“Syndrome of isolated episode of confusion” with amnesia was described by Morris Bender in 1956 and Fisher and Adams gave the condition the name that stuck, Transient global amnesia (TGA), in their article in 1958.

This is an article by Britt Talley Daniel MD, member of the American Academy of Neurology, the American Headache Society, migraine textbook author, and blogger.

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TGA is commonly found with migraine and migraine's spreading wave of depolarization sweeping across the hippocampus may be the cause of the syndrome. I wrote a textbook on TGA and to do that I reviewed the 2 existing textbooks on TGA, the last of which was published in 1991 plus 554 articles from the rich troth of medical literature. I review the early history of amnesia and early articles in the psychiatric literature leading up to Bender's seminal article in 1955. I divided the subject into clinical, EEG, CAT scan, SPECT, PET, sonogram and MRI papers and then discussed the literature on associated medical conditions, review articles, and aetiology, ending with a chapter on clinical work up and treatment. In total the book is 306 pages and 10 chapters.

This book is an extensive review of the subject with 554 bibliography references and 45 digital images written especially for the clinical behavioral neurologist, psychiatrist, or psychologist. It is the first modern review of the subject in 21 years and it discusses the exciting DWI/MRI findings which have set the neurology world on fire.

No recent article or text has reviewed transient global amnesia in such detail as this book. This same painstaking and elaborate literature review style is evidenced throughout the book, placing into one compendium a body of data and references on TGA not available anywhere else.

The MRI scan introducing this article shows one of the mysterious dots in the hippocampus at the end or the arrow that occurs a day or 2 after an attack of TGA that then disappears later.
To really get into this article the reader needs a good update on what Migraine with Aura is first. Read my article on Migraine with Aura on my website, doctormigraine.com. Click here to read.

The medical literature on Migraine and Transient Global Amnesia shows a positive relationship in certain cases.  Transient global amnesia (TGA) is one of the most mysterious clinical conditions in Neurology.

Occurring usually only once in middle to late age, the affected person is suddenly robbed of memory, for the past, the present, and briefly, the future. Repetitive questioning without learning the answers supplied marks the typical case and frightened family members and significant others labor to bring the patient into hospital for scanning and medical evaluation.

Although the cut off time for duration is 24 hours, most cases clear in 4-6 hours, with no memory of what happened during the elapsed time. 

This next segment is from my Textbook on Transient Global Amnesia.

Cases of Migraine and Amnesia

The next series of articles are not cases of transient global amnesia but cases which detail the early literature regarding migraine and amnesia.

Liveing,  neurology’s supreme cataloger and savant regarding all things to do with migraine wrote in 1873:

“We have next to consider the disturbance of the higher cerebral faculties which sometimes attends the megrim paroxysm; this may be regarded for the most part as either intellectual or emotional.  The former is represented in some instances by loss or impairment of memory, and in others by confused, incoherent, or tumultuous ideation, very rarely by hallucination; the later by general depression, or vague subjective feelings of anxiety and dread.…

At this period (i.e., following the affections of sight and touch) her intellect becomes confused, and her memory at the same time, for about half an hour, so much impaired that she cannot even remember the name of any medicine she has just taken…

… as the visual phenomenon passed off his memory usually fail so much that for a time he was mentally incapacitated, and whatever he read or did during that period left no impression….”

At this point it would be helpful to learn about “Confusional Migraine.” Read about it on my website, doctormigraine.com. Click here to read.

Liveing did not describe the typical benign TGA episode but he wrote an encyclopedic monograph  in which he recorded the mental symptoms that his patients had experienced during attacks. Sixteen out of 67 of Liveing’s patients had confusion, trouble with memory, or a disturbance of consciousness.  Nine of the 67 patients had the onset of migraine before age 20, and the youngest was at age 9.  After Liveing confusion as part of a migraine attack was rare in the neurologic literature.

Flatau  writing in Handbuch Der Neurologie in 1914 on “Die Migrane und ihre Abarten” confronted the problem of migraine and mental symptoms.  Flatau called the problem "Dammerzustande" and proposed that the term migraine equivalent not be used unless:

“The psychosis occurs in a person who also suffers from unquestioned migraine attacks; when the cessation of the hemicrania and the beginning of the psychosis approximately correspond in point of time; and when the form of the psychosis is the form most frequently encountered in migraine, i.e., confusional migraine.”

Moersch  writing in 1924 in the American Journal of Psychiatry on “Psychic manifestations in Migraine” said that “During the clouding of consciousness, amnesia frequently occurs” and reported two patients with amnesia during migraine attacks.  Moersch’s review of the literature included:

Hall in 1840 noted the relationship of sick headaches to psychic disturbances, such as stupor, delirium and unconsciousness.  Liveing,  in his excellent review of the subject in 1873, tabulated 67 cases of migraine; in 21 of these “emotional and intellectual disorder,” such as confusion, impaired memory, depression, ill humor, drowsiness, terror, and so forth, were noted.  Mingazzini  coined the term “dysphrenia hemicrania transitoria” to describe these psychic alterations, and classified them as abortive, transitory, or protracted.  Flatau  considers that migraine psychoses are an entity, and not to be confused with epileptic equivalents.  In his study he found that the confusional states (Dammerzustande) are the most commonly associated mental changes.

One of Moersch’s cases with memory loss follows:

Case 1—A man, aged 42 years, had had periodic sick headaches associated with scotomas, nausea and vomiting, since the age of four.  There was no history of migraine in the family.  In July, 1918, he awakened a friend by talking in a natural voice of happenings of the day before.  He was lying limp in bed and could not be aroused, but had no convulsions.  After about 20 minutes he regained consciousness, was extremely nauseated, and for two or three days had a severe bitemporal headache.  In June, 1920, a similar attack occurred during the day, in which he suddenly, while walking, became confused in mind.  This state lasted for about ten minutes, and was followed by nausea, headache and vomiting for the greater part of the day.  In July, and again in August of the same year, he had spells of a similar character with a sudden lapse of memory, lasting for from 5 to 20 minutes, and followed by nausea, headache, and vomiting.  From that time up to the present, he has had several attacks in which he has even fallen, but has never had convulsions.  The attacks are always followed by nausea and headache, and usually by vomiting.  The general and neurologic examinations were negative.

