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case records of the massachusetts general hospital

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Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

Case 8-2014: A 29-Year-Old Man

with Headache, Vomiting, and Diplopia
Tracey A. Cho, M.D., Andrew S. Chi, M.D., Ph.D.,
Pamela W. Schaefer, M.D., and David N. Louis, M.D.

Pr e sen tat ion of C a se

Dr. Xuemei Cai (Neurology): A 29-year-old man was admitted to this hospital because From the Departments of Neurology
of headache, vomiting, and diplopia. (T.A.C., A.S.C.), Radiology (P.W.S.), and Pa-
thology (D.N.L.), Massachusetts General
The patient had been well until 3 weeks before admission, when headaches, Hospital, and the Departments of Neurol-
blurred vision, nausea, and vomiting developed, followed by anorexia and weight ogy (T.A.C., A.S.C.), Radiology (P.W.S.),
loss (7.3 kg). Evaluation at a student health center, including computed tomog- and Pathology (D.N.L.), Harvard Medical
School both in Boston.
raphy (CT) of the brain, reportedly revealed no abnormalities. Three days before
admission, photophobia, diplopia, neck stiffness, tremulousness of the left hand, N Engl J Med 2014;370:1049-59.
DOI: 10.1056/NEJMcpc1214216
and somnolence developed. On the day of admission, the patient became mute. Copyright 2014 Massachusetts Medical Society.
Earlier that day, magnetic resonance imaging (MRI) of the brain and cervical spine
was performed at another hospital after the administration of gadolinium, and a
diffusion-weighted image reportedly showed hyperintensity in the cortex along the
left frontoparietal region, as well as leptomeningeal enhancement (most prominent
along the basal cistern, pons, and cerebellum). He was transferred to this hospital.
The patients history was obtained from his sister. Two months before admis-
sion, he had fallen while snowboarding and had possibly hit his head. He had had
surgery at 11 years of age for eustachian-tube dysfunction. He was born in a refugee
camp in Southeast Asia and possibly received vaccination with bacille Calmette
Gurin; he immigrated to the northwestern United States at 5 years of age. He had
traveled to Texas and the Middle East for military service more than 10 years be-
fore admission and to Texas 3 weeks before admission. His medications were an
unspecified pain medicine for the headaches and suppositories for the vomiting.
He had no known allergies. He was a student and lived with a roommate. He
drank alcohol occasionally and did not smoke or use illicit drugs. While his
mother was in a refugee camp, she had had a prolonged illness requiring multiple
medications; his sisters were healthy, and there was no family history of autoim-
mune diseases or cancer.
On examination, the patients vital signs were normal. He was somnolent but
arousable by verbal stimuli. The neck was rigid. He was nonverbal but could write
his name and current location and follow simple commands. The pupils were
equal, round, and reactive to light (from 4 to 2 mm), without a relative afferent

