J Neurosurg 105:455–460, 2006

Recurrent late cerebral necrosis with aggressive
characteristics after radiosurgical treatment of an
arteriovenous malformation
Case report
H. ISAAC CHEN, B.A., MARK G. BURNETT, M.D., JASON T. HUSE, M.D., PH.D.,
ROBERT A. LUSTIG, M.D., LINDA J. BAGLEY, M.D., AND ERIC L. ZAGER, M.D.
Departments of Neurosurgery, Pathology & Laboratory Medicine, Radiation Oncology, and
Radiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
and Barrow Neurological Institute, Phoenix, Arizona

PLate cerebral radiation necrosis usually occurs within 3 years of stereotactic radiosurgery. The authors report on a
case of recurrent radiation necrosis with rapid clinical deterioration and imaging findings resembling those of a malignant glioma. This 68-year-old man, who had a history of a left posterior temporal and thalamic arteriovenous malformation (AVM) treated with linear accelerator radiosurgery 13 years before presentation and complicated by radiation
necrosis 11 years before presentation, exhibited new-onset mixed aphasia, right hemiparesis, and right hemineglect.
Imaging studies demonstrated hemorrhage and an enlarging, heterogeneously enhancing mass in the region of the previously treated AVM. The patient was treated medically with corticosteroid agents, and stabilized temporarily.
Unfortunately, his condition worsened precipitously soon thereafter, requiring the placement of a shunt for relief of
obstructive hydrocephalus. Further surgical intervention was offered, but the patient’s family opted for hospice care
instead. The patient died 10 weeks after initially presenting to the authors’ institution, and the results of an autopsy
demonstrated radiation necrosis.
Symptomatic radiation necrosis can occur more than a decade after stereotactic radiosurgery, necessitating patient
follow up during a longer period of time than currently practiced. Furthermore, there is a need for more careful reporting on the natural history of such cases to clarify the pathogenesis of very late and recurrent radiation necrosis after radiosurgery and to define patient groups with a higher risk for these entities.
KEY WORDS • arteriovenous malformation • radiation necrosis •
stereotactic radiosurgery

S

INCE the initial report by Steiner, et al.,28 in 1972,

stereotactic radiosurgery has become an increasingly
common modality for the treatment of AVMs. The
stereotactic delivery of radiation held the promise of sparing healthy tissue adjacent to lesions; however, delayed radiation-induced complications remain a significant problem
in some patients treated with radiosurgery. The majority of
these adverse events occur within 3 years of radiosurgical
treatment.38 More recently, focus has shifted to identifying
the long-term risks of radiosurgery in an effort to define better the optimal patient population for this therapeutic option.
We report on a case of histologically proven delayed cerebral radionecrosis reappearing 11 years after an initial episode and 13 years after the radiosurgical treatment of an
Abbreviations used in this paper: AVM = arteriovenous malformation; CT = computed tomography; FLAIR = fluid-attenuated inversion-recovery; LINAC = linear accelerator; MR = magnetic resonance; PCA = posterior cerebral artery; PET = positron emission
tomography.

J. Neurosurg. / Volume 105 / September, 2006

AVM. To our knowledge, this case has the longest interval
between treatment and the manifestation of radionecrosis
reported thus far. Furthermore, there have been no previously reported cases of recurrent cerebral necrosis after stereotactic radiosurgery.
Case Report
History and Examination. This 68-year-old man initially
presented with a sudden headache in December 1990. A
head CT scan showed intraventricular hemorrhage, and
subsequent angiography studies demonstrated a large left
posterior temporal and thalamic AVM and a left superior
cerebellar artery aneurysm. An initial intervention in March
1991 involved microsurgical clip repair of the aneurysm,
which resulted in a full recovery postoperatively. In July
1991, the AVM was treated with embolization, followed by
LINAC radiosurgery 2 months later in September 1991. Imaging studies obtained at the time of radiosurgery are featured in Fig. 1. Because of the size (3.8 cm at its greatest diameter) and location (near the thalamus) of the AVM, a dual
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H. I. Chen, et al.

