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Encephalopathy following arteriography A possible toxic effect of contrast agents.

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Encephalopathy Following
Arteriography :
A Possible Toxic Effect
of Contrast Agents
E Clarke Haley, Jr. MD
Three elderly men being evaluated for cerebrovascular
disease developed acute confusional states following arteriography with approximately 50 m l of meglumine
iothalamate. Two patients became stuporous. All recovered in several days, and no specific cause was found
for t h e disorder. In the absence of other demonstrated
abnormalities, we suggest that in each patient the encephalopathy may have been a toxic reaction to the contrast agent.
Haley EC, Jr. Encephalopathy following
arteriography. a possible toxic effect of contrast
agents Ann Neurol 15.100-102, 1984
From 1980 to 1982 we observed three cases of global
encephalopathy lasting from 2 to 8 days following cerebral arteriography. The clinical and laboratory findings
of the affected patients are presented here, and a possible pathogenetic mechanism is proposed.
Case Reports
Patient I
A 70-year-old man was admitted for evaluation of a 4-hour
episode of transient right monocular blindness occurring on
the day of admission. Physical examination disclosed a right
carotid bruit, normal findings on funduscopic examination,
normal visual acuity, and full visual fields on formal testing.
The remainder of the neurological examination, including
assessment of mental status, showed normal results. Medications included cimetidine for peptic ulcer disease, hydrochlorothiazide for hypertension, and propranolol for stable angina. Laboratory screening data were within normal limits
except for a blood urea nitrogen (BUN) level of 27 mgidl
(normal, 10 to 26 mgidl). Following premedication with atropine (0.4 mg intramuscularly) and diazepam (10 mg orally),
the patient underwent selective bilateral carotid arteriography via the transfemoral route and had selective injections
into the right innominate and left subclavian arteries. A total
of 56 ml of 6057 meglumine iothalamate (Conray 60) was
used. An ulcerated plaque was demonstrated at the origin of
the right internal carotid. Immediately following the proce-
From the Department of Neurology, Box 394,University of Virginia, Charlortesville. VA 22908.
Received Jan 17, 1083, and in revised form May 27. Accepted fur
publication May 30, 1983.
Address reprint requests to Dr Haley.
dure, the patient complained of headache and became progressively confused and combative. Neurological examination revealed no focal deficit except for equivocal bilateral
Babinski’s signs. Over the next 24 hours, the patient became
stuporous and did not speak or respond to commands but
continued to localize painful stimuli bilaterally. Laboratory
data disclosed normal electrolytes, including calcium and
magnesium, as well as normal serum osmolality and arterial
blood gases. A head computed tomographic (CTj scan disclosed no abnormalities. An electroencephalogram (EEG)
demonstrated background slowing in the theta range with
intermittent generalized delta activity compatible with a
global encephalopathy. Cerebrospinal fluid (CSF) was ace11ular and under normal pressure.
After the initial 24 hours, the patient improved progrt:ssively and resumed his pretest state on the eighth day. Renal
function tests showed moderate worsening over the first 6
days, with B U N levels reaching 66 mgidl and creatinine 3.7
mgidl. By 8 days after the arteriogram, the BUN level was 45
mgidl and the creatinine level was 2.8 mgldl. At no time did
the patient become acidotic.
Patient 2
A 78-year-old man was admitted for evaluation of two episodes of aphasia and right upper extremity weakness. He had
a history of hypertension controlled by hydrochlorothiazide
therapy. General examination disclosed no bruits, and results
of neurological examination were normal. Following premedication with arropine (0.4 mg intramuscularly) and
diazepam (10 mg orally j, transfemoral cerebral arteriography
was performed; selective injections were made into the left
and right common carotid arteries and into the right innominate artery. A total of 5 1 ml of 6057 meglumine iothalamate
was injected. A small atherosclerotic plaque withour
significant stenosis was demonstrated in the left internal
carotid. After returning to the ward, the patient called for ii
nurse “to put some urine in a safety deposit box.” He became
progressively disoriented, combative, and delirious. Results
of neurological examination were normal except for the p a
tient’s abnormal mental state. Results of metabolic screening
and head CT scan were normal. Stupor evolved over the next
several hours, but 96 hours after the arteriogram the patient
had returned to his pretest state.