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 The n e w e ng l a n d j o u r na l
pupillary defect, and there was no visual-field
defect. He was unable to fully abduct the right
eye on right lateral gaze. There was lower facial
weakness on the right side. He lifted his limbs
against gravity, without drift. The remainder of
the neurologic and general examinations was
normal. The hematocrit, hemoglobin level, plate-
let count, prothrombin time, erythrocyte sedimen-
tation rate, and results of renal-function tests were
normal, as were blood levels of potassium, calci-
um, phosphorus, magnesium, albumin, globulin,
alkaline phosphatase, total and direct bilirubin,
and C-reactive protein. Testing for antibodies to
the human immunodeficiency virus (HIV) was
negative; other test results are shown in Table 1.
A chest radiograph was normal. An electrocardio-
gram showed sinus rhythm at a rate of 64 beats
per minute and ST-segment elevations in the in-
ferior leads that were not thought to be clinically
significant.
Lorazepam was administered and resulted in
some improvement in speech; levetiracetam was
added. A lumbar puncture was performed; the
results are shown in Table 1. The patient was
admitted to the neurologic intensive care unit.
Three sets of blood cultures were sterile, and
three mycobacterial cultures of induced-sputum
specimens were negative; one sputum culture
grew yeast. Dexamethasone, ethambutol, isonia
zid, rifampin, pyrazinamide, pyridoxine, vanco-
mycin, ceftriaxone, acyclovir, dalteparin, insulin
on a sliding scale, and a 2-day course of ivermectin
were administered.
Dr. Pamela W. Schaefer: MRI of the brain was
performed after the administration of contrast
material (Fig. 1). T1-weighted images show dif-
fuse leptomeningeal enhancement that is most
pronounced in the left frontal region and the
basal cisterns. There is a focus of restricted dif-
fusion in the left precentral gyrus, a finding
consistent with ischemia. Results of magnetic
resonance angiography were normal. Thin-
section, gadolinium-enhanced images of the
orbits, obtained on day 4, show leptomeningeal
enhancement surrounding the optic nerves,
which appear normal on T2-weighted images.
Dr. Cai: On day 2, an electroencephalogram
showed intermittent generalized background
slowing, without epileptiform activity. Ophthal
mologic examination revealed blurred optic-disk
margins, bilateral abducens palsies, and decreased
visual acuity (20/800 in each eye). On day 3, cef-
triaxone and acyclovir were discontinued, and
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of m e dic i n e
the administration of metronidazole and ceftazi-
dime was begun. Liposomal amphotericin B was
administered briefly and stopped because of a
rash. A tuberculin skin test and an interferon-
release assay (QuantiFERON-TB Gold test) were
negative. Myringotomy was performed because
of right-sided serous otitis media; cultures of the
aspirate were sterile. A repeat lumbar puncture
was performed. Cytologic examination of the
cerebrospinal fluid (CSF) disclosed no malignant
cells, and flow cytometry showed no abnormal
lymphocyte populations; other test results are
shown in Table 1.
On day 7, craniectomy and biopsies of the
right frontal meninges and brain were performed
and an external ventricular drain was placed.
Pathological examination of the specimens re-
vealed leptomeningeal fibrosis and reactive glio-
sis in the cortex. Cultures of brain tissue and
CSF were sterile. A test for antinuclear antibody
was positive at 1:40 and 1:160 dilutions, with a
speckled pattern; a test for hepatitis B surface
antibody was also positive, and tests for hepati-
tis C virus antibody, hepatitis B surface antigen,
and antibodies to double-stranded DNA, Ro, La,
Sm, and RNP were negative. The levels of IgG
(total and subtypes) were normal.
During the next 3 weeks, headache, nausea,
vomiting, and decreased appetite persisted; pos-
tural and intention tremors and visual hallucina-
tions developed; and low-grade fevers occurred
intermittently. Ethambutol and ceftazidime were
discontinued, and the administration of moxi-
floxacin, aztreonam, and trimethoprimsulfa-
methoxazole was begun. On day 24, a ventriculo-
peritoneal shunt was placed, and the external
ventricular drain was removed. Blood levels of
lactate dehydrogenase and haptoglobin were
normal; other test results are shown in Table 1.
Three days later, the diplopia and abducens pal-
sies had resolved, the visual acuity had improved
(20/40 in the right eye, and 20/30 in the left eye),
and the optic disks were flat. Vancomycin and
aztreonam were discontinued.
On day 34, the patient was discharged to a
rehabilitation facility. His medications included
rifampin, isoniazid, pyrazinamide, moxifloxa-
cin, pyridoxine, trimethoprimsulfamethoxazole,
a 3-week tapered course of dexamethasone, trazo
done, omeprazole, and ondansetron. During the
