Neuropathology 2008; 28, 627–632

doi:10.1111/j.1440-1789.2008.00898.x

C a se Repor t

Portal-systemic shunt encephalopathy presenting
with diffuse cerebral white matter lesion:
An autopsy case
Noriyuki Kimura, Toshihide Kumamoto, Takuya Hanaoka, Kenichiro Nakamura, Yusuke Hazama
and Ryuki Arakawa
Department of Neurology and Neuromuscular Disorders, Oita University, Faculty of Medicine, Oita, Japan

We report herein an autopsy case of portal-systemic
encephalopathy (PSE) presenting with diffuse tissue rarefaction in the cerebral deep white matter. Clinically, the
patient showed recurrent episodes of unconsciousness,
abnormal behavior and urinary incontinence, as well as
flapping tremor. Cognitive impairment and peripheral neuropathy developed following recurrent episodes. Although
conventional arterial portography revealed a small portalsystemic collateral vessel of a left gastro-renal venous
shunt, abdominal CT and liver biopsy showed no evidence
of liver cirrhosis and serum ammonia level showed a mild
increase. T2-weighted MRI demonstrated symmetrical
signal hyperintensities in the deep white matter. Neuropathological findings showed Alzheimer type II astrocytes
in the deep layers of the cerebral cortices and severe tissue
rarefaction with no or slight reactive astrocytosis in the
subcortical and deep white matter. These white matter
changes have been reported infrequently in patients with
PSE. The present case suggests that chronic PSE without
liver cirrhosis may develop diffuse white matter lesions.
Key words: Alzheimer type II astrocyte, diffuse white
matter lesion, gastro-renal shunt, peripheral nerupathy,
portal-systemic encephalopathy.

INTRODUCTION
Portal-systemic shunt occurs due to liver cirrhosis or idiopathic portal hypertension, and plays an important role in

Correspondence: Noriyuki Kimura, MD, Department of Neurology
and Neuromuscular Disorders, Oita University, Faculty of Medicine,
Idaigaoka 1-1, Hasama, Yufu, Oita 879-5593, Japan. Email: noriyuki@
med.oita-u.ac.jp
Received 5 December 2007; revised 9 January 2008 and accepted 10
January 2008.

© 2008 Japanese Society of Neuropathology

the etiology of recurrent hepatic encephalopathy.1 In the
1950s, Sherlock et al. and White et al. emphasized the
pathophysiological role of ammonia, which is generated
in the intestine and flows directly into the systemic circulation through shunt vessels.2,3 This syndrome is thus
referred to as portal-systemic encephalopathy (PSE) or
Inose’s type hepatocerebral degeneration.4 In general,
PSE is clinically characterized by recurrent episodes of
disturbed consciousness and other neurological symptoms
such as flapping tremor of the outstretched hands,
extrapyramidal symptoms, and hyper-reflexia during the
non-episodic period.5,6 Hyperintensity in bilateral lenticular nuclei on T1-weighted MRI is the characteristic
finding of PSE.7 Neuropathological findings show Alzheimer type II cells and spongiform changes in the gray
matter.8 Some investigators have recently claimed to have
observed PSE in patients without liver cirrhosis or portal
hypertension.9–12 Although clinical and radiological
findings were well described, neuropathological examinations of brain tissue from autopsy were limited in those
cases.
We encountered an autopsy case of PSE due to congenital gastro-renal shunt without liver cirrhosis and portal
hypertension. The patient had experienced recurrent episodes of unconsciousness accompanied by peripheral neuropathy and dementia. Interestingly, pathological findings
showed diffuse tissue rarefaction due to severe loss of
myelin and axons in the cerebral deep white matter, in
addition to Alzheimer type II astrocytes in the cerebral
cortex. Although some reports have described diffuse
white matter lesions in hepatic encephalopathy, such
changes are rare in PSE. We therefore describe the cliniconeuropathological findings of this patient with PSE, and
discuss the correlations between MRI and pathological
findings.

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N Kimura et al.

