Transient global amnesia, a benign condition that resolves within 24 hours, presents unique challenges for the emergency department physician. The predominant clinical challenge is the need to differentiate this syndrome from more serious central nervous system pathology, such as transient ischemic attack or the presence of a brain tumor. The established diagnostic criteria help in the differential, even though the cause of this syndrome and the exact pathophysiology are still subject to debate. The three main hypotheses for the causes of this syndrome are transient ischemia in the inferomedial portion of the temporal lobes, epileptic discharge in the hippocampus, and spreading depression of cortical electrical activity. This article describes the classic presentation of transient global amnesia in the hospital and outlines the approach to the management.

The initial presentation of transient global amnesia (TGA) in the emergency department can be very dramatic. TGA is a benign disorder characterized by a sudden loss of memory about recent events and a transient inability to retain new information. Patients are disoriented to time and place, but never to person. Typically, they ask repetitive questions about transpiring events and quickly forget the answers.¹ Some degree of retrograde amnesia is usually present; its severity varies from hours to years.² A small percentage of patients may also complain of headache, nausea, and dizziness. No other neurologic signs are associated with this condition.

Immediate recall, awareness of personal identity, consciousness, and the ability to perform procedural tasks requiring visual and spatial skills typically remain intact. The anterograde amnesia generally lasts from 4 to 6 hours. As anterograde amnesia improves, the temporal component of the retrograde amnesia also improves. After recovery, the patient retains a permanent inability to recall the period of the TGA episode.¹ TGA is often difficult to diagnosis in the emergency department setting, even though clinical diagnostic criteria have been established.

TGA is an uncommon entity, with an annual incidence of 8.6 to 10.0 cases per 100,000 persons in the general population and 32 cases per 100,000 persons in those older than 50 years.^3,4 The following case report illustrates a classical presentation.

Illustrative Case

A 59-year-old man presented to the emergency department at 11:00 AM accompanied by his wife, with the chief complaint of an abrupt onset of memory loss and confusion characterized by repetitive questioning. The episode began 1.5 hours earlier, when the patient was eating breakfast with his wife. She reported that her husband momentarily paused while speaking, stared blankly, and suddenly became disorientated to time, place, and recent events. He began to state repetitively, "Don't ask me where I am; I really don't know" every 1 to 2 minutes. His wife questioned him about his activities over the past 2 to 3 weeks, but he could not recall any. The man began to feel nauseous and experienced numbness in both arms, along with tinnitus, which he reported to his wife at the time.

The patient was transported to the hospital. He appeared slightly anxious, repeatedly asking questions regarding his location and transpiring events. Bedside examination revealed complete retrograde amnesia, extending all the way back to 11:00 PM the night before (which was the time he went to sleep). The patient could not recall waking up that morning, eating breakfast with his wife, or arriving at the hospital moments earlier.

Further questioning revealed partial retrograde amnesia for events up to 2 weeks before this incident. Although he recalled driving to Vermont 2 weeks ago, he could not remember the reason for the trip, or its duration. His orientation to person was fully intact, but he repeatedly stated the phrase, "Don't ask me where I am; I really don't know." He was told that he was at the hospital, but 1 or 2 minutes later he repeated the same phrase. He denied having numbness in his arms or tinnitus at the time of examination, but he did complain of slight nausea. His wife said he had been under moderate stress concerning their family business in the past month or two, and that the morning before he had received the shocking news that a close family friend had died suddenly.

The patient had no significant medical or surgical history and was not taking any medications. He had no family history of seizures, heart disease, cerebrovascular accident/transient ischemic attack (TIA), hypertension, or diabetes, and he had never had a TGA episode before.

Physical and neurologic examinations were unremarkable, except for the obvious mental status changes. He was alert and cooperative, and his language function was preserved. His immediate recall was normal for up to 1 minute, but not after distraction or after a longer duration of time. Deficits included disorientation to time and place, inability to form new memories, and complete retrograde amnesia to 11:00 PM the previous evening. No epileptic features were evident.

