New insights int transient global amnesia

8/9/2019 New insights int transient global amnesia

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IntroductionTransient global amnesia (TGA) with a sudden onset ofanterograde and retrograde amnesia is a traumatic eventfor patients, relatives, and doctors. Several differentcauses for this syndrome have been proposed; theseinclude ischaemia,1,2 migraine,35 epileptic seizure,4,6,7

venous congestion,8 and psychological disturbances.9

Diffusion-weighted imaging (DWI) is widely used inclinical practice. Although contradictory findings ofDWI abnormalities in TGA have been published,1022

most patients with TGA have small punctate DWIlesions in the lateral hippocampal formation.23 Patientswith TGA and DWI abnormalities have a higher

incidence of carotid atherosclerosis than those withnormal DWI.24 Hypoxic-ischaemic origin of TGA due tohypoxia in susceptible parts of the hippocampus mightbest explain the findings of high prevalence of emotionaldistress,3,4,25 personality traits,9 and valsalva-like activitiesbefore symptom onset as well as the high prevalence ofinsufficient jugular-vein valves2628 and advancedatherosclerosis associated with the disorder.

In this article, we give an overview of former andrecent explanations for the syndrome TGA, particularlyfocusing on findings from studies with with modernimaging techniques and dynamic duplex sonography.

Clinical characteristics

TGAthe term was coined by Fisher and Adams over40 years ago29is characterised by an acute inability toretain new information (anterograde amnesia). Duringthe acute stage of TGA, retrograde amnesia can extendas far back as weeks or months. Many patients with TGArepeatedly ask the same questions and seem to beconfused and disoriented in time and place. However,loss of self-awareness and consciousness excludestypical TGA. Patients are able to do complex activitieslike cooking and driving. During an attack many patientsreport some unspecific syndromes, such as vertigo,nausea, and headache. The amnesic syndrome resolvesspontaneously within 24 h, typically within a few hours,

with a short amnesic gap for the main episode. The mostwidely used diagnostic criteria were devised by Caplan30

and modified by Hodges and Warlow (panel).25,30 Theincidence of TGA is five to 11 per 100 000 people peryear.5,31,32 The mean age of symptom onset is about60 years.35,25,31,3335 TGA is a benign syndrome, but theremay be persistent impairment of cognitive function.3638

These findings have been recently confirmed by Lampland co-workers,39 who, by use of single-photon-emissionCT, found persistent hypoperfusion in patients withTGA with recurrent attacks.

Aetiology and pathogenesisDespite the controversial aetiology of TGA, there isgeneral agreement that pathological changes affect the

mediobasal temporal region, the hippocampus, and theparahippocampus (figure 1).40

Because of the common precipitating factors inpatients with TGA, the accompanying symptoms(headache and dizziness), and a high incidence ofmigraine, some investigators proposed an associationbetween TGA and migraine.35 In migraine, a spreadingdepressiona short lasting wave of depolarisation thatmoves across the cortex resulting in a temporaryfunctional ablation lasting minutes to hours with fullfunctional recoveryhas been proposed as the cause ofthe aura.41

Emotional events in TGA may excite the hippocampusand this neuronal activity could lead to glutamate

release, which triggers the spreading depression andfunctional ablation of the hippocampus.42,43 Thismechanism is supported by the fact that glutamate is a

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

[email protected].

tu-muenchen.de

http://neurology.thelancet.com Vol 4 July 2005 437

Kerstin Sander, Dirk Sander

Transient global amnesia (TGA) is one of the most striking syndromes in clinical neurology. Despite several newhypotheses concerning TGA pathogenesisincluding psychological disturbances, personality traits, and hypoxic-ischaemic origin associated with venous congestion in memory relevant structures or small vessel changesthere isno consensus about the cause. New imaging techniques, particularly diffusion-weighted imaging, open up newinsights into the location of TGA pathology. Studies with dynamic venous duplex sonography confirmed theimportance of jugular-vein-valve insufficiency. We review these new findings and their implications for a betterunderstanding of this remarkable syndrome. Although we still do not have all the answers, the use of new imagingmodalities, neuropsychological findings, and epidemiological data may in future help to unravel the origin of TGA.

