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Neurological complications following liver transplantation.

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Neurological Complications
Following Lver Transplantation
Daniel P. Stein, MD,' &chard J. Lederman, MD, PhD,* David P. Vogt, MD,t William D. Carey, MD,$
and Thomas A. Broughan, MDt
Neurological complications occurred i n 4 (19%) of 2 1 consecutive patients (Group 11) undergoing orthotopic liver
transplantation, compared with a 47% (9119) incidence in our initial series (Group I). In G r o u p 11, the neurological
problems included new recurrent headaches a n d delayed intracerebral hemorrhage (1 patient), partial third nerve
palsy and brachial plexopathy (1 patient), and ataxic dysarthria with encephalopathy (2 patients). Seizures, noted in 8
of 5, neurologically affected G r o u p I patients, were not encountered in G r o u p II. Of the 4 patients in t h e entire series
with the cerebrocerebellar syndrome, 2 had partial recovery after stopping treatment with cyclosporine, 1 stabilized
when cyclosporine was discontinued b u t later worsened when rechallenged, and 1 had full recovery but died follolwing
a second transplantation. Brain magnetic resonance images appeared normal in 3 of the 4 patients. Complication!;
affecting vision included cortical blindness in 2 patients and occipital lobe hemorrhage in 1. All completely recovered.
Survival was comparable for patients with and those without neurological complications (69% and 63%, respectively)..
Immediate withdrawal of cyclosporine at t h e onset of a change in mental status or dysarthria and improvement i n
intra- and postoperative management may have contributed to t h e decreased incidence of neurological complications.
Stein DP, Lederman RJ, Vogt DP, Carey WD, Broughan TA. Neurological complications
following liver transplantation, Ann Neurol 1092;J 1:644-040
-
Liver transplantation has become a practical and effective option for patients with acute and chronic irreversible hepatic disease. Neurological complications occur
in 8.4 to 47.Op4 [ 1-51 of transplant recipients and can
affect many aspects of nervous system function.
Alterations in mental status can range from mild encephalopathy to akinetic mutisrn or coma, and from
mild anxiety or depression to psychosis with visual hallucinations and delusions { 1-61. Seizures, myoclonus,
tremor, quadriplegia, cerebellar dysfunction o r cortical
blindness, brachial plexopathy, poly- o r mononeuropathy, stroke, and central nervous system (CNS) infection are other potential complications { 1-5, 7-12].
A previous report on the first 19 patients undergoing orthotopic liver transplantation at the Cleveland
Clinic Foundation described the form, frequency, and
potential causes of postoperative neurological dysfunction [3}. This article briefly reviews the features of
our initial series and presents our experience with the
subsequent 2 1 patients undergoing orthotopic liver
transplantation. T h e effect of neurological cornplications on survival is also discussed.
Patients and Methods
Forty consccutive pntients undergoing 46 transplantations
between November 1984 and July 1988 were divided into
From the Ilc~pc~rtments
of 'Neurology, i-General Surgery, and $Gastroentenhpy, Clevelaiiit Clinic Founitation, Cleveland, OH.
RetciveLt
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p u b l i c ~ t i o nDec
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644 Lopyright
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two groups. Our initial series [ 5 } ,Group I, included 2 3 transplantations in 19 patients (10 males, 9 females), 18 adults
(19-52 years old) and 1 child Group 11, the subsequent
21 patients (10 males, 11 females) undergoing 2 3 transplantations between September 1986 and July 1988, included 17 adults (19-57 ycars old) and 4 children. Patient
data, including the incidence of neurological complications
and the 1-year survival rate, are displayed in Table 1.
Examination by a neurologist was a standard part of the
pretransplantation assessment. However, 1 patient (Patient
2) who subsequently developed a neurological complication
was not seen by a neurologist preoperatively.
Orthotopic liver transplantation has become a relatively
standardized, although demanding operative procedure { 131.
The operation may be thought of in three stages: dissecrion;
anhepatic stage (removal of the diseased liver and implantation of the donor liver), and reperfusion. In many centers,
venovenous bypass is used routinely during the anhepatic
stage of the procedure. Heparin-bonded cannulas placed in
the saphenous and portal veins return blood via a centrifugal
pump to the axillary vein through another piece of heparinbonded tubing 1141. The routine use of venovenous bypass
during the anhepatic stage of thc procedure has been challenged. Many centers, including the Cleveland Clinic Foundation, have found that bypass is necessary for hernodynamic
stability in only 10V of patients [ 151.
