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case records of the massachusetts general hospital

Founded by Richard C. Cabot


Eric S. Rosenberg, m.d., Editor Nancy Lee Harris, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
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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pupillary defect, and there was no visual-field the administration of metronidazole and ceftazi-
defect. He was unable to fully abduct the right dime was begun. Liposomal amphotericin B was
eye on right lateral gaze. There was lower facial administered briefly and stopped because of a
weakness on the right side. He lifted his limbs rash. A tuberculin skin test and an interferon-
against gravity, without drift. The remainder of release assay (QuantiFERON-TB Gold test) were
the neurologic and general examinations was negative. Myringotomy was performed because
normal. The hematocrit, hemoglobin level, plate- of right-sided serous otitis media; cultures of the
let count, prothrombin time, erythrocyte sedimen- aspirate were sterile. A repeat lumbar puncture
tation rate, and results of renal-function tests were was performed. Cytologic examination of the
normal, as were blood levels of potassium, calci- cerebrospinal fluid (CSF) disclosed no malignant
um, phosphorus, magnesium, albumin, globulin, cells, and flow cytometry showed no abnormal
alkaline phosphatase, total and direct bilirubin, lymphocyte populations; other test results are
and C-reactive protein. Testing for antibodies to shown in Table 1.
the human immunodeficiency virus (HIV) was On day 7, craniectomy and biopsies of the
negative; other test results are shown in Table 1. right frontal meninges and brain were performed
A chest radiograph was normal. An electrocardio- and an external ventricular drain was placed.
gram showed sinus rhythm at a rate of 64 beats Pathological examination of the specimens re-
per minute and ST-segment elevations in the in- vealed leptomeningeal fibrosis and reactive glio-
ferior leads that were not thought to be clinically sis in the cortex. Cultures of brain tissue and
significant. CSF were sterile. A test for antinuclear antibody
Lorazepam was administered and resulted in was positive at 1:40 and 1:160 dilutions, with a
some improvement in speech; levetiracetam was speckled pattern; a test for hepatitis B surface
added. A lumbar puncture was performed; the antibody was also positive, and tests for hepati-
results are shown in Table 1. The patient was tis C virus antibody, hepatitis B surface antigen,
admitted to the neurologic intensive care unit. and antibodies to double-stranded DNA, Ro, La,
Three sets of blood cultures were sterile, and Sm, and RNP were negative. The levels of IgG
three mycobacterial cultures of induced-sputum (total and subtypes) were normal.
specimens were negative; one sputum culture During the next 3 weeks, headache, nausea,
grew yeast. Dexamethasone, ethambutol, isonia vomiting, and decreased appetite persisted; pos-
zid, rifampin, pyrazinamide, pyridoxine, vanco- tural and intention tremors and visual hallucina-
mycin, ceftriaxone, acyclovir, dalteparin, insulin tions developed; and low-grade fevers occurred
on a sliding scale, and a 2-day course of ivermectin intermittently. Ethambutol and ceftazidime were
were administered. discontinued, and the administration of moxi-
Dr. Pamela W. Schaefer: MRI of the brain was floxacin, aztreonam, and trimethoprimsulfa-
performed after the administration of contrast methoxazole was begun. On day 24, a ventriculo-
material (Fig. 1). T1-weighted images show dif- peritoneal shunt was placed, and the external
fuse leptomeningeal enhancement that is most ventricular drain was removed. Blood levels of
pronounced in the left frontal region and the lactate dehydrogenase and haptoglobin were
basal cisterns. There is a focus of restricted dif- normal; other test results are shown in Table 1.
fusion in the left precentral gyrus, a finding Three days later, the diplopia and abducens pal-
consistent with ischemia. Results of magnetic sies had resolved, the visual acuity had improved
resonance angiography were normal. Thin- (20/40 in the right eye, and 20/30 in the left eye),
section, gadolinium-enhanced images of the and the optic disks were flat. Vancomycin and
orbits, obtained on day 4, show leptomeningeal aztreonam were discontinued.
enhancement surrounding the optic nerves, On day 34, the patient was discharged to a
which appear normal on T2-weighted images. rehabilitation facility. His medications included
Dr. Cai: On day 2, an electroencephalogram rifampin, isoniazid, pyrazinamide, moxifloxa-
showed intermittent generalized background cin, pyridoxine, trimethoprimsulfamethoxazole,
slowing, without epileptiform activity. Ophthal a 3-week tapered course of dexamethasone, trazo
mologic examination revealed blurred optic-disk done, omeprazole, and ondansetron. During the
margins, bilateral abducens palsies, and decreased next 2.5 weeks, he was walking and interacting,
visual acuity (20/800 in each eye). On day 3, cef- with less nausea and improved oral intake.
triaxone and acyclovir were discontinued, and Twenty days after discharge from this hospital,

