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NEUROLOGY BOARD REVIEW MANUAL
STATEMENT OF
EDITORIAL PURPOSE
The Hospital Physician Neurology Board Review
Manual is a study guide for residents and
practicing physicians preparing for board
examinations in neurology. Each quarterly
manual reviews a topic essential to the current practice of neurology.
PUBLISHING STAFF
PRESIDENT, GROUP PUBLISHER
Bruce M. White
EDITORIAL DIRECTOR
Debra Dreger
ASSOCIATE EDITOR
Rita E. Gould
EXECUTIVE VICE PRESIDENT
Barbara T. White
CNS Infections in Solid
Organ Transplant
Recipients
Editor:
Catherine Gallagher, MD
Assistant Professor of Neurology, University of Wisconsin Movement
Disorders Program, Staff Physician, Middleton VA Hospital,
Madison, WI
Contributor:
Jeannina A. Smith, MD
Fellow, Division of Infectious Diseases, Department of Medicine,
University of Wisconsin, Madison, WI
EXECUTIVE DIRECTOR
OF OPERATIONS
Jean M. Gaul
Table of Contents
PRODUCTION DIRECTOR
Suzanne S. Banish
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
PRODUCTION ASSISTANT
Kathryn K. Johnson
ADVERTISING/PROJECT MANAGER
Patricia Payne Castle
SALES & MARKETING MANAGER
Deborah D. Chavis
NOTE FROM THE PUBLISHER:
This publication has been developed without
involvement of or review by the American
Board of Psychiatry and Neurology.
Risk of CNS Infection in Transplant
Recipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Clinical Approach to Suspected CNS
Infection in Transplant Recipients . . . . . . . . . . . 4
Agents of CNS Infection in Transplant
Recipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Case Examples . . . . . . . . . . . . . . . . . . . . . . . . . 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Endorsed by the
Association for Hospital
Medical Education
Cover Illustration by Kathryn K. Johnson
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Neurology Volume 9, Part 3 1
NEUROLOGY BOARD REVIEW MANUAL
CNS Infections in
Solid Organ Transplant Recipients
Jeannina A. Smith, MD
INTRODUCTION
With advances in medical care, the number of immunosuppressed patients increases annually, particularly the number of solid organ transplant recipients.
Whereas end-organ dysfunction was once a death sentence, solid organ transplantation now offers a lifesaving option to tens of thousands of patients each year.
In 2004, more than 27,000 solid organ transplants
were performed, including 16,000 kidney, 6168 liver,
2016 heart, 1172 lung, 880 kidney-pancreas, 604 pancreas, 146 intestine, and 39 heart/lung transplants.1
Rapid growth in the use of solid organ transplantation
has necessarily led to advances in the care of patients
receiving transplants, which in turn has allowed for
increased patient and graft survival. For example, the
reported 3-year patient survival rates after transplantation between July 1999 and December 2001 were
87.61% for deceased donor kidney recipients, 93.98%
for living donor kidney recipients, 78.19% for deceased
donor liver recipients, 77.3% for living donor liver recipients, 61.17% for lung recipients, and 55.7% for
heart recipients.2
With greater understanding of the clinical care needs
of transplant recipients have come important lessons
about potential complications of organ transplantation.
These include iatrogenic complications (eg, surgical
misadventures, side effects of immunosuppressive
agents), exacerbation of underlying medical illness by
antirejection therapy (eg, worsening diabetic control
from corticosteroids, hypertension from calcineurin
inhibitors), and new or unusual manifestations of disease (eg, post-transplant lymphoproliferative disease,
transplant-associated infection). Indeed, each year new
information is revealed about unusual clinical presentations of bacterial, viral, and fungal pathogens in recipients of solid organ transplants. Another consequence of
the increase in solid organ transplantation is that medical care for transplant recipients is no longer reserved
for specialized centers. The prevalence of patients with
solid organ transplants mandates that all clinicians ac-
2 Hospital Physician Board Review Manual
quire the knowledge and skills needed to properly care
for these patients.
Neurologic complications are estimated to occur in
30% to 60% of patients after solid organ transplantation.3 – 5 Of these, infections of the central nervous system (CNS) are seen in 5% to 10%.6 The significant
morbidity and mortality from CNS infections in the
solid organ transplant recipient make it important that
all neurologists be able to diagnose these infections
early in the disease course and understand when special
methods for detection and isolation are needed. CNS
infections can be a difficult clinical problem in the
immunosuppressed transplant recipient, and the large
differential diagnosis in this setting can at times seem
daunting. The effects of immunosuppressive medications used after transplantation not only increase susceptibility to infection but also change the presentation
and diagnosis of the infection. However, a systematic
approach allows rapid narrowing to likely pathogens
and facilitates expeditious and accurate diagnosis.
RISK OF CNS INFECTION IN TRANSPLANT
RECIPIENTS
FACTORS INCREASING RISK OF INFECTION
Immunosuppression
Immunosuppression was first used in transplantation
in 1964 and was a combination of azathioprine and corticosteroids. At that time, 1-year renal allograft survival
rates were less than 60%.7 It was not until more than a
decade later, in 1978, that cyclosporine was used for
immunosuppression in solid organ transplant recipients.
Acute rejection rates and 1-year graft outcomes have
improved significantly since the introduction of cyclosporine.8 In the last 20 years, several new immunosuppressive agents and combination therapies have been
used in the induction and maintenance of transplant
immunosuppression and the treatment of rejection.
Newer immunosuppressive agents have dramatically
reduced the rates of acute graft rejection but also
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C N S I n f e c t i o n s i n S o l i d O r g a n Tr a n s p l a n t R e c i p i e n t s
appear to have exacerbated the problem of posttransplantation infections. For example, infection now
exceeds rejection as the precipitating factor in hospitalization of patients in the first 2 years after a solid organ
transplant.9 Indeed, among patients receiving a transplant in 1987, the rate of hospitalization for rejection
exceeded the hospitalization rate for infection in the
early (1–6 months) and later (6–24 months) posttransplantation periods.9 In contrast, among patients
who received transplants in 2000, the hospitalization
rate for infection was twice that for rejection during
both the early and later post-transplantation periods.9
It is well known that the intensity of immunosuppression changes the types and manifestations of opportunistic infections. All transplant patients undergo induction
immunosuppression, and for those patients who do not
ultimately experience graft rejection, induction immunosuppression represents the time of greatest immunocompromise. The period of induction immunosuppression
typically begins during the transplant procedure and
extends to the days and weeks following successful transplantation. Some newer induction methods call for administration of immunosuppressants, including monoclonal antibodies, before transplantation. In preparation
for the intense immune response to the foreign graft,
induction of immunosuppression usually includes agents
that blunt both B- and T-cell function.