CLINICAL SUMMARY
A 61-year-old Japanese woman developed fever, pain in
the upper extremity and confusional state, despite good
health until November 1993. Symptoms lasted for 24 h, and
then subsided without treatment. She had experienced the
same episodes twice before admission. Episodes would
vary in duration from 24 h to 2 weeks and did not correlate
with dietary changes or any other specific factors. She was
admitted to our hospital on April 24, 1996, due to recurrent
episodes of disturbed consciousness, abnormal behavior
and urinary incontinence. No history of alcohol or drug
abuse or significant family history could be elicited. On
admission, no signs of liver disease were apparent such as
jaundice, hepatosplenomegaly or vascular spider, with the
exception of mild palmar erythema. Neurological examination showed drowsy state, disorientation and abnormal
behavior such as restlessness and loud crying. Cranial
nerve signs and muscle strength were normal, but muscle
tone and deep reflexes were decreased. Flapping tremor of
bilateral hands appeared occasionally. She displayed
severe painful paresthesia in the extremities. No other neurological signs were identified, such as dysarthria, incoordination or extrapyramidal signs.
Laboratory findings revealed normal blood count and
mild liver dysfunction as follows: aspartate aminotransferase, 211 IU/L (normal, 13–33 IU/L); alanine aminotransferase, 257 IU/L (normal, 6–27 IU/L); g-glutamyl
transferase, 113 IU/L (normal, 10–47 IU/L). Serum
ammonia level was mildly increased at 42 mmol/L (normal,
9–33 mmol/L). Molar ratio of branched-chain amino acids
(leucine, isoleucine and valine) to aromatic amino acids
(tyrosine and phenylalanine) had decreased to 2.25
(normal, 2.43–4.40). An indocyanine green test showed
15% retention at 15 min (normal, <10%). Serum copper
and ceruloplasmin levels were normal. Hepatitis B surface
antigen and antibody were both negative, as was a test for
hepatitis C virus antibody. A test for antinuclear antibody
was positive, but antimitochondrial antibody and antismooth muscle antibodies were negative. Serum and
urinary amino acid analyses yielded normal results. Specific
patterns of aminograms as in citrullinaemia and argininosuccinic aciduria, which usually accompany hyperammonaemia, were not identified. White blood lysosome enzyme
assay showed normal results. Blood levels of very-longchain fatty acids were within normal limits.Analysis of CSF
was unremarkable for cells, protein and glucose. EEG
showed a diffuse q wave, but not triphasic waves. Brain
MRI demonstrated symmetrical signal hyperintensities in
the deep cerebral white matter on T2-weighted imaging,
but no signal abnormalities in bilateral basal ganglia on
T1-weighted imaging (Fig. 1a,b). Sonography and CT of
the abdomen showed no abnormalities, including shunt

vessels. Endoscopic examination did not reveal esophageal
or gastric varices or Helicobacter pylori infection.
Ultrasound-guided fine needle liver biopsy showed mild
lymphocytic infiltration without fibrosis in the portal tracts,
indicating autoimmune hepatitis without liver cirrhosis.
Conventional arterial portography disclosed a small
portal-systemic collateral vessel of a left gastro-renal
venous shunt (Fig. 1c). However, both the radiologist and
gastroenterologist excluded the contribution of the shunt
to recurrent episodes of unconsciousness because the size
of the shunt vessel was insufficient to result in encephalopathy. Therefore the diagnosis of PSE could not be confirmed, and the hyperammonaemia might occur due to
unknown causes. Conservative treatments such as administration of lactulose and infusion of branched-chain amino
acid-enriched solution were performed for normalization
of blood ammonia levels. The patient became free from
episodes of loss of consciousness after several days of these
treatments and was discharged on July 17.
The patient was subsequently admitted to our hospital
with similar episodes twice over the next 3 years. Although
neurological symptoms and laboratory data were almost
the same as on first admission, cognitive function deteriorated (Mini-Mental State Examination, 21 points; revised
Wechsler Adult Intelligence Scale, 80 points). In addition,
a nerve conduction study revealed reduced conduction
velocity of motor and sensory nerves in all extremities.
Pathological findings of sural nerve biopsy revealed segmental demyelination and myelinated fiber loss without
vascular inflammation (Fig. 2h). A density of the myelinated fibers revealed a decrease number of both largediameter and small-diameter fibers. Teased-fiber analysis
showed 53% were normal fibers, 43% had segmental
demyelination and segmental remyelination, 1% had
axonal degeneration, and 3% were unclassifiable.
Follow-up MRI demonstrated that cerebral white
matter lesions extended from deep to subcortical white
matter. Disturbance of consciousness was also improved
for a few days with antihyperammonaemia therapy, but
neurological symptoms including cognitive impairment
continued to worsen and the patient died of pulmonary
embolism in November 2001. Total duration from onset of
the first episode to death was 8 years.

