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Central Nervous System Pneumocystosis in a Patient with AIDS
John A. Bartlett and Christine Hulette
From the Department of Medicine and the Department of Pathology,
Duke University Medical Center, Durham, North Carolina
Extrapulmonary involvement with Pneumocystis carinii has been described in 0.5% – 2.5% of
persons with AIDS. One hundred nine patients with AIDS and confirmed extrapulmonary pneumocystosis were identified, and seven of these patients (including our patient) had central nervous
system (CNS) pneumocystosis. Of these seven patients, six had prior AIDS-related complications,
and three had previous P. carinii pneumonia. Six patients had CNS symptoms, one of whom
underwent a focal neurological examination. No cases were diagnosed before death. The involved
sites were the cerebral cortex (2 patients), meninges (2), pituitary gland (1), putamen (1), and
nonspecified locations (3). In two patients, organisms were seen around blood vessels, and in five
patients there was concurrent neuropathology. In summary, CNS involvement with P. carinii usually
occurs as a late complication of AIDS and probably represents hematogenous dissemination.
Infection with Pneumocystis carinii remains a common complication in patients with AIDS. P. carinii pneumonia (PCP)
continues to be the initial AIDS-related manifestation in 25%
of patients and occurs in ú50% of patients before they die
[1]. P. carinii infections may extend beyond the lungs, and
extrapulmonary pneumocystosis has been described in 0.5% –
2.5% of persons with AIDS [2, 3].
We recently cared for a woman with AIDS in whom clinically unsuspected CNS pneumocystosis was discovered at
autopsy. We report her case and review the literature on
extrapulmonary pneumocystosis with an emphasis on CNS
involvement.
Case Report
In March 1991, a 41-year-old woman was admitted to Duke
University Medical Center (Durham, NC) because of profound
headache and cough. Culture of her CSF yielded Cryptococcus
neoformans, and she was then discovered to be HIV-seropositive (initial absolute CD4/ lymphocyte count, 51/mm3). An
MRI revealed an increased signal in the region of her left basal
ganglia and in her white matter, which was believed to be due
to HIV encephalitis or cryptococcal infection.
She was treated with amphotericin B and flucytosine followed by oral fluconazole; she also received trimethoprimsulfamethoxazole (TMP-SMZ) as prophylaxis for PCP. She
soon developed a diffuse erythematous rash that resolved after
discontinuation of TMP-SMZ therapy; she began monthly
treatment with aerosolized pentamidine (300 mg). In May 1992,
following introduction of contrast medium, a CT scan of the
head showed a new area of hypodensity without enhancement
Received 7 December 1995; revised 15 January 1997.
Reprints or correspondence: Dr. John A. Bartlett, Box 3238, Duke University
Medical Center, Durham, North Carolina 27710.
Clinical Infectious Diseases 1997;25:82–5
q 1997 by The University of Chicago. All rights reserved.
1058–4838/97/2501–0011$03.00
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in the left caudate nucleus and anterior limb of the internal
capsule, which was believed to be compatible with encephalomalacia due to her past inflammatory process or ischemic
changes.
In July 1992, she was admitted to our center because of
proven PCP, and therapy with TMP-SMZ was started again.
She developed a recurrent rash and then received a 3-week
course of treatment with dapsone and trimethoprim. She resumed monthly therapy with aerosolized pentamidine. In August 1993, she developed disseminated Mycobacterium avium
complex infection, and in March 1994, she developed cytomegalovirus retinitis. In April 1994, she complained of cough, and
a chest roentgenogram revealed a right-upper-lobe infiltrate.
She was treated empirically for recurrent PCP with oral atovaquone for 6 weeks, and her clinical condition improved. During
the summer of 1994, her clinical condition deteriorated, and
she received palliative care. She died on 23 September 1994,
and an autopsy was performed.
Autopsy results. The general autopsy revealed severe necrotizing pneumonia with multiple abscesses and extensive vascular invasion by Aspergillus species. There were multiple septic infarcts containing Aspergillus in both kidneys. Examination
of the eyes showed cytomegalovirus retinitis bilaterally with
retinal degeneration. No Pneumocystis organisms were identified outside of the CNS, despite Grocott-Gomori methenamine – silver nitrate staining of samples from all major organs.