next 2.5 weeks, he was walking and interacting,
with less nausea and improved oral intake.
Twenty days after discharge from this hospital,
 case records of the massachuset ts gener al hospital
the headaches and tremors worsened and he
walked less. Two days later, he was brought to
the neurology clinic; on examination, he was alert
and oriented, with decreased speech output and
impaired attention and repetition (the inability to
repeat others speech). There was a subtle prona-
tor drift in the right hand, moderate postural and
intention tremors bilaterally, and a narrow-based
stance and stride, with unsteadiness and leaning
to the left side. The vital signs, funduscopic ex-
amination, and remainder of the neurologic and
general examinations were normal.
Dr. Schaefer: CT of the head, performed with-
out the administration of contrast material, re-
veals a 3.6-cm mass in the left inferior frontal
lobe with irregular margins and central necrosis.
Gadolinium-enhanced, T1-weighted images that
were obtained the same day show peripheral en-
hancement of the mass (Fig. 2). There are foci of
susceptibility in the mass, a feature consistent
with hemorrhage, neovascularity, or both. There
is also restricted diffusion in the rim of the mass.
T2-weighted images show a moderate amount of
associated edema. There is persistent diffuse lep-
tomeningeal enhancement.
Dr. Cai: The patient was readmitted to this hos-
pital, and a diagnostic procedure was performed.
Differ en t i a l Di agnosis
Dr. Tracey A. Cho: I was involved in the care of the
patient, and I am aware of the final diagnosis.
The syndromic diagnosis in this case is chronic
meningitis.
Chronic Meningitis
This diagnosis is supported by the evolution and
persistence of symptoms over a period of weeks,
pleocytosis and an elevated protein level in the
CSF, and the prominence of headache, neck stiff-
ness, photophobia, nausea, vomiting, and somno-
lence. The decreased visual acuity, papilledema,
diplopia, tremulousness, and somnolence could
all be explained by an increase in intracranial
pressure without direct parenchymal involvement,
a cause supported by the findings on MRI. The
small infarct in the left frontal lobe could be ex-
plained by a vasculopathy in a patient with men-
ingitis at the base of the brain.
Chronic meningitis differs in important ways
from acute meningitis. The symptoms of chron-
ic meningitis are typically milder, and patients
less often present with a complete meningitis
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syndrome. Over time, however, focal and diffuse
neurologic deficits can accrue. Cases that involve
prominent meningitis at the base of the brain
can be particularly severe, with cranial-nerve pal-
sies, vasculopathy in the circle of Willis, and ob-
struction of CSF outflow leading to hydrocepha-
lus. These severe chronic meningitides can be
accompanied by asymmetric multifocal radicu-
lopathies, the cauda equina syndrome, or both.
The differential diagnosis of chronic meningitis
is extremely broad and includes infectious and
noninfectious causes.
Infectious Causes of Chronic Meningitis
Infectious causes of chronic meningitis tend to
be difficult to diagnose, because causative or-
ganisms are frequently indolent, fastidious, or
sequestered in granulomas or exudates bound to
the meninges, or they have a combination of
these traits. Such host factors as immunocom-
promise and travel and immigration history are
central to the differential diagnosis of infectious
causes. Historically, the most common infectious
cause of chronic meningitis in case series has been
Mycobacterium tuberculosis.1 Other organisms that
cause chronic meningitis are Borrelia burgdorferi,
Treponema pallidum, and Ehrlichia chaffeensis. Pyogenic
bacteria rarely cause chronic meningitis but can
do so in persons with a parameningeal focus,
endocarditis, or partially treated acute bacterial
meningitis.
HIV is the most common viral cause of
chronic meningitis, but HIV-related meningitis
is rarely symptomatic.2,3 Fungal organisms are a
typical cause of chronic meningitis in immuno-
compromised persons. However, several fungi,
especially cryptococcus, can cause meningitis
in apparently normal hosts. The other di
morphic fungi that frequently cause meningitis
arecoccidioides, blastomyces, and histoplasma.
Candida is typically an opportunistic cause of
meningitis. Cysticercosis due to Taenia solium in-
fection is the most important parasitic cause of
chronic meningitis; however, meningitis usually
occurs in persons with preexisting subarachnoid
cysticercal cysts.
Noninfectious Causes of Chronic Meningitis
There is an extensive list of noninfectious causes
of chronic meningitis. Several forms of vasculitis
are associated with chronic meningitis, including
primary central nervous system vasculitis, the
ChurgStrauss syndrome, granulomatosis with
1051
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Laboratory Data.*