Patient 3
A 74-year-old man was admitted for evaluation of progressively worsening angina refractory to medical therapy. Medications on admission included tolbutamide for mild adultonset diabetes, and oral and sublingual nitrates for angina. No
history of stroke, transient ischemic attack, o r alcohol abuse
was noted. Baseline neurological examination showed a mild
dementia which had been present for five to seven years.
Because of bilateral carotid bruits, the patient underwent
transfemoral cerebral arteriography. Following premedication with atropine (0.4 mg intramuscularly) and diazepam ( 10
mg orally), selective right and left carotid injections were
made. A total of 48 ml of 60% meglumine iothalamate was
injected. The right internal carotid was mildly narrowed at its
origin; the left was severely narrowed at its origin and showed
evidence of ulceration. Several hours after the study, the
patient became disoriented, confused, and combative. Examination revealed a mental status compatible with delirium, no
lateralizing signs, and no pathological reflexes except for bilateral grasp responses. Metabolic studies showed normal resuits except for a blood glucose level of 193 mg/dl. The
patient remained delirious and required restraint for 12
hours, but thereafter progressively improved. After 48 hours
he returned to his preangiographic status.
With the availability of improved surgical and anesthetic techniques for cerebral revascularization, the
need for safe and accurate cerebral arteriography persists despite the introduction of CT scanning. With
modern catheterization techniques and new contrast
media of low toxicity, cerebral arteriography is a relatively safe procedure in experienced hands. Permanent
complications, including death, occur at a rate of approximately 1 to 39% 191, although both higher [ 2 ) and
lower [lo] complication rates are reported. Transient
neurological complications can be distressingly severe,
however, and present serious differential diagnostic
and management problems to the clinician. The three
patients described above clinically demonstrated
global, rather than focal, cerebral dysfunction as a complication of their arteriograms. All were elderly men
being evaluated for cerebrovascular disease. All had a
history of hypertension, although in each the condition
was under control with medication at the time of the
procedure. The onset of encephalopathic symptoms
varied from immediately following arteriography in patient l to several hours after the study in patient 3. All
three patients were initially confused, agitated, and disoriented, but in patients 1 and 2 progressive stupor
developed and symptoms were of longer duration.
Several potential contributing factors were identified
in these patients. Each had received premedication
with diazepam and atropine. These drugs may have
contributed to the encephalopathy, although the time
and nature of onset as well as the clinical course in each
case seem to exclude them as the primary causative
agents. Patient 1 was taking cimetidine, which has been
reported to cause confusion in elderly patients 1141.
Nevertheless, he had tolerated the drug well in the
past, and the onset of his symptoms was temporally
related to arteriography. Additionally, chemical evidence of mild renal insufficiency, presumably related to
his long-standing hypertension, was present prior to
and transiently increased after the study. The exacerbation of this patient’s renal dysfunction could have contributed somewhat to his altered mental status, but was
not severe enough to account for his degree of disorientation. Furthermore, his level of consciousness
was at its nadir on the first day after the procedure,
while his renal functioning continued to worsen until
the sixth day. Thus, the course of this patient’s enceph-
alopathy did not correlate with the course of his renal
dysfunction. Patient 2 developed mild hyponatremia,
but the condition was not greatly worse than on admission and not severe enough to explain his course. Patient 3 was mildly demented, as well as hyperglycemic,
prior to the procedure. Nonetheless, his behavior after
arteriography represented a distinct departure from his
preangiographic mental state despite little change in his
blood glucose level.
