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Transient global amnesia: current perspectives

Transient global amnesia: current perspectives Journal name: Neuropsychiatric Disease and Treatment Article Designation: Review Year: 2017 Volume: 13 Running head verso: Spiegel et al Neuropsychiatric Disease and Treatment Dovepress Running head recto: Transient global amnesia open access to scientific and medical research DOI: http://dx.doi.org/10.2147/NDT.S130710 Open Access Full Text Article Review Abstract: Transient global amnesia (TGA) is a clinical syndrome characterized by the sudden David R Spiegel onset of an extraordinarily large reduction of anterograde and a somewhat milder reduction Justin Smith of retrograde episodic long-term memory. Additionally, executive functions are described as Ryan R w ade diminished. Although it is suggested that various factors, such as migraine, focal ischemia, Nithya Cherukuru venous flow abnormalities, and epileptic phenomena, are involved in the pathophysiology and Aneel Ursani differential diagnosis of TGA, the factors triggering the emergence of these lesions are still Yuliya Dobruskina elusive. Recent data suggest that the vulnerability of CA1 neurons to metabolic stress plays a Taylor Crist pivotal part in the pathophysiological cascade, leading to an impairment of hippocampal func- Robert F Busch tion during TGA. In this review, we discuss clinical aspects, new imaging findings, and recent Rahim M Dhanani clinical–epidemiological data with regard to the phenotype, functional anatomy, and putative Nicholas Dreyer cellular mechanisms of TGA. Department of Psychiatry and Keywords: transient global amnesia, vascular, migraines, psychiatric Behavioral Sciences, eastern v irginia Medical School, Norfolk, v A, USA Introduction More than 50 years after its initial description, transient global amnesia (TGA) remains one of the most enigmatic syndromes in clinical neurology. TGA is den fi ed as a sudden onset of an anterograde and retrograde amnesia that lasts up to 24 hours, although mild subclinical neuropsychological deficits with concomitant vegetative symptoms can last for days after the episode. The memory impairment of patients with acute TGA shows a profound reduction of anterograde and a milder reduction of retrograde episodic memory, including executive functions and recognition. In this review of TGA, we summarize the epidemiology, symptomatology, pathophysiology, assessment, differential diagnosis, longer-term outcome, and possible treatment recommendations associated with this condition. Literature review Full-text articles and abstracts were selected for this review and were identified through searches of PubMed with the search terms “transient amnesia”, “transient global amnesia”, “hippocampus”, and “amnestic syndromes” between 1985 and 2017. Additionally, more distant seminal articles on this subject matter were included. Only articles published in English were reviewed. The nal fi reference list was chosen on the basis of relevance to the topics covered in this review (eg, their originality, contribution to hippocampal and TGA epidemiology, anatomy and physiology, pathophysiology, diagnosis, and treatment). Correspondence: David R Spiegel Department of Psychiatry and Behavioral Sciences, eastern virginia Medical Epidemiology School, 825 Fairfax Avenue, Norfolk, The following prospective and retrospective systematic studies identify TGA cases vA 23507, USA email spiegedr@evms.edu from either hospitalized or national health registry samples. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 2691–2703 Dovepress © 2017 Spiegel et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/NDT.S130710 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Spiegel et al Dovepress incidence cancer diagnosis carries no increased risk of TGA, according Recent epidemiological data put the annual incidence of TGA to a prospective cohort study with 5,365,608 subjects running 2,3 4 between 3.4 and 10.4/100,000. between 2001 and 2009. Psychiatric comorbidity Age and gender One study compared psychiatric disease in 51 subjects who TGA most commonly presents in the seventh decade of life. experienced a TGA to 51 subjects who experienced a TIA. Across studies, the mean age of an episode ranges from 61 2,4–6 Psychiatric disease was den fi ed as having “a diagnosis of to 67.3 years. In a 2006 study, 96% of subjects with TGA depression or anxiety disorder” or having received “treatment (n=142) presented between the ages of 51 and 80 years. with specic fi drugs for at least 3 months”. TGA subjects had a Epidemiological studies fail to identify any subjects under signic fi antly higher percentage of psychiatric disease compared the age of 55 years. Several small-scale studies show a slight to TIA controls (39.2% vs 13.7%, age- and sex-adjusted odds female predominance. However, a study on 5,097 TGA cases ratio [OR] =2.86). Additionally, a significantly higher per - shows gender distribution to be 50.7% females and 49.3% 4 5 centage of TGA subjects (33.3%) reported a family history of males, consistent with one previous analysis. psychiatric disease as compared with TIA subjects (13.7%). In summary, according to community-based studies, Recurrence the annual incidence of TGA is 5–10/100,000 and 23.5– Depending on the length of follow-up, the annual rate of TGA 32/100,000 for people aged 50 years and older. Peak inci- recurrence varies from 2.9 to 26.3%. A 2005 study with a dence is around the age of 62 years (standard deviation [SD] 7-year follow-up period, which is the longest systematic 10 years). A total of 54%–67% of TGA patients are female. follow-up period reported, found a recurrence rate of 8%. Chances of recurrence are reported variedly from 2.9 to 25%. Another study that recruited subjects over a 10-year period Other than migraine headaches, there are no definitive risk (n=142), however, with no designated follow-up period after factors for the development of TGA. the first occurrence, found a recurrence rate of 6.3%, if prob - able episodes were taken into account. Clinical diagnosis Development of TGA criteria Risk factors TGA is a clinical diagnosis. It was first described in 1956 as A migraine history is one of the more notable risk factors an “isolated episode of confusion with amnesia” not other- associated with developing TGA. In a 2014 population-based 11,12 wise associated with other neurological deficits. Subjects study (n=316,602), migraine patients were signic fi antly more were described as becoming repetitious and asking the same likely to develop TGA than their matched controls, with the 7 questions, although mostly revolved around the memory loss incidence rate ratio of 2.48. Additionally, of the subjects who itself. Fisher and Adams coined the term TGA in 1958; developed TGA after the age of 40 years, those with a history however, it was not until 1964 that they detailed a report of migraine had a significantly younger age of onset (56.6) of 17 patients with sudden onset anterograde amnesia and compared to the control group (61.4). No associations were 7 confusion that resolved within a few hours. found between various migraine subtypes and TGA. Hodges and Warlow later developed criteria for the Cardiovascular risk factors are also well studied in clinical syndrome in 1990 (Table 1), and since then, this TGA. A retrospective case–control study found age- and has been used as the foundation of TGA diagnosis. They sex-matched control subjects (n=293) to have significantly decreased odds of having hyperlipidemia and ischemic heart disease when compared with those subjects with TGA Table 1 Hodges and warlow criteria for TGA (n=293). Within this same study, 632 transient ischemic Diagnostic criteria of TGA – Attacks must be witnessed attack (TIA) subjects had greater rates of hypertension, – There must be anterograde amnesia during the attack diabetes mellitus, ischemic stroke, and atrial b fi rillation when – Cognitive impairment is limited to amnesia compared with TGA subjects, likely indicating differing risk – No clouding of consciousness or loss of personal identity factors between TGA and TIA. Furthermore, a retrospective – No focal neurological signs/symptoms – No epileptic features study of 85 TGA subjects revealed that those with history of – Attack must resolve within 24 hours two episodes of TGA showed a higher frequency of carotid – No recent head injury or active epilepsy atheromasia and ischemic heart disease than those with a Note: Data from Hodges and warlow. history of just one episode of TGA. Also, of note is that Abbreviation: TGA, transient global amnesia. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Dovepress Transient global amnesia divided patients into the following three categories: pure Disorders, fourth edition criteria of panic attacks. While TGA, probably epileptic amnesia, and probably TIA. Exclu- these symptoms have been useful in identifying areas of sionary criteria for pure TGA included focal neurological dysfunction, TGA diagnosis should be made based on criteria symptoms, such as ataxia, limb weakness, and sensory dis- listed in Table 1. turbances. Of the 153 patients reviewed between 1984 and In summary, while multiple exclusionary criteria exist, 1987, 114 patients met the proposed criteria for pure TGA. heteroanamnestic confirmed anterograde amnesia in a clear The majority of attacks in this group lasted between 1 and sensorium and cognitive impairment limited to amnesia is the 8 hours. Both TGA and non-TGA groups showed disorien- main “rule-in” criteria for TGA. Additionally, the amnesia tation in time and repetitive questioning, although the TGA must last 24 hours. Headache, dizziness, and nausea are group demonstrated more repetitive questioning with 92% the most common accompanying complaints. Finally, in vs 71% in non-TGA groups. Most patients with TGA had a 89% of cases, some provoking activity can be pointed out permanent retrograde amnesic gap for the events immediately immediately before the attack occurred. Physical exertion prior to and during the attack, although this was also seen (including sexual activity) is the most common precipitat- in non-TGA cases. ing event, followed by emotional stress and sudden change of temperature. Precipitating events Pathophysiology A study of 142 cases of TGA found precipitating factors in 131 of these episodes (89.11%). Emotional stress (ie, trig- Relevant neuroanatomy gered by gastric endoscopy, birth/death announcement, The clinical picture of TGA has led researchers to inves- and difficult/exhausting work day), physical effort (ie, tigate focal injury to the neurological circuits involved in gardening, house work, and sawing wood), and water contact/ memory as a potential etiology of the syndrome. Hodges temperature change (ie, hot bath/shower and cold