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Focal cerebral vasculitis associated with circulating immune complexes and brain irradiation.

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Focal Cerebral Vasculltis
Associated with Circulating
Immune Complexes
and Brain Irradiation
Dennis R. Groothuis, MD,*
and Michael A. Mikhael, MDt
In this report we describe a patient with a benign
glioma treated with surgery and radiation. After a period of stability he developed subacute bacterial endocarditis, and deteriorated neurologically. Computed
tomographic scans did not show recurrent tumor. An
angiogram showed vasculitis restricted to the previously
irradiated area. Secondary to subacute bacterial endocarditis was the presence of high levels of circulating
immune complexes. His neurological status was unchanged after antibiotics, but improved after treatment
with dexamethasone. We interpret the clinical course as
an immune-complex-mediated vasculitis superimposed on
a subclinical radiation vasculitis. This case supports the
hypothesis that immune mechanisms may be involved
in delayed radiation injury to the nervous system.
Groothuis DR, Mikhael MA: Focal cerebral
vasculitis associated with circulating
immune complexes and brain irradiation.
Ann Neurol 19:590-592, 1986
Delayed radiation injury to the nervous system occurs
with a low incidence, but with devastating consequences [8-10]. Despite a voluminous literature dealing with the subject, the mechanism of injury remains
poorly understood. Direct effects of radiation on
either &al cells or vascular endothelium are usually
invoked as the primary pathogenetic mechanism [Sly
but the participation of an immune-mediated process
has also been suggested [lo, 111. Our patient represents a case in which radiation effects and circulating
immune complexes (CIC) were both present, with
clinical effects that were best explained by an interaction of these two disease mechanisms. This case illustrates that immune-mediated processes may play a part
in damage produced by delayed radiation vasculitis.
Case Report
A 38-year-old man was first seen after a three-year history of
temporal lobe seizures. A computed tomographic (CT) scan
From the Departments of *Neurology and ?Radiology, Northwestem University Medical School, Evanston Hospital, Evanston, IL
Received July 19, 1985, and in revised form Oct 14. Accepted for
publication Oct 16, 1985.
Address reprint requests to Dr Groothuis, 2650 Ridge Ave, Evanston, IL 60201.
showed a low-density lesion in the left temporal lobe with
slight contrast enhancement. The patient underwent a left
temporal lobe resection; the tumor was a cellular astrocytoma with microcystic degeneration (grade I). The patient
received a total of 5,040 centigray units (cGy) in 28 treatments (180 cGy per fraction) to left anterior and posterior
oblique wedge fields (Fig 1). H e did well except for occasional psychomotor seizures and a mild aphasia. A CT scan
one year later showed no evidence of tumor recurrence.
Two years later poor memory, moderate aphasia, and mild
right hemiparesis developed. A CT scan was unchanged. His
condition deteriorated over the next week and he developed
a severe aphasia, dense right hemiparesis, and lethargy. An
arteriogram showed attenuation of the left suprasylvian
branches with retrograde filling over the convexity (Fig 2),
believed to be radiation vasculitis. The remainder of the arteriogram was normal. A lumbar puncture was normal except
for an IgG-to-total-protein ratio of 36%. His cardiac examination showed changing murmurs compatible with aortic and
mitral regurgitation and blood cultures grew Streptococcus vzridzns. An echocardiogram showed vegetations on the mitral
and aortic valves.
Antibiotics were started but his neurological condition
worsened. An immune component to his disease was evaluated: concentrations of serum complement, rheumatoid factor, and antinuclear antibody were normal; the Westergren
sedimentation rate was 54 mmlhr. The Raji cell titer was 910
mg aggregated human gamma globulin equivalents per milliliter (AHG eq/ml; normal, <12). C l q binding was 45.0 mg
AHG eq/ml (normal, <30). Because of high levels of CIC
and continued neurological deterioration in the face of
adequate antibiotic treatment, dexamethasone was added.
Within 24 hours his neurological status had improved. By
the time of discharge he had a mild right facial weakness,
mild memory difficulties, and a moderate aphasia. Repeat
assays of circulating immune complexes one month later
yielded a Raji cell titer of 129 mg AHG eq/ml, and C l q
binding of 25 mg A H G eq/ml.
The patient remained neurologically stable. CT scans
showed no tumor recurrence, but did show an area of lucency in the left hemisphere indicative of cerebral infarction
(Fig 3). Forty months after initial presentation, a CT scan
showed a contrast-enhancing mass in the left temporal lobe
with rapid increase in size shown on subsequent CT scans,
interpreted as typical of a malignant glioma. Further therapy
was declined and the patient died 46 months after initial
presentation. An autopsy was not done.
