Journal of Hepatology, 1992; 16:31-37
31
© 1992 ElsevierScientific Publishers Ireland Ltd. All rights reserved. 0168-8278/92/$05.00 HEPAT 01157
Encephalopathy and neuropathy in end-stage liver disease before and after liver transplantation Krister H6ckerstedt a, Soili Kajaste e, Antti M u u r o n e n b, Raili Raininko o, Anna-Maria Sepp~il~iinen c and Matti Hillbom b aFourth Department of Surgery. bDepartment of Neurology, CDivisionof Clinical Neurophysiology, dDepartment of Radiology and CHelsinki University Hospital, Ullanlinna Sleep Disorders Research Centre, Helsinki, Finland
(Received 3 March 1991)
The nervous system involvement of 8 patients with end-stage liver disease was evaluated by means of clinical neurological, neuropsychological, neurophysiological and neuroradiological investigation before and 6-12 months after a successful liver transplantation. Preoperatively, all subjects (7 women, 1 man; mean age 40 years, range 30-54 years) exhibited decreased muscle strength and 2 patients manifested clinical signs of polyneuropathy. In neuropsychological tests, slight visuoconstructive apraxia, and disturbances of verbal memory and cognitive function were observed. Magnetic resonance imaging (MRI) revealed cerebral lesions in two patients. After transplantation, muscle strength reverted to normal in all patients, polyneuropathy improved and in all but 2 patients recovery of neuropsychological functioning was observed. Clinical signs of encephalopathy had disappeared. All patients were emotionally better adjusted after transplantation. Four subjects showed new, albeit mild changes in neurophysiological and neuropsychological tests postoperatively. We conclude that the majority of neurological impairment disappeared after liver transplantation. We want to stress that evaluation of neurological sequelae of liver transplantation needs to be based on assessments both before and after liver transplantation. K e y words: Cirrhosis; Encephalopathy; Liver function; Neurology; Neurophysiology; Neuropsychology;
Neuroradiology; Polyneuropathy
A number of reports have recorded neurologic complications after liver transplantation (1-7). Metabolic and anoxic encephalopathy, cerebrovascular lesions, myelinolysis, central nervous system (CNS) infections, side-effects of immunosuppressive drugs, and mental complications have been described. Previous postoperative studies are all rather inconclusive since they have not included neurological observations of patients before transplantation. Encephalopathy is common in cirrhotics. 50-80% exhibit some degree of cerebral dysfunction when investigated by neuropsychological tests and electroencephalography (EEG) (8-13). Delirium has been described in transplant candidates (14). Comprehensive neurological data before and after liver transplantation have not been previously reported.
In the present study 8 patients with non-alcoholic cirrhosis were prospectively examined both before and after transplantation for possible encephalopathy and peripheral neuropathies.
Patients and Methods
The study included 8 adult patients (7 women and ! man, mean age 40 years, range 30-54 years) with severe chronic end-stage liver disease who underwent liver transplantation in Helsinki. Six had primary biliary cirrhosis (PBC), one chronic active hepatitis (CAH) and one primary sclerosing cholangitis (PSC). One PBC patient was retransplanted twice because of cytomegalo-
Correspondence to: Krister H6ckerstedt,M.D., Fourth Department of Surgery,Universityof Helsinki, Kasarmikatu I l. SF-00130Helsinki,Finland.
32
K. HOCKERSTEDT et al.
virus (CMV) disease and chronic rejection, 9 and 18 months after initial transplantation. All patients had cirrhosis (grade III or IV) established by liver biopsy, and severe complications of portal hypertension. General condition had markedly deteriorated and muscle wasting was evident in all cases. All but one patient had ascites. Five had repeatedly experienced life-threatening variceal bleeding. None of the patients was able to work, mainly due to poor general condition and encephalopathy. The biochemical data relating to the patients (Table 1) revealed marked cholestasis and severely impaired synthesizing capacities of the liver. Patients underwent liver transplantation a mean of 26 days (range 9-44) after assessment. Immunosuppression was undertaken initially with a triple drug regimen of methylprednisolone (MP), azathioprine (Aza) and cyclosporin A (CyA) in tapered doses. After 2-8 weeks Aza was stopped in 7 subjects. At follow-up the mean daily dose during 6-12 months of M P ranged from 0.2 to 0.4 mg/kg body wt./day, and CyA from 6.4 to 10.2 mg/kg/day with dose adjusted to blood trough levels. The mean dose of Aza was neglible in 7 and 1.5 mg/kg/day in one patient.