swim) were and Warlow performed computed tomography (CT) scans observed most frequently immediately before an attack and on 83% of the pure TGA cases in their study (n=95), finding are considered “close events”. Anxiety triggered by conflict small white matter changes, basal ganglia lesions, or periven- at home or work, health problems, and financial stressors tricular lucencies in 12% of these patients (n=11). These were often reported weeks prior to TGA and are considered areas, however, are not located in known memory-related “remote events”. In the TGA series, the percentage of emo- structures. Current evidence points to the formation of early tional stress, physical effort, and water contact/temperature memory within the hippocampal/entorhinal cortex network change was 29, 25, and 14%, respectively, compared to and its eventual transference to remote memories stored in 48, 9, and 0% in control groups, respectively. Remote events the neocortex network. Particular attention has been given of anxiety and exhaustion were reported in 24 and 33% of to the cornu ammonis (CA1) field of the hippocampus, TGA cases and 6 and 90% in controls, respectively. Differ- which has been hypothesized to play a central role in the ences from control subjects in both close (P0.000) and pathophysiology of TGA given its extraordinary sensitivity remote precipitating events were found to be statistically to cell stress. significant, providing strong evidence that TGA occurs in More recent studies have found imaging changes strongly certain contexts. related to TGA using magnetic resonance diffusion-weighted imaging (DWI). These findings are typically unilateral and Associated symptoms tend to be small (1–3 mm), high-signal foci found in the 17–20 Although focal neurological deficits exclude a diagnosis CA1 field of the hippocampus. These lesions are most of TGA, there are several nonfocal symptoms, which are prominent 24–48 hours after the initial TGA episode, which often observed. Headache and nausea/vomiting are the matches the peak activation period for microglia in stroke most common and were each present in 10% of TGA cases models. Alternatively, there are cases of TGA with bilat- immediately after the attack. Dizziness, chills or hot u fl shes, eral and even multifocal hippocampal involvement and also fear of dying, cold extremities, paresthesias, emotionalism, cases with ischemic or hemorrhagic damage to other brain 5 22–27 trembling, chest pain, and sweating have also been reported. regions. These conflicting reports do not help to clarify Quinette et al proposed that such associated symptoms the initial neuronal insult in TGA. were somatic manifestations of anxiety and found that, Similarly, the underlying etiology of TGA remains compared to controls, TGA episodes were more frequently obscure with multiple proposed mechanisms, such as arte- related to the Diagnostic and Statistical Manual of Mental rial ischemia, venous congestion, migraine, and psychogenic submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Spiegel et al Dovepress disorders. Early researchers hypothesized that atherosclerotic Valsalva-like activities, anxious and phobic personality or thromboembolic events disrupt blood flow to the hip - traits, emotional stressors, and immersion in hot or cold 5,30 pocampus, which is supplied by the posterior cerebral artery water) has supported an arterial mechanism. It has been 20,23,24 and the hippocampal arteries. Venous congestion and postulated that an increased prevalence of patent foramen jugular vein valve insufficiency are also hypothesized etiolo - ovale among patients with TGA is responsible for its asso- gies, given that many patients report Valsalva-associated ciation with Valsalva-like activity by means of paradoxical 19,28 maneuvers prior to a TGA event. In addition, severe embolism; however, further attempts to reproduce this 31,32 emotional reactions and migraines may contribute to the association have since failed. Increased incidence of destabilization of the CA1 sector of the hippocampus via TGA among particular personality traits and precipitation by massive glutamate release. The following sections explore emotional stressors suggest that reactive hyperventilation- these postulated mechanisms in greater detail. induced cerebral vasoconstriction can result in changes in the cerebrovascular hemodynamics within the hippocampal Arterial ischemia and venous congestion region. Functional imaging technology supports such There are many parallels between TGA and TIA, which reactive changes, demonstrating relative hypoperfusion support the arterial ischemia hypothesis. TGA and TIA are within the medial temporal lobes (MTLs) in patients with characterized by an abrupt onset of reversible loss of function TGA. Results among other studies, however, have been occurring in patients within similar age group demographics. inconsistent, and it is unclear whether the findings are Reported mean age of onset is 60–66 years for TGA and causative in nature or reactive to derangements in cerebral 33,34 69–71 years for TIA, with modal onset, for both, over the metabolism. age of 50 years. Despite these similarities, statistical analysis Structural magnetic resonance imaging (MRI) also has reliably shown significantly reduced atherosclerotic risk provides support for an ischemic mechanism, with DWI– factor profiles, including decreased prevalence of embolic MRI showing evidence of abnormal lateral hippocampal heart disease, diabetes mellitus, hypertension, and carotid punctate hyperintensities in patients with TGA. Analysis artery atherosclerotic disease, in patients with TGA in com- of the appearance and evolution of these lesions over time parison to those with TIA. Population cohort data have also have displayed similarities to previously described lesions consistently indicated that a history of TGA does not put from cerebral ischemic injury, with reported detection rates 19,35–38 patients at a higher risk of cerebrovascular events, and in ranging from 57 to 100% in patients with TGA. These fact, recent studies suggest a more favorable prognosis for lesions primarily involve the hippocampal CA1 neuronal TGA patients compared to TIA patients in regard to risk of field, a region known to be critically involved in the process future cerebrovascular events. Even more, one retrospective of memory consolidation and to be vulnerable to stress. analysis showed no heightened risk of future cerebrovas- However, several temporal and anatomical aspects of cular event following a TGA event when compared with these lesions are fundamentally inconsistent with conven- healthy matched controls, further refuting an atherosclerotic tional ischemic lesions. Lesions associated with TGA were hypothesis. most reliably seen 24–72 hours after symptom onset and were Several prominent clinical features of TGA additionally shown to disappear soon after. Additionally, the typical dura- argue against arterial ischemia as a likely mechanism. The tion of TGA episodes (4–6 hours) is inconsistent with this mean duration of a TGA episode largely exceeds that seen delayed and reversible nature of DWI–MRI lesions, which in TIA, with a documented mean duration of 4–8 hours when present in the case of TIA are detected much earlier 5 39 and 97% of episodes lasting 1 hour. For TIA, in con- and persist longer. trast, the vast majority of episodes last 60 minutes, with Venous congestion with retrograde cerebral flow is the bulk of these lasting only a few minutes. Also, the another prominent hypothesis for the pathophysiology behind absence of associated focal neurologic dysfunction during TGA. Valsalva-like activity causes transient elevation of the TGA episode, such as lateralizing weakness and visual intrathoracic pressure with obstruction of venous return, field deficits, is inconsistent with the ischemic hypothesis, potentially resulting in retrograde transmission of pressure to which would be expected in cases of an acute ischemic event the cerebral venous vasculature draining the involved struc- involving bordering neuroanatomy. tures. Other frequently cited precipitating events (cold water The pathophysiology behind frequently cited precipitat- immersion, exercise, and emotional stressors) are mechanisti- ing events and comorbidities accompanying TGA (including cally analogous by the way of increasing sympathetic tone submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Dovepress Transient global amnesia with central diversion of peripheral venous volume in effort Migraine to preserve flow to vital organs, which similarly results in Another hypothesis is that TGA may be a sequela of elevated central venous pressures. Proponents also recog- migraines due to sweeping depression of cerebral activity that nize the anatomy of cerebral venous drainage as supportive is found throughout the cortex, extending through the hip- evidence, as venous outflow from bilateral hippocampal pocampus, leading to transient dysfunction and subsequently regions converge to a common great vein of Galen before TGA. It is this same cortical depression that is thought to later diverging at the conu fl ence of venous sinuses supporting give rise to the aura found in migraine sufferers and is caused perturbation of bilateral hippocampal function previously by the release of massive glutamate and a subsequent wave 40 46 unexplained by ischemic hypotheses. of short-lasting cortical depolarization. Numerous studies have demonstrated a significant This mechanism has been demonstrated in animal models increase in the prevalence of jugular venous valve insuf- by local stimulation of the hippocampus, lending to the pos- ficiency with jugular vein retrograde flow among TGA sibility that a similar reaction could be elicited in humans 40–42 patients when compared with healthy matched controls. via the experience of strong emotional events or other This association was detected via MRI and Doppler and intense stimuli leading to a large release of glutamate from was particularly common among patients reporting a hippocampus. Given this relationship between migraines concomitant precipitating event. The largest study dem- and transient hippocampal dysfunction, it is feasible to con- onstrates 80% prevalence of internal jugular venous valve sider the possibility of an etiological relationship between insufficiency with retrograde flow among 142 TGA subjects migraines and the transient memory problems exhibited by compared to only 25% among control subjects. However, patients with TGA. However, there is a dearth of evidence several recent studies have brought the significance of this to support this theory. Currently, the evidence supportive of finding into question. One study using transcranial Doppler a connection between migraines and TGA is mainly asso- sonography of intracranial