Venovenous bypass was routinely used in the first 2 1 patients of our series and not in any of the subsequent l!,
Address correspondence to Dr Stein, Neurornuscular Discdses Section, National Institute of Neurological Llisorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Building 10, Rooin
4N248,Bethrsda, M1> 20892.
1092 b i the Americm Neurological Association
Table I , Patient Data: 46 Transplantations in 40 Patients, from Nowmbev 1984
Patients without neurological complications
Patients with neurological complications
Total
t o J74ly
1988
Group I
11184-8186
Group I1
9/86-7188
Total
1-Yr
Survival Rate
10
17
27
17 (63%)
7 (47%)
19
patients. An analysis of hernodynamic parameters revealed
that cardiac output decreased an average of 40% and systemic vascular resistance increased an average of 90% during
the anhepatic stage of the procedure when bypass was not
used (David Vogt, unpublished data from our center, 1989).
However, blood pressure, pulse, and urine output were
maintained in spite of these temporary hemodynamic
changes. The intraoperative transfusion requirements, postoperative renal function, and survival rate were not significantly different between patients who underwent bypass and
those who did not. No patient in either group had a known
intraoperative air embolic event.
Intravenous corticosteroids and cyclosporine (Cy) were
used for immunosuppression in the early postoperative period. Cy was titrated to a level of 150 to 200 ngiml by measuring daily trough blood levels using high-pressure liquid
chromatography. Intravenous methylprednisolone sodium
succinate (Solu-Medrol) was tapered in 40-mglday decrements over 5 days from an initial dose of 200 mgiday. Prednisone, 20 mg by mouth each day, was then given as maintenance.
Levels of liver enzymes, bilirubin, electrolytes, total protein, albumin, magnesium, calcium, and phosphorus, as well
as complete blood cell count and coagulation parameters,
were determined every day until the time of hospital discharge. Cholesterol was not measured until October 1987,
following a report linking lower levels to neurological complications {l). Cholesterol was thus measured in only 1 neurologically affected patient (Patient 13).
Results
Clinical Data
Of the 40 patients, 13 (33%;) had neurological complications, t h e type and frequency of which are summarized in Table 2. T h e rate of complications in G r o u p
I, 47% (9119), exceeded that in G r o u p 11, 19% (41
2 1). This difference, however, was not significant (p =
0.09). Several patients had more than o n e neurological
complication (Table 3).
Of the 1.3 patients with neurological complications,
4 died within 1 year after transplantation, a 69% survival rate. No o t h e r patients in this g r o u p died during
the second postoperative year. I n the g r o u p without
neurological complications, t h e survival rate was 63%
at 1 year and 5 9 9 ' at 2 years following transplantation.
The underlying liver diseases in the neurologically
4 (19%)
21
9 (69%)
13 (33%)
26 (65%)
40
Table 2. Neurological Complicatiom
Central nervous system
Seizure
Cerebrocerebellar syndrome
Coma
Cortical blindness
Delusions with visual hallucinations
Psychotic behavior without hallucinations
Headache
Intracerebral hemorrhage
Tremorimyoclonus
Peripheral nervous system
Brachial plexopathy
Poly neuropathy
Partial third nerve palsy
Group I
Group I1
8
2
2
2
1
0
2
0
0
1
2
1
2
0
1
1
1
1
1
1
0
1
0
1
affected patients were varied and mirrored the hepatic
diseases in t h e patients without neurological dysfunction. Chronic active hepatitis was most common ( n =
4), followed by sclerosing cholangitis (n = S), cryptogenic cirrhosis (n = 3), Wilson's disease ( n = 2 ) , and
alcoholic cirrhosis (n = 1). Pretransplantation neurological abnormalities included hepatic encephalopathy
in 2 (Patients 1 and 13) and Guillain-Barre syndrome
in 1 (Patient 10).
