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Transient Global Amnesia

      Abstract

      Transient global amnesia (TGA) is a clinical syndrome characterized by the sudden onset of anterograde amnesia (the inability to encode new memories), accompanied by repetitive questioning, sometimes with a retrograde component, lasting up to 24 hours, without compromise of other neurologic functions. Herein, we review current knowledge on the epidemiology, pathophysiology, clinical diagnosis, and prognosis of TGA. For this review, we conducted a literature search of PubMed, with no date limitations, using the following search terms (or combinations of them): transient global amnesia, etiology, pathophysiology, venous hypertension, migraine, magnetic resonance imaging, computed tomography, electroencephalography, prognosis, and outcome. We also reviewed the bibliography cited in the retrieved articles. Transient global amnesia is a clinical diagnosis, and recognition of its characteristic features can avoid unnecessary testing. Several pathophysiologic mechanisms have been proposed (venous insufficiency, arterial ischemia, and migrainous or epileptic phenomena), but none of them has been proved to consistently explain cases of TGA. Brain imaging may be considered and electroencephalography is recommended when episodes are brief and recurrent, but otherwise no investigations are necessary in most cases. Data on long-term prognosis are limited, but available information suggests that the relapse rate is low, the risk of stroke and seizures is not considerably increased, and cognitive outcome is generally good.

      Abbreviations and Acronyms:

      DWI (diffusion weighted imaging), ECG (electrocardiography), EEG (electroencephalography), FLAIR (fluid-attenuated inversion recovery), IJVFR (internal jugular venous flow reversal), IJVVI (internal jugular vein valve incompetency), MRI (magnetic resonance imaging), TEA (transient epileptic amnesia), TGA (transient global amnesia), TIA (transient ischemic attack)
      Article Highlights
      • Transient global amnesia is a condition that can be encountered by internists, emergency department physicians, family medicine practitioners, and, ultimately, neurologists. Its correct diagnosis relies on recognition of the disease, which can prevent unnecessary testing.
      • We propose a diagnostic algorithm for patients with sudden-onset anterograde amnesia and present the diagnostic criteria for transient global amnesia.
      • Episodes are self-limited, and spontaneous improvement is noted within 24 hours of onset.
      • Available data to date indicate that long-term outcome is generally good in terms of relapse rate and risk of stroke and seizures. Information regarding long-term cognitive outcome is scarce but suggests that these patients are not at higher risk for cognitive impairment.
      Transient global amnesia (TGA) was initially described in 1956 by Bender,
      • Bender M.B.
      Single episode of confusion with amnesia.
      and at the same time but independently by Courjon and Guyotat,
      • Courjon J.
      • Guyotat J.
      Amnesic strokes.
      as a syndrome characterized by sudden and temporary memory loss. Yet, it was not until 1964 that it gained recognition as we know it today, when Fisher and Adams
      • Fisher C.M.
      • Adams R.D.
      Transient global amnesia.
      described the syndrome as TGA. Initially referred to as a heterogeneous clinical syndrome, the approach to the condition was refined by the diagnostic criteria proposed by Caplan
      • Caplan L.
      Transient global amnesia.
      and consolidated by Hodges and Warlow
      • Hodges J.R.
      • Warlow C.P.
      Syndromes of transient amnesia: towards a classification: a study of 153 cases.
      • Hodges J.R.
      • Warlow C.P.
      The aetiology of transient global amnesia: a case-control study of 114 cases with prospective follow-up.
      in 1990. Since the first description of the disorder, a lot has been published about its clinical characteristics, and several hypotheses regarding its pathogenesis have been proposed. Yet, the cause and mechanisms of TGA remain unclear.
      Several reviews on TGA have been published,
      • Daniel B.T.
      Transient Global Amnesia.
      • Pantoni L.
      • Lamassa M.
      • Inzitari D.
      Transient global amnesia: a review emphasizing pathogenic aspects.
      • Quinette P.
      • Guillery-Girard B.
      • Dayan J.
      • et al.
      What does transient global amnesia really mean? review of the literature and thorough study of 142 cases.
      • Shekhar R.
      Transient global amnesia: a review.
      • Bartsch T.
      • Deuschl G.
      Transient global amnesia: functional anatomy and clinical implications.
      • Kirshner H.S.
      Transient global amnesia: a brief review and update.
      but they have all been addressed to neurologists. However, TGA can be encountered by internists, emergency department physicians, and family medicine practitioners. We aim to synthetize current knowledge and to propose a practical approach to this condition that can be useful for daily practice. Herein, we also review the epidemiology, pathophysiology, diagnostic criteria, differential diagnosis, and expected long-term outcome of TGA.
      The content of this review is based on a literature search of PubMed, with no date limitations, using the following search terms (or combinations of them): transient global amnesia, etiology, pathophysiology, venous hypertension, migraine, magnetic resonance imaging, computed tomography, electroencephalography, prognosis, and outcome. We also reviewed the bibliographies cited in the retrieved articles. The studies referenced in this article were selected based on study quality and clinical relevance.

