Personal View

New insights into transient global amnesia: recent imaging

and clinical ndings
Kerstin Sander, Dirk Sander

Transient global amnesia (TGA) is one of the most striking syndromes in clinical neurology. Despite several new
hypotheses concerning TGA pathogenesisincluding psychological disturbances, personality traits, and hypoxicischaemic origin associated with venous congestion in memory relevant structures or small vessel changesthere is
no consensus about the cause. New imaging techniques, particularly diffusion-weighted imaging, open up new
insights into the location of TGA pathology. Studies with dynamic venous duplex sonography conrmed the
importance of jugular-vein-valve insufciency. We review these new ndings and their implications for a better
understanding of this remarkable syndrome. Although we still do not have all the answers, the use of new imaging
modalities, neuropsychological ndings, and epidemiological data may in future help to unravel the origin of TGA.

Introduction
Transient global amnesia (TGA) with a sudden onset of
anterograde and retrograde amnesia is a traumatic event
for patients, relatives, and doctors. Several different
causes for this syndrome have been proposed; these
include ischaemia,1,2 migraine,35 epileptic seizure,4,6,7
venous congestion,8 and psychological disturbances.9
Diffusion-weighted imaging (DWI) is widely used in
clinical practice. Although contradictory ndings of
DWI abnormalities in TGA have been published,1022
most patients with TGA have small punctate DWI
lesions in the lateral hippocampal formation.23 Patients
with TGA and DWI abnormalities have a higher
incidence of carotid atherosclerosis than those with
normal DWI.24 Hypoxic-ischaemic origin of TGA due to
hypoxia in susceptible parts of the hippocampus might
best explain the ndings of high prevalence of emotional
distress,3,4,25 personality traits,9 and valsalva-like activities
before symptom onset as well as the high prevalence of
insufcient jugular-vein valves2628 and advanced
atherosclerosis associated with the disorder.
In this article, we give an overview of former and
recent explanations for the syndrome TGA, particularly
focusing on ndings from studies with with modern
imaging techniques and dynamic duplex sonography.

Clinical characteristics
TGAthe term was coined by Fisher and Adams over
40 years ago29is characterised by an acute inability to
retain new information (anterograde amnesia). During
the acute stage of TGA, retrograde amnesia can extend
as far back as weeks or months. Many patients with TGA
repeatedly ask the same questions and seem to be
confused and disoriented in time and place. However,
loss of self-awareness and consciousness excludes
typical TGA. Patients are able to do complex activities
like cooking and driving. During an attack many patients
report some unspecic syndromes, such as vertigo,
nausea, and headache. The amnesic syndrome resolves
spontaneously within 24 h, typically within a few hours,
with a short amnesic gap for the main episode. The most
widely used diagnostic criteria were devised by Caplan30
http://neurology.thelancet.com Vol 4 July 2005

and modied by Hodges and Warlow (panel).25,30 The

incidence of TGA is ve to 11 per 100 000 people per
year.5,31,32 The mean age of symptom onset is about
60 years.35,25,31,3335 TGA is a benign syndrome, but there
may be persistent impairment of cognitive function.3638
These ndings have been recently conrmed by Lampl
and co-workers,39 who, by use of single-photon-emission
CT, found persistent hypoperfusion in patients with
TGA with recurrent attacks.

Lancet Neurol 2005; 4: 43744

Department of Neurology of
the Technical University of
Munich, Germany (K Sander MD,
D Sander MD)
Correspondence to:
Dr Kerstin Sander, Department of
Neurology, Technical University
of Munich, Mhlstrasse 28,
81675 Mnchen, Germany
K.Sander@neuro.med.
tu-muenchen.de