Reference Range, On First Hospital Hospital On Second

Variable Adults Admission Day 5 Day 24 Admission
Blood
Hematocrit (%) 41.053.0 (men) 49.1 43.1 25.7 35.0
Hemoglobin (g/dl) 13.517.5 (men) 17.0 14.9 8.6 12.4
White-cell count (per mm3) 450011,000 8800 8800 6100 5300
Differential count (%)
Neutrophils 4070 79 74 78 70
Lymphocytes 2244 16 17 15 22
Monocytes 411 5 8 6 7
Eosinophils 08 0 1 1 1
Sodium (mmol/liter) 135145 134 140 135 135
Potassium (mmol/liter) 3.44.8 3.5 3.0 4.0 3.5
Chloride (mmol/liter) 100108 91 102 104 96
Carbon dioxide (mmol/liter) 23.031.9 33.1 28.7 23.0 33.7
Glucose (mg/dl) 70110 132 127
Total protein (g/dl) 6.08.3 8.7 6.8
Aspartate aminotransferase (U/liter) 1040 14 113
Alanine aminotransferase (U/liter) 1055 5 161
Cerebrospinal fluid
Opening pressure (cm of water) 620 >53 29 Not mea-
sured
Color Colorless Pale yellow Pink Yellow
Turbidity Clear Clear Slight Slight
Xanthochromia None Yes Yes Yes
3)
Red-cell count (per mm
Tube 1 0 10 3300
Tube 4 0 9 2700
Shunt 385
White-cell count (per mm3)
Tube 1 05 52 53
Tube 4 05 47 40
Shunt 30
Differential count (%)
Neutrophils 0 0 16 1
Lymphocytes 0 35 (tube 1), 43 34
41 (tube 4)
Reactive lymphocytes 0 0 0 1
Monocytes 0 65 (tube 1), 40 58
59 (tube 4)
Eosinophils 0 0 1 0
Macrophages or lining cells 0 0 0 6
Protein (mg/dl) 555 419 580 870
Glucose (mg/dl) 5075 15 18 41
Varicellazoster virus, by PCR Negative Negative
Cytomegalovirus DNA, by PCR Negative Negative Negative
Herpes simplex virus DNA amplification Negative for types Negative for types
1 and 2 1 and 2

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 case records of the massachuset ts gener al hospital

Table 1. (Continued.)

Reference Range, On First Hospital Hospital On Second

Variable Adults Admission Day 5 Day 24 Admission
EpsteinBarr virus DNA, by PCR (copies/ml) None detected None detected
Venereal Disease Research Laboratory test Nonreactive Nonreactive
Angiotensin-converting enzyme (U/liter) <16 <3
Cryptococcal antigen Negative Negative
IgG (mg/dl) 08.0 53.2 86.3
Albumin (mg/dl) 11.050.9 423.0 475.0
Oligoclonal bands on agarose electrophoresis None in CSF None in CSF con- None in CSF con
concentrated 80 centrated 31 centrated <31
Microbiologic tests
Staining No organisms seen Very few neu No neutro-
on Grams staining, trophils and phils or or-
acid-fast staining, no organisms ganisms
or fungal wet seen seen
preparation
Cultures No growth No bacterial, myco- No bacterial or No growth
bacterial, or fungal mycobacterial
growth growth
Mycobacterial DNA, by PCR Negative

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. PCR denotes polymerase chain reaction.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results.
Theymay therefore not be appropriate for all patients.

