Chronic progressive hepatocerebral degeneration with spastic paraparesis, dementia, dysarthria, ataxia, tremor, and neuropsychiatric symptoms follows long-standing portal-systemic shunting, is associated with structural changes in the central nervous system, and does not respond to conventional therapy for hepatic encephalopathy. A case of advanced chronic liver disease with severe, progressive hepatocerebral degeneration after 23 yr of portal-systemic shunting is reported in whom there was significant objective improvement in intellectual function and in the chronic neurological signs 3 mo after orthotopic liver transplantation and further improvement 12 mo after transplantation

Chalk, Jonathan B.

Cheng, Wendy

Cooksley, W. Graham

Kerlin, Paul

Lynch, Stephen

Parkin, Philip J.

Pender, Michael P.

Powell, Elizabeth E.

Powell, Lawrie W.

Strong, Russell

University of Queensland eSpace

Gastroenterology 1990; 98 (4): 1079-1082. 
 
Improvement in Chronic Hepatocerebral 
Degeneration Following Liver Transplantation 
 
Elizabeth E. Powell, Michael P. Pender, Jonathon B. Chalk, 
Philip J. Parkin, Russell Strong, Stephen Lynch, Paul Kerlin, 
W. Graham Cooksley, Wendy Cheng, and Lawrie W. Powell 
 
Departments of Medicine and Biochemistry, University of Queensland, Department of Neurology, Royal 
Brisbane Hospital, Departments of Gastroenterology and Surgery, Princess Alexandra Hospital, 
Brisbane, Australia; and Department of Neurology, Christchurch Hospital, Christchurch, New Zealand 
 
 
Abstract 
Chronic progressive hepatocerebral degeneration with spastic paraparesis, 
dementia, dysarthria, ataxia, tremor, and neuropsychiatric symptoms 
follows long-standing portal-systemic shunting, is associated with 
structural changes in the central nervous system, and does not respond to 
conventional therapy for hepatic encephalopathy. A case of advanced 
chronic liver disease with severe, progressive hepatocerebral degeneration 
after 23 yr of portal-systemic shunting is reported in whom there was 
significant objective improvement in intellectual function and in the 
chronic neurological signs 3 mo after orthotopic liver transplantation and 
further improvement 12 mo after transplantation. 
 
Abbreviations used in this paper:  
CT, computed tomographic; EEG, electroencephalogram; HE, hepatic encephalopathy; OLT, 
orthotopic liver transplantation. 
 
Hepatic encephalopathy (HE) complicating chronic liver disease is characterized by 
episodes of acute neuropsychiatric dysfunction often with a precipitating factor, 
superimposed on a background of chronic neurological disease. Acute HE is a 
potentially reversible encephalopathy due to a metabolic disturbance, probably causing 
widespread alteration in cerebral neurotransmission (1). This should be distinguished 
from the less-common chronic progressive encephalopathies such as “acquired 
hepatocerebral degeneration” (2) and the persistent neuropsychiatric syndromes 
associated with cirrhosis (3). Chronic progressive encephalopathy is characterized by 
dementia, dysarthria, ataxia, tremor, extrapyramidal signs, and spastic paraparesis (2,4). 
It is more common in patients with large portal-systemic shunts, and usually does not 
respond to therapy for HE. Structural changes in the central nervous system have been 
reported in association with this rare, more persistent neuropsychiatric syndrome (2,3). 
Liver transplantation provides an opportunity to study the extent to which the chronic 
neuropsychiatric syndrome is reversible. 
A patient is reported with advanced chronic liver disease and 23 yr of portal-systemic 
shunting in whom severe long-standing neuropsychiatric dysfunction was a major 
manifestation of illness. Following successful orthotopic liver transplantation (OLT), 
there was a significant objective improvement in cerebral function and in the long-
standing neurological signs. 
 
Case Report 
 
A 44-yr-old woman was referred in April 1988 for consideration for OLT. Splenomegaly 
was first noted at 19 yr of age. Two years later she had massive upper gastrointestinal 
Gastroenterology 1990; 98 (4): 1079-1082. 
 