The fresh brain weighed 918 g. The meninges over the superior parietal lobe were cloudy. The brain was sectioned in 1cm slices in a coronal fashion. There was a 0.9-cm cystic defect
in the anterior limb of the left internal capsule, and no other
gross lesions were found. Examination of the cyst showed
subacute infarction characterized by a macrophage infiltrate
with adjacent severe gliosis and edema.
Grocott-Gomori methenamine – silver nitrate staining of the
perivascular space of a juxtaposed blood vessel demonstrated
Pneumocystis organisms. In the adjacent putamen, areas of
vacuolation with a bubbly appearing neuropil that was most
pronounced around blood vessels were seen in virtually every
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CNS Pneumocystosis and AIDS
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Figure 1. Photomicrograph revealing focal
edema and vacuolation ( arrows ) of the neuropil in the basal ganglia of a patient with
AIDS and CNS pneumocystosis. Note the
small cystlike spaces in the vicinity (hematoxylin-eosin/luxol fast blue stain; original magnification 1 130).
section (figure 1). Grocott-Gomori methenamine – silver nitrate
staining of the vacuolated space demonstrated many Pneumocystis organisms (figure 2). Pneumocystis organisms were also
seen in the meninges and adjacent to an area of acute hemorrhage in the caudate nucleus. Multiple areas of ischemic damage characterized by tissue edema, reactive astrocytosis, and a
scanty macrophage infiltrate were associated with perivascular
accumulations of Pneumocystis organisms. In addition, pallor
of cerebral myelin and severe myelopathy of the posterior white
columns (findings consistent with HIV encephalopathy and my-
elopathy) were found. Pneumocystis organisms were not seen
in the cerebral myelin or the posterior white columns.
Literature Review
A search of the English-language literature from 1981 to
1995 was performed to identify reports or reviews of cases
of histologically confirmed extrapulmonary pneumocystosis.
These cases were reviewed for the sites of P. carinii infection,
and the cases of patients with CNS pneumocystosis were reviewed in greater detail.
Results
Figure 2. Photomicrograph of the same area in figure 1 at a higher
magnification; characteristic boat-shaped Pneumocystis organisms are
demonstrated ( arrow ) (Grocott-Gomori methenamine – silver nitrate
stain; original magnification, 1 680).
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One hundred eight cases of extrapulmonary pneumocystosis
were reported in the literature. The sites of documented extrapulmonary pneumocystosis included the liver (41% of cases),
spleen (34%), lymph nodes (28%), thyroid gland (23%), kidneys (19%), bone marrow (18%), adrenal glands (15%), eyes
(11%), and others.
Nervous system localization was documented in seven cases
(6%), including CNS pneumocystosis in six cases and involvement of ganglia in the sympathetic nervous system in one case.
The six patients with CNS involvement [3 – 8] and our patient
are described in table 1. Of these seven patients, six had a
history of at least one AIDS-related clinical complication, and
five had at least two prior AIDS-related clinical complications.
Three patients had a history of PCP. Five patients (71%) were
receiving aerosolized pentamidine prophylaxis, and two (29%)
were not receiving any prophylaxis.
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CID 1997;25 (July)
Table 1. Summary of data on CNS pneumocystosis in seven patients.