Previously, complications of cerebral arteriography
have been divided into two large pathogenetic groups:
those related to the technique of the procedure (e.g.,
embolus from the catheter, or subintimal injections)
and those related to the contrast medium itself. That
contrast media are neurotoxic has been well recognized, but the mechanism of neurotoxicity remains debatable. Deleterious reactions have been attributed to
the hyperosmolality of the media [ I , 41,resulting in
hernodynamic and blood brain barrier alterations, to
their ability to agglutinate red blood cells (resulting in
microvascular sludging) { 7 ] , and to arterial spasm [ 131.
Even so-called safe, modern contrast media may cross
the blood-CSF barrier, as has been shown experimentally [ S , 81 and seen occasionally in humans [lb]. Once
past the blood-CSF barrier, contrast agents vary widely
in their neurotoxicity, as demonstrated in studies using
intracisternal application of the agents. Tuohimaa and
Melartin 117) showed in rats that the median lethal
dose and the threshold for convulsions of intracisternally injected contrast was related to the amount of
uptake by brain gray matter. Relative neurotoxicity
also depended on the nature of the cation and increased with increasing concentration, both in the hypertonic and hypotonic ranges. Rapoport and Levitan
112) have shown that the neurotoxicity of contrast
agents can be related to the lipid solubility of the
iodine-containing moiety. These studies suggest that
contrast agents may possess inherent neurocytotoxicity
once they gain access to the extravascular compartment, either through a previously altered blood-CSF
(brain) barrier or via an incompetent barrier induced by
their high osmolality.
We suspect that the encephalopathy seen in our patients may have been caused by the direct toxic effect
of meglumine iothalamate on the brain. At no time was
it demonstrated, either by examination or laboratory
studies, that focal vascular changes were causative. That
this encephalopathy arose without previous alterations
in mental status contradicts the prevailing view in the
literature that changes in mental status after arteriography usually represent “an increase of prearteriographic
neurological deficit” [ 151. Indeed, this complication is
unreported in many large series [2, 3, 61,although
Olivecrona 111) reported agitation in 65 (1.7%) of
3,730 patients and coma without focal signs in another
6 (0.2%).Our three patients were culled from approxiBrief Communication: Haley: Contrast Enccphalopathy
10 1
mately 1,350 studies, though retrospective review of
all cases was not performed.
Brain Trace Elements
in Pick's Disease
The author thanks Dr T. R. Johns, D r Wayne Cail, D r G. Frederick
Wooten, Elizabeth Wright, and Rose Powell for their advice and
assistance in the preparation of this manuscript.
W. D. Ehmann, PhD," M. Alauddin, PhD,"
T. I. M. Hossain, PhD," and W. R. Markesbery, MD'FS,$
1. Broman T, Olsson 0:The tolerance of cerebral blood vessels to
a contrast medium o f the Diodrast group: an experimental study
of the effect on the blood-brain barrier. Acta Radiol 30:326,
2. Faught E, Trader SD, Hanna GR: Cerebral complications of
angiography for transient ischemia and stroke: prediction of risk.
Neurology (NY) 29:4-15, 1979
3. HISS WK, Fields WS, North RR, et al: Joint study of extracranial
arterial occlusion. 11. Arteriography, techniques, sites, and complications. JAMA 203961-368, 1968
4. Hilal SK: Hemodynamic changes associated with the intraarterial injection of contrast media. Radiology 86:615-633,
5 . Hilal SK: Trends in preparation o f new angiographic contrast
media with special emphasis on polymeric derivations. Invest
Radiol 5:458-472, 1970
6.Huckman MS, Shenk GI, Neems RL, Tinor T: Transfemoral
cerebral arteriography versus direct percutaneous carotid and
brachial arteriography: a comparison of complication rates.