Four patients developed a multifocal neurological
disorder, which we have characterized as a cerebrocerebellar syndrome, including altered sensorium, aphasia, dysarthria, ataxia, quadriparesis, and seizures. This
was a monophasic illness with partial recovery and significant residua in 2 (Patients 3 and 71, and was a fluctuating disorder with mild residua in 1 (Patient 13).
In Patients 3 and 13, neurological symptoms clearly
improved when the dosage of C y was lowered or discontinued. Symptoms in Patient 13 later worsened
when Cy was restarted. The fourth patient with cerebrocerebellar dysfunction (Patient 11) had mild encephalopathy and dysarthria b u t also had worsening
failure of the first hepatic graft. She seemed t o recover
from t h e neurological disorder b u t subsequently died
following a second liver transplantation.
Stein et al: Liver Transplant Complications
645
Table 3 Clrnziai Datu
-
Patient No
Age (yr)
8
0
Groul’ I1
10
I1
12
13
sex
Complications
F
M
M
M
M
M
M
F
M
Seizure, delusions, visual hallucinations
Seizure
Seizure, coma, cerebrocerebellar syndrome, polyneuropathy, cortical visual cicfcct
Seizure
Brachial plexopathy
Seizure, myoclonus, headache
Cerebrocerebellar syndrome, manic event, seizure, coma
Psychotic depression, seizure, headache, cortical blindness
Seizure
F
F
M
M
Headache, intracercbral hemorrhage
Cerebrocerebellar syndrome, paranoid ideation, tremor
Brachial plexopathy, partial third nerve palsy
Cerebrocerebellar syndrome, visual hallucinations, delusions
-
Two brief case histories illustrate the major features
of this complication.
P A T I F N ’ ~7.
A 42-year-old man underwent liver transplantation for chronic active hepatitis. From the third to the ninth
postoperative d a y . progressive dysarthria, agraphia, and lethargy developed. Seizure activity began on the eleventh postoperative day and continued sporadically over the next 4 days
despite treatment with phenytoin and intermittent diazepam.
Cy was stopped on the twelfth postoperative day. By postoperative day 19, he was in a state of vigilant unresponsiveness.
The patient stabilized over the next several weeks and subsequently became more responsive. He was able to communicate, dthough his speech was extremely slurred and often
unintcllipible. He had marked weakness as well as ataxia of
the extremities. By the sixth postoperative month, he could
ambuliite with a walker, feed himself, and communicate with
moderate dysarthria. At the time of writing, he had had no
further seizures, hut moderate ctysarthria and ataxia with mild
weakness persisted.
13. A 5)-year-old man with a history of cirrhosis
of uncertain origin, insulin-&pendent diabetes, and aortic
stenosis had two episodes of- hepatic encephalopathy prior
to transplanration. Eight days postoperatively, h e was more
lethargic; at 9 days, he was alert and oriented, with moderate
memory impairment and mild dysarthria. He had visual hallucinations and delusions, which were controlled with thiothixene. Cy was discontinued and he was maintained on
azathioprine and prednisone. Three months following transplantation, the liver function worsened and he was again
started o n Cy. Two months later, his mental status and speech
were again worse and the Cy was discontinued. O n neurological reevaluation 10 months after transplantation and 3
months after stopping Cy for the second time, he had moderate memory impairment, mild dementia, moderate ataxic dpsarthria. and normal motor and sensory function.
PATIENT
Seizures were the most commonly observed compli-
646 Ann‘ils of Neurology
Vol 3 I
No 6 June l‘Y12
cation overall, occurring in 8 ( 2 0 5 ) of the ,irO patienrs.
T h e seizures were usually generalizeci, a i d almost always multiple or recurrent. Onset occurred during the
first postoperative week in 4 patients, during the second postoperative week in 3, anti at 8 weeks following
transplantation in 1. O n e patient (Patient 3 ) had a scizure prior to transplantation. This was thought t o he
secondary to alcohol withdrawal; a preoperative eleitroencephalogram (EEG) and computed tomography
(CT) scan in this patient appeared normal. All patients
with seizures were in Group 1. O n e patient with
multiorgan failure, who had a seizure just prior t o
death, was not considered to have a neurological complication.