vessels to record blood flow ciative and causality cannot be stated with any significant direction and velocity at the internal jugular veins, basal level of confidence given the observational nature of these 5,28 veins of Rosenthal, and great vein of Galen compared studies. findings at rest and during Valsalva-like maneuvers. Although confirming an elevated prevalence of jugular Psychogenic causes valve insufficiency among TGA patients, intracranial One of the lesser studied etiologies of TGA is of psycho- venous reflux was not seen in TGA or in control subjects. genic origin. In these cases, the precipitating trigger is This was confirmed by a study utilizing time of flight often an emotional event or psychological stressor. It is magnetic resonance angiography to observe abnormal encountered classically in younger populations and is often jugular venous reflux within TGA and control patients but associated with a subjective indifference to the memory similarly found low rates in each study group (intracranial loss experienced. In most cases, autobiographical memory retrograde flow in 7/167 in TGA group, 8/167 in emergency deficits, which are most often intact in TGA, are appreciated room visitor control group, and 3/167 in healthy matched with relatively functioning anterograde memory formation control group). capabilities. Physiologically, the insult appears to disrupt In summary, although the physiological n fi dings suggest the affective learning circuit formed between amygdala, a meaningful association with TGA, there is limited evidence hippocampus, striatum, and prefrontal cortex. TGA could for venous congestion as an etiology for TGA. Current evi- be viewed as an illness of temporary hippocampal insuf- dence is unable to explain the lack of association with other ficiency, where its inhibitory effects to the amygdala are causes of venous congestion, including congestive heart disrupted, which could precipitate a disruption in memory 18 28 failure and cerebral venous thrombosis. It is also unclear formation. why such transient pressures can induce the long-lasting Other evidence suggests that approximately half of the effects seen in TGA. Further questions surround the true patients with psychological disturbances as the precipitating eti- association with reported precipitating events, including ology of TGA also had associated phobic personality trait. why episode recurrence is so uncommon when they can be Psychogenic amnesia can be linked to several psychi- prompted by a Valsalva-like activity. It is likely that vascular atric disorders including posttraumatic stress disorder and mechanisms play a role in the pathophysiology of TGA, but dissociative disorders, where the loss of memory could be the exact role remains to be discovered. considered a defensive psychological mechanism. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Spiegel et al Dovepress Summary of pathophysiology neurological dec fi its, which by den fi ition preclude TGA from There are several potential etiologies that may be responsible the working diagnosis. However, to confound matters, unilat- for TGA, including arterial ischemia, venous congestion, eral, isolated hemispheric infarction of the hippocampus or migraine, and psychogenic disorders. It is possible that the thalamus may present with amnesia as the sole manifestation mechanisms described earlier are associated with TGA by of the CVA, thus becoming difficult to differentiate from 55,56 which they are involved in a common pathway that ultimately TGA. Similarly, ischemia within the MTL with involve- destabilizes the CA1 region of the hippocampus. At this time, ment of the hippocampus, caudate, or fornix has also been 25,57–60 discovery of a specific cause may not change the course of associated with a TGA-like presentation. Neuroimaging management or the outcome, as the nature of the disease is strongly recommended. For this reason, neuroimaging is process is self-limiting. strongly recommended in atypical presentations of TGA or unwitnessed episodes, due to the risk of head trauma 43,61,62 Differential diagnosis or CVA. While TGA does not typically show acute The differential diagnosis of TGA includes those disease changes on brain imaging, MRI with DWI or T2-weighted states that can present with transient anterograde amnesia imaging may reveal hyperintense punctate lesions in the lat- (Table 2). Other causes of such disease states are ruled out eral hippocampal regions in the subacute phase ~48–72 hours 110,111 prior to reaching the diagnosis of TGA (Figure 1). after the onset of TGA symptoms. These lesions are visible 17,19,36,61,62 for up to 7–10 days after onset. Transient epileptic amnesia (TeA) Brain MRI is usually performed to exclude stroke at the TEA is a form of adult-onset MTL epilepsy that presents time of symptoms; however, this may be too early to discover 7,48–50 as recurrent, transient episodes of acute memory loss. the findings associated with TGA. Additionally, typical risk This amnesia may be antero-retrograde or only retrograde. factors associated with cerebrovascular disease should be This is distinct from TGA, in which patients always have assessed in the patient’s history. The likelihood of CVA/ anterograde memory loss and may have permanent retro- TIA as the etiology of transient anterograde amnesia may be 61,62 grade amnesia that spans hours to days prior to the onset of increased with the presence of these risk factors. the episode. Patients with TGA are more likely to exhibit agitation or anxiety. While some authors report repetitive Migraines questioning as a feature indicative of TGA, others have found Migraine is an episodic headache disorder accompanied 48,49,52 that TEA patients also exhibit this behavior. by various neurological, gastrointestinal, and autonomic Important features of TEA that differ from TGA include changes. In those with migraine headaches, ~20% experi- occurrence upon awakening, duration 1 hour, interictal ence an aura, either during or before the development of the retrograde amnesia incomplete anterograde amnesia (able to headache. Similar to glutamate-mediated transient neuronal remember not being able to remember), temporal lobe features depolarization followed by prolonged quiescence of neuronal such as olfactory/gustatory hallucinations, oral automatisms, activity, CSD may be explained by hypoperfusion that is 7,48,53 18 and interictal EEG abnormalities. Controversy exists over preceded by transient hyperperfusion in the cortex. CSD abnormal EEG being a diagnostic factor of TEA, as only a has been proposed as the neurophysiological explanation of third are found to have abnormalities, while the other two- migraine with auras, as it propagates at a similar velocity as 5,44,48 63 thirds show focal slowing or normal findings. Subsequent visual scotomata during an aura. follow-up reveals that TEA has a higher recurrence rate than There are multiple case reports suggesting that TGA 5,44,48 TGA. The diagnosis of TEA carries a favorable prognos- occurs as either an aura to or, “associated with”, migraine 49,52,53 64–69 tic response to antiepileptic drugs but may yield persist- headaches. Otherwise, in two larger scale studies, the 53,54 ing interictal memory deficits. This includes accelerated association between TGA and migraines is mixed. For long-term forgetting and autobiographical amnesia. instance, in an 11-year retrospective study reported in 2015, among 8,821 new migraine patients, six cases of TGA ischemic events were identified during a migraine attack. For a majority Ischemic events such as cerebrovascular accidents (CVAs) of these patients, TGA occurred after the beginning of the and TIAs must be excluded prior to arriving at a diagnosis attack. Alternatively, in a 1998 case–control study, TGA of TGA, as the former typically requires emergent treatment. patients with migraine were identified from a group of 57 CVAs and TIAs are most commonly associated with focal TGA patients. The former group was then compared with submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Dovepress Transient global amnesia submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Table 2 Differential diagnosis of TGA: transient anterograde amnesia Condition Risk factors Precipitating factors Duration Associated neuro MRI EEG Recurrence Response to symptoms of attacks anti-epileptics TGA Migraine Yes 4–6 hours No Hippocampal Dwi Normal Low No hyperintensity w/o permanent lesion TeA No No/yes (waking) 60 minutes No/yes (oral automatism, Normal/hippocampal Abnormal (temporal High Yes (often, a few olfactory or gustatory sclerosis or atrophy or frontotemporal minutes) hallucinations) regions) TiA/thrombo-embolic vascular No Minutes to No/yes (any) Dwi with T2-FLAiR Normal Low No permanent permanent or lesion impairment Dissociative amnesia Trauma/abuse Yes, emotional stress variable No Normal Normal varies No Migraine headache Genetic; dietary Yes, fasting, premenstrual, 4–72 hours Auras (visual, sensory, Normal Normal High Yes, especially, emotional stress, sleep motor, or language valproic acid problems abnormalities) up to 30% and topiramate Hypoxic states (such as aortic increased Underlying stress reaction 10–12 hours No Normal Normal None known, No dissection with pure TGA) intrathoracic triggered by the acute although death is pressure pain event not uncommon Hypoxia inducing events vascular No 24 hours Yes Yes/ischemic lesions No Rare No of vertebrobasilar system in hippocampus a b 71 78 79 Notes: valsalva maneuver, emotional stress, immersion in cold or hot water, sexual intercourse, or pain. Anterograde amnesia not associated with dissociative amnesia. Data from Kumral e et al ; April MD et al ; irioka T et al ; 80 108 109 Bonnet P et al ; Ryoo i et al ; Arena Je and Rabinstein AA. Abbreviations: 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. 