an autopsy case of brain stem encephalitis with spinal cord involvement

Folia Psychiatrica et Neurologica Japonica, Vol. 26, No. 2, 1972

An Autopsy Case of Brain Stem Encephalitis with Spinal Cord Involvement

Teruo SHIRABE, M.D., Emiko TATSUTA, M.D., Yoshigoro KUROIWA, M.D. and Kenzo TANAKA, M.D.

Department of Neurology and Department of Pathology, Faculty of Medicine, Kyushu University, Fukuoka

INTRODUCTION In 1957, under the name of brain stem

encephalitis, Bickerstaff2) described cases of encephalitis of gradual onset in which developed almost total paralysis in the cranial region, accompanied by only mild pyramidal or long tract sensory disturbance, with dramatic total recovery except for only one case. In 1961, Moller et a1.12) documented clinical cases showing acute cranial neuropathy with favorable course as brain stem encephalitis. In 1963, I i ~ u k a ~ * ~ ) described three fatal cases of brain stem encephalitis with a unique, chronic course. He suggested that this type of brain stem encephalitis might be a specific category distin- guished clinico-pathologically from other known encephalitides. Some additional cases of brain stem encephalitis have appeared thereafter4~10~11.15.1a.17~10). At present, the term of brain stem encephalitis has been generally used to indicate a sporadic encephalitis of unknown etiology in which lesions were mainly localized in the brain stem. The clinical course and pathological findings are variable, and the etiologies of

Received for publication April 14, 1972. Dr. Shirabe's present address is Section of

Neuropathology, Kawasaki Medical College, Oka- yama.

the disorders may be diverse. Recently we experienced a case of brain

stem encephalitis resembling to one reported by Iizuka, which had been clinically diagnosed and pathologically verified. The pur- pose of this paper is to describe the clinical and neuropathological features of our case and to discuss the etiology of the illness.

CASE REPORT A 32-year-old farmer was admitted to the

Kyushu University Hospital on Febraury 7, 1969, because of progressive dysphagia, dysarthria and gait disturbance. He was suffered from measles in infancy. Grand ma1 seizure occurred a few times a year from the age of nine and subsided spontane- ously at twenty-five. He complained of severe headache in January 1968, which persisted until the terminal stage of the illness. He noted double vision for a week in April, May and June. On September 25, he developed fever, severe headache, nuchal pain and gait disturbance. Next day he was found to have horizontal nystagmus, dysarthria and ataxic gait at the Out-patient Department of the Kyushu University Hos- pital. Character change with forced laugh- ing, dysphagia and weakness of the right lower extremity were recognized in Octo- ber. Weakness of the left lower extremity

134 T. Shirabe. E. Tatsuta, Y. Kuroiwa and K. Tanaka

Fig. 1 . Clinical course.

occurred on January 3, 1969. Dysphagia, dysarthria and gait disturbance progressed thereafter. Clinical course was summarized schematically in Fig. 1.

On admission, he was unremarkable in physical examination. Neurologically be was alert, but his character was childish and euphoric. Visual acuity was normal. Pupils were isocoric with prompt light reaction. There was no paresis in the facial muscles. Dysphagia and dysarthria of moderate degree were seen. There was nuchal rigidity. Muscle strength was slightly weak in the upper extremities and moderately weak in the lower ones. Deep tendon reflexes in the jaw and extremities were hyperactive symmetrically with positive Babinski’s sign and ankle clonus. Kernig’s sign was positive. Sensory impairment and sphincter disturbance were not detected. Standing was possible with support, but gait was impossible.

Laboratory examinations were as follows. Blood sedimentation rate was 10 mm per an hour. Serological tests for syphilis were

negative. Peripheral blood picture, urinaly- sis, feces, liver functions, serum electrolytes, serum protein fractions and chest X-ray were all unremarkable. Electrocardiogram showed sinus tachycardia and WPW’s syndrome. ASLO was 50 units, CRP was re- markably positive, RA was negative. Im- munoelectrophoresis of the serum proteins revealed: IgG, 760 mg/dl; IgM, 336 mg/dl; IgA, 285 mg/dl. Opening pressure of the cerebrospinal fluid was 145 mmH20, final pressure was 100 mmH,O after removal of 7 ml. The cerebrospinal fluid was crystal clear and contained 15 lymphocytes per cubic millimeter. Protein was 89 mg/dl: pre-albumin, 3.2%; albumin, 56.1 ”/. ; alpha- 1 globulin, 9.7%; alpha-2 globulin, 8.4% ; beta globulin, 11.6 ”/. ; and gamma globulin, 11.0%. Sugar was 36 mg/dl. Chloride was 126 mEq/l. Bacterial and viral cultures of the fluid were negative. Electro- encephalogram revealed slightly abnormal pattern containing sporadic slow waves.

