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Cerebral necrosis following radiotherapy of extracranial neoplasms.

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Cerebral Necrosis Following Radiotherapy
of Extracranial Neoplasms
David A. Rottenberg, MD, Norman L. Chernik, MD, Michael D. F. Deck, MD,
Frank Ellis, MD, and Jerome B. Posner, M D
We have examined 6 patients with delayed cerebral necrosis following irradiation of extracranial neoplasms. Four of
the 6 patients received 1,760 rets (or less) tumor dose. The initial symptoms attributable to radiation necrosis
appeared 4 co 31 months after irradiation and were those of a focal supratentorial mass. Cerebral angiography
delineated an avascular frontal or temporal lesion in all 6 patients; in 1,case a magnification study revealed
narrowing, irregularity, and occlusion of small cortical vessels. Four of our 6 patients underwent craniotomy
with partial or complete surgical extirpation of necrotic brain tissue. Two operated patients are alive and without
disabling neurological symptoms 30 and 25 months, respectively, after the operation. The characteristic
neuropathological fedtures of delayed radiation necrosis of brain suggest that vascular injury rather than neuronal or
glial damage is of primary pathogenetic significance.
Rottenberg DA, Chernik NL, Deck MDF, et al: Cerebral necrosis following radiotherapy of extracranial neoplasms.
Ann Neurol 1:339-357, 1977
Cerebral necrosis is an infrequent, delayed, and often
unrecognized sequel to the radiotherapy of extracranial
neoplasms. Beginning with Fischer and Holfelder’s
original description in 1930, only 19 cases with full
clinical ahd pathological documentation have been
reported [1-15] (see Table 1). During the past nine
years we have encountered 6 patients at Memorial
Sloan-Kettering Cancer Center (MSKCC) who developed symptoms and signs of an intracerebral mass
following irradiation of extracerebral cranial neoplasms and who were found at operation or at autopsy
to have the characteristic pathological changes associated with delayed radiation necrosis of brain. This
large experience indicates either that the illness is
more common than has been reported or that more
effective and more radical radiotherapy allows patients with extracranial neoplasms to survive longer,
thus increasing the incidence of delayed cerebral necrosis. Furthermore, our experience suggests that the
“latent period” between radiation therapy and the
onset of symptoms of radiation necrosis may be much
shorter than was heretofore believed and that radiation doses within the currently accepted “safe” limits
may on occasion produce radiation necrosis of brain.
This report details the clinical, radiological, and
pathological findings in patients with cerebral radiation necrosis and emphasizes that effective treatment
is possible if a correct diagnosis is made.
From the Departments of Neurology, Pathology, Radiology, and
Radiation Therapy, Memorial Sloan-Kettering Cancer Center and
Cornell University Medical College, New York, NY.
Case Reports
Patient 1
A 28-year-old man developed osteogenic sarcomaof the left
maxillary antrum in November, 1968, and underwent a left
radical maxillectomy with orbital exenreration. The tumor
recurred in the inferolateral orbital wall in March, 1969, and
the tumor bed was irradiated through anterior and left
lateral portals to a total dose of 6,100 R in 30 treatments
over 52 days (1,750 rets; see Radiation Dosimetry under
Discu.isio~z).A left gasserian ganglion block was performed
with absolute alcoholin July because ofintractable pain, and
in August a superficial left temporal abscess was drained.
On September 1, 1969, the patient was admitted to
MSKCC following two generalized seizures. His temperature was 18.1”C.Neurological examination revealed a right
Horner’s syndrome and right-sided E r b s palsy (both congenital by history),complete anesthesia and analgesia in the
distribution of the first and second divisions of the left
trigeminal nerve, peripheral left facial palsy, fasciculations
of the left side of the tongue, hyperactive deep tendon
reflexes, and bilateral knee and ankle clonus; no pathological reflexes were elicited. A lumbar puncture was performed; opening pressure was 130 mm CSF with 10
mononuclear cells per cubic millimeter, 79 m d d l ofprotein
and 68 m$dl of glucose. Cultures of cerebrospinal fluid
were sterile, and cytological examination was negative. An
electroencephalogram revealed bilateral slowing with left
frontal phase reversal, and a technetium 99m brain scan
suggested the presence of a large left temporal lesion. Left
carotid arteriography performed on September 4 demon-
Accepted for publication Oct 4 , 1976.
Addressrepriiitrequeststo Dr Pusner, 1275 York Ave, New York,
N Y 10021.
339
strated an avascular mass within the left temporal lobe
associated with an 8 mm left-to-right shift o f t h e left pericallosal artery. Direct extension of the tumor into the brain or a
brain abscess were considered the most likely diagnostic
possibilities, and the patient was treated with antibiotics. O n
October 4 he suffered another generalized convulsion preceded by an hour-long prodromal aphasia. A repeat carotid
arteriogram demonstrated an increase in size of the previously described avascular left temporal mass, and an exploratory craniotomy was performed.
At operation the left temporal pole was firmly attached to
the subjacent dura. The anterior 2 cm of the temporal lobe,
which contained a golf ball-sized mass on its inner aspect,
was excised. Grossly, the mass had a rubbery consistency;
histological examination revealed widespread coagulation
necrosis of the brain parenchyma, intense gliosis surrounding the necrotic foci, vascular necrosis and thrombosis, and
scattered inflammatory infiltrates consistent with the degree
of tissue destruction (Fig 1). The patient's postoperative
recovery was uneventful until October 21, when he suddenly became unresponsive and his temperature spiked to
39.8"C. Emergency decompression was attempted the following day, and a deep wound infection containing 100 ml
of pus was encountered and drained. Postoperatively he
developed a fulminating mixed gram-negative meningitis
and died on November 14.
At autopsy there was n o gross or microscopical evidence
of recurrent tumor. No communication was discernible
between the left orbital cavity and the anterior or middle
cranial fossae. The brain weighed 1,300 gm and was grossly
edematous. A massive greenish subdural empyerna extended from the base of the brain down around the entire
spinal cord. Large areas of necrotic cerebral cortex were
encountered in relation to the infected craniotomy site. The
histological changes of radiation necrosis observed in the
biopsy specimen were not present in the autopsy material. I t
appeared that the necrotic focus had been completely removed at the first operation.
