ischemic attack and transient global amnesia (141). 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 (141).

Prognosis and complications

Prognosis is usually excellent. Patients usually make a good recovery from the event, except for amnesia during and around the event, with little or no risk for cerebrovascular disease (50; Mueller 1989; 42; 09). 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 4 patients (4%) later developed a stroke (42). Mueller reported that within a mean period of observation of 5 years, a first recurrence was followed by 1 further amnesic attack in one fifth and by 2 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 patients with transient global amnesia when time to cerebrovascular, seizure, or cognitive impairment occurrences was controlled. Compared to patients diagnosed with migraine or seizure, patients with transient global amnesia do not seem to face a heightened risk of stroke (98). Others have reported a lower rate of recurrence, 2.5% to 5% per year for at least 5 years after the first event (160; 85). The incidence of subsequent epilepsy is also low. Interestingly, it has been suggested that transient global amnesia represents a risk factor for mild cognitive impairment (20).

Varied recurrence rates from 2.9% to 25% for transient global amnesia have been reported (141). 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 (109).

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 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 (138; 50; 37; 154; 141), migraine (157; 61; 94; 141), epilepsy (39), vein thrombosis (139), central nervous system tumors (32), saline-contrast transthoracic echocardiography (151), drug intoxication (08) or other toxic and metabolic disturbances (105), and hysteria (60). 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 (138; 50; 92; 34), although many contest this view (44; 61; 108). 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 (142; 145; 93; 04; 10; 104). Furthermore, transient global amnesia may result in permanent hippocampal changes (134; 80; 68; 69). Using high-resolution, T2-reversed MRI, Nakada and colleagues observed that the incidence of hippocampal cavities increased with normal aging up to about 40% (111; 117). Cavities, however, were found in all the patients who recovered from an episode of transient global amnesia. The authors concluded that hippocampal neuronal loss represents an important sequelae of transient global amnesia. Park and colleagues found in 80 patients that 51% revealed MRI hippocampal cavities, but there were no differences in the clinical factors between the patients with and without such cavities; by the same token, diffusion-weighted imaging revealed that 24% of the studied cases exhibited high signal intensity in the hippocampus, but again, there were no differences in the clinical factors between the patients with and without high signal intensities in the hippocampus on diffusion-weighted imaging (124; 09; 79; 81). The authors concluded that significant structural differences in the limbic areas between patients with transient global amnesia and the controls could be found.

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 (102). Functional changes in temporal lobe activity, particularly the temporolimbic circuits, during transient global amnesia have been reported (86; 155). Interestingly, sometimes the changes have been reported in the right (102), other times in the left, hippocampus (66), and sometimes bilaterally (93). Guillery and colleagues reported the concomitant neuropsychological and PET assessment of 2 patients (51). Episodic disturbance was characterized by a storage disturbance for 1 case and an incapacity to learn episodic associations in the other, illustrating cognitive heterogeneity despite similar neurologic presentation. PET findings disclosed 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. Tiny hippocampal lesions have been associated with transient global amnesia (72). Takeuchi and colleagues studied the areas involved in episodes of transient global amnesia by calculation of cerebral blood flow (144). Single-photon emission tomography was performed during and after transient global amnesia attacks in 8 patients. The 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, SPET was performed on 8 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 2 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 3 patients with recurrent transient global amnesia episodes, the brain perfusion remained abnormal after 1 year (87).

Possible explanations for the transient ischemic attack have included thromboembolic occlusion including paradoxical embolus through a patent foramen ovale (138; 82; 96), vasospasm, hemodynamic mechanisms (50; 160), and acute infarcts in the left mesial temporal lobe (49) and left cingulate gyrus (24). 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 (48). However, the hypothesis of arterial vasoconstriction as a pathogenic factor in transient global amnesia has been controversial (11). 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, and thyroid disorders had been reported in patients with transient global amnesia (120; 133). Winbeck and colleagues suggested that 2 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 1 subgroup of patients (those with increased vascular risk factors) but due to venous ischemia in another subgroup (with Valsalva-like activities before symptom onset) (156; 96).