Clinical neurological examination Preoperatively, all the patients were assessed after they had been accepted on the waiting list for liver transplantation. Care was taken to record any history of head injury or other conditions that could alter neurological and neuropsychological functioning (Table 2). Postoperatively all tests were repeated 6 or 12 months
after transplantation. The cerebrospinal fluid was examined if a CNS infection was suspected. The clinical neurological examination (M.H., A.M.) included tests for all cranial nerves, motor and sensory functions, station and gait, coordination, tremor, muscle tone and strength, deep tendon reflexes and mental functions. Muscle strength was tested with a standard handgrip d y n a m o m e t e r and by asking the patient to squat down and stand up as well as to walk on tiptoe and heels. If the patient was bedridden, movements and muscle contractions after voluntary efforts were examined. Muscle strength was tested according to the following scale: normal s t r e n g t h = 5 , decreased strength= 4, lifting a limb against g r a v i t y = 3 , movement of a limb but not lifting against gravity = 2, voluntary contraction of muscle o b s e r v e d = l , absence of voluntary muscle contraction = 0. Polyneuropathy was defined clinically as diminished or loss of tendon reflexes and defective perception of touch and vibration sensation and weakness.
Neurophysiological methods The peripheral nervous system was studied by measuring the m o t o r conduction velocity (MCV) and the F-wave of the right median, ulnar and deep peroneal nerves (15). The sensory conduction velocities (SCV) from finger to wrist in the right median and ulnar nerves, and from calf to ankle in the right sural nerve were examined. The somatosensory evoked potential (SEP) was measured by stimulating the median nerve (each side separately) at the wrist with 0.2-ms electrical pulses
TABLE I Laboratory tests in 8 patients before and 6-12 months after liver transplantation Reference values~
Haemoglobin Bilirubin Albumin Factor V NH4 115-180 g/1 2-20 lamol/I 35-55 g/l 76-124 % 6-50 lamol/I Before 88.4 + 4.1 194.6__+30.4 22.4 + 1.3 40.5 _ 4.3 88.5 + 7.3 After 124.9+ 3.2 20.6 + 1.8 37.8 ___1.6 99.3 ___5.0 39.9 ___4.1 Values are mean + S.E.M. 90% confidence limits of healthy subjects. A highly significant improvement was seen in all tests after transplantation (p < 0.01). TABLE 2 Motor (MCV) and sensory (SCV) nerve conduction velocities (m/s) before and after liver transplantation in 7 patients (mean+ S.D.) Nerve and conduction velocity Median nerve
MCV SCV Peroneal nerve MCV Sural nerve SCV a90% confidence limits of healty subjects.
Transplantation Before After 54.2__+6.1 56.8+2.0 49.9+5.7 51.8__+3.7 45.1 + 6 . 1 45.5+3.7 40.6+6.7 42.4+9.1
Reference values~ 50-65 50-65 45-55 40-50
ENCEPHALOPATHYIN LIVERTRANSPLANTATION strong enough to elicit a minor motor response, and recording at the C VII spine and electrodes C3 and C4. Usually 200 responses were averaged. The brainstem auditory evoked potential (BAEP) was recorded by separately stimulating each ear with short pulses of white noise. Electrodes were placed on the ipsilateral mastoid process and the forehead. Four sets of 1000 responses were averaged and the peak latencies were measured from the grand averages. Electroencephalograms (EEG) were recorded using the international 10-20 electrode placement system. Postoperatively one patient refused to allow MCV, F-wave and SEP measurements.
