REVIEW ARTICLE
Neurotoxicity of Immunosuppressive Drugs
Eelco F.M. Wijdicks
The clinical profile of neurotoxicity caused by immuno-
suppression has changed. When toxic levels are reached,
both cyclosporine and tacrolimus may produce a clinical
spectrum that varies from tremor and acute confusional
state to status epilepticus and major speech or language
abnormalities. Coma has become an unusual manifesta-
tion. Magnetic resonance imaging has been better defined,
and abnormalities may be more widespread than those in
the posterior lobes. These white matter lesions are caused
by vasogenic edema, but may lead to apoptosis and cyto-
toxic edema if exposure is prolonged. Recent evidence
suggests inhibition of a drug-efflux pump and dysfunction
of the blood-brain barrier by enhanced nitric oxide
production. (Liver Transpl 2001;7:937-942.)
R egimens of immunosuppression have been reshaped
since the discovery of cyclosporine. The elucidation
of cyclosporine’s pharmacological properties has been very
relevant to the field of transplantation, and its impact on
survival has been most pronounced in liver and heart
transplantation. The discovery of immunosuppressive
metabolites of Trichoderma polysporum refai in a Norwe-
gian soil sample led to cyclosporine.1 Years later, a similar
discovery was made in Tsukuba, Japan, and cultured
broths of soil samples detected a strain designated Strep-
tomyces tsukubaensis, which led to tacrolimus.2,3
Despite these revolutionary finds, neurotoxicity
became one of the earliest concerns in the management
of transplant recipients. Many of the dramatic presen-
tations of patients rapidly lapsing into coma and status
epilepticus now can be explained largely by unfamiliar-
ity and erroneous titration of the drug in earlier days.
However, neurotoxicity associated with the introduc-
tion of immunosuppressive agents has remained a sig-
nificant postoperative complication. Neurotoxicity is
particularly prevalent in agents active through the
mechanism of calcineurin inhibition.4,5 The spectrum
of neurotoxicity has changed over the years, and differ-
ences in severity of manifestation are apparent. This
review focuses on the current understanding of patho-
physiological characteristics, clinical recognition, neu-
roimaging, and management of certain unique manifes-
tations in immunosuppression neurotoxicity.
Prevalence of Neurotoxicity in
Transplantation
The incidence of neurotoxicity varies according to the
organ transplanted and is markedly dependent on whether
Liver Transplantation, Vol 7, No 11 (November), 2001: pp 937-942
minor side effects are reported. For example, tremor devel-
ops in approximately 40% of patients on cyclosporine and
tacrolimus therapy, which currently may not be consid-
ered serious and tabulated as a side effect. Yesterday’s side
effects may be today’s accepted nuisance. The prevalence
of neurological complications and neurotoxicity remains
an approximation unless a neurologist performs rounds
with the transplantation team. All studies that have
reported cyclosporine and tacrolimus neurotoxicity are
retrospective. Immunosuppression neurotoxicity from
cyclosporine or tacrolimus seems to occur in 25% of
patients after lung or liver transplantation.6-9 Some studies
included postoperative confusion, a condition that may
have multifactorial triggers.
It is uncertain whether the incidence of neurotoxic-
ity and its severity have decreased with the intravenous
formula of cyclosporine, but one may expect that a
learning curve existed. However, the initial experience
with Neoral (Novartis, East Hanover, NJ) suggests that
severity is much less than with the intravenous form of
cyclosporine. This microemulsion may result in less
erratic absorption.7,10 What may be a fairly constant
clinical observation is that immunosuppressive neuro-
toxicity, which occurs in most patients during the intra-
venous loading of tacrolimus or cyclosporine, is much
less common and often much less severe after the post-
operative phase has subsided and the patient is stable.
Cyclosporine neurotoxicity occurs in less than 5% of
patients after renal and bone marrow transplantation.
Reasons remain unknown.
Clinical Features of Neurotoxicity
Neurotoxicity from calcineurin inhibitors can be subtle
in its presentation, but fortunately, the first signs now
are easily recognized. An overwhelming proportion
of patients with immunosuppression neurotoxicity
develop a tremor. This fine tremor in the upper extrem-
From the Department of Neurology, Mayo Clinic, Rochester, MN.