FIG. 1. Imaging studies obtained at the time of LINAC radiosurgery in September 1991. Anteroposterior (A) and lateral (B) left vertebral artery injection angiograms demonstrating an approximately 3 3 3 3 2–cm AVM nidus supplied by
the left PCA with deep venous drainage. Axial enhanced CT scan (C) revealing the left posterotemporooccipital/thalamic
AVM nidus in intimate association with the left lateral ventricle. Enlarged deep draining veins are present.

isocenter approach involving the delivery of a 1900-cGy
dose to the 90% isodose line was prescribed. Using Boston
arcs to each isocenter, radiation was delivered to the 100
and 70% isodose lines using 3.5- and 2-cm collimators,
respectively. In April 1993 (19 months later), the patient
was rehospitalized after a homonymous hemianopia and a
mixed dysphasia had developed. Imaging studies revealed
changes consistent with radiation necrosis together with
associated edema and mass effect. A 3-week course of
steroid therapy successfully reversed the symptoms, and a
follow-up cerebral angiogram obtained 6 months thereafter
(October 1993) demonstrated no residual arteriovenous
shunting but did show possible arteritis involving the left
PCA branches. Because the patient’s clinical status had
improved, no tissue samples were obtained at that time. In
the subsequent 11 years, the patient was neurologically stable with only a mild short-term memory deficit. In
November 2004, the patient presented to our institution
with a history of hypertension and new-onset aphasia
accompanied by right hemiparesis and neglect. He was
awake but oriented only to his own identity and had a slow
verbal response time.
First Hospital Course. He was admitted to the neurosurgical intensive care unit and treated with steroid agents. Magnetic resonance images revealed hemorrhage with surrounding edema, signal abnormality, and enhancement
centered in the left thalamus, involving the left basal ganglia
and medial temporal lobe (Fig. 2A–C). These imaging findings were consistent with a malignant glioma, radiation
necrosis, or radiation-induced vasculitis. A cerebral angiogram revealed a paucity of vessels in the region of the hematoma, with no evidence of arteriovenous shunting (Fig.
2D–G). It also demonstrated occlusion of the distal left
PCA with proximal irregularity. The patient was discharged
in stable condition to a local rehabilitation center 1 week
later with plans for further evaluation of the cause of the cerebral hemorrhage.
Second Hospital Course. Sixteen days later, the patient
was readmitted for a worsening mental status. He was
awake but unable consistently to follow commands. Magnetic resonance imaging studies obtained at this time were
notable for worsening hydrocephalus with probable trapping of the left temporal horn and increased vasogenic ede456

ma, enhancement, and mass effect in the left hemisphere
(Fig. 2H–J). A ventriculoperitoneal shunt was inserted into
the left temporal horn. Postoperative CT scans demonstrated resolution of the hydrocephalus, and the patient returned
to his baseline mental status. A PET scan did not reveal hypermetabolic activity in the region of the hematoma. The
patient was again discharged to the local rehabilitation center on a 4-week steroid taper.
During the next month, in January 2005, the patient’s
condition steadily deteriorated. He became obtunded with
no coherent speech or ability to follow commands. Concurrently, he suffered progressive quadriparesis. Computed tomography and MR imaging studies were notable for stable
dilation of the left temporal horn but increased edema and a
left-to-right midline shift (Fig. 2K). The patient’s family decided to forgo additional surgery and instead sought hospice
care. The patient died 1 week later.
Pathological Examination. Because it was unclear whether a tumor or radiation necrosis was responsible for the
patient’s rapid demise, a brain autopsy was performed. On
gross examination, left subfalcine (3 mm), left uncal (3
mm), and bilateral orbital gyrus (6 mm) herniation was noted along with a hemorrhagic lesion situated directly deep
to the left insular cortex and measuring 4 cm at its greatest
diameter. This lesion consisted of tortuous blood vessels
and necrotic tissue. On microscopic examination, abnormal
arteries and veins were visualized, some with abnormally
thickened vessel walls (Fig. 3A). Extensive necrosis with
gliosis and edema of the surrounding tissue was also noted,
but there was no evidence of any neoplastic process in the
lesion or adjacent tissue (Fig. 3B and C). No antibody staining was deemed necessary given the lack of evidence for
neoplasia. After review by the neuropathology department
personnel, the final diagnosis was designated “arteriovenous malformation, extensively necrotic.”
Discussion
The long-term complications of stereotactic radiosurgery,
including necrosis, hemorrhage, cyst formation, increased
seizure frequency, and arterial stenosis,11,25 have been reported to occur in 3.2 to 19.8% of patients undergoing treatment for AVMs.38 Of these late effects, perhaps the most
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Recurrent late cerebral necrosis after stereotactic radiosurgery

