CLINICAL CARE CONUNDRUM
The approach to clinical conundrums by an expert clinician is revealed through presentation of an actual
patient’s case in an approach typical of morning report. Similar to patient care, sequential pieces of information
are provided to the clinician who is unfamiliar with the case. The focus is on the thought processes of both the
clinical team caring for the patient and the discussant.

Iris O. Yung, MD1
Thomas E. Baudendistel, MD1
Gurpreet Dhaliwal, MD2
1

Department of Medicine, California Pacific
Medical Center, San Francisco, California.
2
Department of Medicine, University of California, San Francisco and San Francisco Veterans
Affairs Medical Center, San Francisco, California.

A Diagnosis of Exclusion

A

26-year-old woman was brought to the emergency department following several episodes of seizures. The patient’s
friend witnessed several 15-minute episodes of sudden jerks
and tremors of her right arm during which the patient bit her
tongue, had word-finding difficulty, had horizontal eye deviation, and was incontinent of urine. She became unresponsive
during the episodes, with incomplete recovery of consciousness
between attacks. She was afebrile. Her neurologic exam 4 hours
after several seizures revealed word-finding difficulty and right
arm weakness. A complete blood count, chemistry panel
including renal and liver function tests, urine toxicology
screen, and computed tomography (CT) of the head were normal. After a loading dose of fosphenytoin, the patient did not
experience further seizures and was discharged on a maintenance dose of phenytoin.
Over the next week, the patient continued to note a sensation of heaviness in her right arm and felt fatigued. The
patient’s mother brought her back to the emergency department after witnessing a similar seizure episode that persisted
for an hour. On arrival, the patient was no longer seizing.
Although it can sometimes be difficult to differentiate between
seizure, stroke, syncope, and other causes of transient loss of consciousness, this constellation of symptoms strongly points to a
seizure. I would classify the patient’s focal arm movements associated with impaired consciousness as partial complex seizures.
One of the first considerations is determining whether the seizure
is caused by a systemic process or by an intrinsic central nervous
system disorder. Common systemic illnesses include infections,
metabolic disturbances, toxins, and malignancies, none of which
are evident on the preliminary evaluation. The absence of fever is
important as is the time frame (now extending over 1 week) in
excluding acute bacterial meningitis. A negative urine toxicology
is very helpful but does not exclude the possibility that the seizure
is from unmeasured drug intoxication, for example, tricyclic
antidepressants, or from drug withdrawal, for example, benzodiazepines, barbiturates, ethanol, and antiepileptic drugs. The persistent right arm heaviness and right arm jerking during the seizures
suggest a left cortical focus that the CT scan did not detect. Without a clear diagnosis and with recurrent seizures despite antiepileptic drugs, hospitalization is warranted.

162

ª 2008 Society of Hospital Medicine

DOI 10.1002/jhm.297
Published online in Wiley InterScience (www.interscience.wiley.com).

The patient experienced migraine headaches
each month during menses. There was no family
history of seizures. Her only medication was phenytoin. The mother was unaware of any use of
tobacco, alcohol, or recreational drugs. The
patient was raised in New Jersey and moved to
the San Francisco Bay area 9 months ago. She
had no pets and had traveled to Florida and
Montreal in the past 6 months. She was a graduate student in performing arts. During the preceding 2 weeks she had been under significant
stress and had not slept much in preparation for
an upcoming production. The patient’s mother
was not aware of any head trauma, recent illness, fevers, chills, weight loss, photosensitivity,
arthralgias, nausea, vomiting, or diarrhea.
Recent sleep deprivation could provoke seizures in
a patient with a latent anatomic focus or metabolic predisposition. Nonadherence to antiepileptic drug therapy is the most common reason for
patients to present to the ED with seizures; therefore, I would check a phenytoin level to assess
whether she is at a therapeutic level and would consider administering another loading dose. In the absence of immunocompromise or unusual activities
or exposures, North American travel does not bring
to mind additional etiologies at this time.
On exam, temperature was 37.3 8C, blood pressure was 148/84 mm Hg, heart rate was 120 per
minute, and respiratory rate was 16 per minute.
The patient was stuporous and withdrew from
painful stimuli. She was unable to speak. Pupils
were 4 mm in diameter and reacted to light. No
gaze preference or nystagmus was present. There
was no meningismus. Deep tendon reflexes were
1+ and symmetrical in both upper and lower
extremities. Plantar reflexes were extensor bilaterally. The tone in the right upper extremity was
mildly increased compared to the left. The
patient demonstrated semipurposeful movement
of the limbs, such as reaching for the bed rails
with her arms. Examination of the heart, lungs,
abdomen, skin, and oropharynx was normal.
The white blood cell count was 22,300/mm3
with 50% neutrophils, 40% lymphocytes, 7%
monocytes, and 3% eosinophils. Results of the
chemistry panel including electrolytes, glucose,
creatinine, and liver enzymes, urinalysis, and
thyroid-stimulating hormone were normal. Serum phenytoin level was 8.1 lg/mL. Urine toxi-

