Folia Psychiatrica et Neurologica Japonica, Vol. 26, No. 1, 1972

An Autopsy Case of “Pseudo-Ulegyric Type” of Hepatocerebral Disease

Hiroshi ISHINO, M.D., Jun’ichiro HIRATA, M.D., Shigetoshi KURODA, M.D. and Saburo OTSUKI, M.D.

Department of Neuro-psychiatry, Okayama University Medical School, Okayama

“Pseudo-ulegyric type” of hepato-cerebral disease was separated by Shiraki et a1.O) in 1962, and is characterized clinically by 1) Occurrence of the disease in young people 2) Marked discrepancy between severe mental symptoms and a slight degree of liver function damage 3) Pronounced re- gression of personality, and pathologically by 1) Pseudo-ulegyric and laminar or pseudo-laminar necrosis of the cerebral cor- tex without tendency to organisation. Dif- fuse demyelination in the white matter. 2 ) Changes common to Inose type of hepato- cerebral disease3v4). 3) Ischemic changes of the nerve cells.

The growing number of such verified ob- servation will lead to a correct determination of the essential pathognomonic lesions of this type of hepato-cerebral disease, so that the authors report in this paper one autop- sied case.

CASE REPORT M.H., a male aged 21 years at the time

of death. The grand father had died of liver disease. The father had died of tuber- culous anal fistula and the mother had died of abdominal typhus. Of his 3 siblings, one had died of pulmonary tuberculosis.

Past history. Birth normal. The devel- opment of gait and speech had retarded.

Received for publication Feb. 16, 1972

Somatic and mental development also some- what retarded. The patient had inadequate and unbalanced diet. After poor perfor- mance in the secondary school, he had worked as an iron-worker. From June, 1965 he was admitted to Red Cross Hospital at Mihara, because of pulmonary tuber- culosis.

Clinical course. From the end of Octo- ber 1965, he developed insomnia and be- came confusional during the night. These symptoms became marked from the middle of November, and during the night he mono- logized, laughed and wept without reason. In the night of November 20, the patient showed a confusional-oneiroid episode, mis- took a string for a snake and he thought he saw a ghost at the sight of a fluorescent lamp and slept little that night.

Therefore he was transfered to Mihara Mental Hospital on November 22, 1965. On admission, however, he was quite alert, oriented well in time and space and replied to almost all questions, so that between December 2, 1965 and January 14, 1966, he was again admitted to the Red Cross Hospital. The symptoms became progres- sively worse and confusion, disorientation, incoherent mumbling speech, illusion and agitation were the outstanding manifesta- tions of the illness, and they had a relapsing course. For one hour after waking, he

46 H. Ishino, J. Hirata, S. Kuroda and S. Otsuki

used to stand apathetically, take no notcie of his surroundings, put on trousers with the front side back and forget to fasten the belt.

On readmission on January 15, 1966 to Mihara Mental Hospital, he was inattentive, disoriented in space, slow in replying to questions and following commands.

During the morning of February 19, he was restless, unsettled and salivation was ob- served. He was found to show peculiar to and fro swaying movements of his own arm. When spoken to, he merely repeated isolated words and did not reply to questioning. Pupils were considerably dilated and sen- sorium was clouded. Hypoglycemic con- fusional state was suspected, but the injec- tion of glucose was without change in his condition.

On March 19, the patient showed an excito-confusional episode, i.e. he was semi- stuporous and incoherent, cried continuous- ly all day long. His facial expression was mask-like with fixed staring and he was un- responsive to painful stimuli. Pupils were dilated. These episodes of clouding of con- sciousness lasting several hours recurred periodically. From April the patient be- came almost bedridden and decubitus ap- peared in the sacral part.

Between April 20 and May 31, he was admitted again to another hospital. From April 21, he was comatose for 2 days which was followed by transient remission. Dur- ing these recurring attacks of clouding of consciousness, he agitated and cried, with chewing movements. He declined mentally and in character and became child-like.

From June to the end of August, the periods of clouding of consciousness varying in intensity from a semi-stuporous state to a deep coma were getting longer and the intermittent periods of apparent normality

became shorter. From time to time he lapsed into stupor of variable intensity. Muscular rigidity went hand in hand with the appearance of clouding of consciousness.