Address reprint requests to Eelco F.M. Wijdicks, MD, Department of
Neurology, W8A, Mayo Clinic, 200 First St, Rochester, MN 55905. Tele-
phone: 507-538-1032; FAX: 507-266-4419; E-mail: wijde@mayo.edu.
Copyright © 2001 by the American Association for the Study of
Liver Diseases
1527-6465/01/0711-0101$35.00/0
doi:10.1053/jlts.2001.27475
937
938 Eelco F.M. Wijdicks
ities becomes more evident when holding hands in pos-
ture. It can become extremely severe and prevent pa-
tients from using their signatures for writing checks or
signing contracts.11 If unrecognized, patients may lapse
into a psychotic stage. This may vary from extreme
restlessness, insomnia, and marked disorientation to an
acute manic syndrome.12 Visual hallucinations consist-
ing of bright colors are part of this acute confusional
state. Spontaneous hallucinations of kaleidoscopic con-
figurations and increased sensitivity to bright colors
punctuate the picture.6 Delusions are common, and the
patient may develop rambling speech.13
Articulation of speech may become less precise, and
vowel distortions, as if a patient suddenly spoke with a
foreign accent, seem rather characteristic for this type of
toxicity. In some patients, action myoclonus speech is
more evident. These patients stutter when speaking at a
normal pace, but when instructed to speak very slowly,
they are able to speak without interruptions. Mutism
may occur, but it is often a speech apraxia in which the
patient is unable to protrude the tongue, blow a kiss, or
whistle.14,15 Sometimes only sounds are produced, and
swallowing may become involved. A purely extrapyra-
midal syndrome with pseudobulbar dysarthria may
occur, and opisthotonus and severe rigidity have been
found in the most severe cases.16
More severe involvement includes cortical blind-
ness, in which the patient confabulates his environ-
ment.17,18 In most cases with worsening neurotoxicity,
seizures have emerged. It appears, at least in the liver
transplant population, that generalized tonic-clonic sei-
zures occur most commonly in patients who have
immunosuppressive neurotoxicity. However, other
possible causes, particularly an acute structural lesion,
such as intracranial hematoma or lymphoma, should be
considered.19 Status epilepticus may evolve if all these
warning symptoms are not recognized, and patients
may remain postictally in a deep unresponsive coma.
All these severe manifestations are reversible in most
instances. Neurotoxicity is mainly characterized by
patients who rage and ramble, shiver and shake.
Muromonab (CD3; OKT3) has a role as a rescue
agent for failing grafts and may be a primary agent,
particularly in heart and lung transplantation. Apart
from the well-known acute adverse effects (cytokine
release syndrome) noted within 1 hour of the dose
(fever, chills, diarrhea, and myalgias), headache associ-
ated with low-grade fever and meningism may occur.
Cerebrospinal fluid samples remain aseptic, and exam-
ination shows polymorphic or mononuclear cells. It is
apparent in less than 2% of cases and is rapidly revers-
ible.20 Toxic leukoencephalopathy with wild psychotic
episodes, asterixes, and seizures is now uncommon.21 A
more recently developed humanized anti-CD3 anti-
body had a threefold lower incidence of headaches.22
Pathogenesis
Both cyclosporine and tacrolimus are highly lipophilic
drugs and contain many aliphatic groups. Their chemical
structure is totally different, but these groups reduce polar
charges and make them virtually insoluble in water. Thus,
these drugs need to be dissolved in oils or alcohols.
The lipophilic nature of both substances does not
imply that they rapidly enter brain tissue. Several bar-
riers have to be overcome. The most important is the
blood-brain barrier, created by an anatomic barrier
and transport system that extrude drugs. One possible
mechanism of entry is at the capillary level. Injury to
brain capillary endothelial cells may inhibit the expres-
sion of a p-glycoprotein, which has been recognized
as a drug-efflux pump (Fig. 1).23-25 Cyclosporine also
appears to enhance nitric oxide production, which also
may cause dysfunction of the blood-brain barrier.