cology screen, obtained after the patient had
received lorazepam, was positive only for benzodiazepines. A chest radiograph was normal.
The cerebrospinal fluid (CSF) was colorless,
containing 35 white blood cells/mm3 (48% lymphocytes, 30% neutrophils, 22% monocytes), 3 red
blood cells/mm3, 62 mg/dL protein, and 50 mg/dL
glucose. There was no xanthochromia. The CSF
was negative for cryptococcal antigen, antibodies
to West Nile virus, PCR for herpes simplex viruses-1
and -2, and PCR for Borrelia burgdorferi. CSF bacterial culture, cryptococcal antigen, and AFB stain
were negative. The serum antinuclear antibody,
rheumatoid factor, and rapid plasma reagin were
negative. Serum antibodies to human immunodeficiency virus, hepatitis B and C viruses, Borrelia
burgdorferi, and herpes simplex viruses were negative. The erythrocyte sedimentation rate was 25
mm/hr. There was no growth in her blood cultures.
These CSF findings have to be interpreted in light of
her clinical picture, as they are congruent with both
an aseptic meningitis and encephalitis. In practice,
these can be hard to distinguish, but the early and
dominant cortical findings (focal neurologic deficits,
prominent altered mental status, bilateral extensor
plantar reflexes) and absence of meningeal signs
favor encephalitis. This CSF profile can be seen in a
variety of disease processes causing a meningoencephalitis, including partially treated bacterial meningitis; meningitis due to viruses, fungi, mycobacteria,
or atypical bacteria (eg, Listeria); neurosarcoidosis;
carcinomatous meningitis; and infection or inflammation from a parameningeal focus in the sinuses,
epidural space, or brain parenchyma. Seizure itself
can lead to a postictal pleocytosis in the CSF,
although this degree of inflammation would be unusual. Many tests can be sent, and the clinicians
appropriately focused on some of the most treatable
and serious etiologies first. The negative HIV test
limits the list of opportunistic pathogens. The negative ANA substantially lowers the likelihood of systemic lupus, an important consideration in a young
woman with an inflammatory disorder involving the
central nervous system.
Magnetic resonance imaging (MRI) of the brain
showed cortical T2 prolongation with significant
enhancement with gadolinium in the cortex and
leptomeninges of the left parietal and posterotemporal lobes and right cingulate gyrus region (Fig.
1). The patient was admitted to the intensive care
Diagnosis of Exclusion / Yung, Baudendistel, and Dhaliwal

163

FIGURE 1. Brain MRI showed significant enhancement with gadolinium in
the cortex and leptomeninges of left parietal and posterotemporal lobes and
right cingulate gyrus region.