On clinical examination on last admission to the Mental Hospital on August 30, the patient was extremely emaciated. His facial expression was apathetic, he could not per- form simple commands and could answer simple questions, “Yes”, “No” etc. There was marked rigidity in all four extremities, especially on the left side. Kayser-Fleischer corneal rings were not noted.

In October he lay quietly in his bed with eyes open. Pupils were dilated. Sometimes he cried, spoke desultory words and uttered sounds without significance. Corneal reflex could be elicited. There was patellar clonus bilaterally.

By November-December 1966, he was somewhat somnolent with few spontaneous movements and his level of consciousness fluctuated. There were times, even, when for a few moments his speech was sensible. Severe muscular rigidity was noted in all four limbs and flexion contractures devel- oped in the elbows and knees. He died on November 28, 1966. The duration of the illness was about one year.

EEG findings: First record (22.11.1965). Basic pat-

tern was symmetrical 5-7 cps 80-180 pV slow waves mixed with 2-3 cps 8-waves, and it reacted little to opening of the eyes. By hyperventilation, these findings became marked. Impression: abnormal continuous.

Second record (30.1 1.1965). Basic rhythm was irregular 1Ocps a-wave. By hyperventilation, 8-9 cps slightly high vol- tage waves appeared. Impression: almost within normal.

Third record (20.1.1966). In resting record, 1 1 cps a-waves were dominant in

An Autopsy Case of “Pseudo-Ulegyric Type” 41

the parieto-occipital region, which was at- tenuated by eye opening. There were, in addition, burst-like 8-10 cps slightly high voltagc wave mixed with 6 cps slow waves. Impression : borderline.

Basic pat- tern was poor in a-waves. Bipolar record showed flat pattern.

Ophthalmological examinations: normal. Pneumoencephalogram : normal. X-rays of the skull: many figures of

digital impression. CSF: normal. Liver function test (Serum) (7.6.1966) :

Total protein; 5.8 g/dl, Takata; itt, Co; R4, CCLF;-, TTT; 1.2 units, Jaundice index; 5 units, A-P-ase; 3.13 units, GOT; 52 units, GPT; 27 units. (Underline means abnormal

Fourth record (31 51966) .

_ _ ~

value) Pathological findings of the brain, Macroscopic findings. The brain weighed

1040 g. The meninges and vessels were normal. The frontal and parietal lobes ap- peared normal, while atrophy was found symmetrically in the temporal pole and was seen to extend backwards to the temporo- occipital region. Furthermore it was mark- ed in T.2 and T.3, less conspicuous in T.l, and the hippocampal convolutions were quite normal (Fig. 3). These atrophied convolutions showed a granular atrophy (Fig. 2 ) .

On coronal section through the frontal lobes, the anterior horns of the lateral ven- tricles were slightly enlarged. Otherwise the cerebral cortex as well as white matter showed no abnormality.

On coronal section through the optic chiasm, the cortex of the transition zone between the inferior part of the insular re- gion and T.l exhibited a granular appear- ance. In T.l there was slight atrophy, but the boundaries between the cortex and white

matter were distinct. T.2 and T.3 showed, as mentioned above, marked atrophy and the cortex was poorly demarcated from the white matter. The cortex as well as white matter was discoloured, and of somewhat firm consistency and the tissue was friable.

On coronal section through the mamillary bodies (Fig. 3 ) , in addition to the findings of the temporal lobes, bilateral postcentral region showed similar changes. Particularly in the depths of the furrows was there a marked cortical granular atrophy. The hip- pocampal formation was normal. T.3 was somewhat softened, and showed greyish dis- coloration, the left being marked than the right.

On coronal section through the splenium of corpus callosum, there was no atrophy in the cingulate gyrus and the hippocampal formations. The posterior horns of the ven- tricles were symmetrically dilated.

The brain stem and cerebellum were nor- mal.

Microscopic findings. The topographical distribution of the lesions is illustrated in Fig. 1.

