Susmitha Apuri1, Kristin Carlin1, Edward Bass2, Phuong Thuy Nguyen3 and John N. Greene4
1
Internal and Hospital Medicine, Moffitt Cancer Center, University of
South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida
33612-9497, USA.
2 Department of Neurology, Moffitt Cancer
Center,
University of South Florida College of Medicine, 12902 Magnolia Drive,
Tampa, Florida 33612-9497, USA.
3 Department of Infectious Diseases. University
of
South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida
33612-9497, USA.
4 Infectious Diseases and Hospital
Epidemiologist,
Moffitt Cancer Center, University of South Florida College of Medicine,
12902 Magnolia Drive, FOB-3, Tampa, Florida 33612-9497, USA.
This
is an Open Access article distributed
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|
Abstract Tacrolimus is an immunosuppressive drug mainly used to lower the risk of transplant rejection in individuals who are post solid organ or hematopoietic transplantation. It is a macrolide which reduces peptidyl-propyl isomerase activity and inhibits calcineurin, thus inhibiting T-lymphocyte signal transduction and interleukin-2 (IL-2) transcription. It has been associated with Posterior Reversible Encephalopathy Syndrome (PRES), a disease of sudden onset that can present as a host of different symptoms, depending on the affected area of the brain. While infectious causes of encephalopathy must always be entertained, the differential diagnosis should also include PRES in the appropriate context. We report three cases of PRES in patients with acute myeloid leukemia (AML) placed on tacrolimus after receiving a bone marrow transplant (BMT). The focus of this review is to enhance clinical recognition of PRES as it is related to an adverse effect of Tacrolimus in the setting of hematopoietic transplantation. |
Introduction
Tacrolimus
is a macrolide lactone derived from the bacteria Streptomyces
tsukubaensis, which is used in the treatment of various immune-mediated
disorders. This drug binds with cyclosporine to form a drug-receptor
complex. This complex then competitively binds to and inhibits
calcineurin. It functions by inhibiting the transcription of
Interleukin-2 (IL-2) by T-helper lymphocytes, as well as inhibiting
T-helper lymphocyte growth and proliferation.[17-18]
Unfortunately, tacrolimus is associated with renal and neural toxicity,
among its other side effects of immunosuppression. One of the more
uncommon presentations of neurotoxicity is posterior reversible
encephalopathy syndrome (PRES). PRES was initially described by Hinchey
et al.[1] in 1996 as a clinical
neuroradiological
entity. It is characterized by generalized seizures, headache, vision
changes, coma, paresis, hemianopsia, nausea, altered mental status,
and/or focal neurological deficits.[2]
There are varying reports of neurotoxicity related to tacrolimus
ranging from 7 to 32% in solid organ transplants (SOT).[47]
The overall incidence of PRES occurs in 0.5%-5% of SOT recipients and
is most commonly associated with tacrolimus.[50]
We are describing 3 cases of neurotoxicity related to tacrolimus in the
hematopoietic transplant population.
Patient One
Our
patient is a 36-year-old white female with a history of AML, who
underwent allogeneic BMT 41 days prior to the onset of her neurologic
symptoms. Her posttransplant course was complicated by mild graft
versus host disease (GVHD) of the gastrointestinal tract and skin, for
which she was placed on tacrolimus on day 16. On day 29, she was also
started on prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) for
pneumocystis jiroveci pneumonia (PCP). Additionally, she was diagnosed
with cytomegalovirus (CMV) reactivation and BK virus hemorrhagic
cystitis. She was placed on valgancyclovir (day 19) and Cidofovir (day
27) respectively. She subsequently developed acute renal failure with
creatinine levels peaking at 3.7 mg/dL and BUN peaking at 88 mg/dL on
day 34. Cidofovir was presumed to be the likely causative agent for the
acute kidney injury; although she had recently been placed on multiple
additional nephrotoxic agents, including the aforementioned tacrolimus,
TMP-SMX, and pyridium.
On day 41, she presented with sudden onset of altered mental status
manifesting as staring into space and right gaze preference.