hemorrhage secondary to bleeding esophageal varices, and after stabilization, an end-to-
side portacaval anastomosis was performed. A liver biopsy performed during the 
laparotomy showed “post necrotic scarring with regenerative nodules.” Her splenomegaly 
subsequently resolved, and she had no further hematemeses. She had no history of risk 
factors for liver disease, specifically no blood transfusions before the initial presentation, 
no prescription or illegal drug use, and no relevant family history. She did not drink alcohol 
and had no symptoms suggestive of connective tissue disease. At 37 yr of age, she had her 
first episode of clinical hepatic encephalopathy, although her family de scribed episodes 
of intermittent confusion and abnormal behaviour for the previous 5 yr. She had 
several subsequent hospital admissions with ascites, peripheral edema, and recurrent 
chest infections. 
On admission in April 1988, she complained of lethargy and an inability to perform 
simple household duties. She was unable to shop or manage her finances and was 
cared for at home by her daughters. They had noted progressive deterioration in 
speech and memory and an altered gait over the 2 yr before admission. During this 
time, she had become more jaundiced, her pruritus had worsened, easy bruising had 
occurred, and she had lost 13 kg in weight. 
Physical examination showed a thin pigmented woman with scleral icterus who 
looked much older than her stated years. The liver and spleen were not palpable. She 
had thin skin with a few spider nevi, but no other peripheral signs of chronic liver 
disease. Examination of the higher functions was conducted with the Mayo Clinic 
short test of mental status (5) and with assessment by a speech therapist. Her 
orientation was correct for all items except the state. She was able to repeat up to 6 
numbers forwards. She could repeat the names of 4 objects on the second attempt, but 
could not recall any of these names after 5 min. Arithmetic calculation was correct for 
3 items of 4 but was very slow. For paired items in which she was required to name an 
abstract feature common to both items, she obtained 1 correct response from 3 pairs. 
On information testing, she obtained 2 correct responses from 4 items. She was able 
to construct a clock showing the time as 11:15, but was unable to copy a cube. Her 
total score was 23 of a possible 38 (5). Serial 2’s and 7’s were performed slowly, with 
4 errors out of 14 calculations and 3 errors from 7 calculations, respectively. In 
naming the months of the year backwards, she omitted 2 months. She deleted 3 letters 
from the alphabet. A Reitan’s number connection test with 25 points took 180 s to 
complete. 
Assessment by a speech therapist showed that she had delayed and poor auditory 
comprehension and recall of a paragraph. She was unable to accurately complete tasks 
requiring reading of whole paragraphs, and had mild word-finding difficulty. She was 
unable to write her name and address without making spelling errors and was unable 
to complete a dictation task. A mild ataxic dysarthria was present. The glabellar tap 
test was positive. A coarse and irregular tremor was present in the outstretched arms 
when the wrists and fingers were extended. Clasp-knife rigidity was present in the 
lower limbs, with nonsustained ankle clonus. Bradykinesia and symmetrical mild 
weakness were present in the upper and lower limbs. The deep tendon reflexes were 
symmetrically increased. The right plantar response was equivocal, and the left was 
flexor. Her gait was slow and ataxic. Joint position sense was reduced in the toes 
bilaterally. The remainder of the sensory examination was normal. 
Laboratory investigations showed the following concentrations: serum total bilirubin, 
165 µM(3-20); conjugated bilirubin, 96 µM(0-7); albumin, 20 g/L (35-50); globulin, 
45 g/L (21-41); alkaline phosphatase, 242 µ/L (30-115); aspartate amino transferase, 
89 µ/L (5-40), γ glutamyl transferase, 18 µ/L (5-65); and prothrombin time was 42 s 
(12-16). An abdominal ultrasound examination revealed a small echo-genic liver with 
marked splenomegaly and a patent porta-caval shunt. Results of other investigations, 
including iron and copper studies, α fetoprotein, human immunodeficiency virus and 
hepatitis serology, α-1 antitrypsin, and antinuclear antibody tests were normal. Her 
Gastroenterology 1990; 98 (4): 1079-1082. 
 
electroencephalogram (EEG) showed an α rhythm of 8-9 Hz and was otherwise 
normal. A computed tomographic (CT) brain scan showed generalized cerebral 
atrophy of similar degree to that present on a CT scan performed in 1983. 
Orthotopic liver transplantation was performed on May 1, 1988. The operation was 
uncomplicated. Histological study of her liver revealed micronodular cirrhosis with 
no evidence of cholestasis, Mallory’s hyaline, α-1 antitrypsin globules, copper-
associated protein, hepatitis B surface antigen, iron-storage disease, or malignancy. She 
had no postoperative complications, and was discharged from the hospital 18 days after 
surgery on a normal diet and a standard immunosuppressive regimen (6). This 
consisted of initial therapy preoperatively and perioperatively with methylprednisolone 
(1 g i.v.), azathioprine (2 mg/kg i.v.) and the introduction of cyclosporin A (6 mg/kg), 
with appropriate adjustment of doses according to response and blood levels of 
cyclosporin. Azathioprine was ceased 3 mo after OLT, and cyclosporin and 
prednisolone were continued indefinitely in low doses (cyclosporin 17.5 mg/kg, 
adjusted by blood levels and prednisolone, 5-10 mg/day). She remains well and has 
had normal biochemical parameters since OLT (Table 1). 
 
