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Calcification in a Recent Cerebral Infarct
- Radiologic and Pathologic Correlation
J. Parisi, C. Place and S. Nag

ABSTRACT: This 60 year old male developed a right hemiplegia and aphasia. A C.T. head scan showed a cerebral
infarct which appeared hyperdense on a subsequent scan done 18 days after presentation. This was interpreted as
indicating a hemorrhagic transformation resulting in discontinuation of anticoagulation therapy. At autopsy, the area
of infarction in the left frontoparietal hemisphere appeared intensely green due to breakdown of the blood-brain
barrier in the presence ofjaundice. A strikingfindingon microscopy was the presence of calcium salts throughout the
area of infarction but most prominent in the grey matter at the periphery of the infarct corresponding to the areas
which appeared hyperdense on the CT head scan and stained intensely with bilirubin. There was no evidence of recent
hemorrhage. This case illustrates that calcification can occur within weeks after the onset of a recent cerebral infarct
and should be considered when interpreting the development of C.T. scan hyperdensity in recent cerebral infarcts.
RESUME: Calcification au niveau d'un infarctus cerebral recent - correlations radiologiques et anatomopathologiques
Chez un homme age" de 60 ayant d^veloppe" une hdmipUSgie droite avec aphasie, un CT scan ce>6bral a montre" un
infarctus c6r6bral qui semblait hyperdense lors d'un scan subsequent fait 18 jours apres l'accident c£r6brovasculaire.
Ce pr6nomene a €i€ interpret comme indiquant une transformation hgmorragique et conse"quemment,
l'anticoaguloth£rapie a €\€ discontinued.
A l'autopsie, la zone infarcisee dans l'hemisphere frontoparietal gauche semblait d'un vert intense, due a l'effondrement
de la barriere hdmo-encephalique en presence d'ictere. A la microscopie, nous avons constate une particularity
frappante: la presence de sels de calcium dans toute la zone infarcisee, mais surtout dans la substance grise en
periphdrie de l'infarctus correspondant aux zones qui apparaissaient hyperdenses au CT scan cerebral et qui 6taient
color6es intens£ment par la bilirubine. II n'y avait pas d'evidence d'h6morragie r6cente.
Ce cas illustre la possibility que le processus de calcification puisse survenir en dedans de quelques semaines apres un
infarctus ceYdbral recent et devrait etre consideree lors de 1'interpretation d'une hyperdensity au CT scan, se
ddveloppant sur un infarctus cerebral recent.
Can. J. Neurol. Sci. 1988; 15:152-155

Cerebral calcification has been observed in association with
diverse lesions such as tumors, infections, and vascular
malformations. Calcification of basal ganglionic vessels is a
frequent finding in brains of elderly patients and has also been
observed in association with disturbances of calcium and phosphate metabolism, in conditions such as hypoparathyroidism.
Calcification of cerebral infarcts is a very rare occurrence. A
few case reports demonstrate hyperdensity in C .T. scans months
to years after the presence of infarcts suggesting the presence
of calcification.1,2 However, in none of these cases was a
pathological follow-up available. In this case report the
hyperdensity observed in a recent infarct on C. T-. scan 18 days
after onset of symptoms was confirmed to be calcification by
subsequent post-mortem studies.

CASE REPORT

A 59 year old male with a past history of three myocardial infarcts
underwent a triple coronary bypass operation. Twenty-one days later
he presented with a three day history of cough and an acute onset of
chest pain, dyspnea and hypoxemia. In the Emergency Room he rapidly developed a dense right hemiplegia and aphasia with a declining
level of consciousness.
Physical examination revealed a blood pressure of 90/60 mmHg,
pulse of 121/min, respiratory rate of 33/min, an elevated jugular venous
pressure and a precordial auscultatory gallop. On chest examination,
decreased air entry, coarse rales, and dullness to percussion were
noted in the left base. Asymmetricrightleg swelling was also present.
Neurologic assessment snowed hemiparesis, decreased corneal reflex
and hemi-inattention on therightside and aphasia.
Laboratory studies demonstrated a pH of 7.53, a p02 of 46 mmHg
and a PC02 of 21.7 mmHg on room air. A chest x-ray revealed a left

From the Departments of Pathology (Neuropathology) and Radiology, Queen's University and Kingston General Hospital, Kingston
Received September I, 1987. Accepted December 12, 1987
Reprint requests to: Dr. S. Nag, Department of Pathology, Queen's University, Kingston, Ontario, Canada K7L 3N6

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Figure I — Non-contrast C. T. scans of head (A)
At 4 hours there is mild swelling of the left
frontoparietal area with compression of the
ipsilateral lateral ventricle.