Moersch commented:

When one realizes the vagaries of migraine, there seems every reason to believe that these interparoxysmal mental changes are an index of the innate constitutional make-up.  It is possible that many of the peculiarities which are ascribed to certain persons, such as occasional vague visual phenomena, mild recurring headaches and apathy, periodic mental dullness or other periodic mental fluctuations, are larvated forms of migraine.  It is also true that the headache in a migraine attack may be replaced entirely by a visual aura which, in turn, is followed by a psychic disturbance.

Moersch’s cases were not the typical attack described by Bender, however, with anxiety, retrograde amnesia, and repetitive questioning.

Nielsen  writing in the American Journal of Psychiatry in 1930 on “Migraine Equivalent” commented that “Psychic disturbances entirely replacing the usual symptoms of an attack of migraine have led to a great deal of discussion and some controversy during the last three decades.” In this article Nielsen reported a single case:

The patient is a physician, aged 37, who comes with no complaint except episodes of mental disturbance.  These do not incapacitate him; but he has worried for years about their possible significance, because genius and dementia praecox occur in the family of a paternal half uncle; and he has consequently feared for his own mental state.  Aside from the above facts he knows of no nervous or mental disturbances or of migraine in the family.

The attacks of mental disturbance may be described as follows:  He feels a mild emotional depression come on.  Things in general seem serious.  Then a feeling of strangeness supervenes and this is followed by a peculiar confusion.  During this he is perfectly oriented yet cannot give an orderly account of anything.  He is in possession of a multitude of facts concerning medicine and his environment, but there are large defects in his memory and hence organization of his knowledge is lacking.  Actually the defects are so large that it seems to him as though only small groups of facts make their unbidden appearance in his consciousness.  This isolation of facts and events, he says, is the outstanding difficulty in the episode.  There is no association of any kind between these groups of facts.  Further, he remembers nothing during an attack for more than half a minute.  He says he feels as though he sees events through a long tube or under the high power of a microscope and is unable to establish the relations between the various fields observed.  He can move the tube to another field, but then has no recollection of the one just observed.  This soon leads to confusion.

Practically, this state has the following effect.  He cannot recall events, lodge pass-words, formulas, dates, names, appointments, or promises at will.  They may all come to him but he cannot command them.  It is difficult for him to carry on a conversation because he cannot recall at any moment the last statement.  By the time he receives a reply to a question he does not know what he has asked.  Consequently he cannot deal with people, cannot take a history from a patient, cannot dictate.  He repeats questions and appears to others very absent-minded.  He feels as though he were in unfamiliar surroundings and everything seems unreal.  The unreality is the most distressing, feature of the whole episode, he states.  Fortunately the disturbance lasts only from three to six hours and the episodes appear only about once in every 6 to 12 months.  After the episode he has a perfect recollection of the events and can recall all his confusion and embarrassment.

After studying medicine he became more observant and noticed that a severe nervous or mental strain frequently preceded the attack.  He was questioned for symptoms of migraine but persistently denied any tendency toward migraine until fractional attacks were discussed and fortification spectra were shown to him.  It was then revealed that he suffered from attacks which he had never understood, referable only to the eyes.  These attacks also followed unusual strain but were never associated with the mental symptoms described above.  They began as blind spots with concentric rings running in the upper right quadrants of the fields of vision.  Soon they would spread to become a quadrant amblyopia or a right homonymous hemianopsia.  At times both upper halves of the fields of vision were involved.  He had great difficulty driving a car during an attack and could not read ordinary print because of inability to follow a line.  These disturbances were always sooner or later accompanied by typical fortification spectra.  These attacks were never accompanied by nausea, headache, pain, dizziness, or weakness, but were associated with a very mild confusion.  The invariably lasted only 15 minutes to one hour and were considerably more frequent than the attacks of confusion described in the foregoing. 

Evans  writing in Brain in 1966 on “Transient Loss of Memory, An Organic Mental Syndrome,” stated that:

Sudden loss of memory without gross evidence of clouding of consciousness is often regarded as consciously or unconsciously motivated, but some recent reports have indicated an organic amnesia can occur without associated impairment of consciousness and can be distinguished on clinical grounds from motivated amnesia.

Evans presented 3 patients, 2 of whom gave a history of migraine, and described migraine type symptoms during the attack (teichopsia or one-sided headache) which occurred after a very hot bath.  

Evans stated “The clinical histories of these 3 patients have so much in common that it may be assumed that they are expressions of the same disease process.”  One of his patients was 35 years old which is younger than the 56-80 year old range offered by Fisher and Adams .  Regarding causation he said, “No firm conclusion can be made about the pathological basis of these episodes.  In older patients a transient ischemic episode seems the more likely while in younger patients epilepsy or an equivalent of migrainous hemiplegia are possible causes.”  He treated his patients with reassurance and advice to avoid hot baths.

Get my textbook on Transient Global Amnesia here.

Classic Attacks of Transient Global Amnesia

Most writers credit Morris Bender with the first, modern description of a spontaneous attack of transient global amnesia.  In 1956 Bender   wrote in the Journal of Hillside Hospital his account of a “Syndrome of isolated episode of confusion with amnesia.”  Dr. Bender described twelve patients he had seen for a “single brief period of defective memory and confusion with a complete retrograde amnesia.”  He noted that “This particular syndrome is difficult to classify.  It does not seem to fit into any of the known etiologic categories.”  At the end of the article he stated:

From the foregoing deliberations an anatomic or etiologic classification of the twelve patients with episode of defective memory and subsequent amnesia cannot be made at this time with any degree of certainty.  Of the various possibilities considered a transient circulatory disturbance of the brain would seem to be most acceptable.

