Transient Global Amnesia Associated With
Cardiac Arrhythmia and Digitalis
Intoxication
BY JOHN E. GREENLEE, M.D., RICHARD S. CRAMPTON, M.D.,
AND JAMES Q. MILLER, M.D.
• A 54-year-old woman with transient global amnesia (TGA) was found to have digitalisinduced bradyarrhythmia with atrioventricular dissociation. The amnesia cleared only upon
resolution of the arrhythmia. Cardiac arrhythmia has been postulated as a cause, but TGA in
the setting of cardiac arrhythmia has not been documented previously. Cardiac arrhythmia
should be excluded in patients with TGA, and TGA, a syndrome diagnosed on clinical grounds
alone, must be recognized as one possible manifestation of treatable, potentially serious cardiac
or cerebrovascular disease.
Abstract:
Transient
Global
Amnesia
Associated
With
Cardiac
Arrhythmia
and
Digitalis
Intoxication
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Additional Key Words
vertebrobasilar arterial system
• Transient global amnesia (TGA), an important
organic altered mental state with a striking clinical
presentation, may be the only manifestation of
cerebral ischemia. It is sufficiently uncommon that its
victims may be incorrectly considered hysterical or
psychotic despite showing clinical features unique to
this condition. TGA most commonly involves patients
in thefifthor later decades of life and occurs without
warning. During the attack profound loss of recent
memory and remarkable attenuation of immediate
recall appear with sparing of remote memory and all
other modalities of intellect.1"3 Initially the patient
may be amnesic for a period before and after the attack encompassing a few hours or as long as 48 to 72
hours. Subsequently, the span of altered memory
shrinks from both ends until memory is completely
normal except that there is no recollection of the TGA
itself. During the attack the patient is alert, appropriately concerned, and aware something is amiss.
He asks the same questions repeatedly ("What
happened?," "What is going on?," etc.), immediately
forgetting both the answers and asking the questions.
A single cause has not been identified, but TGA
often occurs under circumstances compatible with
transient cerebral ischemia and hypoperfusion of the
hippocampus, brain stem reticular formation and
From the Departments of Neurology and Internal Medicine,
University of Virginia School of Medicine, Charlottesville,
Virginia.
Reprint requests to Dr. Miller, Box 147, University of Virginia
Hospital, Charlottesville, Virginia 22901.
Supported in part by Training Grant No. 5120-18, National
Institute of Neurological Diseases and Stroke.
Slrokt, Vol. 6, Stpttmbw-Odobv
1975
cerebrovascular disease
hypoperfusion
cerebral ischemia
atherosclerosis
other structures served by the vertebrobasilarposterior cerebral arterial systems.1"7 It has complicated aortic and cardiac cathetcrization8 and has
occurred in persons without'110 and with7 angiographical evidence of occlusive cerebrovascular disease. Causes of cerebral hypoperfusion other than
atherosclerosis alone have been sought, including
episodic reduction of cardiac output. Although cardiac arrhythmias have been suggested as a possible
cause,11 the occurrence of arrhythmias in close
association with TGA has not been documented, nor
has attention been drawn to the possibility that a
potentially dangerous or iatrogenic cardiac
arrhythmia may present as TGA.
Case Report
A 54-year-old hypertensive black woman had good
neurological health until the day of admission when she
arose, dressed, conversed with her family and was considered normal in every way. She arrived at work without
difficulty, but failed to recognize her fellow workers. She approached several persons asking what she was to do and,
after receiving instructions, returned within a few minutes to
ask the same question. Her employers became concerned
about her behavior, found her confused, and brought her to
the hospital.
For the past 15 years she had had hypertension in the
range of 170 to 200 systolic and 100 to 125 diastolic mm Hg.
She took reserpine, 0.25 mg, and hydrochlorothiazide, 100
mg, daily and a potassium supplement occasionally. Fifteen
months before admission she began digitoxin, 0.1 mg daily,
for mild left ventricular failure due to hypertensive heart disease.
