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J Neurosurg 55:590-603, 1981

Neuropathological and computerized tomographic


findings in experimental brain abscess
RICHARD H. BRITT, M.D., PH.D., DIETER R. ENZMANN, M.D., AND
ANNE S. YEAGER, M.D.
Department of Surgery, Division of Neurosurgery, Department of Radiology, Division of Neuroradiology,
and Department of Pediatrics, Division of Pediatric Infectious Disease, Stanford University School of
Medicine, Stanford, California

Vt The neuropathological progression of brain abscess formation was studied experimentally at sequential
stages in dogs, and the findings correlated with the appearance on computerized tomographic (CT) brain
scans. The evolution of brain-abscess formation was divided into four stages based on histological criteria:
early cerebritis (Days 1 to 3); late cerebritis (Days 4 to 9); early capsule (Days 10 to 13); and late capsule
formation (Day 14 and later). The cerebritis stage was characterized by prominent perivascular cuffing by
inflammatory cells in the area adjacent to the developing necrotic center. However, the early elements of
capsule formation appeared with the presence of fibroblasts by Day 5. The CT scans showed ring-shaped
contrast enhancement by Day 3. Delayed scans at 30 minutes revealed diffusion of the contrast material
into the developing necrotic center, forming a solid lesion. In lesions that were well encapsulated (14 days
and older), five distinct histological zones were apparent: 1) a well formed necrotic center; 2) a peripheral
zone of inflammatory cells, macrophages, and fibroblasts; 3) the dense collagenous capsule; 4) a layer of
neovascularity associated with continuing cerebritis; and 5) reactive astrocytes, gliosis, and cerebral edema
external to the capsule. The CT appearance of well encapsulated abscesses showed a typical ring-shaped
contrast-enhancing lesion. On delayed scans, the "ring" did not fill in with contrast enhancement. The
diameter of the ring correlated best with the presence of cerebritis (perivascular infiltrates in the adventitial
sheaths of vessels surrounding the abscess). The discussion focuses on the relevance of this study to the
current management of patients with brain abscess.

KEY WORDS 9 brain abscess 9 cerebritis 9 computerized tomography 9


ring-like contrast e n h a n c e m e n t 9 capsule formation

F
AILURE to identify and accurately localize brain as to which lesions will respond to antibiotics alone
abscesses is a major factor that contributes to and which will require surgical aspiration or excision
the high mortality and morbidity rates associ- for cure have not been established.
ated with these lesions. 4'12'2~ The introduction We have developed an animal model for studying
of computerized tomographic (CT) brain scans has the CT findings associated with the evolution of brain
been a significant advance in localizing suspected abscesses. The histological progression o f experimen-
intracranial infection. 12'14'27'29'39'43-47'51'59'61'62'68'71'75-77It tal brain abscess in this model is analyzed from the
has been assumed that the cerebritis stage of abscess stage of early cerebritis through the stage of well
formation correlates with the CT finding o f a low- encapsulated lesions. The dynamic aspects o f con-
density lesion with little or no contrast enhance- trast enhancement have been reported in a previous
ment, 12'27'~''4~'76 and the appearance of ring-shaped paper. 17
contrast enhancement represents an encapsulated ab-
scess. 12'27'29'43'44'61'62'76'77 Based on these assumptions M a t e r i a l s and M e t h o d s
and the accuracy o f CT scanning, a new conservative In 19 dogs, intracranial abscess formation was in-
approach to brain abscess management has emerged duced by intracranial injection of a bacterial strain of
using antibiotics alone. 3,21'24,3x'33'~4'~G'G5Precise criteria alpha streptococcus. For both the surgical procedures