The earliest abnormality in cyclosporine or tacroli-
mus neurotoxicity appears to be fluid extravasation
(vasogenic edema), not cell destruction (cytotoxic
edema). A recent magnetic resonance (MR) study of a
patient with cyclosporine neurotoxicity using diffusion
mapping showed increased diffusion on the apparent
diffusion coefficient (ADC) map that was highly sug-
gestive of vasogenic edema.26 Cytotoxicty and cytotoxic
edema may occur after prolonged drug exposure.27-29
When this occurs, severe vasoconstriction, caused by a
disturbance in endothelial control of the vascular tone
involving endothelium, leads to ischemia.
Similarities between hypertensive encephalopathy
and immunosuppression neurotoxicity that cause pos-
terior reversible leukoencephalopathy are striking, lead-
ing some investigators to propose that hypertension is
the main common pathway in this entity.30 However,
many patients with cyclosporine neurotoxicity do not
have severe hypertension, and a significant increase in
mean arterial blood pressure is a feature that typically
occurs 1 month after transplantation, far beyond the
interval of maximal risk for neurotoxicity.31
Another attractive early hypothesis has been the effects
of hypocholesterolemia on the transport of cyclosporine.12
This typically applies to patients who develop neurotoxic-
ity after liver transplantation, and this mechanism is not
operative in other types of transplantation. Hypocholes-
terolemia is expected in patients with significant liver fail-
ure before transplantation, and this condition facilitates
the alternative route of cyclosporine binding to low-den-
 Neurotoxicity of Immunosuppression 939

Figure 1. Proposed mechanism of cyclosporine neurotoxicity. Disturbance of the blood-brain barrier (BBB) may lead to
vasogenic edema, but prolonged exposure may trigger apoptosis. Nitric oxide and possibly anoxic injury may facilitate
opening of the blood-brain barrier.

sity lipoprotein particles. Hypocholesterolemia may also
upregulate low-density lipoprotein receptors in the brain,
increasing the chance of entry into the brain.12 However,
again, the major stumbling block in this hypothesis is the
need for this complex particle to overcome the blood-brain
barrier.32 Previous studies have found that cyclosporine
does not cross the blood-brain barrier. However, in a
recent unconfirmed study, 4 of 14 patients had metabo-
lites in cerebrospinal fluid without measurable levels of the
parent drug. These patients had significantly greater blood
urea nitrogen levels and liver function test results than
patients without these traces. None of these patients had
cyclosporine neurotoxicity, which makes the relevance of
this finding uncertain.33 Also, previous injury to the
blood-brain barrier, e.g., caused by significant hypoten-
sion, is not a common feature in patients with neurotox-
icity.
Whatever mechanism has a role, several observations
are important. Neurotoxicity is much more common
during the intravenous administration of cyclosporine.
This implies a sudden high exposure to cyclosporine,
which may cause endothelial damage and vasogenic
edema. The severity of neurotoxicity has been dramat-
ically reduced with the use of Neoral, which reduces
erratic absorption because of its microemulsion prepa-
ration.7,34 If endothelin has an important role in immu-
nosuppressive agent neurotoxicity, trials of endothelin
inhibitors may be considered; they have shown some
effect in experiments with nephrotoxicity. Prolonged
exposure leads eventually to apoptosis, and oligoden-
droglial cells are more susceptible than astrocytes.29
This fits nicely with the white matter abnormalities on
MR imaging (MRI). A few biopsy results have been
reported and varied from edema to overt demyelination
and one exceptional case of vasculitis.32,35-37
Neuroimaging
Neuroimaging abnormalities with cyclosporine and
tacrolimus immunosuppressive toxicity have been well
940 Eelco F.M. Wijdicks

Figure 2. Symmetric hypodense, partly hemorrhagic, lesions in the occipital lobes and basal ganglia on computed
tomography scan associated with cyclosporine neurotoxicity (A) and resolution on follow up study (B).