Thus, with these words Dr. Bender swept into neurology and into medical awareness this unusual, fascinating, and disturbing clinical syndrome of middle to late age life.  The same year, 1956, as Bender’s original article, Guyotat and Courjon  in France wrote “Les ictus amnesiques” in the Journal de medicine de Lyon and described the same syndrome.  They did not refer to Bender’s paper but described similar clinical events which they attributed to a vascular cause—“une ischemie cerebrale, spasm vasculaire.”  These writers used the same phrase, “les ictus amnesiques,” that Benon had first used in 1909.

Then in 1958 Fisher and Adams  writing in Transactions of the American Neurologic Association gave the syndrome its English name with the title of their article:  “Transient Global Amnesia.”  This is the name that stuck and the extensive literature written since the 1950’s all call the syndrome “Transient Global Amnesia.”  They pointed out that the “clinical manifestations were limited for the most part to a defect of memory, involving the events of the recent past and of the present, but leaving personal identification intact.  Recovery appeared to be complete.”  Fisher and Adams claimed they described a “distinct clinical syndrome which has not been clearly described in the medical literature.”  The attacks came suddenly and without warning or symptoms of seizure or motor or sensory deficit. 

Cases of Transient Global Amnesia and Migraine

Gilbert and Benson  writing in The Journal of Nervous and Mental Disease in 1972 on “Transient Global Amnesia:  Report of Two Cases With Definite Etiologies” described two cases, the first with a typical attack of amnesia with repetitive questioning, right frontal throbbing headache, and remission of symptoms in a few hours.  The patient had a “25-year history of paroxysmal, throbbing hemicranial headache, often proceeded by scintillating scotomata and associated with photophobia.”  He experienced a period of amnesia for a period of several hours the night of admission. 

Heathfield, et al,  writing on “The Syndrome of Transient Global Amnesia” in Brain in 1973 described 31 patients with amnesia from differing etiologies including:  transient global amnesia, epilepsy, migraine, temporal lobe encephalitis, and psychogenic. 

Before the reports by Fisher and Adams sudden attacks of loss of memory were usually regarded as being of hysterical origin, although evidence had accumulated, during many years, that such attacks might occur as manifestations of temporal lobe epilepsy (Jackson, 1888) and also, rarely during episodes of migrainous headache, or as a migrainous equivalent (Moersch, 1924).  In addition, the psychological origin of some attacks of loss of memory, particularly the amnesia which invariably accompanies fugue states, had become well-established (Kennedy and Neville, 1957).

Olivarius and Jensen  writing on “Transient Global Amnesia in Migraine” in Headache in 1979 reported five migraine patients with TGA.  Patient 2 from their series follows:

58-year-old woman without a family history or migraine.  Since the age of 25 she had suffered from attacks of unilateral, shooting headache on either side, and accompanied by nausea, vomiting, photo- and phonophobia.  Previously attacks occurred on weekends, for the past three years every 2 or 3 weeks.  Some years ago she had consumed considerable amounts of ergotamine (Gynergen com.).

14 days before admission she awakened in the morning with headache which had subsided following the administration of one suppository of Gynergen. She has full memory of the following 10 to 12 hours.

Then 15 to 20 minutes following the intake of another suppository, sudden and total amnesia occurred and continued for the following 12 hours.  Her husband found her disoriented, and asking the same questions repeatedly.

She was initially admitted to the local hospital and was found oriented with regard to personal data, but not to time and place.  She had no memory of the events that day.  The following day her behavior was normal.  On admission to our department, neurological examination was normal:  BP: 160/90 mm HG.; fasting plasma glucose, normal; EEG showed left temporal theta with scattered sharp-waves, Brain scan normal.

Caplan, et al,  writing in Neurology in 1981 on “Transient global amnesia and migraine” described 12 patients with TGA and migraine.  Six of the patients had common migraine and six had classical migraine in this article written before the first international classification of headache in 1988 after which common migraine would be called migraine without aura and classical migraine would be called migraine with aura.  Three patients had classical migraine with their TGA and 9 had severe headache with the amnesia.  Caplan, et al, defined TGA as:

“(1) inability to form new memories, (2) repetitive inquiries, (3) retrograde amnesia, initially encompassing a period of days, months, or years before the attack but gradually shrinking after the attack, leaving permanent amnesia only for the events during the attack, and (4) absence of other neurologic symptoms and signs.

This definition eliminated from consideration any patient with permanent retrograde memory loss or stroke or TIA type symptoms.  Caplan, et al, advanced theoretical considerations that supported the possibility that TGA might be a migrainous phenomenon.  These considerations included:

The abrupt onset and transient nature suggest a vascular etiology.  However, patients with documented posterior circulation strokes had no preceding TGA episodes.  Writers who included amnestic deficits with posterior circulation occlusive disease also had other signs and symptoms and the memory deficits were not transient.  Vertebrobasilar occlusive disease is common; if TGA is a manifestation of vertebrobasilar disease, it should occur more frequently.

Migraine is a common vascular disturbance with an unexplained bias for posterior circulation vessels.  Basilar migraine accounts for posterior circulation disease but it is very rare.  The most common symptoms of classic migraine are visual and sensory.

Migrainous vascular disease often causes symptoms rare in occlusive vascular disease.  “Positive” phenomena such as scintillating scotomas, migrating paresthesias, and the gradual spread of symptoms from one sensory modality to another are all commonplace in migraine but are uncommon features of occlusive vascular disease.

