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Opening Casesand coordination). The classic TGA patient exhibitsthe “broken-record” phenomenon (asking the samequestions repeatedly) in the absence of other signs orsymptoms. Typical questions include “How did I getto the hospital?” and asking medical staff, “Have wemet?” despite several introductions.The mean duration of symptoms in TGA eventsis approximately 4 to 6 hours and, in a majority ofcases, symptoms resolve within 8 hours of initialonset.1-3 In TGA, symptoms resolve gradually andspontaneously within 24 hours without the need formedical intervention.4 The definitive diagnosis ofTGA cannot be made until symptoms have resolved.Failure of symptom resolution and other worrisomesigns and symptoms excludes the diagnosis.Descriptions of TGA first appeared in the medical literature in the 1950s.5-7 In the following decades,consensus emerged regarding the clinical featuresrequired for diagnosis. Classically, the syndrome occurs in a functional middle-aged or elderly patient;fewer than 10% of cases present in patients aged 50years.3 TGA patients are notable to the clinician andtheir family and friends for repetitive questioning,but patients remain oriented to person and place. Inuncomplicated cases (ie, in which TGA is not coincidentally presenting with another unrelated process),TGA patients maintain hemodynamic stability andare otherwise cognitively intact, retaining the abilityto perform complex tasks. Often, the patient will havelittle to no memory of the entire event.8,9In order to confidently make the diagnosis ofTGA, a prehospital witness is helpful in providing areliable history of the symptoms, including a description of the onset. By convention, patients withhead trauma in the preceding 72 hours, those withknown epilepsy, patients with any other neurologicabnormalities (motor deficits, aphasia, dysarthria,cognitive impairment, loss of attention span, etc),and patients with known psychiatric disorders areexcluded from the diagnosis of TGA.8,9While diagnostic criteria are clear, disagreementas to the causes and etiology of TGA continues. Inthe past 2 decades, neuroimaging and other testingmodalities have suggested potential etiologies, butcontroversies among researchers persist amid limitedand conflicting evidence. From the standpoint of theemergency clinician, however, a definition of the clinical syndrome and the required features for diagnosisare now widely agreed upon, and TGA is a relativelyeasy diagnosis to make when it presents with classic features; however, upon initial presentation, raremimics must be considered and any unusual featuresand symptoms must be investigated. (See Table 1,page 3.) It is the role of the emergency clinician torecognize TGA syndrome and to exclude other moredangerous conditions that present with an amnesticcomponent among a constellation of other featuresthat, though exceedingly rare, can mimic TGA.8,10A 60-year-old man with no significant medical historyis brought to the ED by EMS after 2 hours of suddenmemory loss. His wife has been with him since the onsetof symptoms, when he started asking her the same question repeatedly every few minutes. The patient is calm, cooperative, and oriented to person, place, and time, but hefrequently repeats himself and does not appear to be forming new memories. He knows what he did yesterday andthis morning but cannot seem to recall events of the pastfew hours. He is perseverating about what he was doing 1hour ago. When you step away and subsequently returnto the bedside a few minutes after the initial encounter,the patient does not recognize you and asks, “Have wemet before?” The patient has no other complaints, andthere are no neurologic or infectious symptoms. His vitalsigns are normal. You wonder if you should activate thestroke team and order an emergent CT of the brain.A 54-year-old woman with hypertension presentswith sudden memory loss. She was smoking a cigarettewith her friend when she became confused and startedasking, “How did we get here?” repeatedly. The witnesscalled 911. EMS providers detected no stroke symptomsand transported her to your ED. In the ED, the patientis alert and oriented to self and place, but not to time.She demonstrates clear anterograde amnesia, failing toremember you on multiple occasions. She also complainsof a mild diffuse headache, but she has no other symptomsand is found to be neurologically and, otherwise, cognitively normal. She states that she feels fine and wants tosign out against