In the ulegyric atrophic areas (Fig. 8) as found in both insula, T.2 and T.3, the surface of the brain was granular and the width of the cortex was reduced to about half of the normal. The distinction between the white and grey matter was blurred. The nerve cells of the cortex had completely dis- appeared and the glial nuclei were markedly increased in number. The ground substance became spongy or showed loosened texture, in which a large number of gemistocytic astrocytes were found. Gemistocytic glia cells were found not only in the cortex but also in the subcortical white matter. How- ever, Alzheimer’s type I1 glial cells were not found in these completely devastated areas. A large quantity of sudanophilic materials

48 H. Ishino, J. Hirata, S. Kuroda and S. Otsuki

were encountered, but without a transport around the vessels (Fig. 6). Numerous small droplets of fat were found in the cyto- plasm of the gemistocytic astrocytes, and there was no mobilization to fat granule cells. Holzer stain did not demonstrate glial fibers in these areas.

In the areas of necrosis with pseudo- laminar aspect encountered in the insula or in the side of some convolutions (Fig. l ) , the nerve cells of I, I1 and outer portion of 111 layer had disappeared completely and the ground substance became spongy or loosened. In other part, V and VI laminae was involved or only the deep portion of 111 layer had preserved (Fig. 5 ) . In these laminally disintegrated regions, the ground substance became also spongy. The remain- ing nerve cells showed more or less regres- sive changes such as hyperchromatosis and chronic cell changes. In certain place, some of the preserved nerve cells showed ischemic ccll change (Fig. 1). In these necrosed area, Alzheimer cells of type I1 were not seen, while where the texture was well pre- served there were numerous Alzheimer’s type I1 glial cells (Fig. 7), in the nuclei of which small Carmin-positive substances were found. These substances were, in gen- eral, larger than the nucleolus and found in the center or in the margin of the nucleus.

In the laminally necrosed areas, a clear accentation of the changes was, in general, found in the depths of the sulci with gradu- ally diminishing severity towards the top of the sulci (Fig. 1 ) , For example, in the top of a sulcus the cortex was well preserved, and as approaching the bottom of the sulcus the cortex was laminally necrotized with preservation of the deeper cortical layers. In the bottom of the sulcus, the cortex was completely disintegrated and in the opposite side of the convolution, as approaching the

top of the gyrus the nerve cells of 111 layer gradually appeared and return to the nor- mal cyto-architecture in the top of the con- volution.

The Ammon’s horn was well preserved in contrast with the severe lesions in T.2 and T.3.

In the well preserved cortex, Alzheimer’s type I1 glial cells were diffusely found. Some of them gathered together, forming glial syncytium.

In the white matter, there was diffuse moderate demyelination in the centrum semi-ovale and temporal white matter (Fig. 4). In Holzer preparations, a slight degree of fibrous gliosis was found in the centrum semi-ovale.

In the thalamus and lenticular nucleus, the nerve cells were well preserved, but there were numerous Alzheimer cells of type 11. In the grey matter around the aqueduct, a number of Alzheimer’s type I1 glial cells were encountered. In the medulla oblongata, the nerve cells of the olivary nucleus showed lipochrome granules with hyperchromatosis of the nucleus.

In the cerebellum, there was a slight loss of Purkinje cells. Alzheimer cells of type I1 were found in the Purkinje cell layer. The dentate nucleus was well preserved and there was no abnormality in the cerebellar white matter.

DISCUSSION The clinical symptoms of this case are

characterized by the onset of the disease with insomnia and confusional state during the night. Afterwards the periods of cloud- ing of consciousness fluctuating from a semi- stuporous state to a deep coma recurred periodically, during which the patient cried and agitated. In the advanced stage of the illness, the intermittent periods of apparent

An Autopsy Case of “Pseudo-Ulegyric Type” 49

normality became shorter. At the same time he had regressed mentally and in char- acter and became infantile, i.e. he was like a child of 3 or 4 years, He seemed not to think, and sensation and feeling was seemed to turn directly to acts. He was not autis- tic, had certain relation with the surround- ings.

General emaciation was very marked. In the later stage, flexion contractures, mus- cular rigidity as well as tremor of the left hand was noted.