Neuropsychological methods Neuropsychological tests were selected to allow comprehensive study of cognitive deficits and emotional disturbances in a short 2-h test (16). Intellectual ability was evaluated using the Wechsler Adult Intelligence Scale (WAIS) and the information, comprehension, similarities, digit symbol, picture completion and block design subtests. Memory was examined by means of the Wechsler Memory Scale (WMS), which mainly involves verbal tasks. Recollection of the logical stories of the WMS was checked twice at every examination: immediately at onset of testing and after 1 h in order to test retention (WMS%). Trail-making tests were used to assess visuomotor tracking. Stroop tests were used to evaluate capacity to resist mental interference. In Stroop C and Trail-making B tests we used a reversed scale, in which low values indicate best function, whereas in the other tests a high value is a sign of good function. Visuoconstructive function was examined by having the subjects perform drawing tasks (16). Data on emotional adjustment were obtained by questionnaires as the Cornell Medical Index Form N2 (17), or the SCL-90-R questionnaire (18). Each patient served as her or his own control. The findings were compared with results relating to a control group of 53 healthy subjects, 41-50 years old. Neuroradiological methods We used magnetic resonance imaging (MRI) examination since it has been found more useful than CT-scan of the brain (19). The examination was performed using an Acutscan MR imager (Instrumentarium Corporation, Finland) operating at 0.02 T. The slice thickness was 10 mm and the matrix size 128 x 256 mm. Contiguous T2-weighted axial and coronal slices using a pulse sequence of SE 2000/150 were obtained at each examination. One patient refused to be examined because of claustrophobia.
33
Statistics Wilcoxon's signed rank test was used to compare the pre-operative and postoperative biochemical test results. The significance of differences of the nerve conduction time and the neuropsychological findings were assessed using Student's paired t-test.
Results
Case 1 At the time of transplantation this 32-year-old man with PSC was cachectic with grade II clinical encephalopathy. He was unable to stand up. Muscle strength was quantitated to be grade 3. Deep tendon reflexes were absent from lower extremities, but pain, touch and vibration sensitivities were present. Polyneuropathy was confirmed by electroneuromyography (ENMG) and a slow F-wave. BAEP findings were abnormal with bilaterally prolonged central conduction times. The patient exhibited slight verbal memory and visuomotor tracking disturbances. The postoperative course was complicated by acute rejection (20) and CMV disease. Six months after transplantation his clinical condition was good and he was doing heavy work. His muscle strength was normal (grade 5), and the signs of polyneuropathy had disappeared. Neurophysiological findings concerning polyneuropathy had partly improved as was BAEP. His EEG, which preoperatively had been normal now showed some sharp transients on posterior temporal areas; on the other hand, the frequency of the background activity had increased. Verbal memory and visuomotor tracking had improved. Case 2 This 30-year-old woman suffering from PBC had a normal preoperative clinical neurological status, but was emotionally labile and exhibited slight memory function problems. Muscle strength was grade 4. On re-testing 6 months after operation her general condition was fairly good. She was easily managing as a housewife. However, moderate dysfunction of the graft was found. Acute rejection had been treated twice and she had repeatedly suffered CMV disease. She had a mild tremor in her hands. It did not seem to be druginduced, since she received only low doses of MP and CyA. Her EEG had become abnormal with scattered 0 waves. MRI of the brain revealed general mild cortical
34 atrophy. Emotionally she was more stable. Her memory function had improved. After 9 months this patient was retransplanted in hepatic coma, caused by CMV disease and chronic rejection. In spite of aggressive CMV prophylaxis with anti-CMV hyper-7-globulin and gancyclovir, both conditions recurred. MRI 7 months later showed progression of the cortical atrophy of the brain. A third transplantion was performed, again 9 months after the preceding operation. The same sequence of events again followed and the patient died 27 months after her first transplant in CMV disease and chronic rejection. Case 3
Before operation, this 39-year-old woman with PBC and severe osteoporosis exhibited an abnormal EEG with a moderate number of scattered 0 waves. The F-wave was slightly abnormal, too. Her memory was markedly impaired, as were her intelligence and capacity to resist mental interference. Muscle strength was grade 4. After transplantation, she experienced slight acute rejection. At re-testing 6 months after the operation she was in good condition. Her EEG had improved with fewer 0 waves and better background activity, however, some abnormality remained. Except for memory, all of her mental functions had improved. Case 4