medical advice. You explain to her repeatedly that, because she is not encoding memories, she cannot be discharged, and lacks decisional capacity. You placeher on hospital involuntary hold. Twenty hours later, heramnesia has fully resolved. She has not repeated any questions during the past 2 hours and remembers your latestconversations. In the meantime, she has developed newmild ataxia. She says “I’m not worried about that. I’ll befine once I have a cigarette. I’d like to sign out againstmedical advice.” She is alert and oriented and lacks psychiatric risk factors. She consistently and accurately verbalizes, without reminders, several times over 30 minutes,the risks associated with leaving. You wonder: Should youdischarge this patient against medical advice?IntroductionTransient global amnesia (TGA) is a clinical syndrome marked by the acute onset of profoundanterograde amnesia (the inability to form newmemories) lasting up to 24 hours in the absenceof other neurologic deficits or changes in alertness and cognition. Retrograde amnesia (the lossof pre-existing memories) can also occur. In TGA,isolated loss of new memory formation is limited tofacts and events (declarative memory), and patientsretain implicit and procedural memory (motor tasksCopyright 2016 EB Medicine. All rights reserved.2Reprints: www.ebmedicine.net/empissues

Once definitively diagnosed, patients and theirfamilies need education on the diagnosis and itsbenign prognosis. This issue of Emergency MedicinePractice provides a comprehensive review of theliterature on TGA and its diagnostic criteria. We alsosuggest a simplified workflow in order to facilitatedecision-making and minimize unnecessary diagnostic testing.any medical intervention has ever been reported inthe medical literature.EpidemiologyThe incidence of TGA ranges from 5.2 to 10 per100,000 patients per year.11-14 The mean age of TGApatients is 65 years. The highest risk factor for TGAappears to be the occurrence of a past TGA event,with yearly recurrence rates ranging from 2.5%to 5.8%, representing an approximately 1000-foldincreased risk over the baseline population. Longerterm recurrence rates of up to 14.1% have beenreported.15 Other risk factors include advanced ageand/or a history of migraine headaches.8,16 In olderpersons, the incidence of TGA ranges from 23.5 to 32per 100,000 patients per year, representing a 4.5- to6-fold increase. There are no gender or ethnic predispositions currently identified. While the increasedincidence of TGA coincides with age groups inwhich cardiovascular risk factors are higher than average, studies have demonstrated that the presenceof vascular risk factors does not confer a higher rateof TGA.17-20 Several case reports and case series havesuggested an increased predisposition to TGA basedon a yet-to-be identified genetic inheritance.21 Thesereports describe several first-degree relatives, eachof whom experienced TGA at different times in theirlives. However, no predisposing gene has been identified, and it is unclear what fraction of TGA casesmay reflect any underlying genetic disorder.22-25Critical Appraisal Of The LiteratureA PubMed literature search was performed using the search terms transient global amnesia as wellas amnesia and emergency. The National Guideline Clearinghouse (www.guideline.gov), and theCochrane Database of Systematic Reviews weresearched with the term amnesia; this search yieldedonly mentions of amnesia in the context of differential diagnoses for stroke syndromes, but noguidelines, policies, or reviews focused primarily onamnesia were found. We also searched for guidelinesreleased by the American College of EmergencyPhysicians and the American Academy of Neurology. There are no known published guidelines bythese bodies related specifically to amnesia.Little high-quality research on TGA exists. Mostof the literature is comprised of case reports andcase series. Unfortunately, close reading of manycase reports of TGA with unusual features revealsa frequent, incorrect conflation of TGA as a distinctclinical entity and its sine qua non symptom, anterograde amnesia. However, much has been learnedthrough higher-quality retrospective chart reviews,retrospective cohort studies, prospective case-control studies, and prospective cohort studies. Casecontrol studies have been performed in an attemptto understand the etiology of TGA. These studiesprimarily focused on imaging and electroencephalogram (EEG) studies in an attempt to elucidate theetiology of TGA. Several studies