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Abbreviations: AAm, anterograde amnesia; eeG, electroencephalogram; HSe, herpes simplex encephalitis; Le, limbic encephalitis; LOC, loss of consciousness; PCA, posterior cerebral artery; PTA, posttraumatic amnesia; RAm, retrograde amnesia; TBi, traumatic brain injury. two groups of patients, one with TGA only and the other with arterial insufficiency etiologies have been described in the normal controls. Despite the prevalence of both migraine literature as causes of TGA-like symptoms. For instance, and tension headaches being increased in those patients with cardioembolism and large-artery disease of the vertebrobasi- TGA, there was no evidence of an increased frequency in lar system can lead to hippocampal infarcts. Five variants TGA features in those with migraines. have been described including anterior, posterior, unilateral complete, bilateral, and small circumscribed (punctiform) Hypoxia hippocampal infarcts. Prominent clinical acute anterograde In addition to ischemia in the setting of TIA/CVA, hypoxia- amnesia and retrograde amnesia were present in more than inducing events with vasospastic, vasoconstrictive, or two-thirds of patients. In most of the patients, the lesions submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress <H <H <H <H Dovepress Transient global amnesia involved the anterior and medial aspects of the hippocampus retrograde memory, it is generally episodic, and it is often along the complete length of the head, body, and tail of the accompanied by intense psychological distress. While often hippocampus. Such evidence supports that TGA’s etiology times complicated medical disorders become labeled as may be a compromised vertebrobasilar system leading to the “psychogenic” if the etiology is unknown, there is literature dysfunction of MTL and subsequently memory formation. that supports a psychogenic origin to TGA. Several case reports describe TGA-like symptoms Data gathered from two geriatric studies utilized the 51,71–75 after vascular procedures or intravenous contrast use. Geriatric Depression Scale in patients with TGA, showing Contrast media are sterile iodine-containing solutions used that 40% of TGA patients had depressive symptoms. in diagnostic imaging procedures. Older agents generally fall A more detailed study investigated phobic personality traits into the class of ionic monomers, which have a high osmo- of 51 TGA patients and established that 82% had pathological lality and a high chemotoxicity. Nonionic agents have been avoidance behaviors. developed to overcome the adverse events associated with TGA patients have a high prevalence of comorbid 5,85 older contrast media. While there have been cases describ- emotional distress and anxious personality traits. About ing nonionic angiographic contrast medium neurotoxicity, one-third of TGA episodes occur after physical or psycho- the risk of neurotoxicity remains higher in the ionic class of logical stress, which suggest disruption of memory forma- contrast media. Furthermore, it has been suggested that the tion due either to ischemic or stress-induced catecholamine 86,87 risk of neurotoxic effects might be increased by preexisting disruption. Some authors believe that stress-induced cat- abnormalities of the blood–brain barrier and by repeated echolamine release may lead to hypoxia or ischemia, whereas contrast injections. others believe that the neurotransmitters involved may affect 88–93 Other postulated mechanisms by which cerebral angiog- the formation of memory. There is some evidence of an raphy produces TGA symptoms include epilepsy and association between TGA and Takotsubo syndrome. The 73,74 ischemia. latter is characterized by transient, acute left-ventricular Other case reports support an arterial insufficiency etiol - myocardial dysfunction mimicking myocardial infarction ogy, describing TGA symptomatology secondary to vascular that also occurs after physical or psychological stress. 76–80 disease processes. Intriguingly, aortic dissection, a poten- If the clinical picture remains unclear, neuropsychological tially critical break in the lining of the main arterial outflow testing or other neurological tests (electroencephalogram from the heart classically associated with severe chest pain and neurological examination) may be helpful in distin- and frequently a devastating diagnosis, has been reported guishing psychogenic amnestic disturbances from neuro- to present with TGA-like symptoms in nine cases, five of logical amnestic conditions, especially in patients who have whom were without chest pain, although the latter could be secondary gain or overembellish symptoms. attributed to the patients’ altered mental status. Regardless, In summary, to make a diagnosis of TGA, all strict clinical recognition of painless aortic dissection in the differential criteria as shown in Table 1 should be met. The differential of TGA is imperative. While the latter is generally a benign diagnosis includes structural (vascular) disease, epileptic syndrome, the former could result in signic fi ant morbidity or amnesia, delirium, intoxication, and head injury and migraine mortality. Thus, in those patients presenting with TGA-like headaches. When a general physician is presented with a symptoms and accompanying cardiovascular changes such typical case, no additional diagnostic tests, such as MRI and as hypotension and hypertension or asymmetric extremity EEG, are needed. This even holds when such a patient has blood pressures, CT angiography of the abdomen may be vascular risk factors. However, when focal neurological signs warranted. accompany anterograde amnesia, neuroimaging is warranted Finally, others report the development of TGA after use and potentially a neurology consult. If retrograde amnesia is of phosphodiesterase type 5 inhibitor and sexual activity. also affected and emotional distress is present, the clinician However, it is unclear whether the phosphodiesterase inhibi- needs to consider psychogenic amnesia. Alternatively, albeit tor or the sexual activity caused the vasospasm, as both are rare but more ominous, are those cases of “painless” aortic known to involve significant changes in blood flow. dissection, where TGA is the primary symptom as chest pain is lacking. Finally, research findings using DWI–MRI Psychogenic amnesia/dissociative amnesia support the concept of focal ischemia. These focal lesions Psychogenic amnesia, often labeled as dissociative amnesia, have a maximum detectability between 48 and 72 hours after is differentiated from TGA, in which the former affects the start of TGA. Focal lesions have been demonstrated in the submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Spiegel et al Dovepress CA1 area of the cornu ammonis of the hippocampus (MTL), Treatment mostly unilateral. However, in up to 35% of TGA patients, By definition, TGA is a self-limited condition that resolves no such abnormalities are demonstrable. without intervention; thus, there is no specific treatment indicated. Although the mean time course of an amnestic Beyond 24 hours: outcomes episode in TGA is 4–6 hours, with most resolving by 8 hours, According to the standard accepted criteria, deficits of TGA proposed treatments could depend on uncovering the under- 15 5 resolve within 24 hours. There has been considerable lying etiology. research dedicated to the cognitive profile of TGA patients If the presentation in TGA was secondary to reversible following the resolution of acute-phase symptoms; however, ischemia, as has been suggested by some case reports using results have been mixed. DWI, as well as other reports that noted onset of TGA epi- A 2009 meta-analysis examined data from 25 different sodes after Valsalva-like maneuvers that may temporarily studies and compared 374 TGA subjects to 760 control reduce cerebral blood flow, then optimization of cardiovas - subjects in the following five domains: anterograde episode cular factors similar to treatments implemented for cardiac long-term memory, retrograde episode long-term memory, ischemia, such as antiplatelets, managing blood pressure, and 98–101 short-term memory, semantic memory, and executive func- heart rate, or statin therapy could be beneficial. tion. Beyond the first 24 hours, there was no significant differ - Some studies suggest an epileptic etiology of TGA, as ence between patients and controls in any of the v fi e domains electroencephalogram findings have been suggestive of epi - for the 30-day period following TGA onset. Similarly, a leptic discharges, but other case–control studies have found 102–104 study with a median follow-up period of 1,128 days found no such correlation. Thus, anticonvulsant medications no significant difference in performance between TGA would not be a proposed treatment option based on the patients and controls on tasks of episodic memory, seman- available evidence. tic memory, working memory, executive functions, and Evidence suggesting that TGA is secondary to cortical attention. Alternatively, one study with follow-up periods depression following cortical hyperstimulation does not of 4 months and 1 year found dec fi its in anterograde memory support theoretical treatment options with the exception of in TGA subjects when compared with controls; however, those related to migraine headaches. Triptans have not been only when data from both follow-up periods were pooled studied in TGA. together. Additionally, at the 4-month follow-up visit, higher Ultimately, there are no established, evidence-based scores on anxiety and depression scales correlated with worse treatments for TGA to date, likely due to the short duration performance on tests of retrograde and anterograde memory of symptoms experienced as well as a lack of universally tests, respectively. accepted pathophysiology. Given the cardiovascular hypothesis of TGA and the interest in the field in cardiovascular risk factors of the Conclusion/future directions disease, one study examined the subsequent risk of expe- The yearly incidence of TGA is 3–8 cases per 100,000 people, riencing CVA in patients with a history of TGA vis-a-vis although 6%–10% of patients with TGA will experience a comparing the rate of CVA following TGA to the rate of second or third episode. Thus, while it may be difficult CVA following migraine, seizure, and TIA at time points of to predict an index episode of TGA, it may be possible to 1 and 5 years after the event. The results of this study did not decrease the risk of future episodes. The latter could be support an increased risk of CVA after TGA, with the risk accomplished through clinical trials by addressing differ- of CVA at 1 year being similar to that after migraine (0.54 ent proposed etiologies associated with TGA. For instance, and 0.22%, respectively) and lower than after TIA (4.54%). despite significantly reduced atherosclerotic risk factor The 5-year rates for CVA following TGA, migraine, and TIA profiles in patients with TGA in comparison to those with were 2.44, 0.86, and 12.23%, respectively. TIA, ie, diabetes mellitus and hypertension, can statins, In a 12-year follow-up study, the longest in the literature antihypertensives, and/or hypoglycemics decrease the risk to date, TGA patients were compared with controls on end of arterial ischemia, which has been proposed to explain points of CVA/TIA, seizures, and cognitive impairment (mild TGA? Can prophylactic treatment of migraines with triptans cognitive impairment or dementia). TGA patients were not decrease the risk of TGA, as this is the only identified risk found to be at a higher risk of developing any of the included factor in the development of TGA in those under the age of conditions than the control subjects. 56 years? 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Transient global amnesia: current perspectives

