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case records of the massachusetts general hospital
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Case 16-2003: A 58-Year-Old Woman with Left-Sided
Weakness and a Right Frontal Brain Mass
Robert M. Friedlander, M.D., R. Gilberto Gonzalez, M.D., Nadeem A. Afridi, M.D.,
and Rolf Pfannl, M.D.
presentation of case
A 58-year-old, right-handed woman was admitted to the hospital because of left hemiparesis.
The patient had been well until five days earlier, when a right frontal headache developed, with radiation to the right eye and right ear; suspecting sinusitis, her physician prescribed amoxicillin. Four days before admission, weakness developed in the left
arm, and she began to drop items that she was holding in her left hand. During the next
three days, the weakness worsened. On the day of admission, she awoke with weakness
in the left leg; at one point, she fell from a chair and was unable to rise or walk. She was
brought to this hospital, where a right-sided intracranial mass was detected and she
was admitted.
The patient was married and was employed as an executive. There was a history of
similar headaches, without radiation to the eyes or ears, associated with bouts of sinusitis that had been treated with antibiotics; these headaches had usually been accompanied by rhinorrhea, which was absent on this occasion. Her family had noted increasing
somnolence during recent days but had observed no confusion or other neurologic
symptoms except for the left hemiparesis. She was in excellent health and ordinarily took
no medications. She did not smoke and consumed alcohol in moderate amounts. Four
dental cavities had been filled during the preceding two weeks. She was allergic to sulfonamide.
The temperature was 36.8°C, the pulse 65 beats per minute, and the respiratory rate
16 breaths per minute. The blood pressure was 125/80 mm Hg. On physical examination, the patient appeared well. Findings on a general examination were unremarkable,
and no cardiac abnormality was detected.
On neurologic examination, the patient was sleepy but alert and oriented, with fluent speech. Both pupils were 3 mm in diameter and constricted to 2 mm on exposure to
light; extraocular movements and the visual fields were intact. Weakness in the central
area of the left side of the face was noted. Strength was 4/5 in the left deltoid, biceps, triceps, and forearm and hand grip muscles and in the interosseous, iliopsoas, quadriceps,
hamstring, soleus, and gastrocnemius muscles and was 5/5 in the same muscles on the
right side. There was no pronator drift of the outstretched arms. The sensation of a
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From the Department of Neurosurgery,
Brigham and Women’s Hospital (R.M.F.);
the Divisions of Neuroradiology (R.G.G.),
Cardiology (N.A.A.), and Neuropathology
(R.P.), Massachusetts General Hospital;
and the Departments of Neurosurgery
(R.M.F.), Radiology (R.G.G.), Medicine
(N.A.A.), and Pathology (R.P.), Harvard
Medical School — all in Boston.
N Engl J Med 2003;348:2125-32.
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light touch was preserved. The deep-tendon reflexes were ++ bilaterally, and the plantar responses
were flexor.
The urine was normal. The hematocrit was 36.2
percent; the white-cell count was 7000 per cubic
millimeter, with 82 percent neutrophils, 13 percent
lymphocytes, 4 percent monocytes, and 1 percent
eosinophils; the platelet count was 308,000 per cubic millimeter, and the mean corpuscular volume
88 µm3; the prothrombin and partial-thromboplastin times were normal. The phosphorus level was
2.1 mg per deciliter (0.68 mmol per liter). The aspartate aminotransferase level was 48 U per liter,
and the alanine aminotransferase level 60 U per liter.
The levels of urea nitrogen, creatinine, glucose, conjugated and total bilirubin, calcium, magnesium,
total protein, albumin, globulin, electrolytes, creatine kinase, creatine kinase isoenzymes, troponin
T, and alkaline phosphatase were normal. An electrocardiogram showed a normal rhythm at a rate of
60 beats per minute, with low T waves throughout.
