J Neurosurg 89:460-464, 1998

Late postirradiation occlusive vasculopathy in childhood
medulloblastoma
Report of two cases
YANNICK GRENIER, M.D., TADANORI TOMITA, M.D., MARyANNE H. MARYMONT, M.D.,
SHARON BYRD, M.D, AND DELILAH M. BURROWES, M.D.

Divisions ofPediatric Neurosurgery and Neuroradiology, Children's Memorial Hospital, Chicago,
Illinois, and Northwestern University Medical School, Chicago, Illinois
Y" The authors report two cases of ischemic stroke secondary to occlusive vasculopathy two decades after radiation therapy CRT) for medulloblastoma. Both patients underwent posterior fossa medulloblastoma partial resection, followed by
craniospinal RT in which a cobalt 60 source was used; 40 Gy were given to the whole brain plus a 15-0y boost to the posterior fossa. Both patients received multiagent chemotherapy, immediately following radiation therapy in the first case and
after repeated craniotomy for recurrence 13 years after radiation in the second case. They experienced multiple sequelae
from radiation and chemotherapy, including growth retardation and psychomotor delay. However, 20 years after treatment,
they remained tumor free and able to work, until they presented with focal neurological deficits and seizures. Computerized
tomography and magnetic resonance imaging of the brain in both cases showed no tumor recurrence, but did demonstrate
ischemia in a posterior cerebral artery distribution. Cerebral angiography revealed multiple mid-sized arterial wall irregularities as well as focal stenoses consistent with a postirradiation vasculopathy. The pathophysiological mechanisms, radiological appearance, and incidence of this syndrome are reviewed from the literature.

KEy \VORDS

•

medulloblastoma • radiation therapy

• ischemic infarction

•

stroke

•

children

M

EDULLOBLASTOJ'vLA.S represent 15 to 20% of intracranial childhood tumors. Approximately 250
new cases in the United States are diagnosed
each year. In the past 20 years, improved neurosurgical
techniques and the use of craniospinal irradiation have
contributed to improved life expectancy following treatment of childhood medulloblastoma. 1,5,6 Hence, the longterm side effects following treatment are now apparent.v
This paper presents the cases oftwo patients who presented with ischemic strokes 20 years after undergoing a
combination of radiation therapy and chemotherapy for
medulloblastoma. The magnetic resonance (MR) imaging, MR spectroscopy, and angiographic fmdings are presented to show how they contribute to the diagnosis ofthis
rather rare complication of treatment. The possible pathophysiological mechanisms of this vasculopathy is discussed. The goal of these studies is to optimize the neurological outcome of these survivors who already have
significant cognitive and social deficits secondary to treatment.

Case Reports
Case 1
History. This 25-year-old man presented in 1974 with

460

signs and symptoms of hydrocephalus. He had been treated in November 1974 at the age of 4 years by subtotal
resection of a posterior fossa medulloblastoma and insertion of a ventriculoperitoneal shunt. Postoperatively, he
underwent 6OCO external beam radiation over a 6-week
period (December 1974-January 1975). Initially 40 Gy
was delivered using a parallel opposed custom-shaped
cranial field to the whole brain, followed by a 15-Gy posterior fossa boost for a total dose of 55 Gy to the tumor
bed. Unfortunately, the charts but not the portal films from
1975 were available for review. The spine was radiated
concurrently by using an enface posterior field with a 35Gy dose. The patient was subsequently treated from 1975
to 1977 with adjuvant chemotherapy, including vincristine, cyclophosphamide, and lomustine. He had shown
normal height growth in the 10th percentile until October
1975; however, he did not grow the following year despite
positive arginine and insulin tolerance testing in November 1976. Because his linear height growth completely
ceased, he received growth hormone replacement therapy
from July 1977 to October 1982 but with a poor response.
In July 1982, he was found to have an elevated thyroidstimulating hormone level (34.7 mID/ml), at which time
he began thyroid hormone replacement therapy. The patient also received testosterone replacement therapy. In
March 1978, a bone scan showed a high uptake at the
J Neurosurg. / Volume 89/ September, 1998

Radiation vasculopathy in medulloblastoma

FIG. 1. Case 1. a: Right occipital lobe ischemic changes
demonstrated on Tj-weighted MR image with loss of sulci and
swelling of gyri. b: Postgadolinium Tj-weighted MR image
demonstrating diffuse cortical and subcortical enhancement.