This patient's illness represents a unique sequence of
events that may shed light on the pathogenesis of delayed radiation injury to the nervous system. After
surgical resection, the glioma was treated with a dose
of radiation below that usually believed to cause
radionecrosis [S-101. A year and a half later, when
there was no clinical or CT scan evidence of tumor
recurrence, he developed subacute bacterial endocarditis (SBE) that was associated with high levels of CIC,
and cerebral vasculitis that was restricted to the field of
previous irradiation C91. We do not believe the vasculitis was solely due to the radiation, because the dose
Fig 1. Isodose values of externally administered cranial iwadiation. The total cumulative dose o j radiation, in centigray units
( G y ) ,for each isodose line is 1 = 5,500, 2 = J,280, 3 =
5,040, 4 = 4,752, 5 = 2,640, and 6 = 1,584. Note that the
affected area of brain in Figures 2 and 3 lies entirely within the
5,040 cGy-isodose line.
Fig 2. Arterial phase of a left-carotid-injection cerebral angiogram, showing paucity of vessels in the territory of frontal opercukzr branches (asterisk).
of administered radiation was low; there was no contrast enhancement on CT, which usually accompanies
radionecrosis; and the rate of the development of
neurological signs (7 to 10 days) was more rapid than
that seen in delayed radiation injury. Nor do we believe that SBE or the high levels of CIC were solely
responsible. SBE commonly produces neurological
deficits by producing cerebral embolization, manifested by the abrupt onset of clinical signs and accom-
F i g 3 . Cranial computed tomographic scan done with contrast
injection after recovery from the episode of cerebral vasculitis,
showing a low-density lesion in the lejit posteriorfrontal area
underlying the craniotomy. There is no mass effect or abnormal
enhancement, suggesting that the lesion is most likely an old infarct and not recurrent tumor.
panied by arteriographic evidence of arterial occlusion.
It would be unusual for cerebral emboli from SBE to
affect multiple vessels around the site of the treated
tumor but nowhere else in the brain. CIC have not
been reported to cause cerebral vascditis, although
they are suspected of participating in the disease process in systemic lupus erythematosus [12}.
Instead, we believe that radiation injury and CICmediated processes interacted to produce the clinical
syndrome in this patient. We speculate that the cerebral irradiation, even though too low to cause frank
radionecrosis {S- 101, in some way damaged or altered
the cerebral endothelial cells in the radiation field with
the highest accumulated radiation dose 191. Radiation
can increase vascular permeability in the nervous system [I, 71 and endothelial cells in the brain seem to
have a lower threshold but a longer latent period for
radiation injury than do neuroglia [S}. CIC do not
cause increased permeability of the blood-brain barrier r41, but do localize in sites in which vascular permeability is increased [2}. Thus the stage was set for
the events that were observed in our patient. We do
not believe the CIC had specific affinity for the cerebral endothelial cells, but that the CIC localized
nonspecifically to a site of previous endothelial damage
and then caused a focal cerebral vasculitis, which responded promptly to corticosteroids, which is characteristic of CIC-mediated vasculitis [2, 6}.
The events of this patient’s illness permit additional
speculation about the phenomenon of delayed cerebral
necrosis and suggest testable hypotheses. Some neuropathologists have speculated about the possibility of
Brief Communication: Groothuis and Mikhael Immune Vasculitis and Radiation 591
an immune-mediated mechanism in delayed radiation
injury to the brain, principally because of inflammatory
infiltrates that are so frequently seen on microscopical
examination IS, 10, 11). Recently, H
art and associates
131 demonstrated that cerebral vasculitis can be produced by transfer of lymphocytes activated in vivo or
in vitro after exposure to cerebral capillary endothelial
cells. Endothelial cells injured or altered by radiation
may also be capable of serving as a source of antigen to
initiate a cerebral vasculitis.
Several approaches can be envisioned to define
whether immune-mediated mechanisms contribute to
the pathogenesis of delayed radiation necrosis. First,
human biopsy or autopsy material can be studied immunohistochemically to search for antibody, complement, or immune complex localization. Second, the
possibility of an immune contribution should be
studied in a more controlled setting in experimental
animals, in which models of radiation vasculitis have
been developed 17, 11). If an immune mechanism contributes in any way to the pathogenesis of delayed radiation necrosis, then immunosuppressive therapy may
be beneficial in radiation brain injury.
Dr Groothuis is supported by grants from the National Institutes of
Health (NS12745, NS00814, and NS20023). This project was also
supported by the Boothroyd Foundation and the Richard M. Lilienfeld Brain Tumor Research Fund.