polyangiitis (formerly known as Wegeners gran-
ulomatosis), and Cogans syndrome. Connective-
tissue diseases associated with meningitis include
systemic lupus erythematosus, rheumatoid arthri-
tis, and Sjgrens syndrome. Several other systemic
inflammatory processes have been associated with
chronic meningitis, the most important of which
is neurosarcoidosis. Chemical irritation can cause
chronic meningitis in persons who have a der-
moid cyst with intermittent release of cholesterol
crystals, in those who have undergone a cranioto-
my, and in those who have received treatment with
intravenous immunoglobulin or trimethoprim
sulfamethoxazole. Finally, neoplasms, most com-
monly breast carcinoma, lung carcinoma, mela-
noma, and leukemia, are relatively frequent causes
of chronic meningitis.
Clues to the Diagnosis in this Case
In this case, several clues narrow the differential
diagnosis. First, the syndrome is dominated by
meningitic symptoms with little primary paren-
chymal or systemic involvement. The patient pre-
sented with a severe subacute form of meningitis
manifested by cranial-nerve palsy, increased in-
tracranial pressure, and an infarct that is possibly
due to vasculopathy. Examination of the CSF
profile reveals a high protein level, a low glucose
level (hypoglycorrhachia), and only moderate mono-
nuclear pleocytosis. We can thus narrow the dif-
ferential diagnosis to entities that cause severe
chronic meningitis. Possible infectious causes are
tuberculosis, fungi, and parasites, and possible
noninfectious causes are hypertrophic pachy-
meningitis, neoplasms, primary central nervous
system vasculitis, and antineutrophil cytoplasmic
antibodyassociated vasculitis. Although there is
an extensive differential diagnosis for causes of
hypoglycorrhachia, the most prominent infectious
causes are pyogenic bacteria, tuberculosis, and
fungi, and the most important noninfectious
causes are neoplasms, sarcoidosis, and subarach-
noid blood; pyogenic bacteria and neoplasms tend
to cause the lowest glucose levels. Thus, the dif-
ferential diagnosis is further narrowed to enti-
ties that cause both severe chronic meningitis
and low CSF glucose levels; these are tuberculo-
sis, fungi, and neoplasms.
There is evidence in support of a diagnosis of
tuberculous meningitis in this case. The patient
was born in an area where tuberculosis is en-
demic and was possibly exposed to it by his
mother. Other evidence includes the subacute on-
set of symptoms, the typical CSF profile, the stroke

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B C

D E F

Figure 1. MRI Images of the Brain Obtained on the First Admission.

Gadolinium-enhanced, T1-weighted sagittal (Panel A) and axial (Panels B, C, and D) images show diffuse leptomen-
ingeal enhancement that is most pronounced in the left frontal region and the basal cisterns. A fluid-attenuated
inversion recovery (FLAIR) image (Panel E) and a diffusion-weighted image (Panel F) show a hyperintense lesion
(arrows) in the left precentral gyrus that is consistent with a subacute ischemic focus.

that occurred early in the disease course, and
the apparent improvement of symptoms with
antituberculous treatment, with the caveat that
glucocorticoids were also administered and di-
version of the CSF was performed. Arguments
against a diagnosis of tuberculous meningitis
in this case include the negative tuberculin skin
test and interferon- release assay, the normal
chest radiograph, the moderate pleocytosis, the
negative acid-fast stain and culture of the CSF,
and the negative stains and culture of the
meningeal-biopsy specimens. Serial high-volume
lumbar punctures can be helpful in establish-
ing the diagnosis of tuberculous meningitis,
but even with multiple samples and immediate
processing, CSF testing has a sensitivity of only
80%.4 In this patient, lumbar punctures were
performed in the emergency department and
on hospital days 1, 3, and 5 but did not yield a
diagnosis.
Cryptococcal meningitis and coccidioidal men-
ingitis are other strong considerations. The pa-
tients CSF profile and the increased intracranial
pressure are typical of each infection. However, the
patient did not have a fever or apparent immuno-
compromise, features that are also typical of these
infections. Stroke due to vasculopathy is character-
istic of coccidioidal meningitis but not of crypto-
coccal meningitis. Also, coccidioides is endemic in
parts of the southwestern United States, including
Texas, where this patient had visited. It is impor-
tant to note that the CSF test for cryptococcal
antigen is highly sensitive and was negative in
this patient.5
A diagnosis of neoplastic meningitis in this
patient is supported by the absence of fever, the
subacute onset of symptoms, and the low CSF
glucose level. The unusual combination of a
high CSF protein level and relatively moderate
pleocytosis is characteristic of neoplastic menin-
gitis. An argument against a diagnosis of neo-
plastic meningitis in this patient is the absence

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 case records of the massachuset ts gener al hospital

A B C

D E F

Figure 2. MRI Images of the Brain Obtained on the Second Admission.