fourth thoracic vertebral body. A biopsy specimen was
obtained via a thoracotomy and showed necrotic bone tissue without evidence of malignancy. In 1979, an audiology evaluation demonstrated bilateral neurosensory hearing disturbance (left side greater than right), requiring a
hearing aid. The Wechsler Intelligence Scale For Children-Revised in 1992 yielded a verbal intelligence quotient (IQ) of 52, a performance IQ of 48, and full scale IQ
of 46. The patient completed high school in the learning
disabled program and is currently employed full time as a
bag boy at a supermarket.
In January 1996, the patient presented with a 6-month
history of recurrent staring spells. His parents noticed that
he seemed to ignore objects placed on his left visual field
and that he would turn his entire body to pick up an object
on his left side.
On examination he was a short (122 em) and very thin
(21.6 kg) young man with alopecia. His head size was 51
em. He had a homonymous visual field defect on confrontation testing. A funduscopic examination failed to reveal any optic nerve or retinal disease. The results of the
remaining neurological examination were normal.
Computerized tomography (CT) scanning demonstrated right occipital cortex enhancement after administration
of contrast medium. This finding is consistent with luxury perfusion observed in subacute ischemic strokes. An
electroencephalogram revealed evidence of epileptiform
activity and the patient was started on a course of Dilantin.
Magnetic resonance images, with and without gadolinium
enhancement, were obtained, which showed old changes
consistent with previous radiation therapy, such as calcification within the basal ganglia and within the left posterior temporal region, as well as new right occipital cortex
diffuse enhancement without associated mass effect (Fig.
1). Magnetic resonance spectroscopy of the posterior interhemispheric gray matter as well as the right posterior
parietal white matter showed decreased N-acetylaspartate
levels without elevated choline consistent with neuronal
loss. The acquisition of the spectrum over the right occipJ Neurosurg. / Volume 89/ September, 1998

FIG. 2. Case 1. Vertebral angiogram obtained at the time of the
initial infarction, revealing multiple focal irregularities (arrows) of
the right posterior cerebral artery.

ital region failed because of artifacts. A cerebral angiogram revealed multiple vessel wall abnormalities in medium- and large-sized vessel walls. The right posterior cerebral artery had a fetal origin and was marked by multiple
focal irregularities, as well as poor distal flow to the right
calcarine artery and the right parietooccipital artery (Fig.
2). The left vertebral artery was very hypoplastic and
filled only slowly after right vertebral artery injection. The
A, segment of the right anterior cerebral artery was very
small caliber.
A posttreatment occlusive vasculopathy was diagnosed
in the patient and he was treated with one baby aspirin (81
mg) per day. Examination 3 weeks after this episode
showed that his hemianopsia had totally resolved, and he
returned to his full-time job. A repeated MR image obtained 6 weeks after the initial MR image revealed almost
complete resolution of the right occipital cortex enhancement (Fig. 3). The patient has been on daily aspirin therapy for 19 months without further neurological deterioration.
Case 2
History. This 23-year-old man underwent a partial resection of a fourth ventricle medulloblastoma and a placement ofventriculoperitoneal shunt in February 1975 when
he was 2 years old. Pathological examination revealed a
poorly differentiated desmoplastic variant of medulloblastoma. From February 24 to April 4, 1975, the patient received 60CO radiation therapy by means of two opposed
ports, which consisted of a 40-Gy dose to the whole brain
plus a 15-Gy boost to the posterior fossa in 180-cGy fractions, as well as 34 Gy delivered to the spinal cord in 190cGy fractions.
The patient presented to Children's Memorial Hospital
in June 1988, with dizziness, blurred vision, ataxia, and

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Y. Grenier, et al.

FIG. 5. Case 2. a: Axial T2-weighted MR spectroscopic image
of the left occipital infarction with a voxel (arrow) over the area of
infarction. b: An MR spectroscopy spectrum with a STEAM
pulse sequence showing elevated lactate peaks (lac) and ahnost
completely absent N-acetylaspartate (naa), creatinine (ere), and
cholme (cho) peaks.

FIG. 3. Case 1. Gadolinium-enhanced MR image obtained 6

weeks after the initial infarction, demonstrating only a small area
of enhancement (arrow).

sleepiness. Computerized tomography scanning of the
head showed a partly calcified and contrast-enhancing
fourth ventricular mass, as well as multiple calcified foci
in the bilateral basal ganglia and subcortical regions ofthe
occipital lobes. The patient underwent a repeated posterior fossa craniotomy for resection of a recurrent medulloblastoma of the fourth ventricle. Postoperative myelography scanning revealed multiple drop metastases, and the
results oflumbar cerebrospinal fluid cytology were posi-

FIG. 4. Case 2. a: Magnetic resonance Tj-weighted image of
left.occipital infarction demonstrating increased signal (luxury perfusion, small arrow). b: A T2-weighted MR image showing hyperintensity (large arrow). c: Postgadolinium Tj-weighted image
demonstrating enhancement (arrowheads) in the area of infarction.

