Shor t communication
Could transient global amnesia be an epileptic
phenomenon?
n
a
b
D. Eschlea, H.-G. Wieser b
RehaClinic Zurzach, Bad Zurzach
Abteilung für Epileptologie und EEG, Neurologische Klinik und Poliklinik, Universitätsspital Zürich
Summary
Table 1
Eschle D, Wieser H-G. Could transient global
amnesia be an epileptic phenomenon? Schweiz
Arch Neurol Psychiatr. 2009;160:73–6.
Definition of transient global amnesia (TGA) according
to www.dgn.org and Hodges and Warlow 1990 [3]. The
distinctions between transient global amnesia and transient
epileptic amnesia – as outlined in the tables – were somewhat blurred in the older literature on amnesic episodes.
This mini-review entertains the concept that transient global amnesia (TGA) could possibly be part
of the spectrum of transient epileptic amnesia
(TEA), which is considered the most important differential diagnosis by many clinicians. To support
this hypothesis we analysed EEG data, where
conventional scalp recording was unrevealing, but
nasopharyngeal electrodes demonstrated epileptic
discharges in the medial temporal lobe, the region
implicated in memory dysfunction during transient
global amnesia.
Keywords: transient global amnesia; transient
epileptic amnesia; EEG
Introduction
From what we know about memory function, transient global amnesia (TGA) is considered a transient disturbance of one or both medial temporal
lobes (MTL), but its aetiology remains controversial. Historical case series and reports of “transient
global amnesia” have often been heterogeneous,
e.g. including amnesia induced by benzodiazepines
[1] or probable stroke (cases with additional focal
signs) [2]. Over time a strict definition was established that identifies a very homogeneous population. The typical patient is aged between 50 and
70 years, and no additional features beyond isolated amnesia resolving within 24 hours are present
[3], see table 1. According to present guidelines no
additional work-up is needed, if the episode in
Correspondence:
Daniel Eschle, MD
Facharzt für Neurologie FMH
RehaClinic Zurzach
Quellenstrasse
CH-5330 Bad Zurzach
e-mail: [email protected]
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transient global amnesia
Attacks have to be witnessed by a reliable obser ver.
Acute anterograde amnesia and a variable amount of retrograde amnesia are the only neuropsychological deficits
during an episode of transient global amnesia; there is
no loss of personal identity, no aphasia, apraxia, clouding
of consciousness and so on.
No focal neurological deficits during the attack.
No epileptic features during the attack.
Attacks last at least one hour and no more than 24 hours.
No recent histor y of head trauma or known epilepsy.
question fulfils the case definition [4]. Nonetheless,
many centres perform various auxiliary examinations to either reassure patients (and maybe themselves) that the condition is benign, or to elucidate
the pathophysiology of transient global amnesia.
This has brought forward a number of hypotheses
and counterarguments on the aetiology of transient global amnesia. This mini-review entertains
the concept that at least some episodes of transient
global amnesia could be part of the spectrum of
transient epileptic amnesia, which is considered
the most important differential diagnosis by most
clinicians.
Some other hypotheses regarding the pathophysiology of transient global amnesia
1) Transient global amnesia is caused by a mechanism akin to migraine, namely cortical spreading
depression [4]. This leaves unexplained, why the
episodes are not associated with further migraine
and/or aura symptoms, and why the population at
risk is older than the average migraine patient.
2) Transient global amnesia is a form of transient ischaemic attack (TIA). MRI studies using
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Table 2
Definition of transient epileptic amnesia (TEA) according to
Zeman, Boniface and Hodges 1998 [10]. Transient epileptic
amnesia is also called EAA (epileptic amnesic attacks)
or PAS (pure amnestic seizures) by some authors.
transient epileptic amnesia
A histor y of recurrent witnessed episodes of transient
amnesia.
Cognitive function was intact except for amnesia.