New insights into transient global amnesia: recent imaging

and clinical findings

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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neurotransmitter in most excitatory synapses in the

hippocampus and has an important role in cognition,emotion, and anxiety.44 However, in migraine thespreading-depression theory is unproven. By use ofelectrocorticography, Strong and colleagues45 reportedcortical spreading and synchronous depression in 14patients after head injury or intracranial haemorrhage.Schmidtke and co-workers46 compared patients withTGA with controls and found no evidence of anassociation between TGA and migraine.

Characteristics of TGA suggest that the disorder isnot epileptic in originthese include long duration,the absence of impaired consciousness and othercortical dysfunction, the low recurrence rate ofepisodes even in short-lasting TGA, as well as the lack

of generalised convulsion.4,6,7In patients with transient ischaemic attacks DWI

lesions were detected in up to 67%.47 In patients withTGA small punctate lesions in memory relevantstructures were detected on DWI in up to 84%. 23 As anincreased intimamedia thickness of the carotid arteryis a strong predictor for further cerebrovascular eventseven in the absence of plaques,48 the finding of anincreased intimamedia thickness in patients with TGAwith DWI lesions24 further supports a hypoxic-ischaemic origin. Although definitive proof is lacking,DWI hyperintensities strongly suggest cerebralischaemia.47 Moreover, as TGA is a syndrome of elderlypeople, age-related small-vessel disease might also be apredisposing factor.49

Psychological disturbances in TGA

A probable psychogenic origin of TGA was firstdiscussed more than 40 years ago.50 TGA is common inperiods of stress, overwork, and after emotionalarousal.3,4,25,51 Inzitari and colleagues9 analysed the role ofemotional stress (eg, after a quarrel or sexualintercourse) or phobogenic events (eg, visiting a dentist)as well as personality traits in patients with TGA ascompared with controls with transient ischaemic attackin a case-control paradigm. Using the phobic attitudesscale, the authors described a phobic personality trait inabout half of the patients with TGA and concluded thatthis might be a predisposing factor for TGA.9 A highprevalence of stressful life events before symptom onsetis common.24,26,27,46 In addition to emotional stress,

physical exertion, immersion into cold water, and sexualintercourse commonly coincide with onset ofTGA.35,9,24,26,27,34,46 These situations in combination withstressful events might lead to a hyperventilation inducedvasoconstriction of cerebral resistance vessels, followedby a consecutive hypoperfusion in memory relevantstructures.49 The phobic personality traits in patientswith TGA mentioned above might lead to a highlikelihood of hyperventilation.49

Duplex ultrasonography in TGAAs already pointed out, precipitating activities likephysical exercise, immersion in cold water, and sexualintercourse were reported in up to 65% of patientsbefore symptom onset.3,5,24,26,27,34,46,49,5254 When the data of

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

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


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12 TGA studies including 837 patients were combined,

the mean prevalence of precipitating activities was 44%(absolute range 2665%; figure 2).3,5,9,24,2628,34,46,5254 On thebasis of these findings, Lewis proposed a newhypothesis about the cause of TGA.8 He suggested thathigh venous pressure and increased venous returntowards the superior vena cava induced by valsalva-likeactivities might lead to ischaemia in memory relevantstructures. Lewis8 proposed that his thesis could beproved by comparison of jugular-vein-valve competenceduring valsalva manoeuvre in patients with TGAcompared with that in controls. In a recent study of theability of duplex ultrasonography to detect internaljugular-valve insufficiency, 29% of valves were notfunctioning properly in healthy people.55 94 patients

with TGA and 154 controls were examined with duplexultrasonography during a valsalva manoeuvre to assessthe percentage of insufficient jugular-vein valves.2628

One of us and co-workers26 studied the changes ofinternal jugular-vein flow patterns in patients with TGAby use of colour-coded duplex ultrasonography duringtwo defined valsalva procedures as compared withhealthy control individuals matched for age and gender(figure 3). The prevalence of insufficient jugular-veinvalves was 81% in patients with TGA compared with38% in controls during a moderate valsalva manoeuvre.Maalikjy Akkawi and co-workers27 as well as Schreiberand collegues28 confirmed these findings and described

a higher prevalence of jugular-valve incompetence inpatients with TGA than in controls. Combining thesestudies, a retrograde flow pattern in the jugularvein during valsalva manoeuvres was found in 734%of patients with TGA compared with 357% ofcontrols (p00001; table 1). These findings corroborateLewis hypothesis.8