After induction, immunosuppressants are tapered to
maintenance levels. Most contemporary maintenance
immunosuppression regimens involve 3 agents: a corticosteroid (prednisone, methylprednisolone), a calcineurin inhibitor (cyclosporine, tacrolimus), and a
nucleotide synthesis inhibitor (azathioprine, mycophenolate mofetil). Although dose, duration, and temporal
sequence of individual agents vary among transplant
centers, the level of immunosuppression generally
decreases with time in patients with an uncomplicated
post-transplantation course. However, in patients who
experience graft rejection or infection with an immunomodulating virus, immunosuppression may actually
exceed that given in the induction phase. These patients may receive very large doses of corticosteroids,
anti-lymphocyte preparations, and/or plasmapheresis
to reduce the immune assault on the graft. This treatment places the patient at high risk for infection.
Epidemiologic Exposures
Information about a transplant recipient’s epidemiologic exposures is important in determining which CNS
infections the patient may be at greatest risk of acquiring. Unfortunately, the donor’s exposures may also be
critical to diagnosing the infection. Obviously, epidemi-
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ologic risk in the donor is more difficult to discern, and
for this reason extensive questioning of donor next of
kin and medical evaluation are undertaken prior to
organ donation. However, even this extensive preparation sometimes does not reveal an infection that may be
transmitted with the donated organ, and retrospective
review of the donor medical record may be necessary for
deciphering the nature of the CNS process.
Epidemiologic risk in a solid organ transplant recipient is more complex than in the immunocompetent
patient. In the setting of intense immunosuppression,
the patient with a new organ transplant is at risk from
many sources. Examples of recently contacted pathogens (eg, infectious agents in the recipient’s community) that may cause clinically relevant CNS infection include food-borne agents such as Listeria. In the patient
with a solid organ transplant, contact with Listeria is likely to cause symptomatic infection soon after exposure.6,10,11 The transplant recipient is also usually at high
risk for infection by nosocomial pathogens. Many transplant patients spend a great deal of time in hospitals
and other medical care centers (eg, dialysis centers)
prior to and after transplantation and, thus, are at risk
for harboring or contacting drug-resistant and difficult
to treat pathogens.
Finally, the immunosuppressed patient is at risk for
reactivation of infection acquired in the distant past.
Exposure to the endemic fungi (eg, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum) may
cause disease with recent exposure or by reactivation of
latent disease from remote exposure.6,10,11 The same
holds true for the important CNS pathogen Mycobacterium tuberculosis.6 Although the host’s immune response can hold the pathogens at bay for many years,
the immunosuppression required to prevent transplant
rejection blunts the immune siege. This decreased
immune response amplifies the effects of these infections, increasing the risk of tissue invasion, dissemination, and superinfection.
In the solid organ transplant recipient, infection
with endemic fungi or M. tuberculosis can result in 3 patterns of disease manifestation: progressive primary infection, reactivation infection, and reinfection. Systemic
dissemination is common, and it is usually in this setting
that CNS disease is seen. These infections may all present as fever of unknown origin, progressive pneumonitis, or metastatic infection to such sites as the liver,
mucocutaneous surfaces, bones and joints, genitourinary tract, and CNS. As a result, the history must
include careful questioning about recent and remote
contacts and risk factors.11 For example, if fungal meningitis is suspected in a patient who has not lived in
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California since childhood, C. immitis should still be
included in the differential diagnosis, as this infection
can reactivate in the solid organ transplant recipient
many years after initial exposure.
Pretransplantation evaluation can be invaluable for
assessing the transplant recipient’s risk of reactivation
disease. This evaluation usually includes assessing for
tuberculosis risk factors as well as testing for latent
tuberculosis; serologic testing for endemic fungal disease and prior exposure to toxoplasmosis; and testing
for viral infections such as Epstein-Barr virus (EBV),
cytomegalovirus (CMV), herpes simplex virus (HSV),
and varicella-zoster virus (VZV). This may also be an
ideal time to minimize epidemiologic risk via immunization (while the patient is able to mount a superior
immune response prior to intense post-transplantation
immunosuppression) and targeted chemoprophylaxis
or treatment of latent infection.
INFECTION PROPHYLAXIS
Patients routinely receive prophylaxis for opportunistic infection after undergoing solid organ transplantation. The length and nature of prophylaxis varies
by patient risk and transplant center. Knowledge of the
type of prophylaxis a given patient has received is valuable in the work-up for suspected CNS infection.
The most effective prophylactic therapy is trimethoprim-sulfamethoxazole (TMP-SMX), prescribed as a
single-strength tablet containing 80 mg of trimethoprim
and 400 mg of sulfamethoxazole and taken daily for the
first 4 to 12 months after transplantation. The primary
objective of TMP-SMX prophylaxis is to prevent Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia,
a once-common post-transplantation infection in patients who did not receive prophylaxis. Routine use of
TMP-SMX also reduces other typical communityacquired infections (eg, urinary tract infection, urosepsis) as well as upper respiratory infections that may have
important CNS implications (eg, sinusitis, otitis). Additionally, TMP-SMX reduces the risk of infection with several other opportunistic CNS pathogens, such as Listeria
monocytogenes, Nocardia asteroides, and Toxoplasma gondii.
In transplant recipients receiving prophylaxis with TMPSMX, the incidence of CNS toxoplasmosis is low—
similar to that in patients with AIDS who are receiving
TMP-SMX prophylaxis.11
Other anti-infective agents are used prophylactically
in transplant recipients at highest risk for certain types
of infections but are not routinely offered to all patients
with a solid organ transplant. Treatment with acyclovir
is offered to reduce the risk of infection by HSV, VZV,
and EBV.12 Ganciclovir is used for patients at risk for
4 Hospital Physician Board Review Manual
early CMV disease. Antifungal prophylaxis is generally
offered only to patients at highest risk for fungal disease, such as high-risk liver transplant recipients.