Precipitants frequently cited as provoking TGA are also known to bring on migraine in susceptible individuals.  Immersion in cold water, hot showers or baths, and coition may precipitate TGA.  Both TGA and migraine may come after travel and trips.  Angiography can precipitate migraine and no definite embolism was documented in the cited cases.

EEG changes are sometimes mentioned in TGA and are cited as favoring a seizure mechanism.  However, the EEG changes are also quite consistent with migraine.

TGA is basically benign if one includes only typical patients with pure transient amnestic spells unaccompanied by other phenomenon and associated with repetitive queries.  Migraine is also benign in contrast to occlusive posterior circulation disease.”

Caplan, et al, pointed out that vascular spasm can be documented by cardiologists during coronary angiography in some patients with angina pectoris.  Vascular spasm occurs experimentally in the brain by putting blood in the subarachnoid space and occurs clinically after subarachnoid hemorrhage.  Caplan, et al, wondered if there might be “instances of cerebral vascular spasm distinct from that usually labeled as migraine.”  They closed stating "Vascular spasm may explain TGA in some patients not known to have migraine."

In 1982 Fisher  summarized 78 cases, writing in the Archives of Neurology in an article entitled “Transient Global Amnesia Precipitating Activities and Other Observations.” 

Regarding migraine and headache Fisher’s patients noted:

TGA occurred during a severe headache in two patients.  Seven other patients had symptoms as follows:  one recalled having migrainous scintillations earlier on the day of his spell, two complained of suboccipital headaches during their spells, two had had a headache earlier on the day of the spell, one had had a headache on the preceding day, and in one a headache developed after the spell had subsided.

Caplan admitted that TGA “had no definitive confirmatory laboratory investigations and fuzzy boundaries.”  His analysis provided later writers with a firm structure for defining the syndrome.

Olesen and Jorgensen  writing in Acta Neurologica Scandinavica in 1986 on “Leao’s spreading depression in the hippocampus explains transient global amnesia” stated that “TGA is of unknown etiology.”  They acknowledged that the two most favorable etiologic hypotheses have been a TIA in the posterior cerebral artery or epileptic discharge in the hippocampus but they felt that neither of the two proposed mechanisms seemed likely.  TGA is not associated with an increased risk of TIA in the posterior cerebral arteries and epilepsy is “unlikely because the events are not repetitive, never generalized, and because the EEG is usually normal.”

Olesen and Jorgensen noted that spreading depression (SD) could “be elicited mechanically, electrically, chemically, thermally and by sensory stimulation in experimental animals.”  Spreading depression is associated with depolarization of neurons and glial cells, change in electrical chemical gradients, slow potential changes, depression of EEG activity, and increased glucose consumption and cerebral blood flow.  These changes return to normal quickly but occur in a narrow zone of brain tissue which spreads at a rate of 2-4 mm/min.  The EEG recovers within minutes but cerebral blood flow may remain depressed for an hour or longer.

Attacks of migraine are associated with changes of regional cerebral blood flow (rCBF) whereby at the onset of symptoms, rCBF is reduced at the posterior pole of the hemisphere, and the reduction spreads anteriorly at a rate of 2-3 mm/min.  The authors thought that the relationship between SD and migraine was “so striking that SD can be regarded as the most likely explanation of the aura symptoms of classic migraine.”

Olesen and Jorgensen stated that previous authors had noted a relationship between TGA and migraine and they thought that “Theoretically, SD thus seems to be a very likely pathogenetic mechanism of TGA.”  Topical glutamate has been known to cause SD in the cortex and could possibly be liberated in the brain by emotional events.  Jensen and Jorgensen closed with the following statement:

Since the hippocampus plays a central role in human emotions, the following sequence of events could possibly explain TGA:  A highly emotional experience excites the hippocampus.  Neuronal activity liberates glutamate, which triggers a spreading depression, resulting in reversible functional ablation of the hippocampus.

 Spreading depression, Migraine, and TGA

Olesen and Jorgensen  wrote in Acta Neurologica Scandinavia in 1986 on “Leao’s spreading depression in the hippocampus explains transient global amnesia.”  Olesen and Jorgensen stated:

Spreading depression (SD) can be elicited mechanically, electrically, chemically, thermally and by sensory stimulation in experimental animals.  It consists of a depolarization of neurons and glial cells with electrolytes distributing according to electrochemical gradients, slow potential changes, depression of EEG activity and markedly increased glucose consumption and cerebral blood flow.  Most of these changes normalize quickly and therefore take place in a narrow zone which spreads slowly and contiguously at a rate of 2-4mm/min.

Since the hippocampus plays a central role in human emotions, the following sequences of events could possibly explain TGA:  a highly emotional experience excites the hippocampus.  Neuronal activity liberates glutamate, which triggers a spreading depression resulting in reversible functional ablation of the hippocampus.

Bartsch and Deuschl  wrote in 2010 in Lancet Neurology on “Transient global amnesia: functional anatomy and clinical implications.” 

Regarding TGA and migraine-related mechanisms, Bartsch and Deuschl stated:

Pathophysiological mechanisms linking migraine and migraine with aura with TGA have been widely discussed, as several studies have reported a higher incidence of a history of migraine in patients with TGA than in healthy controls.  However, patients rarely had active migraine in the months before TGA or migrainous features during the acute TGA, indicating that an acute TGA is not a reflection of an episode of acute migraine with or without aura.  The occurrence of headaches during the acute TGA episode is not associated with a history of migraine.

A key pathophysiologic mechanism in migraine is cortical spreading depression that mirrors a glutamate-mediated transient neuronal and glial depolarization, which is followed by a long-lasting suppression of neuronal activity.  Cortical spreading depression propagates across the cortex with a speed of 3-5 mm/min and is accompanied by a short-lasting hyperperfusion followed by a hypoperfusion.  Experimental and clinical findings strongly suggest that cortical spreading depression is the neurophysiological correlate of migraine with aura.  This event can also be elicited in the hippocampus, where it propagates across the cortical surface and modulates excitability of CA1 neurons and alters the distribution of excitatory transmitter receptors, including glutamate.  Furthermore, cortical spreading depression is accompanied by a decrease in the apparent diffusion coefficient, indicating decreased cellular diffusion.