Hemagglutination titer of measles virus was 32 X, Neutralizing antibody titer of

An Autopsy Case of Brain Stem Encephalitis with Spinal Cord Involvement 135

measles virus was 40 X. Hemagglutination titer and complement fixation titer of Japa- nese B encephalitis were 80 X (normal below 160 X ) and 4 X (normal below 8 X), respectively. Lymphocytes transformation by phytohemagglutinin was seen in 66.7%.

Diagnosed clinically as brain stem encephalitis, he was treated with corticotropins (ACTH), adrenal steroids and some anti- biotics. During the first three months after admission, his symptoms and signs were slightly improved, but thereafter they had constantly progressed. In April 1969, gen- eralized convulsive seizure with unconsci- ousness occurred. From this time, total nine seizures were observed until October 1970. In May 1969, standing became impossible and in September his extremities were almost completely paralysed. At this time, he began to complain of blurred vision. Facial paresis appeared. Open mouth was difficult. There were grinding of teeth and myoclonic involuntary movement in the extremities. Double incontinence developed. In October, he became drowsy. In Decem- ber, anisocoria was seen.

Chinoform was prescribed for diarrhea from January 26 to July 28, 1970, 0.6 or 1.2 g daily, of total dosis of 168.6 g. He noted numbness under the knee bilaterally on February 27. The numbness extended over the whole lower extremities in March. It ascended to the umbilical level in May, to the level of the nipple in October. The nature and strength of the sensory impairment were obscure for confusion and dysarthria.

On October 16, tracheotomy was done for dyspnea. In December, there was pit- ting edema in the hands and feet. Next month he became to the state of akinetic mutism. Fever was seen intermittently during the whole course. At the end stage,

fever of 39°C was continued. Adrenal steroids were administered totally 790.5 g as Betamethasone. He died of concomitant bronchopneumonia on June 27, 197 1, at the age of thirty-five, three years and six months after the onset.

Postmortem examinations. Autopsy was done one hour and forty-five minutes after death, General autopsy findings included: marked emaciation, bilateral inhalation pneumonia with bronchiectasia in the right lower lobe, tracheal ulcer and tracheoeso- phageal fistula due to tracheotomy, diffuse fibrous adhesion of the left pleura, fatty liver, chronic pyelonephritis, chronic cystitis, adrenocortical atrophy, edema in the hands, feet and scrotum, retention of ascites of 50 ml, and decubitus formation in the back.

The leptomeninges of the cerebral convolution were slightly turbid. The cerebral hemispheres were symmetrical with unremarkable gyri and sulci, and there was no evidence of atrophy. On coronal sections of the cere- brum, the cerebral cortex and white matter appeared normal, but the lateral and third ventricles were dilated moderately. The leptomeninges of the base and spinal cord were markedly turbid and thickened. The cerebellum was grossly unremarkable. The midbrain, pons and medulla oblongata were severely atrophied, dark brown in color and elastic hard on the external and cut surface. But only the inferior olives seemed rather hypertrophic. There were no atherosclero- tic lesions in the basilar artery and its branches. The spinal cord was extremely atrophic in the cervical and thoracic cord. The transverse sections of each level showed firm and homogeneously dark brown, with loss of differentiation of the gray and white matter markings. The lumbar cord was also slightly atrophic and revealed definite pal-

The brain weighed 1,170 g.

136 T. Shirabe, E. Tatsuta, Y. Kuroiwa and K. Tanaka

C

T

Fig. 2. Illustration of sites of lesions.

lor of the lateral and posterior columns, but hematoxylin, luxol fast blue, Holzer’s, cresyl the architecture of the gray and white mat- violet, Bodian’s, periodic acid-Schiff, van ter remained unimpaired. Gieson’s, and Sudan 111 stains. Sites of

On microscopic examination, sections of lesions were illustrated in Fig. 2. the brain and spinal cord were stained with There were irregularly confluent demyeli- hematoxylin and eosin, phosphotungstic acid nated lesions in the hypothalamus, lower ____

Fig. 3. Midbrain. There are irregularly confluent demyelinated lesions mainly in the cerebral peduncles, of which margins are indistinct. Luxol fast blue and cresyl violet double stain, x2.8.