590 J. Neurosurg. / Volume 55 / October, 1981


Evolution of experimental brain abscess

and the subsequent CT scanning procedures, the dogs used to evaluate the presence of bacteria. To evaluate
were tranquilized using acepromazine maleate, 10 mg the progression of encapsulation, the reticulin stain
/15 kg injected intramuscularly, and then anesthetized was used to evaluate reticulin or pre-collagen deposi-
with intravenous pentobarbital (60 rag/2.5 kg). The tion 6~ and Masson's trichrome and hematoxylin van
animal's head was fixed to a standard stereotaxic Giesen (HVG) stains were used to determine the
apparatus. The shaved scalp was prepared with a presence and extent of mature collagen. Phospho-
5-minute lavage with Betadine and was aseptically tungstic acid hematoxylin (PTAH) and glial fibrillary
draped. A scalp incision was made in the midline, and acid protein (GFAP) stains were used to evaluate the
the left temporalis muscle was reflected. A single burr presence of gliosis and reactive astrocytes. The gross
hole was placed using a Hudson brace with perforator dimensions of the lesions were compared with the size
and burr. The bone margin was waxed, and the wound of the lesions on CT scans, assuming a 17% shrinkage
flushed of any debris using normal saline. An in- artifact of the tissue due to formalin fixation. Twenty-
oculum of alpha streptococci was drawn into a 1-cc one animals were sacrificed at the following time
syringe, and 0.2 cc (approximately 6 • 10 7 colony- intervals: 1, 3, 5, 6, 7, 8, 9, 10, 14, 19, 21, 22, and
forming units in 0.5% agarose) was injected 5 mm 38 days.
deep into the left parietal white matter with a No. 25 Results
needle. The needle was withdrawn and the wound
flushed with saline. Immaculate hemostasis was Classification of Findings
established to prevent an epidural hematoma, and Based on the detailed histological evaluation of the
the wound was closed in layers. The outer skin was material from the 19 experimental animals, four stages
sprayed with Aeroplast. of brain abscess formation were defmed: early cere-
Two dogs served as controls. In the first, 0.1 cc of britis (1 to 3 days); late cerebritis (4 to 9 days); early
saline was injected into the posterior parietal lobe of capsule formation (10 to 13 days); and late capsule
the left hemisphere, and 2 months later 0.2 cc was formation (14 days and later). To some extent this is
injected into the same location in the right hemi- an arbitrary division, since the evolution of brain
sphere. In the second animal, 0.1 and 0.2 cc of 1% abscess formation is a continuing process. However,
agarose without organisms was injected at similar there were salient features to be discussed that justified
times and locations as the normal saline. this division into four stages. In each of the four
The alpha streptococcus was grown in Todd-Hewitt stages, the histological criteria for each of five zones
broth in an overnight culture at a temperature of present in all well developed abscesses were evaluated.
36~ In each experiment, the exact number of col- The five zones were as follows: Zone 1, the necrotic
ony-forming units inoculated was determined by mak- center; Zone 2, an inflammatory infiltrate mixed with
ing serial dilutions of an aliquot of the broth culture macrophages and fibroblasts surrounding the necrotic
and inoculating 0.1 cc of each 10-fold dilution on a center; Zone 3, collagenous capsule formation; Zone
blood agar plate. 4, cerebritis: perivascular infiltration of inflammatory
Computerized tomographic brain scans were ob- cells in the adventitial sheaths of blood vessels sur-
tained in the coronal plane by using a custom-made rounding the lesion; neovascularity; and Zone 5, re-
Plexiglas holder and polystyrene rings to position the active astrocytes, gliosis, and cerebral edema. Table 1
head. Scans were obtained both before and after summarizes the salient features of each stage de-
injection of 66% diatrizoate meglumine and 10% dia- scribed below.
trizoate sodium (4 ml/kg) (Renografin 76). Serial
scans were made at the following time intervals: 0 to Early Cerebritis (1 to 3 Days)
5, 10 to 15, 20 to 25, 30 to 35, 45 to 50, and 60 to 65 Twenty-four hours after inoculation with alpha
minutes. Serial scans were obtained in each animal at streptococcus organisms, a marked inflammatory in-
2- to 3-day intervals during the first 2 weeks, and then filtrate comprised of polymorphonuclear cells, lym-
every 5 to 7 days in lesions older than 2 weeks. phocytes, and plasma cells was seen interspersed
Brains were removed on the day of sacrifice, and among the residual agarose (Zone 1, Fig. 1A). A
placed in 10% formalin solution for a minimum of 3 Gram stain showed Gram-positive cocci scattered
weeks. The brains were cut in 1-cm coronal sections, throughout this developing necrotic center. At this
photographed, and representative sections were taken early stage, there had not been time for a significant
for processing and embedding in paraffin. Routine inflammatory response to be induced in the brain
hematoxylin and eosin (H & E) staining was per- peripheral to the developing necrotic center (Zone 2).
formed for general morphology. The Gram stain was However, there was early infiltration of acute inflam-

J. Neurosurg. / Volume 55 / October, 1981 591


R. H. Britt, D. R. Enzmann and A. S. Yeager

TABLE 1
Histological and computerized tomography (CT)findings in sequential stages of brain-abscess development

Early Cerebritis Late Cerebritis Early Capsule Formation Late Capsule Formation
Findings (Days 1-3) (Days 4-9) (Days 10-13) (Day 14 and later)
Histological Features
Zone 1: necrotic inflammatory cells inter- necrotic center enlarged & necrotic center began to necrotic center continued
center spersed among residual reached its maximal size decrease in size to decrease in size with
agarose; bacteria present further encapsulation of
on Gram stain abscess

Zone 2: acute inflammatory cells inflammatory cells mixed increased numbers of fi- number of fibroblasts con-
inflammatory seen between the develop- with macrophages & fi- broblasts & macrophages tinued to increase in rela-
border ing necrotic center & broblasts appeared during this stage tion to inflammatory cells
brain & macrophages