CLINICAL APPROACH TO SUSPECTED CNS
INFECTION IN TRANSPLANT RECIPIENTS
CLINICAL PRESENTATION
The usual clinical presentation of a CNS infection
may be different in a patient with a solid organ transplant
than in an immunocompetent patient. As with any patient, in transplant recipients, CNS infections may be
associated with fever, headache, meningismus, newonset seizure, altered sensorium, and/or focal neurologic deficit. Because any or all of these manifestations may
be subtle or absent as a result of the anti-inflammatory
effects of immunosuppressants,13 the threshold should
be lower for suspecting CNS infection in the transplant
recipient who presents with 1 or more of these symptoms. The most reliable features that suggest CNS infection are unexplained fever with headache.13
FACTORS THAT NARROW THE DIFFERENTIAL DIAGNOSIS
Clinicians approaching a transplant recipient with
suspected CNS infection are often overwhelmed with
the broad differential diagnosis, thinking that the infectious agent “could be anything.” However, several clinical factors significantly narrow the differential diagnosis
and are important to understand when assessing such a
patient.
Time Frame of Transplant-Related Infection
Perhaps the most important factor is timing. The
time frame of transplant-related infections is classically
defined as early (perioperative period to 1 month posttransplantation), intermediate (1–6 months post-transplantation), or late (> 6 months post-transplantation)
(Figure 1). Deviations from the usual sequence of infections after transplantation suggest the presence of
unusual epidemiologic exposure or excessive immunosuppression. In times of intensified immunosuppression, such as while undergoing treatment of rejection,
the “clock” is reset and the patient is again at increased
risk for the same opportunistic pathogens as those seen
in the early post-transplantation period.14
Early post-transplantation period. It is a generally
held concept that early infections are the same as those
typically occurring in any postsurgical patient. As such,
wound infection, line sepsis, postoperative urinary tract
infection, and pneumonia are to be expected in this
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C N S I n f e c t i o n s i n S o l i d O r g a n Tr a n s p l a n t R e c i p i e n t s
Conventional
nosocomial
infections
Community-acquired or
persistent infections
Conventional or opportunistic infections
Viral
HSV
Onset of CMV
CMV retinitis or colitis
EBV, VZV (shingles), influenza, RSV, adenovirus
Papillomavirus, PTLD
Onset of hepatitis B or hepatitis C
Bacterial
Wound infections, catheter-related infections, pneumonia
Nocardia
Listeria, Mycobacterium tuberculosis
Fungal
Pneumocystis
Aspergillus
Cryptococcus
Candida
Geographically restricted, endemic fungi
Parasitic
Strongyloides
Toxoplasma
Leishmania
Trypanosoma cruzi
0
1
2
3
4
5
6
7
8
Months post-transplantation
Figure 1. Usual sequence of infections after organ transplantation. Zero indicates the time of transplantation, solid lines indicate the
most common period for the onset of infection, and dashed lines indicate periods of continued risk at reduced levels. CMV = cytomegalovirus; EBV = Epstein-Barr virus; HSV = herpes simplex virus; PTLD = post-transplantation lymphoproliferative disease; RSV =
respiratory syncytial virus; VZV = varicella-zoster virus. (Adapted with permission from Fishman JA, Rubin RH. Infection in organtransplant recipients. N Engl J Med 1998;338:1743. Copyright © 1998, Massachusetts Medical Society. All rights reserved.)
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period. Most cases of CNS infection in the early period
are caused by common bacterial pathogens (eg, gramnegative bacteria, staphylococcal species), often from
dissemination of one of the infectious processes mentioned earlier.5 Nosocomial meningitis, however, is not
common, and even postsurgical CNS infection is almost
exclusively seen in patients who have undergone a
neurosurgical procedure. However, a smaller number
of cases of CNS infection in the immediate posttransplantation period have been associated with excess
epidemiologic exposure, such as outbreaks of disseminated Aspergillus infection.14
Also in contrast to the general concept, there have
been several recent reports of unusual CNS infections
transmitted from donor to recipient that bear particular
consideration in the early post-transplantation period.
Although extremely rare, these infections are noteworthy, and all clinicians should be aware of their potential
occurrence. Donor-transmitted CNS infections may be
of 2 types: infections that were not symptomatic in the
donor but are unusual or unusually severe in the recipient as a direct result of intense induction immunosuppression, and infections that resulted in unrecognized
CNS disease, often even the death of the donor. Recent
examples include the transmission of lymphocytic
choriomeningitis (LCM) virus and West Nile virus
encephalitis to organ transplant recipients by infected
donors and a tragic case of rabies transmitted to 4 recipients of organs from a single donor (see pages 12 and 13
for further discussion). Any unexpected infectious syndromes in recipients of solid organ or tissue transplants
should raise concern about the possibility of transplantassociated transmission of an infectious agent. Providers
should alert the associated organ procurement organization, tissue bank, and public health authorities when
such events are suspected.
Intermediate post-transplantation period. Most classic opportunistic pathogens are seen during the intermediate period.14 This is also the time when immunomodulating viruses appear and begin to further perturb
the host immune response.6 The most prevalent and clinically important virus that alters the immune response is
CMV; however, the other human herpesviruses (HHVs)
as well as hepatitis viruses and HIV, if active in the early
post-transplantation period, can all produce significant
CNS as well as immunomodulatory effects.6 Interestingly,
these viral infections can also precipitate rejection.
Whether immunomodulating viruses are involved at the
onset or not, in the 5% to 10% of transplant recipients
who experience recurrent or chronic rejection,15 a chain
reaction of infections and rejection is often set into motion. Rejection, both acute and chronic, results in greater
6 Hospital Physician Board Review Manual
exposure to immunosuppressive agents, which often
facilitates the same chronic and immunomodulating
viral infections. Thus begins the downward spiral of infection precipitating more difficult to control rejection, precipitating more difficult to control infection, and so on.