Evidence of a diagnosis of epilepsy provided by an EEG,
other types of seizures and/or a response to anticonvulsant
therapy.
diffusion-weighted images could not demonstrate
signal abnormalities in the acute phase, but only
after a certain delay; this does not fit the picture
of typical transient ischaemic attacks [5]. However,
the localisation of abnormalities in the medial
temporal lobes is clearly in accordance with our
understanding of memory function. Although the
age group of TGA patients is similar to those at
risk of transient ischaemic attacks, no increased
occurrence of stroke or other vascular events have
been observed in TGA patients during follow-up
[3].
3) Benzodiazepines have an affinity to certain
receptors in the medial temporal lobes (i.e. the
hippocampus), explaining their amnesic properties; the hypnotic effect being mediated by receptors in other brain regions [6]. Therefore, transient
global amnesia could be provoked by endogenous
benzodiazepine-like molecules that have an affinity to GABAA receptors in the hippocampus.
Only one case report deals with this interesting
idea: Danek et al. [7] reasoned that flumazenil, a
benzodiazepine antagonist, should reverse transient global amnesia. They treated one patient with
flumazenil during her transient global amnesia and
believe she recovered more rapidly because of the
drug. However, the details of this case are not very
convincing, and the idea has not been put to the test
again.
4) Imaging studies have shown that a majority
of patients with transient global amnesia tended to
have abnormalities in the cerebral venous system
compared to controls. Cerebral venous congestion
due to retrograde flow during physical exertion
could lead to transient circulatory dysfunction of
the medial temporal lobe in these predisposed
individuals [8]. However, about 26% did not show
such abnormalities. Also, it is unclear, why transient
global amnesia is not more frequent in settings
where venous congestion (as a result of a Valsalva
manoeuvre) is expected: crying children, wheezing
asthmatics, weight lifters, cerebral vein thrombosis
and so on.
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5) Other authors have proposed that “emotional arousal and phobia are involved in transient
global amnesia” [9]. Although the TGA patients
as a group had significantly higher mean scores
on a scale that measured phobic attitudes compared to matched controls (patients with transient
ischaemic attack), the values showed a large standard deviation. So, an individual patient’s score
would not help in clinical decision making.
Further hypotheses regarding the aetiology of
transient global amnesia have been proposed, but
an in-depth discussion would be beyond the scope
of this mini-review; for a quick overview we refer
the reader to www.dgn.org [4].
Are transient global amnesia and transient
epileptic amnesia related?
The current literature stresses that epilepsy should
be suspected if amnesic episodes are very short
(<1 hour) and/or occur very frequently [3]. Typical
transient global amnesia lasts several hours (<24),
and recurrence is rare in the majority of patients.
More importantly, patients with transient epileptic
amnesia (TEA) have a history at one time or
another of some other features of seizures [10, 11],
see table 2. Yet nevertheless, when we encounter
a patient with his or her first episode of amnesia,
we never know, if she or he will not go on to develop
epilepsy eventually, because not all episodes of
transient epileptic amnesia are <1 hour and so may
be indistinguishable from transient global amnesia.
Patients who fulfil the diagnostic criteria for
transient epileptic amnesia do not necessarily have
an abnormal interictal EEG, but this is supposed
to reflect the low sensitivity of a single conventional EEG. To overcome this difficulty, EEG is
often performed after sleep deprivation (which increases the yield during interictal registration) or,
more ideally, during the actual episode of amnesia.
Conventional EEG has been performed during
many episodes of transient global amnesia (as defined by the criteria in table 1), and in a majority
of cases no epileptic activity has been reported to
date [12]. At first glance this would convincingly
exclude transient global amnesia as part of the
transient epileptic amnesia spectrum in most instances. However, regarding transient epileptic
amnesia – and by consequence this could also apply
to transient global amnesia – there is some debate
if it is actually an ictal phenomenon or rather postictal, similar to Todd’s paralysis [13–15].