Aetiology and pathogenesis

Despite the controversial aetiology of TGA, there is
general agreement that pathological changes affect the
mediobasal temporal region, the hippocampus, and the
parahippocampus (gure 1).40
Because of the common precipitating factors in
patients with TGA, the accompanying symptoms
(headache and dizziness), and a high incidence of
migraine, some investigators proposed an association
between TGA and migraine.35 In migraine, a spreading
depressiona short lasting wave of depolarisation that
moves across the cortex resulting in a temporary
functional ablation lasting minutes to hours with full
functional recoveryhas been proposed as the cause of
the aura.41
Emotional events in TGA may excite the hippocampus
and this neuronal activity could lead to glutamate
release, which triggers the spreading depression and
functional ablation of the hippocampus.42,43 This
mechanism is supported by the fact that glutamate is a

Panel: Diagnostic criteria for TGA25,30

Attacks witnessed by objective observer
Acute onset of anterograde amnesia
No change of consciousness or loss of self-awareness
Cognitive impairment limited to amnesia
No recent history of head trauma or seizures
Duration of symptoms 124 h
No neurological symptoms beside dizziness, vertigo,
or headache

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Figure 1: Locations of the hippocampus and parahippocampus

Hippocampus (green) and parahippocampus (yellow) are projected onto axial MRI scans of the Montreal Neurology Institute (MNI) standard brain. Pictures are
derived from the Wake Forest University Pick atlas as implemented in SPM2 (major update of statistical parametric mapping).40

neurotransmitter in most excitatory synapses in the

hippocampus and has an important role in cognition,
emotion, and anxiety.44 However, in migraine the
spreading-depression theory is unproven. By use of
electrocorticography, Strong and colleagues45 reported
cortical spreading and synchronous depression in 14
patients after head injury or intracranial haemorrhage.
Schmidtke and co-workers46 compared patients with
TGA with controls and found no evidence of an
association between TGA and migraine.
Characteristics of TGA suggest that the disorder is
not epileptic in originthese include long duration,
the absence of impaired consciousness and other
cortical dysfunction, the low recurrence rate of
episodes even in short-lasting TGA, as well as the lack
of generalised convulsion.4,6,7
In patients with transient ischaemic attacks DWI
lesions were detected in up to 67%.47 In patients with
TGA small punctate lesions in memory relevant
structures were detected on DWI in up to 84%.23 As an
increased intimamedia thickness of the carotid artery
is a strong predictor for further cerebrovascular events
even in the absence of plaques,48 the nding of an
increased intimamedia thickness in patients with TGA
with DWI lesions24 further supports a hypoxicischaemic origin. Although denitive proof is lacking,
DWI hyperintensities strongly suggest cerebral
ischaemia.47 Moreover, as TGA is a syndrome of elderly
people, age-related small-vessel disease might also be a
predisposing factor.49
438

Psychological disturbances in TGA

A probable psychogenic origin of TGA was rst
discussed more than 40 years ago.50 TGA is common in
periods of stress, overwork, and after emotional
arousal.3,4,25,51 Inzitari and colleagues9 analysed the role of
emotional stress (eg, after a quarrel or sexual
intercourse) or phobogenic events (eg, visiting a dentist)
as well as personality traits in patients with TGA as
compared with controls with transient ischaemic attack
in a case-control paradigm. Using the phobic attitudes
scale, the authors described a phobic personality trait in
about half of the patients with TGA and concluded that
this might be a predisposing factor for TGA.9 A high
prevalence of stressful life events before symptom onset
is common.24,26,27,46 In addition to emotional stress,
physical exertion, immersion into cold water, and sexual
intercourse commonly coincide with onset of
TGA.35,9,24,26,27,34,46 These situations in combination with
stressful events might lead to a hyperventilation induced
vasoconstriction of cerebral resistance vessels, followed
by a consecutive hypoperfusion in memory relevant
structures.49 The phobic personality traits in patients
with TGA mentioned above might lead to a high
likelihood of hyperventilation.49

Duplex ultrasonography in TGA

As already pointed out, precipitating activities like
physical exercise, immersion in cold water, and sexual
intercourse were reported in up to 65% of patients
before symptom onset.3,5,24,26,27,34,46,49,5254 When the data of
http://neurology.thelancet.com Vol 4 July 2005