Bartsch and Deuschl suggested that the following pathophysiological mechanisms may play a part in hippocampal dysfunction.  Some sort of a trigger—activates cellular correlates which lead to metabolic stress of CA1 neurons--which results in increased glutamate-mediated calcium influx-anaerobic glycolylis (increased lactate)-and decreased cellular diffusion.  These cellular activisms cause structural/MRI changes such as the transient evolution of the diffusion lesion on MRI, reversible T2 prolongation, cytotoxic edema, and a lactate peak as a marker of anaerobic glycolysis (MRS).  After this behavioral/clinical changes would be noted of acute perturbation of CA1 circuits which leads to acute TGA, followed by rapid functional compensation in (4-12 hours) and then final structural and functional restitution.

Bartsch and Deuschl noted that "several pathophysiological mechanisms, such as migraine- related mechanisms, hypoxic-ischemic events, venous flow abnormalities, psychological mechanisms, and epilepsy-related activity have been suggested to be associated with the pathophysiology of TGA.” 

K-H Lin, et al, wrote in Eur J Neurol 2014 May;21(5):718-24 on Migraine is associated with a higher risk of transient global amnesia: a nationwide cohort study.

Abstract

Background and purpose: The association between migraine and transient global amnesia (TGA) is not determined. Only two clinic-based studies showed that TGA patients had a higher frequency of migraine history. Our population-based study aimed to investigate whether migraine patients were associated with a higher risk of developing TGA.

Methods: Patients with migraine aged ≥18 years were identified from the Taiwan National Health Insurance Research Database between 2005 and 2009. Each migraine patient was randomly matched to one subject without migraine or other headache disorders based on age, sex and cardiovascular comorbidities. Patients with antecedent stroke, epilepsy or TGA were excluded. Both cohorts were followed up until the end of 2010. The incidence rates of TGA were compared and risk factors were identified.

Results: A total of 158 301 patients in the migraine cohort and 158 301 patients in the matched control cohort were enrolled. During a mean follow-up of 3.0 years (range 0-6 years), the migraine cohort had a greater risk of developing TGA than the control cohort [7.59 vs. 3.06 per 100 000 person-years, incidence rate ratio (IRR) = 2.48, P = 0.002]. Compared with the matched cohort, only female migraine patients aged 40-60 years showed a significantly higher risk of TGA [IRR = 3.18 (1.31-8.82), P = 0.005]. Of note, the incidence rates did not differ between migraine patients with and without aura.

Conclusions: This population-based study demonstrates that migraine is associated with an increased risk of TGA, particularly in female patients aged 40-60 years.

General Comments on Aetiology of TGA

There is no generally agreed on explanation of the etiology of TGA as of the time of this writing.  There has been a tremendous nosological effort by various writers to restrict the phrase “transient global amnesia” to the benign, “pure” form as laid out by Bender, Fisher, Caplan, Hodges, and Warlow.  The distinction between “pure” TGA and “symptomatic” TGA has been mentioned many times in the articles reviewed in this book.  Does TGA have several mechanisms of pathology, some involving migraine and spreading depression, and others concerning internal venous valve incompetence and venous congestion and hippocampal ischemia?  It is not decided.

We have Caplan  stating “The aetiology of TGA remains obscure,” and his hypothesis that TGA is due to “acute arterial dyscontrol.”  Olesen and Jorgensen  claim that “Leao’s spreading depression” causes TGA.  Melo  stated “migraine is probably a marker in the genesis of TGA,” and Hodges and Warlow  claimed migraine linked with TGA causally, that epilepsy may mimic TGA, and stated that “In the remaining cases the cause remains unknown.”  Lauritzen  discussed his opinion of a link between migraine and spreading depression.  Sakashita, et al,  believe TGA relates to “transient cerebral blood flow reduction.”  Bugarski-Kirola, et al,  related TGA to “atherosclerotic changes of the vascular system” causing ischemia.

Lewis  discussed his hypothesis that TGA results from “transient retrograde venous congestion and venous ischemia to bilateral diencephalic or hippocampal structures.”  Rosler, et al,  stated that “SD may provide a unifying explanation for TGA.”  Santos, et al,  thought TGA followed “a transient ischemic phenomenon triggered (or not) following an attack of migraine.”  Gorji  thought “SD serves as the most likely explanation for TGA.”  Tong and Grossman  discussed the issues but thought TGA to be an “enigmatic process.”  Sedlaczek, et al,  thought that “TGA remains mysterious pathophysiologically,” but found delayed ischemic mechanisms “appealing.”

Solheim and Skeidsvoll  thought that “most cases of TGA may be due to small thrombi in the deep cerebral venous system.”  Alblas, et al,  thought the etiology of TGA “is probably multifactorial, with cerebral venous stasis probably playing an important role.”  Roach  thought that TGA was “a symptom complex rather than a specific disease entity” and didn’t think there was a “single cause.”  He thought “a possible unifying theme is abnormal cerebral vasomotor control.”  Gonzalez and Rivera  thought TGA had “a multifactorial triggering mechanism” and “stems from venous dysfunction.”  Toledo, et al,  thought that “TGA is not related to cerebral arterial ischemia.”  Altamura and Vernieri  thought TGA related to “a high prevalence of IJV incompetence” but “the mystery remains partly unresolved.”