There is a 3.6-cm mass in the left inferior frontal lobe. Gadolinium-enhanced, T1-weighted axial (Panel A), coronal
(Panel B), and sagittal (Panel C) images show that the mass has thick, irregular rim enhancement. A diffusion-weighted
image (Panel D) shows restricted diffusion in the rim. A gradient-echo image (Panel E) shows foci of susceptibility,
a feature consistent with hemorrhage, neovascularity, or both. A FLAIR image (Panel F) shows a moderate amount
of associated edema.

of systemic symptoms and signs of a malignant
condition; there are no parenchymal mass lesions
to give any clues. Patients with neoplastic men-
ingitis do not commonly present with stroke,
although it is not impossible. The results of cy-
tologic tests and flow cytometry of the CSF and
examination of the meningeal-biopsy specimens
were normal, but these tests have only moderate
sensitivity for malignant conditions.6,7
Summary
The patients initial clinical improvement could
be attributed to a specific response to antituber-
culous treatment but was more likely a nonspe-
cific response to CSF diversion and glucocorti-
coids. The subsequent development of focal signs
and a mass lesion could represent a paradoxical
reaction to appropriate antituberculous treatment
or the evolution of a neoplastic mass lesion.
Based largely on the patients demographics and
the normal meningeal- and brain-biopsy speci-
mens, my diagnosis was tuberculous meningitis
with a paradoxical response to antimycobacterial
treatment. However, a biopsy and possible re-
section of the mass lesion were necessary to es-
tablish a definitive diagnosis and determine fur-
ther treatment.
DR . T R ACE Y A . CHOS DI AGNOSIS
Tuberculous meningitis with a paradoxical re-
sponse to antimycobacterial treatment.
Pathol o gic a l Discussion
Dr. David N. Louis: The initial biopsy specimen
from the right frontal lobe showed only fibrosis
in the leptomeninges and reactive gliosis in the
cortex. The diagnostic procedure on the second
admission was a right frontal craniotomy (per-
formed by Dr. Emad Eskandar), and the original
intention was to perform a biopsy and possible

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 The n e w e ng l a n d j o u r na l of m e dic i n e

ma. Neither biopsy nor resection of the mass lesion

A
was performed, pending final classification of the
tumor. Additional specimens of the gelatinous
material were obtained for permanent sections.
Examination of permanent sections revealed a
markedly cellular neoplasm in the leptomeninges,
consisting of small, poorly differentiated cells
(Fig. 3A), and reactive gliosis in the adjacent cere-
bral cortex. Immunohistochemical staining of the
tumor cells revealed glial fibrillary acidic protein
(Fig. 3B) but no synaptophysin or lymphocyte
markers (Fig. 3C). The neoplasm featured micro-
vascular proliferation and necrosis. The findings
B were diagnostic of glioblastoma, World Health
Organization (WHO) grade IV of IV, and were
consistent with the small-cell variant of glioblas-
toma. Amplification of the gene encoding epi-
dermal growth factor receptor (EGFR) is common
in small-cell glioblastomas,8 and glioblastomas
with EGFR amplification may undergo rapid growth
between neuroimaging examinations.9 Thus, fluo-
rescence in situ hybridization was performed in
this patient to assess the gene copy number of
EGFR; gene amplification was not present.
It is not uncommon for primary parenchymal
malignant gliomas, such as glioblastoma, to in-
C volve the leptomeninges, but there was no evidence
of glioblastoma in the underlying brain paren-
chyma in this case, and the left frontal mass that
was seen on imaging could have been extraaxial.
These features suggest that this case could rep-
resent a rare example of primary leptomeningeal
gliomatosis (i.e., a glioma arising in the leptomen-
inges). However, without a detailed examination
of the brain, we cannot rule out the possibility
that the leptomeningeal disease represents diffuse
dissemination from a parenchymal glioblastoma.

Figure 3. Leptomeningeal-Biopsy Specimens. Discussion of M a nagemen t

The tumor is markedly cellular and consists of small,
poorly differentiated cells (Panel A, hematoxylin and
eosin). Immunohistochemical staining of the tumor
cells reveals glial fibrillary acidic protein (Panel B) but
no leukocyte common antigen (Panel C).
excision of the mass in the left frontal lobe. How-
ever, on opening the dura, gelatinous material was
seen covering the brain and exuding from the inci-
sion. An intraoperative frozen-section examination
of this material revealed a small-cell malignant neo-
plasm; the differential diagnosis included lympho-
ma and other small-cell neoplasms, such as glio-
Dr. Andrew S. Chi: I became involved in this pa-
tients care after the diagnosis of glioblastoma
was made. Standard therapy for newly diagnosed
glioblastoma consists of 6 weeks of fractionated
radiotherapy to the involved field and concur-
rent daily administration of temozolomide, an
oral alkylating chemotherapy agent. Chemo-
radiation is then followed by six 28-day treat-
ment cycles in which a higher dose of temozolo-
mide is given during the first 5 days of each
cycle.10 However, because of the unusual pre-
sentation in this case, it was uncertain whether
standard therapy was indicated.