Fig. 4. There is marked gliosis in the demyelinated areas in the midbrain. Holzer’s stain, ~ 2 . 8 . Fig. 5. Pons. Dernyelinated lesions are scattered predominantly in the long tracts. Luxol fast

Fig. 6. Marked gliosis is seen in the demyelinated areas in the pons. Holzer’s stain, x3.5. Fig. 7. Mild leptomeningeal and perivascular collections of chronic inflammatory cells in the

Fig. 8. Perivascular accumulations of macrophages in the midbrain lesion. Hematoxylin and

Fig. 9. Macrophages are scattered and fibrous astrocytes are proliferated in the demyelinated

Fig. 10. Intranuclear inclusion body (arrow) is seen in the nerve cell in the substantia nigra.

blue and cresyl violet double stain, ~ 3 . 5 .

midbrain. Hematoxylin and eosin, x 150.

eosin, ~ 3 4 0 .

lesions in the pons. Hematoxylin and eosin, x350.

Hematoxylin and eosin, ~ 5 9 0 .


end of the internal capsule, optic ’ chiasm, midbrain (Fig. 3), pons (Fig. 5 ) and medulla oblongata (Fig. I I ) . Weithin the demyelinated areas, there were loss of axons, lipid-laden macrophages (Fig. 9) and marked gliosis (Fig. 4, 6, 12). Blood vessels in the lesions were often surrounded by lymphocytes (Fig. 7 ) and macrophages (Fig. 8). Eosinophilic droplets were seen in the cerebral peduncles and a few glial nodules were seen in the medulla oblongata (Fig. 16). Perivascular prolifera- tion of mesenchymal nets was detected with van Gieson’s stain. Nerve cells in the hypothalamus, substantia nigra, red nucleus, pontine nucleus and cranial nerves were relatively well preserved. The nerve cells in the inferior olives showed vacuolar degeneration, atrophy or loss, and there was marked gliosis in the region (Fig. 17). In- tranuclear inclusion bodies of Cowdry B type were found in the nerve cells in the substantia nigra (Fig. 10). The leptomeninges of the brain stem were thickened fibrously and were infiltrated with a few lymphocytes.

In the spinal cord, there were transverse and extensive demyelination and axonal de-

~ -~ ~- -~ __ .

struction in the cervical (Fig. 13) and thoracic cord (Fig. 14), with sparing only parts of the bilateral lateral columns. The stroma was spongy and numerous lipid- laden macrophages were seen (Fig. 18). There were mild gliosis and perivascular lymphocytes intiltration. The nerve cells of the anterior horn were almost disappeared. Changes were less severe in the lumbar cord. There were partial demyelinated zones in the lateral and posterior columns in this area, and alterations were not observed in the gray matter.

Atrophy or loss of Purkinje cells and Tor- pedo formation were found in the cerebellar cortex. The white matter of the cerebellum showed mild but diffuse microglial prolifera- tion. Small ischemic foci were scattered here and there in the cerebral cortex (Fig. 19). The cerebral white matter was unremarkable except for localized mild pallor with the myelin staining. Neuronophagia was not detected in the central nervous system.

The sciatic nerves showed demyelination, destruction or swelling of axis cylinders, and proliteration of Schwann cells and histio- cytes. Denervated atrophy of mild degree, ___ --___ . ~ .

Fig. I I . Medulla oblongata is atrophied severely, but only the inferior olives are rather hypertrophic. Luxol fast blue and cresyl violet double stain, ~ 3 . 3 .

Fig. 12. Gliosis is seen in the demyelinated zones in the medulla oblongata. Holzer’s stain, x3.3.

Fig. 13. Lower cervical spinal cord. There i s extensive demyelination of all columns with sparing only parts of the lateral columns. Luxol fast blue and cresyl violet double stain, x 9 .

Fig. 14. Middle thoracic spinal cord. The same findings are seen. Luxol fast blue and cresyl violet double stain, X9.

Fig. IS. Lumbar spinal cord. There is secondary degeneration in the corticospinal tract. Luxol fast blue and cresyl violet double stain, x 9 .

Fig. 16. A glial nodule is seen in the medulla oblongata. Hematoxylin and eosin, x410. Fig. 17. The nerve cells in the inferior olives show vacuolar degeneration, atrophy or loss.

Fig. 18. Lower cervical spinal cord. Stroma is spongy and numerous macrophages are scattered.

Fig. 19. Gray matter of the temporal lobe. Small ischemic focus is seen. Hematoxylin and



eosin, x210.