On examination the patient was an alert, anxious,
afebrile, middle-aged woman. She weighed 91.6 kg and her
513
CIAMFTON,
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height measured 127 cm. The pulse rate ranged from 48 to
56 beats per minute with occasional irregular beats. The
blood pressure was 150/190 mm Hg without orthostatic
change and respirations were 16 pcT minute. There were
mild bilateral cataracts. Fundi showed sharp optic disk
margins with marked arteriolar narrowing, A-V nicking,
and many small, hard exudates. The neck was supple. There
were scattered bibasilar rales which did not clear after
coughing. Cardiac apex beat was displaced 2 cm to the left
of the midclavicular line in the fifth interspace. Auscultation
disclosed an intermittent fourth sound, a loud aortic second
sound, and a grade 2/6 high-pitched holosystolic apical murmur which radiated to the left axilla. The left carotid pulse
was normal; the right was slightly decreased, but without
bruit. The remainder of the general physical examination
was normal.
Although alert and cooperative, she was disoriented to
place, time, and person. She worried about her present situation and repeatedly asked "What happened?" After being
told she was in the hospital and the circumstances of her admission, she would repeat the question within one or two
minutes, having forgotten that she had asked the question or
received an answer. She could carry out one-step addition
and subtraction to three digits without use of pencil or paper
but could not subtract serial sevens. She was unable to
remember commands, names, or her own correct answers to
questions posed moments before. There was no dysphasia
and visual fields, including formal tangent screen and
perimetry examinations, were normal. There were minimal
left central facial weakness and minimal weakness of the left
arm and leg. Tone and coordination were normal. Sensory
examination initially revealed slight left-sided tactile inattention and diminished graphcsthesia, but these findings
cleared within a few hours after admission. There was no
reflex asymmetry or Babinski's sign, but Hoffmann's sign
was present bilaterally. The patient had a snout reflex and a
brisk jaw jerk.
The hematocrit was 35%, white blood cell count
was 5,500 per cubic millimeter with normal differential, and
erythrocyte sedimentation rate was 38 mm per hour. The
serum sodium was 144, potassium 3.2, chloride 99, and CO,
combining power 32 mEq/L. The serum calcium was 10,
.
Ti"
....
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•MB mm
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;
phosphate 3.8, and blood urea nitrogen 16 mg %. The
glucose, cholesterol, total protein, albumin, glutamic oxalacctic transaminase and creatine phosphokinase were normal, and the latter two serum enzymes did not rise on serial
determinations. The serum uric acid was elevated at 7.1 mg
%. The serum digitoxin level was 12.2 ng per milliliter (normal range 10 to 20). Electrocardiogram (ECG) showed sinus
bradycardia at 48 per minute with intermittent A-V dissociation (fig. 1). There were occasional ventricular
premature beats and S-T and T changes of digitalis treatment. The chest x-ray showed an enlarged heart. Electroencephalograms were obtained on the day of admission
and the second and third hospital days. The initial recording
revealed brief, generalized theta slowing, at times more
prominent over the left hemisphere. A second tracing
showed decrease in the amount of theta slowing, and a third
was normal.
The patient was believed to be in the midst of an
episode of TGA and to have digitalis-related
bradyarrhythmia exacerbated by both rescrpine treatment
and hypokalcmia and hypomagncsemia induced by thiazide
diuretic treatment. The cardiac rate increased to 60 to 70 per
minute after intravenous atropine treatment, and potassium
chloride was begun, but intermittent A-V dissociation persisted. Amnesia improved, but did not clear. On the second
hospital day intramuscular injection of magnesium sulfate
was followed by prompt return of normal sinus rhythm at a
rate of 66 to 80 per minute. Coincident with permanent
restoration of sinus rhythm, the patient's immediate recall
and recent memory returned except that she remained
amnesic for a period of two hours on the day of admission.
Sinus rhythm persisted, although the rate occasionally fell as
low as 58 per minute. Memory remained intact. During the
subsequent two years, no episodes of amnesia occurred, and
no congestive heart failure supervened after withdrawal of
digitalis glycosides. Despite a prescribed diet, she has failed
to lose weight. The hypertension persists intermittently, but
under better control with hydrochlorothiazide, guanethidine,
diazepam, and alpha methyldopa in various combinations.
The blood pressure has fluctuated from 140/90 to 200/100
mm Hg.