      Basic Concepts on Memory

      Memory is the brain function that allows us to encode, store, and retrieve information. It can be divided into 3 different types: immediate or working memory, short-term memory, and long-term memory.
      • Daroff R.B.
      • Bradley W.G.
      Bradley's Neurology in Clinical Practice.
      Immediate memory refers to the information that can be retained for a short period of time without active involvement of the memory pathways. It can be simply tested by asking the patient to repeat a 7-digit number. This type of memory can be affected by attention or language impairment or by a lesion to the superior frontal neocortex. Short-term memory (also called episodic memory) implies the ability to encode, store, and retrieve information after minutes or hours; this is the type of memory that requires normal functioning of the hippocampus and parahippocampal areas located in the medial temporal lobe. It can be tested at the bedside by asking the patient about his or her activities earlier in the day. Long-term or remote memory relates to long-known information (where we were born, which school we attended); it includes semantic memory, which enables us to have a general knowledge of concepts, facts, and meanings (eg, definitions of words), and it is supposed to rest in multiple cortical regions, including the visual association cortex, temporal cortex, and other cortical structures according to the type of memory involved.
      A simplified memory circuit includes the hippocampus on each side projecting to the septal areas via the fornix, then to the mammillary bodies, and subsequently to the anterior nucleus of the thalamus; from there it projects to the cingulate gyrus of the frontal lobe and back to the hippocampus, thus completing the Papez circuit, crucial for short-term memory (Figure 1). Amnesia is caused by the disruption of these pathways. Specific memory impairments are determined by the site of involvement. Affection of the hippocampus will produce anterograde amnesia, characterized by the inability to lay down new information.
      Figure thumbnail gr1
      Figure 1The Papez circuit of short-term memory. The hippocampus on each side projects to the septal areas via the fornix, then to the mammillary bodies, the anterior nucleus of the thalamus, the cingulate gyrus of the frontal lobe, and back to the hippocampus.

      Epidemiologic Profile

      Transient global amnesia affects predominantly middle-aged or elderly patients. Its annual incidence has been reported to be 3.4 to 10.4 per 100,000 people.
      • Hodges J.R.
      • Warlow C.P.
      The aetiology of transient global amnesia: a case-control study of 114 cases with prospective follow-up.
      • Miller J.W.
      • Petersen R.C.
      • Metter E.J.
      • Millikan C.H.
      • Yanagihara T.
      Transient global amnesia: clinical characteristics and prognosis.
      • Koski K.J.
      • Marttila R.J.
      Transient global amnesia: incidence in an urban population.
      • Lauria G.
      • Gentile M.
      • Fassetta G.
      • Casetta I.
      • Caneve G.
      Incidence of transient global amnesia in the Belluno province, Italy: 1985 through 1995: results of a community-based study.
      If we narrow it to the population older than 50 years, the incidence increases to 23.5 per 100,000 per year.
      • Miller J.W.
      • Yanagihara T.
      • Petersen R.C.
      • Klass D.W.
      Transient global amnesia and epilepsy: electroencephalographic distinction.
      It is more common in individuals with migraine.
      • Zorzon M.
      • Antonutti L.
      • Mase G.
      • Biasutti E.
      • Vitrani B.
      • Cazzato G.
      Transient global amnesia and transient ischemic attack: natural history, vascular risk factors, and associated conditions.
      • Lin K.H.
      • Chen Y.T.
      • Fuh J.L.
      • et al.
      Migraine is associated with a higher risk of transient global amnesia: a nationwide cohort study.