PATHOLOGICAL FINDINGS
Macroscopic findings
The brain, weighing 1100 g after fixation, showed slight
cerebral atrophy. Coronal sections revealed moderate
atrophy of cerebral white matter with dilatation of the
lateral ventricle. Tissue softening was observed diffusely in
the white matter. Multiple small lesions with greyish dis© 2008 Japanese Society of Neuropathology

Autopsy case of portal-systemic shunt encephalopathy

629

Fig. 1 T1- and T2-weighted MRI and
conventional
arterial
portography.
(a) T1-weighted MRI shows no abnormal
signals in bilateral basal ganglia.
(b) T2-weighted MRI shows diffuse
signal hyperintensities in the deep cerebral white matter. (The right side is
shown on the left-hand side of each
figure). (c) Conventional arterial portography revealed small portal-systemic
collateral vessel of a left gastro-renal
venous shunt (arrowhead).

coloration were scattered in the subcortical white matter
(Fig. 2a). Deep white matter revealed diffuse greyish discoloration. The cerebral cortex, subcortical gray matter,
brainstem and cerebellum appeared normal.

Microscopic findings
Histological examinations were performed using HE,
KB and Bielschowsky stains and immunohistochemical
methods. HE staining revealed slight dilatation of perivascular and perineuronal spaces in the deep layer of the
cerebral cortex (Fig. 2b), multiple focal tissue rarefaction in
the subcortical white matter, and diffuse tissue rarefaction
in the deep white matter (Fig. 2c). Bilateral putamina,
globus pallidi, caudate nuclei and thalami were well preserved. There were Alzheimer type II astrocytes (Fig. 2d),
which showed large, pale nuclei with marginated chromatin
and scanty cytoplasm, some in the cerebral cortices, globus
pallidus, and thalamus, a few in the putamen, caudate
nucleus, and claustrum. No Alzheimer type I glial cells or
Opalski’s cells were present. KB and Bielschowsky staining
© 2008 Japanese Society of Neuropathology

revealed severe myelin pallor and axonal loss in the subcortical and deep white matter, including the U-fiber area
(Fig. 2e,f). Subcortical white matter lesions were small and
distributed in multiple regions, whereas deep white matter
lesions were most severe and diffusely extended. Conversely, the internal capsule and pyramidal tract of the
brainstem and cerebellar white mater were relatively
spared. Immunostaining for GFAP (Dako, Glostrup,
Denmark) showed no or only slight proliferation of reactive
astrocytes in the cerebral cortex and white matter lesion
(Fig. 2g). Proliferation of reactive astrocytes was slight compared with the severity of tissue degeneration.These pathological findings were observed at almost the same intensity
throughout the frontal, temporal and occipital lobes. No
fat-laden macrophages or metachromatic substance were
evident. No arteriolosclerosis or infiltration of inflammatory cells was evident in the cerebral white matter. Senile
plaques and neurofibrillary tangles were not observed in the
hippocampus. These pathological findings were consistent
with hepatic encephalopathy and final diagnosis was PSE
without portal hypertension and liver cirrhosis.

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N Kimura et al.

b

a

c

d

f

e

g

h
DISCUSSION

The clinical picture in the present case was characterized
by recurrent episodes of confusion, flapping tremor, cognitive impairment and polyneuropathy. Laboratory data
showed slight hyperammonaemia and MRI demonstrated
diffuse white matter lesions. A lysosomal enzyme, amino
acid and long-chain fatty acid analysis excluded the known
leukodystrophies and inherent metabolic disorders.

