Case Reports
Emotional Arousal-Induced Transient Global Amnesia A Clue to the Neural Transcription ofEmotion? ARNOLD
E.
MERRIAM, M.D.
BERNARD WYSZYNSKI, M.D. THOMAS BETZLER, M.D.
T
ransient global amnesia (TGA) syndrome consists of an episode of anterograde and retrograde amnesia of acute onset that is temporally self-limited. lasting less than a day. and most often leaves behind no discernible cognitive residua. During the event. the individual typically acts in an anxious and bewildered fashion. repetitively asks orienting questions. the answers to which cannot be retained. and manifests clear consciousness. Despite the syndrome's rather uniform clinical presentation. episodes ofcharacteristic TGA have been documented to result from a multiplicity of etiologies. These include migrainous attacks. transient ischemia due to intrinsic cerebrovascular or thromboembolic disease. and partial seizures. 1-4 In most cases. however. no clear etiology is established. Among the more puzzling aspects of the syndrome is the occurrence of typical episodes in the wake of emotionally intense or stressful events. This phenomenon is far from uncommon. Fisher. in reviewing the specific circumstances surrounding episodes of TGA. discovered that in 26 of 85 cases, the syndrome followed an identifiable physical or emotional stressor. s Ofthese 26 cases. 7 occurred during sexual intercourse, 8 during a painful or invasive medical procedure. 3 during exposure to cold water. and 8 in the midst of a purely emotional stressor. Those examples resulting from emotional trauma are of particular interest to psychiatrists. who are likely to be VOLUME 33· NUMBER I • WINTER 1992
referred such cases for evaluation due to the dual circumstances of an emotionally stressful life event and the anxious bewildered behavior typically displayed during the TGA episode. Clinicians unfamiliar with the syndrome may be liable to misdiagnose the disorder as psychogenic amnesia. Neurobiologically. the disorder is of interest because it may serve as a means to better understand the connections between traumatic life events and alterations of brain function. We have previously called attention to this disorder and have hypothesized that emotional arousal-induced TGA may result from a disturbance in the brain's intrinsic benzodiazepine ligand system. 6 This system was proposed as an etiologic candidate for the emotional arousal-related variety ofTGA on the basis of both its likely role in emotional stress-related events and on the well-known ability of benzodiazepine compounds to evoke transient amnestic episodes. We report here an additional example of emotional
Received August 6. 1990: revised October 24. 1990: accepted November 5. 1990. From the Division of Neuropsychiatry. Depanment of Psychiatry and the Depanment of Neurology. Alben Einstein College of MedicineIMontefiore Medical Center. Bronx. NY. Address reprint requests to Dr. Merriam. Depanment of Psychiatry. Room 1020. Bronx Municipal Hospital Center. Pelham Parkway and Eastchester Road. Bronx. NY 10461. Copyright © 1992 The Academy of Psychosomatic Medicine.
109
Case Reports
arousal-induced TGA. highlighting the diagnostic difficulties such cases pose for clinicians.
Case Report A 59-year-old woman was noted by co-workers to be behaving in an unusual fashion upon arriving to work one morning. This well-organized and competent assistant director of a large institutional food service suffered from stable hypertension that was treated with verapamil. but had no history of other medical. neurological. or psychiatric disorder or treatment. The major stresses in her life had been the deaths of her husband and her mother. which had elicited nonpathological grief reactions. On the day of her presentation she had arrived at the workplace in a bewildered and distressed state. She was unable to keep track of conversation from one minute to the next. was disoriented as to the date and the day of week, and anxiously asked orienting questions regarding the date and day, how she had gotten to work that morning, and what was happening in her workplace. She was unable to retain the answers to these questions, and therefore asked them of her colleagues again and again. She had no recollection of most events of the preceding 24 hours. For example, she did not remember her substantial preparations the previous day for the annual employee Christmas party. She did not remember having taken the bus to work that morning. although she subsequently discovered a transfer slip indicating that she had indeed taken her customary bus. She was brought for medical evaluation and when cognitively tested several hours into the episode was noted to have an impaired short-term memory. being able to recall only one of three items after 5 minutes, with no improvement after being given the opportunity to pick the remaining two items from a list. The presence of an approximately 24hour retrograde amnesia was confirmed. Her attention, measured by a digit span of seven numbers forward. was intact, as was her ability to calculate, to copy complex constructional diagrams. to name objects. to comprehend. speak. repeat. read, and write. Examination of the cranial nerves, reflexes. and motor. sensory. and cerebellar systems was normal. Medical staff initially considered that the patient had suffered an acute psychicgenic disorder. and she was therefore referred for psychiatric evaluation. The patient was found to be a well-dressed and groomed individual who was alert and well-related. 110
but perplexed and very upset; she repetitively asked the same questions in an attempt to orient herself. She was disoriented to time and was unable to retain any information provided to her for more than 30 seconds or so. Her mood was anxious but appropriate to thought content. There was no formal thought disorder. The patient denied hallucinations of any kind. No delusions could be elicited. No vegetative signs of mood disorder were described.