Tonic-clonic activity, incontinence, or tongue biting was not observed,
but concern was raised for new onset of seizures given the episode of
unresponsiveness with fixed gaze. She was started on treatment with 2
mg of intravenous lorazepam (AtivanTM) and 500 mg of levetiracetam
(KeppraTM). She underwent imaging of the brain with a non-contrast
computed tomography (CT). The CT scan did not demonstrate any acute
findings. A non-contrast magnetic resonance imaging (MRI) was then
obtained. The MRI study showed increased FLAIR and T2 signal in the
cortex of the infero-posterior, posterior temporal and occipital lobe
with absence of diffusion abnormality consistent with PRES (Figure 1).
An EEG was negative for epileptiform activity. Cerebrospinal fluid
analysis was performed for possible encephalitis as well as
lepto-meningeal recurrence with negative results.
Figure 1. |
Interestingly,
the patient was taken off of tacrolimus on day 34 at the onset of acute
renal failure, prior to the onset of PRES. The tacrolimus levels were
within the desired range of 10-15 ng/ml throughout this course.
She was switched to sirolimus one week after the onset of PRES,
maintaining serum levels within the desired range of 8-12 ng/ml. At
this time her neurological symptoms had improved although not
completely resolved. Three weeks following the diagnosis of PRES, a
repeat MRI with gadolinium was performed showing resolution of the
posterior areas and a small focus on FLAIR in the right frontal lobe.
Levetiracetam was discontinued and sirolimus was maintained. The
patient was followed for an additional year. She had a complete
recovery from this event. No additional seizures or new neurological
findings occurred during this time.
Patient Two
Altered
mental status and severe headache developed in a 54 year old
female, previously diagnosed with acute myeloid leukemia, four weeks
after admission for high dose chemotherapy followed by matched
unrelated donor stem cell transplant. Following her conditioning
chemotherapy, which consisted of busulfan and fludarabine and
subsequent bone marrow transplant, she developed a nodular pneumonia
thought to be fungal in nature but culture negative by bronchoscopy
specimens. During this time, the patient was on tacrolimus for graft
versus host disease prophylaxis. This was started 25 days prior to the
onset of mental status changes. Tacrolimus levels were maintained in a
therapeutic target range of 10-15ng/ml during this time frame. On day
27 of the admission, she complained of severe headache which was
followed by confusion. Also of note, the patient developed accelerated
hypertension in the 48 hours surrounding the episode of confusion.
Neither visual disturbance nor seizure activity was noted. Prior to
this event, the patient was fairly normotensive with a systolic blood
pressure range of 120-130 mmHg. At the peak of confusion, she was noted
to have blood pressure of 188/90 mmHg. Calcium channel blocker therapy
was then started and normotension was achieved.
Cranial T2-weighted MRI showed increased FLAIR and signal in the left
and right cerebellar hemispheres that did not enhance or show
restricted diffusion. There was also increased flair signal in the left
and right posterior parietal occipital cortex consistent with posterior
reversible leukoencephalopathy. Tacrolimus was discontinued and
mycophenaolate mofetil was initiated. Within 24 hours of
discontinuation of the tacrolimus, the neurologic symptoms began to
resolve and the patient was again normotensive. Subsequent to this, she
did develop grade II graft versus host disease of skin requiring high
dose steroids and sirolimus was then added to the regimen. Because of
the concern for potential worsening of the nodular pneumonia, steroid
taper was initiated as soon as clinically feasible. Ultimately, she
recovered and was discharged from the hospital in stable condition,
with resolution of all neurologic findings.
Patient Three
Our third patient with a history of AML, refractory to
chemotherapy,
underwent a matched unrelated donor BMT. On transplant day 2, the
patient was started on tacrolimus for graft versus host prophylaxis.
Tacrolimus levels were maintained between 15.2 ng/ml and 17.3 ng/ml.
Concurrently, she was found to have confusion, visual hallucinations,
headaches, gait disturbances, nausea and vomiting. CT scan of the head
showed no acute findings. These complaints were soon attributed to
hyponatremia of 121mEq/L. As the sodium was gently corrected, her
mental status returned to normal baseline within three days.
On transplant day 6, the patient again developed neurologic changes
including visual disturbances, cerebellar ataxia, and headache. The
visual disturbance consisted of seeing flashing lights as well as the
inability to distinguish faces or colors. She had labile blood pressure
throughout the hospital stay with systolic blood pressures ranging from
120mmHg to 180mmHg. CT scan of the head showed decreased attenuation in
the bilateral mesial aspect of posterior parietal cortex as well as
occipital cortex. MRI showed new areas of increased signal on the
cortical gyral surfaces of both occipital lobes and portions of the
temporal lobes. There was no diffusion restriction. There was no
evidence of hemorrhage or acute stroke. These findings were consistent
with PRES. EEG showed moderately severe slowing of the background
rhythm, consistent with encephalopathy. There was no evidence of focal
abnormalities or epileptiform discharges.
