Acta neuropath. (Berl.) 34, 95--103 (1976)
Acta Neuropathologica
9 by Springer-Verlag1976
Neuro-Behget's Disease Showing Severe Atrophy of the Cerebrum Taihei Miyakawa 1, Eiichi Murayama 1, Motonori Deshimaru 1, Isao Shikai 1, and Shiro K6zuma 2 1 Department of Neurology, Toxicology Institute, Kumamoto University School of Medicine, Kumamoto 2 Kozuma Hospital, Kumamoto
Summary. A 38-year-old female died 6 years after the onset of what was, clinically and histopathologically, consistent with Neuro-Beh~et's disease. Pathologically the cerebrum showed severe atrophy. The main changes were observed in the grey and white matter, the diencephalon and the basal ganglia by light microscopy. All these changes originated in softenings around blood vessels, especially small vessels or capillaries. These foci fused together to form large regions of softening. Gtial or mesenchymal reactions were minimal. In the white matter there was slight perivascular-infiltration, mainly consisting of lymphocytes. In view of these findings, it is suggested that these changes were caused by an allergic vasculitis. The present case of Neuro-Behget's disease is the first one showing general atrophy of the cerebrum. It is very important in relation to demyelinating encephalitis. Key words: Neuro-Beh~et's disease -- General atrophy of the cerebrum -Perivascular softenings. In 1937, Behget reported a syndrome which is characterised by relapsing iritis and recurrent ulceration in the mouth and on the genitalia (Beh~et's syndrome). Following this, some cases of Behget's syndrome accompanied by neuro-psychiatric signs were reported (Berlin, 1944; Hermann, ] 953) and Cavara (1954) gave the name "Neuro-Behget's syndrome" to such cases. Since then, many authors have used this title for cases of Behget's syndrome accompanied by neuro-psychiatric disorders. Up to the present, many cases of Neuro-Behget's syndrome have been reported clinically. Neuro-anatomical reports have however been few, so that the neuropathological entity of Neuro-Behget's syndrome has not yet been fully established. CASE R E P O R T
Clinical History Y. K., a woman aged 38, had nothing in her family history to suggest a similar disease or a hereditary disease. When 28 years old, in t959, she had had aphtosis in the mouth
96 Table 1.
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and erythema of the thigh. Next year, she began to have attacks of unconsciousness with generalized convulsions. F r o m 1962 to 1963, status epilepticus occasionally occurred. Following this, she gradually developed slurred speech and she was prone to speak and laugh. On her first admission (Sept. 30, 1963), her speech was slurred and her gait was unsteady. She had central paresis of the right facial nerve, slight hypertonic spasms of muscles in all extremities, increase of tendon reflexes in all extremities, with ankle clonus. She was ataxic, with dysdiadochokinesis and, primitive reflexes, such as grasp reflexes, support reactions and forced laughing-crying. Psychologically, she was flaccid and apathetic or euphoric and emotionally uncontrolled. Judgement, calculation and orientation were disturbed. On examination the optic discs showed papilloedema, but it disappeared in a few days. Electroencephalography showed diffuse slow a with 0 waves and in the frontal area 6 waves appeared. Five lumbar puncture were done: pressure 180--150mm, lymphocytes 58--21/mm 3, total protein 90 -- 60 mg/100 ml. Pneumoencephalography showed dilatation of the lateral ventricles and the III ventricle. Angiography showed no abnormality. Serum Wassermann reaction was negative. After admission, convulsive seizures were controlled with antiepileptic drugs, but in January, 1964, she sometimes lost consciousness. At that time she had furunculosis and ulceration of the skin. After readmission she was feverish, with erythema nodosum of the upper limbs, aphthosis in the mouth and she complained of pain in her joints. She showed
Neuro-Behqet's Disease
97
disorientation, forced laughing-crying and emotional incontinence. Intellectual functions, such as calculation, recent and remote memory were poor. Her neuro-psychiatric symptoms gradually progressed, with athetoid movement of the fingers, pathologic reflexes and severe ataxic gait. Since July, 1967, the patient became cachectic, and this state continued until she died on October 28, 1968, at the age of 38, 9 years after the first attack of the genito-oral aphthosis, 6 years after the appearance of neuropsychiatric symptoms.
RESULTS
Necropsy The brain weight weighed 920 g. The leptomeninges were slightly opaque and thick. The brain was generally shrunken with thin gyri. The basal arteries were slender. The right optic nerve and the white matter of the cerebrum were severely shrunken except the occipital lobe. The lateral and third ventricles showed marked dilatation. The cerebellum appeared normal and the brain stem was slightly small.