have attemptedto link TGA to serologic markers, and the resultshave been marked by minimal success. Retrospective studies designed to identify risk factors forthe development of TGA have been conducted andhave also yielded mixed results. No trial assessingInciting FactorsSeveral inciting factors for TGA events have beendescribed. While no associations have been validated in large-scale studies, correlations with certainhistorical features have been observed, includingemotional stress directly before onset (18%-29%of cases) and intense physical effort (25%-31% ofcases).3,26 Other “everyday life” factors such assexual activity, recreational substance use, and rapidchanges in temperature have been described, butless frequently.3,27-33 Some of these, including swimming, sexual activity, and intense emotional arousal,are associated with Valsalva-like maneuvers.3,34,35Finally, medical procedures such as stress salinecontrast echocardiography, cerebral angiography,trigeminal neuralgia treatments, and enemas havebeen reported as precipitating TGA events.6,36,37Among a variety of concurrent symptoms that havebeen described in TGA, headache, nausea, and vomiting appear to be the most common, occurring inapproximately 17% of patients.11Table 1. Transient Global Amnesia Mimics Seizure/transient epileptic amnesiaStroke, cardiovascular accident (rare)Atypical migraineHead injury/occult trauma/concussion syndromeMedication and recreational drug side effectHerpetic encephalitisEarly neurosyphilisHuman immunodeficiency virus dementiaAlcohol psychosisAlcohol blackoutAugust 2016 www.ebmedicine.netPathophysiologyThe pathophysiology of TGA remains controversial, and several theories have been proposed.3Copyright 2016 EB Medicine. All rights reserved.

Differential DiagnosisOne theory suggests that TGA is a manifestationof short-lived, reversible ischemia resulting fromtemporary intracranial venous stasis surrounding the hippocampus, a region found in the medialtemporal brain known to be crucial for memorystorage. Supporting this theory are case reports ofTGA events with abnormal hippocampal findings onmagnetic resonance imaging (MRI), some of whichresolved on follow-up imaging.38-43 The reversibleischemia hypothesis is further supported by theobservation that Valsalva-like maneuvers (which cancause temporary cerebral ischemia) have been seenas inciting features of TGA.3,44,45 In some studies, duplex ultrasonography of TGA patients demonstratedan increased prevalence of insufficient jugular veinvalves in comparison to healthy controls; however,other studies failed to find an effect compared toage- and sex-matched controls.26,34,35,46-53Arterial insufficiency has also been proposedas etiology, but recent evidence shows no difference between TGA patients and controls.54,55 Anembolic etiology for TGA based on the observationof increased rates of patent foramen ovale in a studyof TGA patients was not confirmed, and the lack ofischemic findings in most patients with TGA furtherundermines this explanation.51,56Another explanation for TGA is spreadingcortical depression, in which a reduction of brainactivity following hyperstimulation triggers suddenmemory loss.57 This theory is supported by theprevalence of migraine headaches in patients withTGA, and observational studies linking TGA andemotional events.58-60 A further proposal suggestsa nonconvulsive epileptic etiology. This theory issupported by studies showing abnormal EEGsin TGA patients both during TGA attacks and atfollow-up. One study found that as many as 7%of TGA patients manifested EEG signs of epilepsywithin 1 year, a substantial increase over baselinepopulation estimates for new-onset epilepsy (whichrange between 77 and 237 per 100,000 patients peryear).18,61-63 However, other studies showed noincreased risk of epilepsy in TGA patients at followup compared to the baseline population, and othershave noted that many of the EEG findings in asubset of acutely amnestic patients do not constituteepilepsy.14,64,65The disagreements in the data from variousstudies have not been explained, and no theory iswithout contradictory evidence. Disagreement maystem from study population differences or inclusion/exclusion criteria. Alternatively, TGA maysimply turn out to be a pathophysiologically heterogenous condition comprised of components ofseveral of these proposals, or another model yet tobe elucidated.Copyright 2016 EB Medicine. All rights reserved.TGA is such a distinct clinical entity that when itis observed in the absence of