Patient 2
A 9-year-old girl was transferred to MSKCC in May, 1969,
for treatment of an embryonal rhabdomyosarcoma of the
right parotid gland that had produced facial palsy. Between
May 8 and July 9 she received 6,000 R (1,675 rets) to the
right parotid region through anterior and right lateral portals. She was also treated with several chemotherapeutic
agents. In November she developed increasingly frequent
frontal headaches and unexplained fever. Neurological examination at that time revealed hypesthesia over the right
lower lip, right facial palsy, conductive hearing loss in the
right ear, mild left-sided weakness, and an equivocal extensorplantar response on the left. In December she developed
otitis externa of the right ear, which progressed rapidly to a
chronically draining wound infected with Pseudomonas
aerzlginosa. O n March 26, 1970, she awakened with a right
frontal headache; later in the day she experienced an
episode of vertigo lasting one hour and associated with
horizontal diplopia. She also complained of deafness in the
right ear. Neurological examination the following day revealed bilateral papilledema with retinal exudates, decreased visual acuity in the right eye, right lateral rectus
340 Annals of Neurology Vol 1 No 4
April 1977
palsy, hypesthesia over the third division of the right trigeminal nerve, and right facial palsy. Both plantar responses
were equivocal. A lumbar puncture was performed; the
opening pressure was above 350 mm CSF with 2
mononuclear cells per cubic millimeter, 118 mg/dl of protein, and 57 mg/dl of glucose. An EEG revealed slowing
over the entire right hemisphere. Laminagrams of the base
of the skull demonstrated extensive bony destruction in the
floor of the middle cranial fossa, the right orbit, and the
inferior aspect of the right petrous bone. Cerebral arteriography on March 31 delineated a large, avascular right temporal mass producing a 4 mrn right-to-left shift of the right
anterior cerebral artery.
Because the patient's symptoms were attributed to tumor
eroding the base of the skull and invading the brain, intensive chemotherapy was instituted and an additional 1,600 R
was administered to the base of the tumor between July 10
and July 15. Thereafter she became increasingly irritable
and forgetful, and she died in October, 1970, of respiratory
insufficiency due to progressive pulmonary metastases.
At autopsy, irregular penetrating ulcers were described i n
the right cheek, right preauricular region, and right external
auditqry meatus. The dura lining the right middle cranial
fossa was chin and discolored adjacent to a necrotic cavity
associated with the preauricular ulceration. However, the
leptomeninges and superficial cortical vessels appeared
normal. A large area of softening was noted along the
ventrolateral extent of the right temporal lobe. Coronal
sections of this region (Fig 2) revealed extensive cavitation
of the white matter of the rostra1 half of the right temporal
lobe. More posteriorly, smooth, white nodular densities and
rust-colored glial scar tissue involved the cortical and subcortical layers of the inferior temporal gyrus. Microscopical
examination of the temporal lobe revealed the characteristic
changes of cerebral radiation necrosis (Figs 3, 4).
Patient 3
A 29-year-old man underwent right orbital exenteration in
September, 1967, for an adenoid cystic carcinoma of the
right lacrimal gland. Recurrent orbital tumor was noted in
May, 1968, and radiation therapy was advised. A total of
6,355 R was administered to the superolateral right orbit
through a 2 cm cone in 13 treatments between May 10 and
June 7, 1968. A further recurrence involving the right
optic nerve was documented in August, 1969, and an additional 6,000 R (betatron) was delivered to the right orbit
between November 25, 1969, and January 9, 1970 (total
tumor dose, 2,574 rets).
In July, 1972, the patient was examined and found to b e
free of disease. O n e month later, however, he began complaining of intermittent light-headedness, a tight feeling
across his forehead, a dull ache at the back of his neck, and
bizarre auditory phenomena (eg, sounds seemed to wax and
F i g 1 , Biops2 Jpecimen from Patient I . (A)There is
coagdation necrosis of the brain parenchyma withjibrinoid
necrosis and thrombosis of the penetrating vessels. (HGE;
x40 before 45 9& reduction.) (B) Marked reactive gliosis is
present in the udjucent tissues. Hypertrophied binucleate
celh are seen (arrows). IHCE; x 100.)
A
B
Rottenberg et al: Cerebral Necrosis following Radiotherapy 341
A
B
F i g 2 . Coronalsections of thehxed brain from Patient 2. (A)
A largr cystic cazity VeplaCKS the temporal white matter: the
ca Pity is hOUndedexterna~/yby a relatizdy preserved ribbon
u f cortex. ( B ) More posteriorly the h i o n is confined t o the
white matter of the g y r d coves und t o a small area of
suhjacent cortex. The preserved cortical mantle is sharplji
delineated b?; the altered uhite matter in the depths of the
S27lC-i.
wane). An EEG in August was abnormal, with bilateral
frontotemporal slowing. He began to experience transient
sensations of unsteadiness, and h e hallucinated unpleasant,
sweet odors. Neurological examination in September was
essentially normal except for loss of sensation over the first
division of the right trigeminal nerve. Headaches and lightheadedness became more severe. An EEG in October disclosed a right-sided slow-wave focus. He was admitted to
MSKCC for evaluation on December 17, 1972, following a
poorly documented episode of staggering and urinary incontinence. Neurological examination revealed impairment
of cognitive functions, a flat affect, right-sided anosmia,
gross papilledema, and mild left hemiparesis. Laminagrams
of the base of the skull demonstrated a destructive lesion
involving the right sphenoid bone. Carotid arteriograph y
delineated a large, avascular right frontal mass (Fig 5) associated with transtentorial herniation of the right temporal
lobe.
342
Annals of Neurology
Vol 1 No 4
April 1977
An exploratory craniotomy on December 28 revealed a
large subcortical cyst in the right frontal region, from which
approximately 100 ml of fluid was drained. The cyst fluid
was cultured and was sterile. Histopathological examination
of the cyst wall failed to reveal evidence of malignancy.
Instead, the changes in adjacent subcortical white matter
suggested the diagnosis of radiation necrosis. Vascular
alterations-including
fibrinoid necrosis and medial
hyperplasia of vessel walls and the presence of multiple,
dilated, thin-walled vascular channels-were prominent.
There were areas of gliosis containing many large, hypertrophied binucleate cells.
At the time of his discharge o n January 7, 1973, the
patient's mental state had returned to normal. Papilledema
was no longer present, and his left hemiparesis had resolved.
In March he began to complain ofpain in the right side ofhis
face and jaw. Neurological examination in May revealed
weakness of the right pterygoid and masseter muscles,
complete sensory loss over the first division of the right
trigeminal nerve, and marked hypalgesia and hypesthesia
over the second and third divisions. There was no evidence
of increased intracranial pressure or of recurrent orbital
tumor. The onset of intermittent pain and discomfort i n the
right pectoral region in April, 1974, led to the discovery of
bilateral pulmonary metastases. An EEG revealed focal
theta and delta wave slowingin the right frontal region with
some spread to the right anterior and midtemporal regions;
no epileptiform discharges were observed.
The patient was readmitted to MSKCC on June 18,1974,
with a one-week history of bifrontal headache and neck
stiffness. His temperature on admission was 37.6"C. He was
lethargic and impersistent. There was papilledema, right
motor and sensory trigeminal dysfunction, left hemiparesis,
and a left extensor plantar response. A C T scan demonstrated a partially cystic mass in the right frontotemporoparietal region, extending across the midline and obstructing the foramen of Monroe. A right carotid arteriogram
confirmed the presence of a large, avascular right temporal
lobe mass associated with a 2.5 cm right-to-left shift of the
anterior cerebral arteries. It also revealed irregularities of
the temporal branches of the right middle cerebral artery
that resembled the vascular lesions of radiation necrosis. A
second craniotomy was performed on June 28, and the
anterior 5 to 7 cm of the right temporal lobe was found to be
discolored and scarred. A reddish mass was encountered
just beneath the cortical surface, displacing and infiltrating
the brain parenchyma. The intracranial tumor and approximately 7 cm of the right anterior temporal lobe were
excised; the pathological diagnosis was metastatic adenoid
cystic carcinoma. The patient was discharged in satisfactory
condition o n July 15.