Abnormalities in vision included hallucinations, cortical blindness, and in Patient 13, transient bilateral
cecocentral scotomata. In Patient 8, cortical blindness
followed recurrent generalized seizures and resolved
over 24 hours.
I n Patient 6, recurrent, throbbing headache with
nausea and vomiting subsided after stopping treatment
with Cy but later recurred when Cy was resrarteil. This
patient then developed a chronic pain syndrome with
an addiction to oxycodone. In Patient 10, headache and
hypertension heralded a left occipiral lobe hemorrhage.
Peripheral nervous system complications of orthotopic h e r transplantation included brachial plexopathy
in 2 patients and sensorimotor polyneuropathy in 1
patient. In Patient 5 , the affected plexus was ipsilateral
to an axillary seroma, which developed at the site ~ u e J
for venovenous shunting. T h e plexopathy in Patient 12
was axon ioss in type, involving the left lateral and
posterior cords. Venovenous shunting was not employed in this patient. In Patient 3, the sensorimotor
polyneuropathy, axon loss in type, became apparent 5
weeks following transplantation as the patient recovered from a comatose state complii:-ated by peritonitis.
Table 4.Labaratov Data
Patient No.
Cerebrospinal
Fluid Analysis
Electroencephalography
Computed Tomography
NL
NL
NL
20 WBCs
Protein, 95 mgidl
ND
ND
NL
Protein, 75 mg/dl
10 WBCs
Protein, 56 mg/dl
Gen slow
Gen slow
Gen slow
Gen slow
BlED
ND
NL
Gen slow
NL
ND
...
NL
NL
Cortical atrophy
NL
ND
ND
ND
NL
ND
Delta coma
ND
Gen slow
Left occipital hemorrhage
ND
ND
Cortical atrophy, basal
ganglia infarctions
Magnetic
Resonance
Imaging
Group I
1
2
3
4
5
h
7
8
9
ND
ND
ND
ND
...
ND
ND
NL
ND
ND
...
...
ND
NL
NL
NL
NL
...
Group I1
10
11
12
13
NL
=
normal; Gen
=
generalized; ND
=
not done; BIED
=
bilateral independent epileptiform discharges; WBCs
Lboratov Studie.r
Table 4 lists the cerebrospinal fluid (CSF), EEG, CT,
and magnetic resonance imaging (MRI) findings in the
neurologically affected patients.
Cy levels were not abnormally high in 12 of the 13
affected patients. In Patient 1, however, following an
intravenous bolus of Cy and the occurrence of generalized seizure activity, the blood level was 3,015 ng/ml.
The use of high-dose steroids and the presence of
hypertension, fluid retention, or hyperosmolality could
not be uniformly associated with the neurological complications. Serum magnesium levels in all patients and
cholesterol levels in 1 patient (Patient 13) were normal
during neurologically symptomatic periods.
Autopsy Data
A postmortem examination was performed on 2 patients with neurological abnormalities.
PATIENT 1. Death was caused by an overwhelming cytomegalovirus infection 2 months following transplantation.
Examination of the brain and spinal cord revealed diffuse
subarachnoid hemorrhage with areas of demyelination surrounding blood vessels. Alzheimer type I1 astrocytes were
seen in the globus pallidus and glial nodules were seen in
cortical gray matter. Glial proliferation was also seen in the
inferior olives and areas of the cerebellum. A single intranuclear cytomegaloviral inclusion was noted in a cerebellar
vessel.
11. Death occurred 10 days following the second
transplantation in the setting of disseminated intravascular
coagulation. Brain weight was 1,190 gm. There was a yellow-
PATIENT
ND
ND
NL
Cortical atrophy,
basal ganglia
infarctions
=
whire blood cells.
green discoloration of the dura. Except for Alzheimer type
I1 astrocytes (prominent in the basal ganglia), there were no
other significant findings in the CNS.
Discussion
Orthotopic liver transplantation is currently performed
in at least 85 medical centers in the United States.
In 1990 there were 2,656 liver transplantations,
compared with 1,199 in 1987 (M. A. Wirtz, United
Network of Organ Sharing, personal communication,
1791). The frequency of neurological complications in
our patients is within the range reported by various
groups [I-51. Mortality at 1 and 2 years following the
transplantation did not seem related to the occurrence
of neurological complications.