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Journal name: Neuropsychiatric Disease and Treatment Article Designation: Review Year: 2017 Volume: 13 Running head verso: Spiegel et al Neuropsychiatric Disease and Treatment Dovepress Running head recto: Transient global amnesia open access to scientific and medical research DOI: http://dx.doi.org/10.2147/NDT.S130710 Open Access Full Text Article Review Abstract: Transient global amnesia (TGA) is a clinical syndrome characterized by the sudden David R Spiegel onset of an extraordinarily large reduction of anterograde and a somewhat milder reduction Justin Smith of retrograde episodic long-term memory. Additionally, executive functions are described as Ryan R w ade diminished. Although it is suggested that various factors, such as migraine, focal ischemia, Nithya Cherukuru venous flow abnormalities, and epileptic phenomena, are involved in the pathophysiology and Aneel Ursani differential diagnosis of TGA, the factors triggering the emergence of these lesions are still Yuliya Dobruskina elusive. Recent data suggest that the vulnerability of CA1 neurons to metabolic stress plays a Taylor Crist pivotal part in the pathophysiological cascade, leading to an impairment of hippocampal func- Robert F Busch tion during TGA. In this review, we discuss clinical aspects, new imaging findings, and recent Rahim M Dhanani clinical–epidemiological data with regard to the phenotype, functional anatomy, and putative Nicholas Dreyer cellular mechanisms of TGA. Department of Psychiatry and Keywords: transient global amnesia, vascular, migraines, psychiatric Behavioral Sciences, eastern v irginia Medical School, Norfolk, v A, USA Introduction More than 50 years after its initial description, transient global amnesia (TGA) remains one of the most enigmatic syndromes in clinical neurology. TGA is den fi ed as a sudden onset of an anterograde and retrograde amnesia that lasts up to 24 hours, although mild subclinical neuropsychological deficits with concomitant vegetative symptoms can last for days after the episode. The memory impairment of patients with acute TGA shows a profound reduction of anterograde and a milder reduction of retrograde episodic memory, including executive functions and recognition. In this review of TGA, we summarize the epidemiology, symptomatology, pathophysiology, assessment, differential diagnosis, longer-term outcome, and possible treatment recommendations associated with this condition. Literature review Full-text articles and abstracts were selected for this review and were identified through searches of PubMed with the search terms “transient amnesia”, “transient global amnesia”, “hippocampus”, and “amnestic syndromes” between 1985 and 2017. Additionally, more distant seminal articles on this subject matter were included. Only articles published in English were reviewed. The nal fi reference list was chosen on the basis of relevance to the topics covered in this review (eg, their originality, contribution to hippocampal and TGA epidemiology, anatomy and physiology, pathophysiology, diagnosis, and treatment). Correspondence: David R Spiegel Department of Psychiatry and Behavioral Sciences, eastern virginia Medical Epidemiology School, 825 Fairfax Avenue, Norfolk, The following prospective and retrospective systematic studies identify TGA cases vA 23507, USA email spiegedr@evms.edu from either hospitalized or national health registry samples. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 2691–2703 Dovepress © 2017 Spiegel et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/NDT.S130710 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Spiegel et al Dovepress incidence cancer diagnosis carries no increased risk of TGA, according Recent epidemiological data put the annual incidence of TGA to a prospective cohort study with 5,365,608 subjects running 2,3 4 between 3.4 and 10.4/100,000. between 2001 and 2009. Psychiatric comorbidity Age and gender One study compared psychiatric disease in 51 subjects who TGA most commonly presents in the seventh decade of life. experienced a TGA to 51 subjects who experienced a TIA. Across studies, the mean age of an episode ranges from 61 2,4–6 Psychiatric disease was den fi ed as having “a diagnosis of to 67.3 years. In a 2006 study, 96% of subjects with TGA depression or anxiety disorder” or having received “treatment (n=142) presented between the ages of 51 and 80 years. with specic fi drugs for at least 3 months”. TGA subjects had a Epidemiological studies fail to identify any subjects under signic fi antly higher percentage of psychiatric disease compared the age of 55 years. Several small-scale studies show a slight to TIA controls (39.2% vs 13.7%, age- and sex-adjusted odds female predominance. However, a study on 5,097 TGA cases ratio [OR] =2.86). Additionally, a significantly higher per - shows gender distribution to be 50.7% females and 49.3% 4 5 centage of TGA subjects (33.3%) reported a family history of males, consistent with one previous analysis. psychiatric disease as compared with TIA subjects (13.7%). In summary, according to community-based studies, Recurrence the annual incidence of TGA is 5–10/100,000 and 23.5– Depending on the length of follow-up, the annual rate of TGA 32/100,000 for people aged 50 years and older. Peak inci- recurrence varies from 2.9 to 26.3%. A 2005 study with a dence is around the age of 62 years (standard deviation [SD] 7-year follow-up period, which is the longest systematic 10 years). A total of 54%–67% of TGA patients are female. follow-up period reported, found a recurrence rate of 8%. Chances of recurrence are reported variedly from 2.9 to 25%. Another study that recruited subjects over a 10-year period Other than migraine headaches, there are no definitive risk (n=142), however, with no designated follow-up period after factors for the development of TGA. the first occurrence, found a recurrence rate of 6.3%, if prob - able episodes were taken into account. Clinical diagnosis Development of TGA criteria Risk factors TGA is a clinical diagnosis. It was first described in 1956 as A migraine history is one of the more notable risk factors an “isolated episode of confusion with amnesia” not other- associated with developing TGA. In a 2014 population-based 11,12 wise associated with other neurological deficits. Subjects study (n=316,602), migraine patients were signic fi antly more were described as becoming repetitious and asking the same likely to develop TGA than their matched controls, with the 7 questions, although mostly revolved around the memory loss incidence rate ratio of 2.48. Additionally, of the subjects who itself. Fisher and Adams coined the term TGA in 1958; developed TGA after the age of 40 years, those with a history however, it was not until 1964 that they detailed a report of migraine had a significantly younger age of onset (56.6) of 17 patients with sudden onset anterograde amnesia and compared to the control group (61.4). No associations were 7 confusion that resolved within a few hours. found between various migraine subtypes and TGA. Hodges and Warlow later developed criteria for the Cardiovascular risk factors are also well studied in clinical syndrome in 1990 (Table 1), and since then, this TGA. A retrospective case–control study found age- and has been used as the foundation of TGA diagnosis. They sex-matched control subjects (n=293) to have significantly decreased odds of having hyperlipidemia and ischemic heart disease when compared with those subjects with TGA Table 1 Hodges and warlow criteria for TGA (n=293). Within this same study, 632 transient ischemic Diagnostic criteria of TGA – Attacks must be witnessed attack (TIA) subjects had greater rates of hypertension, – There must be anterograde amnesia during the attack diabetes mellitus, ischemic stroke, and atrial b fi rillation when – Cognitive impairment is limited to amnesia compared with TGA subjects, likely indicating differing risk – No clouding of consciousness or loss of personal identity factors between TGA and TIA. Furthermore, a retrospective – No focal neurological signs/symptoms – No epileptic features study of 85 TGA subjects revealed that those with history of – Attack must resolve within 24 hours two episodes of TGA showed a higher frequency of carotid – No recent head injury or active epilepsy atheromasia and ischemic heart disease than those with a Note: Data from Hodges and warlow. history of just one episode of TGA. Also, of note is that Abbreviation: TGA, transient global amnesia. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Dovepress Transient global amnesia divided patients into the following three categories: pure Disorders, fourth edition criteria of panic attacks. While TGA, probably epileptic amnesia, and probably TIA. Exclu- these symptoms have been useful in identifying areas of sionary criteria for pure TGA included focal neurological dysfunction, TGA diagnosis should be made based on criteria symptoms, such as ataxia, limb weakness, and sensory dis- listed in Table 1. turbances. Of the 153 patients reviewed between 1984 and In summary, while multiple exclusionary criteria exist, 1987, 114 patients met the proposed criteria for pure TGA. heteroanamnestic confirmed anterograde amnesia in a clear The majority of attacks in this group lasted between 1 and sensorium and cognitive impairment limited to amnesia is the 8 hours. Both TGA and non-TGA groups showed disorien- main “rule-in” criteria for TGA. Additionally, the amnesia tation in time and repetitive questioning, although the TGA must last 24 hours. Headache, dizziness, and nausea are group demonstrated more repetitive questioning with 92% the most common accompanying complaints. Finally, in vs 71% in non-TGA groups. Most patients with TGA had a 89% of cases, some provoking activity can be pointed out permanent retrograde amnesic gap for the events immediately immediately before the attack occurred. Physical exertion prior to and during the attack, although this was also seen (including sexual activity) is the most common precipitat- in non-TGA cases. ing event, followed by emotional stress and sudden change of temperature. Precipitating events Pathophysiology A study of 142 cases of TGA found precipitating factors in 131 of these episodes (89.11%). Emotional stress (ie, trig- Relevant neuroanatomy gered by gastric endoscopy, birth/death announcement, The clinical picture of TGA has led researchers to inves- and difficult/exhausting work day), physical effort (ie, tigate focal injury to the neurological circuits involved in gardening, house work, and sawing wood), and water contact/ memory as a potential etiology of the syndrome. Hodges temperature change (ie, hot bath/shower and cold swim) were and Warlow performed