ISSN 0017-8748 doi: 10.1111/head.12305 Published by Wiley Periodicals, Inc.
Headache © 2014 American Headache Society
Correspondence and Clinical Note Transient Global Amnesia as a Presenting Aura G. Dalla Volta, MD; P. Zavarise, MD; G. Ngonga, MD; C. Agosti, MD; E. Premi, MD; A. Padovani, MD, PhD
Since the large case series of Fisher and Adams,1 the clinical characteristics of transient global amnesia (TGA) have been well described, including an acute amnesic episode with anterograde amnesia and no other cognitive impairment, no disturbances of consciousness, reiteration of questions, and a high rate of trigger factors (ie, pain, medical procedures, emotional stress, sexual activity). Although an exhaustive definition of the etiology and pathophysiology behind the disorder is missing, the transient dysfunction of the bilateral hippocampi (and in particular of CA1 neurons, particular susceptible to metabolic stress) represents the neuroanatomical basis for this clinical picture, and different hypothesis have been postulated on the pathological mechanisms that lead to this clinical symptomatology, like hypoxic–ischemic events, migraine-related mechanisms, venous flow abnormalities, psychological mechanisms, and epilepsy-related activity.2 Such heterogeneity makes the everyday practice very challenging, requiring a careful evaluation of the clinical picture to find out even small elements supporting a specific etiology (ie, presence of repeated episode, vascular risk factors, and slight objective neurological signs). Focusing on
the potential relationship between migraine and TGA, epidemiological data support a higher incidence of migraine in patients with TGA than in healthy controls. Even if the presence of symptoms of migraine during a TGA episode is quite infrequent and not related to a positive past history of migraine,3 this association could be present in a clinically defined subgroup of patients (younger than 60 years).3 Furthermore, no data are available at the moment about the relationship between migraine symptoms and TGA recurrence. From this perspective, we presented a case of a patient with recurrent TGA followed by migraine attacks. A 70-year-old woman was admitted to hospital for evaluation for repeated episodes of memory loss. She was also affected by hypertension, hypercholesterolemia, and mood disorders. Since her 20s, the patient was affected by migraine without aura (about 6 episodes/month with phono- and photophobia, nausea, and vomiting, partially nonsteroidal antiinflammatory drugs responsive). From November 2004 to September 2010, the patient experienced 7 episodes characterized by sudden onset of memory loss with an inability to form new memories, repetitive questioning (anterograde amnesia), and impaired access to memories for past events (retrograde amnesia). The patient reported no stressful activities before (in just 2 cases, she was performing light housework). Furthermore, the patient remained amnesic for the entirety of the event itself. These attacks lasted less than 24 hours (approximately 4 hours). In all cases, the patient reported an intense headache (resembling her usual migraine episodes)
From the UO Neurologia, Istituto Clinico Città di Brescia, Brescia, Italy (G. Dalla Volta, P. Zavarise, and G. Ngonga); Clinica Neurologica, Dipartimento Scienze Cliniche e Sperimentali, Università degli Studi di Brescia, Brescia, Italy (C. Agosti, E. Premi, and A. Padovani). Address all correspondence to G. Dalla Volta, Istituto Clinico “Città di Brescia,” Neurology Unit, Via Bartolomeo Gualla 15, Brescia, Italy. Accepted for publication October 30, 2013.
Conflict of Interest: The authors report no conflicts of interest.