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the headaches and tremors worsened and he syndrome. Over time, however, focal and diffuse
walked less. Two days later, he was brought to neurologic deficits can accrue. Cases that involve
the neurology clinic; on examination, he was alert prominent meningitis at the base of the brain
and oriented, with decreased speech output and can be particularly severe, with cranial-nerve pal-
impaired attention and repetition (the inability to sies, vasculopathy in the circle of Willis, and ob-
repeat others speech). There was a subtle prona- struction of CSF outflow leading to hydrocepha-
tor drift in the right hand, moderate postural and lus. These severe chronic meningitides can be
intention tremors bilaterally, and a narrow-based accompanied by asymmetric multifocal radicu-
stance and stride, with unsteadiness and leaning lopathies, the cauda equina syndrome, or both.
to the left side. The vital signs, funduscopic ex- The differential diagnosis of chronic meningitis
amination, and remainder of the neurologic and is extremely broad and includes infectious and
general examinations were normal. noninfectious causes.
Dr. Schaefer: CT of the head, performed with-
out the administration of contrast material, re- Infectious Causes of Chronic Meningitis
veals a 3.6-cm mass in the left inferior frontal Infectious causes of chronic meningitis tend to
lobe with irregular margins and central necrosis. be difficult to diagnose, because causative or-
Gadolinium-enhanced, T1-weighted images that ganisms are frequently indolent, fastidious, or
were obtained the same day show peripheral en- sequestered in granulomas or exudates bound to
hancement of the mass (Fig. 2). There are foci of the meninges, or they have a combination of
susceptibility in the mass, a feature consistent these traits. Such host factors as immunocom-
with hemorrhage, neovascularity, or both. There promise and travel and immigration history are
is also restricted diffusion in the rim of the mass. central to the differential diagnosis of infectious
T2-weighted images show a moderate amount of causes. Historically, the most common infectious
associated edema. There is persistent diffuse lep- cause of chronic meningitis in case series has been
tomeningeal enhancement. Mycobacterium tuberculosis.1 Other organisms that
Dr. Cai: The patient was readmitted to this hos- cause chronic meningitis are Borrelia burgdorferi,
pital, and a diagnostic procedure was performed. Treponema pallidum, and Ehrlichia chaffeensis. Pyogenic
bacteria rarely cause chronic meningitis but can
Differ en t i a l Di agnosis do so in persons with a parameningeal focus,
endocarditis, or partially treated acute bacterial
Dr. Tracey A. Cho: I was involved in the care of the meningitis.
patient, and I am aware of the final diagnosis. HIV is the most common viral cause of
The syndromic diagnosis in this case is chronic chronic meningitis, but HIV-related meningitis
meningitis. is rarely symptomatic.2,3 Fungal organisms are a
typical cause of chronic meningitis in immuno-
Chronic Meningitis compromised persons. However, several fungi,
This diagnosis is supported by the evolution and especially cryptococcus, can cause meningitis
persistence of symptoms over a period of weeks, in apparently normal hosts. The other di
pleocytosis and an elevated protein level in the morphic fungi that frequently cause meningitis
CSF, and the prominence of headache, neck stiff- arecoccidioides, blastomyces, and histoplasma.
ness, photophobia, nausea, vomiting, and somno- Candida is typically an opportunistic cause of
lence. The decreased visual acuity, papilledema, meningitis. Cysticercosis due to Taenia solium in-
diplopia, tremulousness, and somnolence could fection is the most important parasitic cause of
all be explained by an increase in intracranial chronic meningitis; however, meningitis usually
pressure without direct parenchymal involvement, occurs in persons with preexisting subarachnoid
a cause supported by the findings on MRI. The cysticercal cysts.
small infarct in the left frontal lobe could be ex-
plained by a vasculopathy in a patient with men- Noninfectious Causes of Chronic Meningitis
ingitis at the base of the brain. There is an extensive list of noninfectious causes
Chronic meningitis differs in important ways of chronic meningitis. Several forms of vasculitis
from acute meningitis. The symptoms of chron- are associated with chronic meningitis, including
ic meningitis are typically milder, and patients primary central nervous system vasculitis, the
less often present with a complete meningitis ChurgStrauss syndrome, granulomatosis with