Computed tomographic (CT) scanning of the
head, performed without intravenous injection of
contrast material, revealed a large, complex, predominantly low-attenuation mass in the right frontal lobe, measuring 7.3 cm in the anteroposterior
projection and 5.8 cm in the transverse direction; a
component located more centrally and measuring
3.5 cm in diameter was observed in the region of
the lentiform nucleus and had a level of attenuation
similar to that of the brain. There was effacement
of the overlying sulci and the temporal horns of the
right lateral ventricle and probably some degree of
uncal herniation on the right side. A midline shift
of 7 to 8 mm to the left was noted; no hydrocephalus, evidence of infarction, intraparenchymal hemorrhage, abnormal collection of extra-axial fluid, or
osseous abnormalities were noted.
A magnetic resonance imaging (MRI) study of
the brain (Fig. 1) disclosed a mass, 3.7 by 2.5 by 2.9
cm, in the right lentiform nucleus; on T2-weighted
images the mass was surrounded by an area of hyperintensity, a finding consistent with edema. There
was a mass effect, with effacement of right hemispheric sulci, partial effacement of the right lateral
ventricle, a midline shift of approximately 8 mm,
and slight right-sided uncal herniation. On a diffusion MRI study (Fig. 2), evidence of restricted diffusion was observed centrally in the region of the
mass that was hyperintense on diffusion-weighted
images and hypointense on apparent-diffusioncoefficient images; no other abnormalities were
identified. Chest radiographs showed a probable
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A
B
Figure 1. MRI Study of the Brain Showing a Heterogeneous
Mass in the Right Frontal Lobe That Compresses the Right
Lateral Ventricle.
A T2-weighted image without contrast (Panel A) shows a
mass (arrow) with high signal intensity centrally, a heterogeneous peripheral ring of signal intensity similar to that
of the brain parenchyma, and a surrounding area of bright
signal in the white-matter tracts. On the contrast-enhanced
T1-weighted image (Panel B), the mass has low signal intensity in the central region, suggesting the presence of
fluid, and is surrounded by a ring of enhancement. Beyond
the ring of enhancement, a less well-defined area of abnormal low signal extends along the white-matter tracts.
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case records of the massachusetts general hospital
granuloma, 3 mm in diameter, in the middle zone
of the left lung peripherally; the lungs were clear in
other respects. The bones appeared osteopenic; the
aorta was tortuous and ectatic, and the heart was
normal in size and configuration.
Several hours after admission, the temperature
rose to 38.3°C. Phenytoin and dexamethasone were
given intravenously, and the temperature was normal on all subsequent occasions.
A diagnostic procedure was performed.
A
differential diagnosis
Dr. Robert M. Friedlander: May we review the radiographs?
Dr. R. Gilberto Gonzalez: A CT scan of the head, obtained without the intravenous administration of
contrast material, revealed a large, heterogeneous
mass in the right frontal lobe. The mass was centrally hypodense. Surrounding this central component was a ring of material that was isodense relative to the brain parenchyma. Beyond this ring was
a further area of hypodensity along the white-matter tracts. There was evidence of subfalcine herniation, a midline shift, and compression of the right
lateral ventricle.
Several hours later, MRI scanning was performed
before and after the administration of contrast material. There is a heterogeneous mass in the right
frontal lobe. On T2-weighted images (Fig. 1A), the
mass has high signal intensity centrally, has a heterogeneous peripheral ring of signal intensity similar to that of the brain parenchyma, and is surrounded by bright signal in the white-matter tracts.
There is a mass effect involving compression of the
right lateral ventricle. T1-weighted images obtained
after the administration of contrast material (Fig.
1B) show that the peripheral ring is enhanced; the
central component of the mass and the surrounding white-matter tracts are hypointense on T1weighted images, both with and without the use of
contrast.
A diffusion MRI study was also performed. The
diffusion-weighted image reveals a hyperintense
central area (Fig. 2A), which appears hypointense
on the apparent-diffusion-coefficient image (Fig.
2B) — a finding indicating restricted diffusion, a
characteristic of viscous materials. Surrounding
the areas of restricted diffusion are areas of increased signal intensity, consistent with the presence of extracellular edema.
Dr. Friedlander: The patient is a 58-year-old wom-
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B
Figure 2. Diffusion MRI Study of the Brain.