Table 1. Biochemical Parameters Before and After Liver Transplantation 
 
           After OLT 
Biochemical parameter Before OLT          3 mo       12 mo
STB (3-20) 165 µM 5 5 
CB (0-7) 96 µM   
S Alb (35-50) 20 µ/L 37 41 
S Glob (21-41) 45 µ/L   
SAP (30-115) 242 µ/L 120 100 
AST (5-40) 89 µ/L 22 15 
GGT (5-65) 18 µ/L 67 18 
 
STB, serum total bilirubin; CB, conjugated bilirubin; S Alb, serum albumin; S Glob, serum globulin; 
SAP, serum alkaline phosphatase; AST, serum aspartate aminotransferase; GGT, γ-glutamyl 
transferase. Reference ranges given in parentheses. 
 
A detailed neurological assessment was performed 3 mo and again 12 mo after 
OLT. At 3 mo, the score of the Mayo Clinic short test of mental status had improved 
from 23 to 29. Her orientation, attention, and immediate recall were unchanged. 
Arithmetic calculation was again correct for 3 of 4 items; however, she performed 
calculations much faster. Tests for abstraction were now all performed normally. 
Information testing improved from 2 to 3 items. She was now able to copy a cube 
correctly. She could not recall any of 4 objects after 5 min. Serial 2’s and 7’s were 
performed much faster, with no errors from 14 calculations and 3 errors from 7 
calculations, respectively. She named the months of the year backwards and the letters 
of the alphabet correctly. The Reitan’s test took 100 s to complete. Assessment by the 
same speech therapist showed improvement in auditory comprehension and recall of a 
paragraph. Reading comprehension was normal. Improvements in naming, verbal 
explanation, and verbal reasoning abilities were present. The dysarthria was still present 
but had improved in comparison with an audio recording of her speech before 
transplantation. Results of the glabellar tap test remained positive. The postural tremor was 
reduced in amplitude. The tone in the limbs was normal. The bradykinesia had improved 
considerably, but the mild weakness in the upper and lower limbs remained. The deep 
tendon reflexes remained increased. The right plantar response was extensor and the left 
was flexor. Joint position sense was normal in the lower limbs. Her gait had improved 
markedly, but on tandem walking she continued to fall to either side. The EEG showed an α 
rhythm of 11 Hz. The findings are summarized in Table 2. 
Gastroenterology 1990; 98 (4): 1079-1082. 
 
Twelve months after OLT, she was fully independent in all aspects of daily living, e.g., 
managing her finances, running the household, and shopping in a normal manner. 
Although formal assessment showed some abnormalities in intellectual and motor function, 
her family regarded her as functioning in a completely normal way. On examination, the 
improvement noted at 3 mo had been sustained, and there had been additional 
improvement. Her score on the Mayo Clinic short test of mental status had improved further 
to 32. In particular, her short-term memory had improved: she was now able to recall 3 of 4 
items after 5 min. The time to complete the Reitan’s test had improved further to 47 s. The 
dysarthria was unchanged from 3 mo after OLT, but the glabellar tap test was now only 
weakly positive. The postural tremor had completely resolved. There was mild weakness of 
hip flexion and knee flexion, but muscle strength was otherwise normal. There was mild 
bilateral slowing of rapid alternating movements. The deep tendon reflexes including the 
jaw jerk remained increased, but the plantar responses were flexor. Gait and tandem gait 
were normal. There was mild impairment in proprioception in the toes, but sensation was 
otherwise normal. A CT scan showed no change in the cerebral atrophy from that observed 
preoperatively. The findings are summarized in Table 2. 
 
Table 2. Response of Neurological Features to Liver Transplantation 
 
Neurological feature 3 mo after OLT 12 mo after OLT 
   
Short-term memory U I 
Arithmetic ability I I 
Abstract reasoning N N 
Language skills I I 
Number connection I N 
Constructional ability N N 
Bradyphrenia I I 
Bradykinesia I I 
Glabellar Tap U I 
Dysarthria I I 
Postural tremor I N 
Clasp-knife rigidity N N 
Deep tendon reflexes U U 
Plantar reflexes U N 
Gait I N 
EEG N N 
CT brain scan U U 
 
U, unchanged compared with before OLT; I, improved compared with before OLT; N, improved to 
normal. 
 