Subsequently he developed intractable right facial pain,
controlled only with high doses of parenteral narcotics, and
widespread osseous and pulmonary metastases. He died in a
terminal-care facility o n September 8, 1975; an autopsy was
not performed.
Putient 4
A 57-year-old man developed a superficially infiltrating
squamous cell carcinoma of the right external auditory canal
that was partially excised in August, 197 1.Recurrent tumor
was resected in October of that year, and postoperatively
6,000 R was delivered to the tumor bed over a period of six
weeks through two 9 x 6 cm wedge portals (total dose,
1,760 rets). He underwent a right radical neck dissection in
May, 1972, for metastatic disease, and in August, 1973, he
began to have focal seizures heralded by a peculiar medicinal odor. The seizures were characterized by facial pallor,
sweating, and abnormal movements of the left lower
extremity. Consciousness was transiently lost, and he was
confused and lethargc postictally. Subsequently he complained of progressive unsteadiness of gait, a tendency to
drift off to the left, and brief vertiginous sensations. Neurological examination in October, 197 3, revealed impairment
of recent memory, right facial palsy (dating from his previous operation), mild left hemiparesis, and bilateral extensor
plantar responses. A YgmTc
brain scan indicated the presence
of a doughnut-shaped mass in the right temporal region. The
EEG was abnormal, with right temporal delta activity and
sharp waves and phase reversals over the right midtemporal
region. A right carotid arteriogram performed on October
12 delineated a large, avascular mass within the right temporal lobe.
At craniotomy on October 22 a large, multiloculated
temporal lobe abscess was encountered and successfully
drained, and a portion of the anterior right temporal lobe
was excised. The abscess was seen to communicate with the
external ear cavity and with the right lateral ventricle.
Cultures taken from the temporal lobe at the time of
operation grew out Proteus mirabilzs, as did subsequent
cultures of right ear drainage. Histopathological examination of the wall of the abscess cavity and adjacent temporal
lobe revealed severe coagulation necrosis with fibrinoid
thrombosis of almost all vessels. An intense inflammatory
reaction was present in some tissue fragments. Marked
gliosis with multiple hypertrophied binucleate cells was
observed in the vicinity of necrotic foci. These changes,
which were similar to those described in Patients 1,2, and 3,
suggested cerebral radiation necrosis.
His postoperative course was stormy, and he remained in
coma with intermittent signs of brainstem compression for
almost two weeks. Thereafter, he made a gradual recovery
and was discharged from the hospital on December 15,
1973. At the time of discharge he was fully oriented, and
except for a peripheral right facial palsy and diffusely increased muscle tone, neurological examination was unremarkable. Since then he has been asymptomatic.
Patient S
A 30-year-old woman developed an anaplastic squamous
cell carcinoma of the left ethmoid sinus that was diagnosed
by biopsy in November, 1972. Between December 18,
1972, and January 31, 1973, she received a total 0f6,oOo R
to the tumor bed in 30 treatments through anterior and
left lateral portals (1,760 rets). Subsequent laminagrams
documented extensive residual disease, and the patient was
admitted to MSKCC o n April 1 for radical extirpation.
Accordingly, on April 5 a left maxillectomy, left orbital
exenteration, left ethmoidectomy, and resection of the left
cribriform plate were accomplished through a left frontal
craniotomy.
At home shortly after her discharge she became pro-
foundly depressed and complained of headache and dizziness; she was noted by her family to have become forgetful,
apathetic, and lethargic. Neurological examination on May
2 4 revealed an expressionless face, bradykinesia, lack of
spontaneity, decreased attention span, and inability to concentrate. Hoffmann’s sign was present on the right, but no
other focal neurological abnormalities were recorded. An
EEG was abnormal, with left frontal delta activity and mild
bilateral slowing. A g g m Tbrain
~
scan revealed areas of
increased uptake over the left orbit and in the left frontoparietal region. Consequently, a left carotid arteriogram
was performed on May 29; in addition to demonstrating a
localized left frontal mass effect. it revealed irregularity,
narrowing, and occlusion of small cortical vessels, suggestive of radiation necrosis (Fig 6). Following the arteriogram a
lumbar puncture was performed; opening pressure was 165
mm CSF with 1 mononuclear cell per cubic millimeter, 7 9
m$dl of protein, and 5 5 m$dl of glucose. Although radiation necrosis was considered the most likely diagnosis, itwas
not possible to rule out the presence of a brain abscess, and
the patient was treated with antibiotics. H e r neurological
deficits did not, however, improve, and she continued to
complain of headache even after her discharge home on
June 30.
O n July 15, 1973, she was readmitted with fever,
headache, and a stiff neck; her CSF was under increased
pressure and contained 1,054 white cells. A diagnosis of
acute purulent meningitis was made, and antibiotics were
administered intravenously. Cultures of the left orbital cavity grew out ten different (mostly gram-negative) organisms,
although repeated cultures of the CSF were sterile. O n July
23 the patient was taken to the operating room for debridement of her left orbital cavity. “Gliotic” brain tissue was
observed by the neurosurgeon to be herniating into the
orbit superomedially through a small dural defect. Biopsy of
this tissue revealed the histopathological features of radiation necrosis: marked fibrous proliferation of the meninges,
severe coagulation necrosis of brain tissue, and fibrinoid
necrosis and thrombosis of the vasculature. H e r postoperative course was stormy, punctuated by recurrent fevers and
focal seizure activity involving the right upper and lower
extremities. She died three months postoperatively on October 23, 1973.
At postmortem examination purulent material was present over the dura covering the left frontal lobe adjacent to
the craniotomy defect, to which the underlying brain was
firmly attached. Purulent exudate surrounded the base of
the brain. Serial coronal sections revealed a 3 x 6 cm cystic
cavity within the subcortical white matter of the inferior
portion of the left frontal lobe. The ventricles were dilated
and contained purulent exudate. Sections from the left
frontal lobe cyst revealed extensive necrosis and gliosis,
consistent with radiation effect. Thrombosed meningeal
vessels were associated with scattered areas of acute ischemic necrosis of the brain parenchyma.
Patient 6
A 41-year-old man with nasopharyngeal carcinoma metastatic to cervical lymph nodes received 2,900 R to the left
side of the neck between February 28 and March 12,1968,
through a 14 X 16 cm portal. O n March 14 he underwent
Rottenberg et al: Cerebral Necrosis following Radiotherapy 343
A
B
Fig 3. Damaged temporal rortex from Patient 2,
ilhstrating widespread nec-rosi.r o f brain parenchyma and
ocerlying meninges. (A) Note Ihirkened, hyalinized
meningeal arterj (upper left) and dilated, t h i n - u d e d
rortical i,essels. Sewral vessels are thromhosed. Higher
magnifiration of cortical i:essels iB) and offibrocollagenouJ
344
C
D
proliferation o f the meninges adjacent t o an area o f
radiation necrosis /CJ. /Dj Minerakzation and
proteinaceous deposits are present as nodular densities
within unureuofcorticalnecroJis. (AllHG-E:A ~ 4 0B;, C,
and D X100, all before 10% redurtion.)