Imaging in TGAFunctional imagingAt the beginning of the 1990s, there were several studieswith imagingmainly single-photon-emission CTinpatients with acute TGA. Pantoni and colleagues49

recently reviewed these studies. In the acute andpostacute (within 24 h after TGA) stage of TGA there is adecrease in cerebral blood flow in the temporal lobe andthe hippocampal region in most patients.39,5667 Otherinvestigators observed additional changes in thalamic orstriatal structures by use of single-photon-emissionCT.46,65,66,68,69 Only four patients reported so far have hadhigh cerebral blood flow during TGA.6971 At the postacute

stage (within 48 h of onset of TGA) cerebral blood flowmay be high in the left hippocampus69,72 and amygdala,72

left and right thalamus,69 right hippocampus,71 andbilateral temporal and occipital69 regions. Cerebral bloodflow typically decreases in these regions within3 weeks.6972 However, in most patients the follow-upexamination (1 week until 3 months) showed anormalisation of cerebral haemodynamics.56,58,6062,69,73 Twostudies 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 theacute stage. After 3 months, cerebral blood flow wasnormal in all patients with a first-ever attack, whereas in

patients with a recurrent attack (n=3) cerebral-blood-flowchanges could be detected for up to 1 year.


Physical

exercise

Precipitating factor

Sexual

intercourse

Pain or

medical

intervention

Swimming

60

50

40

30

20

10

0

Other

valsalva

manoeuvre

n=181

n=50

n=34

n=51n=42

Prevalen

ce(%)

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 was44%.3,5,9,24,2628,34,46,5254

Figure 3:Jugular-vein valve competency

Colour-coded duplex ultrasonography of an internal jugular vein at rest (left) with normal flow and during a

moderate valsalva manoeuvre (right). An orthograde flow direction (away from brain) of the jugular vein

indicating valve competency was colour-coded in blue and a retrograde flow direction (towards the brain)

indicating incompetent valves was colour-coded in red.

Participants Mean age Insufficient jugular Patients with

valves (%) precipitating factors

Pa tients Cont rols Patient s Cont rols Patient s Contr ol s

Sander et al26 21 21 650 650 17 (810) 8 (380)* 10

Maalikjy Akkawi et al27 48 48 636 624 35 (729) 19 (395) 31

Schreiber et al28 25 85 610 620 17 (680) 28 (330) 9

Total 94 154 632 631 69 (734) 55 (357) 50

Significance for differences in jugular-valve insufficiency between patients and controls measured with Fishers exact test:

*p=001; p001; p=00025; p00001.

Table 1: Clinical characteristics and prevalence of insufficient 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 flow in seven patients with transient ischaemicattack and in four patients with TGA and showed abetter preserved cerebral blood flow in each area of thebrain in patients with TGA than in those with transientischaemic attack.74 Two studies showed hypoperfusion ofthe prefrontal cortex and the lentiform nucleus duringTGA.75,76 Guillery and colleagues77 reported mildhypoperfusion of the amygdala and of the left posteriorhippocampus in two patients with TGA. Interestingly,the vasomotor response in patients with TGA wasimpaired in the parts of the brain with high blood flowduring TGA.69 Takeuchi and co-workers73 reported a poorvasomotor response after acetazolamide administrationin the left temporal lobe (including the hippocampus).

Recently, a combined study with single-photon-emission CT and transcranial magnetic stimulation wasdone.66 The researchers observed thalamic and striatalhypoperfusion in all patients with TGA and additionalunilateral or bilateral hypoperfusion of the temporallobe in four patients, as well as low intracorticalinhibition in patients compared with that in the controlgroup.66 The researchers stated that the corticalabnormalities might be caused by a deafferentation dueto thalamic damage and that these changes mightexplain the hypometabolism seen in PET studies.