Caplan, in his most recent statement, doubted TGA related causally to “venous phenomenon” and restated his opinion that TGA “is most often caused by arterial vasoconstriction”; and that migraine “is an important cause of transient global amnesia.”  Cejas, et al,  thought their findings “support the hypothesis of venous congestion,” and quibbled with Caplan over vasoconstriction.

End of information from Transient Global Amnesia textbook.

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Continued Reference data

A. Pradalier, G. Lutz MD, D. Vincent MD wrote in Headache 2000:40;324-327 on Transient Global Amnesia, Migraine, Thalamic Infarct, Dihydroergotamine, and Sumatriptan

Abstract

This case report describes an episode of transient global amnesia that occurred during a migraine attack, which had been treated with vasoconstrictors. Magnetic resonance imaging showed a small lesion with an ischemic appearance in the right thalamus.

Transient global amnesia (TGA) is a frequent transient neurological event, with an incidence of 23.5 cases per year per population of 100 000 over the age of 50 years. Its pathophysiology remains unknown, as various hypotheses, including epilepsy and embolic or vasospastic transient ischemic attack (often associated with migraine, in the latter case), have not yet been formally demonstrated by clinical and epidemiological studies. We recently observed an episode of TGA in a patient with migraine, apparently following the injection of vasoconstrictors.

CASE HISTORY

A 54‐year‐old woman had had migraine without aura since the age of 20 years, with a frequency of three to four episodes per month. She had been treated with nasal dihydroergotamine (Diergospray) or sumatriptan, 100‐mg tablets (Imigrane), for several years, with no particular adverse effects.

Starting at about 9 pm on a Friday, the patient had an attack of migraine without aura that was similar to her usual episodes. She took dihydroergotamine that night. As the migraine persisted, she took a second dose of the nasal spray at 4 pm the next day with three or four Propofan (paracetamol, caffeine, dextropropoxyphene) tablets. She went to bed at about 11 pm and woke up at 6 am on Sunday with migraine. At about 6:15 or 6:30 am, the patient, who had a persistent and severe hemicrania, asked her husband to administer a 6‐mg subcutaneous injection of sumatriptan in her thigh. This was the first time she had taken such medication, and her husband administered it without difficulty. Approximately 30 to 45 minutes later, the patient could repeat questions and comments but immediately forgot the answers to questions regarding her children. However, her husband did not report any other abnormality apart from the acute memory disorder. There was no speech disorder or confusion, as the patient clearly recognized her husband and her apartment, nor was there any visual or motor disorder.

Two or 3 hours later, the patient went back to sleep. She woke up on Sunday at 11 am for the arrival of her family doctor who had been called by her husband. At this time, all the symptoms (migraine, TGA) had disappeared without any disability remaining other than partial amnesia regarding this episode. The findings of the neurological examination were normal, as were her blood pressure (130/80 mm Hg) and heart rate.

The patient had no history of neurological or cardiovascular disorders. Clinical examination, with memory testing, laboratory assessment (search for a thrombophilic state, platelets, monoclonal Ig, proteins C or S, factor V Leiden, antithrombin III, antiphospholipid antibodies, etc), cervical and transcranial ultrasound assessments, and transesophageal ultrasonography, performed after the TGA, was normal. Magnetic resonance imaging (MRI) was, unfortunately, only obtained 5 weeks after the episode and consequently gadolinium was not injected. The MRI showed a small ischemic lesion of indeterminate age in the antero‐inferior part of the right thalamus. The same investigations were also negative 12 months later, except for the persistence of the right thalamic lacune.

This patient has not developed any further episodes of TGA or any other disease, over the 2 years since the episode reported here. Migraine still occurs at a frequency of two to three attacks per month. During these attacks, the patient has taken nasal dihydroergotamine or oral sumatriptan (but not together) on five or six occasions with no particular problems.

COMMENTS

Transient global amnesia has been defined by the following criteria:

There must be clear‐cut anterograde amnesia during the attack.

Clouding of consciousness and loss of personal identity must be absent, and the cognitive impairment must be limited to amnesia.

There should be no accompanying focal neurological symptoms or functionally relevant focal signs.

Epileptic seizures must be absent.

Attacks must be resolved within 24 hours.

Patients with recent head injury or known active epilepsy are excluded.

There must be a witness to the attacks.

These criteria rule out other amnestic disorders such as amnestic seizures and amnestic strokes. According to nosology, TGA associated with other neurological deficits is defined as an amnestic stroke. 3

A vascular cause of TGA has been suggested frequently, but this hypothesis remains controversial. Although it is difficult to accept the hypothesis of an embolic cause for this type of neurological event, many authors have suggested the role of vasospasm or, similar to that proposed for migraine, Leão's spreading depression in the physiopathology of TGA, 4 as recently suggested by diffusion‐weighted MRI. With this technique, Strupp et al 5 showed an elevated signal intensity in 7 of 10 patients with pure TGA (unilaterally in the left mesial temporal region for four patients, and in both mesial temporal lobes for the other three). These changes were reversible. In contrast, conventional T1‐ and T2‐weighted images were normal.

Several elements support the hypothesis of a migrainous origin of TGA. A personal and family history of migraine is significantly more frequent in patients with TGA than in individuals without TGA, or in patients with transient ischemic attacks. 6-9 Some cases of TGA occurring during a migraine attack are described in the literature. 10-13 Generally, TGA is associated with migraine with aura; six of seven patients had migraine with aura in the Caplan et al series. 6 In most cases, TGA was preceded by the migrainous attack as in our patient.

Few authors have studied brain computed tomography (CT) scans in patients with TGA. There is rarely evidence of infarction. However, some scans have shown definite lesions: in 3.3 % of patients with TGA in one study 3 and 9.3 % in another. 14 Low resolution may explain why patients with TGA may have normal CT scans, but a circumscribed lesion in the left hippocampus shown on MRI was described by Tanabe et al. 15 Unfortunately, systematic studies of patients experiencing TGA during a migraine attack have not been published.