      Clinical Presentation and Diagnostic Criteria

      Transient global amnesia is a clinical syndrome characterized by the sudden onset of anterograde amnesia, accompanied by repetitive questioning, sometimes with a retrograde component, lasting up to 24 hours, and without compromise of other neurologic functions. Typically, TGA is encountered in patients aged 50 to 70 years who are brought to medical attention because they are noticed to have acutely lost the ability to understand their situation and grasp their surroundings. Patients repeatedly ask questions, such as “Why are we here?” “What time is it?” or “How did I get here?” The answers are immediately forgotten owing to their inability to encode new information. Other neurologic functions are preserved, including procedural memory. Thus, these patients can perform previously learned activities (eg, driving) without impairment. These episodes are sometimes preceded by a precipitating event, such as an activity associated with a Valsalva maneuver, emotional stress, immersion in cold or hot water, sexual intercourse, or pain.
      Patients having an episode of TGA are characteristically not well aware of their problem, and that is why they are often brought to consultation by an observer of the episode. They may appear restless or nervous and confused, but alertness, self-orientation, recognition of family members, speech, and motor, sensory, and coordination functions are preserved. Mild vegetative symptoms may occur, such as nausea, dizziness, and headache. If other neurologic signs are present or consciousness is impaired, other diagnoses should be excluded. The memory deficit typically lasts a few hours, often 4 to 6 hours, and always less than 24 hours.
      • Quinette P.
      • Guillery-Girard B.
      • Dayan J.
      • et al.
      What does transient global amnesia really mean? review of the literature and thorough study of 142 cases.
      • Zeman A.Z.
      • Hodges J.R.
      Transient global amnesia.
      Then the patient progressively recovers the ability to register and store new memories. A residual amnestic gap for the duration of the episode is common.
      No laboratory investigations can presently confirm the diagnosis of TGA. Thus, the diagnosis relies on a detailed clinical history, cognitive evaluation, and physical examination. The physician should bear in mind the differential diagnoses to run the tests necessary to discard them when pertinent. Diagnostic criteria have been proposed (Table 1).
      • Caplan L.
      Transient global amnesia.
      • Hodges J.R.
      • Warlow C.P.
      Syndromes of transient amnesia: towards a classification: a study of 153 cases.
      • Hodges J.R.
      • Warlow C.P.
      The aetiology of transient global amnesia: a case-control study of 114 cases with prospective follow-up.
      These criteria remain valid, with a few modifications. The possibility of associated retrograde amnesia is not included in the criteria, but it is well recognized that patients with TGA can have some degree of retrograde amnesia during the episode, especially for memories of events that occurred in recent years.
      • Fisher C.M.
      Transient global amnesia: precipitating activities and other observations.
      • Hodges J.R.
      Transient Amnesia: Clinical and Neuropsychological Aspects (Major Problems in Neurology).
      There are also some studies indicating that other cognitive functions could also be mildly affected, such as visuoperceptual ability.
      • Gallassi R.
      • Stracciari A.
      • Morreale A.
      • Lorusso S.
      • Rebucci G.G.
      • Lugaresi E.
      Transient global amnesia: neuropsychological findings after single and multiple attacks.
      Table 1Diagnostic Criteria for Transient Global Amnesia
      Attack must be witnessed and information available from a capable observer who was present for most of the attack
      Clear-cut anterograde amnesia during the attack
      Cognitive impairment limited to amnesia, without clouding of consciousness or loss of personal identity
      No accompanying focal neurologic symptoms during the attack and no significant neurologic signs afterward
      Absence of epileptic features
      Resolution of the attack within 24 h
      Patients with recent head injury or active epilepsy are excluded

      Additional Investigations

      When making a diagnosis of TGA, the question is whether to pursue additional testing. The main value of additional testing in TGA is to exclude alternative diagnoses.
      Brain imaging is often considered by clinicians who suspect TGA, but findings from head computed tomography are typically normal, and evidence on the utility of brain magnetic resonance imaging (MRI) is conflicting. Case series and studies comparing patients with TGA and those with transient ischemic attack (TIA) or control cohorts have reported that patients with TGA may frequently, but not always, show hyperintense signal on diffusion-weighted imaging (DWI) and sometimes on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences on either or even both hippocampi, provided that the MRI is performed within 48 hours of symptom onset.
      • Woolfenden A.R.
      • O'Brien M.W.
      • Schwartzberg R.E.
      • Norbash A.M.
      • Tong D.C.
      Diffusion-weighted MRI in transient global amnesia precipitated by cerebral angiography.
      • Strupp M.
      • Bruning R.
      • Wu R.H.
      • Deimling M.
      • Reiser M.
      • Brandt T.
      Diffusion-weighted MRI in transient global amnesia: elevated signal intensity in the left mesial temporal lobe in 7 of 10 patients.
      • Sedlaczek O.
      • Hirsch J.G.
      • Grips E.
      • et al.
      Detection of delayed focal MR changes in the lateral hippocampus in transient global amnesia.
      • Yang Y.
      • Kim S.
      • Kim J.H.
      Ischemic evidence of transient global amnesia: location of the lesion in the hippocampus.
      • Winbeck K.
      • Etgen T.
      • von Einsiedel H.G.
      • Rottinger M.
      • Sander D.
      DWI in transient global amnesia and TIA: proposal for an ischaemic origin of TGA.
      Conversely, other studies reported no MRI changes even in patients scanned early.
      • Gass A.
      • Gaa J.
      • Hirsch J.
      • Schwartz A.
      • Hennerici M.G.
      Lack of evidence of acute ischemic tissue change in transient global amnesia on single-shot echo-planar diffusion-weighted MRI.
      • Huber R.
      • Aschoff A.J.
      • Ludolph A.C.
      • Riepe M.W.
      Transient global amnesia: evidence against vascular ischemic etiology from diffusion weighted imaging.
      Even when there is evidence of hippocampal restricted diffusion on DWI, these changes are often reversible, as manifested by the lack of persistent signal change on T2-weighted or FLAIR sequences. Signal changes on T2-weighted or FLAIR sequences can also be reversible.
      • Matsui M.
      • Imamura T.
      • Sakamoto S.
      • Ishii K.
      • Kazui H.
      • Mori E.
      Transient global amnesia: increased signal intensity in the right hippocampus on diffusion-weighted magnetic resonance imaging.
      • Felix M.M.
      • Castro L.H.
      • Maia Jr., A.C.
      • da Rocha A.J.
      Evidence of acute ischemic tissue change in transient global amnesia in magnetic resonance imaging: case report and literature review.
      This would indicate that the changes are not due to ischemia or that ischemia is not critical enough to cause an infarction. In addition, the abnormal DWI signal is characteristically confined to one or both hippocampi, which is a very unusual pattern for ischemic stroke. In typical cases of TGA, it is not necessary to pursue a comprehensive stroke work-up (ie, vascular imaging, cardiac evaluation, and coagulation studies) as long as brain MRI abnormalities are restricted to hippocampal regions.
      Internal jugular venous flow reversal (IJVFR) and internal jugular vein valve incompetency (IJVVI) have been proposed as potential pathophysiologic mechanisms, and these phenomena can be documented by Doppler studies of the internal jugular veins or by air-contrast ultrasound. However, not all patients with TGA show IJVVI or IJVFR, and not all individuals with IJVVI will have an episode of TGA. In addition, jugular venous flow studies are not commonly performed, and, consequently, their reliability may vary across centers. Hence, these studies cannot be recommended as routine investigations to confirm or discard the diagnosis of TGA.
      The value of electroencephalography (EEG) is also limited. During and after typical TGA episodes, EEG findings have been reported to be normal.
      • Miller J.W.
      • Yanagihara T.
      • Petersen R.C.
      • Klass D.W.
      Transient global amnesia and epilepsy: electroencephalographic distinction.
      • Cole A.J.
      • Gloor P.
      • Kaplan R.
      Transient global amnesia: the electroencephalogram at onset.
      • Jacome D.E.
      EEG features in transient global amnesia.
      However, transient episodes of amnesia can be caused by seizures. These episodes, known as transient epileptic amnesia (TEA), tend to be shorter and recurrent, and they may be accompanied by other manifestations, such as oral automatisms and olfactory or gustatory hallucinations. Hence, EEG should be performed when TEA is considered likely and not to support or disprove the diagnosis of TGA.