unit, and phenytoin and levetiracetam were administered. Over the next several days, she remained
afebrile, and her leukocytosis resolved. She continued to have seizures every day despite receiving
phenytoin, levetiracetam, and lamotrigine. She
was alert and complained about persistent right
arm weakness and word-finding difficulties. Posterior cervical lymphadenopathy at the base of her
left occiput was detected on subsequent exam.
An excisional lymph node biopsy demonstrated extensive necrosis without evidence of
granulomata, malignancy, or lymphoproliferative
disease. Stains and cultures for bacteria, fungi,
and mycobacteria were negative. The patient’s
electroencephalogram captured epileptiform activity over the left hemisphere 2 hours after a
cluster of seizures. MR angiography and cerebral
angiography demonstrated no abnormalities.
Despite this additional information, there is no
distinguishing clue that points to a single diagnosis. This is a 26-year-old healthy, seemingly immunocompetent woman who has had a 2-week
progressive and refractory seizure disorder secondary to a multifocal neuroinvasive process with
a CSF pleocytosis. She does not have evidence of a
systemic underlying disorder, save for nonspecific
localized lymphadenopathy and a transient episode
of leukocytosis on admission, and has no distinguishing epidemiological factors or exposures.
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Despite my initial concerns for infectious
meningoencephalitis, the negative stains, serologies, and cultures of the blood, CSF, and lymph
nodes in the setting of a normal immune system
and no suspect exposure substantially lower this
probability. Arthropod-borne viruses are still possible, especially West Nile virus, because the serological tests are less sensitive early in the illness,
acknowledging that the absence of fever, weakness, and known mosquito bites detracts from this
diagnosis. Pathogens that cause regional lymphadenopathy and encephalitis such as Bartonella
remain possibilities, as the history of exposure to
a kitten can be easily overlooked.
Rheumatologic disorders merit close attention
in a young woman, but the negative ANA makes
lupus cerebritis unlikely, and the 2 angiograms did
not detect evidence of vasculitis. Finally, there is
the question of malignancy and other miscellaneous infiltrative disorders (such as sarcoid), which
are of importance here because of the multifocal
cortical involvement on imaging.
At this point, I would resample the CSF for viral etiologies (eg, West Nile virus) and cytology
and would send serum Bartonella serologies. If
these studies were negative, a brain biopsy, primarily to exclude malignancy but also to uncover
an unsuspected process, would be indicated. I
cannot make a definitive diagnosis or find a perfect fit here, but in the absence of strong evidence
of an infection, I am concerned about a malignancy, perhaps a low-grade primary brain tumor.
Brain biopsy of the leptomeninges and cortex of
the left parietal lobe showed multiple blood vessels
infiltrated by lymphocytes, neutrophils, and eosinophils (Fig. 2). The pattern of inflammation was
consistent with primary angiitis of the central
nervous system (PACNS). The patient received 1 g of
intravenous methylprednisolone on 3 consecutive
days, followed by oral prednisone and cyclophosphamide. The seizures ceased, and she made steady
progress with rehabilitation therapy. Four months
after discharge a cerebral angiogram (done to
ensure there was no interval evidence of vasculitis
prior to tapering therapy) demonstrated patency of
all major intracranial arteries and venous sinuses.

COMMENTARY
When a patient presents with symptoms or signs
referable to the central nervous system (CNS),

TABLE 1
Systemic Diseases That Cause CNS Vasculopathy
Infection: Viruses (HIV, varicella-zoster virus, hepatitis C virus), syphilis, Borrelia
burgdorferi, Bartonella, Mycobacterium tuberculosis, fungi (Aspergillus,
Coccidioides), bacteria.
Autoimmune: Polyarteritis nodosa, Wegener’s granulomatosis, temporal arteritis,
cryoglobulinemic vasculitis, lupus vasculitis, rheumatoid vasculitis.
Toxins: Amphetamine, cocaine, ephedrine, heroin.
Malignancy: Primary CNS lymphoma, angioimmunoproliferative disorders,
infiltrating glioma.

FIGURE 2. Biopsy of the leptomeninges and cortex of the left parietal lobe
showed multiple blood vessels infiltrated by lymphocytes, neutrophils, and
eosinophils consistent with PACNS.

hospitalists must simultaneously consider primary
neurologic disorders and systemic diseases that
involve the CNS. Initial evaluation includes a thorough history and physical examination, basic lab
studies, routine CSF analysis, and neuroimaging
(often a CT scan of the head). Complicated neurologic cases may warrant more elaborate testing
including EEG, brain MRI, cerebral angiography,
and specialized blood and CSF studies. Clinicians
may still find themselves faced with a patient who
has clear CNS dysfunction but no obvious diagnosis despite an exhaustive and expensive evaluation. Several disorders match this profile including
intravascular lymphoma, prion diseases, paraneoplastic syndromes, and cerebritis. Primary angiitis
of the central nervous system (PACNS), a rare disorder characterized by inflammation of the medium-sized and small arteries of the CNS, is
among these disorders. Although the aforementioned diseases may sometimes have suggestive or
even pathognomonic features (eg, the ‘‘string of
beads’’ angiographic appearance in vasculitides),
they are challenging to diagnose when such findings
are absent.
Like any vasculitis of the CNS, PACNS may
present with a wide spectrum of clinical features.1–2 Although headache and altered mental
status are the most common complaints, paresis,
seizures, ataxia, visual changes, and aphasia have
all been described. The onset of symptoms ranges