The combination of increased immunosuppression and
viral infection places a patient at greatest risk for opportunistic infections. These include reactivation of infections previously controlled by the patient’s own immune
response as well as new infections by pathogens that
would not normally harm a person with an intact immune system in the absence of an excess epidemiologic
exposure (eg, L. monocytogenes, N. asteroides, Cryptococcus
neoformans, Aspergillus species).10,16
Late post-transplantation period. In most transplant
recipients, immunosuppressive therapy is tapered after
the first 6 months. This period is generally associated
with a decreased risk of opportunistic infection. However, it should be noted that most cases of progressive
multifocal leukoencephalopathy (PML) and cryptococcal meningitis occur 6 or more months after solid organ
transplantation.11
Clinical Syndrome
Classifying the CNS syndrome also helps to narrow
the field of potential pathogens in the transplant recipient with suspected CNS infection (Table). Although
many opportunistic agents can cause more than one
syndrome, defining the syndrome helps to assign likelihood of a specific pathogen for a given patient based on
the constellation of symptoms, risk factors, and preliminary testing. For example, Listeria, Cryptococcus, and
Aspergillus account for 90% of the nonviral CNS infections in renal transplant recipients; however, if focal neurologic deficits are present, the etiology is most likely
aspergillosis, toxoplasmosis, PML, or a fungal abscess.13
Meningitis. Meningitis in the transplant recipient
has 4 distinct types defined by length of symptoms.
Each type has a different clinical presentation and different likely etiologic agents. It must be emphasized,
however, that many of the expected features of meningitis may be absent or diminished in solid organ transplant recipients as the result of the anti-inflammatory
properties of transplantation immunosuppressants.
Acute bacterial meningitis typically presents as rapid
evolution of fever, headache, and meningeal signs over
the course of hours to days. In transplant recipients,
meningitis usually is caused by L. monocytogenes,2 although these patients are still at risk for the conventional culprits, including Streptococcus pneumoniae and
Neisseria meningitidis.
Subacute meningitis typically presents as fever and
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Table. Central Nervous System Syndromes and their Infectious Causes
Meningitis
Encephalitis
Acute
Herpes simplex virus (types 1 and 2)
Listeria monocytogenes
Streptococcus pneumoniae
Neisseria meningitides
Subacute
Cryptococcus neoformans
West Nile virus
Focal brain lesion
Aspergillus species
Zygomycetes
Mycobacterium tuberculosis
Bacteria (gram-positives, gram-negatives,
anaerobes)
L. monocytogenes
Candida species
Histoplasma capsulatum
C. neoformans
Nocardia asteroides
Endemic fungi
Strongyloides stercoralis
L. monocytogenes
Coccidioides immitis
Toxoplasma gondii
Epstein-Barr virus (EBV)*
N. asteroides
Candida species
EBV*
Chronic
M. tuberculosis
C. neoformans
M. tuberculosis
H. capsulatum
N. asteroides
Spirochetes
S. stercoralis
Progressive neurocognitive decline
Chronic meningitis
Progressive multifocal leukoencephalopathy
Herpes simplex virus
Cytomegalovirus
C. immitis
EBV*
Recurrent
Herpes simplex virus
L. monocytogenes
*EBV-associated post-transplantation lymphoproliferative disease.
headache evolving over several days to weeks and is
often associated with mental status changes. Although
most commonly caused by C. neoformans, several other
infectious agents also produce subacute meningitis,
especially with disseminated infection. These agents
include M. tuberculosis, L. monocytogenes, H. capsulatum,
N. asteroides, Strongyloides stercoralis, and C. immitis. EBVassociated post-transplantation lymphoproliferative disease can also produce a syndrome with a presentation
similar to subacute meningitis.14
Chronic meningitis may present as progressive neurocognitive decline and signs and symptoms of meningeal
inflammation over weeks to months. M. tuberculosis, H. capsulatum, N. asteroides, C. immitis, spirochetes, or chronic
viral infection may be implicated in chronic meningitis.
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Finally, recurrent meningitis may manifest as clearly
separate bouts of acute or subacute meningitis with
intervening periods of normalcy. Most cases of benign
recurrent aseptic meningitis (Mollaret’s meningitis) are
caused by HSV, especially HSV-2, although this has not
been studied specifically in patients with solid organ
transplants.17 Recurrent meningitis due to bacteria, including L. monocytogenes, has also been reported in
transplant recipients.18
Progressive neurocognitive decline. Progressive
neurocognitive decline or dementia, with or without
focal abnormalities or seizures, may be related to an
infectious process in the solid organ transplant recipient. As noted, some cases are secondary to chronic
meningitis. Progressive neurologic decline may also be
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related to an accelerated medical illness seen after
transplantation. For example, steroid-induced diabetes and hypertension predispose the transplant
recipient to premature cerebral vascular disease or
occasionally to demyelination or other toxic effects of
immunosuppressive medications such as cyclosporine
or tacrolimus. The most classically associated infection
causing this clinical syndrome is PML due to the JC
virus, a polyomavirus.11 However, progressive neurologic decline may be the result of other viral infections,
including HSV, CMV, EBV, and HIV infection.
Abscess. Focal CNS lesions may be infectious or noninfectious. Focal brain infections, often presenting as
seizures or focal neurologic abnormalities, have been
documented in 0.36% to 1% of solid organ transplant
recipients.19 It should be noted, however, that unlike
immunocompetent patients with a brain abscess, patients who are receiving transplantation immunosuppressants may not show evidence of a focal neurologic
defect and may present with only headache, fever, or
altered cognition.11 Aspergillus species are the most frequent causes of post-transplantation brain abscess.
Toxoplasma, Cryptococcus, Nocardia, L. monocytogenes, and
M. tuberculosis can also produce brain abscess.19 Aside
from those atypical bacteria just mentioned, bacteria
are only infrequently associated with brain abscess in
transplant recipients.19
Transplanted Organ
Finally, the specific organ that is transplanted can
influence the nature of infection in the transplant
recipient. Not all organs require the same depth of immunosuppression. For example, a lung transplantation
requires more intense immunosuppression than a renal
transplantation. Also, certain organs appear to be more
susceptible to infection by specific pathogens after
transplantation. For example, there is an association of
T. gondii infection with heart transplantation, Aspergillus
infection with lung transplantation, C. neoformans infection with liver transplantation, and resistant gramnegative infections with renal transplantation.11
DIAGNOSTIC EVALUATION
The diagnostic evaluation of the transplant recipient
with a suspected CNS infection must expeditiously pursue a definitive diagnosis, as the sequelae may be serious and the risk of a poor outcome increases with time.