462

tive for tumor cells. From 1988 to June 1989 the patient
r~ceiv~d 12 courses of "~-in-l" chemotherapy, including
cisplatin, cyclophosphamide, cytarabine, hydroxyurea, 10mustine, methylprednisolone, procarbazine, and vincristine. His posttreatment course was remarkable for growth
retardation and learning difficulties. His height was 140
cm and his body weight was 55 kg at 23 years of age.
Neuropsychological evaluation disclosed a prorated performance IQ of 55 on the Wechsler Adult Intelligence
Scale-Revised. The patient's vocabulary, visual motor
integration, and perceptual process were at the 5-year-old
level; however, he was able to begin a high school equivalency program and helped the family business in landscaping.
In May 1994 the patient presented with transient paresthesias in his left hand and leg. The results of electroencephalography and MR angiography performed at that
time were negative. In July 1994, the patient experienced
s1!~den onset of mental status changes, headaches, blurred
VISIOn, and sleepiness. On physical examination, he was
awake but confused, with an unsteady gait. Seizures were
diagnosed and treated. Magnetic resonance images revealed no tumor recurrence; however, there were abnormal Trweighted densities in the right posterior temporal
and left occipital cortex. Only the left occipital region
enhanc~d after administration of gadolinium (Fig. 4).
Magnetic resonance spectroscopy scanning in this region
demonstrated a markedly increased lactate doublet peak
and decreased N-acetylaspartate, creatinine, and choline
peaks, consistent with infarction (Fig. 5). With time and
supportive care, his confusion gradually cleared, and his
neurological status returned to baseline. He was able to
resume classes in September 1994.
~he patient remained stable on anticonvulsant therapy
until November 1995, when he experienced recurrent
intermittent episodes of confusion, anxiety, and left-sided
facial twitching. In December 1995, he experienced a generalized seizure and was found to have severe hyponatremia presumably due to inappropriate secretion of antidiuretic hormone. A head CT scan demonstrated old
infarctions in the left occipital and right posterior temporal lobes. After treatment of aspiration pneumonia and
J Neurosurg. / Volume 89/ September, 1998

Radiation vasculopathy in medulloblastoma
correction of his hyponatremia, the patient's mental status
and neurological function gradually improved. A cerebral
angiogram at that time showed multiple medium-sized
vessel wall irregularities, including a 50% narrowing of
the supraclinoid right internal carotid artery, a greater than
50% stenosis of the horizontal segments of bilateral middle cerebral arteries, greater on the right side than the left,
irregularities of the right posterior temporal branch of the
right middle cerebral artery, irregularity of the left vertebral artery, and occlusion of the left posterior cerebral
artery (Fig. 6).
Occlusive vasculopathy and postirradiation arteritis involving medium- and large-sized cerebral arteries were
diagnosed in the patient. He has remained on a regimen of
one baby aspirin per day for longer than 1 year. The patient's mental status recovered completely, and his speech
and gait returned to baseline; however, he has a residual
right homonymous hemianopsia. On his last follow up in
September 1996, his hemianopsia was unchanged but his
memory had improved. Completion of the patient's work
up included a coagulation profile, including prothrombin
time, partial thromboplastin time, fibrinogen, immunological work up, autoimmune antibody panel, and phospholipid panel; the results were negative for any coagulation
or immunological abnormality.

Discussion
This paper presents the cases of two patients with medulloblastoma who developed ischemic neurologic deficits 21 years and 20 years, respectively, after receiving
combined radiation and chemotherapy treatment. They
were both treated at a very young age, 4 and 2 years,
respectively. Both received a relatively high dose of 40 Gy
to the whole brain via two opposite 60CO beams plus a 15Gy boost to the posterior fossa. Both patients also received multiagent chemotherapy, one immediately following radiation treatment, the other 13 years after
radiation treatment. Both patients had significant psychomotor and growth retardation that are known to be due
to treatment. Each presented with delayed new transient
neurological deficits and seizures secondary to focal cerebral ischemia. The second patient (Case 2) experienced
more severe and recurrent symptoms, which correlated
with a more severe occlusive vasculopathy found on cerebral angiography. The vasculopathy primarily involved
the posterior circulation, which was within the higher
radiation dose volume, as well as the anterior circulation
to a lesser extent. The diagnosis was based on the MR
imaging, MR angiography, and MR spectroscopy as well
as on the angiographic findings. The patients have remained clinically stable on a regimen of one baby aspirin
per day for longer than 1 year. Common causes of delayed
neurological dysfunctions after radiation therapy for
childhood brain tumors include local or subarachnoid
recurrence of primary tumor, radiation-induced second
tumor, and endocrinological dysfunction. The recurrence
of medulloblastoma after 13 years such as in Case 2 is
exceptional, as most medulloblastoma recurrences occur
within 5 years.'
The pathological examination of endothelial cells in
small arteries and capillaries allowed us to visualize their
J Neurosurg. / Volume 89/ September, 1998