34 5
left radical neck dissection at MSKCC, and between March
15 and April 26 he received an additional 6,000 R to the
nasopharynx through opposing 8 x 7 cm portals (1,760
rets).
H e remained asymptomatic until July, 1972, when he
developed a left abducens palsy; in August he complained of
decreased visual acuity in the left eye. Recurrent disease at
the base of the skull was suspected but never documented.
Nevertheless, further radiotherapy was administered at
another hospital; 5,000 R was delivered through 8 x 8
cm opposed lateral portals in 25 treatments between
November 22 and December 27, 1972 (1,466 rets; total
cerebral radiation, 3,226 rets). The patient was lost to
follow-up until February, 1974, at which time he complained of dizzy spellsand flashes of light in front ofhis eyes.
These flashing lights were associated with lapses ofmemory
and feelings of unreality. For the preceding several months
h e had been troubled by left frontal headache and pain in the
left eye, and his family had noted progressive intellectual
deterioration and unsteadiness of gait.
H e was admitted to MSKCC in March, 1974, at which
time neurological examination revealed aphasia, bilateral
papilledema, decreased visual acuity in the left eye (light
perception only), left abducens palsy, right lower facial
weakness, and a left extensor plantar response. The left
eyelid was edematous and the left eye proptotic. Skull
roentgenograms and laminagrams of the floor of the middle
brain scan revealed ‘a
fossa were normal. However, a 99n1T~
346 Annals of Neurology
Vol 1 X o
4 April 1977
Fig 4. Altevations in the white matter adjacent t o areas o f
coagulation necv0.w (Patient 2).Hperplastic vesseluall ir
totally veplarrd by collagentius mutevial. IHEsE; x 100.)
circumscribed 4 cm area of increased uptake in the left
temporal region adjacent to the left sphenoid ridge. Left
temporal delta activity and mild bilateral theta wave slowing
were present o n the EEG. Bilateral carotid arteriogams
delineated an avascular temporal opercular mass associated
with an 8 mm left-to-right shift of the left anterior carotid
artery and a 1 mm left-to-right shift of the left internal
cerebral vein. Magnification views failed to reveal any pathological circulation or significant irregularity of small temporal vessels. A C T scan demonstrated a well-circumscribed
mass in the middle portion of the left temporal lobe, with
surrounding edema extending anteriorly into the left frontal
lobe and posteriorly into the left parietal lobe (Fig 7).
O n April 9 a 5 x 4 x 1.5 cm piece of necrotic tissue was
removed through a left temporal craniotomy and submitted
for neuropatholog~calexamination. Grossly, the cortex appeared markedly edematous but was otherwise unremarkable; the white matter was largely necrotic and contained
multiple pinpoint hemorrhages. Microscopical examination
of the surgical specimen revealed the characteristic features
of radiation necrosis (Figs 8, 9).
Postoperatively the patient improved tu the extent that he
was able to lead a completely independent existence. When
Discussion
F i g 5 . (Patient 3.) Right carotid arteriogram
demonstrating an avascular frovital mass with irregular
narrowing and stretihing of the anterior, middle,
and poJterior cerebra/ arteries (arrows).
hfarked displacement of the prricallosal arterj and lesser
displacement of the callosomarginal artery are apparent:
boi~thuesJels are narruwed.
Clinical Findings
last examined on April 22, 1976, he was moderately aphasic.
There was mild pallor of both optic discs, but visual acuity
was normal. The left corneal response was absent, and there
was marked hypalgesia over the second and third divisions
of the left trigeminal nerve. The left sixth nerve palsy was
still present, and there was mild left facial weakness and
contracture. The remainder of the examination was within
normal limits. A repeat CT scan with and without intravenous contrast was obtained, and the only abnormality noted
was an area of low density adjacent to the left temporal
craniotomy site. There was no midline shift or dilatation of
the ventricular system and no evidence of bone destruction
in the floor of the left middle cranial fossa.
Table 1details the vital statistics of our 6 patients and of
those culled from the literature. Our patients ranged
in age from 9 to 57 years and suffered from a variety of
extracranial neoplasms. Biopsy or surgical extirpation
of the extracranial tumor established the diagnosis
prior to the commencement of radiation therapy. All
6 were irradiated in such a way that a portion of the
brain was included within the radiation portals. After a
delay of from 4 to 31 months following radiotherapy,
each of our patients developed symptoms attributable
to cerebral radiation necrosis. The diagnosis of radiation necrosis was made by biopsy in 5 patients and at
postmortem examination in the remaining patient.
The symptoms, signs, and laboratory findings in our
6 patients and in the 19 described previously in the
literature are listed in Table 2. In general, patients
presented with symptoms and signs suggesting an
intracerebral mass. In 2 of our patients the onset was
Rottenberg et al: Cerebral Necrosis following Radiotherapy
347
A
B
348 Annals of Neurology
Vol 1 No 4 April 1977
Table I . Cerebral Radiation Necrosis: Rez:iew of the Literature and MSKCC Series
Radiarion
Dose
Age
and
Author (Dare)
Fischer and Holfcldfr (19301 [ I 1
Pmnybackrr and Russell (1948) [ L I
Lowenberg-Scharenherg
and Hassetr (1950) 131
Polti er al (1953) [4J
nugget er a1 (1954) 151
Bucliaard ana Jacoby (1962) 161
Chandler ef al (1964) [71
Sex
Extrxranral Neoplasm
(rrrr)
Latcniya
Operation
Ourcome
45, M
52, M
Epithchal Ca, righr remple
Rodent ulcer, left parietal scalp
7 yt
Curt
9mo
Yes
Yes
42, F
Basal cell Ca, left rcmplc
2,900
2,400
2,840
5 11/12 yr
56, M
45, F
54, M
50, F
48. F
59, F
Fungaring Ca, right pricral scalp
Basal cell rpithrliuma. right pnrictal scalp
1,400
2,500
Squamoiis cell Ca. skin ahove lrtt car
Epithtiioma, left pariersl scalp
Epithelioma, right temple
Subcuraneous neurofibrosarroma, right remplt.