A 40-year-old woman with CAH had a history of slight cerebral concussion. Correspondingly, she had a mild left hemiparesis, of which she was not aware. She displayed positional tremor in both hands and the muscle strength was grade 4. BAEP showed prolonged conduction time on the left and in EEG, scattered 0 waves were displayed in this area. Correspondingly, she was found to have a right parietal lesion by MRI brain scan. Her visual memory was impaired and this correlated with the localization of the MRI finding, which was probably due to the previous cerebral concussion. The tremor disappeared after operation, as well as all neurophysiological abnormalities. Muscle strength was normal, too. Her mental functions were found to have improved slightly. Her visual memory was, however, no better. Case 5
A 47-year-old woman with PBC exhibited decreased perception of vibration and had no tendon jerks. These findings were in agreement with abnormal ENMG, F-wave and SEP findings. Her main symptom was
K. Ht3CKERSTEDTet al. fatigue, and muscle strength was grade 4. Her mental function was reasonably good. Six months after operation, signs of polyneuropathy had improved markedly, but memory function had become abnormal. BAEP findings had also become slightly abnormal, revealing a clearly attenuated peak III on the left. The cause of these impairments was not clear. Case 6
This 50-year-old woman with PBC exhibited a focal lesion of the right parietal lobe of the brain on MRI both before and after transplantation. The presence of this lesion correlated with minor left hemiparesis of which she was not aware and which could have been a consequence of a cerebrovascular accident some years previously. EEG showed mild bi-temporal 0 abnormality. Muscle strength was grade 4. The patient's abnormal F-wave was normal 12 months after transplantation, but the EEG abnormalities were slightly increased. Her memory function was slightly improved. Case 7
Severe osteoporosis was present in this 41-year-old woman with PBC. Muscle strength was grade 3. Results of all tests were normal preoperatively, except for the EEG which revealed moderate bi-temporal slow wave abnormality. Mental functions were marginally impaired. The postoperative course was complicated by moderate acute rejection and CMV disease. On testing 6 months after surgery, mental function was slightly more impaired. EEG remained unchanged, but E N M G conduction velocities and F-wave had become pathological. Cerebrospinal fluid (CSF) showed normal cell content but leukocytes were slightly elevated (5" 106/1), the production of immunoglubulins was not increased. CMV could not be cultured from the CSF. MRI findings were still normal. She was suffering from severe headaches, probably caused by a spontaneous osteoporosis-induced fracture of the spinous process of the sixth cervical vertebra. The headache disappeared after fracture healing over the following 6 months. Case 8
This 39-year-old woman with PBC was also suffering from severe osteoporosis. Results of neurophysioiogical tests and MRI findings were normal, but mental functions were obviously markedly impaired. Muscle strength was grade 4. After transplantation, which was complicated by mild
ENCEPHALOPATHY IN LIVER TRANSPLANTATION acute rejection and C M V disease, her mental capacity improved slightly but was still markedly below normal on testing 12 months after transplantation. E E G and BAEP remained normal, she refused other neurophysiological tests.
Summary of case histories The results of biochemical liver tests of the 8 patients are shown in Table 1. The m o t o r (MCV) and sensory (SCV) nerve conduction velocities are displayed in Table 2 and the main neurophysiological results in Table 3. The neuropsychological results are summarized in Table 4. Preoperatively every patient exhibited fatigue, muscle wasting, and signs of encephalopathy. Emotional lability and impairment of neuropsychological function were apparent in all patients. Five had moderate defects in verbal memory. Visuo-constructive apraxia was evident in 5 subjects. Four patients had a diffuse type of abnormality in their EEGs. Three patients exhibited clear signs of polyneuropathy. In 2 patients M R I revealed a local cerebral lesion. They both had a history of head injury. After operation the general condition was good in all subjects. Muscle strength was regained. Neurological TABLE 3 Neurophysiological findings 6-12 months postoperatively in comparison with preoperative findings in liver transplant patients ENMG n=7
F-wave SEP n=6 n=7
BAEP EEG n=8 n=8
Improvement 4 3 1 3 2 Unchanged, normal 2 4 4 2 Unchanged, abnormal 1 2 1 Impairment 1 2 I 3 n = number of patients; BAEP = brainstem auditory evoked potential; EEG = electroencephalography; ENMG = electro-neuromyography; F-wave=latency indicating proximal motor conduction velocity; SEP=somatosensory evoked potential. TABLE 4 Neuropsychological test results in 8 patients before and 6-12 months after liver transplantation and in 53 healthy subjects (controls) Before After Controls transplant transplant WAIS VS 103 + 11.9 104+ 6.4 110+ 13.3 WAIS VS 91 + 13.4 105 ___10.3"* 109 + 12.9"* WMS 103+11.7 107+16.2 118+15.6" WMS% 84+9.7 81 _ 16.8 91 +9.1 Stroop C 107 + 11.6 87 ___11.3"* 110 _ 24.6 Trail B 112+29.5 97+21.4 101 +__46.0 Mean+S.D. *p