An unusual cerebrocerebellar syndrome was observed in 4 patients. The morbidity from this condition
was significant in 3 and at least partially reversed following discontinuation of Cy in 1. We believe that Cy
is causally related to both this syndrome and perhaps
other neurological abnormalities observed in these patients. This hypothesis is supported by the following:
1. There have been similar reports of neurological
dysfunction in renal [6, 16-18}, bone marrow
[19-221, and cardiac 123, 241 transplant recipients
treated with Cy.
2. Clinical recovery and resolution of white matter abnormalities seen on CT [ l , 18, 22) or MRI [ l , 17,
23, 241 may follow a reduction or discontinuation
of Cy.
3. In several instances, discontinuation and rechal-
Stein et al: Liver Transplant Complications
647
lenge with Cy were associated with recovery from
and relapse of neurological dysfunction, respectively [ l , 8, 163.
Cy is a lipophilic, cyclic endecapeptide with a molecular weight of approximately 1,203 Da C251. Cy selectively affects the adaptive immune response through
the inhibition of helper-inducer T-cell activities and
the promotion of suppressor-cell function 1251. The
principal Cy metabolite (M17) has been found in abnormally high amounts in patients with neurological
dysfunction when Cy levels were considered “therapeutic” 1261.
The mechanism(s) by which Cy could cause neurological complications is unknown. We suggest the following two possibilities:
1. Primarily, by direct toxic effect on cellular processes within the exposed areas.
2. Secondarily, through ischemia caused by Cy’s effect
on the intracranial vasculature.
Our knowledge of the effects of Cy on the vascular
endothelium is derived mainly from research on the
pathogenesis of renal toxicity, which occurs in nearly
all patients taking Cy {25]. Cy alters the balance of
prostacyclin and thromboxane such that vasoconstriction predominates. This effect may be mediated
through an augmentation of thromboxane A> generation, as evidenced by the capacity for thromboxane
synthetase inhibitors to reduce Cy-induced renal dysfunction [251. Angiographic visualization of the cerebral vessels or attempts to treat neurologically affected
patients with vasoactive drugs have not been documented, to our knowledge.
The association between neurological abnormalities
and Cy in the setting of hypomagnesemia [20), hypocholesterolemia { I], aluminum overload 1271, hypertension, high-dose corticosteroid therapy {28), or
beta-lactam antibiotic therapy has been well documented. We were unable, however, to substantiate a
cause-effect relarionship among any of these variables
in our patients.
In a report from Martinez and associates [9}$complete neuropathological studies on 5 5 adults and 30
children following orthotopic liver transplantation revealed various forms of cerebral ischemia, most commonly global, various infectious processes, and very
common astrocyrosis with prominent Alzheimer type
I1 cells suggesting hepatic or other metabolic encephalopathy. Among this group, 61 patients had encephalopathy, 14 had coma of sudden onset, 30 had seizures,
and 15 had focal abnormalities. Subsequent reports C7,
10, 29) correlated the occurrence of seizures, mental
status changes, and focal deficits with ischemic or hemorrhagic strokes, niyelinolysis, and CNS infection. Bra-
648 Annals of Neurology Vol 31 No 6 June 1992
chial plexus injury, as observed in 2 of our patients,
was the subject of a recent report by Katirji 112).
Development of alternative immunosuppressants,
such as FK 506, will provide options for both primary
treatment and rescue therapy in those patients who do
not tolerate Cy. The neurological side effects a?9soc1’
ated with FK 506 include headache, paresthesias, and
tremor {30].
Cy remains a mainstay in our immunosuppressive
armamentarium. Its use in the liver transplant recipient
has resulted in an increase in the 1-year survival rate
by about 20% [ 3 11. Nonetheless, our data suggesit that
neurological complications may be lessened or reversed by discontinuation of Cy following the ap:pearance of mental status changes or cerebellar dysfunction. Routine preoperative neurological evaluation and
careful postoperative examination will allow further
definition of the causes and consequences of neurological dysfunction in the liver transplant recipient.
i
Presented at the annual meeting of the American Neurological Association, Atlanta, GA, October 16, 1990
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649
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