described, but remain uncommon, including patients
who have significant psychiatric and neurological man-
ifestations.38-43 The most characteristic feature is poste-
rior leukoencephalopathy on computed tomographic
scan or MRI. Cortical hyperintensity has been reported
in liver transplant recipients with cyclosporine neuro-
toxicity. This unusual feature, predominantly localized
in the cingulate gyrus and occipital lobe, has been
explained by blood-flow reduction in pial vessels and
supports the vasoconstriction hypothesis. The true
prevalence of MRI abnormalities in patients with cyclo-
sporine or tacrolimus neurotoxicity is not known. In
our series of patients with tacrolimus neurotoxicity,
which included patients with speech abnormalities and
seizures, no MRI abnormalities could be detected.
Several later case reports showed similar MRI findings
as with cyclosporine. These MRI abnormalities involved
white matter abnormalities, but also may involve the cor-
tex, cerebellum, and such deeper structures as the basal
ganglia.38 These abnormalities are quickly reversible after
discontinuation of the drug, again supporting vasogenic
edema. Examples of CT and MRI are shown in Figures 2
and 3. Single-photon emission computed tomography
may become a useful diagnostic test in uncertain cases
because asymptomatic patients treated with cyclosporine
have normal perfusion parameters.39
Management
The diagnosis remains tentative in many patients. Con-
sulting neurologists are challenged to consider the diag-
nosis in patients with a confusional state, no evidence of
abnormalities on neuroimaging, and increasing cyclo-
sporine or tacrolimus levels, which are deliberately
increased by the transplant team to postoperatively load
the patient. Moreover, a well-recognized phenomenon
is the poor correlation with tacrolimus and cyclosporine
trough levels. (Peak levels have not been studied system-
atically, but may prove more useful.) Thus, the most
severe reversible manifestations may appear in patients
with subtherapeutic trough levels.
It is important first to consider discontinuation of
cyclosporine or tacrolimus therapy. It can be briefly
replaced by mycophenolate mofetil and restarted with
 Neurotoxicity of Immunosuppression
Figure 3. MRI in a patient with tacrolimus neurotoxicity.
Note that diffuse white matter hyperintensities with no
specific predilection to the posterior lobes.
adjustment to a lower target level. It is important to iden-
tify drugs that may increase levels of immunosuppressive
agents and trigger neurotoxicity. For cyclosporine, these
are many of the cephalosporins, diltiazem, verapamil, and
high-dose methylprednisolone. For tacrolimus, erythro-
mycin, danazol, and fluconazole commonly decrease the
breakdown of tacrolimus. Switching to cyclosporine ther-
apy in patients with tacrolimus neurotoxicity and vice
versa has been studied in two large series, with resolution of
neurotoxicity in virtually all cases. Rejection was approxi-
mately 30% in both studies, but surprisingly, there was no
recurrence of neurotoxicity after restarting the medica-
tion.9,44
An acute confusional state is best treated with halo-
peridol and lorazepam. Seizures are best treated with
intravenous lorazepam, but if the metabolic cause can-
not be easily corrected and electroencephalography
shows epileptic activity, it is important to add phenyt-
oin for approximately 1 month. All patients with sei-
zures should have serum magnesium levels measured.
Cyclosporine neurotoxicity is understandably associ-
ated with hypomagnesemia because cyclosporine
increases the urinary excretion of magnesium because of
its interference with tubular reabsorption. Supplemen-
tation with magnesium resulted in resolution of seizures
in some reports.45,46
941
Headache is a common symptom, but poorly char-
acterized.47,48 It has many features of a vascular-type
headache and may increase in frequency after pro-
longed exposure. Switching to another immunosup-
pressive agent can result in dramatic relief.49 High-dose
aspirin (1,300 mg) may suffice in other patients if head-
aches are not particularly severe. Verapamil, a drug
commonly used for migraine, should be discouraged
because it may increase cyclosporine levels and paradox-
ically worsen headaches. Grapefruit juice consumption
may also enhance absorption and should be eliminated.
Propranolol (20 mg every 6 to 8 hours) has been very
effective in these patients, who eventually may ask for
narcotics for pain control.50
Conclusion
The clinical features of immunosuppression neurotox-
icity have become well understood, but not its mecha-
nism, predictive factors, and best management. Its true
relevance becomes clear when seizures, cortical blind-
ness, mutism, and coma occur. Failure to recognize its
heralding symptoms may potentially increase morbid-
ity and length of stay in the transplant intensive care
unit.
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