(B)At seven days a well-defined area ofhypodensity
is present in the region of the recent infarct.
There is shift of structures across the midline
with cingulate herniation and compression of
the ipsilateral lateral ventricle.

basal infiltrate and effusion while a radionuclide perfusion lung scan
demonstrated multiple perfusion defects in radiographically normal
lung which was interpreted as probable for pulmonary embolism.
A C.T. head scan done four hours after admission showed subtle
changes suggestive of an extensive recent left frontoparietal infarction.
The neurologic status continued to deteriorate and anticoagulant therapy was instituted to obtain a prothrombin time which was 1.25 times
control values. Repeat radionuclide perfusion lung scan showed a
changing pattern of defects. Anticoagulation and ventilatory support
were continued but there was no improvement in neurologic function
and a steady worsening of the patient's respiratory status. The l.C.U.
course was complicated by superimposed sepsis, the onset of renal
failure and intrahepatic cholestatic jaundice as manifested by mildly
elevated transaminase (A.S.T. 35 U/L, normal range less than 21 U/L)
and marked elevation of total bilirubin (total bilirubin 195 umol/L,
normal range less than 17 umol/L). Alkaline phosphatase was normal
and ultrasound examination excluded extrahepatic obstruction. Serum
calcium levels also rose slightly (2.95 mmol/l, normal 2.15 to 2.65
mmol/1) three days prior to death.
Serial C.T. scans performed one and seven days after admission
(Figures 1A, B) confirmed the presence of a large frontoparietal cerebral infarction. However, the scan done eighteen days after admission
showed striking hyperdensity of the basal ganglia and cortical ribbon in
the infarcted region (Figure 1C). The possibility that the hyperdensity
might represent calcification was not entertained and the hyperdensity
was interpreted as hemorrhage into the infarct and anticoagulation was
stopped.
In view of the continued deterioration and extensive cerebral damage further aggressive therapy was withheld and the patient expired 22
days after admission.

AUTOPSY FINDINGS

The cause of death was septicemia and bilateral acute bronchopneumonia with a left lower lobe abscess, due to Aerobacter
aerugenes. In addition, a large saddle thromboembolus was
present in the mainstems of both pulmonary arteries. The source
of the emboli was the right femoral vein which showed a residual organising thrombus. Additional findings were old myocardial infarcts and chronic passive congestion of liver with
cholestasis. Three small organising infarcts were observed in
the spleen and kidneys.

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(C)Atl8 days there is hyperdensity of the cortical
ribbon, the caudate nucleus and putamen on
the infarcted side.

The brain and attached dura weighed 1451 g prior to formalin
fixation. The left frontoparietal region was soft and swollen in
the area of the recent infarction. In this region, the gyri were
flattened and sulci effaced and the cortex was green due to
breakdown of the blood-brain barrier in the presence of
hyperbilirubinemia.
On horizontal sectioning of the brain, the infarct was found to
extend from the left frontal pole to the parieto-occipital junction in the area of distribution of the anterior and middle cerebral arteries (Figure 2A, B). Both the grey and white matter
within the area of infarction showed bilirubin staining however
green staining was more intense in the grey matter regions and
this included the frontal, parietal, and temporal cortex, the
anterior caudate nucleus, putamen, globus pallidus, claustrum,
and insular cortex along the Sylvian fissure. The hyperdensity
seen on CT scanning corresponded to the areas of intense green
discoloration seen in the grey matter regions. There was no
shift of midline structures nor was there evidence of recent or
old hemorrhage in the area of infarction.
Microscopic sections of the brain were stained with hematoxylin-eosin and solochrome-cyanine. Sections from the left
hemisphere revealed the typical histological features of a recent
infarct. The centre of the infarct showed liquefaction necrosis
with disruption of the neuropil and large numbers of foamy
macrophages. There was preservation of the subpial rim of the
molecular layer in the region of infarction. The surrounding
white matter appeared pale using myelin stains and a marked
gemistocytic response was present. In addition, vascular proliferation with endothelial hyperplasia was evident at the margins
of the infarct. These features were consistent with an infarct of
about three weeks duration as suggested by the history.
An additional and striking finding was the presence of amorphous calcium salts throughout the infarcted area but most
prominent in the grey matter at the periphery of the infarct
corresponding to the areas which appeared hyperdense on the
CT head scan and stained intensely with bilirubin (Figure 3A,
B). The nature of the material was confirmed with a von Kossa

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stain for calcium phosphate. Calcium deposition was predominantly perivascular and no calcium was observed in vessel
walls (Figure 4). Cytoplasmic calcium deposition allowed visualisation of dead neurons in the cortex and putamen.
The left internal carotid artery was completely occluded
from the bifurcation to its termination into the left anterior and
middle cerebral arteries by a recent thromboembolus (Figure
2B). The right internal carotid and remaining major cerebral
arteries were patent revealing only patchy atherosclerosis. By
microscopy the age of the thromboembolus corresponded with
the age of the infarct.
DISCUSSION