Zone 3: collagen no evidence of reticulin fibroblasts appeared with mature collagen evolved a collagen capsule was
capsule formation until Day 3 rapid formation of reticu- from reticulin precursors; completed by end of 2nd
lin surrounding necrotic forming capsule was less week; during 3rd week,
center developed on ventricular capsule increased in den-
side of lesion sity of collagen deposition
& thickness

Zone 4: cerebritis & perivascular infiltration of cerebritis reached its max- cerebritis was less acute; cerebritis was restricted to
neovascularity polymorphonuclear leuko- imal extent during this maximal degree of neo- area immediately outside
cytes, plasma cells, & stage; new vessel forma- vascularity developed at collagen capsule; perivas-
mononuclear cells (cere- tion rapidly increased this stage cular infiltrate contained
britis) developed rapidly around developing abscess fewer inflammatory cells
& more fibroblasts; neo-
vascularity was less
marked

Zone 5: reactive marked cerebral edema cerebral edema continued cerebral edema started to surrounding cerebral
gliosis & cerebral surrounded lesion at this to be prominent in sur- regress; number of reac- edema regressed as cap-
edema stage rounding white matter; re- tive astrocytes increased sule developed; in 3rd
active astrocytes began to week, marked gliosis
appear late in this stage developed outside the
capsule; large numbers
of reactive astrocytes
surrounded abscess

Computerized Tomography
CT scan findings partial ring contrast en- ring enhancement with ring enhancement with ring enhancement without
hancement on Day l diffusion of contrast me- less diffusion of contrast diffusion of contrast mate-
evolved to well developed dium into the lucent cen- material into lucent center rial into lucent center was
ring enhancement by ter on delayed scans was was seen in incompletely salient feature of well en-
Day 3 salient CT finding of encapsulated abscesses capsulated abscess
cerebritis stage

m a t o r y cells in the adventitial sheaths o f vessels sur- in or adjacent to the vessel walls (Fig. IF). There was
r o u n d i n g the i n o c u l u m (Fig. 1B). P o l y m o r p h o n u c l e a r m a r k e d e d e m a o f the white matter surrounding the
leukocytes, small lymphocytes, a n d a few large m o n o - lesions during this phase o f abscess formation.
nuclear cells were present. T h e reticulin stain showed In the early cerebritis stage, C T brain scans at
the splitting o f the vessel walls caused by the perivas- D a y 1 generally demonstrated low-density lesions
cular cuffmg (Zone 4, Fig. 1C). A G F A P stain showed with some degree o f partial ring-like enhancement.
no evidence o f reactive astrocytes at this early stage By D a y 3, there was a p r o m i n e n t ring enhancement,
(Zone 5). Meningitis was p r o m i n e n t at D a y 1 and the diameter o f which best correlated with the diam-
extended d o w n the V i r c h o w - R o b i n spaces near the eter o f cerebritis (vessels with perivascular cuffing o f
site o f injection (Fig. 1D). i n f l a m m a t o r y cells) present surrounding the develop-
By D a y 3, there was a m a r k e d increase in the ing necrotic center.
perivascular infiltration o f i n f l a m m a t o r y cells in the
vessels surrounding the developing necrotic center Late Cerebritis (4 to 9 Days)
(Fig. IE). A few blood vessels began to show sprouting T h e most significant histological changes began to
o f reticulin, indicating the early presence o f fibroblasts take place on D a y 4 and extended t h r o u g h D a y 9. A

592 J. Neurosurg. / Volume 55 / October, 1981


Evolution of experimental brain abscess

FIG. 1. Photomicrographs showing early cerebritis (Days 1 to 3). A: On Day 1, an inflammatory


infdtrate consisting of polymorphonuclear leukocytes, lymphocytes, and plasma cells was seen interspersed
among the residual agarose (Zone 1). H & E, • 300. B: Early cerebritis on Day 1 consisting of a modest
perivascular infdtrate as seen in this section around two vessels (Zone 4). H & E, x 300. C: On Day 1,
there was no evidence of new reticulin formation in vessels adjacent to the developing necrotic center.
Reticulin stain, x 300. D: There was prominent meningitis at the site of needle entry for inoculating the
organisms into the brain during the early cerebritis stage. H & E, • 300, E: By Day 3, the degree of
perivascular infdtrate or cerebritis markedly increased compared with Day 1 (B). H & E, x 300, F: By
Day 3, there was early sprouting of reticulin, extending from the sides of a few vessels near the developing
necrotic center. Reticulin stain, x 300.
593
R. H. Britt, D. R. Enzmann and A. S. Yeager