The diffusion-weighted image (Panel A) shows an area
of hyperintensity corresponding to the central area of the
mass (arrow). The apparent-diffusion-coefficient image
(Panel B) shows that the central component of the mass
has a very low signal (arrow), indicating that the diffusion of water is highly restricted and suggesting the
presence of viscous fluid. A surrounding area of high signal suggests edema along the white-matter tracts.
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an with a five-day history of headache and progressive left-sided weakness. The patient had previously been healthy, except for occasional bouts of
sinusitis that had been treated with antibiotics. Of
note, she recently had four dental cavities filled.
Imaging performed on admission showed a cystic,
ring-enhancing lesion in the right frontal lobe of
the brain.
Thirty years ago, the diagnostic questions in
this case would have been daunting. The patient’s
clinical findings would have allowed the location
of the lesion to be identified as the right cerebral
hemisphere. However, without the assistance of
CT or MRI studies, it would have been impossible
to be sure whether the patient’s neurologic deficits
were due to a lesion that was infectious, neoplastic,
vascular, or inflammatory in origin. In this patient,
modern imaging studies show a space-occupying,
ring-enhancing, cystic lesion surrounded by edema, with no evidence of infarction. From that information alone, we can refine our focus dramatically (Table 1).
primary concern, but in this case that information
provides only limited guidance in narrowing the
list of diagnostic possibilities.
From this patient’s history, we learn that her
symptoms began five days before admission with a
right frontal headache; one day later, progressive
weakness of the left arm developed, followed on the
day of admission by the onset of weakness of the
left leg. These symptoms help to identify the likely
site of the lesion as the right cerebral hemisphere,
and although in themselves they do not indicate the
cause, the course and progressive nature of the
symptoms are informative. Symptoms from a vascular event such as an infarction or hemorrhage
would be expected to reach their peak in less than
five days, and usually within hours. At the other end
of the spectrum, patients with primary or secondary
cerebral neoplasms tend to present with symptoms
of several weeks’ duration, although a much shorter duration is not uncommon. Symptoms associated with brain abscesses have a brief course and progressive nature, as did those seen in this patient.1-5
We also learn that the patient had had bouts of
important features
sinusitis and in the preceding two weeks had unConsideration of a patient’s history, findings on dergone treatment of dental cavities. Both sinus inphysical examination, and laboratory data are of fections and dental procedures are well-known risk
factors for the development of cerebral abscesses.
Dental procedures increase the risk of brain abTable 1. Differential Diagnosis of Ring-Enhancing Brain
scesses on a continuum ranging from simple cleanLesions.
ing, which is associated with the lowest risk, to
tooth extraction, which is associated with the highInfections
est risk. Some authors believe that although dental
Pyogenic brain abscess
infections are a risk factor for the development of
Toxoplasmosis
brain abscesses, dental procedures alone may not
Cysticercosis
raise the risk of brain abscess at all.6
Other clinical and laboratory data in this case
Necrotic fungal infection
provide some useful information. The patient was
Neoplasms
initially afebrile but had a temperature of 38.3°C
Primary brain tumors
several hours after admission. The elevated temAggressive glial tumors, especially glioblastoma
perature strongly suggests the presence of an inmultiforme or anaplastic astrocytoma
Primary central nervous system lymphoma
fection. The laboratory data show an elevated percentage of neutrophils in the context of a normal
Demyelinating diseases
white-cell count. It would be interesting to know
Vascular lesions
this patient’s level of C-reactive protein, since in one
Resolving infarction
study of patients with cystic ring-enhancing brain
Hematoma
lesions, this value was elevated in nearly 80 percent
of those with a brain abscess and was not elevated
Thrombosed giant aneurysm
in those with a brain tumor.7
Other
The MRI studies in this case provide the most
Radiation necrosis
specific and objective path to the probable diagnoPostoperative changes
sis. Many of the diseases listed in Table 1 may appear on presentation as cystic-appearing lesions
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with surrounding ring enhancement. However,
the diffusion-weighted images in this case allow us
nearly to clinch the diagnosis. A lesion that has a
ring of enhancement on contrast-enhanced imaging, a central core of restricted diffusion on diffusion-weighted imaging, and a thin rim of low signal
on T2-weighted imaging is essentially diagnostic
of a brain abscess.