The work-up should include sophisticated neuroimaging (eg, magnetic resonance imaging [MRI], computed
tomography [CT]), with and without a contrast agent if
at all possible. If signs and symptoms of infection are
present (eg, new-onset headache, fever, mental status
8 Hospital Physician Board Review Manual
change) or if symptoms are not explained by imaging
findings, a lumbar puncture should be performed if no
contraindication exists.
Cerebrospinal fluid (CSF) evaluation should include
cell count/differential, glucose, protein, Gram stain,
and bacterial culture in all patients. Other testing should
be dictated by the clinical presentation, the phase of
immunosuppression, and other clinical criteria previously discussed. Depending on the clinical circumstances, fungal staining and culture, Ziehl-Nielsen acidfast staining and mycobacterial culture, VDRL (Venereal
Disease Research Laboratories) testing, cryptococcal
antigen (CrAg) testing, West Nile IgM, and polymerase
chain reaction (PCR) assay (for HSV, EBV, CMV, VZV,
HHV-6, measles virus, BK virus/JC virus, or M. tuberculosis) may be diagnostic.
Occasionally, a diagnosis cannot be made via noninvasive or minimally invasive tests. Brain biopsy may be
required for a definitive diagnosis.11 In most cases, biopsy can be made less invasive using a stereotactic technique. If CNS herniation is imminent or the tempo of
disease progression is very rapid, open biopsy with surgical decompression may be preferred. Because most
focal CNS infections in transplant recipients are secondary to disseminated processes, cultures from other
tissues (eg, skin, lung, solid organ), pulmonary secretions (eg, sputum, bronchoalveolar lavage fluid, chest
tube drainage), or the blood may afford a diagnosis
without the need for brain biopsy.
AGENTS OF CNS INFECTION IN TRANSPLANT
RECIPIENTS
TYPICAL BACTERIA
Patients with solid organ transplants are at risk for
bacterial meningitis, which may be secondary to a
number of agents.
Listeria monocytogenes
Although an infrequent cause of illness in immunocompetent persons, L. monocytogenes is an important
cause of life-threatening infections, including sepsis
and meningoencephalitis, in solid organ transplant recipients. L. monocytogenes has tropism for the brain and
the meninges. Infection with L. monocytogenes often results in a diarrheal illness followed by meningitis in the
solid organ transplant recipient.
Clinical presentation and diagnosis. Meningitis is the
most common manifestation of L. monocytogenes infection, although meningoencephalitis, rhombencephalitis
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(encephalitis involving the brainstem), cerebritis, and
CNS abscess formation also may occur.20 The onset of
infection may be acute or subacute. The clinical picture
may include high fever, nuchal rigidity, movement disorders (eg, tremor, ataxia), and seizures. Indeed, seizures are seen more commonly in meningitis caused by
Listeria than in other types of meningitis. Patients with
listerial meningoencephalitis have subacute onset of
symptoms, which often include focal neurologic findings in the hindbrain (eg, ataxia) and may include multiple cranial nerve abnormalities. Fever may be absent or
go unnoticed in 15% of cases.20 CSF analysis may show a
negative Gram stain. Additionally, the Gram stain may
be initially misread as pneumococcal infection. There is
often a pleocytosis and an elevated protein but a normal
glucose concentration. Blood cultures are usually positive before the CSF culture.21
Treatment. Treatment of transplant recipients with
suspected bacterial meningitis should always cover drugresistant pneumococci, N. meningitidis, and L. monocytogenes. A combination of 3 drugs, such as vancomycin, ceftriaxone, and high-dose ampicillin, are often given until
cultures and susceptibility panels return.22 A relapse rate
of 35% is reported in transplant patients with listerial
meningitis and/or bacteremia who are treated for less
than 3 weeks; high-dose penicillin or ampicillin therapy
for 4 to 6 weeks is recommended for this patient
group.23,24
Streptococcus pneumoniae
Organ transplant recipients are at increased risk for
developing invasive pneumococcal disease, the incidence of which has been calculated at 36 per 1000
patient-years for recipients of heart transplants and
28 per 1000 patient-years for recipients of kidney
transplants—rates that exceed the estimated incidence
of invasive pneumococcal disease in the general population.25 Interestingly, despite an excess of cases of disseminated pneumococcal disease in transplant recipients, most of these infections were actually blood
stream infections; pneumococcal meningitis is rarely
seen in solid organ transplant recipients. Infections
with S. pneumoniae usually occur at least 3 months after
transplantation.26 Many transplant patients harbor
some of the known risk factors for drug-resistant pneumococci, such as recent antibiotic use. This should be
kept in mind when prescribing antimicrobial therapy
for suspected pneumococcal meningitis.
Neisseria meningitidis
There is no evidence that patients with solid organ
transplants are at increased risk for CNS infections from
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Neisseria species. Indeed, it has recently been shown that
it is safe to transplant organs procured from donors
who died of bacterial meningitis due to N. meningitis.27
ATYPICAL BACTERIA
Nocardia asteroides
N. asteroides is an increasingly important opportunistic pathogen in immunosuppressed patients, particularly transplant recipients. Dissemination to other
organs, especially the CNS and skin, occurs in up to
40% of transplant recipients with Nocardia infection.28 A
presumptive diagnosis can be made by the direct visualization of filamentous, gram-positive, beaded rods that
are partially acid fast in clinical specimens. The organism grows slowly in culture. Therefore, samples should
be held for at least 3 weeks when Nocardia is suspected.28
Sulfonamides are considered standard therapy, although there is little evidence or data from comparative
trials to support this. The clinical course is similar to
that seen in patients without transplants.29
Mycobacterium tuberculosis
Tuberculosis is a major source of morbidity and mortality in solid organ transplant recipients worldwide.30,31
In the United States, M. tuberculosis infection has been
reported infrequently after renal transplantation
(1%–4%)32 but is 20 times more frequent in this group
than in the national population. Important risk factors
for M. tuberculosis infection following transplantation
include long duration of hemodialysis before transplantation, a history of tuberculosis, poor socioeconomic
status, high-dose corticosteroid therapy for acute rejection, and residence in areas with a high prevalence of
M. tuberculosis infection.33
Clinical presentation and diagnosis. Patients with solid
organ transplants have a higher rate of extrapulmonary
and disseminated mycobacterial disease.34 M. tuberculosis
infection of the CNS is an uncommon disease manifestation, but when it occurs, 3 main forms have been described: cerebral tuberculoma, meningitis, and myelopathy. M. tuberculosis is not the only species of mycobacteria
that causes disease in patients with solid organ transplants. Transplant recipients also are susceptible to infections with M. avium and M. chelonae as well as other nontuberculous mycobacteria. Acid-fast stains of the CSF
should be obtained, and any biopsy specimens should be
sent for mycobacterial culture. Since M. tuberculosis grows
slowly, the specimens should be held for 6 weeks. Unfortunately, the sensitivity of the PCR assay for CNS tuberculosis is limited (approximately 80%).35,36
Treatment and prognosis. A decision to treat for
tuberculous meningitis should not depend entirely on
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a PCR result, and therapy with a minimum of 3 drugs
with CSF penetration should be initiated as soon as the
disease is suspected.37 The outcome in cases of mycobacterial CNS infection is poor, with an estimated mortality of 14%.37
PARASITES
Toxoplasma gondii
Cats are the definitive hosts of T. gondii; they excrete
infectious oocysts in their feces. Humans generally
become infected by ingesting contaminated soil, food,
or undercooked meat but can also acquire infection via
maternal-fetal transmission, blood transfusion, or organ transplantation. In the United States, 10% to 40%
of people are seropositive for Toxoplasma antibodies,
which is considered evidence of latent infection.38 Reactivation of latent infection is responsible for most
opportunistic CNS infections caused by T. gondii. In
transplant recipients, toxoplasmosis may occur as the
result of primary infection (ie, transplantation of an
infected donor organ into a seronegative recipient) or
reactivation of latent infection.