Fro. 2. Photomicrographs showing late cerebritis (Days 4 to 9). A: The necrotic center had developed
and consisted of inflammatory cells and debris (Zone 1). H & E, x 300. B: Along the margin of the
necrotic center, a mixture of inflammatory ceils, large foamy macrophages, and fibroblasts (spindle-shaped
celts) was seen (Zone 2). H & E, x 300. C: New vessels formed around the necrotic center and had
perivascular inflammatory infiltrates containing fibroblasts. H & E, x 300. D: In places along the
periphery of the developing necrotic center, the reticulin stain demonstrated a marked proliferation of
reticulin in areas comparable to photomicrographs B and C. x 300. E: Only a minimal amount of
maturing collagen was associated with the neovascularity. Masson's trichrome, x 300. F: During the
cerebritis stage, a few reactive astrocytes were seen in the white matter overlying the developing abscess.
GFAP, x 300.
594
Evolution of experimental brain abscess

well formed necrotic center developed and enlarged, cant difference in the amount of reticulin deposition
consisting of a mixture of tissue debris and inflam- on the cortical (Fig. 4C) and the ventricular (Fig. 4B)
matory cells (Zone 2). The agarose was nearly de- sides of the lesions. Mature collagen was seen bridging
pleted (Fig. 2A). At the periphery of the developing the spaces between vessels on Masson's trichrome and
necrotic center, there was a zone of inflammatory HVG stains (Fig. 4E, Zone 3). Outside the developing
cells, macrophages (foam cells), and scattered fibro- capsule, there was a region of continued cerebritis and
blasts (Zone 2, Fig. 2B). The fibroblasts were char- neovascularity (Fig. 4D, Zone 4). The number of
acterized by oval nuclei with spindle-shaped cyto- reactive astrocytes in Zone 5 had increased by this
plasm. Cerebritis (Zone 4) was maximal during this time (Fig. 4F). The degree of edema in the white
time. In addition, the microscopic features of the matter gradually began to diminish.
perivascular cuffing changed with the appearance The CT appearance during the early stages of cap-
of fibroblasts in addition to inflammatory cells. The sule formation was similar to that previously described
rapid increase in new vessel formation during this for the cerebritis stage. The necrotic center seen on
stage at Zones 3 to 4 is shown on H & E stain (Fig. the CT scan was smaller, and this was verified histo-
2C), reticulin stain (Fig. 2D), and Masson's trichrome logically. Serial scans continued to show some diffu-
stain (Fig. 2E). By Day 7, there was a significant sion of contrast material into the necrotic center.
amount of reticulin bridging the neovascularity (Fig.
2D). Masson's trichrome and HVG stains showed
only modest amounts of maturing collagen in Late Capsule Stage (14 Days and Later)
the immediate vicinity of blood vessels. There was Histologically, the late capsule stage showed a con-
still a considerable amount of white matter edema tinuation of the process already in progress. The
beyond Zone 4. Beginning on Day 7, GFAP-stained necrotic center continued to get smaller in the majority
sections showed the presence of early reactive astro- of cases (Fig. 5A, Zone 1). In one lesion, however, a
cytes in the area just outside the zone of cerebritis multiloculated abscess with daughter abscesses devel-
(Zone 5, Fig. 2F). oped. In Zone 2, adjacent to the necrotic center, the
Late cerebritis was characterized on CT scan by a percentage of inflammatory cells and macrophages
well formed ring 10 minutes after infusion of contrast decreased while fibroblasts increased (Fig. 5B). The
medium (Fig. 3). The contrast medium gradually capsule was well developed and was comprised of
diffused into the lucent center and gave the appear- fibroblasts, reticulin, and mature collagen (Zone 3).
ance of a homogeneous lesion. This was the salient The increased thickness of the capsule was seen on
feature of cerebritis on CT in this experimental model. both reticulin (Fig. 5D) and Masson's trichrome (Fig.
5E) stains. Mature collagen was present in abundance
Early Capsule Formation (10 to 13 Days) beginning in the 3rd week of abscess formation. The
At 10 to 13 days, the necrotic center (Zone 1) capsule increased in thickness due to the migration of
decreased slightly in size. There was a marked increase fibroblasts migrating from new vessels adjacent to the
in the number of fibroblasts in the zone of inflam- capsule (Zone 4, Fig. 5F). Cerebritis, although pres-
matory cells surrounding the necrotic center (Zone 2, ent, continued to show fewer infammatory cells (Zone
Fig. 4A). By this time, a well developed layer of 4, Fig. 5C). The number of reactive astrocytes contin-
fibroblasts had been established. There was a signifi- ued to increase both in numbers and in the intensity

FtG, 3. Computerized tomography findings of late cerebritis. Sequential scans in a 5-day-old lesion
after contrast infusion showed a gradual diffusion of the contrast medium into the lucent center forming
a solid lesion at 0 to 5 minutes (left), 10 to 15 minutes (center left), 20 to 25 minutes (center right), and 45
to 50 minutes (righO.