An underlying impairment of cerebral venous outflow has been suggested in some patients (26; 56). 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 (50). 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 (50; 61; 160; 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 3 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 (64).

Bartsch and colleagues identified lesions in the hippocampus through the use of diffusion-weighted imaging, with the majority of lesions identified in the hippocampal cornu ammonis, specifically the CA1 sector (12; 13). 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. The majority of lesions (94%) were found in the CA1, as 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 (13). Despite its likely involvement in the pathophysiology of transient global amnesia, the etiology of these episodes continues to remain largely unknown (141; 153).

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 (13). Diffusion-weighted imaging in the acute phase of transient global amnesia allows for better detection rates of hippocampal lesions (119). 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 (119). 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 (159).

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. 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 (135). 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 (135). Additionally, patients with lesions in the CA1 field of the hippocampus can also experience significant impairments in autobiographical memory (14).

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: 9 patients had leptomeningeal cysts, 2 had falx meningiomas, 1 had a cerebellum hemangioma, and 1 had white matter parieto-temporal hyperintensities (01). A case of transient global amnesia associated with a unilateral infarction of the fornix was reported (53).

Interestingly, patients with transient global amnesia have fewer vascular risk factors than patients with transient ischemic attack (Maalikjy et al 2003) and do not appear to be at greater risk for a vascular event subsequent to the transient global amnesia episode (160). 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 (122).

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 (61; 160; 94; 127; 31). 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 (97). Maggioni and colleagues’ work has been corroborated by many studies (137; 141). Also, patients have had episodes of transient global amnesia after typical attacks of basilar migraine (157; 128; 139; 18). 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 (118; 47; 77; 110). However, only a quarter of patients with transient global amnesia have migraine (160; 09; 141), 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 (160). 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 6 cases of transient global amnesia occurring during a migraine attack among 8,821 patients (33). Donnet’s work was supported by similar studies (123; 141).

As lesions on the hippocampus can also be found in epilepsy, seizure disorders have often been associated with the pathophysiology of transient global amnesia (112). 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 (103). 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 (106).

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 (62; 28). Consequently, a genetic predisposition has also been suggested (136; 30). Agosti and colleagues, however, did not find evidence of a genetic relationship (03). Consequently, a genetic predisposition has also been suggested (136; 30); however, Agosti and colleagues did not find evidence of such (03).

Potential risk factors for transient global amnesia are still controversial. Maalikjy and colleagues selected 138 subjects; these included 48 patients with transient global amnesia, 42 age-matched patients with transient ischemic attack, and 48 controls (Maalikjy et al 2003). 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 3 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 patients with transient ischemic attack. This study was supported by subsequent studies about amnesia (96; 56). Although jugular valve incompetence is commonly described (23; 101; 25; 56), 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; 70; 09). In young people, it has been reportedly associated with migraine and mild head injuries (eg, while playing football) (07; 149; 115; 141). A case of recurrent transient global amnesia associated with high altitude, and consequently reduced oxygen availability, has been reported (22; 100; 89); another case relates it with prolonged underwater swimming (71; 65); in another reported case, transient global amnesia is observed after prolonged and abnormal head posture (19); and, also, there are at least 2 case reports of marijuana-induced transient global amnesia (99; 140).

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 (60). It has also been suggested that transient global amnesia is related to a functional disturbance in the brain episodic-memory network (126).

Amnestic states are well known to correlate with damage to components of the limbic system, such as the hippocampi and other mesial temporal structures. SPECT and PET studies conducted during episodes of transient global amnesia show hypoperfusion, and PET studies indicate hypometabolism in the hippocampus and mesial temporal lobe (142; 46; 145). 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 (125). Kim and colleagues reported the presence of significant hypoperfusion in 6 patients in the left hippocampus, left thalamus, and bilateral cerebellum, which was congruous with previous findings of hypoperfusion of the left hemisphere hippocampal and thalamic structures (78). Follow-up SPECT scans noted resolution of regional cerebral blood flow within the hippocampus and thalamus (78). 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.