Clinical manifestations and diagnosis. Clinical manifestations of CNS toxoplasmosis in transplant recipients
may include headache, altered mental status, seizures,
focal neurologic deficits, hemiparesis, ataxia, and cranial neuropathy.6 Primary toxoplasmosis in the heart
transplant recipient generally presents as myocarditis or
cardiomyopathy. Rarely, the disease disseminates and
may present as encephalitis or chorioretinitis in this setting.39 Definitive diagnosis requires identification of
tachyzoites in biopsy samples, but identification of anti–
T. gondii antibodies by enzyme-linked immunosorbent
assay (ELISA) is a sensitive and specific method for
determining exposure. PCR assay of CSF is highly specific and sensitive in some laboratories, but its sensitivity has been shown to be variable by laboratory and technique. Therefore, PCR assay should not be used to
exclude the diagnosis of toxoplasmosis.40
Treatment. Solid organ transplant recipients with
suspected CNS toxoplasmosis should receive pyrimethamine, folinic acid, and sulfadiazine. For patients who
report a sulfa allergy, sulfa desensitization or alternatives to sulfadiazine (eg, atovaquone, clarithromycin,
azithromycin) should be considered.
FUNGI
Aspergillus
Aspergillus is a common cause of CNS infection in the
transplant recipient. CNS aspergillosis generally occurs
during periods of more intense immunosuppression
(eg, during treatment of rejection). CNS disease is gen-
10 Hospital Physician Board Review Manual
erally accompanied other markers of disseminated disease, including evidence of pulmonary and/or gastrointestinal involvement.41
Clinical presentation and diagnosis. CNS aspergillosis
is often rapidly progressive. It typically presents as altered
mental status. Up to 41% of patients have seizures, and
a focal neurologic defect is seen in approximately 30%
of patients.42 The most common location for brain abscess is the frontoparietal region of the cerebral hemispheres, but the cerebellum or brainstem also may be
involved. Diagnosis is made by identifying branching
septate hyphae in patient specimens (sputum, CSF, biopsy material) or by positive culture in brain biopsy specimens, CSF, or pulmonary secretions. Aspergillus also
has characteristic features on imaging. Chest CT may reveal the classic crescent or halo sign, and brain CT may
show diffuse meningeal enhancement or multiple nonenhancing hypodense lesions in the basal ganglia or at
the junction of the gray and white matter. Aspergillus is an
angioinvasive fungus; thus, infarcts or hemorrhagic CNS
lesions may also be observed.42
Treatment. Most experts recommend a combination
of voriconazole and caspofungin for treatment of CNS
aspergillosis.43 Although caspofungin’s penetration into
the CSF is poor, there are anecdotal reports of enhanced success in treating CNS aspergillosis when this
agent is combined with voriconazole.44,45
Candida
Candida may cause CNS disease in the setting of disseminated invasive candidiasis, manifesting as either
meningitis or candidal CNS abscess. Imaging is often
normal unless abscess is detected. Diagnosis is made by
demonstration of the pathogen in CNS tissue or CSF.11
Treatment is with antifungal agents with good CSF penetration (eg, fluconazole).
Cryptococcus neoformans
C. neoformans has a propensity to cause CNS disease
in patients with solid organ transplants.
Clinical presentation and diagnosis. C. neoformans
causes meningitis in 98% of patients with CNS infection. Cryptococcoma presenting as a focal lesion is an
unusual manifestation of CNS infection.46 Most cases of
C. neoformans infection occur 6 months or more after
transplantation. In a recent series of patients with CNS
cryptococcosis, 62% had headache, 74% were febrile,
and 48% had confusion or lethargy.46 Imaging may be
normal or may reveal meningeal enhancement or an
enhancing lesion. Diagnosis is made by detection of
C. neoformans or CrAg in the CSF.
Treatment. Transplant patients require treatment
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C N S I n f e c t i o n s i n S o l i d O r g a n Tr a n s p l a n t R e c i p i e n t s
only for active infection.6 Treatment is with intravenous
(IV) amphotericin B and flucytosine until the CSF is
culture negative, at which point oral fluconazole may
replace the IV antifungal agents. Fluconazole should be
continued while the patient is maximally immunosuppressed. Lumbar puncture with culture and CrAg testing should be repeated after IV therapy is stopped and
oral therapy is started and then repeated again every 2
to 4 weeks or if clinical deterioration occurs. If the CSF
CrAg titer rises above the titer at initial diagnosis, treatment with amphotericin B and flucytosine should be
repeated. Prophylactic treatment is required for 2 to
6 weeks after clearance of CrAg.
Endemic Fungi
As noted, the endemic fungi (ie, H. capsulatum,
B. dermatitidis, C. immitis) usually cause CNS infection in
the setting of systemic dissemination.