J. Neurosurg. / Volume 55 / October, 1981 595


R. H. Britt, D. R. Enzmann and A. S. Yeager

FIG. 4. Photomicrographs showing early capsule formation (Days 10 to 13). A: At the periphery of
the necrotic center, the number of fibroblasts increased significantly (top right) (Zones 1 to 2). H & E,
x 300. B and C: Reticulin increased greatly, but there was an asymmetry in the majority of lesions, with
more dense deposition on the cortical surface (C) compared with the ventricular surface (B) (Zone 3).
Reticulin stain, x 300. D: Cerebritis, although still present on the margin of the developing capsule,
consisted of fewer inflammatory cells and more fibroblasts (Zone 4). H & E, • 300 E: A dense deposition
of mature collagen extended between new vessels which have developed (Zones 3 to 4). Masson's trichrome,
x 300. F: There was an increase in the number of reactive astrocytes in the surrounding white matter
compared with the late cerebritis stage (Fig. 2F) (Zone 5). GFAP, X 300.

596
Evolution of experimental brain abscess

Flo. 5. Photomicrographs of late capsule formation (Day 14 and on). A: The necrotic center was
filled with increasing amounts of acellular debris and was diminished in size (Zone 1). Inflammatory cells
were still scattered throughout. H & E, • 300. B: At the periphery of the necrotic center, the number of
fibroblasts continued to increase (top left, Zones 2 to 3). Foamy macrophages and a few inflammatory ceils
were present close to the necrotic center (Zone 2). H & E, x 300. C: Cerebritis was present outside the
capsule associated with the neovascularity which had evolved (Zone 4). H & E, • 300. D: Reticulin
increased in both density and amount in the well developing capsule. Reticulin stain, x 300. E: A thick,
loosely woven collagen capsule matrix can be seen surrounding the necrotic center (Zone 3). Masson's
trichrome, • 300. F: The reticulin stain demonstrated the significant neovascularity present outside the
capsule. It also demonstrated the process by which the capsule thickens: the neovascularity allowed
increased numbers of fibroblasts to migrate into the area, which in turn generated reticulin and mature
collagen. Reticulin stain, • 190. 597
R. H. Britt, D. R. Enzmann and A. S. Yeager

F1o. 6. Photomicrographs showing mature capsule for-


mation. A: The degree and extent of reticulin formation
continued to increase and, by the end of the 3rd week, a
solid mature capsule was present surrounding a small ne-
crotic center. Reticuhn stain, x 300. B: A thick mature
collagen capsule can be seen. Masson's trichrome, x 300.
C: Reactive astrocytes proliferated and were most nu-
merous in the overlying gray and subcortical white matter.
Note the astrocytic foot-processes lining the blood vessel.
GFAP, • 300.

of staining with GFAP. The white matter edema The CT appearance of well encapsulated brain
lessened as encapsulation increased. abscesses continued to show ring-like contrast en-
By the end of the 3rd week, the capsule was very hancement 10 minutes after infusion. The necrotic
thick and was intensely reactive to both reticulin (Fig. center did not fill in by diffusion of contrast medium
6A) and collagen (Fig. 6B) stains. The reaction of the as seen in the lesions in the cerebritis stage on delayed
surrounding brain was easily detected by the end of scans (Fig. 7). Unfortunately, the majority of these
the 3rd week, and was well developed by 38 days. experimental lesions had necrotic centers that were
Staining with PTAH demonstrated an increase in the microscopic in size and therefore were below the
number of astrocytes associated with positive-reacting spatial resolution of the CT scanner.
glial filaments in the area immediately outside the
developing capsule. By 38 days, thick glial fibrils were Discussion
easily identified; they were maximal immediately ad-
jacent to the capsule, and were intertwined with the Experimental Models of Brain Abscess
neovascularity (Zone 4, extending into Zone 5). The Experimental brain abscess models have been de-
G F A P stain demonstrated the presence of glial fila- veloped in the primate, 73'74 dog, 17'25'38'4~ cat, ls'22 rab-
ments adjacent to the capsule, but also revealed large bit, 19'23'25'5~guinea pig, 25 and rat. 69'7~The majority of
numbers of reactive astrocytes that were concentrated authors have inoculated organisms in a suitable me-
in the cortical gray matter and the subcortical white dium directly into the brain, 17-ta'22,23,25,3s'50,67'69,70,T3but
matter overlying the lesion (Fig. 6C). two studies utilized septic emboli 4~ to induce

598 J. Neurosurg. / Volume 55 / October, 1981


Evolution of experimental brain abscess

FIG. 7. Sequential computerized tomography (CT) findings from late cerebritis to a well encapsulated
brain abscess. These serial CT scans were performed l0 to 15 minutes after contrast infusion. A: Day 5.
The ring enhancement was thick in the late cerebritis stage and diffused into the lucent center. B: In the
early capsule stage (Day 13), the ring enhancement was thinner and contrast material did not diffuse into
the lucent center. C: In the late capsule stage (Day 19), the lucent center was much smaller, but it did not
fill in with contrast material.