Workup included a complete blood cell (CBC) count and measurements of electrolytes, glucose, calcium, magnesium, phosphorous, blood urea nitrogen (BUN), creatinine levels, prothrombin time (PT), partial thromboplastin time (PTT), cardiac enzymes, and liver function. A toxicology screening was performed. All results were normal. An electrocardiogram and noncontrast computed tomography (CT) scan of the brain were normal, as were carotid artery Doppler examination and echocardiography.

The patient met all the diagnostic criteria for TGA, and the neurologist who was consulted diagnosed the patient with TGA. The patient was admitted to the hospital for observation and given 325 mg of aspirin. By 2:30 PM he was able to recall the name of the hospital after he was told the name. As the afternoon progressed, the repetitive questioning subsided. By 3:30 PM, the anterograde amnesia had begun to resolve, and the patient became oriented to place and time.

The next morning the patient's mental status was back to normal, and no evidence of anterograde amnesia was found. He was able to recall waking up the previous morning and sitting down at the kitchen table but remained amnesic to events that transpired from 9:30 AM to roughly 3:00 PM. He was able to recall events that occurred during the previous 2 weeks but was unable to retrieve specific details when questioned. He could, however, remember details after his wife reminded him about them. The patient was discharged, reassured about the transient nature of the disorder, and scheduled for a follow-up visit.

Clinical Features

The clinical features of TGA were first described by Bender in 1956⁵ and were further characterized by Fisher and Adams in 1964.⁶ Most attacks occur in otherwise healthy, middle-aged or elderly patients who have no major vascular risk factors; the majority of attacks are singular.⁷ Confusion surrounding the causes and precipitating factors of this syndrome may result in misdiagnosis. When the diagnosis of TGA is suspected, the physician should determine whether the patient meets the established diagnostic criteria (Table 1), which were first set forth by Caplan in 1985⁸ and subsequently refined by Hodges and Warlow in 1990.²

Risk Factors

Although specific diagnostic criteria are available, the exact pathophysiology and precipitants of TGA are debated. Common precipitating events include immersion in cold water, sexual intercourse, physical exertion, stressful events, and certain medical procedures. Whether a greater incidence of TGA is associated with individuals with vascular risk factors or with other neurologic events, such as chronic headaches, is still debated. Our patient had no history of migraines, seizures, or head trauma, but he did have an emotionally traumatic event within 24 hours of the attack (the unexpected death of a close family friend) and a vascular risk factor—smoking for 15 years.

In one study, 14% of the 114 patients with TGA reported that the attack was preceded by a stressful event, such as witnessing a motor vehicle accident, receiving news of serious family illness, attending a funeral, or giving evidence in court.⁹

Controversial Pathogenesis

Despite the quandary surrounding its precise etiology, TGA is generally thought to be caused by a transient decrease in cerebral blood flow in the inferomedial portion of the temporal lobes.¹⁰ Current hypotheses on the pathogenesis of TGA include transient global ischemia in the inferomedial portion of the temporal lobes, epileptic discharge in the hippocampus, and spreading depression of cortical electrical activity similar to that seen in migraines.³ Experimental and pathoanatomical animal studies have shown that amnesic disorders are associated with bilateral dysfunction of the hippocampus.¹¹ Infarction of both inferior and medial regions of the temporal lobe (including the hippocampus) is known to produce a memory defect in rats that, apart from its permanence, is similar to that seen in patients with TGA.¹¹ Imaging studies of patients with TGA show localized baseline changes in cerebral blood flow and metabolism to temporal lobe structures.