Fig. 2 (a) Multiple small lesions with
greyish discoloration were scattered in
the subcortical white matter. Diffuse
greyish discoloration in the deep white
matter. (b) Slight dilatation of perivascular and perineuronal space in the deep
layer of the cerebral cortex (HE ¥50). (c)
Severe tissue rarefaction in white matter
(HE ¥100). (d) Alzheimer type II astrocytes in the cerebral cortex. (HE ¥200).
(e) Severe tissue rarefaction with loss of
myelin in the frontal lobe (KB, scale bars
1 cm). (f) Severe tissue rarefaction with
loss of axons in the frontal lobe (modified Bielschowsky, scale bars 1 cm). (g)
Slight proliferation of reactive astrocytes
(immunostain for GFAP ¥100). (h)
Biopsy specimens from sural nerve
showing the loss of large myelinated
fibers. (Toluidine blue, ¥50).

Although conventional arterial portography identified left
gastro-renal shunt, the patient showed no sign of portal
hypertension or liver cirrhosis. Venous shunt was thought
to be congenital, because of the lack of any prior history of
abdominal disease, trauma or operation until admission. To
conclude that the gastro-renal shunt contributed to neurological symptoms is difficult, because of the slight increase
in serum ammonia level and small shunt vessels. The shunt
vessels were large enough to develop the encephalopathy
© 2008 Japanese Society of Neuropathology

Autopsy case of portal-systemic shunt encephalopathy
and serum ammonia levels were high in previous reports of
PSE.9–12
However, pathological findings were consistent with
PSE, with the exception of severe tissue rarefaction due to
severe loss of myelin and axons in the cerebral deep white
matter. Thus PSE was diagnosed on the basis of neurological symptoms and pathological findings. Patients with PSE
without portal hypertension or liver cirrhosis are often
misdiagnosed with dementia or other psychoneurological
diseases and occasionally hospitalized in psychiatric
departments.6 This report suggests that a slight increase in
serum ammonia and very small shunt vessels might be
sufficient to cause development of PSE.
Peripheral demyelinating neuropathy was one of the
clinical features in our patient. Nerve conduction studies
for patients with liver disease have shown that both demyelination and axonal degeneration could develop.13 Two
factors postulated for hepatic neuropathy are portalsystemic shunt and hepatocellular damage,14 so portalsystemic shunt appears to have been involved as a cause of
peripheral neuropathy in the present case.
Neuropathological findings in PSE commonly include
pseudolaminar spongiform change associated with numerous Alzheimer type II astrocytes in the deep layers of
cerebral cortices and loss of myelin and axons in the
subcortical white matter. Alzheimer type II astrocytes are
distributed to the cerebral cortex, basal ganglia and
cerebellum.15 In the present case, neuropathological evaluation also demonstrated slight dilatation of perivascular
and perineuronal spaces in the cerebral cortex with some
Alzheimer type II astrocytes, which displayed a limited
distribution to the cerebral cortex and basal ganglia. These
findings may be attributed to a slight increase in serum
ammonia levels due to small shunt vessels. In addition,
degeneration of deep white matter with diffuse tissue rarefaction was a unique pathological finding, corresponding
to hyperintensity on T2-weighted MRI. We suggest that the
portal-systemic shunt participated in the development of
cerebral white matter lesions, which expanded with disease
progression. Although we were not able to find a similar
case in the literature, some MRI studies reported on
the cerebral deep white matter lesions in hepatic
encephalopathy.16–18 They suggested that cerebral white
matter lesions might be due to mild brain edema by the
impairment of the blood–brain barrier. Several experimental studies have suggested that swelling of cerebral cortical
astrocytes is observed following ammonia infusion in primates or exposure of primary astrocyte cultures to ammonia.19,20 We speculate that tissue rarefaction in the white
matter may have been caused by chronic brain edema due
to dysfunction of astrocytes in the present case. Further
studies are needed to clarify correlations between brain
edema and astrocyte dysfunction in PSE.
© 2008 Japanese Society of Neuropathology

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© 2008 Japanese Society of Neuropathology