Calcification of cerebral infarcts is an exceedingly rare
occurrence. The recent literature contains two reports describing a total of six cases.1'2 Kapila (1984)1 described the development of calcification in non-hemorrhagic infarcts of three patients
as detected by serial C.T. scans which showed calcium nine,
twelve, and forty-one months after the onset of infarction.
None of the patients had elevated serum calcium levels. Kuzuhara
et al. ,2 (1985), reported three patients in whom calcification was
detected by C.T. scan two, five, and thirteen years after cerebral infarction. No calcification was noted on the initial C.T.
head scans of these patients. These reports, however, describe
only radiologic evidence of calcification and pathologic confirmation was not available. Furthermore, calcification in these

cases occurred much later than in our patient. Calcium deposition occurring so early in the evolution of a cerebral infarct is
most unusual and to our knowledge has not been previously
described. A review of the last 150 cases of cerebral infarction
at our institution revealed only one in which there was a large
mass of unresorbed mummified tissue remaining in the centre
of a massive ancient infarct. A post-mortem C.T. scan of this
brain showed a hyperdensity at the rim of this necrotic tissue
which on histology showed calcification.
In the present case, the initial interpretation of the C.T. scan
hyperdensity was that of hemorrhage into the infarct. The risk
of hemorrhage is known to increase with the size of the ischemic lesion and is higher if a mass effect is present or if there is a
severe neurologic deficit.3 All of these correlating features
were present in this case. A recent prospective study reported
embolism as the cause of 29 percent of secondary hemorrhagic
infarctions.34 Since our patient recently underwent major cardiac surgery, an embolic etiology was suspected. In addition he
was anticoagulated in view of a suspected pulmonary embolism.
Gross and microscopic examination, however, revealed no
evidence of hemorrhage, and a post-mortem C.T. scan showed
the same pattern of hyperdensity that was present preterminally.

A
Figure 2 — Horizontal section ofthe brain (A) showing the area ofrecent infarction in the leftfronto-parietal area. The dark grey discoloration of the grey matter in
the area of infarction indicates the areas of green staining due to bilirubin extravasation. (B) The left internal carotid artery is occluded by a recent
thromboembolus.

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Figure 4 — Microscopy of the left basal ganglionic region showing calcium
phosphate deposition in neurons (arrowheads) and around the proliferated vessels at the margin of the infarct, x 175

Figure 3 — (A) Whole mount showing the area of infarction in the left basal
ganglionic region. (B) An adjacent section stained with Von Kossa shows
massive calcium phosphate deposition in the periphery of the infarct in
grey matter structures such as the caudate, putamen and cerebral cortex.
A,B,x4.5.

The observed green staining of the brain parenchyma is
attributed to leakage of bilirubin across a damaged blood-brain
barrier in the presence of jaundice. The distribution of calcium
salts suggests the same mode of deposition along with serum
protein leakage, but the exact pathophysiologic mechanisms
are uncertain. The pattern is that of dystrophic calcification,
having occurred in the absence of significant hypercalcemia.
The serum calcium on a post-mortem blood sample was 1.80
mmol/L and the highest recorded level during hospitalization
was 2.95 mmol/L (2.15 - 2.65). Calcification was not found in
any of the other body tissues including the small recent infarcts
in the spleen and kidneys.

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Apart from the formation of pigment stones in the gall bladder calcium and bilirubin are not known to complex. They both,
however, bind to plasma albumin and are considered to have
been deposited independently of each other or in combination
with albumin. The alcohol soluble bilirubin was washed out in
the processing of the tissue sections and could not be demonstrated histologically. Clearly, as demonstrated by the previously reported cases, hyperbilirubinemia is not a requirement
for the deposition of calcium. As well, a case on file at our
institution with jaundice showed bilirubin staining of the infarct
without development of calcification.
The importance of this case, however, lies in the rapidity of
the onset of calcification. Recognition that this phenomenon
could occur rapidly should be kept in mind if C.T. scan
hyperdensity develops following recent infarction since the
radiologist can by appropriate window settings differentiate
between calcification and hemorrhage and thus assist with
subsequent management decisions, particularly with regard to
anticoagulation.
REFERENCES

1. Kapila A. Calcification of cerebral infarction. Radiology 1984; 153:
685-687.
2. Kuzuhara S, Naito Y, Namura Y, et al. C.T. demonstration of
calcification within old cerebral infarcts. J Comput Assist Tomogr
1985; 9(2): 268-271.
3. Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic cerebral infarction - a prospective study. Stroke 1986; 17(2): 179-184.
4. Hakim AM, Ryden-Cooke A, Melanson D. Sequential computerized tomographic appearance of strokes. Stroke 1983; 14(6);
893-897.

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