In the past ten years, there have been six other patients
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ECG leads II, V, and V, show sinus and A Vjunctional bradycardia with A V dissociation induced by digitalis. In lead II,
the fourth complex shows depressed left ventricular conduction after the conducted sinus impulse in the supernormal
phase.
514
Strokt. Vol. 6, StptvnbT-Octobr 1975
TRANSIENT GLOBAL AMNESIA
with TGA recognized at this hospital. In two patients, ECGs
obtained during or soon after the episode of" TGA showed
sinus bradycardia at rates of S3 and SS per minute, respectively, with the latter patient having a rate of 60 per minute
after TGA cleared. No other ECG abnormalities were present. ECGs were not obtained in two patients whose rate and
rhythm were normal during TGA. Two additional patients
underwent surveillance with a 24-hour Holter ECG recording without detection of arrhythmia. In none was the ECG
obtained at the onset of TGA.
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Discussion
Damage to hippocampal formations during temporal
lobectomy may produce permanent total loss of immediate recall and recent memory without impairment of consciousness, remote memory or intelligence.1216 A similar clinical state may follow
bilateral posterior cerebral artery occlusion with hippocampal infarction.6-8 The hippocampal formations,
particularly Ammon's horn, are especially vulnerable
to hypoxia, leading many investigators to suspect that
TGA represents reversible ischemia of this portion of
the brain.4-10' '*• " TGA has been reported in a variety
of situations capable of compromising cerebral blood
2 3, 18, 18, 17
flow: hypertension,
'
migraine,9'1S temporal
16
arteritis, aortic valve prosthesis and bicuspid aortic
valve with aortic insufficiency,19 long-standing atrial
fibrillation,2 coronary angiography with suspected
arterial embolization,8 cerebral angiography,6 and
carotid stenosis.4 Also, there are reports of TGA during events stressful to the cardiovascular system: sexual intercourse,2 hot baths,4' " swimming in cold
water,2' n spinal anesthesia,20 and hyperventilation
followed by prolonged Valsalva maneuver.11
Both digitalis and hypomagnesemia have been
implicated in confusional states. Before the advent of
cardiac monitoring, digitalis intoxication was thought
to produce confusion, the so-called digitalis delirium,2124 but not a memory deficit in an otherwise intact patient. Digitalis-induced bradyarrhythmia with
cerebral hypoperfusion secondary to altered cardiac
output is now felt to be the explanation rather than a
direct, central effect of the drug. Hypomagnesemia
also is associated with confusion, seizures, and
tetany2627 and may be responsible for prolongation of
the Wernicke-Korsakoff syndrome despite thiamine
therapy,28 but it is not associated with amnesia alone.
Reserpine itself has not been reported to cause TGA.
The patient reported here had digitalis-induced
bradyarrhythmia contributed to by reserpine treatment and by hypokalemia and hypomagnesemia induced by thiazide diuretic treatment. Depletion of
either or both minerals and the parasympathetic
predominance resulting from sympathetic depression
during reserpine treatment promote cardiac sensitivity
to digitalis glycosides"129~32 and hence to the observed
bradyarrhythmia and ventricular ectopy.
The only subjective accompaniment of this potentially dangerous arrhythmia was TGA. Its course
coincided with the arrhythmia and resolved only upon
Stroke, Vol. 6, September-October 7975
the patient's permanent return to normal sinus
rhythm. None of the more common manifestations of
cardiac arrhythmias such as palpitation, syncope,
dyspnea, or chest pain occurred. In two of our TGA
patients, sinus bradycardia was present, raising the
possibility of a more severe bradyarrhythmia at the
time TGA began. The course of these patients
suggests that cerebral hypoperfusion caused by
bradyarrhythmia may be etiological. Arrhythmias
should be suspected and excluded in every patient with
TGA.
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SIS
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516
Stroke, Vol. 6, September-October 1975
Transient Global Amnesia Associated With Cardiac Arrhythmia and Digitalis Intoxication
JOHN E. GREENLEE, RICHARD S. CRAMPTON and JAMES Q. MILLER
Stroke. 1975;6:513-516
doi: 10.1161/01.STR.6.5.513
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