Transient global amnesia can also occur in a context of cardiovascular disease (atherosclerosis, cardiac arrhythmia, etc), but in this situation it is generally associated with other symptoms (either during the episodes or previously) such as drop attacks, cortical blindness, hemianopia, and cerebellar or vestibular syndromes. More rarely, TGA has been reported immediately after trauma and exceptionally associated with certain tumors or toxins. However, in our experience, these potential causes are not common.

Clinical and biological investigations were unable to explain the thalamic infarct in our patient, therefore, in our opinion, ischemia may have been responsible. Apart from the migraine phenomenon itself, treatment with vasoconstrictors, namely, nasal dihydroergotamine 17 and 9 hours before sumatriptan by injection, followed 45 minutes later by the onset of TGA, suggests a triggering role for one of these drugs or more probably the association of the two vasoconstrictor drugs with the neurological event. Conversely, Bates et al 16 administered subcutaneous sumatriptan during the aura (the phase thought to be related to vasoconstriction and ischemia) and found no change in aura duration or aura symptoms.

Transient global amnesia classically occurs after cerebral or coronary angiography, even when the findings are normal, suggesting a role for vasospasm. Juni et al 17 even visualized spasm of the basilar artery and concomitant onset of TGA during vertebral angiography. In the patient described here, repeat angiography, 3 months later, was normal, and an ischemic lesion in the thalamus was demonstrated on MRI. Investigation of isolated TGA usually does not reveal any abnormality of the cervical vessels, and transcranial ultrasound assessment and CT scan are generally normal. However, as previously noted, infarction has sometimes been demonstrated on CT scans. In other studies, the CT scan was normal, but MRI or single photon emission computed tomography (SPECT) revealed abnormalities. Lin et al 18 observed multiple perfusion defects on SPECT in both occipital lobes, the left temporal lobe, and the left thalamus 6 hours after the onset of TGA. The SPECT was normal 28 days later. These findings, therefore, suggest the existence of ischemia in the territory of the posterior cerebral arteries during TGA. A reduction of thalamic perfusion was also recently reported by Goldenberg et al, 19 again by means of the SPECT technique. These authors observed a marked reduction of the regional blood flow in the left thalamus and a less marked reduction in the right thalamus. Forty days later, the thalamic blood flow on SPECT had returned to normal. In our case, it is, therefore, likely that migraine and vasoconstrictors induced ischemia of this territory, sufficient to be visualized as a persistent defect on MRI.

Finally, this observation suggests care in the use of vasoconstrictors in severe and lasting migraine and the need to respect the recommended delay of 24 hours after the use of ergot derivatives before prescribing sumatriptan.

Anne Donnet writing in Headache in 2015 Jun;55(6):853-9 on Transient Global Amnesia Triggered by Migraine in a French Tertiary-Care Center: An 11-Year Retrospective Analysis.

Abstract

Objective: The etiology of transient global amnesia (TGA) remains unclear, and flow disturbances in the mesial temporal lobes secondary to venous congestion have been proposed as a potential cause. The occurrence of TGA during a migraine attack is a rare condition.

Methods: This 11-year retrospective study in one French center describes patients' characteristics, type of migraine, investigations, treatment with vasoconstrictor during the TGA/migraine attack, and outcome in patients who had TGA during a migraine attack.

Results: Among 8821 new patients, 6 cases of TGA occurring during a migraine attack were identified. For a majority of patients, TGA occurs after the beginning of the attack. TGA always occurs during a severe migraine attack, with vomiting or vomiting efforts. Vomiting or vomiting efforts always precede a TGA episode.

Conclusions: TGA occurring during a migraine attack is rare. Since a Valsalva maneuver, such as forceful vomiting, is frequently described at the origin of the attack, blocking venous return through the superior venous cava may allow brief retrograde transmission of high venous pressure from the arms to the cerebral venous system, resulting in venous ischemia to the diencephalon or mesial temporal lobes and causing TGA.

Minju Yi 1, Ayesha Z Sherzai 1, Chizobam Ani 1, David Shavlik 1, Mark Ghamsary 1, Evelyn Lazar 1, Dean Sherzai wrote in J Neuropsychiatry Clin Neurosci. 2019;31(1):43-48 on Strong Association Between Migraine and Transient Global Amnesia: A National Inpatient Sample Analysis

Abstract

The purpose of this article was to explore sex- and race-specific variables and comorbidities associated with transient global amnesia (TGA) using a nationally representative database. Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.

Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia. The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/Other, compared with Caucasians. TGA was associated with lower hospital charges ($14,242 versus $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] versus 4.72 [SE=0.025]), and routine hospital discharges (91.4% versus 74.5%). Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with TGA. All minority populations showed a lower rate of diagnosis that fell short of statistical significance.

Overview of TGA

Transient global amnesia is a sudden, temporary episode of memory loss that can't be attributed to a more common neurological condition, such as epilepsy or stroke.

During an episode of transient global amnesia, your recall of recent events simply vanishes, so you can't remember where you are or how you got there. In addition, you may not remember anything about what's happening in the here and now. Consequently, you may keep repeating the same questions because you don't remember the answers you've just been given. You may also draw a blank when asked to remember things that happened a day, a month or even a year ago.

The condition most often affects people in middle or older age. With transient global amnesia, you do remember who you are, and you recognize the people you know well. Episodes of transient global amnesia always improve gradually over a few hours. During recovery, you may slowly begin to remember events and circumstances. Transient global amnesia isn't serious, but it can still be frightening.

Book: Mayo Clinic Family Health Book, 5th Edition

Transient global amnesia is identified by its main symptom, which is the inability to form new memories and to recall the recent past. Once that symptom is confirmed, ruling out other possible causes of amnesia is important.