Personal View

12 TGA studies including 837 patients were combined,

the mean prevalence of precipitating activities was 44%
(absolute range 2665%; gure 2).3,5,9,24,2628,34,46,5254 On the
basis of these ndings, Lewis proposed a new
hypothesis about the cause of TGA.8 He suggested that
high venous pressure and increased venous return
towards the superior vena cava induced by valsalva-like
activities might lead to ischaemia in memory relevant
structures. Lewis8 proposed that his thesis could be
proved by comparison of jugular-vein-valve competence
during valsalva manoeuvre in patients with TGA
compared with that in controls. In a recent study of the
ability of duplex ultrasonography to detect internal
jugular-valve insufciency, 29% of valves were not
functioning properly in healthy people.55 94 patients
with TGA and 154 controls were examined with duplex
ultrasonography during a valsalva manoeuvre to assess
the percentage of insufcient jugular-vein valves.2628
One of us and co-workers26 studied the changes of
internal jugular-vein ow patterns in patients with TGA
by use of colour-coded duplex ultrasonography during
two dened valsalva procedures as compared with
healthy control individuals matched for age and gender
(gure 3). The prevalence of insufcient jugular-vein
valves was 81% in patients with TGA compared with
38% in controls during a moderate valsalva manoeuvre.
Maalikjy Akkawi and co-workers27 as well as Schreiber
and collegues28 conrmed these ndings and described
a higher prevalence of jugular-valve incompetence in
patients with TGA than in controls. Combining these
studies, a retrograde ow pattern in the jugular
vein during valsalva manoeuvres was found in 734%
of patients with TGA compared with 357% of
controls (p00001; table 1). These ndings corroborate
Lewis hypothesis.8
60

Prevalence (%)

50

n=181

40
30

Figure 3: Jugular-vein valve competency

Colour-coded duplex ultrasonography of an internal jugular vein at rest (left) with normal ow and during a
moderate valsalva manoeuvre (right). An orthograde ow direction (away from brain) of the jugular vein
indicating valve competency was colour-coded in blue and a retrograde ow direction (towards the brain)
indicating incompetent valves was colour-coded in red.

Imaging in TGA
Functional imaging
At the beginning of the 1990s, there were several studies
with imagingmainly single-photon-emission CTin
patients with acute TGA. Pantoni and colleagues49
recently reviewed these studies. In the acute and
postacute (within 24 h after TGA) stage of TGA there is a
decrease in cerebral blood ow in the temporal lobe and
the hippocampal region in most patients.39,5667 Other
investigators observed additional changes in thalamic or
striatal structures by use of single-photon-emission
CT.46,65,66,68,69 Only four patients reported so far have had
high cerebral blood ow during TGA.6971 At the postacute
stage (within 48 h of onset of TGA) cerebral blood ow
may be high in the left hippocampus69,72 and amygdala,72
left and right thalamus,69 right hippocampus,71 and
bilateral temporal and occipital69 regions. Cerebral blood
ow typically decreases in these regions within
3 weeks.6972 However, in most patients the follow-up
examination (1 week until 3 months) showed a
normalisation of cerebral haemodynamics.56,58,6062,69,73 Two
studies described normalisation within 48 h of TGA.65,66
The largest single-photon-emission-CT study of TGA
(16 patients) was recently done by Lampl and colleagues,39
who observed a hypoperfusion in all patients during the
acute stage. After 3 months, cerebral blood ow was
normal in all patients with a rst-ever attack, whereas in
patients with a recurrent attack (n=3) cerebral-blood-ow
changes could be detected for up to 1 year.

20
n=51

n=50
n=34

10

n=42

0
Physical
exercise

Sexual
intercourse

Other
Pain or
valsalva
medical
intervention manoeuvre

Swimming

Sander et al26
Maalikjy Akkawi et al27
Schreiber et al28
Total

Participants

Mean age

Patients Controls

Patients Controls

Patients

21
48
25
94

650
636
610
632

17 (810) 8 (380)* 10
35 (729) 19 (395) 31
17 (680) 28 (330) 9
69 (734) 55 (357) 50

21
48
85
154

Insufcient jugular
valves (%)

650
624
620
631

Patients with
precipitating factors

Controls

Precipitating factor
Signicance for differences in jugular-valve insufciency between patients and controls measured with Fishers exact test:
*p=001; p001; p=00025; p00001.