Table 2. Microbiologic Pathogens in Brain Abscesses, According to Major
Primary Source of Infection.*
Source of Infection
Pathogens
Paranasal sinuses
Streptococcus (especially Streptococcus
milleri), haemophilus, bacteroides,
fusobacterium
Odontogenic sources
Streptococcus, bacteroides, prevotella,
fusobacterium, haemophilus
Otogenic sources
Enterobacteriaceae, streptococcus,
pseudomonas, bacteroides
Lungs
Streptococcus, fusobacterium, actinomyces
Urinary tract
Pseudomonas, enterobacter
Penetrating head trauma
Staphylococcus aureus, enterobacter,
clostridium
Neurosurgical procedure
Staphylococcus, streptococcus, pseudomonas, enterobacter
Endocarditis
Viridans streptococcus, S. aureus
Congenital cardiac malformations
(especially right-to-left shunts)
Streptococcus
brain abscesses
The spectrum of organisms found in brain abscesses reflects the range of underlying primary sources
of infection. Approximately 60 percent are multimicrobial.1 A brain abscess can develop as a result
of contiguous spread from the sinuses or odontogenic or otic primary sources, as a result of hematogenous spread from distant locations, or after
penetration of the brain during surgery or trauma,
particularly when bone fragments are retained. In
10 to 60 percent of patients with a brain abscess, no
underlying source of infection is found.1,3,5 Table 2
outlines the major primary sources of infection
that can lead to the development of a brain abscess.
Odontogenic brain abscesses and those arising from the frontal and ethmoid sinuses have a
predilection for the frontal lobe. Sphenoid sinusitis and otic infections involve a higher incidence
of abscess formation in the temporal lobe than in
other lobes.1,3,8 Abscesses that develop owing to
hematogenous seeding from distant locations are
located in proportion to regional blood flow; therefore, they occur most commonly in the area of the
middle cerebral artery1,8 and are more likely to occur as multiple abscesses than as single ones.
neoplasms
The other major entity to be considered in this case,
besides a brain abscess, is a primary or metastatic
neoplasm. In particular, aggressive primary brain
tumors, such as glioblastoma multiforme or anaplastic astrocytoma, as well as metastases from lung
and breast cancer, can present with many of the
same imaging characteristics, although a thin rim
of low signal on T2-weighted images, which is
thought to represent collagen, subtle hemorrhage,
or macrophages containing free radicals, is more
characteristic of an abscess than of a neoplasm.9,10
Over the past decade, diffusion-weighted imaging has greatly improved our ability to differentiate
abscesses from other cystic, ring-enhancing brain
lesions. Many recent studies have shown that this
method of imaging is sensitive and specific in dif-
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* The information is adapted from Calfee and Wispelwey,1 Roos and Tyler,3 and
Mathisen and Johnson.5
ferentiating abscesses from neoplasms as a cause
of ring-enhancing lesions.11,12 As in this case, the
central core of an abscess shows a hyperintense signal on diffusion-weighted images and a hypointense
signal on apparent-diffusion-coefficient images, a
finding indicating an area of restricted diffusion.
Necrotic or cystic brain tumors have central areas
of hypointense signal on diffusion-weighted imaging, unless there is a hemorrhagic or proteinaceous
component, which may appear as an area of heterogeneous or bright signal. As Dr. Gonzalez mentioned, it appears that the increased viscosity of the
fluid in an abscess, along with the hypercellularity
of the inflammatory response, contributes to decreased water proton mobility and results in restriction of diffusion.12,13
conclusions
The differential diagnosis in this case includes a
brain abscess and a cystic neoplasm. The imaging
characteristics, particularly the presence of a central
core of restricted diffusion within the lesion, point
convincingly to a cerebral abscess. Possible sources
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of infection are suggested by the patient’s several
bouts of sinusitis and the recent filling of several
dental cavities. Because there is no current evidence
of sinusitis, an odontogenic source is more likely.