Histopathological Findings The primary changes were found in the cortex and white matter of the cerebrum, the diencephalon and the basal ganglia. The secondary change was observed in the brain stem. In the cerebral hemisphere through the chiasm, demyelination was observed diffusely in the white matter and the basal ganglia, especially from the lateral ventricles to the centre of the white matter. The right optic nerve was completely without myelin (Fig. 1 a). Glial fibres were increased in all the white matter and the optic nerves, but fibre formation was slight in the serverely demyelinated area, whilst marked gliosis was observed in the relatively slightly demyelinated area (Fig. 1 b). In the parts with severe demyelination, nerve fibres were also deleted. In the occipital lobes, only slight demyelination and slight glial fibre-formation were found. The cerebellum did not show any change. In the brain stem, slight demyelination and glial fibre formation were found at the
b Fig. 1. (a) Coronal section through posterior part of anterior comissure. Confluent foci of myelin loss in white matter, especially adjacent to lateral ventricles and right optic nerve (Woelcke myelin stain). (b) Section close to l a . Gliosis corresponds with loci of myelin loss, especially where slight, such as in temporal lobes and left optic nerve (Holzer stain)
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Fig.2. (a) Transverse section of left midbrain. Slight myelin loss from the corticospinal tract and superficial pontine fibres (arrow) (Woelcke myelin stain). • 1.9. (b) Midbrain at the same transverse section to 2 a. Slight gliosis at the cortico-spinal tract,a part of superficial pontine fibres and from the part of nigra to tegmentum. • 1.9 Fig.3. (a) Transverse section of pons. Myelin loss from the cortico-spinal tracts and deep pontine fibres (Sugamo myelin stain). • 1.5. (b) Ports at the same transverse section to 3a. Gliosis corresponds with foci of myelin loss (Holzer stain). • 1.5 Fig.4. (a) Transverse section of medulla oblongata. Atrophic cortico-spinal tracts and slight myelin loss from the cortico-spinal tract (Woelcke myelin stain). • 1.8. (b)Medulla oblongata at the same transverse section to 4a. Slight gliosis in cortico-spinal tracts and white matter around olivary nucleus (Holzer stain). • 1.8
cortico-spinal tracts and the superficial pontine tracts in the midbrain (Fig.2a, b), the pyramidal tracts in the pons (Fig. 3 a, b) and a part of the pyramidal tracts in the medulla oblongata (Fig.4a, b). Both cortex and white matter contained innumerable small softenings around small vessels (Fig. 5). Small softenings gradually fused with each other into large loci. Glial and mesenchymal reactions were scarcely observed, except for slight gliaI-fibre formation (Fig. 6), There were slight perivascular infiltrations in the white matter. The investing cells were mostly lymphocytes (Fig.7). In the damaged regions of the white matter, foci of myelin loss began around the blood vessels and gradually fused with each other to form large foci of myelin loss (Fig. 8). In addition to these changes, chronic nerve cell change was found in a part of the frontal, parietal and temporal cortex and deletion of pyramidal cells from the hippocampal formation, especially in Sommer's sector was
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found. In the leptomeninges of the right optic nerve, which showed complete loss of myelin, innumerable cells, such as lymphocytes and histiocytes, were found. In the diencephalon and basal ganglia, the same changes were observed as in the cerebrum. In the brain stem, slight secondary degeneration was observed. Fat granule cells were not found in the softenings on the perivascular spaces. Glial cell nodules and inclusion bodies were not found. Several parts of the brain were examined by the electron microscope, but virus-like particles were not found.
