CHEST

Postgraduate Education Corner
PULMONARY AND CRITICAL CARE PEARLS

A 46-Year-Old Man With Seizures, Brain
Lesions, and Pulmonary Infiltrates
Rachel L. Zemans, MD; Amanda R. Stream, MD; Ali I. Musani, MD, FCCP;
and Gurpreet Dhaliwal, MD

CHEST 2012; 141(1):265–269

man with no medical history presented
A 44-year-old
with multiple new-onset seizures during 1 week.

He denied tobacco, alcohol, or illicit drug use. He
worked for 15 years spraying pesticides and herbicides
on farms. On presentation, the patient was actively
seizing. He was treated with antiepileptic medications and intubated for airway protection.
Physical Examination
His vital signs were normal. Physical examination
was unremarkable except for crackles at the lung

bases. Neurologic examination was limited by sedation. The WBC count was 14,100/mL, and the remainder of his CBC, electrolytes, and renal and liver
function results were normal. MRI of the brain
showed multiple lesions in the right occipital lobe,
left temporal lobe, and bilateral frontal and parietal
lobes (Fig 1).
Laboratory Findings
A transesophageal echocardiogram was negative
for vegetations and shunt. Blood cultures were negative. Chest radiograph revealed atelectasis vs consolidation at the lung bases. CT scan of the chest is shown

Figure 1. A, B, Two views of a brain MRI demonstrating multiple focal white matter lesions with some
cortical involvement.
Manuscript received June 4, 2011; revision accepted June 16, 2011.
Affiliations: From the Department of Medicine (Drs Zemans
and Musani), National Jewish Health, Denver, CO; Department
of Medicine (Drs Zemans, Stream, and Musani), University of
Colorado Denver, Aurora, CO; and Department of Medicine (Dr
Dhaliwal), San Francisco VA Medical Center, and Department of
Medicine (Dr Dhaliwal), University of California San Francisco,
San Francisco, CA.
Funding/Support: This work was supported by the National
Institutes of Health [grant HL103772] (to Dr Zemans).
www.chestpubs.org

Correspondence to: Rachel L. Zemans, MD, Department of
Medicine, National Jewish Health, 1400 Jackson St, #A555,
Denver, CO 80206; e-mail: ZemansR@NJHealth.org
© 2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (http://www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.11-1397
CHEST / 141 / 1 / JANUARY, 2012

265

Figure 4. Chest radiograph 2 weeks later showing resolution of
the lower-lobe consolidation.

Figure 2. A, Chest CT scan demonstrating patchy ground glass
in the upper lobes bilaterally. B, Chest CT scan demonstrating
consolidation in the lower lobes bilaterally.

in Figure 2, and abdominal CT scan was normal.
BAL cultures were negative, and no malignant cells
were present. Brain biopsy specimen revealed an
abscess with numerous branching, filamentous bacteria consistent with Nocardia species (Fig 3). HIV
antibody was negative, and immunoglobulin levels
were normal.
The patient was treated with a 1-year course of
trimethoprim/sulfamethoxazole for cerebral nocardiosis, a 14-day course of amoxicillin/clavulanate
for aspiration pneumonia, and antiepileptics. Chest
radiograph 2 weeks later showed resolution of the
lower lobe consolidation (Fig 4). One year later, MRI

Figure 3. A, Brain biopsy specimen demonstrating an abscess with central necrosis and surrounding multinucleated giant cells (hematoxylineosin stain, original magnification 3 20). B, Brain biopsy specimen demonstrating numerous branching, filamentous bacteria consistent with
Nocardia species within the necrotic center (Grocott methenamine silver, original magnification 3 60).
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Postgraduate Education Corner

Figure 5. Chest CT scan demonstrating upper-lobe airspace
opacities increased but in the same distribution as 1 year prior
and now accompanied by septal thickening in a “crazy paving”
pattern.

revealed resolution of the brain lesions, but dyspnea
and cough productive of white sputum developed in
the patient. His oxygen saturation was 94% on room
air, and lungs were clear to auscultation. Pulmonary
function testing revealed normal lung volumes and
flows and a diffusing capacity of 78% predicted.
Chest CT scan is shown in Figure 5.
What is the diagnosis?

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Diagnosis: Pulmonary alveolar proteinosis