The likely organisms include one or more of the following: streptococcus (Streptococcus milleri being the
most common), bacteroides, haemophilus, prevotella, and fusobacterium.
The next step in this case should be image-guided, stereotactic needle aspiration of the contents of
the lesion. This procedure is both diagnostic and
therapeutic. The analysis and culture of the contents
would confirm the diagnosis and allow tailoring of
the antibiotic regimen. Drainage of the contents
would decrease the infectious burden.
A Physician: How do you explain the response of
the patient’s fever to corticosteroids?
Dr. Friedlander: Fever in patients who have brain
abscesses often responds to corticosteroids.
A Physician: Is the granuloma that appears on the
radiograph of the chest relevant to the diagnosis?
Dr. Friedlander: I think the granuloma is an incidental finding.
Dr. Nancy Lee Harris: Dr. Medlock will describe
the clinical thinking and the diagnostic procedure.
Dr. Michael D. Medlock (Neurosurgery): We strongly suspected a brain abscess. The patient was taken
to the operating room, where a Cosman–Roberts–
Wells frame was attached and a contrast-enhanced
CT scan was obtained. We targeted points so that
we could aspirate the contents of the cyst and obtain a biopsy specimen of the cyst wall. We made
a small burr hole, and the computer-guided needle
was inserted into the cyst. Approximately 15 ml of
fluid with the color and consistency of pus was aspirated and sent to the microbiology laboratory, and
a biopsy specimen of the wall was sent for frozensection examination.
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pathological discussion
Dr. Rolf Pfannl: We received specimens from the
right frontal lobe (Fig. 3), including an aggregate
of soft tissue (1 cm in diameter) and about 1.5 ml of
mucoid material admixed with blood. Examination of a smear and frozen sections revealed acute
inflammatory cells, macrophages, and necrotic debris. No tumor cells were found. Histologic sections stained with hematoxylin and eosin consisted
predominantly of necrotic tissue with a neutrophilic
infiltrate. A few viable fragments of brain contained
granulation tissue. There was no evidence of tumor.
A Gram’s stain revealed innumerable gram-positive cocci. The findings are those of a brain abscess
of bacterial origin.
A
B
clinical diagnosis
Brain abscess.
dr. robert m. friedlander’s
diagnosis
Pyogenic brain abscess in the right frontal lobe
with an odontogenic source of infection (streptococcus [most likely Streptococcus milleri], haemophilus, bacteroides, prevotella, or fusobacterium).
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Figure 3. Biopsy Specimen of the Mass in the Right Frontal Lobe.
Granulation tissue from the edge of the cavity (Panel A)
contains proliferating small blood vessels, neutrophils,
macrophages, and fibroblasts (hematoxylin and eosin,
¬500). Gram’s staining (Panel B) reveals numerous cocci,
both singly and in clusters and short chains (Brown–
Hopps stain, ¬624).
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Smears prepared in the microbiology laboratory
and subjected to Gram’s staining showed grampositive cocci in pairs and short chains. Cultures of
the abscess contents revealed mixed flora, including S. milleri and Haemophilus aphrophilus. S. milleri is
a non–group-B, beta-hemolytic organism associated with deep suppurative infections such as brain
abscesses.14,15 H. aphrophilus is considered part of
the normal oral flora but is occasionally associated
with upper and lower respiratory tract infections; it
may cause bacteremia, endocarditis, and brain or
dental abscesses.
The evolution of a cerebral abscess can be roughly divided into four pathologic stages.16,17 On days
1 to 2 after infection, focal suppurative encephalitis
or cerebritis occurs, with swelling of endothelial
cells and perivascular and parenchymal infiltration
by neutrophils. Between days 2 and 7, confluent areas of necrosis develop, with a prominent infiltrate
of macrophages, lymphocytes, and plasma cells.
Between days 5 and 14, there is early encapsulation,
with a granulation-tissue response around the margins, as in this case. After two weeks, encapsulation
by a thick, collagenous wall occurs, and the necrotic center is surrounded by granulation tissue and
by concentric layers of fibroblasts, reticulin fibers,
collagen, and reactive glial cells.