FIG. 2. Axial FLAIR MR image (A) obtained in November 2004, demonstrating hemorrhage and signal abnormality
within the left thalamus, the striatocapsular and subinsular regions, and the splenium of the corpus callosum with surrounding vasogenic edema. There is mild mass effect in the left hemisphere, manifested by sulcal effacement and shift of
the third ventricle to the right. Axial unenhanced (B) and Gd-enhanced (C) T1-weighted MR images obtained in November
2004, revealing hemorrhage in the posteromedial left temporal lobe together with mild circumferential enhancement and
trapping of the left temporal horn. Anteroposterior (D) and lateral (E) left vertebral artery and anteroposterior (F) and lateral (G) left common carotid artery digital subtraction angiograms showing no AVM nidus. Left vertebral artery injections
exhibited a distally occluded left PCA. Mild areas of narrowing and irregularity appear within the proximal left PCA
branches, possibly caused by arteritis. Axial FLAIR image (H) obtained in December 2004, demonstrating worsening
hydrocephalus with marked dilation of the left temporal horn. Residual hemorrhage is apparent in the left medial posterior temporal lobe together with increased vasogenic edema in the left hemisphere. New signal abnormality has developed
in the midbrain. Axial FLAIR MR image (I) obtained at the level of the lateral ventricles in December 2004, revealing
worsened vasogenic edema in the left hemisphere about the residual hematoma with increased compression of the left lateral ventricle and midline shift. Axial Gd-enhanced T1-weighted MR image (J) obtained in December 2004, demonstrating enhancement surrounding the hematoma, particularly extending medially into the thalamus as well as the corpus callosum. Axial FLAIR MR image (K) obtained in January 2005, exhibiting residual hematoma as well as extensive
surrounding edema, severe hydrocephalus, and pronounced mass effect with increased midline shift.

devastating is delayed cerebral radiation necrosis, which
typically manifests as cognitive dysfunction, language impairment, focal weakness, sensory loss, or apraxia.5 This
entity has been well described in the field of conventional
radiotherapy, and cases of necrosis have been reported to
occur even two to three decades after the initial treatment.9,19,32 With respect to radiosurgery, the literature on cerebral radionecrosis is more limited. Whereas necrosis may
be histologically evident in up to 33% of patients,1 the inciJ. Neurosurg. / Volume 105 / September, 2006

dence of symptomatic necrosis ranges from 1.7 to 7.6%.11
Although complications after radiosurgery can occur up to
10 years after treatment,11 the majority of observed cases of
radiation necrosis have appeared within 3 years of radiosurgical intervention.12,14,22,23,26,27,30,31 One notable exception is
the case presented by Yamamoto, et al.,37 of a necrotic white
matter lesion appearing 7 years after radiosurgical treatment
of an AVM.
In the present report, a necrotic lesion associated with in457

H. I. Chen, et al.

FIG. 3. Photomicrographs of the patient’s vascular lesion demonstrating abnormal arteries (A, arrowhead) and veins (A, arrow) and
some necrosis (B, arrow). Photomicrograph (C) showing extensive
necrosis adjacent to gliotic, edematous brain tissue (arrow) and numerous hemosiderin-laden macrophages (arrowhead). H & E, original magnification 3 100.

tracerebral hemorrhage arose 13 years after the patient had
undergone LINAC radiosurgery for an AVM in the same
region as a lesion radiographically diagnosed as radiation
necrosis 11 years prior. Three features of this case deserve
458