It was recognized that the patient was suffering from an episode of TGA on the basis of clinical profile. TGA manifests as an anterograde amnesia. with an inability to retain new information for more than a minute or so and a temporally graded retrograde amnesia extending back prior to onset for hours up to years but with preservation of still earlier memories and preservation of personal memories related to one's identity. The amnesia of the patient under discussion spontaneously remitted. as is the rule in TGA. in less than a day. The duration of the episode after her appearance at work was between 3 and 4 hours. Because the episode' s time of onset cannot be reliably determined. the total duration can only be said to have been between 3 and 18 hours. Later that day. after the episode' s resolution. the patient was able to spontaneously recall five of five learned phrases and had returned to her usual self behaviorally. The patient denied having recently ingested any medication other than her usual doses of verapamil. There was no evidence gleaned from a subsequent inspection of her home to suggest that she had taken either a benzodiazepine compound or an over-the-counter hypnotic. the ingestion of which she might have been unable to recall because of the amnestic episode. There was no previous history of somatization or hysterical reactions. An EEG performed within a day of the event showed somewhat excessive fast activity but no focal or epileptiform features. A follow-up EEG 1 week later was unchanged. Both computed tomography and magnetic resonance imaging scans of her head were normal. The emotional context in which this event occurred was remarkable for its intensity and stressfulness for the patient. Several months previously she had requested her supervisor to allow PSYCHOSOMATICS
Case Reports
her to take annual leave to join relatives in another state for Christmas. This holiday was especially important to her because it would be her first family gathering since her mother had died earlier in the year. Her supervisor denied the request, creating a situation in which the patient would be alone and in mourning during a holiday that was for her an important and traditional family event. The patient struggled with feelings of emotional distress and a sense of longing to return to her home of origin for Christmas. Her distress became progressively acute as the holiday approached. On the evening prior to her amnestic episode she received a Christmas card from her son pleading with her to join the family for the holiday. She felt she had been placed in an unbearable situation. This quiet, well-mannered, and restrained individual had characteristically dealt with interpersonal conflict through rationalization or denial rather than confrontation. Although she subsequently acknowledged feeling quite resentful toward her superior, she had no conscious awareness of anger at the time. She had never expressed hostility toward a superior at work, and was considered a reliable and compliant employee. Discussion
The patient's transient disorder of anterograde and retrograde memory in clear consciousness is a classic example ofTGA. This diagnosis is liable to be missed by the clinician unfamiliar with the disorder, since it depends largely on syndrome recognition rather than on laboratory testing or characteristic findings on the aspects of the noncognitive neurological examination. Because the amnesia ofTGA is typically associated with anxiety and bewildered, repetitive requests for orienting information, there is a well-recognized propensity for the disorder to be misdiagnosed as psychogenic amnesia. This is particularly the case in those instances, such as the one presented here, in which the episode appears to be triggered by an emotionally stressful event. Psychogenic amnesia, in contrast to TGA, particularly affects personal memories, such as knowledge of one's VOLUME 33· NUMBER I' WINTER 1992
