Clinical examination

TGA is a clinical diagnosis. It was originally described in 1956 as an "isolated episode of confusion with amnesia" unassociated with other neurological conditions. Participants were reported to become repetitive and repeat questions, although more commonly centred on the memory loss itself. Fisher and Adams (Citation13) first used the term TGA in 1958; however, it wasn't until 1964 that they presented a report of 17 patients who had sudden onset anterograde amnesia and confusion, which cleared up within a few hours.

Hodges and Warlow (Citation 15) subsequently established criteria for the clinical syndrome in 1990 (Table 1), and this has since been employed as the basis of TGA diagnosis. They classified patients into the following three groups: pure TGA, probably epileptic amnesia, and probably TIA. Exclusionary criteria for pure TGA were focal neurological symptoms, including ataxia, limb weakness, and sensory disturbances. Of the 153 patients evaluated between 1984 and 1987, 114 patients qualified for the proposed criteria for pure TGA. Most attacks in this population lasted 1 to 8 hours. 

Disorientation to time and repetitive questioning occurred in both the TGA and non-TGA groups, but were more common in the TGA group, with 92% compared to 71% in the non-TGA group. The majority of TGA patients had a permanent retrograde amnesic gap for the period immediately before and during the attack, though this was also observed in non-TGA patients.¹

History of the patient

• The inability to create new memories during an episode, frequently accompanied by repeating questions (e.g., "Where am I?"), is known as sudden anterograde amnesia
• Identification and consciousness are preserved: Neither personal identification nor consciousness is lost
• Precipitants include physical strain, emotional strain, Valsalva techniques, or submersion in water (although there is frequently no known cause)
• Duration: The symptoms go away in a day, usually in four to six hours

Neurological assessment

• Patients with orientation impairment may have trouble recognising time and location, but not their own identities
• Patients with memory loss sometimes ask the same questions over and over again
• Procedural memory and attention are intact, preserving the capacity to carry out complex tasks like speaking or driving
• There are no localised neurological abnormalities, and motor, sensory, and reflex functions are normal
• Absence of seizures or head trauma: Crucial to the diagnosis

Imaging and testing

• MRI (Diffusion-Weighted Imaging):

Can reveal tiny punctate hippocampal lesions 2–3 days after the episode, consistent with transient ischemia.

Employed to exclude stroke or structural abnormalities38.

• CT Scan:

Generally normal; employed to rule out acute haemorrhage or mass lesions38.

• Electroencephalography (EEG):

Normal results are used to distinguish TGA from transient epileptic amnesia57.

• Lab Tests:

Blood tests (e.g., alcohol, clotting disorders) and urine toxicology to rule out metabolic or drug-induced causes^1,2

Differential diagnosis

Transient ischemic attack (TIA)

There are numerous similarities between TGA and TIA, which lend credence to the arterial ischemia hypothesis. TGA and TIA share a sudden onset of reversible impairment of function in patients within comparable age group demographics. 

Reported mean age of onset is 60–66 years for TGA and 69–71 years for TIA, with a modal onset, for both, above the age of 50 years.5 Notwithstanding these parallels, statistical analysis has consistently demonstrated significantly lower atherosclerotic risk factor profiles, such as lower prevalence of embolic heart disease, diabetes mellitus, hypertension, and carotid artery atherosclerotic disease, in TGA patients compared to TIA patients.⁶ 

Population cohort data have also consistently demonstrated that a history of TGA does not place patients at an increased risk of cerebrovascular event, and in fact, more recent studies demonstrate an improved prognosis for TGA patients versus TIA patients in terms of risk of future cerebrovascular event.8 Even more, one retrospective analysis demonstrated no increased risk of subsequent cerebrovascular event after a TGA event compared with healthy matched controls, further negating an atherosclerotic hypothesis.

Epileptic amnesia (Transient epileptic amnesia - TEA)

TEA is an adult-onset MTL epilepsy that manifests as recurrent, transient acute memory loss. This amnesia can be anterograde or retrograde only. This differs from TGA, where patients always have anterograde memory loss and sometimes have permanent retrograde amnesia lasting hours to days before the episode starts.45 TGA patients are more likely to be agitated or anxious. While repetitive questioning is reported as a characteristic in TGA by some authors, others have also encountered this behaviour in TEA patients.

Key characteristics of TEA that vary from TGA are onset upon awakening, less than 1 hour duration, incomplete interictal amnesia for anterograde memories (can remember not remembering), temporal lobe manifestations like gustatory/olfactory hallucinations, oral automatism, and interictal EEG abnormalities. Precariousity surrounds abnormal EEG as a factor in diagnosing TEA because only one-third have abnormalities, with the remaining two-thirds having focal slowing or normal results. Later follow-up indicates that TEA is more likely to recur than TGA. 

Diagnosis of TEA has a good prognosis for response to antiepileptic drugs, but can produce long-lasting interictal memory impairment. This includes enhanced long-term forgetting and autobiographical amnesia.

Psychogenic amnesia (Dissociative amnesia)

Psychogenic amnesia, also known as dissociative amnesia, is distinguished from TGA in that the former disrupts retrograde memory, is usually episodic, and is typically associated with severe psychological distress. Although many times complex medical illness gets pejoratively termed "psychogenic" if the cause is unclear, there is evidence to support a psychogenic cause of TGA.

TGA patients have a high prevalence of comorbid emotional distress and anxious personality traits.5,85 Approximately one-third of TGA attacks follow physical or psychological stress, which implies disruption of memory formation due either to ischemic or stress-induced catecholamine disruption.86,87 

It is speculated by some authors that stress-induced release of catecholamines can result in hypoxia or ischemia, while others speculate that the involved neurotransmitters may impact memory formation.88–93 Some evidence exists regarding an association between TGA and Takotsubo syndrome. The latter is defined by transient, acute left-ventricular myocardial dysfunction that mimics myocardial infarction and also develops after physical or psychological stress.¹

Conclusion

The differential diagnosis is structural (vascular) disease, epileptic amnesia, delirium, intoxication, head injury and migraine headache. In the typical case, no further investigation with MRI and EEG is required to present to a general physician. This is even true if the patient has vascular risk factors. But with focal neurological signs, anterograde amnesia needs neuroimaging and possibly neurology consultation.

 If retrograde amnesia is also compromised and emotional distress is noted, the clinician must consider psychogenic amnesia. Alternatively, though uncommon, but more sinister, are those instances of "painless" aortic dissection, in which TGA is the sole presenting symptom since chest pain is absent. 

Lastly, research results using DWI–MRI corroborate the theory of focal ischemia. These focal lesions are maximally detectable from 48 to 72 hours from the beginning of TGA. Focal lesions have been shown in the CA1 region of the cornu ammonis part of the hippocampus (MTL), invariably unilateral. However, no such abnormalities are demonstrable in as many as 35% of patients with TGA.¹