Discussion 
 
This report documents significant objective improvement both in cerebral function and 
neurological signs following successful orthotopic liver transplantation in a patient with 
severe long-standing neuropsychiatric dysfunction and cirrhosis. The neurological 
symptoms and signs manifested by this patient comprise the syndrome of the acquired 
type of chronic hepatocerebral degeneration as described by Victor et al (2). Earlier 
reports by Parkes et al. (7) and Chu et al. (8) have described electroencephalographic 
and somatosensory-evoked potential changes following OLT. Parkes et al (7) describe 
improvement in confusional state, depression, intelligence quotient, and a motor disorder 
following OLT in a cirrhotic patient with a 5-yr history of encephalopathy following a 
Gastroenterology 1990; 98 (4): 1079-1082. 
 
portacaval anastomosis. The current patient is similar but differs in that the duration of 
both the portal-systemic shunting (23 yr) and the history of neuropsychiatric disturbance 
(12 yr) were significantly longer. The slow deterioration in cerebral function was 
punctuated by episodes of acute HE that responded to standard medical therapy. Other 
common causes of dementia, such as hypothyroidism and vitamin B12 deficiency, were 
excluded. 
In this patient, there was objective evidence of improvement in arithmetic ability, 
abstract reasoning, language skills, constructional ability, Reitan’s number test, and 
dysarthria. Her short-term memory, however, remained impaired at 3 mo, but had 
significantly improved 12 mo after transplantation. The clasp-knife rigidity in the lower 
limbs resolved completely. Although the reflexes remained brisk, ankle clonus 
disappeared and both plantar responses became normal. The bradyphrenia improved 
considerably, but not completely. The postural tremor was reduced in amplitude at 3 mo 
and had completely resolved at 12 mo. The positive glabellar tap test result remained 
weakly positive. The gait returned, over many months, to normal. The increase in the 
frequency of the α rhythm on the EEG after OLT provided further evidence of 
improvement of cerebral function. 
The degree of improvement in neurological manifestations of chronic hepatocerebral 
degeneration in this patient following successful OLT and while ingesting a normal daily 
protein intake is of interest, and is not known to have been previously documented in a patient 
with such long-standing portal-systemic shunting. Acute HE is reversed by dietary protein 
restriction, lactulose, and neomycin, and is worsened by hypokalemia, constipation, and drugs 
that increase γ-aminobutyric acid-ergic activity (9,10). However, the chronic neuropsychiatric 
syndromes and chronic hepatocerebral degeneration have been regarded as largely 
irreversible and caused mostly by organic structural changes in the brain and spinal cord (2). 
It is noteworthy that significant improvement in the neuropsychiatric syndrome has been 
defined following prolonged lactulose usage and by Freund et al. (11) using a branched 
chain-enriched amino acid diet. The neuropathological changes observed in non-Wilsonian 
hepatocerebral degeneration include diffuse astrocytic hyperplasia, microcavitation and 
zonal necrosis of the deeper parts of the cerebral cortex and of the lenticular nuclei, loss of 
nerve cells in the cerebral cortex, putamen, thalamus, cerebellar cortex, and dentate nuclei, 
and loss of axons in the corticospinal tracts in the spinal cord with fibrous gliosis (2,4,12). In 
the current patient, in whom a portal-systemic shunt had been present for 23 yr, significant 
neurological improvement had occurred by 3 mo after OLT, and this continued. Although 
ongoing neurological improvement was observed in most aspects, late recovery was most 
obvious in the abnormal motor signs. Thus, whereas the tremor, gait disturbance, and upper 
motor neuron signs showed some early improvement, by 12 mo, tremor had disappeared, 
gait was normal, and the other abnormal motor findings were substantially improved. It is 
unlikely that the immunosuppressive regimen contributed to the neurological improvement; 
there has been progressive improvement despite reduction of doses to low maintenance 
levels, as has been discussed. 
This case illustrates that even after 23 yr of portal-systemic shunting and 12 yr of 
symptoms of chronic HE, a significant degree of reversibility of symptoms and signs may 
be observed. Thus, chronic neuropsychiatric syndromes and chronic progressive 
hepatocerebral degeneration should not be regarded as a contraindication to liver 
transplantation. 
 
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Improvement in Chronic Hepatocerebral Degeneration Following Liver Transplantation

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Improvement in Chronic Hepatocerebral Degeneration Following Liver Transplantation

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