Fig. 20. Electron-micrograph of nerve cell in the substantia nigra. Inclusion body shows concentric double structure of conglomeration of dense granules with hollow in the centrurn. Uranyl acetate and lead citrdde. X13,200.

with simple atrophy was seen in the skeletal muscles of the lower extremities.

At the time of necropsy, small specimens from the brain stem lesions were taken asep- tically for virus isolation and immunofluorescence study without fixation. Virus isolation study from the specimens by Vero cells and kidney cells of African green monkey was negative. Brain stem lesions including the intranuclear inclusion bodies in the substantia nigra were studied for virus particles electron-microscopically. The inclusion bodies showed concentric double structure of conglomeration of dense granules, in which the inner layer was more dense with hollow in the centrum, but virus particles were not detected (Fig. 20). In- direct immunofluorescence examination was

carried out on the specimens. They were treated with the serum of the patient and human gamma globulin, but any parts of them did not fluoresce.

DISCUSSION Clinical characteristics of our patient were

( I ) onset of young adult, (2) slowly progressive course with transient remissions, ( 3 ) symptoms and signs of the brain stem and pyramidal tract involvement, (4) inter- mittent fever and inflammatory findings in the cerebrospinal fluid, ( 5 ) character change without severe dementia, ( 6 ) no remarkable disturbance of consciousness. Principal morphological observations of the patient were as follows. The lesions were main!y localized in the brain stem, extending from


the hypothalamus to the spinal cord. The nature of the lesions was chronic inflammation or demyelination with marked gliosis. Nerve cells in the lesions were relatively well preserved. There was no neuronophagia, but a few glial nodules were seen in the medulla oblongata.

These clinicopathological features were most similar to that of brain stem encephalitis documented in detail by Iizuka7t8). How- ever, in our case, perivascular and meningeal inflammation was more inactive, probably because of prolonged course and the extensive use of ACTH and adrenal steroids, and the spinal cord involvement was more intense. Being considered its severity, this spinal cord lesion will not be regarded as the secondary degeneration due to the brain stem lesion. It was suggested that the spinal cord lesion was more fresh than the brain stem lesion, because there were more numerous macrophages and lesser gliosis in the cord lesion. Clinically, he developed numbness in the lower extremities on February 27, 1970, to ascend to the level of the nipple several months later. It is presumed that this intense spinal cord lesion had re- lated to this history. Recently, chinoform toxicity for the nervous system is being studied. The main features of the spinal cord in subacute myelo-optico-neuropathy (SMON), or chinoform intoxication, are systemic degeneration of the lateral corticospinal tract and Goll’s f a~c icu lus~~) . In our patient, chinoform was prescribed in large quantity for diarrhea from a month before the symptoms and signs of the spinal cord involvement had appeared. But the partici- pation of chinoform in the formation of this spinal cord lesion will be questionable.

The most peculiar pathological finding of this case was hypertrophic degeneration of the inferior olives. As its pathogenesis,

transsynaptic degeneration of the olives due to injury in the central tegmental tract in the pons will be considered’). But since the hypertrophic degeneration is sometimes seen in SMON the influence of chinoform also should be taken in considera- tion. Small ischemic foci scattered in the cerebral cortex may be due to repeated epileptic attacks, although no remarkable changes were seen in the hippocampus.

Iizuka71s) has mentioned that in the brain stem encephalitis convulsions do not occur. But in our case convulsions had been observed occasionally, which may not be due to brain stem encephalitis, but recurrence of epilepsy of childhood.

Neuropathological findings in our patient have some resemblances to those of demyeli- nating disorders, especially those of neuromyelitis optica. Indeed, Harada and Shi- rakic) have suggested that their case might possibly belong to the category of the de- myelinating disorders in their report of brain stem encephalitis, But, compared with neuromyelitis optica, demyelination was more vague in margin and irregular in shape, and gliosis was more prominent in our case. Axis cylinders were also involved in the demyelinated lesions. Clinical course and neuropathological findings in our case is more suggestive of some chronic inflammatory process, regardless of transient remissions in the early stage. Demyelination is probably secondary to the chronic inflammation. It is said that lymphoytes from multiple sclerosis patients show increased transformation by the immunosuppressive agents. The rate of lymphocytes transformation in our patient was not increased, counting as 66.7%. This fact also keeps away from diagnosing our case as multiple sclerosis. Low gamma globulin of CSF in the case is also unlikely to multiple sclerosis.