      Differential Diagnosis

      The differential diagnosis of TGA includes TIA or stroke in the posterior cerebral circulation, focal seizures (including TEA), postictal state, dissociative disorders or psychogenic amnesia, posttraumatic amnesia, and metabolic disorders such as hypoglycemia. The differentiating features of some of these alternative diagnoses are reviewed on Table 2. It is particularly important to remember that isolated memory loss is a very infrequent presentation of acute ischemic stroke. Meanwhile, seizures are characteristically shorter in duration than TGA and more frequently recurrent.
      Table 2Differential Diagnosis of TGA
      DWI = diffusion-weighted imaging; EEG = electroencephalography; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging; TEA = transient epileptic amnesia; TGA = transient global amnesia; TIA = transient ischemic attack.
      ConditionRisk factorsPrecipitating factorsDurationAssociated neurologic symptomsMRIEEGRecurrence of attacksResponse to anticonvulsant medications
      TGAMigraineYes
      Valsalva maneuver, emotional stress, immersion in cold or hot water, sexual intercourse, or pain.
      4-6 hNoHippocampal DWI hyperintensity, without permanent lesionNormalLowNo
      TEANoNo/yes
      Waking.
      <60 min
      Often a few minutes.
      No/yes (oral automatisms, olfactory or gustatory hallucinations)Normal/hippocampal sclerosis or atrophyAbnormal (temporal or frontotemporal regions)HighYes
      TIA/strokeVascular risk factorsNoMinutes to permanent impairmentNo/yes (any)DWI with T2-FLAIR permanent lesionNormalLowNo
      a DWI = diffusion-weighted imaging; EEG = electroencephalography; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging; TEA = transient epileptic amnesia; TGA = transient global amnesia; TIA = transient ischemic attack.
      b Valsalva maneuver, emotional stress, immersion in cold or hot water, sexual intercourse, or pain.
      c Waking.
      d Often a few minutes.
      A diagnostic algorithm for a patient presenting with acute-onset anterograde amnesia is proposed in Figure 2.
      Figure thumbnail gr2
      Figure 2Diagnostic algorithm for a patient presenting with sudden onset anterograde amnesia. ECG = electrocardiography; EEG = electroencephalography; MRI = magnetic resonance imaging; TEA = transient epileptic amnesia; TGA = transient global amnesia.