Given the diagnosis of PRES, the tacrolimus was discontinued
cyclosporine and mycophenalate mofetil were initiated. By the time of
her discharge on transplant day 20, her mental status improved
significantly however she was left with a broad based gate. This was
thought to be due to busulfan toxitcity. Mycophenalate mofetil was
discontinued once engrafted and rapamune initiated. Cyclosporine was
continued upon discharge. On day 46, she was readmitted to the hospital
with alteration in mental status, hyponatremia and was found to have
GVHD grade 1 of the duodenum and Grade 1-2 GVHD of the rectum.
Infectious work up was negative as a cause of encephalopathy. During
this admission, the patient remained normotensive. Repeat MRI showed
evidence of recurrent PRES and was thought to be now related to
cyclosporine. Unfortunately, the patient continued to decline and
enrolled in hospice services, dying shortly thereafter.
Discussion
AML is a disease of the bone marrow where abnormal cancer
cells grow
rapidly and replace healthy marrow. This process increases the
susceptibility for bone pain, bleeding and infections, anemia and
recurrent fevers. Initial treatment almost always consists of
chemotherapy regimen, such as duanorubicin and cytarabine. BMT is an
option often reserved for chemotherapy failure. Three distinct
modalities of BMT include autologous transplant, allogeneic transplant
and umbilical cord transplant. In allogeneic transplant, hematopoietic
stem cells are collected from a donor and ultimately infused into a
patient after high-dose chemotherapy. Complications from this procedure
include immunosuppression, anemia, bleeding, fever, and infections as
well as rejection or GVHD.[19]
The primary role of tacrolimus (also FK-506, or Fujimycin) is to
prevent GVHD in the post-allogeneic solid organ transplant patient. In
recent years, it has been increasingly used as an immunosuppressive
agent in hematopoietic stem cell transplantation as well. Neurotoxicity
secondary to tacrolimus has been well described, particularly in solid
organ transplant recipients.[15]
PRES, as the name suggests, is a constellation of symptoms associated
with vasogenic edema, most commonly, of the posterior cerebral
vasculature, often affecting the parietaloccipital region. Other
vascular territories can also be affected in PRES, such as the
posterior portion of frontal lobe and temporal lobe.[23]
The abnormalities primarily affect white and gray matter, but the
cortex can also be involved. Although the diagnosis may be suggested by
CT, MRI of the brain is the most sensitive diagnostic tool.[3]
Distinguishing between vasogenic edema in PRES and cytotoxic edema in
the setting of cerebral ischemia can be reliably determined by
diffusion weighted MR imaging.[46]
PRES is typically
a reversible phenomenon, as indicated by the name, but if not
recognized early and treated appropriately, permanent brain injury may
ensue.[8] Many agents and
etiologies have been linked to PRES (Table
1).
Table 1. Common causes of PRES |
Table 2. Differential Diagnosis of PRES |
PRES
is an increasingly recognized neurologic disorder with characteristic
image findings. Clinically, its presentation can be variable and the
differential is wide (Table
2).
The pathophysiology of PRES still remains unclear. The mechanism of
action of Tacrolimus induced PRES may be similar to Cyclosporine.