name, family, occupation, address, and personal history. This finding is never seen in neurologically authentic amnestic syndromes except in the context of severe dementia. In the midst of the episode, patients with TGA are typically bewildered, anxious, and frightened, as they repetitively ask the same orienting questions again and again. Psychogenic amnesia patients, in contrast, are characteristically more accepting of their plight. Other potentially helpful characteristics in distinguishing the two disorders include the presence in some TGA patients of cerebrovascular risk factors, migraine, or epilepsy, and a generally older age of onset, although the most important distinctions are the clinical features of the amnesia. It is commonly accepted that events that seem to occur in the purely psychological sphere are in fact processed via neural mechanisms and are influenced by and exert an influence on other brain activities, blurring the traditional distinction between functional and organic behavioral disorders. This point is well demonstrated by cases such as the one presented here, in which an emotional stimulus provokes a disorder phenomenologically identical to disorders known to be caused by brain insults such as ischemia or epileptic discharges. No differential features exist to distinguish the clinical phenomena of TGA due to emotional or stressful physical precipitants (the disorder has also been reported to be provoked by pain or coldS) from TGA produced by such recognized etiologies as epileptic discharges or ischemia. except in those cases in which the epilepsy or ischemia causes additional neurological dysfunction outside the arena of memory. The etiologies of TGA include cerebrovascular disease, migraine, and epilepsy. all of which have been documented to provoke typical attacks. ' -4 Most work investigating the cause of TGA has centered on the search for an epileptic7- 9 or ischemic 2- 3 etiology. Although individual cases deemed to result from partial seizures have been identified, these are distinctly in the minority, and most examples of TGA appear to occur in individuals without epileptiform EEG activity either during or subsequent to their attacks. 1o III
Case Reports
Similarly. although amnesic attacks resulting from posterior circulation transient ischemic attacks have been documented. and some individuals so affected go on to develop repeated episodes of posterior circulation ischemia. 3 most examples of TGA consist of an isolated attack without evidence of an ischemic etiology. The diagnostic assessment should include a search for a specific inciting factor. including physical or emotional stress. The medical evaluation ofTGA should include a careful neurological examination. looking in particular for posterior circulation ischemic signs. an EEG. and neuroimaging. In many examples those tests are negative and the etiology remains obscure. We suggest. given the peculiar circumstances of its occurrence. that emotionally provoked TGA has an etiology distinct from the etiologies postulated in other forms of the disorder. We have previously suggested that the benzodiazepine system is a candidate for the neurological substrate of this variety of TGA. 6 Although benzodiazepine-induced amnesia in humans spares retrograde memories. 7 it is nevertheless a close mimic of idiopathic TGA by virtue of its dense interference with anterograde episodic memory functions. Numerous case reports of transient amnesia after benzodiazepine ingestion have been documented. The occurrence of a TGA-like episode after ingestion of short-acting benzodiazepine hypnotic compounds for the purpose of sleeping during transcontinental airplane flights has gained attention under the term "traveler's amnesia."I I Volunteers given similar compounds display the same neuropsychological characteristics as do individuals with amnesias such as TGA: short-term episodic memory is impaired while semantic memory is preserved. 12- 14 Specific benzodiazepine receptors linked to GABA A receptors have been shown to exist in the human brain; 15 the entity of benzodiazepine-induced amnesia may be related to the presence in high density of such receptors in the hippocampUS.