31
© 1992 ElsevierScientific Publishers Ireland Ltd. All rights reserved. 0168-8278/92/$05.00 HEPAT 01157
Encephalopathy and neuropathy in end-stage liver disease before and after liver transplantation Krister H6ckerstedt a, Soili Kajaste e, Antti M u u r o n e n b, Raili Raininko o, Anna-Maria Sepp~il~iinen c and Matti Hillbom b aFourth Department of Surgery. bDepartment of Neurology, CDivisionof Clinical Neurophysiology, dDepartment of Radiology and CHelsinki University Hospital, Ullanlinna Sleep Disorders Research Centre, Helsinki, Finland
(Received 3 March 1991)
The nervous system involvement of 8 patients with end-stage liver disease was evaluated by means of clinical neurological, neuropsychological, neurophysiological and neuroradiological investigation before and 6-12 months after a successful liver transplantation. Preoperatively, all subjects (7 women, 1 man; mean age 40 years, range 30-54 years) exhibited decreased muscle strength and 2 patients manifested clinical signs of polyneuropathy. In neuropsychological tests, slight visuoconstructive apraxia, and disturbances of verbal memory and cognitive function were observed. Magnetic resonance imaging (MRI) revealed cerebral lesions in two patients. After transplantation, muscle strength reverted to normal in all patients, polyneuropathy improved and in all but 2 patients recovery of neuropsychological functioning was observed. Clinical signs of encephalopathy had disappeared. All patients were emotionally better adjusted after transplantation. Four subjects showed new, albeit mild changes in neurophysiological and neuropsychological tests postoperatively. We conclude that the majority of neurological impairment disappeared after liver transplantation. We want to stress that evaluation of neurological sequelae of liver transplantation needs to be based on assessments both before and after liver transplantation. K e y words: Cirrhosis; Encephalopathy; Liver function; Neurology; Neurophysiology; Neuropsychology;
Neuroradiology; Polyneuropathy
A number of reports have recorded neurologic complications after liver transplantation (1-7). Metabolic and anoxic encephalopathy, cerebrovascular lesions, myelinolysis, central nervous system (CNS) infections, side-effects of immunosuppressive drugs, and mental complications have been described. Previous postoperative studies are all rather inconclusive since they have not included neurological observations of patients before transplantation. Encephalopathy is common in cirrhotics. 50-80% exhibit some degree of cerebral dysfunction when investigated by neuropsychological tests and electroencephalography (EEG) (8-13). Delirium has been described in transplant candidates (14). Comprehensive neurological data before and after liver transplantation have not been previously reported.
In the present study 8 patients with non-alcoholic cirrhosis were prospectively examined both before and after transplantation for possible encephalopathy and peripheral neuropathies.
Patients and Methods
The study included 8 adult patients (7 women and ! man, mean age 40 years, range 30-54 years) with severe chronic end-stage liver disease who underwent liver transplantation in Helsinki. Six had primary biliary cirrhosis (PBC), one chronic active hepatitis (CAH) and one primary sclerosing cholangitis (PSC). One PBC patient was retransplanted twice because of cytomegalo-
Correspondence to: Krister H6ckerstedt,M.D., Fourth Department of Surgery,Universityof Helsinki, Kasarmikatu I l. SF-00130Helsinki,Finland.
32
K. HOCKERSTEDT et al.
virus (CMV) disease and chronic rejection, 9 and 18 months after initial transplantation. All patients had cirrhosis (grade III or IV) established by liver biopsy, and severe complications of portal hypertension. General condition had markedly deteriorated and muscle wasting was evident in all cases. All but one patient had ascites. Five had repeatedly experienced life-threatening variceal bleeding. None of the patients was able to work, mainly due to poor general condition and encephalopathy. The biochemical data relating to the patients (Table 1) revealed marked cholestasis and severely impaired synthesizing capacities of the liver. Patients underwent liver transplantation a mean of 26 days (range 9-44) after assessment. Immunosuppression was undertaken initially with a triple drug regimen of methylprednisolone (MP), azathioprine (Aza) and cyclosporin A (CyA) in tapered doses. After 2-8 weeks Aza was stopped in 7 subjects. At follow-up the mean daily dose during 6-12 months of M P ranged from 0.2 to 0.4 mg/kg body wt./day, and CyA from 6.4 to 10.2 mg/kg/day with dose adjusted to blood trough levels. The mean dose of Aza was neglible in 7 and 1.5 mg/kg/day in one patient.