metastatic brain abscess formation. Histological eval- only necrotic areas could be found. The control ani-
uation of sequential stages of brain-abscess formation mals had well encapsulated lesions. The difference in
has been documented in relatively few of these these two studies can be explained by immunological
studies. 17-19,25,69,70 studies which suggest that rats, mice, and rabbits are
In the present study, the dog was used to develop extremely sensitive to corticosteroids with respect to
this model for two reasons: 1) the brain size was large lymphoid depletion, circulating antibody production,
enough to image with the resolution of current CT and cell-mediated immunity, whereas man, guinea
scanners, and 2) the response of the dog's central pig, 11and probably dogs are more resistant to steroids.
nervous system to infection is comparable to that of The formation of the collagen capsule in a devel-
man. Although classical evolution of brain-abscess oping abscess is the single most important response
formation with encapsulation can occur in any of the that limits the spread of infection in the brain. The
animal models cited, there are species differences. In biosynthesis of collagen has largely been worked out
1913, Hom~n 25 used a mixture of streptococci, staph- biochemically,4a'4a and is known to originate from
ylococci, and Bacillus perfringens (Clostridium welchii) fibroblasts derived from the connective tissue ele-
to obtain brain abscesses in dogs, rabbits, and guinea ments associated with blood vessels. 1~ With respect
pigs. In the rabbit, all components of capsule forma- to brain abscess, two particular features of collagen
tion were more poorly formed and appeared later formation are of interest. The first is that encapsula-
than in the dog. It was Hom6n's conclusion that, in tion is more rapid on the cortical side of the lesion
the dog, abscess formation approximated most closely compared with the ventricular side. The second is the
the disease as it occurs in humans. relatively limited encapsulation seen with metastatic
Species differences are of even more importance brain abscesses caused by septic emboli, as compared
when it comes to manipulating an experimental model with those caused by direct extension or trauma. Both
to study the effects of different treatment modalities of these features of encapsulation can be explained by
or the influence of steroids on encapsulation. 72 Long the fact that oxygen is required for pro-alpha chains
and Meacham, a8 in a study using dogs, found that to form the triple-helix strands of collagen. 1~ The
dexamethasone given at the time of inoculation with increased vascularity of normal cortical gray matter
Staphylococcus aureus or Proteus mirabilis retarded, allows for faster proliferation of new capillaries, which
but did not totally inhibit, capsule formation. Dexa- in turn release more fibroblasts in a relatively oxygen-
methasone started a few weeks after inoculation had rich environment compared with the more poorly
no apparent effect on further encapsulation. 38 Quar- perfused deep white matter. The thinner capsules of
tey, et al., 5~ studied the effect of dexamethasone and metastatic brain abscesses 73'74 can also be explained
antibiotics administered at the time of inoculation by this theory. The vegetative embolus initially causes
with Streptococcus pyogenes or Staphylococcus aureus an infarct. This area of nonviable tissue is hypoxic
on brain abscess formation in rabbits. In the rabbits and impedes new vessel formation and the collagen-
treated with dexamethasone and antibiotics, no evi- forming process of the fibroblasts.
dence of encapsulation was present at 10 days, and The glial reaction of the brain to abscess formation