      Pathophysiologic Mechanisms

      The debate regarding the pathogenesis of TGA has focused mainly on 3 distinct mechanisms: vascular (due to venous flow disturbances or focal arterial ischemia), epileptic, and migraine related. It has also been reported that the CA1 subfield of the hippocampal cornu ammonis (which is the part of the hippocampus most affected by TGA) would have a particular vulnerability to metabolic stress caused by hypoxemia, B-amyloid–induced neurotoxicity, and ischemia; the degree of this local susceptibility could be genetically determined.
      • Bartsch T.
      • Deuschl G.
      Transient global amnesia: functional anatomy and clinical implications.
      • Calabresi P.
      • Centonze D.
      • Pisani A.
      • Cupini L.
      • Bernardi G.
      Synaptic plasticity in the ischaemic brain.
      • Kosuge Y.
      • Imai T.
      • Kawaguchi M.
      • Kihara T.
      • Ishige K.
      • Ito Y.
      Subregion-specific vulnerability to endoplasmic reticulum stress-induced neurotoxicity in rat hippocampal neurons.
      Perhaps the leading hypothesis is that TGA is caused by abnormal cerebral venous drainage from the temporal lobes.
      • Lewis S.L.
      Aetiology of transient global amnesia.
      It argues that precipitating events associated with a Valsalva maneuver and increased intrathoracic pressure would prevent venous return to the superior vena cava and, consequently, would lead to retrograde jugular venous flow in the presence of jugular valve incompetence. The resulting venous hypertension in the medial temporal lobes could explain memory impairment (Figure 3). Several studies have shown that patients with TGA have IJVFR or IJVVI more frequently than control subjects, and this finding is even more prevalent in patients with TGA starting after a Valsalva maneuver.
      • Sander D.
      • Winbeck K.
      • Etgen T.
      • Knapp R.
      • Klingelhofer J.
      • Conrad B.
      Disturbance of venous flow patterns in patients with transient global amnesia.
      • Maalikjy Akkawi N.
      • Agosti C.
      • Anzola G.P.
      • et al.
      Transient global amnesia: a clinical and sonographic study.
      • Schreiber S.J.
      • Doepp F.
      • Klingebiel R.
      • Valdueza J.M.
      Internal jugular vein valve incompetence and intracranial venous anatomy in transient global amnesia.
      • Nedelmann M.
      • Eicke B.M.
      • Dieterich M.
      Increased incidence of jugular valve insufficiency in patients with transient global amnesia.
      • Cejas C.
      • Cisneros L.F.
      • Lagos R.
      • Zuk C.
      • Ameriso S.F.
      Internal jugular vein valve incompetence is highly prevalent in transient global amnesia.
      • Agosti C.
      • Borroni B.
      • Akkawi N.M.
      • Padovani A.
      Cerebrovascular risk factors and triggers in transient global amnesia patients with and without jugular valve incompetence: results from a sample of 243 patients.
      Patients with TGA also have retrograde venous flow more commonly than patients with TIA.
      • Maalikjy Akkawi N.
      • Agosti C.
      • Anzola G.P.
      • et al.
      Transient global amnesia: a clinical and sonographic study.
      Figure thumbnail gr3
      Figure 3Venous hypothesis for the pathogenesis of transient global amnesia (TGA). It is proposed that retrograde venous flow and the ensuing venous hypertension could explain the occurrence of TGA. Increased intrathoracic pressure, as caused by a Valsalva maneuver, could trigger retrograde venous flow in patients with valve incompetence in the internal jugular veins. The resulting venous congestion would preferentially affect the function of the medial temporal lobes, thus inciting the anterograde amnesia. The graphic on the right illustrates the venous blood drainage from the medial temporal lobes. Blood from the temporal lobes is drained by the basal veins of Rosenthal and the internal cerebral veins, which, in turn, drain into the vein of Galen, and from there to the straight sinus, confluens, transverse sinuses, and sigmoid sinuses, and, finally, into the internal jugular veins.
      Yet, there are some unresolved questions regarding this hypothesis. It is not entirely clear how IJVVI causes symptoms referable only to the medial temporal lobes. The persistence of memory impairment long after resolution of the typically short-lasting intrathoracic hypertension also remains unexplained. One proposed possibility is that intracranial venous hypertension could cause reactive arterial vasoconstriction to compensate for the increased cerebral blood volume, and the resulting relative hypoperfusion would be responsible for the amnesia in susceptible individuals.
      • Caplan L.R.
      Transient global amnesia and jugular vein incompetence.
      This could be supported by evidence of temporal hypoperfusion during TGA episodes, as occasionally disclosed by single-photon emission computed tomography.
      • Di Filippo M.
      • Calabresi P.
      Ischemic bilateral hippocampal dysfunction during transient global amnesia.