There is only one case report in which perfusion-weighted-imaging was used during acute TGA and no

regions with changes in cerebral haemodynamics weredetected.13 Another case report with functional MRIdescribed increased activation followed by recovery infrontoparietal regions during the acute phase of TGA. 20

Diffusion-weighted imaging in TGAAlthough diffusion-weighted imaging is commonly usedin clinical practice, contradictory findings concerning thevisualised abnormalities in TGA have been reported.Thus far, there are published reports of 99 patients withacute 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 transienthyperintensities in the left or bilateral mesial temporallobes in seven of ten patients with acute TGA. Theauthors believed these findings to be consistent withspreading depression. As the investigators used steady-state free-precession sequences of DWI with a singlediffusion gradient direction, this technique is susceptibleto several artifacts, and without the opportunity toanalyse these lesions quantitatively with apparent-diffusion-coefficient maps these findings shouldbe interpreted cautiously. Moreover, comparablewidespread lesions have not been reported in any otherstudy. Two large studies using up-to-date DWItechniques found no DWI abnormalities in acuteTGA.15,18 However, several case reports described DWI

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

Sedlaczek and colleagues23 recently described very smallpunctate DWI lesions (12 mm) in the lateral aspect ofthe hippocampal formation in 26 of 31 patients withTGA. The researchers showed that all lesions weredetectable on day 2. In 11 patients, the lesions were alsovisible on the first image after re-evaluation. Theinvestigators pointed out that these findings mightexplain the incongruence among several recent DWIstudies and explained the unusual time course of DWIlesions by anatomical and functional characteristics of

the hippocampus: the hippocampal artery supplies aninternal anastomosis forming a link between an upperand a lower artery.23 The watershed area between both isthe hypoxia-susceptible sector of Sommer (figure 4). Themost important finding was the consistent location of theDWI abnormalities in anatomical regions likely involvedin memory processing. The researchers hypothesisedthat hypoperfusionparticularly in patients with pre-existing mild vascular changesfollowed by delayedischaemic mechanisms might cause TGA.

One of us and colleagues24 analysed 28 patients withTGA within 48 h of symptom onset and found DWIabnormalities in nine with a similar anatomicaldistribution to that described by Sedlaczek andcolleagues (figure 5).23


Number Time to DWI abnormalities

of patients DWI (h)Woolfenden et al,10 1997 1 6 Right hippocampus and

bilateral occipital

Ay et al,11 1998 1 6 Left splenium, corpus

callosum, and left

parahippocampus

Strupp et al,12 1998 10 2144 Bilateral hippocampus

(n=3) and left

hippocampus (n=4)

Budson et al,13 1999 1 12 None

Tanabe et al,14 1999 1 3 Hippocampus bilateral

and cerebellum

Gass et al,15 1999 8 18 None

Greer et al,16 2001 1 4 Left medial temporal lobe

Matsui et al,17 2002 1 44 Right hippocampus

Huber et al,18 2002 10 644 None

Savitz et al,19 2002 1 12 None

LaBar et al,20 2002 1 12 NoneJeong et al,21 2003 1 4872 Left hippocampus

Saito et al,22 2003 1 Left retrosplenium and

corpus callosum

Michel et al,78 2004 1 13 Left thalamus

Ravindran et al,79 2004 1 7 Right caudate nucleus

Sedlaczek et al,23 200 4 31 24 48 Bil ateral hippocampus

(n=5), left hippocampus

(n=15), right

hippocampus (n=6)

Winbeck et al,24 2005 28 248 Right hippocampus (n=3),

left hippocampus (n=4)

left mesial temporal lobe

(n=3)

Total 99 52

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

acute TGA


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On the basis of these results, there may no longer beany 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 becauseDWI abnormalities were in fact highly sensitive forischaemia but not specific.

Comparison of TGA and transient ischaemicattackTGA was thought to be a result of transient ischaemiain memory relevant structures.1,2 Several case-controlstudies comparing patients with TGA with either anage-matched general population or with patients withtransient ischaemic attack show that patients with TGAhave fewer cardiovascular risk factors and a betterprognosis than those with transient ischaemic

attack.