Righr ethmordoorbital epirhelioma
Rtttculum cell Earcoma, left frontal sinus
Lginphorcticulosar'onia, lcfr
occipital scalp
Basal cell Ca, right side of scalp
Biopsy
Biopsy
Yes
Cure
1 Yr
Biopsy
3 4/12 yr
2 6!12 y r
Yes
Cure
Cure
>
Biopsy
47!12 yr
Biopsy
2,1ou
2 2/12 y r
Yes
1,255
1 6 / 1 2 yr
Ye5
Cure
Cure
4 wk
3,000
Yrs
2,700
3 mu
19yr
2,231
2,285
2,275
4 yr
2 3/12 y r
3 yr
YCS
2,232
4yr
Yes
Died: abdominal I 4/12 yr
sepsis
Autopsy
D I sab 1e d
3v
Biopsy
Autopsy
7 mo
Yes
No
Yes
4 yr
Biopsy
Yes
Y?S
Yes
Yes
Cure
Curc
Mandybur and Gore (1969) [ I I1
54. F
62, F
Basal cell La, right irontoparietal scalp
Cambier et al (19721 I121
Krayenbuhland Rurmer (1973) 1111
69>F
Spinocellular eprthrlionia, lcft scalp
Unknown 3 yr
2,772
3 yr
19, M
Undiferenriated Ca, right eustachian tuhe
7,700
69. M
62, F
Epiphargngeal Ca
2,500
1 6 / 1 2 yr
Yes
Okcda and Shibara (19'3) 1141
Epidermoid Ca. epipharynx
3,?50
2yr
Nn
Dled: neurological
symptoms
Eyrtrr er al (1974) 1151
50, M
EEthesioneuroepithelioma,
right ethmoid sinus
2,133
2 It
Yes
.i
MSKCC series
Parienr 1
28. M
Ostengemc sarcoma, left maxillary antrum
1,750
IS wk
Yes
Died: CNS
Cure
Curc
Cure
Died
Died: tumor
recurrence
Cure
Cure
Biopsy
Parienr 3
29, M
Pdricnr 4
57,
Patie IIt 5
30, F
Patient 6
41, M
hf
Embryonal rhabdomyosarcoma, right
ydrorld gland
l,6'5
9 mo
No
Adenoid rystic Ca, righr lacrimal gland
2,574
2 7/12 y r
Yes
Squamous cell Ca. right external auditory
meatus
Anaplasric squamous cell Ca, left crhmoid
labgrinrh
1,760
1 9/12 yr
Yes
1,760
11-16wk
Yes
Anaplarrrr epdcrrnold Ca, nasopharynx
3,226
9-10mo
YCS
Died: neurological
symptoms
lied. nmrologlial
symptoms
Cure
Died: neurological
qunproms
Curc
Biopsy
7 yr
Fhopsy
i
B1opsy
14/12 yr
Biopsy
Biops?
Biopsy
? 6 yr
2 6/12 y c
14 days
Biopsy
3 yr
Autopsy
2 Yr
Biopsy
4 1/2 wk
Biopsy,
auropsy
29 wk
Autopsy
3 yr
Biopsy
2 7/12 y r
Biopsy
6 *no
BIOPSY,
autopsy
2 1/12 yr
Fhopsy
sepsis
9, F
Diagnosis
Cure
54, F
48, M
Patient 2
Method
oi
6 mo
3 314 yr
Bernasronl e t al 11967) L81
Arniio and Cangtr (1967) [9J
Mama and Giuffre i1968) [I01
44, M
FollowUP
aLatency refers to the interval between the lasr radiation trearrnent and the onset of sympcorns of cerebral radiation necrosis.
apoplectiform, with generalized seizures in 1 instance
and the sudden onset of headache, vertigo, and diplopia in the other. Four patients suffered from a subacute illness characterized by headache, personality
change, and focal neurological deficits. All patients
had focal neurological signs when they were first examined, and papilledema was present in 3 of our patients as well as in 6 of those reported in the literature.
In the MSKCC series the CSF was under increased
pressure in 2 of the 3 patients in whom it was measured, and in all 3 instances the CSF protein was
moderately elevated. The EEG was abnormal in all
our patients and was characterized by slow-wave activF i g 6. (Patient 5 . ) Left carotid arteriogram (lateral
projection). (A) Early arterial phase with magnification
and subtraction. There is irregular narrowing of seeeral
ascending froiital branches of the middle cerebral artery
(arrows). (B) I n the late arterial phase (not subtracted),
additional areas OJ narrowing are demonstrated (arrows)
u i t h delayed emptying of the more distal brani-hes.
ity lateralized to the side of the lesion. Radionuclide
brain scans were abnormal in 4 patients, but because
the parenchymal lesions were adjacent to extracranial
tumor and to necrotic bone, it was often difficult to be
certain that an area of increased isotope uptake was
intracerebral. A CT scan was performed in 1 patient
(No. 6 ) and revealed an irregular area of decreased
absorption with displacement of the lateral and third
ventricles to the contralateral side (see Fig 7).
In our 6 patients and in 3 of 10 previously reported
cases, cerebral arteriography delineated an avascular
mass with appropriate contralateral displacement of
the anterior cerebral artery or internal cerebral vein
or both. In the temporal lobe lesions the "sylvian
triangle" was elevated, with stretching of the temporal
branches of the middle cerebral artery. Careful subtraction techniques in each case failed to reveal a
tumor stain. Selective external carotid injections were
performed in 3 of our 6 patients; no pathological
circulation or displacement of the middle meningeal
artery was observed.
Rottenberg et al: Cerebral Necrosis following Radiotherapy 349
F i g 7 . (Patient 6.) C T srans at the level of the
intracaentricularforamina and the bodies of the lateral
ventricles. The lateral ventricles und third ventricle are
displared t o the right, and an irregular area of decreased
ahorption coefficient i s seen i n the left temporal lobe with
extension into the left frontal lobe.
Table 2. Cerebral Radiation Necrosis: Symptoms, Signs. and Diagnostii Procedures
Manifestations and Tests
Symptoms
Personality change
Seizures
Headache
Dizzinesslver tigo
Gait ataxia
MSKCC (N = 6)"
1930-1976 (N = 19)a
3
3'
9d
4
8
5
2
1
1
7h
Signs
Impairment of consciousness
Dysphasia
Papilledema
Focal motor weakness
4
Lumbar puncmre
Pressure > 160 mm CSF
Protein > 50 mg/dl
213"
313
417
Electroencephalogram
Focal slowing
616
7 19
Isotope brain scan
Focal uptake
4 14
3I4
Cerebral arteriograph y
Avascular mass
Small vessel abnormalities
616
216f
9/10
2110~
C T scan
Decreased density
Midline shift
111
111
...
3
4
6
14
217
aThe 6 MSKCC patients and the 19 patients culled from the world literature.
bThree patients were described as "confused."
'One patient had both focal and generalized seizures.
"Four patients had focal seizures, of whom 2 also had generalized sei7ures.
'Fractions compare the number of patients with positive findings (numerator) to the number of patients for whom data are available
(denominator).
'Two patients had irregular narrowTing and occlusion of small vessels.
g"Questionable small vessel changes" were described by Mandybur and Gore (Case Z), and "a skein of delicate pathological vessels" was
observed by Krayenbuhl and Ruttner (Case 1).