Next, Neuro-Behcet’s syndrome is to be thought for differential diagnosis, as the pre- dilection of its lesions in the central nervous system are the diencephalon and brain stem. The problem is the abortive or atypical form with obscure signs of Behcet’s syndrome, In a report of brain stem encephalitis, Ta- tetsu et a1.I8) have postulated that their case is possible for Neuro-Behcet’s syndrome due to the iritis seen in the early stage. But in our patient there were not any sings suggestive of Behcet’s syndrome clinically, and the individual lesions was not so closely connected with the vessels as in Neuro- Behcet’s syndrome pathologically.

Our patient is too unusual as infantile subacute necrotizing encephalomyelo- pathysI0), which shows lesions in the diencephalon and brain stem, because of chronic clinical course and inflammatory changes without capillary formation.

Brain stem involvement is said to be dominant in some cases of subacute sclerosing panencephalitis (SSPE)6), but SSPE is denied on the fact that the titer of the measles virus antibody is not elevated at all. The possibility to be a prolonged case of Japanese B encephalitis is denied on the low titer of its virus antibody as well. It is difficult to comment on the possibility of a prolonged case of encephalitis of known virus encephalitis other than SSPE or Japa- nese B encephalitis. But cultures of the brain stem specimens with Vero cells and Kidney cells of monkey yielded no virus. Further, electron-microscopic examination of the lesions, including the intranuclear inclusion bodies of Cowdry B type, failed to show any virus particles. These inclusion bodies may correspond to Marinesco’s cor- puscles, having no relation to viral infection.

From the pathological findings some viral infection is still possible. The genesis might

be solved by measurements of the titers of much more viruses or changes of the cul- ture media.

Finally, the result of the immunofluorescence examination with the raw brain ma- terial was not agreeable to autoimmunity as the etiology of this illness, even if not de- cisive.

Anyway, our patient will be said to be a case of sporadic and chronic encephalitis of obscure origin of which lesions are prin- cipally located in the brain stem and spinal cord, most similar to those described by Iizuka. It is possible to label similar cases13) including ours together as the brain stem encephalitis of Iizuka’s type. How- ever, as the term of brain stem encephalitis of Iizuka’s type is not based on the etio- logical classification, it is necessary to study further on the etiologies in the future.

SUMMARY

An autopsy case was presented of brain stem encephalitis diagnosed clinically. A patient was taken ill with headache and double vision. He developed character change, dysphagia, dysarthria, nuchal rigidity and spastic quadriparesis with intermit- tent fever, following the disappearance of double vision. These symptoms and signs progressed slowly with transient remissions. He died at the age of thirty-five years, three years and six months after the onset. On neuropathological examination, there were chronic inflammatory lesions together with demyelination and gliosis in the hypothalamus, lower end of the internal capsule, optic chiasm, midbrain, pons, medulla oblongata and spinal cord. The clinicopathological features of our case were most similar to those of brain stem encephalitis described by Iizuka. However, the spinal cord involvement was severe in our case. Viral


studies examined were all negative, despite that the neuropathological findings were suggestive of some viral infection.

ACKNOWLEDGEMENT We are grateful to Dr. Mori, Department

of Bacteriology, Faculty of Medicine, Kyu- shu University, for the viral study.

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Mukoyama, M., Nagata, Y., Ando, I. and Sobue, I.: A case of encephalitis localized in the brain stem, simulating the occlusion syndrome of the anterior and posterior inferior cerebellar arteries, Clin Neurol, 5: 270-277, 1965. Shirabe, T., Kikuchi, M. and Fukamachi, K.: An autopsy case of subacute myelo-optico- neuropathy (SMON) accompanying ab- dominal symptoms with hypertrophic degeneration of the inferior olives, Fukuoka acta med, 61: 739-747, 1970. Shirabe, T., Inokuchi, T., Mikagi, Y. and Ito, K.: An autopsy case of necrotizing brain stem encephalitis, Kyushu Neuro- Psychiat, 17: 61-66, 1971. Takahata, N., Kobayashi, Y., Ito, K. and Kato, Y.: Two cases of brain stem encephalitis with specific psychic symptom and ataxia, Clin Neurol, 8: 69-77, 1969. Tateishi, J., Yamasaki, Y., Yoshimura, H. and Kunimitsu, S.: An adult caes of necrotizing encephalopathy of brain stem, Brain Nerve, 22: 969-976, 1970. Tatetsu, M., Toya, A. and Miyagawa, T.: An autopsy case of brain stem encephalitis, Psychiat Neurol jap, 70: 1-10, 1968. Verhaart, W. J. C.: A case of brain stem encephalitis, Neuropat pol Suppl, 4: 701- 703, 1966.

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an autopsy case of brain stem encephalitis with spinal cord involvement

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