      But other questions still demand answers. Why do TGA episodes not happen more often in people with IJVVI (ie, each time they have a Valsalva-like episode)? Why do some individuals with proven IJVVI never develop TGA? Why do some episodes of TGA seem to occur in the absence of a triggering factor conceivably associated with increased intrathoracic venous pressure?
      The arterial ischemia hypothesis is mostly supported by the DWI changes on MRI. However, as previously mentioned, these changes are inconsistently present, reversible with time, and do not respect a clear arterial territory. Hypoperfusion has been shown to occur in patients with TGA,
      • Di Filippo M.
      • Calabresi P.
      Ischemic bilateral hippocampal dysfunction during transient global amnesia.
      but the frequency and severity of this phenomenon is not well examined. Ischemic symptoms lasting as long as most TGA episodes are commonly associated with permanent lesions on MRI, which is not the case in most patients with TGA.
      • Matsui M.
      • Imamura T.
      • Sakamoto S.
      • Ishii K.
      • Kazui H.
      • Mori E.
      Transient global amnesia: increased signal intensity in the right hippocampus on diffusion-weighted magnetic resonance imaging.
      • Felix M.M.
      • Castro L.H.
      • Maia Jr., A.C.
      • da Rocha A.J.
      Evidence of acute ischemic tissue change in transient global amnesia in magnetic resonance imaging: case report and literature review.
      • Easton J.D.
      • Saver J.L.
      • Albers G.W.
      • et al.
      Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease.
      Several studies on vascular risk factors identified only migraine as being more prevalent in patients with TGA compared with those with TIA and healthy age- and sex-matched control subjects,
      • Hodges J.R.
      • Warlow C.P.
      The aetiology of transient global amnesia: a case-control study of 114 cases with prospective follow-up.
      • Zorzon M.
      • Antonutti L.
      • Mase G.
      • Biasutti E.
      • Vitrani B.
      • Cazzato G.
      Transient global amnesia and transient ischemic attack: natural history, vascular risk factors, and associated conditions.
      whereas hypertension, diabetes mellitus, previous ischemic stroke, and atrial fibrillation were found to have a lower prevalence in patients with TGA.
      • Jang J.W.
      • Park S.Y.
      • Hong J.H.
      • Park Y.H.
      • Kim J.E.
      • Kim S.
      Different risk factor profiles between transient global amnesia and transient ischemic attack: a large case-control study.
      Transient global amnesia was also proposed to share pathophysiologic mechanisms with migraine. A large population-based study indicated that patients with migraine, particularly middle-aged women, are more prone to experience TGA.
      • Lin K.H.
      • Chen Y.T.
      • Fuh J.L.
      • et al.
      Migraine is associated with a higher risk of transient global amnesia: a nationwide cohort study.
      It has been proposed that cortical spreading depression could explain both conditions, in the case of TGA by altering CA1 neuron excitability.
      • Bartsch T.
      • Deuschl G.
      Transient global amnesia: functional anatomy and clinical implications.
      • Schwedt T.J.
      • Dodick D.W.
      Advanced neuroimaging of migraine.
      Cortical spreading depression would act like a glutamate-mediated transient depolarization, followed by long-lasting suppression of neuronal activity, and may lead to damage to CA1 neurons.
      • Bartsch T.
      • Deuschl G.
      Transient global amnesia: functional anatomy and clinical implications.
      • Pomper J.K.
      • Haack S.
      • Petzold G.C.
      • et al.
      Repetitive spreading depression-like events result in cell damage in juvenile hippocampal slice cultures maintained in normoxia.
      However, it seems that the threshold for triggering a cortical spreading depression response in the hippocampus is much higher than that needed in other cortical regions, and patients do not usually experience symptoms of migraine during TGA,
      • Bartsch T.
      • Deuschl G.
      Transient global amnesia: functional anatomy and clinical implications.
      which makes the hypothesis of a shared pathogenesis less likely.
      Although focal seizures arising from the mesial temporal lobe can mimic episodes of TGA,
      • Pantoni L.
      • Lamassa M.
      • Inzitari D.
      Transient global amnesia: a review emphasizing pathogenic aspects.
      the absence of epileptiform abnormalities during and after episodes of TGA and the relatively prolonged duration of the amnesia without propagation of the cerebral dysfunction to other brain regions argue against the notion that most TGA episodes could be epileptic in nature.
      • Miller J.W.
      • Yanagihara T.
      • Petersen R.C.
      • Klass D.W.
      Transient global amnesia and epilepsy: electroencephalographic distinction.
      • Cole A.J.
      • Gloor P.
      • Kaplan R.
      Transient global amnesia: the electroencephalogram at onset.
      • Jacome D.E.
      EEG features in transient global amnesia.