Clinical neurological examination Preoperatively, all the patients were assessed after they had been accepted on the waiting list for liver transplantation. Care was taken to record any history of head injury or other conditions that could alter neurological and neuropsychological functioning (Table 2). Postoperatively all tests were repeated 6 or 12 months
after transplantation. The cerebrospinal fluid was examined if a CNS infection was suspected. The clinical neurological examination (M.H., A.M.) included tests for all cranial nerves, motor and sensory functions, station and gait, coordination, tremor, muscle tone and strength, deep tendon reflexes and mental functions. Muscle strength was tested with a standard handgrip d y n a m o m e t e r and by asking the patient to squat down and stand up as well as to walk on tiptoe and heels. If the patient was bedridden, movements and muscle contractions after voluntary efforts were examined. Muscle strength was tested according to the following scale: normal s t r e n g t h = 5 , decreased strength= 4, lifting a limb against g r a v i t y = 3 , movement of a limb but not lifting against gravity = 2, voluntary contraction of muscle o b s e r v e d = l , absence of voluntary muscle contraction = 0. Polyneuropathy was defined clinically as diminished or loss of tendon reflexes and defective perception of touch and vibration sensation and weakness.
Neurophysiological methods The peripheral nervous system was studied by measuring the m o t o r conduction velocity (MCV) and the F-wave of the right median, ulnar and deep peroneal nerves (15). The sensory conduction velocities (SCV) from finger to wrist in the right median and ulnar nerves, and from calf to ankle in the right sural nerve were examined. The somatosensory evoked potential (SEP) was measured by stimulating the median nerve (each side separately) at the wrist with 0.2-ms electrical pulses
TABLE I Laboratory tests in 8 patients before and 6-12 months after liver transplantation Reference values~
Haemoglobin Bilirubin Albumin Factor V NH4 115-180 g/1 2-20 lamol/I 35-55 g/l 76-124 % 6-50 lamol/I Before 88.4 + 4.1 194.6__+30.4 22.4 + 1.3 40.5 _ 4.3 88.5 + 7.3 After 124.9+ 3.2 20.6 + 1.8 37.8 ___1.6 99.3 ___5.0 39.9 ___4.1 Values are mean + S.E.M. 90% confidence limits of healthy subjects. A highly significant improvement was seen in all tests after transplantation (p < 0.01). TABLE 2 Motor (MCV) and sensory (SCV) nerve conduction velocities (m/s) before and after liver transplantation in 7 patients (mean+ S.D.) Nerve and conduction velocity Median nerve
MCV SCV Peroneal nerve MCV Sural nerve SCV a90% confidence limits of healty subjects.
Transplantation Before After 54.2__+6.1 56.8+2.0 49.9+5.7 51.8__+3.7 45.1 + 6 . 1 45.5+3.7 40.6+6.7 42.4+9.1
Reference values~ 50-65 50-65 45-55 40-50
ENCEPHALOPATHYIN LIVERTRANSPLANTATION strong enough to elicit a minor motor response, and recording at the C VII spine and electrodes C3 and C4. Usually 200 responses were averaged. The brainstem auditory evoked potential (BAEP) was recorded by separately stimulating each ear with short pulses of white noise. Electrodes were placed on the ipsilateral mastoid process and the forehead. Four sets of 1000 responses were averaged and the peak latencies were measured from the grand averages. Electroencephalograms (EEG) were recorded using the international 10-20 electrode placement system. Postoperatively one patient refused to allow MCV, F-wave and SEP measurements.