350
Annals of Neurology Vol 1 No 4 April 1977
A
B
F i g 8. (Patient 6.1 (A) Fibrocollagenous alteration of
raJrzllar media and adventitia. A large bipolar celf in the
adventitia is indirated bj an arrow. (B) Perivascular
pmlifrration surrounding diluted, thin-zuulled vu.ri.cdar
channels (arrows). Note large bipolar cells. (Both HCE: A
x40: B x100, both before 10% reductiori.)
A
B
352
Annals of Neurology
F i g 9. (Patient 6.1New vesselformation. (A)Aggregates of
large, thick-walled vascdar structures. !HG.E; x40 before
10% redzlction.) (9)Dilated, thin-walled vessels
resembling telangertasia. (PTAH; ~ 2 before
5
I 0 04,
reduction.)
Vol 1 No 4
April 1977
Magnification angiograms in lateral projection were
performed in 3 patients with a 0.3 X 0.3 mm focal
spot, centering over the mass. In 2 patients changes in
small cortical branches of the anterior and middle
cerebral arteries were demonstrated. In Patient 5 (see
Fig 6) irregular narrowing was seen in the region of the
mass, with actual interruption and delayed emptying
in adjacent arterial branches. These abnormalities
closely resemble those observed in meningeal carcinomatosis, “vasculitis” due to collagen disease, and
infectious processes associated with an avascular
mass; they are also occasionally seen in relation to
malignant brain tumors when there is actual invasion
of the vessel wall. Similar arteriographic changes in
patients with radiation necrosis have been described
by Kagan, Bruce, and DiChiro [16] and by Kramer
and Lee [l?]. Both reports contain examples of attenuation and “beading” of cortical arterial branches,
and Kramer and Lee described an associated avascular
mass. Kagan et a1 also observed narrowing of the
cisternal portion of the internal carotid artery and the
main trunk of the middle cerebral artery, changes that
are not infrequent in subarachnoid hemorrhage,
meningeal carcinomatosis, and purulent meningitis.
The differential diagnosis of cerebral radiation necrosis includes: (1) brain tumor (direct extension or
metastasis in the case of extracranial neoplasms, recurrence in the case of primary CNS tumors); and (2)
brain abscess (bone and soft tissues within the radiation portals are often necrotic and chronically infected). The correct diagnosis was suspected initially
in only 2 of our 6 patients. Indeed, intracranial infection was associated with radiation necrosis in 2 patients (Nos. 4 and 5), and intracranial extension of the
extracranial tumor followed treatment of radiation
necrosis in Patient 3. Two patients (Nos. 2 and 6)
received additional irradiation for symptoms that
were attributed at the time to tumor recurrence but
later proved to be due to cerebral radiation necrosis.
It is not possible on the basis of the clinical examina-
tion alone to distinguish these entities, and except for
the characteristic arteriogram in Patient 5 , none of the
currently available laboratory aids or neuroradiological procedures enabled us to arrive at an unequivocal
diagnosis of radiation necrosis. A definitive diagnosis
can be established only by surgical exploration and
biopsy. Four of our 6 patients underwent craniotomy
with partial o r complete surgical extirpation of necrotic brain tissue. Two operated patients are alive and
without disabling neurological symptoms 3 1 and 25
months after operation, respectively. The 2 nonoperated patients died 29 weeks and six months following
the onset of neurological symptoms attributable to
radiation necrosis. In 1 of the 3 autopsied patients
there was no evidence of residual tumor; both surviving patients are without evidence of recurrent disease.
Since useful survival is possible following successful
surgical intervention and since, if left untreated, cerebral radiation necrosis is usually fatal [181, surgical
exploration and extirpation of necrotic brain tissue are
Indicated once the diagnosis of focal cerebral radiation
necrosis is suspected. This diagnosis should be considered whenever a patient who received therapeutic
irradiation months or years previously for an extracranial neoplasm develops symptoms and signs of an
intracerebral mass within the path of the radiation
beam.
Pathological Findings
Table 3 summarizes the pathological findings in our 6
patients. Their abnormalities resemble those previously reported [19].Grossly, the characteristic
changes are best illustrated by Patient 2, whose autopsy specimen (see Fig 2) was uncontaminated either
by prior operation or by intracranial infection. The
posterior portion of the irradiated temporal lobe contained an area of coagulative necrosis affecting white
matter more than the overlying gray matter. More
anteriorly the liquefactive necrosis resulted in cavity
formation resembling ischemic infarction, which may
Table 3. Pathologiuzl Finding.[ i n 6 hfSKCC Patients with Cerebral Rudiution Necrosis
Vaiiular Lesions
Parrndryrnal l e s m n s
Cys1,c
Paritnr
N”.
Examinarim
Coagulation
Necrosis
Cavitation
(white
matter)
zarion
Necrosis
Thrnmhnsis
Proliferation
lariTdilOn
Inflammarory
Rearrinn
1
Biopsy
++
0
0
+i
t t
+t
0
+t
-+
0
+t
tt
+-
0
0
t+
t+
0
t+
++
++
++
--I
t t
ti
+‘1
0
++
0
++
t+=
0
+-
0
n
0
++
++
++
0
0
++-
+t
0
++
0
t i
u
t t a,b
t
Minerall-
Glioqir
i t
Pcrivascular
Ncovasru-
and
2
3
auropsy
Autopsy
4
5
Biopsy
Blopsy
Biopsy
and
autopsy
6
Biopsy
++
+
I +t
aDilated, thin-walled channels.
hLarge, thick-walled vessels.
0 = absent;
+ = present but not prominent; ++ = moderately severe; +++ = severe
Rottenberg et al: Cerebral Necrosis following Radiotherapy 353
have resulted from vascular thrombosis. Just as in the
more posterior region, there was relative sparing of
the overlying cortex. Similar cystic changes were seen
in 2 other autopsied patients, but it was not possible to
distinguish the effects of radiation damage from those
of surgical intervention o r suppuration.
Microscopically there were changes in blood vessels, in brain parenchyma, and in fibroblasts. The most
striking abnormality, seen in all our patients, was
hyalinized thickening and necrosis of blood vessels;
this was associated with vascular thrombosis in 4 patients (see Figs l A , 3A,B). There was new vessel formation in 3 patients. Dilated, thin-walled, telangiectatic channels were observed in Patients 2,3, and 6, and
Patient 6 had focal accumulations of large-caliber,
thick-walled vessels (see Fig 9).An inflammatory reaction, consisting primarily of perivascular infiltration
with lymphocytes, was a prominent feature only i n
Patient 5 , in whom the radiation necrosis was complicated by meningitis. Milder inflammatory changes
were also seen in Patients 1 and 4, in whom infection
may have played a role as well. In Patients 2 and 3,
who had no complicating infections, no inflammatory
changes were seen.
Fibrocollagenous proiiferation involved the adventitia of vessels of all calibers, at times reaching massive
proportions. Bipolar cells with prominent nucleoli,
which morphologically resembled altered fibroblasts,
were frequently observed in these areas of fibrocollagenous proliferation (see Fig 8). These large,
transformed fibroblasts have not been previously
described and may represent a transition between
radiation necrosis and radiation-induced sarcoma
[201.
