Eur Radiol (2003) 13:L133–L137
DOI 10.1007/s00330-002-1744-0

Osman Kizilkilic
Sait Albayram
Özgür Kasapcopur
Ismail Mihmanli
Naci Kocer
Civan Islak

Received: 18 February 2002
Revised: 28 June 2002
Accepted: 7 October 2002
Published online: 22 November 2002
© Springer-Verlag 2002

O. Kizilkilic · S. Albayram · I. Mihmanli
N. Kocer · C. Islak (✉)
Department of Radiology,
Division of Neuroradiology,
Cerrahpasa Medical Faculty,
34300 Istanbul, Turkey
e-mail: cislak@istanbul.edu.tr
Tel.: +90-212-5861586
Fax: +90-212-5884884
Ö. Kasapcopur
Department of Pediatrics,
Cerrahpasa Medical Faculty,
34300 Istanbul, Turkey

P E D I AT R I C

MRI findings of hypoxic cortical laminar
necrosis in a child with hemolytic anemia
crisis

Abstract We present magnetic resonance imaging findings of a 5-yearold girl who had a rapidly installing
hemolytic anemia crisis induced by
trimethoprim–sulfomethoxazole,
resulting in cerebral anoxia leading
to permanent damage. Magnetic
Resonance imaging revealed cortical
laminar necrosis in arterial border
zones in both cerebral hemispheres,
ischemic changes in subcortical
white matter of left cerebral hemisphere, and in the left putamen.
Although cortical laminar necrosis is
a classic entity in adulthood related
to conditions of energy depletions,
there are few reports available in
children. A wide review of the literature is also presented.

Keywords Hypoxic encephalopathy ·
Hemolytic anemia · Cortical laminar
necrosis · MRI

Introduction

Case report

In most type of anemias in the long term, compensatory
mechanisms preserve brain oxygenation, but if anemia
settles in a very short time, these compensatory mechanisms cannot be enough or in time, and it occasionally
causes cerebral ischemia. In this report, we present a
case of acutely settled hemolytic anemia that resulted in
global cerebral hypoxia/anoxia and permanent damage.
In rapidly settled anemia, such as hemolytic crisis, neurologic functions should be closely observed and every
effort should be made in preserving enough oxygen supply to the brain. If there is any alteration of consciousness or appearance of convulsion observed during such a
crisis, anemic-type hypoxia/anoxia should be kept in
mind in differential diagnosis. Magnetic resonance imaging is the method of choice for demonstrating the lesions
and making differential diagnosis.

We present a 5-year-old girl who had been surgically treated for
lumbar meningomyelocele in immediate neonatal period. Urinary
tract infection and bilateral grade-4 hydronephrosis and neurogenic bladder appeared a year later. Recurrent urinary infection necessitated repeated antibiotic treatment. Last time she admitted to the
hospital with suffering of fever while she was under trimethoprime–sulfomethaxazol (TMP–SMX) prophlaxis regimen for
nearly 6 months. Body temperature was 38.7°C. Leukocytosis and
urine data confirmed urinary infection and third-line ceftriaxone
was added to TMP–SMX. Neurologic examination was normal.
On the third day of admission, hematuria and automatic mastication were observed. She had a generalized tonic–clonic seizure
and she deteriorated. At the same time, blood data showed hemolysis and hemoglobin (Hb) level of 3.2 g/dl. Urine analysis
revealed profound hemoglobinuria and microscopic hematuria.
Direct Coombs test was positive. Hemolytic uremic syndrome
(HUS), which is a disease of infancy and early childhood, was
excluded by absence of thrombocytopenia, hypertension, and
acute renal failure. The glucose-6-phosphate dehydrogenase level
(8.7 U/g hemoglobin) was normal (6.4–15.6 U/g hemoglobin).

L134

Fig. 1 a T1-weighted sagittal image shows Arnold-Chiari type-I
malformation; both b and c axial T1-weighted define show highintensity lesions in right parieto-occipital and left fronto-parietooccipital regions, distributed laminarly in the cerebral cortex and
in the left putamen, and marked ventricular enlargement

In addition, subcortical white matter hyperintensities were observed on T2WI (Fig. 2). Computed tomography did not show any
high-density lesion on the same day (Fig. 3).
On tenth day of admission, hemolysis regressed and Hb level
of 9 g/dl was achieved. Diagnosis of TMP/SMX-induced hemolysis strongly supported clinical outcome of patient.