Figure 2: Distribution of different precipitating factors in TGA

This analysis is based on 12 studies (837 patients) with every study including
20 patients with TGA. The overall prevalence of precipitating factors was
44%.3,5,9,24,2628,34,46,5254

http://neurology.thelancet.com Vol 4 July 2005

Table 1: Clinical characteristics and prevalence of insufcient jugular vein valves measured with dynamic
duplex ultrasonography in patients with TGA and controls

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A PET study, published in 1989, reported the cerebral

blood ow in seven patients with transient ischaemic
attack and in four patients with TGA and showed a
better preserved cerebral blood ow in each area of the
brain in patients with TGA than in those with transient
ischaemic attack.74 Two studies showed hypoperfusion of
the prefrontal cortex and the lentiform nucleus during
TGA.75,76 Guillery and colleagues77 reported mild
hypoperfusion of the amygdala and of the left posterior
hippocampus in two patients with TGA. Interestingly,
the vasomotor response in patients with TGA was
impaired in the parts of the brain with high blood ow
during TGA.69 Takeuchi and co-workers73 reported a poor
vasomotor response after acetazolamide administration
in the left temporal lobe (including the hippocampus).
Recently, a combined study with single-photonemission CT and transcranial magnetic stimulation was
done.66 The researchers observed thalamic and striatal
hypoperfusion in all patients with TGA and additional
unilateral or bilateral hypoperfusion of the temporal
lobe in four patients, as well as low intracortical
inhibition in patients compared with that in the control
group.66 The researchers stated that the cortical
abnormalities might be caused by a deafferentation due
to thalamic damage and that these changes might
explain the hypometabolism seen in PET studies.
There is only one case report in which perfusionweighted-imaging was used during acute TGA and no
regions with changes in cerebral haemodynamics were
detected.13 Another case report with functional MRI
described increased activation followed by recovery in
frontoparietal regions during the acute phase of TGA.20

Diffusion-weighted imaging in TGA

Although diffusion-weighted imaging is commonly used
in clinical practice, contradictory ndings concerning the
visualised abnormalities in TGA have been reported.
Thus far, there are published reports of 99 patients with
acute TGA and DWI investigations (table 2).1024,78,79
52 patients had DWI abnormalities; in most (45)
the lesion was located in the hippocampal region
(25 left; nine bilateral; 11 right). The report by Strupp
and co-workers12 described widespread transient
hyperintensities in the left or bilateral mesial temporal
lobes in seven of ten patients with acute TGA. The
authors believed these ndings to be consistent with
spreading depression. As the investigators used steadystate free-precession sequences of DWI with a single
diffusion gradient direction, this technique is susceptible
to several artifacts, and without the opportunity to
analyse these lesions quantitatively with apparentdiffusion-coefcient maps these ndings should
be interpreted cautiously. Moreover, comparable
widespread lesions have not been reported in any other
study. Two large studies using up-to-date DWI
techniques found no DWI abnormalities in acute
TGA.15,18 However, several case reports described DWI
440

Number
Time to DWI abnormalities
of patients DWI (h)
Woolfenden et al,10 1997

Ay et al, 1998

11

Strupp et al,12 1998

10

2144

Budson et al,13 1999

Tanabe et al,14 1999

1
1

Gass et al,15 1999

Greer et al,16 2001
Matsui et al,17 2002
Huber et al,18 2002
Savitz et al,19 2002
LaBar et al,20 2002
Jeong et al,21 2003
Saito et al,22 2003