One study using functional magnetic resonance imaging (MRI) studies demonstrated that during an attack, the functional changes in a distributed temporolimbic circuit included the retrosplenial cortex, parahippocampal gyrus, and temporal stem/pole.¹² These regions are important components of the long-term memory system. This finding is consistent with findings from studies that have used single-photon emission CT (SPECT), that have also shown bilateral temporal lobe hypoperfusion during TGA, secondary to a primary perfusion deficit or to a fall in cerebral metabolism.¹³

This reduced cerebral metabolism theory is strongly supported by studies that have used either positron-emission tomography or SPECT to document reductions in cerebral blood flow, the cerebral metabolic rate of oxygen, and tissue oxygenation extraction in the temporal lobes.^14,15

Arterial thromboembolic disease has been postulated as a possible etiology of TGA, but the evidence suggests otherwise.⁹ One case-control study that compared 64 patients who had a TGA episode with 64 gender- and age-matched controls who had a first TIA showed no evidence for increased incidence of cerebrovascular risk factors—such as ischemia, heart disease, smoking, or peripheral vascular disease—in the patients with TGA.¹⁶ Our patient's major vascular risk factor was his 15 pack-year smoking history. The authors of this study concluded that risk factors for cardiovascular disease are no more common among patients with TGA than among the general public.¹⁶ Follow-up data confirmed the benign prognosis of TGA compared with TIA, in terms of subsequent vascular risk.¹⁷

Seizures are unlikely to be a cause of TGA, since patients with TGA rarely have electroencephalography abnormalities and do not have convulsions or impaired consciousness and no other cortical features to link them to seizures.¹⁸

Spreading depression is a short-lasting wave of depolarization that extends across the cortex at a rate of 3 to 5 mm/min.¹⁰ This phenomenon, which is also believed to be responsible for migraine aura, has been observed in studies using local brain stimulation in animals.¹⁹ The many precipitants of TGA are believed to result in the release of glutamate in the hippocampus, which triggers spreading depression and transient hippocampal dysfunction. Spreading depression has also been linked to a reduction in cerebral blood flow and glucose consumption²⁰ and is believed to cause local nerve-cell edema.²¹ This theory is supported by evidence from diffusion-weighted MRI studies,²² as well as by the increased incidence of migraine reported in patients with TGA.^9,10

Differential Diagnosis

The presentation of TGA in the emergency department can be very striking, because it can incapacitate the patient. The major clinical dilemma is differentiating TGA from other, more serious causes of central nervous system pathology (Table 2).

Initial workup in the emergency department should include a CBC count; electrolyte panel; urinalysis; toxicology screen; measurements of BUN, creatinine, PT, and PTT, and cardiac enzymes; liver function tests; and noncontrast brain CT. Further inpatient or outpatient workup may include brain MRI, electroencephalography, Holter monitoring, echocardiography, and magnetic resonance angiography of the anterior and posterior circulation.²³

If the results of all these studies are normal, a definitive diagnosis of TGA can be made in the emergency department. Our patient's anterograde amnesia resolved within 5 to 6 hours, as expected, and his retrograde amnesia had resolved by the next morning.

Conclusion

TGA is a well-described syndrome whose exact etiology is still being defined. Any patient who presents with a transient loss of memory function must have a thorough workup to rule out more serious pathology. Vascular risk factors—such as hypertension, smoking, diabetes, and hypercholesterolemia—should be discussed with the patient and appropriately treated. Once TGA is diagnosed, the physician can provide reassurance to the patient and suggest a follow-up appointment with a neurologist.

SELF-ASSESSMENT TEST

1. Which of these findings is the most characteristic sign of TGA?

1. Patient does not recognize spouse
2. Impaired consciousness
3. Focal neurologic deficit
4. Disorientation to place

2. All the following elements are diagnostic criteria for TGA, except:

1. Attack was witnessed by observer
2. No history of recent head trauma
3. Resolution of attack within 6 to 8 hours
4. Absence of epileptic features

3. Which of these is not a common precipitating factor of TGA?

1. Immersion in cold water
2. Sexual intercourse
3. Medical procedures
4. Sleep deprivation

4. All the following features of TGA generally resolve, except:

1. Anterograde amnesia
2. Retrograde amnesia
3. Amnesia for events during the TGA episode
4. Disorientation to time

5. Which of the following diagnostic tests is not generally included in the emergency department workup of a patient with suspected TGA?

1. CBC count
2. CT scan of the brain
3. Electroencephalography
4. Urinalysis

(Answers at end of references list)

References

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Answers: 1. D; 2. C; 3. D; 4. C; 5. C.