Discussion

Hemolytic anemia induced by TMP–SMX was the final diagnosis
with these data.
Both TMP–SMX and ceftriaxone immediately stopped after
these hemolytic findings. Antibiotic regimen changed with imipenem–cilastatin combination. Packed red blood cells transfused to
patient with dosage of 10 cc/kg. Intravenous supportive treatment
maintained blood pressure in normal limits. Anti-epileptic treatment was given and seizure stopped but consciousness never came
back. She underwent cranial MR imaging on fifth day of deterioration because of extended unconsciousness. Sagittal T1-weighted
images (T1WI) were revealed Arnold-Chiari type I coupled with
high signal intensity lesions in the right parieto-occipital, left fronto-parieto-occipital, in the arterial border-zone distributed laminarly in the cerebral cortex, and in the left putamen (Fig. 1). The cerebellum and brain stem were normal. T2-weighted images (T2WI)
revealed that some of these lesions were hypointense and some of
these lesions were hyperintense compared with the normal cortex.

Cerebral hypoxia/anoxia occurs when there is an inadequate amount of oxygen delivered to the brain and its
causes are categorized as follows:
1. Stagnant hypoxia (ischemic and oligemic)
2. Hypoxic hypoxia (airway obstruction, drowning, reduced inspired oxygen content)
3. Anemic hypoxia (carbon monoxide intoxication)
4. Histotoxic hypoxia affecting cellular respiratory enzymes (cyanide intoxication)
Although hypoglycemia is not a hypoxemic condition,
since hypotension is usually associated with hypoglycemia and results in hypoxia, hypoglycemia is classified as
the fifth group of cerebral hypoxia/anoxia. All types of
cerebral hypoxic/anoxic conditions are generally associated with one type of anoxia or another. For example, in
hypoxemic hypoxia, hypotension usually occurs and
stagnant-type hypoxia follows [1].
Neurologic involvement can also be seen in HUS,
which may cause acute hemolysis and has classical triad
of microangiopathic hemolytic anemia, thrombocytope-

L135

Fig. 2a, b T2-weighted axial MRI depicts the same lesions. Instead of cortical signal intensity, widespread hyperintensity on
T1WI and T2WI is shown: both hypointense and hyperintense
(dominant on left parietal lobe) lesions in the same areas. White
matter involvement in subcortical region, and left putaminal ischemic changes, are seen as hyperintensities on T2WI. Prominent
ventricular enlargement is also seen

nia, and uremia. Pathologic examination of brain in patients who die of HUS and neurologic dysfunction shows
microthrombi in cerebral vessels and nonspecific changes or cerebral edema. Although the HUS is not a radiologic diagnosis, cerebral MRI findings of HUS include

Fig. 3a, b Axial CT images reveal absence of high-density lesions
in same areas

high signal intensity on both T1WI and T2WI, in lentiform nucleus, in the internal–external–extreme capsule,
which indicates infarct with focal hemorrhage. Low signal intensity on T1- and high signal intensity on T2WI in
the splenium of the corpus callosum also could be seen
[2, 3]. The distributions of these lesions are different
from those in our patient. Lesions in HUS are infarctions
due to thrombi in microvessels, such as perforating arteries, which supply affected brain regions.

L136

Although the sulfonamides are accepted as safe drugs,
their list of possible adverse reactions is very long. They
may cause a number of allergic reactions, from relatively
minor skin rashes to severe or even life-threatening reactions. Their hematologic complications, which include
agranulocytosis, hemolytic and megaloblastic anemia
and thrombocytopenia, are usually dose related and frequently seen in patients with glucose-6-phosphate dehydrogenase deficiency. Although TMP–SMX rarely causes hemolysis in normal subjects, it was thought to be the
cause of hemolysis in our patient and also glucose6-phosphate dehydrogenase deficiency [4, 5]. This serious hemolysis resulted in deep anemia in very short
time.
Anemia refers to low blood Hb level from whatever
cause. Although oxygen carrying capacity of blood is
compromised in anemia, in the mid- and long term, the
compensatory mechanisms preserve adequate tissue oxygenation [1, 6]. The most prominent of such mechanisms
is augmentation of cerebral blood flow (CBF). Regulation of CBF is a function of cerebral perfusion pressure
(CPP) and cerebrovascular resistance (CVR). The CVR
is synergistically mediated by chemical and neurogenic
factors. Cerebral perfusion pressure is a function of
mean arterial blood pressure and intracranial pressure.
Any change in these variables will induce autoregulatory
responses. Hematocrit also plays an important role for
CBF regulation, and since it is the major determinant of
blood viscosity any decrease in hematocrit level is associated with an increase in CBF and CBV. The increase of
CBF is also related to active cerebrovascular dilation in
response to reduced oxygen delivery and hypercapnia
and improved rheology [6].
In chronic anemias, despite the very low Hb levels,
sufficient oxygen supply to the brain is maintained. But
if the Hb level decreases in a short time, or very rapidly
as occurred in our patient, compensatory mechanisms
cannot be enough or in time and cerebral hypoxia/anoxia
may ensue reversible or irreversible cerebral ischemic
changes [1]. There is no threshold value defined for Hb
level below which cerebral hypoxia/anoxia may occur.
Young and co-workers reported [7] a 2-year-old child
with cerebral anoxia in whom Hb level of 4 g/dl and
carotid stenosis were detected. In our patient, although
no additional diseases were found, by the onset of hemolytic crisis Hb level had decreased from 9.8 to 3.2 g/dl
within less than 6 h probably precluding the compensatory mechanisms from taking place or making them insufficient.
The clinical findings of cerebral ischemia vary with
age and it tends to present with seizures, unconsciousness, and fever in children younger than 10 years [8]. In
this patient, the beginning of the seizures after acute
hemolytic crisis suggests that acute anemia resulting in
anoxia was the triggering mechanism. Although the
seizures stopped and normal blood pressure was main-