A particular case report by Lee et al. [16] of a
patient with prolonged transient epileptic amnesia
demonstrates that scalp EEG is not reliable in
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cases of isolated medial temporal lobe (amnestic)
seizures and sheds light on the problem of ictal
versus postictal amnesia. The patient in question –
a 38-year-old woman – demonstrated isolated
amnesia with no other signs or symptoms of epilepsy for a total of 12 days (until she was treated
with antiepileptic drugs). On day 1 her scalp EEG
was normal. On day 4 intermittent interictal and
ictal epileptiform discharges were registered with
nasopharyngeal electrodes, which facilitate recording from the medial temporal lobes; to a lesser extent these potentials were also seen in the scalp
leads. The patient was then taken from hospital by
her relatives, as they could not accept the diagnosis of a seizure disorder with amnesia as its sole
manifestation. Eventually, on her return to hospital, during 4 hours of EEG monitoring with
nasopharyngeal electrodes, 22 episodes of ictal
discharges between 60 and 120 seconds were seen.
Again, the nasopharyngeal electrodes were more
revealing than scalp leads. A further paper also
demonstrates that nasopharyngeal electrodes can
show abnormalities, when scalp EEG is normal
[17]. This is supported by our experience during
long-term invasive and semi-invasive EEG monitoring of MTL seizures with customised electrodes
[18].
The unique case described above [16] demonstrates that scalp EEG is not entirely reliable to
exclude seizure activity in the medial temporal
lobes and weakens arguments that a normal scalp
EEG during transient global amnesia excludes
an epileptic aetiology. Considering the fact that
during her prolonged amnesia seizure activity was
only present part of the time, would suggest that
amnesia in this patient was both ictal and postictal.
Butler et al. [11] demonstrate the possibly postictal
nature of amnesia in a TEA patient with an episode
during EEG: “a brief (<1 minute) burst of left temporal spikes, during which the patient was unresponsive to speech, was followed by normalisation
of the EEG and a 10-minute-period of amnesia
characterised by repetitive questioning about recent events”. In another case, an EEG with sphenoidal electrodes during transient global amnesia
was reported as normal [19], leaving the question
unanswered if the recording excludes an epileptic
mechanism or was performed in the postictal state.
Thus, the current definition of transient global
amnesia might be an “artificial” construct and might
only help to identify a subpopulation of TEA patients at low risk of recurrent episodes of amnesia
or obvious seizures/epilepsy, but does not exclude
an epileptic mechanism. To substantiate the hypothesis that transient global amnesia could be part
of the spectrum of transient epileptic amnesia, in-
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vasive or semi-invasive EEG with electrodes near
the medial temporal lobes would have to be performed systematically during typical episodes
(no such study has been performed until now).
However, in terms of risk to the patient, discomfort,
personnel and cost this might be hard to justify.
Furthermore, it is debatable if the patient would
reap any benefit if transient global amnesia was
aborted with an anticonvulsant a few hours before
its natural termination. Due to pathophysiological
considerations, one could not use benzodiazepines,
which would abort seizure activity, but might provoke amnesia by another mechanism (an alternative would probably be i.v. valproic acid).
Magnetoencephalography might offer more
insight into the pathophysiology of transient global
amnesia with less discomfort and risk for the patient. This expensive technology, restricted to a few
tertiary referral centres, has to date never been
used during transient global amnesia (only afterwards) [20, 21]. For lack of a better alternative,
immediate scalp EEG during transient global
amnesia is still reasonable (but patient and physician have to be fully aware of the low sensitivity
of this procedure).
Conclusion
The aetiology of transient global amnesia remains
an enigma. Data from invasive and semi-invasive
EEG recordings demonstrate that conventional
scalp EEG might not be sufficiently reliable to
exclude that transient global amnesia could be
an ictal phenomenon (i.e. part of the spectrum of
transient epileptic amnesia). However, data from
certain cases of transient epileptic amnesia also
show that in some instances a postictal depression
of memory function as a form of Todd’s paralysis
has to be considered. Immediate examination of
suspected TGA cases by means of nasopharyngeal
electrodes or magnetoencephalography could in
future shed more light on its pathophysiology.
References
1
Morris HH, Estes ML. Traveler’s amnesia.
JAMA. 1987;258:945–6.
2
Müller HR. Die Transient Global Amnesia. Mit einem
Beitrag zu ihrer Prognose.
Schweiz Rundsch Med Prax. 1989;78:970–5.
3
Hodges JR, Warlow CP. Syndromes of transient amnesia:
towards a classification. A study of 153 cases.