computed tomography (CT) scans observed most frequently immediately before an attack and on 83% of the pure TGA cases in their study (n=95), finding are considered “close events”. Anxiety triggered by conflict small white matter changes, basal ganglia lesions, or periven- at home or work, health problems, and financial stressors tricular lucencies in 12% of these patients (n=11). These were often reported weeks prior to TGA and are considered areas, however, are not located in known memory-related “remote events”. In the TGA series, the percentage of emo- structures. Current evidence points to the formation of early tional stress, physical effort, and water contact/temperature memory within the hippocampal/entorhinal cortex network change was 29, 25, and 14%, respectively, compared to and its eventual transference to remote memories stored in 48, 9, and 0% in control groups, respectively. Remote events the neocortex network. Particular attention has been given of anxiety and exhaustion were reported in 24 and 33% of to the cornu ammonis (CA1) field of the hippocampus, TGA cases and 6 and 90% in controls, respectively. Differ- which has been hypothesized to play a central role in the ences from control subjects in both close (P0.000) and pathophysiology of TGA given its extraordinary sensitivity remote precipitating events were found to be statistically to cell stress. significant, providing strong evidence that TGA occurs in More recent studies have found imaging changes strongly certain contexts. related to TGA using magnetic resonance diffusion-weighted imaging (DWI). These findings are typically unilateral and Associated symptoms tend to be small (1–3 mm), high-signal foci found in the 17–20 Although focal neurological deficits exclude a diagnosis CA1 field of the hippocampus. These lesions are most of TGA, there are several nonfocal symptoms, which are prominent 24–48 hours after the initial TGA episode, which often observed. Headache and nausea/vomiting are the matches the peak activation period for microglia in stroke most common and were each present in 10% of TGA cases models. Alternatively, there are cases of TGA with bilat- immediately after the attack. Dizziness, chills or hot u fl shes, eral and even multifocal hippocampal involvement and also fear of dying, cold extremities, paresthesias, emotionalism, cases with ischemic or hemorrhagic damage to other brain 5 22–27 trembling, chest pain, and sweating have also been reported. regions. These conflicting reports do not help to clarify Quinette et al proposed that such associated symptoms the initial neuronal insult in TGA. were somatic manifestations of anxiety and found that, Similarly, the underlying etiology of TGA remains compared to controls, TGA episodes were more frequently obscure with multiple proposed mechanisms, such as arte- related to the Diagnostic and Statistical Manual of Mental rial ischemia, venous congestion, migraine, and psychogenic submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Spiegel et al Dovepress disorders. Early researchers hypothesized that atherosclerotic Valsalva-like activities, anxious and phobic personality or thromboembolic events disrupt blood flow to the hip - traits, emotional stressors, and immersion in hot or cold 5,30 pocampus, which is supplied by the posterior cerebral artery water) has supported an arterial mechanism. It has been 20,23,24 and the hippocampal arteries. Venous congestion and postulated that an increased prevalence of patent foramen jugular vein valve insufficiency are also hypothesized etiolo - ovale among patients with TGA is responsible for its asso- gies, given that many patients report Valsalva-associated ciation with Valsalva-like activity by means of paradoxical 19,28 maneuvers prior to a TGA event. In addition, severe embolism; however, further attempts to reproduce this 31,32 emotional reactions and migraines may contribute to the association have since failed. Increased incidence of destabilization of the CA1 sector of the hippocampus via TGA among particular personality traits and precipitation by massive glutamate release. The following sections explore emotional stressors suggest that reactive hyperventilation- these postulated mechanisms in greater detail. induced cerebral vasoconstriction can result in changes in the cerebrovascular hemodynamics within the hippocampal Arterial ischemia and venous congestion region. Functional imaging technology supports such There are many parallels between TGA and TIA, which reactive changes, demonstrating relative hypoperfusion support the arterial ischemia hypothesis. TGA and TIA are within the medial temporal lobes (MTLs) in patients with characterized by an abrupt onset of reversible loss of function TGA. Results among other studies, however, have been occurring in patients within similar age group demographics. inconsistent, and it is unclear whether the findings are Reported mean age of onset is 60–66 years for TGA and causative in nature or reactive to derangements in cerebral 33,34 69–71 years for TIA, with modal onset, for both, over the metabolism. age of 50 years. Despite these similarities, statistical analysis Structural magnetic resonance imaging (MRI) also has reliably shown significantly reduced atherosclerotic risk provides support for an ischemic mechanism, with DWI– factor profiles, including decreased prevalence of embolic MRI showing evidence of abnormal lateral hippocampal heart disease, diabetes mellitus, hypertension, and carotid punctate hyperintensities in patients with TGA. Analysis artery atherosclerotic disease, in patients with TGA in com- of the appearance and evolution of these lesions over time parison to those with TIA. Population cohort data have also have displayed similarities to previously described lesions consistently indicated that a history of TGA does not put from cerebral ischemic injury, with reported detection rates 19,35–38 patients at a higher risk of cerebrovascular events, and in ranging from 57 to 100% in patients with TGA. These fact, recent studies suggest a more favorable prognosis for lesions primarily involve the hippocampal CA1 neuronal TGA patients compared to TIA patients in regard to risk of field, a region known to be critically involved in the process future cerebrovascular events. Even more, one retrospective of memory consolidation and to be vulnerable to stress. analysis showed no heightened risk of future cerebrovas- However, several temporal and anatomical aspects of cular event following a TGA event when compared with these lesions are fundamentally inconsistent with conven- healthy matched controls, further refuting an atherosclerotic tional ischemic lesions. Lesions associated with TGA were hypothesis. most reliably seen 24–72 hours after symptom onset and were Several prominent clinical features of TGA additionally shown to disappear soon after. Additionally, the typical dura- argue against arterial ischemia as a likely mechanism. The tion of TGA episodes (4–6 hours) is inconsistent with this mean duration of a TGA episode largely exceeds that seen delayed and reversible nature of DWI–MRI lesions, which in TIA, with a documented mean duration of 4–8 hours when present in the case of TIA are detected much earlier 5 39 and 97% of episodes lasting 1 hour. For TIA, in con- and persist longer. trast, the vast majority of episodes last 60 minutes, with Venous congestion with retrograde cerebral flow is the bulk of these lasting only a few minutes. Also, the another prominent hypothesis for the pathophysiology behind absence of associated focal neurologic dysfunction during TGA. Valsalva-like activity causes transient elevation of the TGA episode, such as lateralizing weakness and visual intrathoracic pressure with obstruction of venous return, field deficits, is inconsistent with the ischemic hypothesis, potentially resulting in retrograde transmission of pressure to which would be expected in cases of an acute ischemic event the cerebral venous vasculature draining the involved struc- involving bordering neuroanatomy. tures. Other frequently cited precipitating events (cold water The pathophysiology behind frequently cited precipitat- immersion, exercise, and emotional stressors) are mechanisti- ing events and comorbidities accompanying TGA (including cally analogous by the way of increasing sympathetic tone submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Dovepress Transient global amnesia with central diversion of peripheral venous volume in effort Migraine to preserve flow to vital organs, which similarly results in Another hypothesis is that TGA may be a sequela of elevated central venous pressures. Proponents also recog- migraines due to sweeping depression of cerebral activity that nize the anatomy of cerebral venous drainage as supportive is found throughout the cortex, extending through the hip- evidence, as venous outflow from bilateral hippocampal pocampus, leading to transient dysfunction and subsequently regions converge to a common great vein of Galen before TGA. It is this same cortical depression that is thought to later diverging at the conu fl ence of venous sinuses supporting give rise to the aura found in migraine sufferers and is caused perturbation of bilateral hippocampal function previously by the release of massive glutamate and a subsequent wave 40 46 unexplained by ischemic hypotheses. of short-lasting cortical depolarization. Numerous studies have demonstrated a significant This mechanism has been demonstrated in animal models increase in the prevalence of jugular venous valve insuf- by local stimulation of the hippocampus, lending to the pos- ficiency with jugular vein retrograde flow among TGA sibility that a similar reaction could be elicited in humans 40–42 patients when compared with healthy matched controls. via the experience of strong emotional events or other This association was detected via MRI and Doppler and intense stimuli leading to a large release of glutamate from was particularly common among patients reporting a hippocampus. Given this relationship between migraines concomitant precipitating event. The largest study dem- and transient hippocampal dysfunction, it is feasible to con- onstrates 80% prevalence of internal jugular venous valve sider the possibility of an etiological relationship between insufficiency with retrograde flow among 142 TGA subjects migraines and the transient memory problems exhibited by compared to only 25% among control subjects. However, patients with TGA. However, there is a dearth of evidence several recent studies have brought the significance of this to support this theory. Currently, the evidence supportive of finding into question. One study using transcranial Doppler a connection between migraines and TGA is mainly asso- sonography of intracranial vessels to record blood flow