Parenchymal changes in the brain were, in all instances, more striking in white matter than in the
overlying gray matter. Coagulation necrosis was
present in 5 of our 6 patients; cystic cavitation of the
white matter occurred in 3. Mineralization and extensive deposits of proteinaceous material in the cerebral
parenchyma, however, were observed only in Patient
2 (see Fig 3D). Marked astrogliosis surrounded the
foci of necrosis in all 6 patients, and large, irregular,
and often bizarre multinucleated cells were frequently
observed. Characteristically, the astroglial cytoplasm
had a coarse, granular appearance, and cytoplasmic
processes were prominent (see Fig 1B). In general, the areas with the most severe vascular injury (fibrocollagenous thickening, hyalinization, and
thrombosis) were the most necrotic and cavitated.
Patchy demyelination without marked degenerative
changes in blood vessels but with perivascular infiltration by lymphocytes and plasma cells has been described by Lampert and Davis [2 11 and is believed to
represent an “early delayed” effect of irradiation.
Such changes were not observed in our patients.
Thus, in our patients the characteristic neu354 Annals of Neurology Vol 1 No 4 April 1977
ropathological changes of delayed radiation necrosis were coagulative necrosis and cavitation of
white matter occurring within the volume of cortex
traversed by the radiation beam; relative preservation
of the cortical cytoarchitecture; glial proliferation
with bizarre, multinucleated astrocytes in relation to
the foci of necrosis; small vessel changes (fibrinoid
necrosis with associated thrombus formation, luminal
occlusion, medial fibrosis and adventitial proliferation, and frequently perivascular accumulation of
homogeneous fibrinoid material); and large, transformed fibroblasts.
Pathogenesis
Three hypotheses have been advanced to explain the
pathology of cerebral radiation necrosis: (1) a vascular
hypothesis-that the brunt of radiation damage is
borne by small and medium-sized blood vessels in the
brain and that tissue necrosis is secondary to ischemia;
(2) a glial hypothesis-that radiation-induced mutations in glial cells, particularly oligodendroglial cells,
are responsible for the prominent white matter damage and the frequently observed demyelination; and
(3) an immunological hypothesis-that irradiated cells
release antigens into the brain and that the necrosis
and vascular changes observed pathologically are the
result of a hypersensitivity response to released antigen.
The vascular hypothesis was advanced by Lyman,
Kupalov, and Scholz [22], who irradiated the occiputs of adult dogs, observed delayed behavioral
changes and neurological signs, and described the
neuropathological lesions in an animal sacrificed six
months following irradiation. They recognized that
areas of cerebral necrosis were “founded on larger
blood vessels” and concluded that “roentgen rays may
alter the function of the central nervous system but
their action does not seem to be primarily on cells of
the cerebral cortex.” In 1949 Russell, Wilson, and
Tansley [23] irradiated young adult rabbits and observed delayed behavioral changes and neurological
signs; at postmortem examination they remarked the
relative preservation of cerebral cortex but noted
fibrinoid necrosis of arteriolar and capillary walls (associated with luminal thrombosis and occlusion) and
hemorrhages and necroses of varying ages in the cerebrum and cerebellum. They concluded that “the initial
histological changes consist of minute foci of hemorrhage and necrosis which are intimately related to the
perforating vessels and, in particular, capillaries.”
Courville and Myers [24] examined the brain of a
15-year-old boy who died 28 months after receiving a
single, excessive radiation dose for ringworm of the
scalp. They concluded that the radiation damage depended primarily on a vascular lesion characterized by
progressive thickening and hyalinization of arteriolar
walls.
There is more recent clinical and experimental evidence to support the vascular hypothesis: Hopewell
and Wright [25, 261 compared the effects of single
doses of 1,000 t o 4,000 R on the brains of normal rats
and of rats made hypertensive by the kidney infarct
technique. Hypertension appeared to shorten the latent period between irradiation and death for exposures of 2,000 and 3,000 R and to lower the threshold
for radiation damage at 1,000 R. There was, however,
an apparent paradoxical lengthening of the latent
period at 4,000 R. They concluded that at lower radiation exposures death “was probably due to a sudden
vascular accident,” whereas at higher exposures death
was a consequence of white matter damage, perhaps
related to subependymal stem cell depletion and failure of neuroglial migration along white matter tracts.
Preexisting hypertension had no effect on the latter
process.
Blood vessels of all sizes are known to be sensitive
to x- and gamma radiation. Wright and Bresnan [27]
recently reported the occurrence of internal carotid
artery occlusion in a child six years after therapeutic
irradiation of a facial hemangioma, and Conomy and
Kellermeyer [28] reviewed the pertinent literature on
radiation-induced cerebrovascular disease in adults.
The mechanism of vascular occlusion following radiation exposure is not known, but Hopewell and Wright
[25, 261 postulated a gradual depopulation of cells in
(moderately) irradiated vessel walls as irradiated cells
die on attempting division. The remaining viable cells
“multiply in response to this cell loss and produce
localized clones of muscle cells at irregular intervals,’’
leading to luminal constriction and vascular occlusion.
At high doses of radiation such vascular changes d o
not occur because endothelial cells are “rendered reproductively non-viable” [26]. Decreases in regional
blood flow during the development of experimental
radiation necrosis in brain [29] and other organs [30]
support this hypothesis, as does the interesting finding
of de Ruiter and van Putten [30] that 14 to 17 months
after mouse tails were irradiated there was a decrease
in tail blood flow if the animals had received up to
2,500 R, whereas at doses higher than 2,500 R an
increase in blood flow was observed. The striking
vascular lesions in our own patients also lend support
to the vascular hypothesis.
The second hypothesis, which was proposed by
Zeman [ 3 1, 321, holds that radiation-induced mutations in glial cells, particularly oligodendroglial cells,
are responsible for the demyelination and white matter necrosis observed inpatients with delayed cerebral
radiation injury. This explanation has both clinical and
experimental support. As noted, Hopewell and
Wright found that preexisting hypertension did not
shorten the latent period between irradiation and
death in their rats exposed to 4,000 R and thar the
primary neuropathological lesion appeared to be glial
cell depletion. The frequent appearance of a transient
Lhermitte sign after irradiation of the cervical cord
[3 31 suggests that transient demyelination resulting
from oligodendroglial injury may be relatively common, even at doses that do not produce permanent
radiation damage. Demyelinative lesions of the brain
following radiation therapy, in the absence of marked
vascular alterations, have been reported by Lampert,
Tom, and Rider [34],by Rider [35], and by Lampert
and Davis [2 11. These demyelinative lesions, like the
Lhermitte sign of cervical cord injury, often appear
after a short latent period (weeks rather than months
or years) and may heal spontaneously. We did not
observe such “early lesions” despite the fact that 2 of
our patients (Nos. 1 and 5) developed symptoms of
radiation necrosis less than 16 weeks after radiation
therapy was completed. These are among the shortest
latencies reported for delayed hemispheral necrosis
after irradiation of extracranial neoplasms (see Table
1).Such short latencies are said to be more consistent
with brainstem or spinal cord demyelinative lesions
[2 11than with the vascular lesions and necrosis that we
actually observed. The striking glial proliferation observed in our material, associated with bizarre,
malignant-appearing cells and giant multinucleated astrocytes, lends support to a primary effect of radiation
on glial cells.