Neuropsychological methods Neuropsychological tests were selected to allow comprehensive study of cognitive deficits and emotional disturbances in a short 2-h test (16). Intellectual ability was evaluated using the Wechsler Adult Intelligence Scale (WAIS) and the information, comprehension, similarities, digit symbol, picture completion and block design subtests. Memory was examined by means of the Wechsler Memory Scale (WMS), which mainly involves verbal tasks. Recollection of the logical stories of the WMS was checked twice at every examination: immediately at onset of testing and after 1 h in order to test retention (WMS%). Trail-making tests were used to assess visuomotor tracking. Stroop tests were used to evaluate capacity to resist mental interference. In Stroop C and Trail-making B tests we used a reversed scale, in which low values indicate best function, whereas in the other tests a high value is a sign of good function. Visuoconstructive function was examined by having the subjects perform drawing tasks (16). Data on emotional adjustment were obtained by questionnaires as the Cornell Medical Index Form N2 (17), or the SCL-90-R questionnaire (18). Each patient served as her or his own control. The findings were compared with results relating to a control group of 53 healthy subjects, 41-50 years old. Neuroradiological methods We used magnetic resonance imaging (MRI) examination since it has been found more useful than CT-scan of the brain (19). The examination was performed using an Acutscan MR imager (Instrumentarium Corporation, Finland) operating at 0.02 T. The slice thickness was 10 mm and the matrix size 128 x 256 mm. Contiguous T2-weighted axial and coronal slices using a pulse sequence of SE 2000/150 were obtained at each examination. One patient refused to be examined because of claustrophobia.
33
Statistics Wilcoxon's signed rank test was used to compare the pre-operative and postoperative biochemical test results. The significance of differences of the nerve conduction time and the neuropsychological findings were assessed using Student's paired t-test.
Results
Case 1 At the time of transplantation this 32-year-old man with PSC was cachectic with grade II clinical encephalopathy. He was unable to stand up. Muscle strength was quantitated to be grade 3. Deep tendon reflexes were absent from lower extremities, but pain, touch and vibration sensitivities were present. Polyneuropathy was confirmed by electroneuromyography (ENMG) and a slow F-wave. BAEP findings were abnormal with bilaterally prolonged central conduction times. The patient exhibited slight verbal memory and visuomotor tracking disturbances. The postoperative course was complicated by acute rejection (20) and CMV disease. Six months after transplantation his clinical condition was good and he was doing heavy work. His muscle strength was normal (grade 5), and the signs of polyneuropathy had disappeared. Neurophysiological findings concerning polyneuropathy had partly improved as was BAEP. His EEG, which preoperatively had been normal now showed some sharp transients on posterior temporal areas; on the other hand, the frequency of the background activity had increased. Verbal memory and visuomotor tracking had improved. Case 2 This 30-year-old woman suffering from PBC had a normal preoperative clinical neurological status, but was emotionally labile and exhibited slight memory function problems. Muscle strength was grade 4. On re-testing 6 months after operation her general condition was fairly good. She was easily managing as a housewife. However, moderate dysfunction of the graft was found. Acute rejection had been treated twice and she had repeatedly suffered CMV disease. She had a mild tremor in her hands. It did not seem to be druginduced, since she received only low doses of MP and CyA. Her EEG had become abnormal with scattered 0 waves. MRI of the brain revealed general mild cortical
34 atrophy. Emotionally she was more stable. Her memory function had improved. After 9 months this patient was retransplanted in hepatic coma, caused by CMV disease and chronic rejection. In spite of aggressive CMV prophylaxis with anti-CMV hyper-7-globulin and gancyclovir, both conditions recurred. MRI 7 months later showed progression of the cortical atrophy of the brain. A third transplantion was performed, again 9 months after the preceding operation. The same sequence of events again followed and the patient died 27 months after her first transplant in CMV disease and chronic rejection. Case 3
Before operation, this 39-year-old woman with PBC and severe osteoporosis exhibited an abnormal EEG with a moderate number of scattered 0 waves. The F-wave was slightly abnormal, too. Her memory was markedly impaired, as were her intelligence and capacity to resist mental interference. Muscle strength was grade 4. After transplantation, she experienced slight acute rejection. At re-testing 6 months after the operation she was in good condition. Her EEG had improved with fewer 0 waves and better background activity, however, some abnormality remained. Except for memory, all of her mental functions had improved. Case 4