Neurotoxicity associated with Cyclosporine was thought to be
facilitated by hypomagnesemia, hypocholesterolemia, hypertension and
the vasoactive agent endothelin.[53]
Cyclosporine is also believed to exacerbate hypertension by inhibiting
nitric oxide production.[54]
The mechanism of cellular injury is thought to be secondary to
mitochondrial dysfunction as the symptoms of Cyclosporine induced
neurotoxicity and mitochondrial encephalopathy appear to be similar.[55]
Schwartz et al assessed sixteen patients by evaluating the factors
responsible for the neurotoxic effects of Cyclosporine using
neuroimaging as well as clinical and laboratory data. The only major
factor associated with neurotoxic effects of Cyclosporine was systemic
hypertension although thrombocytopenia, microangiopathic hemolytic
anemia and hypoalbuminemia are common.[56]
The
syndrome is likely initiated by a breakdown in the blood brain barrier
leading to a leakage of fluid into the interstitium of the brain tissue
and the development of vasogenic edema.[9]
In addition, immunosuppressant drugs exert cytotoxic effects on the
vascular endothelium.[10,11] It is
unknown whether vasospasm plays a clear role in the genesis of local
ischemia.[12]
Sympathetic innervation regulates the vessels of the brain during acute
elevations in blood pressure. Because auto-regulatory mechanisms are
dependent on the neurogenic response, the more poorly innervated areas
in the posterior circulation are more vulnerable to increased blood
pressure.[12,13] As PRES may occur
in patients with
hypertensive encephalopathy where the limits of autoregulation are
exceeded, hypertension has been suggested as a potential risk factor
for neurotoxicity induced by tacrolimus and other drug related cases of
PRES. It is important to exclude unrecognized increases in blood
pressure that can be overlooked or occur in the outpatient setting. Two
of our three patients were hypertensive surrounding the PRES event and
a careful review of the chart records failed to show any elevations in
the third case.
Unfortunately, immune suppressant blood levels do not appear to
correlate with severe neurotoxicity or PRES, but discontinuation or
change in the offending immunosuppressant can lead to clinical
improvement. Grimbert et al reported significant levels of Tacrolimus
in the CSF which suggests that this molecule can cross the blood brain
barrier. Demyelination was noted in two cerebral biopsies associated
with leukoencephalopathy in patients who underwent liver and lung
transplantation.[57]
Immune challenges post-transplant (i.e. transplant rejection, GVHD),
effects of chemotherapy, and the risks of infection in the
immunosuppressed state may further contribute to toxicity. Clearly, a
balance exists between adequate immunosuppression and infection risk.[14]
The diagnosis of tacrolimus-associated PRES was made by the following
criteria: (1) characteristic clinical findings (headache, mental status
changes, seizures, visual abnormalities and/or focal neurological
deficits) with the exclusion of other possible causes (i.e. infection,
metabolic disturbances and structural neurological lesions) and (2)
characteristic findings of subcortical white matter lesions on CT or
MRI of the brain.[16]
Our patients presented with classic MRI findings of PRES at the onset
of symptoms, and had appropriate response to treatment in the expected
timeframe. Patients affected by PRES may experience some or all of the
following: visual disturbances, altered mental status, seizures, and
headaches. Of note, the association of hypertension with PRES is well
reported; however is not always a component of PRES in patients on
immunosuppressive therapy.[49]
These cases demonstrate the challenge of understanding the
pathophysiology of PRES, since tacrolimus use would appear to be the
main contributor. However, in the first case, PRES did not appear until
four days after this medication was withheld secondary to acute renal
failure. Although subtherapeutic levels of immunosuppressants have been
reported as causing PRES, observations of the onset of this disease at
the time of declining levels is seemingly paradoxical. There exists the
possibility of delayed onset of symptoms, or perhaps the confounding
factor was related to the acute renal failure itself. Proteinuria and
hypoalbuminemia are known to be associated contributors to the
development of PRES. The time course of developing PRES from the onset
of beginning immunosuppressant therapy is particularly variable;
therefore, the development of PRES, even while maintaining therapeutic
levels, is not surprising.
In addition, our third patient had recurrent PRES with the second event
likely related to cyclosporine. Interim images had revealed resolution
of PRES once the offending Tacrolimus had been discontinued.
Cyclosporine was subsequently initiated and maintained in the
therapeutic target range. Cyclosporine has been reported in the
literature to be an inciting factor in PRES events.[51]
There have been published case reports documenting recurrent episodes
of PRES with varying inciting factors.[52]
Conclusions
Tacrolimus-associated PRES is an uncommon, but serious
complication
after BMT, especially with matched-unrelated or mismatched transplants,
where higher levels of immunosuppression are required to prevent
rejection. It should also be noted that supratherapeutic levels of
tacrolimus need not be present to cause a PRES event.[48]
This syndrome should be promptly recognized as it is potentially
reversible and generally responds to withholding or decreasing the dose
of tacrolimus in addition to controlling hypertension and seizures.
Although there are common yet heterogeneous etiologies that surround
the onset of PRES, more research into the mechanisms surrounding PRES
is needed to understand this disease process. The compilation of these
diseases and a study of the time course of the patient’s history
leading up to and during the presentation of PRES may better elucidate
the means by which we treat and diagnose this disease.
References
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