16
Although the evidence is not yet conclusive. several groups have succeeded in isolating endogenous benzodiazepine-Iike ligands that bind to these receptors. 15 Whether such purported en112
dogenous ligands. or endozepines. are genuine. and what their precise roles are (if genuine). has yet to be determined. Clearly. if the natural role of the system is related at all to the effects of synthetic benzodiazepines given at pharmacologic doses. the system may. in part. mediate the experience of anxiety. There is evidence that the system is capable of modification as a result of emotionally stressful experiences. In mice. emotional stress has been shown to alter benzodiazepine receptor binding characteristics. 16 Such studies have yet to be carried out in humans. Because of the capacity of exogenously administered benzodiazepines to induce transient amnesia and the possible involvement of the endogenous benzodiazepine system in anxiety. this system serves as common ground between the clinical phenomena of anxiety and amnesia. As such. we suggest it as a substrate of emotion-induced TGA. We proposed in our earlier report6 that intense emotional events may have the capacity in susceptible individuals to perturb the function of the brain's normal benzodiazepine system and thereby induce a transient amnestic syndrome similar to that encountered in individuals who have ingested benzodiazepine compounds. We suggest that the entity of emotional arousal-induced TGA is likely to be a fruitful one for better understanding the transcription of stressful life experience into neural expression. It is possible that emotional arousal can exert a deleterious effect on memory through some other unspecified mechanism. That emotional stressinduced TGA is related to a perturbation in the benzodiazepine system is a preliminary attempt to account for the phenomenon. As the brain mechanisms underlying emotional distress are elucidated. other candidates for the pathophysiology of this disorder are likely to emerge. Examples of other mechanisms that may be implicated in the pathogenesis ofTGA are the alterations in local cerebral metabolism and blood flow identified by PET scans after exposure to anxiogenic stimuli. 17 •18 Only as novel techniques become available to assess the in vivo activity in the benzodiazepine system will verification of the hypothesis put forward here be possible. PSYCHOSOMATICS
Case Reports
References I. Caplan L. Chedru F. Lhennitte F. et al: Transient global amnesia and migraine. Neurology 31:1167-1170.1981 2. Shuttlewonh EC. Wise GR: Transient global amnesia due to arterial embolism. Arch NeuroI29:340-342. 1973 3. Mathew NT, Meyer JS: Pathogenesis and natura! history of transient global amnesia. Stroke 5:303-311. 1974 4. Pritchard PB. Holmstrom VL. Roitzeh JC. et al: Epileptic amnesic attacks: benefit from antiepileptic drugs. Neurology35:1 188-1 189, 1985 5. FisherCM: Transient global amnesia: precipitating activities and other observations. Arch Neurol 39:605--608, 1982 6. Merriam AE: Emotional arousal-induced transient global amnesia: case repon. differentiation from hysterical amnesia. and an etiologic hypothesis. Neuropsychiatry,Neuropsychology, and Behavioral Neurology 1:73-78. 1988 7. Lister RG: The amnestic action of benzodiazepines in man. Neurosci Biobehav Rev 9:87-94. 1985 8. Jaffe R. Bender MB: EEG studies in the syndrome of isolated episodes of confusion with amnesia: "transient global amnesia." J Neurol Neurosurg Psychiatry 29:472474,1966 9. Tharp BR: Transient global amnesia: manifestation of medial temporal epilepsy. Clin Electroencephalogr 10:54-56.1979 10. Rowan AJ, Protass LM: Transient global amnesia: clinical and electroencephalographic finding in ten cases. Neurology 29:869-872. 1979 II. Miller JW. Yanagihara T. Petersen RC. et al: Transient
VOLUME 33 • NUMBER I • WINTER 1992
global amnesia and epilepsy: electroencephalographic distinction. Arch Neurol44:629-{)33, 1987 12. Morris HH. Estes ML: Traveler's amnesia: transient global amnesia secondary to triazolam. JAMA 258:945-946. 1987 13. Wolkowitz OM. Weingartner H, Thompson K. et a1: Diazepam-induced amnesia: a neurophannacological model of an "organic amnestic syndrome." Am J Psychiatry 144:25-29. 1987 14. Clark EO, Glanzer M, Tumdorf H: The pattern of memory loss resulting from intravenously administered diazepam. Arch NeuroI35:296-3oo. 1979 15. Lister RG. File SE: The nature of lorazepam-induced amnesia. Psychopharmacology 83:183-187. 1984 16. Miller LG. Thompson ML. Greenblatt OJ. et a1: Rapid increase in brain benzodiazepine receptor binding following stress in mice. Brain Res 414:395-400.1987 17. Stephenson FA: Benzodiazepines in the brain. Trends NeurosciI0:185-186,1987 18. Young WS, Kuhar MJ: Autoradiographic localization of benzodiazepine receptors in the brains of humans and animals. Nature 280:393-395, 1979 19. Zohar J.lnselTR, Bennan KF.et al: Anxiety and cerebral blood flow during behavioral challenge. Arch Gen Psychiatry 46:505-510, 1989 20. Reiman EM. Raichle ME, Robins E, et al: Neuroanatomical correlates of a lactate-induced anxiety attack. Arch Gen Psychiatry 46:493-500, 1989
113
Emotional Arousal-Induced Transient Global Amnesia A Clue to the Neural Transcription ofEmotion? ARNOLD
E.