A 40-year-old woman with CAH had a history of slight cerebral concussion. Correspondingly, she had a mild left hemiparesis, of which she was not aware. She displayed positional tremor in both hands and the muscle strength was grade 4. BAEP showed prolonged conduction time on the left and in EEG, scattered 0 waves were displayed in this area. Correspondingly, she was found to have a right parietal lesion by MRI brain scan. Her visual memory was impaired and this correlated with the localization of the MRI finding, which was probably due to the previous cerebral concussion. The tremor disappeared after operation, as well as all neurophysiological abnormalities. Muscle strength was normal, too. Her mental functions were found to have improved slightly. Her visual memory was, however, no better. Case 5
A 47-year-old woman with PBC exhibited decreased perception of vibration and had no tendon jerks. These findings were in agreement with abnormal ENMG, F-wave and SEP findings. Her main symptom was
K. Ht3CKERSTEDTet al. fatigue, and muscle strength was grade 4. Her mental function was reasonably good. Six months after operation, signs of polyneuropathy had improved markedly, but memory function had become abnormal. BAEP findings had also become slightly abnormal, revealing a clearly attenuated peak III on the left. The cause of these impairments was not clear. Case 6
This 50-year-old woman with PBC exhibited a focal lesion of the right parietal lobe of the brain on MRI both before and after transplantation. The presence of this lesion correlated with minor left hemiparesis of which she was not aware and which could have been a consequence of a cerebrovascular accident some years previously. EEG showed mild bi-temporal 0 abnormality. Muscle strength was grade 4. The patient's abnormal F-wave was normal 12 months after transplantation, but the EEG abnormalities were slightly increased. Her memory function was slightly improved. Case 7
Severe osteoporosis was present in this 41-year-old woman with PBC. Muscle strength was grade 3. Results of all tests were normal preoperatively, except for the EEG which revealed moderate bi-temporal slow wave abnormality. Mental functions were marginally impaired. The postoperative course was complicated by moderate acute rejection and CMV disease. On testing 6 months after surgery, mental function was slightly more impaired. EEG remained unchanged, but E N M G conduction velocities and F-wave had become pathological. Cerebrospinal fluid (CSF) showed normal cell content but leukocytes were slightly elevated (5" 106/1), the production of immunoglubulins was not increased. CMV could not be cultured from the CSF. MRI findings were still normal. She was suffering from severe headaches, probably caused by a spontaneous osteoporosis-induced fracture of the spinous process of the sixth cervical vertebra. The headache disappeared after fracture healing over the following 6 months. Case 8
This 39-year-old woman with PBC was also suffering from severe osteoporosis. Results of neurophysioiogical tests and MRI findings were normal, but mental functions were obviously markedly impaired. Muscle strength was grade 4. After transplantation, which was complicated by mild
ENCEPHALOPATHY IN LIVER TRANSPLANTATION acute rejection and C M V disease, her mental capacity improved slightly but was still markedly below normal on testing 12 months after transplantation. E E G and BAEP remained normal, she refused other neurophysiological tests.
Summary of case histories The results of biochemical liver tests of the 8 patients are shown in Table 1. The m o t o r (MCV) and sensory (SCV) nerve conduction velocities are displayed in Table 2 and the main neurophysiological results in Table 3. The neuropsychological results are summarized in Table 4. Preoperatively every patient exhibited fatigue, muscle wasting, and signs of encephalopathy. Emotional lability and impairment of neuropsychological function were apparent in all patients. Five had moderate defects in verbal memory. Visuo-constructive apraxia was evident in 5 subjects. Four patients had a diffuse type of abnormality in their EEGs. Three patients exhibited clear signs of polyneuropathy. In 2 patients M R I revealed a local cerebral lesion. They both had a history of head injury. After operation the general condition was good in all subjects. Muscle strength was regained. Neurological TABLE 3 Neurophysiological findings 6-12 months postoperatively in comparison with preoperative findings in liver transplant patients ENMG n=7
F-wave SEP n=6 n=7
BAEP EEG n=8 n=8
Improvement 4 3 1 3 2 Unchanged, normal 2 4 4 2 Unchanged, abnormal 1 2 1 Impairment 1 2 I 3 n = number of patients; BAEP = brainstem auditory evoked potential; EEG = electroencephalography; ENMG = electro-neuromyography; F-wave=latency indicating proximal motor conduction velocity; SEP=somatosensory evoked potential. TABLE 4 Neuropsychological test results in 8 patients before and 6-12 months after liver transplantation and in 53 healthy subjects (controls) Before After Controls transplant transplant WAIS VS 103 + 11.9 104+ 6.4 110+ 13.3 WAIS VS 91 + 13.4 105 ___10.3"* 109 + 12.9"* WMS 103+11.7 107+16.2 118+15.6" WMS% 84+9.7 81 _ 16.8 91 +9.1 Stroop C 107 + 11.6 87 ___11.3"* 110 _ 24.6 Trail B 112+29.5 97+21.4 101 +__46.0 Mean+S.D. *p