Radiology 13293-97, 1979
7 . Johnson JH, Knisely MH: Intravascular agglutination of the
flowing blood following the injection of radiopaque contrast
media. Neurology ( N Y ) 12:560-570, 1962
8. h p e KF, James G, Erbesfield M, er al: Cerebrovascular permeability of a water-soluble contrast material, Hypaque (sodium
diatrizoate); experimental study in dogs. Invest Radiol 5:79-85,
9, Lundervold A, Engeset A: Cerebral angiography. In Ansell G
(ed): Complications of Diagnostic Radiology. Oxford, England,
Blackwell Scientific Publications, 1976
10 Mani RL, Eisenberg RL, McDonald EJ, et al: Complications of
catheter cerebral arteriography: analysis of 5000 procedures (3
parts). Am J Roentgenol 131:861-874, 1978
11. Olivecrona H: Complications of cerebral angiography.
Neuroradiology 14:175-181, 1977
12 Rapoport S, Levitan H : Neurotoxicity of x-ray contrast media:
relation to lipid solubility and blood-brain barrier permeability.
Am J Roentgenol 122:186-193, 1974
13 Raynor RB, Ross GR: Arteriography and vasospasm. j Neurosurg 17:1055- 1060, 1969
14 Russell WL, Lopes LM: Cimeridine-induced mental status
changes: case report and literature review (32 ref). Am J Hosp
Pharm 37:1667-1671, 1980
15 Silverstein A: Arteriography of stroke. 111. Complications. Arch
Neurol 15:206-210, 1966
16. Studdard WE, Davis DO, Young SW, et al: Cortical blindness
after cerebral angiography. J Neurosurg 54:240-244, 1981
17. Tuohimaa FT, Melartin E, Dabb R: Neurotoxicity of iothalamates and diatrizoates (2 parts). Invest Radiol 5:13-29, 1970
The trace element content of the brain of two patients
with Pick's disease examined postmortem was studied
using instrumental neutron activation analysis. Results
showed significant increases in chlorine, iron, manganese, sodium, and phosphorus and significant decreases
in chromium, cesium, rubidium, and selenium and in the
mean freeze-dried to wet-weight ratio for patients with
Pick's disease compared with control patients. Brain zinc
content was not elevated in the two patients, a finding
that fails to support the hypothesis that elevated zinc
levels play a role in the pathogenesis of Pick's disease.
Ehmann WD, Alauddin M, Hossain TIM,
Markesbery WR: Brain trace elements in Pick's
disease. Ann Neurol 15:102-104, 1084
Pick's disease (PD) is characterized clinically by progressive dementia and focal cortical signs, and pathologically by circumscribed frontal and temporal lobe
atrophy [7]. Microscopically one finds severe neuron
loss and gliosis and the presence of Pick's cells and
Pick's bodies [3, 7). Recently it has been proposed that
this disorder is related to a generalized elevated zinc
level with accumulation of Zn in the brain [ I , 21. Accordingly, we report the trace element analysis of the
brains of two patients with P D studied postmortem..
Case Reports
Patient 1
A 56-year-old woman developed a gradually progressive, dementing illness. An evaluation revealed no treatable causes,
and she died at age 61 years of bronchopneumonia. At postmortem examination the brain weighed 1,200 gm and
showed moderate frontal pole and medial temporal lobe atrophy. Microscopic findings consisted of severe neuronal loss
and astrocytosis in the temporal lobe and mild to moderate
neuronal loss and astrocytosis in the frontal lobe. Pick's
bodies were present in a variety of sites.
Patient 2
A 67-year-old man died after 10 years of progressive mental
deterioration. The patient's mother had had a similar di:jor-
From the Departments of 'Chemistry, +Pathology, and $Neurology,
and $The Sanders-Brown Research Center on Aging, University of
Kentucky, Lexington, KY 40536-0230.
Received June 3 , 1983. Accepted for publication June 19, 1983.
Address reprint requests to D r Ehmann, Department of Chemistry,
University o f Kentucky, 305 Chemistry-Physics Blrig, LexinJ:ton,
KY 40506 0055.
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effect, encephalopathy, following, contrast, agenti, possible, arteriographic, toxic
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