Dr. Harris: Dr. Beigel saw the patient after the diagnosis was made and will tell us about subsequent
studies and follow-up.
Dr. John H. Beigel (Infectious Disease): We were
consulted after Gram’s staining had shown grampositive cocci in short chains and pairs. Since there
was no evidence on MRI or CT scans of a contiguous focus of infection, we believed that hematogenous spread was likely and that it was probably a
streptococcal species. We were concerned about
pneumococcus since there were gram-positive cocci
in pairs and also about the possible presence of
anaerobes, since brain abscesses are often polymicrobial. The patient was initially treated with vancomycin, ceftriaxone, and metronidazole. Because of
the presumed hematogenous source, we recommended an echocardiogram to look for endocarditis and a “bubble study” (echocardiography after the injection of agitated saline) to look for a
patent foramen ovale. When the culture results
showed S. milleri as well as H. aphrophilus, we thought
that the most likely source of the infection was bacteremia due to the dental procedures. The antibiotic therapy was changed to ceftriaxone alone, which
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was given for six weeks. The patient’s symptoms
and neurologic deficit resolved completely.
Dr. Nadeem A. Afridi: Cardiac ultrasonography
was performed to evaluate the possibility of endocarditis and the possible patent foramen ovale.
There were no valvular vegetations. Two echocardiographic techniques are used to assess the presence of an interatrial communication: color Dop-
A
RA
LA
B
RA
LA
Figure 4. Cardiac Ultrasonographic Study
with Agitated Saline.
A mixture of saline and air bubbles is injected intravenously and appears as a bright signal in the right
atrium (RA) and ventricle between the first and second
heartbeat after injection, as indicated by the bar on the
rhythm strip (Panel A). One beat later, between the
second and third beats after injection, the air bubbles
appear in the left atrium (LA) and ventricle (Panel B),
indicating the presence of a right-to-left shunt through
a patent foramen ovale. (A video clip of a cardiac ultrasonographic study with agitated saline is available with
the full text of this article at http://www.nejm.org.)
(Images prepared with the assistance of Dr. Mary
Etta King.)
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case records of the massachusetts general hospital
pler echocardiography, which can detect a left-toright shunt across the septum, and echocardiography with intravenous agitated-saline injection,
which can detect a right-to-left shunt. In the latter
technique, also known as a bubble study, a small
amount of air is mixed with saline and injected intravenously. The tiny air bubbles are seen as bright
reflections in the right atrium. If there is an intracardiac shunt, the air bubbles will appear in the left
atrium within two, three, or four heartbeats after the
injection. Their appearance after five heartbeats can
result from normal circulation of the air bubbles
through the lung. In this patient, we saw both a leftto-right shunt on the Doppler study and a rightto-left shunt on the study with agitated-saline injection (Fig. 4 and video clip, available with the full
text of this article at http://www.nejm.org), both of
which are consistent with a diagnosis of patent foramen ovale.
Dr. Friedlander: Three important factors contributed to the excellent outcome in this patient, who
had a potentially lethal condition. The first was the
expeditious and correct diagnosis of a brain abscess.
The second was the prompt institution of treatment,
with drainage of the abscess and administration of
antibiotics. The third was the identification of any
abnormalities that would predispose her to future
problems, so that prophylaxis might be undertaken
with subsequent dental procedures.
anatomical diagnosis
Brain abscess due to infection with Streptococcus milleri and Haemophilus aphrophilus.
Dr. Friedlander is indebted to Jonathan Slotkin, M.D., for assistance in the preparation of the case discussion.
references
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electrocardiograms, gross specimens, and photomicrographs of each case. The slides are 2 in. by 2 in., for use with a
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of Pathology to correspond to the week of publication and may be retained by the subscriber. Each year approximately
250 slides from 40 cases are sent to each subscriber. The cost of the subscription is $450 per year. Application forms for
the current subscription year, which began in January, may be obtained from Lantern Slides Service, Department of
Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974).
Slides from individual cases may be obtained at a cost of $35 per case.
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