Transient Global Amnesia

Etiology

The etiology of transient global amnesia remains largely unknown, with multiple theories proposed but none conclusively proven. The most supported theory suggests a link to migraines, as 12% to 30% of transient global amnesia patients have a migraine history. Some researchers propose that transient global amnesia may involve cortical spreading depression similar to migraine aura.[4] Other suspected causes include vascular phenomena, epilepsy, and psychogenic origins. Studies have both supported and refuted arterial ischemia as a cause. Vascular congestion is a leading hypothesis, yet questions about its association with specific age groups and absence in venous thrombosis remain unresolved. Transient global amnesia rarely recurs more than a few times in a patient's life. Ultimately, no single theory fully explains all clinical aspects of transient global amnesia.[5][6][7][8]

Epidemiology

The incidence of transient global amnesia ranges from 3.4 to 10.4 per 100,000 people per year in the general population. In individuals aged 50 or older, this increases to 23.5 to 32 per 100,000 per year, with most cases occurring in those aged 50 to 80. There is no gender difference.[9]

Although no clear risk factors have been identified, transient global amnesia is more frequently noted in patients with a history of ischemic heart disease and hyperlipidemia but not with prior ischemic stroke, diabetes, or hypertension. Individuals with migraine have an increased risk, with an incidence risk ratio of 2.48.[9]

Transient global amnesia recurrence is uncommon but not rare, with rates varying from 2.9% to 26.3%.[9] Interestingly, transient global amnesia episodes occur more often in the morning between 10 and 11 AM and late afternoon between 5 and 6 PM.[10]

Pathophysiology

The origin of transient global amnesia is believed to involve the mediobasal temporal lobe, including the hippocampus, particularly the CA1 or Sommer sector. These structures are crucial for memory consolidation and retrieval.[4] The hippocampus is especially vulnerable to various metabolic stresses, potentially due to its sensitivity to cytotoxic glutamatergic uptake or release. Affected areas can be unilateral or bilateral, although they are more commonly found on the left side. Functional magnetic resonance imaging (MRI) has shown bilaterally reversible defects; both functional MRI and quantitative electroencephalography (EEG) studies have demonstrated changes in functional connectivity in the hippocampus and limbic system.[11][12]

History and Physical

The diagnosis of transient global amnesia is primarily clinical, based on a detailed history and a thorough neurological examination during the acute stage. Advanced neuroimaging, cerebrospinal fluid analysis, and EEG are unnecessary unless the clinical diagnosis is uncertain. Diagnostic criteria have been established by Caplan, Hodges, and Warlow, and most recently, the German Society of Neurology guidelines.[13][14][15]

Patients typically present with a sudden onset of memory loss lasting several hours, featuring retrograde and pronounced anterograde amnesia. They often repeat questions and lack recall of recent events leading up to the episode. Accompanying individuals may report recent vigorous exertion, coitus, or severe stress but no loss of consciousness. Patients retain self-identity and demonstrate no neurological or cognitive deficits. They remain cooperative and can name objects, with no history of trauma or epilepsy. Symptoms last between 1 and 24 hours, typically occurring later in the day rather than after waking.

Clinical features making transient global amnesia unlikely include evidence of toxic or metabolic disturbances, a history of trauma or epilepsy, impaired awareness or consciousness, and focal neurological signs. If a patient can describe the episode details and timing, or if they experience more than 3 episodes a year, transient global amnesia should be strongly reconsidered.[15]

Evaluation

Further evaluation is generally unnecessary when a patient presents to the emergency department with typical clinical features of transient global amnesia. A toxicology screen, alcohol level, and basic laboratory studies, including glucose and electrolytes, are typically performed. Once the amnesic episode resolves, typically within a few hours, the patient can be discharged home.

However, if clinical evidence or routine laboratory studies raise doubts about the diagnosis, the patient should be admitted for monitoring and further diagnostic evaluation. The most important study is brain imaging with MRI. Brain MRI results should be normal during the acute transient global amnesia episode. Diffusion-weighted MRI (DWI) lesions, typical for transient global amnesia, most commonly appear 24 to 72 hours after the episode. These are punctate DWI and T2 hyperintensity lesions in 1 or both hippocampi, particularly in the CA1 region.[16]

EEG results are generally normal in patients with transient global amnesia, except for occasional nonspecific theta and delta waves. EEG is useful in differentiating transient global amnesia from amnestic epileptic episodes or transient epileptic amnesia.[17]

Cerebrospinal fluid analysis is not indicated unless there is clinical suspicion of an underlying infectious or inflammatory cerebral disorder.

Treatment / Management

Treatment for transient global amnesia primarily involves supportive care and reassurance, as no specific therapy is required or available. A thorough examination is crucial to identify any neurological deficits or signs of head trauma that could suggest an alternative diagnosis. Hospital observation may be necessary until the memory deficit resolves. Intravenous thiamine should be considered. Although rare, recurrences can occur. Following the resolution of memory deficits, patients do not require restrictions on activities such as driving.

Differential Diagnosis

In cases where the clinical features of the amnesic episode are unusual, or there is a focal neurological deficit, it is crucial to rule out acute ischemic stroke affecting the hippocampus (posterior cerebral artery territory infarct) through MRI.

Another significant consideration is transient epileptic amnesia, often observed in patients with a history of focal impaired awareness seizures or epilepsy. These episodes typically last less than an hour and may recur frequently (>3 times per year). In seizure-related memory loss, there is typically seizure-like activity before the onset, and the memory loss is almost purely retrograde; this differs from transient global amnesia, which involves anterograde amnesia presenting with minimal retrograde amnesia confined to events surrounding the onset. Interictal EEG is the primary diagnostic tool to distinguish between these 2 conditions.[17]

Other important differential diagnoses include the following:

• Basilar artery thrombosis
• Cardioembolic stroke
• Complex partial seizures
• Lacunar syndrome
• Migraine variants
• Posterior cerebral artery stroke
• Syncope
• Temporal lobe epilepsy
• Hypoglycemia
• Wernicke encephalopathy
• Transient ischemic attack
• Toxic encephalopathy
• Hypoxia
• Head injury
• Substance intoxication

These differential diagnoses frequently involve patients presenting with atypical features, often involving global confusion rather than the specific memory loss and symptoms typical of transient global amnesia.

Prognosis

Most cases of transient global amnesia occur as isolated events with favorable outcomes and negligible morbidity or mortality reported. Although recurrences are possible, their incidence varies from 2.9% to 26.3% over different follow-up periods, with a 10-year study showing a recurrence rate of 6.3%.[18] A recent study from Korea suggested a potential increased risk of epilepsy following a transient global amnesia episode, with an adjusted hazard ratio of 1.46.[19] However, this finding also underscores the importance of confirming the initial diagnosis of transient global amnesia.

Complications

Complications directly attributable to transient global amnesia are rare, given its typically benign and self-limiting nature. However, the episodic nature of transient global amnesia can lead to significant anxiety and distress for patients and their families during the acute episode. Although uncommon, Recurrence can occur, impacting quality of life and necessitating repeated medical evaluations. In a small subset of cases, some studies have reported that transient global amnesia might be linked to an increased risk of developing epilepsy, highlighting the importance of thorough diagnostic evaluation and follow-up care to monitor for any emerging neurological conditions or sequelae. Despite these considerations, most patients with transient global amnesia experience complete resolution of symptoms without long-term complications or functional impairment.