A study using diffusion-weighted MRI of 10 patients with transient global amnesia (almost all of whom had attacks within the preceding 48 hours) found that 7 had signal change in the left hippocampus, 3 with concomitant changes in the right hippocampus (143). The increased signal in the hippocampi on diffusion-weighted MRI likely corresponds to cellular edema in the temporal lobes. Follow-up MRI studies were normal. This study lends strong support to temporal lobe dysfunction, particularly of the dominant lobe, in transient global amnesia. Other SPECT and PET studies performed during or immediately after the period of amnesia have shown unilateral or bilateral alterations in perfusion or metabolism in the thalamic regions, basal ganglia, and various areas of the neocortex (142; 46; 36; 27; 40; 78). 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 (36). 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 (91; 57; 152). 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 (75; 70; 78). 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 carried out in a female patient during the acute phase of the amnesia, which showed no evidence of hemodynamic alterations or significant asymmetries (74). Repeating the test after clinical recovery offered values that were 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 (63; 148).

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) (147). 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 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 (130).

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 (105). Danek and colleagues have suggested an association between transient global amnesia and endogenous benzodiazepines (29). 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) (103).

Epidemiology

Onset is usually after 50 years of age, and the mean age of onset is approximately 60 years of age (160). In most studies, either no difference in incidence between sexes (61; 103) or a slight female predominance is noted (42; 160). The overall incidence has been estimated to be between 3.4 and 10.4 per 100,000 per annum (61; 83; 90; 17; 21). However, when examining individuals aged 50 years or older, incidence increases to between 23.5 to 32 per 100,000 per year (85). Most attacks are singular; the rate of recurrence is 2.5% to 5% per year for at least 5 years after the first event (160). At least one third of attacks have an identifiable physical or psychological precipitant (85).

Prevention

Unless attacks recur, prophylactic treatment is not recommended; rather, prevention management is best done within multidisciplinary teams to provide supportive treatment (113). For those who have recurrent attacks, identification and treatment of associated neurologic disorders may rule out the diagnosis of transient global amnesia. Transient global amnesia has a recurrence rate that ranges between 2.9% to 23.8% with a nonsignificant increase in risk of cerebrovascular events or seizures (09; 131). 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. Transient global amnesia is often associated with migraine, and in those with a history of migraine and recurrent episodes of transient global amnesia, it is reasonable to begin prophylactic antimigraine treatment.

Differential diagnosis

The differential diagnosis for transient global amnesia includes transient ischemic attack or stroke, posttraumatic amnesia due to head injury, epilepsy, migraine, dementia, Korsakoff syndrome, drug or alcohol intoxication, hypoglycemia, and various causes of acute confusional states or delirium. 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) (141). Lanzone and colleagues showed that the presence of interictal epileptiform abnormalities captured during 24-hour ambulatory EEG was helpful in distinguishing between transient epileptic amnesia and transient global amnesia (88). Twenty-four-hour ambulatory EEG was more sensitive in differentiating transient epileptic amnesia than standard EEG.

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 between attacks, memory does not return to normal.

Transient global amnesia may be mistaken for psychogenic amnesia, as both may be preceded by emotional stress (61). 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 (58). 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 (15; 58). 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 (60; 85; 89).

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 (76; 141). 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 lesions that may attributed to hippocampal lesions associated with transient global amnesia (141; 113).

Electroencephalography 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. Twenty-four-hour ambulatory studies may aid in the differential between transient global amnesia and transient epileptic amnesia (88). Interictal EEG findings in transient epileptic amnesia typically fall within 1 of the following 3 categories: unilateral or bilateral temporal sharp waves, nonspecific focal waves, or normal EEG, with ictal findings only being found in rare cases (114). However, transient epileptic amnesia has a higher recurrence rate than transient global amnesia and is more likely to respond favorably to antiepileptic drugs (141).

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.