J. Neurosurg. / Volume 55 / October, 1981 599


R. H. Britt, D. R. Enzmann and A. S. Yeager

has not previously been studied in detail. In this has focused on nonsurgical treatment in which anti-
model, two stains were used to study this response: biotics alone are used. a'21,24,3t'33,54,56,63'65The accuracy
Mallory's phosphotungstic acid hematoxylin (PTAH) of CT scanning has aided in this approach, allowing
and the immunocytochemical localization of the glial the size of the lesions to be followed. Although class-
fibrillary acidic protein (GFAP). The GFAP first ical "ring" enhancement has been equated with
described by Eng, et al., TM has been used extensively capsule formation, 12'27'29'43'44'61'62'76'77this study conclu-
to identify astrocytes, both of neoplastic 13'1~and non- sively demonstrated ring enhancement during the
neoplastic origins, is The GFAP is found in normal cerebritis stage prior to any evidence of capsule
fibrillary astrocytes, and questionably in normal pro- formation. Ring enhancement correlated closely with
toplasmic astrocytes, Bergmann glial cells, reactive the extent of cerebritis (perivascular infiltration of
astrocytes, and reactive fibrillated ependymal ceUs. It inflammatory cells), and is likely due to altered
is not found in fibroblasts, microglial cells, or macro- permeability of the normal blood-brain barrier? 6
phages. ~3 This study represents its first use to study Rapid proliferation of new vessels associated with
intracranial infection and also its first use to demon- cerebritis was seen in this study in the area surround-
strate reactivity in dog brain. This study confirms the ing the developing abscess. Studies have shown that
previously reported finding that there is not always a proliferating capillaries leak protein-containing fluid
direct relationship between GFAP-positivity and the due to incomplete sealing of the endothelial lining. $8
demonstration of glial fibers by traditional neurohis- In a study of regeneration of brain capillaries after
tological stains (PTAH and Holzer crystal violet local freezing injury, it was demonstrated that the new
stains). '3 Whereas GFAP does not stain well the vessels had endothelial cells which lacked intercon-
intricate and closely textured network of glial cell necting tight junctions?
processes and fibers of white matter, it does stain Some preliminary clinical evidence in the literature
intensely the perikarya and cell processes of the re- supports the findings in this experimental study. A
active astrocytes in cortical gray matter. ~3 It has been recent case report of fatal cerebritis in man due to
hypothesized that the soluble form of GFA protein is Clostridiurn septicum showed a ring-like contrast-en-
a subunit or precursor of glial fibers. Indirect evidence hancing lesion with no evidence of capsule formation
suggests the insoluble form of GFAP is associated histologically? 2 Whelan and Hilal 6s also suggested
with glial filaments, ~3 and perhaps this explains the that the results of this study are applicable to man.
difference in the results obtained with the two stains. In a series of 20 cases of brain abscess, 13 patients
In this study, the reactive astrocytes that stained with required surgery because of failure to improve on
GFAP were most marked in the cortical gray and antibiotics alone or because of clinical deterioration.
subcortical white matter, although gliat fibrils were However, a firm capsule was encountered at surgery
prominently stained in some lesions at 3 weeks in in only eight patients. In all eight cases, the symptoms
areas adjacent to the capsule. In contrast, the PTAH had been present for longer than 2 weeks. In the five
demonstrated gliosis and cells of astrocytic origin patients not having capsules at surgery, all had ring-
maximally in the area immediately adjacent to the like contrast-enhancing lesions which the authors felt
outer edge of the capsule. By Day 7, GFAP was represented cerebritis. Since delayed scans were not
weakly reactive in a few astrocytes, but it was not performed in these studies, it is not known whether
until the end of the 2nd week that significant numbers the results would have been similar to those of our
of reactive astrocytes were observed. By the end of the experimental model. Some of the reports purporting
3rd week, this process was even more evident using to have cured brain abscess with antibiotics only may
both GFAP and PTAH stains. have been due to the fact that the lesions were in the
cerebritis stage, since the CT scans showed significant
Clinical Correlates of this Experimental Study diffusion of contrast into the necrotic center. TM
Brain abscesses have been associated with a high Clinically, the cerebritis and well encapsulated
mortality (29% to 64%) and morbidity 1'2'4'6"9'2~ stages may require different treatment. One clinical
30,32,34-37,42.57,64despite the advances of antibiotic ther- study demonstrated that patients with well encapsu-
apy? '26"a4'36'37Lack of clinical suspicion and poor lo- lated lesions, who had adequate killing levels of an-
calization were often cited as reasons for this high tibiotic in the abscess fluid, continued to deteriorate
mortality. 4'9'28'3~ With the advent of CT brain scan- clinically and required aspiration. ~ It was possible to
ning, earlier diagnosis and accurate localization of grow out the offending organisms in each case. ~ Whe-
intracranial suppuration have resulted in a decreased lan and Hilal 6s reported that despite administration of
mortality resulting from brain abscess. 27'43'53'62'68'75 intravenous antibiotics for a minimum of 2 days, eight
Management of brain abscess cases in recent years of 13 surgical specimens had positive cultures.