from acute to chronic, and neurologic deficits can
be focal or diffuse. Systemic manifestations such
as fever and weight loss are rare. The average age
of onset is 42 years, with no significant sex
preponderance. The histopathology of PACNS is
granulomatous inflammation of arteries in the parenchyma and leptomeninges of the brain and
less commonly in the spinal cord. The narrowing
of the affected vessels causes cerebral ischemia
and the associated neurologic deficits. The trigger
for this focal inflammation is unknown.
After common disorders have been excluded
in cases of CNS dysfunction, compatible CSF findings and imaging results may prompt consideration of PACNS. CSF analysis in patients with
PACNS typically demonstrates a lymphocytic pleocytosis. MRI abnormalities in PACNS include multiple infarcts in the cortex, deep white matter, or
leptomeninges.3–4 Less specific findings are contrast enhancement in the leptomeninges and
white matter disease, both of which may direct
the site for meningeal and brain biopsy.
Both brain MRA and cerebral angiography
have a limited role in the diagnosis of vasculitis
within the CNS. In 18 patients with CNS vasculitis
due to autoimmune disease, all had parenchymal
abnormalities on MRA but only 65% had evidence
of vasculitis on angiography. In 2 retrospective studies of patients with suspected PACNS, abnormal
angiograms had a specificity less than 30% for
PACNS, whereas brain biopsies had a negative
predictive value of 70%.5–7 Although in practice
patients with compatible clinical features are
sometimes diagnosed with CNS vasculitis on the
basis of angiographic findings, brain biopsy is
necessary to differentiate vasculitis from other vasculopathies and to establish a definitive diagnosis.
Before a diagnosis of PACNS is made, care
must be taken to exclude infections, neoplasms,
and autoimmune processes that cause angiitis of
the CNS (Table 1). The presence of any extracraDiagnosis of Exclusion / Yung, Baudendistel, and Dhaliwal

165

nial abnormalities (which were not present in this
case) should prompt consideration of an underlying systemic disorder causing a secondary CNS
vasculitis and should cast doubt on the diagnosis
of PACNS. Meningovascular syphilis and tuberculosis are among the long list of infections that
may cause inflammation of the CNS vasculature.
Autoimmune disorders that may cause vasculitis
inside the brain include polyarteritis nodosa and
Wegener’s granulomatosis. Reversible cerebral
vasoconstrictive disease, which is most commonly
seen in women ages 20 to 50, and sympathomimetic toxins such as cocaine and amphetamine
may exhibit clinical and angiographic abnormalities indistinguishable from PACNS.8–9
There are no prospective trials investigating
PACNS treatment. Aggressive immunosuppression
with cyclophosphamide and glucocorticoids is the
mainstay of treatment. The duration of treatment
varies with the severity of the disease and response
to therapy. One study suggests that treatment
should be continued for 6 to 12 months.10 Neurologic deficits may remain irreversible because of scarring of the affected vessels. Serial brain MRI
examinations are often used to follow radiographic
resolution during and after the therapy, although
radiographic changes do not predict clinical
response.11 New abnormalities on MRI, however,
delay any tapering of treatment. The availability
of neuroimaging studies and immunosuppressive
therapy has improved the prognosis of PACNS. One
study reported a favorable outcome with a 29%
relapse rate and a 10% mortality rate in 54 patients
over a mean follow-up period of 35 months.12
PACNS remains a challenging diagnosis
because of its rarity, the wide range of neurologic
manifestations, and the difficulty in establishing a
diagnosis noninvasively. It is an extremely uncommon disease but should be considered in patients
with unexplained neurologic deficits referable to
the CNS alone after an exhaustive workup. Ultimately, the diagnosis is made by a thorough history
and physical examination, exclusion of underlying
conditions (particularly systemic vasculitides and
infections), and histological confirmation.
Key Points for Hospitalists
1. Serious disorders that may present with CNS
abnormalities and nondiagnostic abnormal findings
on lumbar puncture, brain MRI, and cerebral angi-

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Journal of Hospital Medicine Vol 3 / No 2 / Mar/Apr 2008

ography include intravascular lymphoma, prion diseases, cerebritis, paraneoplastic syndromes, and
CNS vasculitis.
2. PACNS is a challenging diagnosis with varied clinical features and often normal angiographic findings. In particular, the specificity of brain MRA and
cerebral angiography is low. Although PACNS is
rare, it should be on the differential diagnosis, as
the condition is fatal without prompt treatment.
3. A diagnosis of PACNS is made only after excluding
secondary causes of CNS vasculitis such as infections, malignancies, autoimmune conditions, reversible cerebral vasoconstrictive disease, and
medications. The diagnosis is confirmed with a biopsy of the brain and meninges.
Address for correspondence and reprint requests: Iris Yung, MD, Department
of Medicine, California Pacific Medical Center, 2351 Clay Street, Suite 380, San
Francisco, CA 94115; Fax: (415) 775-7437; E-mail: iris_yung@yahoo.com
Received 21 June 2007; revision received 8 September 2007; accepted 24
September 2007.

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