[Reference],
age (y)/sex
AIDS-related
complication(s)
Risk behavior
[4], 40/M
Homosexual
KS, cryptococcosis,
CMV retinitis,
Staphylococcus aureus
sepsis, recurrent
bacterial respiratory
tract infections
Four prior episodes of
PCP
[5], 26/M
Transfusion
[3], 33/M
Homosexual
[6], 41/M
Homosexual
KS, candidal esophagitis,
CMV retinitis, MAC
infection, three prior
episodes of PCP
Cryptococcosis
[7], 30/M
IDU
None
[8], 32/M
Homosexual
[PR], 45/F
HSP
Cryptococcosis, CMV
retinitis
Cryptococcosis,
Mycobacterium
kansasii and MAC
infections, CMV
retinitis, aspergillus
pneumonia, two prior
episodes of PCP
Extra-CNS
isolation of
Pneumocystis
CNS localization
of Pneumocystis
Concurrent
neuropathology
Symptoms
Clinical course
Progressive confusion
and withdrawal, severe
dyspnea, decreased
urinary output
Cerebral atrophy by head
CT, no aggressive
measures, death
Lungs, widely
disseminated
Virchow-Robin
spaces,
surrounding
rare cortical
arterioles
HIV encephalopathy
Dry gangrene of toes, no
neurological
symptoms
Lethargy, substernal
chest pain
Sudden death
Lungs, widely
disseminated
Not specified
None
Respiratory insufficiency,
DIC, hypotension,
death
Lungs, widely
disseminated
Pituitary gland
None
Headache, nausea, fever,
cough
Headache, somnolence,
disorientation, fever,
left-leg paresis
Declining mental status,
fever
Declining mental status,
generalized weakness
Sudden death
None
Cryptococcosis
Initial improvement then
bronchopneumonia,
death
Progressive respiratory
insufficiency, death
Progressive clinical
deterioration, death
Lungs
Cerebral cortex
and meninges
Four abscesses
Lungs, widely
disseminated
None
Toxoplasma gondii
infection
Not specified
Cryptococcosis
Putamen around
blood vessels,
meninges over
right parietal
lobe
HIV encephalopathy,
meningeal fibrosis
NOTE. CMV Å cytomegalovirus; DIC Å disseminated intravascular coagulation; HSP Å heterosexual partner of HIV-infected person; IDU Å injecting drug user; KS Å Kaposi’s
sarcoma; MAC Å Mycobacterium avium complex; PR Å present report.
Six patients had potential CNS symptoms, including confusion, disorientation, headache, somnolence, and nausea. Three
patients had fever. One patient had a left-leg paresis at the time
of neurological examination. Two patients underwent CT of
the head; it revealed cerebral atrophy in one patient and abnormalities in one 2 years before Pneumocystis was discovered
at the corresponding sites. No patients underwent lumbar
puncture.
CNS pneumocystosis was not suspected in any of the patients before death. At autopsy, five patients (71%) had concurrent PCP, and four (57%) had widely disseminated pneumocystosis. The involved neuroanatomic locations included
the cerebral cortex (2 patients), meninges (2), pituitary gland
(1), putamen (1), and nonspecified locations (3). In two patients, organisms were seen around blood vessels. In five
patients (71%), there was concurrent neuropathology: HIV
encephalopathy (2 patients), cryptococcosis (2), toxoplasma
abscesses (1), and meningeal fibrosis from treated cryptococcal meningitis (1).
Discussion
Dissemination of Pneumocystis beyond the lungs may involve local areas such as the chest and distant sites, a pattern
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suggesting both lymphatic and hematogenous spread. Numerous reports have documented the predilection of P. carinii for
vascular involvement [2, 5, 8 – 24]. Pneumocystis organisms
have been found to cause vasculitis within the vasa vasorum of
the aorta and within the lumina of small arterioles. In addition,
cocultivation of peripheral blood lymphocytes and PCR amplification of organism-specific nucleic acid have suggested that
P. carinii is present in the bloodstream of patients with PCP
and disseminated disease [25 – 27].
CNS pneumocystosis has now been described in seven patients. Six patients had a history of previous opportunistic infections, including three with a history of PCP. Potential neurological symptoms were present in six patients, but only one had
focal abnormalities at the time of neurological examination. A
head CT of one patient revealed cerebral atrophy, and a head
CT of our patient showed focal abnormalities 2 years before
P. carinii was discovered at the corresponding sites during
autopsy. It is possible that our patient had chronic CNS infection with Pneumocystis that was partially controlled but not
cured by treatment with dapsone and trimethoprim and with
atovaquone.
In two patients with CNS pneumocystosis, organisms were
identified in perivascular spaces. These observations further
support the role of hematogenous dissemination in extrapulmo-
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CNS Pneumocystosis and AIDS
nary pneumocystosis. CNS pneumocytosis was associated with
other active neurological infections in five patients and with
healed cryptococcal meningitis in one patient. It is possible
that these infections may cause alterations in the local vascular
architecture and flow, with the subsequent localization of
P. carinii in the CNS during the hematogenous phase.
Two patients died suddenly, and five patients’ clinical conditions progressively deteriorated before their deaths. CNS pneumocystosis was clinically unsuspected in all patients, and it was
discovered only at autopsy. In most patients (four of seven),
P. carinii had widely disseminated. The contribution of CNS
pneumocystosis to their deaths is uncertain given their comorbid illnesses, and the clinical significance of CNS pneumocystosis remains to be determined.
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