These signs and symptoms must be present to diagnose transient global amnesia:

Sudden onset of memory loss, verified by a witness

Retention of personal identity despite memory loss

Normal cognition, such as the ability to recognize and name familiar objects and follow simple directions

Absence of signs indicating damage to a particular area of the brain, such as limb paralysis, involuntary movement or impaired word recognition

Additional symptoms and history that may help diagnose transient global amnesia:

Duration of no more than 24 hours and generally shorter

Gradual return of memory

No recent head injury

No evidence of seizures during the period of amnesia

No history of active epilepsy

Along with these signs and symptoms, a common feature of transient global amnesia includes repetitive questioning, usually of the same question — for example, "What am I doing here?" or "How did we get here?"

When to see a doctor

Seek immediate medical attention for anyone who quickly goes from normal awareness of present reality to confusion about what just happened. If the person experiencing memory loss is too confused to call an ambulance, call one yourself.

Although transient global amnesia isn't harmful, there's no easy way to distinguish the condition from the life-threatening illnesses that can also cause sudden memory loss.

Causes

The underlying cause of transient global amnesia is unknown. There appears to be a link between transient global amnesia and a history of migraines, though the underlying factors that contribute to both conditions aren't fully understood. Another possible cause is the overfilling of veins with blood due to some sort of blockage or other abnormality with the flow of blood (venous congestion).

While the likelihood of transient global amnesia after these events is very low, some commonly reported events that may trigger it include:

Sudden immersion in cold or hot water

Strenuous physical activity

Sexual intercourse

Medical procedures, such as angiography or endoscopy

Mild head trauma

Acute emotional distress, as might be provoked by bad news, conflict or overwork

Risk factors

Interestingly, high blood pressure and high cholesterol — which are closely linked to strokes —are not risk factors for transient global amnesia. This is probably because transient global amnesia doesn't represent blood vessel diseases of aging. Your sex doesn't seem to affect your risk, either.

The clearest risk factors are:

Age. People age 50 and older have a higher risk of transient global amnesia than do younger people.

History of migraines. If you have migraines, your risk of transient global amnesia is significantly higher than that of someone without migraines.

Complications

Transient global amnesia has no direct complications. It's not a risk factor for stroke or epilepsy. It's possible to have a second episode of transient global amnesia, but it's extremely rare to have more than two.

But, even temporary memory loss can cause emotional distress. If you need reassurance, ask you doctor to go over the results of your neurological exam and diagnostic tests with you.

 Prevention

Because the cause of transient global amnesia is unknown and the rate of recurrence is low, there's no real way to prevent the condition.

By Mayo Clinic Staff

Ken A. Morris, MD, PhD1; Alejandro A. Rabinstein, MD1; Nathan P. Young, wrote in JAMA Neurol on Factors Associated With Risk of Recurrent Transient Global Amnesia.

Key Points

Question  Are there physiological, environmental, or other factors that increase risk for recurrence of transient global amnesia?

Findings.  In this cohort study of 1044 patients with transient global amnesia, recurrence was associated with earlier age at the time of the initial episode and higher prevalence of both personal and family history of migraine, compared with isolated cases.

Meaning  These findings may help clinicians when counseling patients with transient global amnesia on their risk of recurrent episodes.

Abstract

Importance  Transient global amnesia (TGA) is usually considered a benign event with a low recurrence rate. However, recurrence rates vary considerably among studies and there are no known risk factors for TGA.

Objective.  To examine risk factors for the recurrence of TGA.

Design, Setting, and Participants.  This retrospective cohort study involved medical record review of patients with isolated or recurrent TGA presenting to the Mayo Clinic in Rochester, Minnesota, between August 1, 1992, and February 28, 2018. A total of 1491 cases were reviewed and 1044 met diagnostic inclusion criteria for TGA, with the remainder excluded owing to indeterminate or alternate diagnoses or limited information available in the medical record.

Exposures. Single vs recurrent episodes of TGA.

Main Outcomes and Measures  Demographics, precipitating factors, migraine history, imaging and electrodiagnostic findings, and family history of TGA were collected. The main outcome measure was TGA recurrence.

Results.  Of 1044 included patients, 575 (55.1%) were male, and the mean (SD) age at inclusion was 75.0 (11.5) years. A total of 901 patients (86.3%) had a single episode of TGA and 143 (13.7%) had recurrent episodes of TGA. The 2 groups were similar in age at inclusion, sex, identifiable triggers, and duration of anterograde amnesia. The number of recurrences ranged from 1 to 9, with 137 individuals (95.8%) having 3 or fewer recurrences. The mean (SD) age at first episode of TGA was 65.2 (10.0) years for individuals with a single episode vs 58.8 (10.3) years for those with recurrent episodes (P < .001).

There was a personal history of migraine in 180 individuals (20.0%) with a single episode of TGA and 52 individuals (36.4%) with recurrent episodes of TGA (P < .001), and a family history of migraine in 167 individuals (18.5%) with a single episode of TGA and 44 individuals (30.8%) with recurrent episodes of TGA (P = .001). There were no electroencephalographic findings associated with increased risk of TGA recurrence. Acute and subacute temporal lobe abnormalities on results of magnetic resonance imaging were seen rarely and did not require intervention. A family history of TGA was identified in 12 individuals (1.3%) with a single episode of TGA and 4 individuals (2.8%) with recurrent episodes of TGA.

Conclusions and Relevance  This study suggests that, in this large cohort of patients with TGA, recurrent TGA was associated with earlier age at the time of first TGA episode and higher prevalence of both personal and family history of migraine compared with isolated cases. These results can be used to counsel patients about risks of recurrence and may have implications for the understanding of TGA pathophysiology.

In summary

After years of literature and article development since Bender’s seminal article in 1966 this publication shows that there is a large body of information linking TGA and Migraine.  This review testifies to that fact.

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All the best.

Britt Talley Daniel MD