FIG. 6. Case 2. Vertebral cerebral angiogram revealing radiation
arteritis involving the vertebrobasilar arterial distribution.
Complete occlusion of the left posterior cerebral artery (large
arrow) and irregularity, narrowing, and beating of the left anterior
cerebellar artery (small arrows) are seen.

response to radiation. I? The endothelial changes occur
within 48 hours of radiation. This may be the cause of
early postirradiation changes in smaller diameter vessels
perfusing the cortex and basal ganglia. In larger vessels, it
is thought that the damaged endothelial cells cannot guard
against plasma lipoproteins, allowing lipid infitration and
subsequent intimal plaque formations that resemble accelerated atherosclerosis. A recent study in which positron
emission tomography was used showed a significant reduction of cerebral blood flow and cerebral metabolism
only 1 month after radiation therapy. 11
The radiological characteristics of the central nervous
system response to radiation were first studied using CT
scanning and angiography. Arterioles undergo a mineralizing micro angiopathy including dystrophic calcifications, which are most prominent in the lenticular nuclei
and in the cerebral cortex; these were noted in both of our
patients. These characteristics can be seen on x-ray films
and CT scans as soon as 10 months after radiation and are
not associated with specific clinical symptoms. In contrast, middle-sized and larger arteries located within the
confmes of the radiation portal fields are susceptible to
changes that resemble arteritis on angiography. This is
now diagnosed radiographically as postirradiation arteritis, although pathological exmination ofthese vessels does
not demonstrate inflammatory cells in the wall of the
occluded vessels." Experimental study of the effects of
radiation on large arteries in laboratory animals at the light
and electron microscopy levels shows fibrous thickening
of the intima, foam cells, and endothelial proliferation."
No vasculitis is seen. Clinically, we speculate that focal accelerated atherosclerosis may cause thromboemboli
and ischemia, which in turn present as focal deficits or
seizures. Postmortem examination of larger vessels in the
brains ofpatients who have died many years after intracra-

463

Y. Grenier, et al.
nial tumor irradiation showed atherosclerosis of the vessels in the portal fields that was out of proportion to other
intracranial or systemic vesselsy,14,18 Painter, et al.," described the postmortem examination of the brain of a 29year-old man who died 24 years after receiving radiation
therapy for medulloblastoma. Severe atherosclerosis of
the vertebrobasilar system in the portal fields was documented.
In the past 5 years, the late neurotoxic sequelae of combined radiation and chemotherapy have been studied
using MR imaging and MR angiography, with the goal of
identifying acute rather than subacute or chronic ischemic
changes, and comparing the scans from patients exposed
to radiation plus chemotherapy with those from patients
exposed to chemotherapy alone. The incidence of abnormalities in patients exposed to radiation was remarkedly
higher," Comparing the MR images of 35 long-term survivors of acute lymphoblastic leukemia treated with chemotherapy and cranial radiation with those of a control
group of 24 survivors of childhood malignancy treated
with chemotherapy alone, 15 of 35 in the first group had
delayed abnormalities on MR imaging, as opposed to four
of24 in the control group. 10 The only two cases of delayed
large vessel vasculopathy were identified by MR angiography in the radiated group. The spectrum of postirradiation vasculopathy studied by cerebral angiography as reported in the literature includes vessel wall abnormalities,
progressive development of networks of abnormal vessels, and fusiform aneurysms.v Also, clinical correlation
between brain irradiation at a young age and the development of moyamoya disease is well documented. 9,15
Conclusions
Ischemic strokes in young adults are rare and are usually associated with either a coagulation, immunological, or
cardiac abnormality. Of note, neither of our patients presented with any of these problems. The prevalence of occlusive arteriopathy after radiation therapy in the population of children treated for medulloblastoma who survive
through their second decade of life is just now being studied, as the number of survivors increases. The contribution
of chemotherapy to this disease remains an area of active
investigation. Every attempt is now made to limit the
dose or delay radiation therapy as much as possible in
younger children with intracranial tumors, especially
those younger than 3 years of age." The role of aspirin in
preventing strokes in this population is not known, and the
treatment remains supportive. However, identification of
biochemical and imaging markers of reversible ischemia
may in the future guide therapy and affect neurological

outcome."

Acknowledgments
We thank Maria Nieves and Evelyn Garvey for their help in
preparing this manuscript.

464

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Manuscript received October 13, 1997.
Accepted in final form May 4, 1998.
Address reprint requests to: Tadanori Tomita, M.D., Division of
Pediatric Neurosurgery, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, Illinois 60614.

J Neurosurg. / Volume 89/ September, 1998