      Treatment

      There is no specific treatment for TGA. Episodes are self-limited, and improvement is noted within 24 hours without any intervention. It seems prudent to avoid any activity that could raise intrathoracic venous pressure until the amnesia is resolved. When alternative diagnoses are suspected (eg, seizures or ischemic stroke/TIA), focused investigations should be pursued to determine whether acute treatment or secondary prevention for these disorders might be indicated.

      Long-term Outcome in Patients With TGA

      Transient global amnesia is generally considered a benign condition. However, there are few studies on the long-term outcome of patients who have experienced TGA regarding the risk of recurrence and the incidence of cognitive decline, stroke, and seizures over time.
      Reported recurrence rates for TGA have varied considerably (between 2.9% and 23.8%) among different studies (Table 3). The reason for such a spread in the rate of recurrences found in different studies is unclear. There is no correlation with the length of follow-up, and it does not seem to be explained by the size of the cohort. The sensitivity of the definition used to identify cases of TGA may be important, as suggested by the fact that the study reporting the highest recurrence rate included definite and probable episodes of TGA within the recurrences.
      • Miller J.W.
      • Petersen R.C.
      • Metter E.J.
      • Millikan C.H.
      • Yanagihara T.
      Transient global amnesia: clinical characteristics and prognosis.
      Use of less sensitive but more specific definitions could result in lower rates of recurrence. Rates of 8% to 18% over 6 to 7 years may be reasonable to cite to patients, but more precise estimates and information on risk factors for TGA recurrence still need to be acquired through further research.
      Table 3Reported Recurrence Rates for Transient Global Amnesia
      Reference, yearRecurrence rate (%)Size of cohort (No.)Mean length of follow-up (mo)
      Melo et al,
      • Melo T.P.
      • Ferro J.M.
      • Ferro H.
      Transient global amnesia: a case control study.
      1992
      2.95139
      Pantoni et al,
      • Pantoni L.
      • Bertini E.
      • Lamassa M.
      • Pracucci G.
      • Inzitari D.
      Clinical features, risk factors, and prognosis in transient global amnesia: a follow-up study.
      2005
      85181.6
      Zorzon et al,
      • Zorzon M.
      • Antonutti L.
      • Mase G.
      • Biasutti E.
      • Vitrani B.
      • Cazzato G.
      Transient global amnesia and transient ischemic attack: natural history, vascular risk factors, and associated conditions.
      1995
      9.46445.6
      Gandolfo et al,
      • Gandolfo C.
      • Caponnetto C.
      • Conti M.
      • Dagnino N.
      • Del Sette M.
      • Primavera A.
      Prognosis of transient global amnesia: a long-term follow-up study.
      1992
      18.610282.2
      Koltzsch et al,
      • Klotzsch C.
      • Sliwka U.
      • Berlit P.
      • Noth J.
      An increased frequency of patent foramen ovale in patients with transient global amnesia: analysis of 53 consecutive patients.
      1996
      2353NR
      Miller et al,
      • Miller J.W.
      • Petersen R.C.
      • Metter E.J.
      • Millikan C.H.
      • Yanagihara T.
      Transient global amnesia: clinical characteristics and prognosis.
      1987
      23.827780
      NR = not reported.
      Several studies have reported complete recovery of cognitive function 5 days to 6 months after the TGA episode.
      • Bartsch T.
      • Alfke K.
      • Stingele R.
      • et al.
      Selective affection of hippocampal CA-1 neurons in patients with transient global amnesia without long-term sequelae.
      • Jager T.
      • Bazner H.
      • Kliegel M.
      • Szabo K.
      • Hennerici M.G.
      The transience and nature of cognitive impairments in transient global amnesia: a meta-analysis.
      • Kritchevsky M.
      • Squire L.R.
      Transient global amnesia: evidence for extensive, temporally graded retrograde amnesia.
      • Quinette P.
      • Guillery B.
      • Desgranges B.
      • de la Sayette V.
      • Viader F.
      • Eustache F.
      Working memory and executive functions in transient global amnesia.
      However, other investigators have noted that memory dysfunction may persist after the acute phase of the TGA episode, even when patients seem clinically normal or have no awareness of any impairment.
      • Caffarra P.
      • Moretti G.
      • Mazzucchi A.
      • Parma M.
      Neuropsychological testing during a transient global amnesia episode and its follow-up.
      • Hodges J.R.
      Semantic memory and frontal executive function during transient global amnesia.
      • Hodges J.R.
      • Oxbury S.M.
      Persistent memory impairment following transient global amnesia.
      • Le Pira F.
      • Giuffrida S.
      • Maci T.
      • Reggio E.
      • Zappala G.
      • Perciavalle V.
      Cognitive findings after transient global amnesia: role of prefrontal cortex.
      • Mazzucchi A.
      • Moretti G.
      • Caffarra P.
      • Parma M.
      Neuropsychological functions in the follow-up of transient global amnesia.
      Some of them may even fulfill the criteria for mild cognitive impairment.
      • Borroni B.
      • Agosti C.
      • Brambilla C.
      • et al.
      Is transient global amnesia a risk factor for amnestic mild cognitive impairment?.
      Moreover, patients with repeated episodes of TGA have been reported to have greater impairment in memory and visuoperceptual functions than those who experienced a single attack when they were examined at least 1 month after the episode.
      • Gallassi R.
      • Stracciari A.
      • Morreale A.
      • Lorusso S.
      • Rebucci G.G.
      • Lugaresi E.
      Transient global amnesia: neuropsychological findings after single and multiple attacks.
      The long-term risk of cognitive decline has not been sufficiently evaluated, but 1 study with an average follow-up of 82.2 months showed that the incidence of dementia in patients with TGA was 2.9%, and this was similar to the rate in their general population.
      • Gandolfo C.
      • Caponnetto C.
      • Conti M.
      • Dagnino N.
      • Del Sette M.
      • Primavera A.
      Prognosis of transient global amnesia: a long-term follow-up study.
      Transient global amnesia does not seem to confer an increased risk of ischemic stroke. Available information suggests that patients with TGA have a similar risk of stroke, myocardial infarction, and peripheral artery disease as the general population, and this risk is significantly lower than that of patients with TIA or lacunar syndrome.
      • Zorzon M.
      • Antonutti L.
      • Mase G.
      • Biasutti E.
      • Vitrani B.
      • Cazzato G.
      Transient global amnesia and transient ischemic attack: natural history, vascular risk factors, and associated conditions.
      • Pantoni L.
      • Bertini E.
      • Lamassa M.
      • Pracucci G.
      • Inzitari D.
      Clinical features, risk factors, and prognosis in transient global amnesia: a follow-up study.
      • Gandolfo C.
      • Caponnetto C.
      • Conti M.
      • Dagnino N.
      • Del Sette M.
      • Primavera A.
      Prognosis of transient global amnesia: a long-term follow-up study.
      Also, in a subset of 12 individuals from the Framingham Heart Study who had an episode of TGA, the investigators noted that these patients had a similar vascular risk factor profile and risk of future cerebrovascular events as stroke-free and seizure-free controls matched for Framingham Heart Study cohort, sex, and year of birth.
      • Romero J.R.
      • Mercado M.
      • Beiser A.S.
      • et al.
      Transient global amnesia and neurological events: the Framingham Heart Study.
      Recently, a study using a state registry including 4299 patients with TGA demonstrated that the stroke risk after the diagnosis of TGA (0.54%) was similar to that after the diagnosis of migraine (0.22%), was lower than the risk after the diagnosis of seizure (0.90%), and was much lower than that after the diagnosis of TIA (4.72%).
      • Mangla A.
      • Navi B.B.
      • Layton K.
      • Kamel H.
      Transient global amnesia and the risk of ischemic stroke.
      Risk of seizures in patients with TGA has not been demonstrated to be increased compared with other populations. Studies that showed a slightly higher risk of seizures on long-term follow-up concluded that at least some of the patients with later seizures could have had a seizure mimicking TGA on diagnosis. This was suggested by either abnormal interictal EEG findings or reinterpretation of the initial clinical manifestations.
      • Hodges J.R.
      • Warlow C.P.
      The aetiology of transient global amnesia: a case-control study of 114 cases with prospective follow-up.
      • Miller J.W.
      • Petersen R.C.
      • Metter E.J.
      • Millikan C.H.
      • Yanagihara T.
      Transient global amnesia: clinical characteristics and prognosis.
      • Pantoni L.
      • Bertini E.
      • Lamassa M.
      • Pracucci G.
      • Inzitari D.
      Clinical features, risk factors, and prognosis in transient global amnesia: a follow-up study.