MERRIAM, M.D.
BERNARD WYSZYNSKI, M.D. THOMAS BETZLER, M.D.
T
ransient global amnesia (TGA) syndrome consists of an episode of anterograde and retrograde amnesia of acute onset that is temporally self-limited. lasting less than a day. and most often leaves behind no discernible cognitive residua. During the event. the individual typically acts in an anxious and bewildered fashion. repetitively asks orienting questions. the answers to which cannot be retained. and manifests clear consciousness. Despite the syndrome's rather uniform clinical presentation. episodes ofcharacteristic TGA have been documented to result from a multiplicity of etiologies. These include migrainous attacks. transient ischemia due to intrinsic cerebrovascular or thromboembolic disease. and partial seizures. 1-4 In most cases. however. no clear etiology is established. Among the more puzzling aspects of the syndrome is the occurrence of typical episodes in the wake of emotionally intense or stressful events. This phenomenon is far from uncommon. Fisher. in reviewing the specific circumstances surrounding episodes of TGA. discovered that in 26 of 85 cases, the syndrome followed an identifiable physical or emotional stressor. s Ofthese 26 cases. 7 occurred during sexual intercourse, 8 during a painful or invasive medical procedure. 3 during exposure to cold water. and 8 in the midst of a purely emotional stressor. Those examples resulting from emotional trauma are of particular interest to psychiatrists. who are likely to be VOLUME 33· NUMBER I • WINTER 1992
referred such cases for evaluation due to the dual circumstances of an emotionally stressful life event and the anxious bewildered behavior typically displayed during the TGA episode. Clinicians unfamiliar with the syndrome may be liable to misdiagnose the disorder as psychogenic amnesia. Neurobiologically. the disorder is of interest because it may serve as a means to better understand the connections between traumatic life events and alterations of brain function. We have previously called attention to this disorder and have hypothesized that emotional arousal-induced TGA may result from a disturbance in the brain's intrinsic benzodiazepine ligand system. 6 This system was proposed as an etiologic candidate for the emotional arousal-related variety ofTGA on the basis of both its likely role in emotional stress-related events and on the well-known ability of benzodiazepine compounds to evoke transient amnestic episodes. We report here an additional example of emotional
Received August 6. 1990: revised October 24. 1990: accepted November 5. 1990. From the Division of Neuropsychiatry. Depanment of Psychiatry and the Depanment of Neurology. Alben Einstein College of MedicineIMontefiore Medical Center. Bronx. NY. Address reprint requests to Dr. Merriam. Depanment of Psychiatry. Room 1020. Bronx Municipal Hospital Center. Pelham Parkway and Eastchester Road. Bronx. NY 10461. Copyright © 1992 The Academy of Psychosomatic Medicine.
109
Case Reports
arousal-induced TGA. highlighting the diagnostic difficulties such cases pose for clinicians.
Case Report A 59-year-old woman was noted by co-workers to be behaving in an unusual fashion upon arriving to work one morning. This well-organized and competent assistant director of a large institutional food service suffered from stable hypertension that was treated with verapamil. but had no history of other medical. neurological. or psychiatric disorder or treatment. The major stresses in her life had been the deaths of her husband and her mother. which had elicited nonpathological grief reactions. On the day of her presentation she had arrived at the workplace in a bewildered and distressed state. She was unable to keep track of conversation from one minute to the next. was disoriented as to the date and the day of week, and anxiously asked orienting questions regarding the date and day, how she had gotten to work that morning, and what was happening in her workplace. She was unable to retain the answers to these questions, and therefore asked them of her colleagues again and again. She had no recollection of most events of the preceding 24 hours. For example, she did not remember her substantial preparations the previous day for the annual employee Christmas party. She did not remember having taken the bus to work that morning. although she subsequently discovered a transfer slip indicating that she had indeed taken her customary bus. She was brought for medical evaluation and when cognitively tested several hours into the episode was noted to have an impaired short-term memory. being able to recall only one of three items after 5 minutes, with no improvement after being given the opportunity to pick the remaining two items from a list. The presence of an approximately 24hour retrograde amnesia was confirmed. Her attention, measured by a digit span of seven numbers forward. was intact, as was her ability to calculate, to copy complex constructional diagrams. to name objects. to comprehend. speak. repeat. read, and write. Examination of the cranial nerves, reflexes. and motor. sensory. and cerebellar systems was normal. Medical staff initially considered that the patient had suffered an acute psychicgenic disorder. and she was therefore referred for psychiatric evaluation. The patient was found to be a well-dressed and groomed individual who was alert and well-related. 110
but perplexed and very upset; she repetitively asked the same questions in an attempt to orient herself. She was disoriented to time and was unable to retain any information provided to her for more than 30 seconds or so. Her mood was anxious but appropriate to thought content. There was no formal thought disorder. The patient denied hallucinations of any kind. No delusions could be elicited. No vegetative signs of mood disorder were described.