tained, unconsciousness was extended probably due to
permanent brain damage.
In the cerebral global hypoxic/anoxic conditions cerebral cortex is the most commonly affected region and the
white matter is completely or relatively spared. This observation can be explained by the fact that the white matter is metabolically less active than cortex [9, 10, 11].
Other explanations are found in the distribution of excitatory amino acid synapses and local physicochemical
factors at cellular level and in vascular depositions.
The distribution of ischemic lesions of brain can also be
explained by the selective vulnerability of different
regions. Basal ganglia are commonly affected probably
due to their end-artery-type vascularization and lack of
anastomoses and their high metabolic activity. Cerebral
cortex in borderline area is also affected since it is metabolically active and the farthest point from the vascular
supply. In addition, some other probable unknown factors determine the type and place of ischemic lesions in
different etiologic pathologies and age groups.
In the present patient anemic type of global hypoxia/anoxia led to necrosis and demyelination in the watershed distribution of cerebral arteries. The lesions were in
frontal, parietal, and occipital lobes, and in the left putamen. The cortical lesions were distributed with a gyriform pattern in the bases of the sulci and were marked in
the arterial watershed zones. These characteristics are
compatible with the radiologic findings of cortical laminar necrosis [2, 3, 11, 12].
Hyperintense cortical lesions associated with cerebral
ischemia on unenhanced T1WI may represent methemoglobin/hemorrhage, paramagnetic substances, fat tissue,
calcification, high protein concentration, and cortical laminar necrosis [13]. Boyko et al. reported that cortical T1weighted hyperintense lesions in cases of brain infarction
histopathologically presented as cortical laminar necrosis
without hemorrhage or calcification [14]. Computed tomography did not reveal any high-density lesion so we
thought that T1-weighted hyperintense lesions did not reflect calcification or hemorrhage. Cortical laminar necrosis
can be histologically defined as pan-necrosis including
neurons, glia, and blood vessels in the affected area. One
possible result of pan-necrosis is protein degradation. As
T1 shortens, protein degradation is very closely related to
the MR signals [13]. Takahashi et al. reported hypointensity on T2WI with a poor clinical outcome [11]. Although
protons in proteins do not usually contribute to the MR signals, the protein concentration and amount of free water
may influence the T1 and T2 relaxation characteristics [14].
Fluid-attenuated inversion recovery (FLAIR) sequences have been found to be normal in the first month
of cortical lesions. Since we had enough data with conventional sequences, we did not perform FLAIR sequence in this patient. The FLAIR images are superior
for detecting brain infarction, especially of cortical lesions. On the other hand, diffusion-weighted MR imag-

L137

ing has been shown to be highly sensitive for the diagnosis of cerebral infarction in the acute stage, which was
not available in our institution previously.
Although we have no pathologic proof, lesions demonstrated on MRI may be compatible with deposition of
fat-laden macrophages and protein degradation at the
necrosis site, whereas the same lesions were seen as
both hypointense and hyperintense on T2WI due to protein–water content interrelation and deposition of fatladen macrophages.
Cortical laminar necrosis comprises ischemic neuronal
changes and the gliotic reaction. It is accompanied by the
laminar deposition of fat-laden macrophages. It is likely
that the high signal intensity lesions in our patient reflect
necrosis of cortical neurons and the resultant tissue necrosis. Identification of cortical laminar necrosis witnesses
the global nature of ischemia rather than local factors.

Conclusion
In most types of anemias in the long term, compensatory
mechanisms preserve brain oxygenation. Unless anemia
takes place in a very short time and results in very low
Hb levels, it rarely causes cerebral ischemia. Therefore,
in rapidly settled anemias, such as hemolytic crisis, neurologic functions should be closely observed and every
effort should be done in preserving enough oxygen supply to the brain. Although it is rare, if any alteration of
conscious or appearance of convulsion is observed during such a crisis, anemic-type hypoxia/anoxia should be
kept in mind. This appears to be the case especially
when Hb level decreases below 4 g/dl. Magnetic resonance imaging is the method of choice, not only for
demonstrating the lesions but also for making differential diagnosis.

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