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 case records of the massachuset ts gener al hospital
Several genetic subtypes of glioblastoma have
been characterized, and each one is associated with
a substantially different prognosis. For example,
patients whose tumors undergo methylation of
the O6-methylguanineDNA methyltransferase
(MGMT) gene promoter have longer survival times
than patients whose tumors are unmethylated at
this site.11 Also, specific point mutations in two
genes encoding isocitrate dehydrogenase (IDH1
and IDH2) are found in patients with certain
subtypes of glioblastoma that are associated with
younger age at diagnosis and increased survival.12
Yet, despite the different natural histories associ-
ated with each genetic subtype of glioblastoma,
it is uncertain whether the treatment for these
subtypes should differ, because genetic stratifi-
cation has not yet been studied in prospective,
randomized trials.
Furthermore, regardless of their morphologic
features, glial tumors can cause distinct clinical
syndromes that are defined by unique anatomi-
cal and radiographic features; this is the case
with gliomatosis cerebri (which causes diffuse
infiltration throughout the brain) and pontine
and midbrain gliomas (which have markedly dif-
ferent prognoses despite their similar morpho-
logic features). This patient appeared to have a
distinct glioma syndrome primary leptomen-
ingeal gliomatosis which is defined by dif-
fuse infiltration of neoplastic glial cells in the
leptomeninges without evidence of a primary
intraparenchymal tumor. This is a rare diagnosis;
there are approximately 50 autopsy-confirmed
cases reported in the literature.13,14 This disease
tends to affect relatively young people, and the
prognosis is generally extremely poor, with a
median survival time from diagnosis of 4 months
in one review.13 The diagnosis can be challeng-
ing to make, as was the case with this patient,
because the initial symptoms are frequently
nonspecific. Patients usually present with symp-
toms of a subacute meningismus, such as stiff
neck, low-grade fevers, and headache. Treatment
with antituberculous therapy at some point during
the course, as in this case, is common.13 Increased
intracranial pressure and focal neurologic signs
often develop later in the disease course. Cranial
and spinal neuropathies frequently occur, and the
abducens and optic nerves are the cranial nerves
that are the most commonly affected. Bilateral
abducens palsies and optic-nerve palsies devel-
oped in this patient, although these were prob-
ably a result of the increased intracranial pressure,
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rather than a result of direct nerve involvement
of the tumor cells. On imaging studies, frequent
features (in addition to diffuse leptomeningeal
contrast enhancement) include spinal cord involve-
ment and ventriculomegaly.
Diagnostic testing is commonly negative in
cases of primary leptomeningeal gliomatosis, as
it was in this case. Despite extensive involvement
of the leptomeninges, CSF testing is frequently
nondiagnostic; in one review, the first CSF test
was diagnostic in only 1 of 37 cases, and repeat
CSF testing was also often nondiagnostic.13 Even
examination of meningeal-biopsy specimens may
be nondiagnostic; in most reported cases, the di-
agnosis was made post mortem. However, one
apparently universal feature of primary lepto-
meningeal gliomatosis is a markedly elevated total
protein level in the CSF, which was seen in this
patient.
Ultimately, it became clear that this patient
had a glioblastoma and most likely had primary
leptomeningeal gliomatosis. Shortly after the
craniotomy, incontinence and leg weakness de-
veloped, and MRI of the spine was performed.
Dr. Schaefer: Gadolinium-enhanced images of
the spine (Fig. 4), obtained 7 days after the crani-
otomy, show extensive leptomeningeal enhance-
ment along the entire spinal cord and cauda
equina.
Dr. Chi: Therapeutic options were limited.
Involved-field radiation therapy would have re-
quired treatment of the entire neuraxis, a proce-
dure that would have been difficult for the pa-
tient to tolerate. No consensus guidelines could
be ascertained from the literature, which consists
of single case reports and small case series, and
reported chemotherapy regimens varied widely,
ranging from those involving single chemothera-
peutic agents to nine-drug regimens incorporat-
ing intrathecal chemotherapy.15 Anecdotal evidence
suggested that temozolomide can be clinically
active in this disease; one report documented
radiographic regression after three cycles of temo
zolomide.16 Ultimately, none of the methods of
treatment that we considered showed compelling
evidence of efficacy and all were associated with
some risk of toxic effects.
Unfortunately, the patients status rapidly de-
clined despite the administration of high doses
of glucocorticoids and the use of a ventriculo-
peritoneal shunt. He became somnolent and was
arousable only intermittently by vigorous stimu-
lation. Because of his sudden deterioration, poor
1057
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B C