1. Caveness WF, Kemper TL, Brightman MW, et al: Directional
character of vasogenic edema. Adv Neurol29:271-291, 1978
2. Cochrane CG, Dixon FJ: Immune complex injury. In Samter M
(ed): Immunological Diseases. Boston, Little, Brown, 1982, pp
3. Hart MN, Sadewasser KL, Cancella PA, DeBault LE: Experimental autoimmune type of vasculitis resulting from activation
of mouse lymphocytes to cdtured endothelium. Lab Invest
481419-427, 1983
4. Hoffman SA, Arbogast DN, Day TI',et al: Permeability of the
blood cerebrospinal fluid barrier during acute immune complex
disease. J Immunol 130:1695-1698, 1983
5. Hopewell JW:
Late radiation damage to the central nervous
system: a radiobiological interpretation. Neuropathol Appl
Neurobiol2:329-343, 1979
6 Lakha A: Immune complexes. In Jeffery MS, Dick WC (eds):
Clinics in Rheumatic Diseases, Vol 9. Philadelphia, Saunders,
1983, pp 199-225
7 Levin VA, Edwards MS, Byrd A: Quantitative observations of
the acute effects of x-irradiation on brain capillary permeability.
Int J Radiat Oncol Biol Phys 5:1627-1631, 1979
8. Marks JE, Baglan RJ, Prasad SC, Blank W F Cerebral radionecrosis: incidence and risk in relation to dose, time, fractionation
and volume. Int J Radiat Oncol Biol Phys 7:243-252, 1981
9. Mikhael M: Radiation necrosis of the brain: correlation between
computed tomography, pathology, and dose distribution. J
Comput Assist Tomogr 2:71-80, 1978
10. Rottenberg DA, Chernik NL, Deck MDF, et al: Cerebral necrosis following radiotherapy of extracranial neoplasms. Ann
Neurol 1:339-357, 1977
11. Rubenstein LJ: Tumors of the central nervous system. In Atlas
of Tumor Pathology, second series, fascicle 6. Washington, DC,
Armed Forces Institute of Pathology, 1972
12. Seibold JR, Buckingham RB, Medsger TA, Kelly RH: Cerebrospinal fluid immune complexes in systemic lupus erythematosus
involving the central nervous system. Semin Arthritis Rheum
12168-73, 1982
Increased Leukotriene Cqand Vasogenic Edema
Surrounding Brain Tumors
in Humans
Keith L. Black, MD," Julian T. Hoff, MD,"
John E. McGillicuddy, MD,"
and Stephen S. Gebarski, MD'F
Leukotrienes are pharmacologically active compounds
that promote vascular permeability. In this study we
sought to determine whether tissue leukotriene-like immunoreactivity was increased in intracranial tumors associated with peritumoral edema. In 20 patients undergoing craniotomy tissue specimens were immediately
frozen after removal and tissue leukotriene C4 levels
were determined by radioimmunoassay. An index of
peritumoral edema was estimated from preoperative
contrast-enhanced computed tomographic scans. There
was a significant correlation between brain edema and
tissue leukotriene levels ( p < 0.003). Metastatic tumors
(n = 8) had the highest leukotriene C4 level at 13.8 f
8.5 pg/mg tissue (mean 2 SE) and the highest index of
edema 5.7 2 1.8. The mean leukotriene C4 level in the
gliomas (n = 5 ) was 6.2 +- 2.3 pg/mg tissue and the
edema index was 2.1 2 0.6.There was no edema and no
neoplasm in the temporal lobes removed for seizure (n
= 2), and their level of leukotriene C4 was 0.4 2 0.1pg/
mg tissue. The formation of leukotriene C4 is stimulated
by intracranial tumors. Leukotrienes increase bloodbrain barrier permeability and may be important in the
formation of vasogenic edema surrounding tumors.
Black KL, Hoff JT, McGilIicuddy JE, Gebarski SS:
Increased leukotriene C4 and vasogenic
edema surrounding brain tumors in humans.
Ann Neurol 19:592-595, 1986
Leukotrienes (LTs) are biologically active hydroxy
lipids (LTB4) and peptidolipids (LTC4, D4, and E4)
From the *Section of Neurosurgery, University of Michigan, Ann
Arbor, MI 48109, and the tDivision of Neuroradiology, University
of Michigan, Ann Arbor, MI 48109.
Received June 17, 1985, and in revised form Sept 16. Accepted for
publication Oct 27, 1985.
Address reprint requests to Dr Black, Section of Neurosurgery,
2124 Taubman Health Care Center, Box 0338, University of Michigan Hospitals, Ann Arbor, MI 48109.
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associates, focal, immune, vasculitis, brain, complexes, irradiation, circulating, cerebral
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