The third hypothesis, advanced by Lampert, Tom,
and Rider [34] and subsequently championed by
Crompton and Layton [36], attempts to reconcile the
vascular and glial lesions by suggesting that the pathological alterations associated with delayed cerebral
radiation necrosis result from an allergic response to
antigens released from damaged glial cells. According
to this proposal, “such antigens could then stimulate
the local accumulation of plasma cells, with production of antibodies.” Thus, immune complexes might
form in the presence of an intact blood-brain barrier.
Of interest in this regard, Olsson, Klatzo, and Carsten
[ 3 7 ] investigated the effect of acute radiation injury
on the permeability and ultrastructure of intracerebral
capillaries in the rat. They concluded that acute radiation injury produces focal necrosis and separation of
adjacent capillary endothelial cells with extravasation of macromolecular protein tracers into the vascular basement membrane and perivascular space. Except for the presence of perivascular plasma cells and
lymphocytes [2 1,341 and of eosinophils [36], there is
no clinical evidence to support the autoimmune
hypothesis. If an immunological response to “altered
proteins” were the basis of delayed cerebral radiation
necrosis, one might expect that immunologically
compromised patients would tolerate radiation
therapy better than those with normal immune competence. However, it is the impression of one of us
(F. E.) that tolerance to radiation is redaced rather
than increased in patients with Hodgkin’s disease and
Rottenberg ct al: Cerebral Necrosis following Radiotherapy 355
lymphoma, diseases often associated with reduced immune competence. Bornstein’sfinding 1381that 2 of 3
serum samples from patients with CNS neoplasms
treated with cobalt 60 produced in vitro demyelination of cultured rat cerebellum versus neither of 2 sera
from untreated patients with brain tumor is intriguing
but hardly conclusive evidence that therapeutic irradiation induces autoantibody production, since 5 of
16 sera from patients with undiagnosed neurological
diseases and 1of 17 normal control sera also produced
such demyelination.
These three hypotheses are not mutually exclusive,
and it seems likely that both vascular and glial alterations play a role in the pathogenesis of cerebral radiation necrosis. Patient-to-patient differences and the
variable nature of the pathological findings cited by
proponents of the different hypotheses may merely
reflect differences in absorbed dosage since, at least in
experimental animals, it appears that lower doses
damage vessels and higher doses damage glial cells.
However, the clinical evidence suggests the contrary:
that glial cell injury may occur without concomitant
vascular injury.
Radiation Dosimetry
In order to avoid radiation necrosis when extracerebra1 or intracerebral lesions are irradiated, the
radiotherapist must know the biological tolerance of
the normal tissues lying within the radiation portals.
H e must deliver adose large enough to sterilize tumor
cells yet small enough t o spare normal tissue. In a
recent review of the hazards of therapeutic irradiation
of the central nervous system, Kramer [39] concluded
that the normal brain will tolerate tissue doses in
excess of 6,000 rads over six weeks (approximately
1,760 rets). Four of our 6 patients received “safe”
doses by Kramer’s criterion, but the lowest dosage
level producing radiation necrosis according to
Lindgren’s 1958 nomogram [40]was exceeded in all 6
patients.
Kramer’s and Lindgren’s doses are expressed in
terms of the rad, a physical entity. The biological
effect of ionizing radiation depends not only on the
total dose in rads (D) but also on the dose per fraction
(d), the number of fractions (N), the time (T) over
which the total dose is administered, and the energy of
the radiation. Each of these factors must be considered individually in order to calculate a “biological
dose.” In order to relate the total dose in rads to the
biological effect of therapeutic radiation, Ellis [41,42]
has developed the concept of “nominal standard dose”
(NSD), which is expressed in rets. N S D is related to
rads according to the following formula:
D = N S D x No.’4 x To.’1
where D is the total dose in rads, N S D the nominal
standard dose in rets, N the number of fractions, and
356 Annals of Neurology Vol 1 No 4 April 1977
T [he elapsed time in days. This formula applies to
radiation from 6oCo and from other high-energy
sources such as linear accelerators and betatron
machines. Therapeutic irradiation administered before the megavoltageP’Co era had a greater biological
effect per rad. In Table 1 radiation doses are expressed in rets, although many of the calculations are
necessarily inexact inasmuch as all the data required
to convert rads into rets was frequently unavailable.
It would appear from the calculated ret doses in
Table 1 that absorbed doses below 1,700 rets are
probably well tolerated by normal brain but that doses
above 1,760 rets (Kramer’s6,000 rads over six weeks)
may in certain instances lead to delayed cerebral radiation necrosis. Factors other than the radiation dose
may also play a role in the development of radiation
necrosis. Recent reports indicate that both vincristine
[43] and methotrexate [44] may potentiate the
neurotoxic effects of CNS irradiation. It may be that
the administration of systemic chemotherapeutic
agents such as vincristine and methotrexate lowers the
radiation tolerance of the brain and spinal cord or,
alternatively, that craniospinal irradiation damages
the blood-brain barrier, exposing the CNS to toxic
concentrations of subsequently administered chemotherapeutic agents. Hopewell and Wright [251 argued that systemic hypertension lowers the tolerance of the nervous system to therapeutic irradiation,
and our clinical cases suggest that preexisting infection may also act synergistically with high-energy radiation to produce delayed cerebral necrosis. It may
therefore be impossible to calculate in every case an
exact dose below which delayed cerebral radiation
necrosis will not occur; nevertheless, in the absence of
known complicating factors, 1,700 rets would seem to
be a safe dose within the small fields used for extracranial irradiation. Wara et a1 [45]studied the radiation
tolerance of the spinal cord and concluded that 1,O 15
rets (equivalent dose) produces a 1% incidence of
radiation myelopathy in the thoracic cord and that
1,476 rets (equivalent dose) produces a 50% incidence of myelopathy.
Our experience with delayed cerebral radiation
necrosis following the irradiation of extracranial neoplasms suggests that this entity may become an increasingly serious problem as radiation therapy for extracranial tumors becomes more effective in prolonging
survival. The delayed onset of neurological symptoms
and signs of a mass in the brain following irradiation
should lead the neurologist to consider the possibility
of radiation necrosis, even if the patient has received
what most radiotherapists would consider a “safe”
dose of radiation. The diagnosis should be strongly
suspected if narrowing, irregularity, and occlusion of
small cortical vessels are demonstrated by arteriography, but it can be established only by brain biopsy.
Since surgical extirpation of the necrotic lesion is the
treatment of choice and may cure an otherwise
doomed patient, aggressive therapy of this disorder is
warranted.
Supported in part by Grant CA-05826 from the National Cancer
Institute.
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