600 J. Neurosurg. / Volume 55 / October, 1981


Evolution of experimental brain abscess

Ideally, one would like precise criteria that separate 89 cases over a period of 30 years. J Neurol Neurosurg
the cerebritis stage from the encapsulated stage. Clin- Psychiatry 36:757-768, 1973
3. Berg B, Franklin G, Cuneo R, et al: Nonsurgical cure
ically, the first step is treatment with appropriate of brain abscess: early diagnosis and follow-up with
antibiotics. If a presumptive organism is not known, computerized tomography. Ann Neurol 3:474-478, 1978
then one should seriously consider aspirating the le- 4. Bhatia R, Tandon PN, Banerji AK: Brain abscess--an
sion(s), under CT guidance if necessary, 71 to obtain analysis of 55 cases. Int Surg 58:565-568, 1973
material for culture. This is particularly true in the 5. Black P, Grayhill JR, Charache P: Penetration of brain
abscess by systemically administered antibiotics. J Neu-
immunocompromised host, since the offending orga- rosurg 38:705-709, 1973
nism may be either bacterial, fungal, or protozoan in 6. Brewer NS, MacCarty CS, Wellman WE: Brain abscess:
nature. 7 On the basis o f this study, we suggest the use a review of recent experience. Ann Intern Med 82:
of delayed CT scans at least 30 minutes after contrast 571-576, 1975
infusion so that the degree of contrast diffusion into 7. Britt RH, Enzmann DR, Remington JS: Intracranial
infection in cardiac transplant recipients. Ann Neurol 9:
the lucent center can be evaluated. If the contrast 107-119, 1981
material diffuses completely into the necrotic center, 8. Cancilla PA, Robert C, Frommes SP: Regeneration of
then one can presume that the lesion is in the cerebritis cerebral capillaries after local freezing injury. J Neu-
stage and continue the antibiotics alone, providing the ropathol Exp Neurol 33:182-183, 1974 (Abstract)
patient is stable neurologically. If the contrast material 9. Carey ME, Chou SN, French LA: Experience with
brain abscesses. J Neurosurg 36:1-9, 1972
does not diffuse into the center, a well encapsulated 10. Chapman JA: Morphological and chemical studies of
lesion is probably present. The approach will then collagen formation. I. The fine structure of guinea pig
depend on the size o f the abscess and the clinical granulomata. J Biophys Biochem Cytol 9:.639-651, 1961
condition of the patient. Abscess size may be the 11. Claman HN: Corticosteroids and lymphoid cells. N
determining factor whether antibiotics alone will be Engl J Med 287:388-397, 1972
12. Claveria LE, du Boulay GH, Moseley IF: Intracranial
effective or whether surgical aspiration or excision infections: investigation by computerized axial tomog-
will be required. Two studies have shown that lesions raphy. Neuroradiology 12:59-71, 1976
greater than 4 cm in size usually require surgical 13. De Armond SJ, Eng LF, Rubinstein LJ: The application
decompression) 4'~ whereas lesions of less than 2 cm of glial fibrillary acidic (GFA) protein immunohisto-
will respond to conservative therapy. 54 Unfortunately, chemistry in neurooncology. A progress report. Pathol
Res Praet 168:374-394, 1980
data are not available in these studies correlating the 14. Danziger A, Price H, Schechter MM: An analysis of
size of the lesion and the degree of encapsulation. It 113 intracranial infections. Neuroradiology 19:31-34,
is likely that some lesions in the developing stages of 1980
encapsulation will require surgical decompression be- 15. Eng LF, Rubinstein LJ: Contribution of immunohisto-
cause of clinical deterioration. Future work on this chemistry to diagnostic problems of human cerebral
tumors. J Histochem Cytochem 26:513-522, 1978
experimental model will concentrate on developing 16. Eng LF, Vanderhaeghen J J, Bignami A, et al: An acidic
additional methods for separating the cerebritis and protein isolated from fibrous astrocytes. Brain Res 28:
encapsulated stages, and will hopefully lead to precise 351-354, 1971
criteria for determining when surgical intervention is 17. Enzmann DR, Britt RH, Yeager AS: Experimental
required or when antibiotic therapy alone will succeed brain abscess evolution: computed tomographic and
neuropathologic correlation. Radiology 133:113-122,
in curing brain abscesses. 1979
18. Essick CR: Pathology ofexperimental traumatic abscess
Acknowledgments of the brain. Arch Neurol Psychiatry 1:673-703, 1919
We should like to thank Lucien Rubinstein, M.D., and 19. Falconer MA, McFarlan AM, Russell DS: Experimen-
Mary Hermann, M.D., Department of Pathology (Neuro- tal brain abscesses in the rabbit. Br J Surg 30:245-260,
pathology) for reviewing selected cases; Elizabeth Miller- 1943
man, Kaye Jenkins, and David Furgassa for histological 20. Garfield J: Management of supratentorial intracranial
preparation; Robert McGowan for performing the GFAP abscess: a review of 200 cases. Br J Med 2:7-11, 1969
stains; L. F. Eng, M.D., for providing the GFAP antisera; 21. George B, Roux F, Pillon M, et al: Relevance of anti-
Phil Home for microphotography; Charles Sheldon and biotics in the treatment of brain abscesses. Report of a
Bernard Lyons for technical assistance; and Cynthia Holl- case with eight simultaneous brain abscesses treated
man for manuscript preparation. and cured medically. Acta Neurochir 47:285-291, 1979
22. Groff RA: Experimental production of abscess of the
brain in cats. Arch Neuroi Psychiatry 31:199-204, 1934
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602 J. Neurosurg. / Volume 55 / October, 1981


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1979 Manuscript received January 28, 1981.
72. Wood JH: Brain abscess model. J Neurosurg 52:603, Accepted in fmal form May 1, 1981.
1980 (Letter) This work was supported by NIH/NINCDS Grant
73. Wood JH, Doppman JL, Lightfoote WE II, et al: Role 1R01NSI6452, NIH Biomedical Research Support Grant
of vascular proliferation on angiographic appearance 5S07RR05353-18, and the Stanford Neurosurgery Research
and encapsulation of experimental traumatic and met- Fund.
astatic brain abscesses. J Neurosurg 48:264-273, 1978 Address reprint requests to: Richard H. Britt, M.D., Ph.D.,
74. Wood JH, Lightfoote WE II, Ommaya AK: Cerebral Division of Neurosurgery R 155, Stanford University School
abscesses produced by bacterial implantation and septic of Medicine, Stanford, California 94305.

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