35,33

Other investigators have described a similarfrequency of risk factors in transient ischaemic attackand TGA, but a better prognosis for the latter.80 In moststudies, the prevalence of hypertension was 4561%and was similar for patients with TGA and for thosewith transient ischaemic attack.3,24,27 In one study,hypertension was more prevalent in patients with TGAthan in those with transient ischaemic attack.4 Somerecent studies assessed the occurrence ofatherosclerotic lesions in a third to a half of patientswith TGA.23,24,27

We prospectively analysed the incidence of DWIsignal-intensity changes and vascular risk factors in74 patients with transient ischaemic attack and

28 patients with TGA;24 the prevalence of DWIhyperintensities was 28% and 36%, respectively. Inpatients with TGA all the lesions were located inmemory relevant structures, such as the hippocampusor the temporal lobe. In patients with transientischaemic attack, hyperintensities were found in thecortical (n=7) and subcortical (n=9) anterior circulationas well as the brainstem (n=5), no patient had DWIlesions in the hippocampus or mesial temporal lobe.The DWI lesion volume was smaller in TGA than intransient ischaemic attack (102 mm3 vs 191 mm3,p0001). We observed a lower incidence of vascularrisk factors in TGA than in transient ischaemic attack.Interestingly, patients with TGA with signal intensitychanges on DWI compared with those without had a

substantial vascular-risk profile, with high intimamediathickness (103 mm vs 076 mm; p=0002) and highprevalence of carotid atherosclerosis (70% vs 17%;

p=001).24 These findings might support the hypothesisthat small-vessel changes are part of the cause of TGA.49

ConclusionMuch effort has been made to investigate the aetiologyof TGA in more detail. There have been two importantnew findings in patients with TGA.

First, dynamic duplex ultrasonography in a large cohortof patients with TGA and controls2628 showed highprevalence of insufficient jugular-vein valves in patientswith TGA. This finding points to the importance of anincreased venous pressure, particularly in patients withTGA with a precipitating valsalva manoeuvre before

symptom onset. An additional emotional, stressful, orphobogenic event before symptom onset is common inthese patients.49 In combination with a phobic personalitytrait, increased venous pressure might lead tohyperventilation-induced vasoconstriction leading to aconsecutive change of the cerebral haemodynamics ofthe hippocampal region. The particular anatomic andvascular architecture of the hippocampus and the highglutamate concentration in this region of the brain mayfurther support this hypothesis. To summarise thesefindings, TGA might be caused by a temporal hypoxic-ischaemic dysfunction in memory-relevant structuresinduced by haemodynamic factors others than thosecausing transient ischaemic attack.


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

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 tothe hippocampus (right). Slice thickness was 3 mm.


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Second, DWI studies confirmed the location of thetypical abnormality in these patients in memoryrelevant structures. Recently, two large and

independent DWI studies focusing on the hippocampalstructures during TGA investigated 59 patients withTGA and detected small punctate DWI lesions mainlylocated in the left hippocampus in half of thepatients.23,24 Recent data show that patients with TGAwith DWI abnormalities might have a higher prevalenceof vascular risk factors leading to carotid atherosclerosisthan people without such abnormalities.24

Although there is still no consensus about the cause ofTGA, in our opinion these new findings (highprevalence of emotional distress, personal traits,occurrence of valsalva-like activities before symptomonset in combination with a higher prevalence of a

retrograde flow pattern, small vessel changes) point to ahypoxic-ischaemic origin of TGA caused byhypoperfusion in the hypoxia-susceptible parts of thehippocampal and related memory relevant structures.

Clinical implicationsTGA is largely a clinical diagnosis according to thecriteria proposed by Hodges and Warlow (panel).However, if the diagnosis of TGA is doubtful, an imaginginvestigation should be done, particularly if risk factorswere present. If the symptoms have occurred more thanonce, electroencephalography should be done to excludeepileptic origin. To lower the vascular risk, patients withatherosclerosis and risk factors for cerebrovascular

diseases should be treated according to the currentguidelines.81,82 These guidelines provide information forprimary as well as secondary prevention of ischaemicstroke including the management of hypertension,diabetes mellitus, and hypercholesterolaemia, lifestylemodification, and antithrombotic therapy. During timesof increased emotional distress, extraordinary valsalva-like activities should be avoided.

Authors contributions

Both authors contributed equally to this review.

Conflicts of interest

We have no conflicts of interest.

Role of the funding source

We have not been paid to write this review by a pharmaceuticalcompany or other agency.

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Search strategy and selection criteria

References for this overview were identified 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.


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New insights int transient global amnesia