It was recognized that the patient was suffering from an episode of TGA on the basis of clinical profile. TGA manifests as an anterograde amnesia. with an inability to retain new information for more than a minute or so and a temporally graded retrograde amnesia extending back prior to onset for hours up to years but with preservation of still earlier memories and preservation of personal memories related to one's identity. The amnesia of the patient under discussion spontaneously remitted. as is the rule in TGA. in less than a day. The duration of the episode after her appearance at work was between 3 and 4 hours. Because the episode' s time of onset cannot be reliably determined. the total duration can only be said to have been between 3 and 18 hours. Later that day. after the episode' s resolution. the patient was able to spontaneously recall five of five learned phrases and had returned to her usual self behaviorally. The patient denied having recently ingested any medication other than her usual doses of verapamil. There was no evidence gleaned from a subsequent inspection of her home to suggest that she had taken either a benzodiazepine compound or an over-the-counter hypnotic. the ingestion of which she might have been unable to recall because of the amnestic episode. There was no previous history of somatization or hysterical reactions. An EEG performed within a day of the event showed somewhat excessive fast activity but no focal or epileptiform features. A follow-up EEG 1 week later was unchanged. Both computed tomography and magnetic resonance imaging scans of her head were normal. The emotional context in which this event occurred was remarkable for its intensity and stressfulness for the patient. Several months previously she had requested her supervisor to allow PSYCHOSOMATICS
Case Reports
her to take annual leave to join relatives in another state for Christmas. This holiday was especially important to her because it would be her first family gathering since her mother had died earlier in the year. Her supervisor denied the request, creating a situation in which the patient would be alone and in mourning during a holiday that was for her an important and traditional family event. The patient struggled with feelings of emotional distress and a sense of longing to return to her home of origin for Christmas. Her distress became progressively acute as the holiday approached. On the evening prior to her amnestic episode she received a Christmas card from her son pleading with her to join the family for the holiday. She felt she had been placed in an unbearable situation. This quiet, well-mannered, and restrained individual had characteristically dealt with interpersonal conflict through rationalization or denial rather than confrontation. Although she subsequently acknowledged feeling quite resentful toward her superior, she had no conscious awareness of anger at the time. She had never expressed hostility toward a superior at work, and was considered a reliable and compliant employee. Discussion
The patient's transient disorder of anterograde and retrograde memory in clear consciousness is a classic example ofTGA. This diagnosis is liable to be missed by the clinician unfamiliar with the disorder, since it depends largely on syndrome recognition rather than on laboratory testing or characteristic findings on the aspects of the noncognitive neurological examination. Because the amnesia ofTGA is typically associated with anxiety and bewildered, repetitive requests for orienting information, there is a well-recognized propensity for the disorder to be misdiagnosed as psychogenic amnesia. This is particularly the case in those instances, such as the one presented here, in which the episode appears to be triggered by an emotionally stressful event. Psychogenic amnesia, in contrast to TGA, particularly affects personal memories, such as knowledge of one's VOLUME 33· NUMBER I' WINTER 1992