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

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

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

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

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

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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

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- agnosis of tuberculous meningitis has a highest
vant therapy was recommended. He was transi- possible sensitivity of 80%, assuming you have
tioned to hospice care and died several weeks optimal sampling conditions and access to im-
later, 5 months after the onset of symptoms and mediate processing, can obtain large volumes
1 month after the diagnosis. Permission for an of CSF, and can repeat the test several times.
autopsy was not obtained. However, in the resource-limited areas where
Dr. Nancy Lee Harris (Pathology): Dr. Schaefer, tuberculosis is prevalent, the sensitivity of CSF
would you comment on whether the mass in the testing is probably closer to 50%.4 Tuberculous
frontal lobe could have been extraparenchymal? meningitis is a severe disease that is associated
Dr. Schaefer: The mass was peripheral. I initially with high morbidity and mortality, and early
thought that it was intraaxial; however, on sagit- treatment definitely improves outcomes. Subacute
tal and coronal images, it appears to have a broad or chronic meningitis without any identified
base at the interface with the bone, and it could cause, particularly if it is severe, should be
be extraaxial. treated empirically with antituberculous treat-
Dr. Thomas Byrne (Neurology): Since all the diag- ment until an alternative diagnosis is found.
nostic tests for tuberculosis have low sensitivity, This patient had classic symptoms of tubercu-
when is it appropriate to start empirical treat- lous meningitis, but we later learned that he had
ment for tuberculous meningitis? a glioma. Although I got this diagnosis wrong,
Dr. Cho: CSF testing for the microbiologic di- 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 Dr. Chi: Cerebral infarction due to the infiltra-
any other effective therapies. tion of tumor cells in the leptomeningeal vessels
A Physician: Now that the diagnosis is known, has also been described in patients with primary
would you retrospectively comment on the cause leptomeningeal gliomatosis.
of the small infarct that was observed on the
patients first MRI scan? A nat omic a l Di agnosis
Dr. Cho: Vasculopathy may occur in any case of
chronic meningitis that affects the basal cisterns. Glioblastoma, WHO grade IV of IV, involving the
Infarcts tend to occur in the basal ganglia and leptomeninges and consistent with primary lepto
the deeper portions of the brain, including the meningeal gliomatosis.
areas supplied by the medial striate and thalamo This case was presented at Neurology Grand Rounds.
perforating arteries, sometimes referred to as the Dr. Louis reports receiving consulting fees from United States
tuberculosis zone.17 This case was atypical because Diagnostic Standards and payment for expert testimony in cases
involving genetic analyses as evidence of brain-tumor causation
the infarct was in the cortex. Vasculopathy appears on behalf of Rohm and Haas. No other potential conflict of in-
to be more typically associated with infectious terest relevant to this article was reported.
processes than with neoplastic processes, but any Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
process that causes meningitis at the base of the We thank Dr. Thomas Byrne for help with organizing the
brain could affect the vessels passing through. conference.

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