551
552 with the eventual resolution of the amnesic disturbance. After every episode, the patient was admitted to hospital, and in all cases, neurological examination was normal except for the cognitive impairment limited to amnesia. Two magnetic resonance imaging (MRI) scans were performed on the patient (February 2008 and September 2010) with only a small chronic ischemic lesion in the right medial temporal cortex, as confirmed by positron emission tomography (PET) scan with a focal hypometabolism in the corresponding region. Numerous electroencephalogram (EEG) scans were performed over several years, as well as EEG recording after sleep deprivation, all with normal findings. All episodes fulfilled the current diagnostic criteria for TGA, and the more common causes of TGA-like episodes (acute ischemic events, focal seizures) have been ruled out with instrumental exams performed during the admission to hospital. Overall several years, the patient tried different pharmacological agents for migraine prophylaxis (especially Flunarizine) without significant clinical improvement of migraine characteristics. Taking into account the frequency of the migraine episodes (about 6 attacks/month) and the concomitant presence of a mood disorder (anxiety disorder), we started a pharmacological treatment with valproic acid progressively increased until 1000 mg/daily, maintained for 1 year and after that reduced and then stopped. The patients experienced a complete resolution of migraine attacks. Furthermore, no other episodes resembling a TGA attack have since been reported. After 3 years of clinical follow-up from the last episode, the patient is fully asymptomatic. Literature data and our data of up to 200 cases demonstrate that symptoms like headache might be present during a TGA episode.4 Furthermore, in our sample, we found a TGA recurrence of 9% (18 cases on 200 total cases) and 6 of these presented with headache (2 with migraine with aura), confirming previous literature data about this epidemiological association.4 Our patient, however, presented a clinically well-defined migraine attack soon after the conclusion of the amnesic episodes. The clinical course, the
March 2014 frequency of the episodes, the absence of clear electrical abnormalities at EEG recording even after sleep deprivation, make transient epileptic amnesia a less probable diagnosis and allow us to suggest a migraine-related mechanism behind this specific clinical picture in our patient. In this sense, in line with previous studies on a possible cortical spreading depression mechanism during TGA episodes (as potentially supported by the presence of reversible changes at diffusion-weighted MRI), we speculate that, in our patient, the clinical amnestic episode preceding migraine onset could be considered as an atypical prolonged aura. Even without a precise pathophysiological background behind our hypothesis, in our patient, the migraine attacks and the amnestic episodes appeared closely related, along with the complete resolution after a 1-year pharmacological treatment with valproic acid. We are aware that a definitive confirmation of this hypothesis (even only in our patient) is highly improbable, and alternative mechanisms could be hypothesized (like partial seizures or psychological-related events). However, in our opinion, this clinical case highlights the concept that the complex neurofunctional system lying in the hippocampal structures is influenced by the alteration of a variety of mechanisms, despite the clinical presentation may be quite comparable. We suggest that the umbrella term of TGA might encompass different underlying mechanisms, like an atypical presentation of migraine with aura.
REFERENCES 1. Fisher CM, Adams RD. Transient global amnesia. Acta Neurol Scand Suppl. 1964;40:SUPPL-83. 2. Quinette P, Guillery-Girard B, Dayan J, et al. What does transient global amnesia really mean? Review of the literature and thorough study of 142 cases. Brain. 2006;129(Pt 7):1640-1658. 3. Schmidtke K, Ehmsen L. Transient global amnesia and migraine. A case control study. Eur Neurol. 1998;40:9-14. 4. Agosti C, Akkawi NM, Borroni B, Padovani A. Recurrency in transient global amnesia: A retrospective study. Eur J Neurol. 2006;13:986-989.
Headache © 2014 American Headache Society
Correspondence and Clinical Note Transient Global Amnesia as a Presenting Aura G. Dalla Volta, MD; P. Zavarise, MD; G. Ngonga, MD; C. Agosti, MD; E. Premi, MD; A. Padovani, MD, PhD
Since the large case series of Fisher and Adams,1 the clinical characteristics of transient global amnesia (TGA) have been well described, including an acute amnesic episode with anterograde amnesia and no other cognitive impairment, no disturbances of consciousness, reiteration of questions, and a high rate of trigger factors (ie, pain, medical procedures, emotional stress, sexual activity). Although an exhaustive definition of the etiology and pathophysiology behind the disorder is missing, the transient dysfunction of the bilateral hippocampi (and in particular of CA1 neurons, particular susceptible to metabolic stress) represents the neuroanatomical basis for this clinical picture, and different hypothesis have been postulated on the pathological mechanisms that lead to this clinical symptomatology, like hypoxic–ischemic events, migraine-related mechanisms, venous flow abnormalities, psychological mechanisms, and epilepsy-related activity.2 Such heterogeneity makes the everyday practice very challenging, requiring a careful evaluation of the clinical picture to find out even small elements supporting a specific etiology (ie, presence of repeated episode, vascular risk factors, and slight objective neurological signs). Focusing on
the potential relationship between migraine and TGA, epidemiological data support a higher incidence of migraine in patients with TGA than in healthy controls. Even if the presence of symptoms of migraine during a TGA episode is quite infrequent and not related to a positive past history of migraine,3 this association could be present in a clinically defined subgroup of patients (younger than 60 years).3 Furthermore, no data are available at the moment about the relationship between migraine symptoms and TGA recurrence. From this perspective, we presented a case of a patient with recurrent TGA followed by migraine attacks. A 70-year-old woman was admitted to hospital for evaluation for repeated episodes of memory loss. She was also affected by hypertension, hypercholesterolemia, and mood disorders. Since her 20s, the patient was affected by migraine without aura (about 6 episodes/month with phono- and photophobia, nausea, and vomiting, partially nonsteroidal antiinflammatory drugs responsive). From November 2004 to September 2010, the patient experienced 7 episodes characterized by sudden onset of memory loss with an inability to form new memories, repetitive questioning (anterograde amnesia), and impaired access to memories for past events (retrograde amnesia). The patient reported no stressful activities before (in just 2 cases, she was performing light housework). Furthermore, the patient remained amnesic for the entirety of the event itself. These attacks lasted less than 24 hours (approximately 4 hours). In all cases, the patient reported an intense headache (resembling her usual migraine episodes)
From the UO Neurologia, Istituto Clinico Città di Brescia, Brescia, Italy (G. Dalla Volta, P. Zavarise, and G. Ngonga); Clinica Neurologica, Dipartimento Scienze Cliniche e Sperimentali, Università degli Studi di Brescia, Brescia, Italy (C. Agosti, E. Premi, and A. Padovani). Address all correspondence to G. Dalla Volta, Istituto Clinico “Città di Brescia,” Neurology Unit, Via Bartolomeo Gualla 15, Brescia, Italy. Accepted for publication October 30, 2013.