8
1
1
10
1
1
1
1

18
4
44
644
12
12
4872

Michel et al,78 2004

Ravindran et al,79 2004
Sedlaczek et al,23 2004

1
1
31

13
7
2448

Winbeck et al,24 2005

28

248

Total

99

12
3

Right hippocampus and

bilateral occipital
Left splenium, corpus
callosum, and left
parahippocampus
Bilateral hippocampus
(n=3) and left
hippocampus (n=4)
None
Hippocampus bilateral
and cerebellum
None
Left medial temporal lobe
Right hippocampus
None
None
None
Left hippocampus
Left retrosplenium and
corpus callosum
Left thalamus
Right caudate nucleus
Bilateral hippocampus
(n=5), left hippocampus
(n=15), right
hippocampus (n=6)
Right hippocampus (n=3),
left hippocampus (n=4)
left mesial temporal lobe
(n=3)
52

Table 2: Diffusion-weighted imaging (DWI) studies in patients with

acute TGA

signal-intensity changes in patients with TGA.11,16,17,22

Sedlaczek and colleagues23 recently described very small
punctate DWI lesions (12 mm) in the lateral aspect of
the hippocampal formation in 26 of 31 patients with
TGA. The researchers showed that all lesions were
detectable on day 2. In 11 patients, the lesions were also
visible on the rst image after re-evaluation. The
investigators pointed out that these ndings might
explain the incongruence among several recent DWI
studies and explained the unusual time course of DWI
lesions by anatomical and functional characteristics of
the hippocampus: the hippocampal artery supplies an
internal anastomosis forming a link between an upper
and a lower artery.23 The watershed area between both is
the hypoxia-susceptible sector of Sommer (gure 4). The
most important nding was the consistent location of the
DWI abnormalities in anatomical regions likely involved
in memory processing. The researchers hypothesised
that hypoperfusionparticularly in patients with preexisting mild vascular changesfollowed by delayed
ischaemic mechanisms might cause TGA.
One of us and colleagues24 analysed 28 patients with
TGA within 48 h of symptom onset and found DWI
abnormalities in nine with a similar anatomical
distribution to that described by Sedlaczek and
colleagues (gure 5).23
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Figure 4: Lesions evident on imaging in patients with TGA

Schematic drawing of focal DWI lesions in 26 patients with TGA in a segmented hippocampus (left [A], bilateral [B], and right [C]); the red circle (D) indicates a
hippocampal T2 lesion; a schematic drawing (E) of the border zone between the upper and lower hippocampal artery. Reproduced with permission from Lippincott
Williams and Wilkins.23

On the basis of these results, there may no longer be

any doubts about the validity of these small DWI lesions.
Nevertheless, the pathogenesis of these punctate lesions
only detectable on DWI is still a matter of debate because
DWI abnormalities were in fact highly sensitive for
ischaemia but not specic.

substantial vascular-risk prole, with high intimamedia

thickness (103 mm vs 076 mm; p=0002) and high
prevalence of carotid atherosclerosis (70% vs 17%;
p=001).24 These ndings might support the hypothesis
that small-vessel changes are part of the cause of TGA.49

Conclusion
Comparison of TGA and transient ischaemic
attack
TGA was thought to be a result of transient ischaemia
in memory relevant structures.1,2 Several case-control
studies comparing patients with TGA with either an
age-matched general population or with patients with
transient ischaemic attack show that patients with TGA
have fewer cardiovascular risk factors and a better
prognosis than those with transient ischaemic
attack.35,33 Other investigators have described a similar
frequency of risk factors in transient ischaemic attack
and TGA, but a better prognosis for the latter.80 In most
studies, the prevalence of hypertension was 4561%
and was similar for patients with TGA and for those
with transient ischaemic attack.3,24,27 In one study,
hypertension was more prevalent in patients with TGA
than in those with transient ischaemic attack.4 Some
recent studies assessed the occurrence of
atherosclerotic lesions in a third to a half of patients
with TGA.23,24,27
We prospectively analysed the incidence of DWI
signal-intensity changes and vascular risk factors in
74 patients with transient ischaemic attack and
28 patients with TGA;24 the prevalence of DWI
hyperintensities was 28% and 36%, respectively. In
patients with TGA all the lesions were located in
memory relevant structures, such as the hippocampus
or the temporal lobe. In patients with transient
ischaemic attack, hyperintensities were found in the
cortical (n=7) and subcortical (n=9) anterior circulation
as well as the brainstem (n=5), no patient had DWI
lesions in the hippocampus or mesial temporal lobe.
The DWI lesion volume was smaller in TGA than in
transient ischaemic attack (102 mm3 vs 191 mm3,
p0001). We observed a lower incidence of vascular
risk factors in TGA than in transient ischaemic attack.
Interestingly, patients with TGA with signal intensity
changes on DWI compared with those without had a
http://neurology.thelancet.com Vol 4 July 2005