CNS histoplasmosis. Manifestations of CNS histoplasmosis include meningitis, focal CNS lesions, cerebrovascular accidents caused by vascular involvement or
cerebral emboli, and diffuse encephalitis.47 Prolonged
fever is the predominant clinical finding in disseminated histoplasmosis. Patients may also present with subtle
neurocognitive decline and, occasionally, focal neurologic findings. Chronic headache and seizures also may
occur.47 – 49 In patients with meningitis, CSF abnormalities include lymphocytic pleocytosis, elevated protein,
and hypoglycorrhachia. CT or MRI may reveal single or
multiple enhancing lesions in the brain or spinal cord
of patients with parenchymal CNS involvement.47 Fungal stains of CNS tissues and urine testing for H. capsulatum antigen are used to diagnose CNS histoplasmosis.
The course of H. capsulatum infections of the CNS is
progressive and uniformly fatal if not treated. However,
symptoms may at times be quite long-standing, and the
speed of clinical deterioration is variable.47 Approximately 20% to 40% of patients with meningitis succumb
to the infection despite optimal treatment.
CNS blastomycosis. The nervous system is involved
in 5% to 10% of cases of disseminated blastomycosis.
Epidural or cranial abscesses are the most commonly
appreciated manifestations of CNS involvement with
blastomycosis. Meningitis is a less common manifestation. It is not clear that blastomycosis is more common
in patients with solid organ transplants. CNS infection
by B. dermatitidis is notoriously difficult to diagnose. CT
may direct biopsy of a cranial abscess, but identification
of blastomycosis as the cause of meningitis is more
problematic. Evaluation of CSF alone is rarely diagnostic. Ventricular fluid may be necessary to obtain a positive culture. In one series of 22 patients with CNS blas-
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tomycosis, CSF samples provided the diagnosis in only
2 patients, whereas ventricular fluid specimens were
positive in 6 of 7 cases.50
CNS coccidioidomycosis. Symptomatic coccidioidomycosis is more common in patients with abnormal
cell-mediated immune function, such as solid organ
transplant recipients.51 C. immitis infection of the CNS is
the most deadly form of coccidioidomycosis. It most
commonly presents as chronic granulomatous meningitis involving the basilar meninges. C. immitis may also
produce focal CNS abscesses. The most common symptoms of CNS coccidioidomycosis are headache, nausea,
vomiting, and altered neurocognitive status. Other
symptoms and signs that may be observed include
nuchal rigidity, diplopia, and other cranial neuropathies.51 The onset of symptoms is usually subacute to
chronic. Initial CSF findings show a mononuclear pleocytosis, with low glucose and elevated protein concentrations. As many as 70% of patients have eosinophilic
meningitis.51 A definitive diagnosis may be established
by isolating the organism from a clinical specimen
(eg, CSF, CNS tissue). C. immitis grows quickly in culture
and can be seen as early as 2 days after inoculation. It is
important to notify the clinical laboratory if C. immitis
infection is suspected to minimize the risk of accidental
exposure of laboratory personnel to infection.
Treatment. The optimal treatment for meningitis
due to the endemic fungi is unknown, but an aggressive
approach is recommended because of the poor outcome with some infections, such as histoplasmosis.48
Treatment with amphotericin B products over 3 to
4 months has been used most often. High-dose oral fluconazole is often continued for another 9 to 12 months
after completion of amphotericin B therapy to reduce
the risk for relapse. Liposomal amphotericin B might be
considered for patients who have failed therapy with
amphotericin B, followed by fluconazole. Chronic fluconazole maintenance therapy should be considered for
patients who relapse despite full courses of therapy.48
Itraconazole is more active than fluconazole against
H. capsulatum, but because it does not enter the CSF it is
not used for treatment of meningitis. The Infectious
Diseases Society of America (www.idsociety.org) publishes guidelines for the treatment of the endemic fungi.
VIRUSES
Herpesviruses
The human herpesviruses include HSV-1 and HSV-2,
CMV, EBV, VZV, HHV-6, and HHV-8. All of these viruses are known to persist in the host after initial infection.
Herpesviruses are the most frequent causes of infections in solid organ transplant recipients. CNS disease
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can occur as the result of primary infection or reactivation of latent infection.
HSV. HSV is an important cause of CNS infections
and accounts for 2% to 19% of cases of human encephalitis.52 In transplant recipients, prophylactic antiviral medication is typically prescribed, so HSV infection
is uncommon. When HSV encephalitis occurs in such a
patient, the clinician should be concerned about
acyclovir-resistant HSV.
EBV. EBV infection can occur as a primary infection
or reactivation of latent infection in solid organ transplant recipients. EBV has been associated with a number
of neurologic syndromes, including meningoencephalitis, encephalitis, aseptic meningitis, Guillain-Barré
syndrome, and Bell’s palsy.53 In solid organ transplant
recipients, EBV infection and replication may also be associated with an abnormal proliferation of lymphoid
cells. This condition is known as post-transplant lymphoproliferative disease (PTLD). The incidence of
PTLD is highest during the first year after transplantation and most often occurs in patients who were EBVseropositive before transplantation. In a series of 500
patients, PTLD involving the brain was seen in 2% of
liver allograft recipients, 3% of heart transplant recipients, and 7% of heart-lung recipients.3 This variation is
thought to be the result of differences in immune suppression. Patients with CNS involvement from PTLD
generally present with mental status changes or a focal
neurologic deficit. Diagnosis of PTLD is confirmed by
demonstration of abnormal lymphoid proliferation in
biopsy material. Quantitative PCR assay of the serum
for EBV DNA correlates with increased risk of developing PTLD.54
CMV. CMV is an uncommon cause of encephalitis
or Guillain-Barré syndrome in solid organ transplant
recipients. As noted, however, CMV is important as an
immunomodulator and agent precipitating graft rejection.55
VZV. In addition to causing chickenpox and shingles, VZV can produce a variety of CNS manifestations,
including post-varicella cerebellitis, meningoencephalitis, vasculopathy, and acute aseptic meningitis. Primary
infection with VZV can rapidly disseminate to multiple
organs, including the CNS, in patients receiving immunosuppression after organ transplantation. Patients
typically present with disseminated or CNS infection
within 7 months after transplantation.11
HHV-6. HHV-6 infection has been associated with
encephalitis in solid organ transplant recipients. It is
thought that reactivation of latent infection is responsible for most cases of infection, but transmission of virus
from donor tissue can also occur.