special emphasis. First, although rare cases of recurrent
cerebral necrosis exist in the conventional radiotherapy literature,7,13,36 we believe that this is the first report of such a
diagnosis after radiosurgery. Second, the interval between
radiation treatment and the presentation of cerebral necrosis
is, to our knowledge, the longest yet reported for stereotactic radiosurgery. Third, the patient’s condition deteriorated
with surprising rapidity; his admission to our institution in
November 2004 was separated from his death in January
2005 by merely 10 weeks. In its growth characteristics and
appearance on imaging studies, the lesion closely mimicked
a malignant growth. A suspected tumor was the reason that
a PET scan was obtained during the patient’s second hospitalization. However, there was absolutely no sign of neoplastic cells on histological analysis in or around the lesion.
Although remnants of abnormal vessels were seen on pathological analysis, the absence of arteriovenous shunting on
multiple cerebral angiograms suggested that the vessels did
not represent an active AVM nidus.
The most widely accepted theory on the pathogenesis of
delayed cerebral radiation necrosis centers on endothelial
cell damage. Consistent with this theory are the histological
changes associated with radiation necrosis. Early on, fibrinoid necrosis of blood vessel walls occurs; late changes include vessel wall thickening, hyalinization, and telangiectasia.32 Some of these changes can be seen in Fig. 3. In vitro
evidence suggests that radiation alters the production of
hemostatic factors by endothelial cells, skewing the hemostatic balance toward platelet aggregation and thrombosis.3
The disruption of the microvasculature subsequently leads
to astrocyte hypertrophy and hyperplasia, perivascular edema, and ischemia. Moreover, an influx of leukocytes to
damaged areas leads to the expression of various cytokines
that, among other effects, induce oligodendrocyte apoptosis.6,18 Ultimately, injury from ischemia and reperfusion
along with axonal demyelination results in white matter necrosis.8 Alternative theories involve the induction of an autoimmune vasculitis and the perturbation of the fibrinolytic
system by radiation effects.24
The patient in the present case had an increased risk of
late radiation necrosis because of the large area treated,2,4,15,
20,21,35
which required two isocenters, and his history of hypertension. Other risk factors not seen in this patient include
repeated radiosurgery for the same lesion, treatment of gliomas rather than metastases or benign tumors, and the inclusion of healthy brain tissue within the treatment volume.2,34 However, it remains unclear why radiation necrosis
can develop either within a few months or, as in this case,
more than one decade after treatment. Similarly, the triggers
that activate an aggressive, rapidly progressive recurrence
of necrosis are currently unknown. No differences in the
rate of the development of late complications have been reported among the various types of stereotactic radiosurgery,
although the treatment of AVMs with heavy particle radiosurgery has not been studied extensively.
As demonstrated in the present report, the differentiation
of radiation necrosis from tumor growth can be difficult
with conventional imaging. On MR images, changes associated with necrosis can be most easily seen on T2-weighted or FLAIR sequences.5 These lesions usually enhance
following Gd administration, as would be expected given
the breakdown of the blood–brain barrier that accompanies
necrosis. The Swiss-cheese and soap-bubble patterns have
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Recurrent late cerebral necrosis after stereotactic radiosurgery
been ascribed to radiation necrosis,17 but these appearances
are not specific enough for the purposes of a definitive diagnosis. Perfusion-sensitive imaging29 and diffusion-weighted
imaging33 have been suggested to increase the diagnostic
sensitivity and specificity of MR imaging. Magnetic resonance spectroscopy,14 single-photon emission computed
tomography,16 and PET10 have also been found to be useful
in differentiating radiation necrosis from tumor, but concerns about their specificity remain.5 In the case presented
here, hemorrhage in the lesion bed posed a significant technical obstacle to spectroscopy and perfusion imaging. At
the present time, no diagnostic modality has proved superior to the others, and the choice of which test to perform remains a matter of clinical judgment and availability.
Conclusions
We report on a patient in whom fulminant cerebral radiation necrosis developed 13 years after LINAC radiosurgery
for an AVM and 11 years after a previous episode of radionecrosis. This case is significant because of the appearance
of recurrent necrosis more than one decade after both the
initial treatment and a previous episode of necrosis and also because of the speed with which the patient’s condition
worsened. In its rapid progression and its appearance on
imaging studies, the lesion resembled a malignant glioma.
However, results of a brain autopsy confirmed the diagnosis of radiation necrosis while definitively ruling out tumor. Although delayed radiation necrosis most often occurs
within 3 years of stereotactic radiosurgery, the present report indicates that such complications can be seen at much
later times. With this in mind, it may be prudent to monitor
radiosurgically treated patients for very late occurrences of
radiation necrosis. We agree with the assertion by Tandon,
et al.,31 that a cooperative multicenter database of the outcomes of stereotactic radiosurgery is needed to better define
patient risk factors and to decrease the incidence of very late
radiation necrosis.
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Manuscript received September 9, 2005.
Accepted in final form March 2, 2006.
Address reprint requests to: Eric L. Zager, M.D., Department of
Neurosurgery, 3 Silverstein, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. email:
zagere@uphs.upenn.edu.

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