name, family, occupation, address, and personal history. This finding is never seen in neurologically authentic amnestic syndromes except in the context of severe dementia. In the midst of the episode, patients with TGA are typically bewildered, anxious, and frightened, as they repetitively ask the same orienting questions again and again. Psychogenic amnesia patients, in contrast, are characteristically more accepting of their plight. Other potentially helpful characteristics in distinguishing the two disorders include the presence in some TGA patients of cerebrovascular risk factors, migraine, or epilepsy, and a generally older age of onset, although the most important distinctions are the clinical features of the amnesia. It is commonly accepted that events that seem to occur in the purely psychological sphere are in fact processed via neural mechanisms and are influenced by and exert an influence on other brain activities, blurring the traditional distinction between functional and organic behavioral disorders. This point is well demonstrated by cases such as the one presented here, in which an emotional stimulus provokes a disorder phenomenologically identical to disorders known to be caused by brain insults such as ischemia or epileptic discharges. No differential features exist to distinguish the clinical phenomena of TGA due to emotional or stressful physical precipitants (the disorder has also been reported to be provoked by pain or coldS) from TGA produced by such recognized etiologies as epileptic discharges or ischemia. except in those cases in which the epilepsy or ischemia causes additional neurological dysfunction outside the arena of memory. The etiologies of TGA include cerebrovascular disease, migraine, and epilepsy. all of which have been documented to provoke typical attacks. ' -4 Most work investigating the cause of TGA has centered on the search for an epileptic7- 9 or ischemic 2- 3 etiology. Although individual cases deemed to result from partial seizures have been identified, these are distinctly in the minority, and most examples of TGA appear to occur in individuals without epileptiform EEG activity either during or subsequent to their attacks. 1o III
Case Reports
Similarly. although amnesic attacks resulting from posterior circulation transient ischemic attacks have been documented. and some individuals so affected go on to develop repeated episodes of posterior circulation ischemia. 3 most examples of TGA consist of an isolated attack without evidence of an ischemic etiology. The diagnostic assessment should include a search for a specific inciting factor. including physical or emotional stress. The medical evaluation ofTGA should include a careful neurological examination. looking in particular for posterior circulation ischemic signs. an EEG. and neuroimaging. In many examples those tests are negative and the etiology remains obscure. We suggest. given the peculiar circumstances of its occurrence. that emotionally provoked TGA has an etiology distinct from the etiologies postulated in other forms of the disorder. We have previously suggested that the benzodiazepine system is a candidate for the neurological substrate of this variety of TGA. 6 Although benzodiazepine-induced amnesia in humans spares retrograde memories. 7 it is nevertheless a close mimic of idiopathic TGA by virtue of its dense interference with anterograde episodic memory functions. Numerous case reports of transient amnesia after benzodiazepine ingestion have been documented. The occurrence of a TGA-like episode after ingestion of short-acting benzodiazepine hypnotic compounds for the purpose of sleeping during transcontinental airplane flights has gained attention under the term "traveler's amnesia."I I Volunteers given similar compounds display the same neuropsychological characteristics as do individuals with amnesias such as TGA: short-term episodic memory is impaired while semantic memory is preserved. 12- 14 Specific benzodiazepine receptors linked to GABA A receptors have been shown to exist in the human brain; 15 the entity of benzodiazepine-induced amnesia may be related to the presence in high density of such receptors in the hippocampUS.