Figure 4. MRI Images of the Spine Obtained after the Craniotomy.

Sagittal gadolinium-enhanced images of the cervical (Panel A), thoracic (Panel B), and lumbar (Panel C) spine
show extensive, thick leptomeningeal enhancement.

functional status, and poor prognosis, no adju-
vant therapy was recommended. He was transi-
tioned to hospice care and died several weeks
later, 5 months after the onset of symptoms and
1 month after the diagnosis. Permission for an
autopsy was not obtained.
Dr. Nancy Lee Harris (Pathology): Dr. Schaefer,
would you comment on whether the mass in the
frontal lobe could have been extraparenchymal?
Dr. Schaefer: The mass was peripheral. I initially
thought that it was intraaxial; however, on sagit-
tal and coronal images, it appears to have a broad
base at the interface with the bone, and it could
be extraaxial.
Dr. Thomas Byrne (Neurology): Since all the diag-
nostic tests for tuberculosis have low sensitivity,
when is it appropriate to start empirical treat-
ment for tuberculous meningitis?
Dr. Cho: CSF testing for the microbiologic di-
agnosis of tuberculous meningitis has a highest
possible sensitivity of 80%, assuming you have
optimal sampling conditions and access to im-
mediate processing, can obtain large volumes
of CSF, and can repeat the test several times.
However, in the resource-limited areas where
tuberculosis is prevalent, the sensitivity of CSF
testing is probably closer to 50%.4 Tuberculous
meningitis is a severe disease that is associated
with high morbidity and mortality, and early
treatment definitely improves outcomes. Subacute
or chronic meningitis without any identified
cause, particularly if it is severe, should be
treated empirically with antituberculous treat-
ment until an alternative diagnosis is found.
This patient had classic symptoms of tubercu-
lous meningitis, but we later learned that he had
a glioma. Although I got this diagnosis wrong,
I would treat the patient exactly the same given

1058 n engl j med 370;11 nejm.org march 13, 2014

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 case records of the massachuset ts gener al hospital

the available data, particularly given the lack of
any other effective therapies.
A Physician: Now that the diagnosis is known,
would you retrospectively comment on the cause
of the small infarct that was observed on the
patients first MRI scan?
Dr. Cho: Vasculopathy may occur in any case of
chronic meningitis that affects the basal cisterns.
Infarcts tend to occur in the basal ganglia and
the deeper portions of the brain, including the
areas supplied by the medial striate and thalamo
perforating arteries, sometimes referred to as the
tuberculosis zone.17 This case was atypical because
the infarct was in the cortex. Vasculopathy appears
to be more typically associated with infectious
processes than with neoplastic processes, but any
process that causes meningitis at the base of the
brain could affect the vessels passing through.
Dr. Chi: Cerebral infarction due to the infiltra-
tion of tumor cells in the leptomeningeal vessels
has also been described in patients with primary
leptomeningeal gliomatosis.
A nat omic a l Di agnosis
Glioblastoma, WHO grade IV of IV, involving the
leptomeninges and consistent with primary lepto
meningeal gliomatosis.
This case was presented at Neurology Grand Rounds.
Dr. Louis reports receiving consulting fees from United States
Diagnostic Standards and payment for expert testimony in cases
involving genetic analyses as evidence of brain-tumor causation
on behalf of Rohm and Haas. No other potential conflict of in-
terest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Thomas Byrne for help with organizing the
conference.

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