12 Hospital Physician Board Review Manual
Other Viruses
JC virus. PML is a subacute progressive demyelinating disease of the CNS that can occur in transplant
recipients. The clinical presentation in transplant patients is similar to that in patients with AIDS. Unlike
other viral CNS infections, PML usually presents many
months or years after transplantation. In more than
90% of patients with PML, reactivated latent JC virus infection can be detected by PCR assay of the CSF.11
Lymphocytic choriomeningitis (LCM) virus. LCM
virus is a rodent-borne arenavirus that can cause aseptic meningitis, encephalitis, or meningoencephalitis. In
May 2005, the U.S. Centers for Disease Control and
Prevention (CDC) received a report of severe illness in
4 patients who had received solid organ transplants
from a common donor. All 4 patients subsequently were
found to have evidence of infection with LCM virus.
Preliminary findings from the ensuing investigation
indicated that the source of infection likely was an
infected hamster in the donor’s home. Three of the
4 organ recipients died within 27 days after transplantation. Based on the diagnosis of LCM, the surviving
kidney transplant recipient was treated with intravenous
ribavirin and reduction in his immunosuppressive drug
regimen; the patient improved clinically. A similar case
was reported in 2003, which involved the death of
3 patients who received organs infected by LCM virus.
The CDC advises that health care providers should be
aware that LCM virus can be transmitted through organ
transplantation.56
West Nile virus. West Nile virus continues to spread
through North America. In immunocompetent patients, the majority of infections are asymptomatic.
Early in this epidemic, it was observed that patients with
solid organ transplants had unusually severe symptomatic community-acquired West Nile virus infection
and were at greater risk for severe neurologic disease
compared with the general population. In one small
series reported in Canada (4 patients), the presenting
symptoms included fever, confusion, headache, and
weakness.3 The CSF showed a pleocytosis in all patients.
Two patients had a full recovery, 1 had lower limb paralysis, and 1 died.57 Elevated CSF IgM is the test of choice
for diagnosis of West Nile virus infection. Prevention of
virus transmission and patient education about the
mode of acquisition and mosquito bite prevention
strategies may be more important in the transplant population than in the general population.57
Rabies virus. Rabies is an acute, fatal encephalitis
caused by neurotropic viruses in the genus Lyssavirus,
family Rhabdoviridae. Most cases of rabies are caused
by bites by rabid mammals. However, the CDC has
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C N S I n f e c t i o n s i n S o l i d O r g a n Tr a n s p l a n t R e c i p i e n t s
Figure 2. Magnetic resonance images of
the brain of case patient 2, showing late
cerebritis/early abscess in the right frontal
subcortical region.
confirmed that rabies was the cause of death in 4 transplant recipients in whom encephalitis developed 3 to
4 weeks after transplantation.10 The common donor of
all the transplanted organs had died of extensive subarachnoid hemorrhage of unknown etiology. According to eligibility screening and testing, the donor had
had no contraindications to transplantation, although
later a public health investigation revealed that the
donor had reported being bitten by a bat.10 Infection
with rabies virus likely occurred via neuronal tissue contained in the transplanted organs, as rabies virus is not
spread hematologically.
CASE EXAMPLES
CASE 1
Presentation and Diagnostic Evaluation
A 53-year-old man presents to the emergency department for evaluation of the acute onset of a severe
headache. The patient reports that he was doing well,
in his usual state of health, until he recently traveled to
Mexico to visit family. Shortly after his return, he noted
some diarrhea followed by generalized body aches and
then the acute onset of a severe headache. His medical
history is significant for renal transplantation 3 years
previously for obstructive uropathy.
A lumbar puncture is performed. CSF analysis shows a
glucose level of 61 mg/dL, a protein level of 279 mg/dL,
and a nucleated cell count of 1390/mm3. The differential
on the cell count shows 72% neutrophils, 4% lymphocytes, and 24% monocytes. The patient is started on
empiric therapy with ceftriaxone, ampicillin, vancomycin,
and acyclovir. His antibiotic regimen is reduced to ampicillin only when the CSF culture grows out Listeria. The
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patient improves rapidly. Treatment with high-dose ampicillin is continued for 6 weeks.
Discussion
This renal transplant recipient is presenting in the late
post-transplantation period with acute meningitis. The
most common cause of acute bacterial meningitis in the
solid organ transplant recipient is Listeria. The patient
also noted diarrhea prior to the onset of meningitis,
which is commonly seen in Listeria infection. Like many
transplant recipients, this patient’s use of prophylactic
TMP-SMX would have been discontinued 1 year after his
renal transplantation. Use of this drug would have decreased the likelihood of acquiring meningitis from
Listeria. Transplant recipients with Listeria meningitis
require prolonged antibiotic coverage because of the risk
of relapse with shorter courses (< 3 weeks) of therapy.
CASE 2
Presentation and Diagnostic Evaluation
A 39-year-old woman undergoes orthotopic heart
transplantation secondary to giant cell myocarditis with
no significant postsurgical complications. At home
3 months after transplantation, the patient notes a lowgrade fever and headache over a period of several
weeks. At this time, she undergoes a routine myocardial
biopsy to monitor for rejection. During this visit, her
neurologic examination reveals right gaze preference
and left hand clumsiness. MRI of the brain shows a solitary lesion (Figure 2) that enhances with IV gadolinium. The heart biopsy shows filamentous structures in
the endocardium and myocardium, consistant with
Apergillus.
The patient is admitted to the hospital for further
work-up for disseminated fungal infection, which
reveals extensive disease in her lungs, brain, and both
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eyes. She is started on caspofungin and voriconazole
and responds well. One year after treatment, she remains disease free.
Discussion
This patient was in the intermediate post-transplantation period when she demonstrated a solitary brain
lesion. It is in this period when most classic opportunistic pathogens are seen. Like many post-transplantation
patients, this patient had evidence of fungal infection
elsewhere in her body at the time of diagnosis. Diagnosis
of the brain lesion was made by biopsy of her heart.
Aspergillus is the most common cause of brain abscess in
solid organ transplant recipients. CNS aspergillosis was
previously associated with nearly 100% mortality.45 Use
of the new antifungal agents, particularly voriconazole
(because of its enhanced CNS penetration), has been
associated with improved outcomes in CNS aspergillosis.
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