Among the laboratory findings, liver function tests obtained 8 months after the onset of the illness showed a slight damage. EEG records were obtained about 20 days, one month, 3 months and 7 months after the onset of the disease. In the first record, slow waves were found, but the second and third record did not indicate abnormality. In the fourth record, the background activity was replaced by a flattening.

Autopsy findings of the brain showed a granular atrophy in both T.2, T.3, insula and the temporo-occipital region symmetri- cally. Histologically in the granular atrophic areas, there was no tendency to organization by glial fibers and showed “pseudo-ulegyric” changes. With the distribution illustrated in Fig. 1 were found the disintegrated cor- tical areas, and varied in severity from the regions in which the nerve cells were totally disappeared and the ground substance be- came spongy to the areas where the cortex was involved in laminar fashion, and these changes increased in intensity towards the bottom of the convolutions as was always found in the cases with hernodynamic dis- turbances. In addition, Alzheimer’s type I1 glial cells were observed diffusely in the cerebral cortex, and in some of which there were Carmin-positive small substance in the nucleus.

The clinical and pathological findings in

this case are in agreement with the picture of “pseudo-ulegyric type” of hepatocerebral disease postulated by Shiraki et al.D). In our case, the autopsy of the liver was not car- ried out, because the liver function tests showed only a slight degree of damage and the authors did not consider the pos- sibility of hepato-cerebral disease. In the previously reported cases, the liver is af- fected in a way characteristic of “pseudo- ulegyric type”, i.e. pseudo-cirrhosisG), fatty degeneration‘s7) and fatty cirrhosisDJO).

The 6 autopsied cases of “pseudo-ulegyric type” of hepato-cerebral disease are known to date; those of Nogami et al. ( 1960)5), Shiraki et al. (1962)”), Fujii et al. (1961)l), Oda et al. (1963)?1, Takahashi et al. (1963)lO) and Hashi et al. (1965)2). Cli- nical comparison of our case with those in the literature shows that our case is one of the youngest in view of the age of onset, since in the previously described cases it varies ranging from 207) to 31 yearslO). The duration of the illness was about one year in our case. As to the duration of illness, the cases in the literature range from 6 years 7 months&) to 8 rnonthslO). Thus our case had run a relatively short clinical course. The other signs noted in our case such as great emaciation and inadequate and un- balanced diet were recorded in almost all cases.

As to the pathological findings in our case, there was no mobilization of fat gran- ule cells, and the sudanophilic breakdown products were seen in only fixed glia. Holzer preparations showed no indication of fibrous glial reaction in the destructive lesions. These findings are characteristic of “pseudo- ulegyric type” as well as h o s e type3p4) of hepato-cerebral disease, and the important point of pathological differentiation of the former from the latter is the more or less

50 H. Ishino, J. Hirata, S. Kuroda and S. Otsuki

elective involvement of certain regions (in- sula, T.2 and T.3) as well as cortical atro- phy of granular appearance and severe in- volvement of all cortical layers with status spongiosus.

As compared with 6 cases in the litera- ture, the degeneration of the temporal white matter was not marked in our case. Cases were reported with status spongiosus in the subcortical white matter or the cystic soften- ing in the temporal white matterg.6.0J0). These pathological changes are keeping with the clinical piture such as Kluver-Bucy syndromefi) and apallic syndrome2*’J’J0). In our case these symptoms were not noted, since the change of the white matter was less than in the cases previously described.

SUMMARY The authors reported a case of “pseudo-

ulegyric type” of hepatocerebral disease. 1) Clinical course: A male aged 21 at

the time of death. The patient had un- balanced diet. The illness began with in- somnia and confusional state during the night. Recurring periods of clouding of consciousness lasting several hours were noted. About 5 months after the onset, he became bedridden and showed inconti- nence. In the later stage the intermittent periods of normality became shorter, and muscular rigidity set in in four limbs. Ema- ciation was marked, and he regressed men- tally. Liver function test showed a slight degree of damage. Death occurred about one year after the onset of the disease.