other symptoms andchanges, there are exceedingly few mimics thatshould plausibly be included in a differential diagnosis. When other abnormal signs or symptoms arepresent, those symptoms should take precedenceand guide the formulation of a differential diagnosisand investigation. Rarely, however, certain otherentities can present as TGA.Transient epileptic amnesia may present asrepeated short amnestic episodes lasting 1 hour,while TGA rarely resolves in this time frame.8,9,66Exceptionally rare stroke syndromes have beenreported that may appear like TGA.67-69 Importantly, none of the patients in these reported caseswere found to have concerning National Institutesof Health Stroke Scale (NIHSS) findings that wouldhave necessitated immediate guideline-drivenmanagement. More commonly (though still rare),anterograde amnesia can present as a coincidingsymptom among other worrisome stroke symptoms that, by themselves, immediately warranturgent investigation and, by definition, rule outTGA as the definitive diagnosis.68,70Although rare, other cerebrovascular problems,such as subarachnoid hemorrhage or cerebral hematoma, have coincided with amnesia. In these unusual cases, other neurologic deficits and abnormal features (such as nystagmus or syncope) were alwayspresent, and thus need not be normally included inthe differential for acute amnesia.71-73 A comparisonof TGA to transient ischemic attacks (TIAs) has beendiscussed, but, as with rare strokes, the presence ofother acute neurologic symptoms reflexively removes TGA from diagnostic consideration. Further,risk profiles comparing TGA and TIA have demonstrated that patients who experience TGA have cardiovascular and cerebrovascular risk profiles similarto the baseline population, while TIAs confer higherfuture risks.17,74 Thus, TGA should not be consideredas a rare subtype of TIA.In certain at-risk patients, herpes encephalitispresenting with anterograde amnesia can be considered in the differential for TGA; however, in herpesencephalitis, the amnesia fails to resolve within 24hours and other symptoms usually occur.75 Whileanterograde amnesia may be an early finding in neurosyphilis, other findings should emerge on examination and observation.76Patients presenting after witnessed head injurymay present with anterograde amnesia, but amnesiacaused by trauma should be investigated and managed as a concussion/traumatic brain injury, ratherthan as TGA.Rare cases of medication side effects (the gamma-Aminobutyric acid [GABA]-agonist zolpidem4Reprints: www.ebmedicine.net/empissues

diagnosis of TGA. (See Table 2.) While isolatedanterograde amnesia in the absence of other signs,symptoms, or concerning historical features mayquickly render TGA as the leading diagnosis, TGAcannot be definitely diagnosed unless and until allsymptoms have resolved in under 24 hours.Some researchers and clinicians require thepresence of a corroborating witness in order to makethe diagnosis of TGA, as there have been incorrectTGA diagnoses in some cases lacking a witness atonset, and rare cases where witnesses present atonset reported features such as pallor, dizziness,or even forgotten chest pain that led to alternativediagnoses.8,9,83 In the absence of a witness at onset, awell-defined “last seen normal” can be helpful, butdoes not eliminate the possibility of unwitnessedsymptoms or trauma at onset that would requirethe appropriate workup. Further, symptoms lastinglonger than 24 hours excludes the TGA diagnosis, bydefinition. We therefore emphasize the importanceof a reliable witness at onset. In the absence of a witness at onset, an extensive and broader emergencydepartment (ED) workup may be warranted in accordance with the patient’s other symptoms (eg, dizziness, headache, or chest pain) as well as any otherunderlying individual risks. On the other hand, inwitnessed TGA, a remarkably minimalist approachis equally reasonable.