Conflict of Interest: The authors report no conflicts of interest.
551
552 with the eventual resolution of the amnesic disturbance. After every episode, the patient was admitted to hospital, and in all cases, neurological examination was normal except for the cognitive impairment limited to amnesia. Two magnetic resonance imaging (MRI) scans were performed on the patient (February 2008 and September 2010) with only a small chronic ischemic lesion in the right medial temporal cortex, as confirmed by positron emission tomography (PET) scan with a focal hypometabolism in the corresponding region. Numerous electroencephalogram (EEG) scans were performed over several years, as well as EEG recording after sleep deprivation, all with normal findings. All episodes fulfilled the current diagnostic criteria for TGA, and the more common causes of TGA-like episodes (acute ischemic events, focal seizures) have been ruled out with instrumental exams performed during the admission to hospital. Overall several years, the patient tried different pharmacological agents for migraine prophylaxis (especially Flunarizine) without significant clinical improvement of migraine characteristics. Taking into account the frequency of the migraine episodes (about 6 attacks/month) and the concomitant presence of a mood disorder (anxiety disorder), we started a pharmacological treatment with valproic acid progressively increased until 1000 mg/daily, maintained for 1 year and after that reduced and then stopped. The patients experienced a complete resolution of migraine attacks. Furthermore, no other episodes resembling a TGA attack have since been reported. After 3 years of clinical follow-up from the last episode, the patient is fully asymptomatic. Literature data and our data of up to 200 cases demonstrate that symptoms like headache might be present during a TGA episode.4 Furthermore, in our sample, we found a TGA recurrence of 9% (18 cases on 200 total cases) and 6 of these presented with headache (2 with migraine with aura), confirming previous literature data about this epidemiological association.4 Our patient, however, presented a clinically well-defined migraine attack soon after the conclusion of the amnesic episodes. The clinical course, the
March 2014 frequency of the episodes, the absence of clear electrical abnormalities at EEG recording even after sleep deprivation, make transient epileptic amnesia a less probable diagnosis and allow us to suggest a migraine-related mechanism behind this specific clinical picture in our patient. In this sense, in line with previous studies on a possible cortical spreading depression mechanism during TGA episodes (as potentially supported by the presence of reversible changes at diffusion-weighted MRI), we speculate that, in our patient, the clinical amnestic episode preceding migraine onset could be considered as an atypical prolonged aura. Even without a precise pathophysiological background behind our hypothesis, in our patient, the migraine attacks and the amnestic episodes appeared closely related, along with the complete resolution after a 1-year pharmacological treatment with valproic acid. We are aware that a definitive confirmation of this hypothesis (even only in our patient) is highly improbable, and alternative mechanisms could be hypothesized (like partial seizures or psychological-related events). However, in our opinion, this clinical case highlights the concept that the complex neurofunctional system lying in the hippocampal structures is influenced by the alteration of a variety of mechanisms, despite the clinical presentation may be quite comparable. We suggest that the umbrella term of TGA might encompass different underlying mechanisms, like an atypical presentation of migraine with aura.
REFERENCES 1. Fisher CM, Adams RD. Transient global amnesia. Acta Neurol Scand Suppl. 1964;40:SUPPL-83. 2. Quinette P, Guillery-Girard B, Dayan J, et al. What does transient global amnesia really mean? Review of the literature and thorough study of 142 cases. Brain. 2006;129(Pt 7):1640-1658. 3. Schmidtke K, Ehmsen L. Transient global amnesia and migraine. A case control study. Eur Neurol. 1998;40:9-14. 4. Agosti C, Akkawi NM, Borroni B, Padovani A. Recurrency in transient global amnesia: A retrospective study. Eur J Neurol. 2006;13:986-989.