Much effort has been made to investigate the aetiology

of TGA in more detail. There have been two important
new ndings in patients with TGA.
First, dynamic duplex ultrasonography in a large cohort
of patients with TGA and controls2628 showed high
prevalence of insufcient jugular-vein valves in patients
with TGA. This nding points to the importance of an
increased venous pressure, particularly in patients with
TGA with a precipitating valsalva manoeuvre before
symptom onset. An additional emotional, stressful, or
phobogenic event before symptom onset is common in
these patients.49 In combination with a phobic personality
trait, increased venous pressure might lead to
hyperventilation-induced vasoconstriction leading to a
consecutive change of the cerebral haemodynamics of
the hippocampal region. The particular anatomic and
vascular architecture of the hippocampus and the high
glutamate concentration in this region of the brain may
further support this hypothesis. To summarise these
ndings, TGA might be caused by a temporal hypoxicischaemic dysfunction in memory-relevant structures
induced by haemodynamic factors others than those
causing transient ischaemic attack.

Figure 5: DWI presentation of a lesion in TGA

DWI with three brain slices from a patient with TGA 18 h after symptom onset. The lesion of the right
hippocampus is visible on every slide (arrow). Axial direction without angulations in course of the hippocampus
(left); the axial plane aligned to the course of the hippocampus (middle); and the coronal plane perpendicular to
the hippocampus (right). Slice thickness was 3 mm.

441

Personal View

Search strategy and selection criteria

References for this overview were identied by searches of
MEDLINE between January 1989 and March 2005 and of the
references from relevant articles. We searched for human
studies with the terms transient global amnesia and TGA.
Only papers published in English were reviewed. We favoured
results from prospective cohort studies and clinical trials. The
reference list was generated on the basis of originality and
relevance to the topic covered in the overview.

Second, DWI studies conrmed the location of the

typical abnormality in these patients in memory
relevant structures. Recently, two large and
independent DWI studies focusing on the hippocampal
structures during TGA investigated 59 patients with
TGA and detected small punctate DWI lesions mainly
located in the left hippocampus in half of the
patients.23,24 Recent data show that patients with TGA
with DWI abnormalities might have a higher prevalence
of vascular risk factors leading to carotid atherosclerosis
than people without such abnormalities.24
Although there is still no consensus about the cause of
TGA, in our opinion these new ndings (high
prevalence of emotional distress, personal traits,
occurrence of valsalva-like activities before symptom
onset in combination with a higher prevalence of a
retrograde ow pattern, small vessel changes) point to a
hypoxic-ischaemic origin of TGA caused by
hypoperfusion in the hypoxia-susceptible parts of the
hippocampal and related memory relevant structures.

Clinical implications
TGA is largely a clinical diagnosis according to the
criteria proposed by Hodges and Warlow (panel).
However, if the diagnosis of TGA is doubtful, an imaging
investigation should be done, particularly if risk factors
were present. If the symptoms have occurred more than
once, electroencephalography should be done to exclude
epileptic origin. To lower the vascular risk, patients with
atherosclerosis and risk factors for cerebrovascular
diseases should be treated according to the current
guidelines.81,82 These guidelines provide information for
primary as well as secondary prevention of ischaemic
stroke including the management of hypertension,
diabetes mellitus, and hypercholesterolaemia, lifestyle
modication, and antithrombotic therapy. During times
of increased emotional distress, extraordinary valsalvalike activities should be avoided.
Authors contributions
Both authors contributed equally to this review.
Conicts of interest
We have no conicts of interest.
Role of the funding source
We have not been paid to write this review by a pharmaceutical
company or other agency.

442

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