Discussion
BAL revealed milky fluid containing periodic acidSchiff (PAS)-positive proteinaceous material with
foamy macrophages, confirming the diagnosis of pulmonary alveolar proteinosis (PAP). Anti-granulocyte
macrophage colony-stimulating factor (GM-CSF)
antibodies were detected in the serum at 116.7 mg/mL
(normal, , 3 mg/mL). PAP is a rare disease caused
by abnormal accumulation of surfactant in the lung.
It presents with the insidious onset of shortness of
breath sometimes accompanied by cough, weight
loss, and fatigue. Physical examination may be normal, or mild crackles may be present. The subtle and
nonspecific signs and symptoms often lead to delayed
diagnosis. Pulmonary function testing may reveal mild
restrictive disease with a decreased diffusing capacity.
Chest radiograph typically reveals bilateral, patchy
alveolar filling but is insensitive for detecting mild
disease. CT scan findings include patchy ground glass
with superimposed thickened interlobular septae,
resulting in a “crazy paving” pattern. The diagnosis
may be made from BAL fluid, which is milky, reflecting the presence of lipoproteinaceous material that
is PAS positive and contains foamy macrophages.
Open lung biopsy specimens reveal PAS-positive
proteinaceous material in the airspaces with normal
alveolar septae.
PAP is classically divided into three subgroups
based on the pathogenesis of disease: primary, congenital, and secondary. The most common form in
adults is primary (or autoimmune) PAP, which is
caused by neutralizing antibodies against GM-CSF.
These antibodies impair macrophage development,
leading to decreased catabolism of surfactant. Congenital PAP is caused by mutations in the genes for
surfactant proteins or GM-CSF receptors. Secondary PAP develops in the setting of underlying
conditions, including hematopoietic malignancies
and immunodeficiency syndromes, both of which
may be associated with a functional macrophage
deficiency. PAP due to inhalational exposures also
is categorized as secondary PAP, although some have
challenged the classic distinction between primary
(autoimmune) PAP and secondary (antibody negative) PAP due to occupational exposures, reasoning
that inhalational agents may expose sequestered
antigens and trigger autoimmunity. For instance,
this patient was likely predisposed to autoantibody
development and PAP by exposure to insecticides, an
association which has been previously reported.
The anti-GM-CSF antibodies that develop in primary PAP impair the antimicrobial functions of mac268

rophages and neutrophils, leading to susceptibility
to opportunistic infections, including endemic fungi,
mycobacteria, and classically, Nocardia species.
Nocardia infection usually develops in the lungs in
the setting of previously diagnosed PAP. However, the
initial clinical manifestation of PAP can be Nocardia
infection; isolated CNS nocardiosis has been reported
in patients with PAP as well.
Although spontaneous resolution of PAP is
described, most patients are treated with physical
removal of the lipoproteinaceous material through
large-volume lung lavage. Whole-lung lavage is highly
effective in improving symptoms, oxygenation, and
radiographic infiltrates, and likely has a survival benefit; however, symptoms and infiltrates often recur,
and repeat lavages may be necessary. Autoimmune
PAP can be treated with inhaled GM-CSF, which is
effective in ⵑ 69% of patients and generally is well
tolerated. Secondary PAP usually responds to treatment of the underlying disease. The overall prognosis
of primary PAP is favorable because the disease typically becomes quiescent to the extent that continued
therapy is not necessary. Occasionally, pulmonary
fibrosis may develop. The overall 5-year survival rate
of primary PAP is upwards of 90%, but mortality is
well described from PAP and its complications,
such as CNS nocardiosis, which itself carries a mortality rate of up to 44%.
Clinical Course
The extended course of this case demonstrates both
the characteristic features of PAP and the challenges
in making the diagnosis and, therefore, merits brief
discussion. When the patient presented with seizures
and brain lesions, a thorough search for embolic
and metastatic disease (echocardiogram, full-body
CT scan, and bronchoscopy) was undertaken. The
initial brain biopsy specimen findings of nocardiosis
prompted consideration of predisposing conditions
and a pulmonary portal of entry, but given the absence
of immunodeficiency and negative BAL cultures, the
pulmonary infiltrates were reasonably attributed to
a postseizure aspiration pneumonia. Treatment was
directed accordingly, and apparent radiographic
improvement supported this working diagnosis. The
clinical presentation of symptomatic airspace disease
1 year later provided strong evidence that a chronic
pulmonary process was present and forced the clinicians to revisit the previously constructed causeand-effect sequence. The repeat presentation—now
textbook in its features—allowed the treating physicians to recognize that PAP was the underlying condition that explained the patient’s multisystem illness.
The patient underwent whole-lung lavage after
the clinical and radiographic manifestations of the
Postgraduate Education Corner

disease progressed further. His symptoms, infiltrates,
and diffusing capacity improved, and he was maintained on inhaled GM-CSF.
Clinical Pearls

Suggested Readings

1. The insidious onset and the subtle signs,
symptoms, pulmonary function, and chest radiograph findings of PAP may result in a delay in
diagnosis.
2. In PAP, autoantibodies to GM-CSF impair macrophage function, leading to both a defect in surfactant clearance and impaired host defense, which
predisposes to opportunistic infections, such as
nocardiosis.
3. Patients with PAP may present with infection;
PAP should be considered in the search for predisposing conditions in a patient with nocardiosis or other
opportunistic infections.
4. The classic distinction between primary (autoimmune) PAP and secondary (antibody negative)
PAP due to occupational exposures can be misleading because inhaled toxins may expose sequestered antigens and trigger autoimmunity.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be discussed in this article.

www.chestpubs.org

Role of sponsors: The sponsor had no role in the design of the
study, the collection and analysis of the data, or in the preparation
of the manuscript.
Other contributions: We thank James Ellis, MD, and Dennis
Lyu, MD, for thoughtful discussions.

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