16
Although the evidence is not yet conclusive. several groups have succeeded in isolating endogenous benzodiazepine-Iike ligands that bind to these receptors. 15 Whether such purported en112
dogenous ligands. or endozepines. are genuine. and what their precise roles are (if genuine). has yet to be determined. Clearly. if the natural role of the system is related at all to the effects of synthetic benzodiazepines given at pharmacologic doses. the system may. in part. mediate the experience of anxiety. There is evidence that the system is capable of modification as a result of emotionally stressful experiences. In mice. emotional stress has been shown to alter benzodiazepine receptor binding characteristics. 16 Such studies have yet to be carried out in humans. Because of the capacity of exogenously administered benzodiazepines to induce transient amnesia and the possible involvement of the endogenous benzodiazepine system in anxiety. this system serves as common ground between the clinical phenomena of anxiety and amnesia. As such. we suggest it as a substrate of emotion-induced TGA. We proposed in our earlier report6 that intense emotional events may have the capacity in susceptible individuals to perturb the function of the brain's normal benzodiazepine system and thereby induce a transient amnestic syndrome similar to that encountered in individuals who have ingested benzodiazepine compounds. We suggest that the entity of emotional arousal-induced TGA is likely to be a fruitful one for better understanding the transcription of stressful life experience into neural expression. It is possible that emotional arousal can exert a deleterious effect on memory through some other unspecified mechanism. That emotional stressinduced TGA is related to a perturbation in the benzodiazepine system is a preliminary attempt to account for the phenomenon. As the brain mechanisms underlying emotional distress are elucidated. other candidates for the pathophysiology of this disorder are likely to emerge. Examples of other mechanisms that may be implicated in the pathogenesis ofTGA are the alterations in local cerebral metabolism and blood flow identified by PET scans after exposure to anxiogenic stimuli. 17 •18 Only as novel techniques become available to assess the in vivo activity in the benzodiazepine system will verification of the hypothesis put forward here be possible. PSYCHOSOMATICS
Case Reports
References I. Caplan L. Chedru F. Lhennitte F. et al: Transient global amnesia and migraine. Neurology 31:1167-1170.1981 2. Shuttlewonh EC. Wise GR: Transient global amnesia due to arterial embolism. Arch NeuroI29:340-342. 1973 3. Mathew NT, Meyer JS: Pathogenesis and natura! history of transient global amnesia. Stroke 5:303-311. 1974 4. Pritchard PB. Holmstrom VL. Roitzeh JC. et al: Epileptic amnesic attacks: benefit from antiepileptic drugs. Neurology35:1 188-1 189, 1985 5. FisherCM: Transient global amnesia: precipitating activities and other observations. Arch Neurol 39:605--608, 1982 6. Merriam AE: Emotional arousal-induced transient global amnesia: case repon. differentiation from hysterical amnesia. and an etiologic hypothesis. Neuropsychiatry,Neuropsychology, and Behavioral Neurology 1:73-78. 1988 7. Lister RG: The amnestic action of benzodiazepines in man. Neurosci Biobehav Rev 9:87-94. 1985 8. Jaffe R. Bender MB: EEG studies in the syndrome of isolated episodes of confusion with amnesia: "transient global amnesia." J Neurol Neurosurg Psychiatry 29:472474,1966 9. Tharp BR: Transient global amnesia: manifestation of medial temporal epilepsy. Clin Electroencephalogr 10:54-56.1979 10. Rowan AJ, Protass LM: Transient global amnesia: clinical and electroencephalographic finding in ten cases. Neurology 29:869-872. 1979 II. Miller JW. Yanagihara T. Petersen RC. et al: Transient
VOLUME 33 • NUMBER I • WINTER 1992
global amnesia and epilepsy: electroencephalographic distinction. Arch Neurol44:629-{)33, 1987 12. Morris HH. Estes ML: Traveler's amnesia: transient global amnesia secondary to triazolam. JAMA 258:945-946. 1987 13. Wolkowitz OM. Weingartner H, Thompson K. et a1: Diazepam-induced amnesia: a neurophannacological model of an "organic amnestic syndrome." Am J Psychiatry 144:25-29. 1987 14. Clark EO, Glanzer M, Tumdorf H: The pattern of memory loss resulting from intravenously administered diazepam. Arch NeuroI35:296-3oo. 1979 15. Lister RG. File SE: The nature of lorazepam-induced amnesia. Psychopharmacology 83:183-187. 1984 16. Miller LG. Thompson ML. Greenblatt OJ. et a1: Rapid increase in brain benzodiazepine receptor binding following stress in mice. Brain Res 414:395-400.1987 17. Stephenson FA: Benzodiazepines in the brain. Trends NeurosciI0:185-186,1987 18. Young WS, Kuhar MJ: Autoradiographic localization of benzodiazepine receptors in the brains of humans and animals. Nature 280:393-395, 1979 19. Zohar J.lnselTR, Bennan KF.et al: Anxiety and cerebral blood flow during behavioral challenge. Arch Gen Psychiatry 46:505-510, 1989 20. Reiman EM. Raichle ME, Robins E, et al: Neuroanatomical correlates of a lactate-induced anxiety attack. Arch Gen Psychiatry 46:493-500, 1989
113