2 ) Pathological examination showed pseudo-ulegyric change as well as laminar cortial necrosis in the insula, T.2, T.3 and temporo-occipital regions on both sides, which were marked in the bottom of the sulci. Alzheimer’s type I1 of glial cells were found diffusely in the cerebral cortex,

in the nucleus of which Carmin-positive sub- stance was found.

3) Clinico-pathological comparison was made with 6 cases in the literature.

REFERENCES Fujii, M., Murofushi, K. and Shiraki, H.: An autopsy case showing ulegyria-like changes and suspected multiple sclerosis, Rec Adv Kes Nerv Syst, 6: 158-159, 1962. (in Japanese) Hashi, N., Sasaki, T., Tsutsumi, S., Nakata, K. and Suguhara, Y.: An autopsy case of the “Pseudo-ulegyria type” of the hepato- cerebral disease, Clinical Neurology, 5: 569- 577, 1965. (in Japanese) Inose, T.: Contribution to pathology of extrapyramidal disease. A specific form of hepatocerebral degeneration, Psychiat Neurol Jap, 51: 245-268, 1950. (in Japanese) Inose, T.: Hepatocerebral degeneration, a special type, J Neuropathol Exp Neurol, 11: 401-408, 1952. Nogami, Y., Hayashi, E., Yabuki, T., Akai, K., Takeishi, Y., Kita, S., Todoroki, K., Shimada, K., Toyoda, M. and Imamura, M.: A case of diffuse hemisphere atrophy with localized softenings in both temporal lobes, Clinical Psychiatry, 2: 341-350, 1962. (in Japanese) Oda, M.: Ein Beitrag zu den klinischen und histopathologischen Problemen iiber die hepatozerebralen Erkrankungen, insbeson- dere iiber den “Pseudoulegyrie-Typ”, Psy- chiat Neurol Jap, 66: 892-931, 1964. (in Japanese) Oda, M., Yamamoto, T. and Shiraki, H.: An autopsy case of a special type of hepato- cerebral disease, Rec Adv Res Nerv Syst, 7: 173-174, 1963. (in Japanese) Shiraki, H. and Oda, M.: Neuropathology of hepatocerebral disease with emphasis on comparative studies, In Pathology of the Nervous System, Vol. I, ed. by Minckler, J.: 1089-1103, 1968, McGraw-Hill, New York, Toronto, Sydney, London. Shiraki, H., Yamamoto, T., Yamada, K. and Shikata, T.: An autopsied case of the “Pseudoulegyria Type” of the hepatocere- bra1 disease, Psychiat Neurol Jap, 64: 305- 318, 1962. (in Japanese) Takahashi, Y., Oda, M. and Shiraki, H.:

An Autopsy Case of “Pseudo-Ulegyric Type” 51

An autopsy case of the “Pseudolegyria a subacute clinical course, Psychiat Neurol Type” of the hepatocerebral disease with Jap, 65: 513-531, 1963. (in Japanese)

LEGENDS FOR FIGURES

Fig. 1. Diagrams illustrating the topographical distribution of lesion.

Fig. 2. Ulegyria-like appearance of the temporal cortex.

Fig. 3. Coronal section through the mamillary bodies, showing atrophy of the insula, T.2 and T.3, while the hippocampal formations are well preserved.

Fig. 4. Coronal section through the thalamus, showing diffuse demyelination of the centrum semi-ovale and temporal white matter (Woelke).

Fig. 5. Laminar necrosis in the frotal cortex. Only the nerve cells of deep portion of I11 layer are preserved (Nissl, ~40).

Fig. 6. Temporal cortex. A large quantity of sudanophilic breakdown products are found in the fixed glia (Sudan 111, ~100) .

Fig. 7. Numerous Alzheimer’s type I1 glial cells in the deep layer of the temporal cortex (H.E., x250).

Fig. 8. Insular cortex, showing pseudo-ulegyric change with status spongiosus (H.E., x40).

52 H. Ishino, J. Hirata, S. Kuroda and S. Otsuki

1 Area of pseudo-ulegyric atrophy

Area of laminar or pseudo-laminar necrosis a 0 Area of diffuse demyelination

a Ischemic change of the nerve cells

An Autopsy Case of “Pseudo-Ulegyric Type’’ 53

Fig. 2-8.