ciative and causality cannot be stated with any significant direction and velocity at the internal jugular veins, basal level of confidence given the observational nature of these 5,28 veins of Rosenthal, and great vein of Galen compared studies. findings at rest and during Valsalva-like maneuvers. Although confirming an elevated prevalence of jugular Psychogenic causes valve insufficiency among TGA patients, intracranial One of the lesser studied etiologies of TGA is of psycho- venous reflux was not seen in TGA or in control subjects. genic origin. In these cases, the precipitating trigger is This was confirmed by a study utilizing time of flight often an emotional event or psychological stressor. It is magnetic resonance angiography to observe abnormal encountered classically in younger populations and is often jugular venous reflux within TGA and control patients but associated with a subjective indifference to the memory similarly found low rates in each study group (intracranial loss experienced. In most cases, autobiographical memory retrograde flow in 7/167 in TGA group, 8/167 in emergency deficits, which are most often intact in TGA, are appreciated room visitor control group, and 3/167 in healthy matched with relatively functioning anterograde memory formation control group). capabilities. Physiologically, the insult appears to disrupt In summary, although the physiological n fi dings suggest the affective learning circuit formed between amygdala, a meaningful association with TGA, there is limited evidence hippocampus, striatum, and prefrontal cortex. TGA could for venous congestion as an etiology for TGA. Current evi- be viewed as an illness of temporary hippocampal insuf- dence is unable to explain the lack of association with other ficiency, where its inhibitory effects to the amygdala are causes of venous congestion, including congestive heart disrupted, which could precipitate a disruption in memory 18 28 failure and cerebral venous thrombosis. It is also unclear formation. why such transient pressures can induce the long-lasting Other evidence suggests that approximately half of the effects seen in TGA. Further questions surround the true patients with psychological disturbances as the precipitating eti- association with reported precipitating events, including ology of TGA also had associated phobic personality trait. why episode recurrence is so uncommon when they can be Psychogenic amnesia can be linked to several psychi- prompted by a Valsalva-like activity. It is likely that vascular atric disorders including posttraumatic stress disorder and mechanisms play a role in the pathophysiology of TGA, but dissociative disorders, where the loss of memory could be the exact role remains to be discovered. considered a defensive psychological mechanism. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Spiegel et al Dovepress Summary of pathophysiology neurological dec fi its, which by den fi ition preclude TGA from There are several potential etiologies that may be responsible the working diagnosis. However, to confound matters, unilat- for TGA, including arterial ischemia, venous congestion, eral, isolated hemispheric infarction of the hippocampus or migraine, and psychogenic disorders. It is possible that the thalamus may present with amnesia as the sole manifestation mechanisms described earlier are associated with TGA by of the CVA, thus becoming difficult to differentiate from 55,56 which they are involved in a common pathway that ultimately TGA. Similarly, ischemia within the MTL with involve- destabilizes the CA1 region of the hippocampus. At this time, ment of the hippocampus, caudate, or fornix has also been 25,57–60 discovery of a specific cause may not change the course of associated with a TGA-like presentation. Neuroimaging management or the outcome, as the nature of the disease is strongly recommended. For this reason, neuroimaging is process is self-limiting. strongly recommended in atypical presentations of TGA or unwitnessed episodes, due to the risk of head trauma 43,61,62 Differential diagnosis or CVA. While TGA does not typically show acute The differential diagnosis of TGA includes those disease changes on brain imaging, MRI with DWI or T2-weighted states that can present with transient anterograde amnesia imaging may reveal hyperintense punctate lesions in the lat- (Table 2). Other causes of such disease states are ruled out eral hippocampal regions in the subacute phase ~48–72 hours 110,111 prior to reaching the diagnosis of TGA (Figure 1). after the onset of TGA symptoms. These lesions are visible 17,19,36,61,62 for up to 7–10 days after onset. Transient epileptic amnesia (TeA) Brain MRI is usually performed to exclude stroke at the TEA is a form of adult-onset MTL epilepsy that presents time of symptoms; however, this may be too early to discover 7,48–50 as recurrent, transient episodes of acute memory loss. the findings associated with TGA. Additionally, typical risk This amnesia may be antero-retrograde or only retrograde. factors associated with cerebrovascular disease should be This is distinct from TGA, in which patients always have assessed in the patient’s history. The likelihood of CVA/ anterograde memory loss and may have permanent retro- TIA as the etiology of transient anterograde amnesia may be 61,62 grade amnesia that spans hours to days prior to the onset of increased with the presence of these risk factors. the episode. Patients with TGA are more likely to exhibit agitation or anxiety. While some authors report repetitive Migraines questioning as a feature indicative of TGA, others have found Migraine is an episodic headache disorder accompanied 48,49,52 that TEA patients also exhibit this behavior. by various neurological, gastrointestinal, and autonomic Important features of TEA that differ from TGA include changes. In those with migraine headaches, ~20% experi- occurrence upon awakening, duration 1 hour, interictal ence an aura, either during or before the development of the retrograde amnesia incomplete anterograde amnesia (able to headache. Similar to glutamate-mediated transient neuronal remember not being able to remember), temporal lobe features depolarization followed by prolonged quiescence of neuronal such as olfactory/gustatory hallucinations, oral automatisms, activity, CSD may be explained by hypoperfusion that is 7,48,53 18 and interictal EEG abnormalities. Controversy exists over preceded by transient hyperperfusion in the cortex. CSD abnormal EEG being a diagnostic factor of TEA, as only a has been proposed as the neurophysiological explanation of third are found to have abnormalities, while the other two- migraine with auras, as it propagates at a similar velocity as 5,44,48 63 thirds show focal slowing or normal findings. Subsequent visual scotomata during an aura. follow-up reveals that TEA has a higher recurrence rate than There are multiple case reports suggesting that TGA 5,44,48 TGA. The diagnosis of TEA carries a favorable prognos- occurs as either an aura to or, “associated with”, migraine 49,52,53 64–69 tic response to antiepileptic drugs but may yield persist- headaches. Otherwise, in two larger scale studies, the 53,54 ing interictal memory deficits. This includes accelerated association between TGA and migraines is mixed. For long-term forgetting and autobiographical amnesia. instance, in an 11-year retrospective study reported in 2015, among 8,821 new migraine patients, six cases of TGA ischemic events were identified during a migraine attack. For a majority Ischemic events such as cerebrovascular accidents (CVAs) of these patients, TGA occurred after the beginning of the and TIAs must be excluded prior to arriving at a diagnosis attack. Alternatively, in a 1998 case–control study, TGA of TGA, as the former typically requires emergent treatment. patients with migraine were identified from a group of 57 CVAs and TIAs are most commonly associated with focal TGA patients. The former group was then compared with submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Dovepress Transient global amnesia submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Table 2 Differential diagnosis of TGA: transient anterograde amnesia Condition Risk factors Precipitating factors Duration Associated neuro MRI EEG Recurrence Response to symptoms of attacks anti-epileptics TGA Migraine Yes 4–6 hours No Hippocampal Dwi Normal Low No hyperintensity w/o permanent lesion TeA No No/yes (waking) 60 minutes No/yes (oral automatism, Normal/hippocampal Abnormal (temporal High Yes (often, a few olfactory or gustatory sclerosis or atrophy or frontotemporal minutes) hallucinations) regions) TiA/thrombo-embolic vascular No Minutes to No/yes (any) Dwi with T2-FLAiR Normal Low No permanent permanent or lesion impairment Dissociative amnesia Trauma/abuse Yes, emotional stress variable No Normal Normal varies No Migraine headache Genetic; dietary Yes, fasting, premenstrual, 4–72 hours Auras (visual, sensory, Normal Normal High Yes, especially, emotional stress, sleep motor, or language valproic acid problems abnormalities) up to 30% and topiramate Hypoxic states (such as aortic increased Underlying stress reaction 10–12 hours No Normal Normal None known, No dissection with pure TGA) intrathoracic triggered by the acute although death is pressure pain event not uncommon Hypoxia inducing events vascular No 24 hours Yes Yes/ischemic lesions No Rare No of vertebrobasilar system in hippocampus a b 71 78 79 Notes: valsalva maneuver, emotional stress, immersion in cold or hot water, sexual intercourse, or pain. Anterograde amnesia not associated with dissociative amnesia. Data from Kumral e et al ; April MD et al ; irioka T et al ; 80 108 109 Bonnet P et al ; Ryoo i et al ; Arena Je and Rabinstein AA. Abbreviations: 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. 