J Neurol Neurosurg Psychiatr y. 1990;53:834–43.
4
Fur ther information on transient global amnesia (TGA) is
available from the chapter Leitlinien at www.dgn.org, the
homepage of the Deutsche Gesellschaft für Neurologie.
SCHWEIZER ARCHIV FÜR NEUROLOGIE UND PSYCHIATRIE
w w w. a s n p . c h
160 n 2/2009
5
Sedlaczek O, Hirsch JG, Grips E, Peters CNA, Gass A,
Wöhrle J, Detection of delayed focal MR changes
in the lateral hippocampus in transient global amnesia.
Neurology. 2004;62:2165–70.
14 Tassinari CA, Ciarmatori C, Alesi C, Cardinaletti L, Salvi F,
Rubboli R, et al. Transient global amnesia as a postictal
state from recurrent par tial seizures.
Epilepsia. 1991;32:882–5.
6
Savic MM, Obradovic DI, Ugresic ND, Bokonjic DR.
Memor y effects of benzodiazepines: memor y stages
and types versus binding-site subtypes.
Neural Plasticity. 2005;12:289–98.
15 Maheu G, Adam C, Hazemann P, Baulac M, Samson S.
A case of postictal transient anterograde and retrograde
amnesia. Epilepsia. 2004;45:1459–60.
7
Danek A, Uttner I, Straube A. Is transient global amnesia
related to endogenous benzodiazepines?
J Neurol. 2002;249:628.
16 Lee BI, Lee BC, Hwang YM, Sohn YH, Jung JW, Park SC,
et al. Prolonged ictal amnesia with transient focal
abnormalities on magnetic resonance imaging.
Epilepsia. 1992;33:1042–6.
8
Sander K, Sander D. New insights into transient global
amnesia: recent imaging and clinical findings.
Lancet Neurol. 2005;4:437–44.
17 Rowan AJ, Protass LM. Transient global amnesia:
clinical and electroencephalographic findings in 10 cases.
Neurology. 1979;29:869–72.
9
Inzitari D, Pantoni L, Lamassa M, Pallanti S, Pracucci G,
Marini P. Emotional arousal and phobia in transient
global amnesia. Arch Neurol. 1997;54:866–73.
18 Wieser HG, Elger CE, Stodieck SR. The ‘foramen ovale
electrode’: a new recording method for the preoperative
evaluation of patients suffering from mesio-basal
temporal lobe epilepsy.
Electroencephalogr Clin Neurophysiol. 1985;61:314–22.
10 Zeman AZJ, Boniface SJ, Hodges JR. Transient epileptic
amnesia: a description of the clinical and neuropsychological features in 10 cases and a review of the literature. J Neurol Neurosurg Psychiatr y. 1998;64:435–43.
11 Butler CR, Graham KS, Hodges JR, Kapur N, Wardlaw JM,
Zeman AZJ. The syndrome of transient epileptic amnesia.
Ann Neurol. 2007;61:587–98.
12 Quinette P, Guiller y-Girard B, Dayan J, de la Sayette V,
Marquis S, Viader F, et al. What does transient global
amnesia really mean? Review of the literature and
thorough study of 142 cases. Brain. 2006;129:1640–58.
13 Palmini AL, Gloor P, Jones-Gotman M. Pure amnestic
seizures in temporal lobe epilepsy.
Brain. 1992;115:749–69.
76
19 Meador KJ, Loring DW, King DW, Nichols FT. The P3
evoked potential and transient global amnesia.
Arch Neurol. 1988;45:465–7.
20 Mizuno-Matsumoto Y, Ishijima M, Shinosaki K,
Nishikawa T, Ukai S, Ikejiri Y, et al. Transient global
amnesia (TGA) in an MEG study.
Brain Topography. 2001;13:269–74.
21 Stippich C, Kassubek J, Kober H, Sörös P, Vieth JB.
Time course of focal slow-wave activity in transient
ischemic attacks and transient global amnesia as
measured by magnetoencephalography.
Neurorepor t. 2000;11:3309–13.
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