[Ambien , Edluar , Intermezzo , Zolpimist ]) andrecreational drug use (marijuana) causing TGA havebeen described.29,77 Korsakoff syndrome caused bychronic alcoholism can cause anterograde amnesia,but only in a pattern of other neurologic and cognitive changes.78,79 “Alcohol blackout” is a rare, butdistinct, entity characterized by anterograde amnesia during intoxication in the absence of loss ofconsciousness or other skill deficits.80 A psychogeniccause of TGA without other cognitive changes hasnever been described.Prehospital ManagementFrequently, a family member or an acquaintance activates emergency medical services (EMS) regardinga patient displaying sudden amnestic features. EMSproviders should elicit corroborative history fromany witnesses and, when possible, transport family,friends, and/or relevant witnesses to the hospitalwith the patient. EMS providers should attempt toobtain medication history and bring any medication containers a patient may have had at the scene,as the acutely amnestic patient is at risk of having unintentionally overdosed due to unwittinglytaking their medications repeatedly. If the patienthas changed locations or was unwitnessed at onset,family and friends should be engaged to searchthose locations for medications the patient may haveunintentionally overdosed.EMS providers should be educated about TGA,but their primary role is to consider the diagnoses ofstroke or seizure and to transport the patient to themost appropriate medical center if such signs arepresent. EMS providers should perform a basic neurologic examination, including a validated prehospital stroke scale. EMS providers may help delineatewhether the patient has aphasia versus amnesiaduring the initial evaluation.EMS should obtain a point-of-care glucose level.An electrocardiogram (ECG) is indicated only whenthe patient has other symptoms, such as chest pain,palpitations, or shortness of breath. While TGA hasbeen reported after acute myocardial infarctions(AMI), there are no known cases of TGA as the solepresenting symptom of AMI in the presence of completely normal vital signs.81,82Historical Features Of Transient Global AmnesiaWhile TGA is conspicuous, once recognized, certainhistorical features should be ascertained: TGA history. Prior TGA events are the mostlikely risk factor for future events. However, uncovering a history of multiple or closely spacedevents (even in TGA cases that do not coincidewith other unusual symptoms) may trigger abroader workup that may reveal an undiagnosed alternate condition, most often a seizuredisorder. Headache history. Literature points to a strongerconsideration of TGA in patients with headache during a TGA event (which may occur in10%-40% of patients) or in patients with longstanding headaches or who carry a migraineheadache diagnosis.84Table 2. Diagnostic Features Of TransientGlobal Amnesia9Emergency Department EvaluationHistory Witnessed at onset and during attackMust have anterograde amnesiaNo focal neurological symptoms or signs during or afterNo epileptic featuresNo clouding of consciousness, no loss of personal identity, and nocognitive impairment other than amnesia No head injury in the past 72 hours No seizures in the last 2 years, and not on medication for epilepsy Must resolve in 24 hoursThe emergency clinician’s task is to recognize TGAand to consider other conditions that may mimicTGA as well as those that co-present with amnesiaand other symptoms. When other symptoms arepresent, those symptoms—and not the amnesiaalone—should guide the investigation.There are 8 diagnostic features required for theAugust 2016 www.ebmedicine.net5Copyright 2016 EB Medicine. All rights reserved.

Neurologic history. Any seizure activity orknown history excludes the diagnosis of TGA.However, other neurologic history or recentother symptoms should be elicited, as TGA can,rarely, present as a concurrent symptom of otherprocesses.Medication list. For obvious reasons, unintentional overdoses are possible in TGA patientswho may have repeatedly taken their medications. Determine any medications a patient mayhave overdosed. If there is significant concern,this may mean asking family or friends to searchfor pill bottles in the place where the eventstarted, or in the patient’s belongings (purse,handbag, pockets). Isolated case reports of asmall number of medication classes (such asbenzodiazepines) have been reported to inducea TGA-like syndrome.77,85 While not describedin the literature, an unintentional overdose ofmultiple daily aspirin tablets or acetaminophenwould necessitate commensurate workups.Psychiatric history. TGA is generally differentiated from psychosis by its isolated anterogradeamnestic features without other changes orpsychiatric features. Substance abuse may causeamnesia, but it would similarly be expected tocause other symptoms not seen in TGA.Triggers or inciting features. In addition to thediagnostic features required for TGA

Room, St. Joseph’s Hospital and Medical Center, Phoenix, AZ oseph D Toscano, MD Chairman, Department of Emergency Medicine, San Ramon Regional Medical Center, San Ramon, CA International Editors Peter Cameron,