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Abbreviations: AAm, anterograde amnesia; eeG, electroencephalogram; HSe, herpes simplex encephalitis; Le, limbic encephalitis; LOC, loss of consciousness; PCA, posterior cerebral artery; PTA, posttraumatic amnesia; RAm, retrograde amnesia; TBi, traumatic brain injury. two groups of patients, one with TGA only and the other with arterial insufficiency etiologies have been described in the normal controls. Despite the prevalence of both migraine literature as causes of TGA-like symptoms. For instance, and tension headaches being increased in those patients with cardioembolism and large-artery disease of the vertebrobasi- TGA, there was no evidence of an increased frequency in lar system can lead to hippocampal infarcts. Five variants TGA features in those with migraines. have been described including anterior, posterior, unilateral complete, bilateral, and small circumscribed (punctiform) Hypoxia hippocampal infarcts. Prominent clinical acute anterograde In addition to ischemia in the setting of TIA/CVA, hypoxia- amnesia and retrograde amnesia were present in more than inducing events with vasospastic, vasoconstrictive, or two-thirds of patients. In most of the patients, the lesions submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress <H <H <H <H Dovepress Transient global amnesia involved the anterior and medial aspects of the hippocampus retrograde memory, it is generally episodic, and it is often along the complete length of the head, body, and tail of the accompanied by intense psychological distress. While often hippocampus. Such evidence supports that TGA’s etiology times complicated medical disorders become labeled as may be a compromised vertebrobasilar system leading to the “psychogenic” if the etiology is unknown, there is literature dysfunction of MTL and subsequently memory formation. that supports a psychogenic origin to TGA. Several case reports describe TGA-like symptoms Data gathered from two geriatric studies utilized the 51,71–75 after vascular procedures or intravenous contrast use. Geriatric Depression Scale in patients with TGA, showing Contrast media are sterile iodine-containing solutions used that 40% of TGA patients had depressive symptoms. in diagnostic imaging procedures. Older agents generally fall A more detailed study investigated phobic personality traits into the class of ionic monomers, which have a high osmo- of 51 TGA patients and established that 82% had pathological lality and a high chemotoxicity. Nonionic agents have been avoidance behaviors. developed to overcome the adverse events associated with TGA patients have a high prevalence of comorbid 5,85 older contrast media. While there have been cases describ- emotional distress and anxious personality traits. About ing nonionic angiographic contrast medium neurotoxicity, one-third of TGA episodes occur after physical or psycho- the risk of neurotoxicity remains higher in the ionic class of logical stress, which suggest disruption of memory forma- contrast media. Furthermore, it has been suggested that the tion due either to ischemic or stress-induced catecholamine 86,87 risk of neurotoxic effects might be increased by preexisting disruption. Some authors believe that stress-induced cat- abnormalities of the blood–brain barrier and by repeated echolamine release may lead to hypoxia or ischemia, whereas contrast injections. others believe that the neurotransmitters involved may affect 88–93 Other postulated mechanisms by which cerebral angiog- the formation of memory. There is some evidence of an raphy produces TGA symptoms include epilepsy and association between TGA and Takotsubo syndrome. The 73,74 ischemia. latter is characterized by transient, acute left-ventricular Other case reports support an arterial insufficiency etiol - myocardial dysfunction mimicking myocardial infarction ogy, describing TGA symptomatology secondary to vascular that also occurs after physical or psychological stress. 76–80 disease processes. Intriguingly, aortic dissection, a poten- If the clinical picture remains unclear, neuropsychological tially critical break in the lining of the main arterial outflow testing or other neurological tests (electroencephalogram from the heart classically associated with severe chest pain and neurological examination) may be helpful in distin- and frequently a devastating diagnosis, has been reported guishing psychogenic amnestic disturbances from neuro- to present with TGA-like symptoms in nine cases, five of logical amnestic conditions, especially in patients who have whom were without chest pain, although the latter could be secondary gain or overembellish symptoms. attributed to the patients’ altered mental status. Regardless, In summary, to make a diagnosis of TGA, all strict clinical recognition of painless aortic dissection in the differential criteria as shown in Table 1 should be met. The differential of TGA is imperative. While the latter is generally a benign diagnosis includes structural (vascular) disease, epileptic syndrome, the former could result in signic fi ant morbidity or amnesia, delirium, intoxication, and head injury and migraine mortality. Thus, in those patients presenting with TGA-like headaches. When a general physician is presented with a symptoms and accompanying cardiovascular changes such typical case, no additional diagnostic tests, such as MRI and as hypotension and hypertension or asymmetric extremity EEG, are needed. This even holds when such a patient has blood pressures, CT angiography of the abdomen may be vascular risk factors. However, when focal neurological signs warranted. accompany anterograde amnesia, neuroimaging is warranted Finally, others report the development of TGA after use and potentially a neurology consult. If retrograde amnesia is of phosphodiesterase type 5 inhibitor and sexual activity. also affected and emotional distress is present, the clinician However, it is unclear whether the phosphodiesterase inhibi- needs to consider psychogenic amnesia. Alternatively, albeit tor or the sexual activity caused the vasospasm, as both are rare but more ominous, are those cases of “painless” aortic known to involve significant changes in blood flow. dissection, where TGA is the primary symptom as chest pain is lacking. Finally, research findings using DWI–MRI Psychogenic amnesia/dissociative amnesia support the concept of focal ischemia. These focal lesions Psychogenic amnesia, often labeled as dissociative amnesia, have a maximum detectability between 48 and 72 hours after is differentiated from TGA, in which the former affects the start of TGA. Focal lesions have been demonstrated in the submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2017:13 Dovepress Spiegel et al Dovepress CA1 area of the cornu ammonis of the hippocampus (MTL), Treatment mostly unilateral. However, in up to 35% of TGA patients, By definition, TGA is a self-limited condition that resolves no such abnormalities are demonstrable. without intervention; thus, there is no specific treatment indicated. Although the mean time course of an amnestic Beyond 24 hours: outcomes episode in TGA is 4–6 hours, with most resolving by 8 hours, According to the standard accepted criteria, deficits of TGA proposed treatments could depend on uncovering the under- 15 5 resolve within 24 hours. There has been considerable lying etiology. research dedicated to the cognitive profile of TGA patients If the presentation in TGA was secondary to reversible following the resolution of acute-phase symptoms; however, ischemia, as has been suggested by some case reports using results have been mixed. DWI, as well as other reports that noted onset of TGA epi- A 2009 meta-analysis examined data from 25 different sodes after Valsalva-like maneuvers that may temporarily studies and compared 374 TGA subjects to 760 control reduce cerebral blood flow, then optimization of cardiovas - subjects in the following five domains: anterograde episode cular factors similar to treatments implemented for cardiac long-term memory, retrograde episode long-term memory, ischemia, such as antiplatelets, managing blood pressure, and 98–101 short-term memory, semantic memory, and executive func- heart rate, or statin therapy could be beneficial. tion. Beyond the first 24 hours, there was no significant differ - Some studies suggest an epileptic etiology of TGA, as ence between patients and controls in any of the v fi e domains electroencephalogram findings have been suggestive of epi - for the 30-day period following TGA onset. Similarly, a leptic discharges, but other case–control studies have found 102–104 study with a median follow-up period of 1,128 days found no such correlation. Thus, anticonvulsant medications no significant difference in performance between TGA would not be a proposed treatment option based on the patients and controls on tasks of episodic memory, seman- available evidence. tic memory, working memory, executive functions, and Evidence suggesting that TGA is secondary to cortical attention. Alternatively, one study with follow-up periods depression following cortical hyperstimulation does not of 4 months and 1 year found dec fi its in anterograde memory support theoretical treatment options with the exception of in TGA subjects when compared with controls; however, those related to migraine headaches. Triptans have not been only when data from both follow-up periods were pooled studied in TGA. together. Additionally, at the 4-month follow-up visit, higher Ultimately, there are no established, evidence-based scores on anxiety and depression scales correlated with worse treatments for TGA to date, likely due to the short duration performance on tests of retrograde and anterograde memory of symptoms experienced as well as a lack of universally tests, respectively. accepted pathophysiology. Given the cardiovascular hypothesis of TGA and the interest in the field in cardiovascular risk factors of the Conclusion/future directions disease, one study examined the subsequent risk of expe- The yearly incidence of TGA is 3–8 cases per 100,000 people, riencing CVA in patients with a history of TGA vis-a-vis although 6%–10% of patients with TGA will experience a comparing the rate of CVA following TGA to the rate of second or third episode. Thus, while it may be difficult CVA following migraine, seizure, and TIA at time points of to predict an index episode of TGA, it may be possible to 1 and 5 years after the event. The results of this study did not decrease the risk of future episodes. The latter could be support an increased risk of CVA after TGA, with the risk accomplished through clinical trials by addressing differ- of CVA at 1 year being similar to that after migraine (0.54 ent proposed etiologies associated with TGA. For instance, and 0.22%, respectively) and lower than after TIA (4.54%). despite significantly reduced atherosclerotic risk factor The 5-year rates for CVA following TGA, migraine, and TIA profiles in patients with TGA in comparison to those with were 2.44, 0.86, and 12.23%, respectively. TIA, ie, diabetes mellitus and hypertension, can statins, In a 12-year follow-up study, the longest in the literature antihypertensives, and/or hypoglycemics decrease the risk to date, TGA patients were compared with controls on end of arterial ischemia, which has been proposed to explain points of CVA/TIA, seizures, and cognitive impairment (mild TGA? Can prophylactic treatment of migraines with triptans cognitive impairment or dementia). TGA patients were not decrease the risk of TGA, as this is the only identified risk found to be at a higher risk of developing any of the included factor in the development of TGA in those under the age of conditions than the control subjects. 56 years? 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