      Conclusion

      Transient global amnesia is not a rare condition. It typically presents in patients aged 50 to 70 years, and it is frequently preceded by a Valsalva maneuver. Diagnosis is clinical, and its semiological hallmark is the inability to form new memories, although some retrograde amnesia can occasionally be present. Noncognitive functions are always preserved, and the presence of aphasia, hemiparesis, sensory loss, or incoordination indicates a different diagnosis and demands additional evaluation.
      When patients undergo brain MRI within 2 days of the episode, the scan may show some degree of restricted diffusion on the DWI sequence on one or both hippocampi. However, these changes are most often transient, and they are generally not followed up by radiologic evidence of infarction in the affected area. Therefore, vascular work-up is not necessary in typical cases of TGA. An EEG is recommended when the episodes are brief, recurrent, or associated with adventitious movements or sensory disturbances. Regional impairment of venous drainage seems to be the most solid hypothesis to explain the pathogenesis of TGA; although jugular valve incompetence is prevalent in patients with TGA, investigation for this condition with Doppler and air-contrast ultrasound is neither confirmative of the diagnosis of TGA nor necessary for its management. The clinical course is self-limited, and the short-term prognosis is favorable. Memory usually recovers fully within days, but mild residual impairment can occasionally persist for weeks. Less is known about long-term prognosis. Recurrent episodes of TGA are relatively uncommon but can certainly occur over the years. Available data suggest that TGA does not affect the future risk of cerebrovascular events, but more information is needed regarding the long-term risk of epilepsy and, particularly, cognitive decline.

      Supplemental Online Material

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      Linked Article

      • Familial Transient Global Amnesia
        Mayo Clinic ProceedingsVol. 90Issue 5
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          We acclaim the excellent, comprehensive review of transient global amnesia (TGA) by Arena and Rabinstein1 in the February 2015 issue of Mayo Clinic Proceedings. Considering the unknown pathophysiology of TGA, we note the authors make minimal mention of the possible contribution of genetics (on page 267). We request that the authors comment further on this possibility.
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