DISCUSSION The present case presented recurrent aphthosis in the mouth and on the genitalia in the course of the disease. Although papilloedema and opacity of the vitreous body were observed, uveitis did not appear. However, Curth (1952) insisted that Behget's syndrome could be diagnosed if two symtoms appeared. For this reason, a clinical diagnosis of Behget's disease could be made. There are various neuropsychiatric symptoms in Neuro-Behget's disease. According to Schotland (1963), cranial nerve signs, convulsions, hemi or tetraparesis and pseudobulbar signs are the most common manifestations of Neuro-Behget's disease. This is understandable because many cases of Neuro-Behget's disease have predominantly brain stem involvement. In this case, there were cerebral symptoms, such as severe dementia, epileptic convulsions, emotional incontinence, forced laughing-crying, primitive reflexes and clouding of consciousness were remarkable. This is different from many cases reported to date. Pallis et aI. (1956) divided the involvement of the nervous system into following three types: (a) a brain stem syndrome (b) a meningomyelitic syndrome (c) an organic confusional syndrome (possibly encephalitis). According to this classification, this case belongs to an organic confusional syndrome. Regarding laboratory findings, the cerebrospinal fluid shows pleocytosis (above 60 mm a in 81%) and increase of protein (above 50 rag- % in 65 %) of cases of Neuro-Behget's disease (Schotland et al., 1963). Similar findings were present in this case. Pathologically the characteristic findings of this case can be summarized as follows: (1) general atrophy of the cerebrum (2) perivascular softenings in all part of cerebral cortex and white matter. The foci fused with each other into large foci (3) perivascular infiltration in the white matter (4) all loci were free from glial or mesenchymal reactions. Regarding the foci, the question is whether the perivascular changes are softenings or demyelination. In the lesions, there were various grades from myelin loss with destruction and deletion of nerve fibres to foei without severe deletion of nerve fibres. There were thus various grades of changes from demyelinating change to softenings. Perivascular infiltration was slight in the white matter without softenings, whilst it was not found in the blood vessels surrounded by softenings. From this perivascular infiltration might be a primary change and slight infiltration might be the reason for the long duration of the clinical course of the disease. Up to date only a few cases of Neuro-Behget's disease have been examined histopathologically, and predominant brain stem involvement has been reported
100
Figs, 5--8
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in many of them (Berlin, 1944; Silfverski61d, 1951 ; Kurata et al., 1957; Mii, 1961 ; Nakamura et al., 1962; Totsuka et al., 1968, 1972). In the previous reports, some cases which also involved the cerebrum have been described (McMenemey et al., 1957; Kurata et al., 1957; Swa et al., 1960; Alajouanine et al., 1961; Mii, 1961; Nakamura et al., 1962; Shimizu et al., 1963; Strouth, 1964; Hashi et al., 1965; Swa et al., 1966; Hartemann et al., 1966; Kawakita et al., 1966). Hashi et al. (1965) described the pathoanatomical findings in his case and noted that the gyri of the cerebrum were slightly atrophied and contained small softenings in the cortex. McMenemey et al. (1957) found innumerable small softenings in the cortex and white matter. However, there is no case which showed severe atrophy of the cerebrum, and contained innumerable softenings both in the cortex and white matter, as it was found in this case. The changes must be considered in relation to multiple sclerosis (M S). In our case, large foci with demyelination, especially surrounding the ventricles, were observed. This is similar to the findings in M S However. the boundaries of the demyelination are not clear and there is no active reaction of glial and mesenchymal elements to the lesions. In M S the boundaries of demyelination are extremely clearly delineated and an increase of phagocytes and gliosis are observed. However, Shiraki (1961) pointed out that demyelinating disease in Japan has a tendency towards tissue's necrosis and Totsuka et al. (1962, 1966) also had the same opinion in the previous reports. This problem must be carefully examined in the future. The histopathological diagnosis in Neuro-Beh~et's disease is not the same in all cases. It has been called encephalopathy (McMenemey et al., 1957), meningoencephalitis (Rubinstein et al., 1963), Nekrotisierende Encephalitis (Ulrich, 1964), demyelinated encephalomyelitis (Swa et al., 1960), Pan-meningoencephalitis disseminata chronica (Mii, 1961; Hashi et al., 1965) and chronic disseminated encephalomyelitis (Totsuka et al., 1964). This may be because autopsy examination of Neuro-Behget's disease has not been done in many cases. However, these various features in Neuro-Behget's disease might be caused by the variation in the reaction of the living body against a single noxus, rather than a number of noxae.
Regarding the etiology of Neuro-Behr disease, various theories have been proposed, especially virus (Sezer et al., 1956; Evans et al., 1959; Alema et al., 1966), allergy (McMenemey et al., 1957; Hashi et al., 1965; Nazzaro, 1966; Totsuka et al., 1972) and circulatory disturbances (Adams, 1959; Totsuka et al., 1968).
Fig. 5. Parietal cortex. Perivascular softenings in the IlI--Vth layer. Glial or mesenchymal reactions are not visible (H.-E. stain). • 230 Fig. 6. Parietal cortex. Large foci around the blood vessel. Active reactions of glial and mesenchymal elements are not found (H.-E. stain). • 230 Fig. 7. White matter in gyrus cingli. Perivascular infiltration, mostly consisted of lymphocytes. The parenchyma around this vessel is compressed by some substance (H.-E. stain). • 250 Fig. 8. White matter of internal capsule. Perivascular myelin loss gradually extends to fuse each other (Woelcke myelin stain). • 45
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Histopathologically, the findings observed in our case have some similarity to experimental allergic encephalomyelitis which is characterized by previous inflammatory reaction in the white matter (Roizin et al., 1959; Murofushi, 1958). We could not find glial nodules, thrombosis in vessels and inclusion bodies and virus-like particles by means of electronmicroscopy. At present, the etiology of some encephalitides, such as postinfectious encephalitis, serum encephalitis, postvaccinal encephalitis and acute disseminated encephalitis and acute multiple sclerosis is also t h o u g h t to be due to an allergic reaction, but more advanced researches must be done to decide the cause o f them in the future. The present case is of importance concerning the etiology of Neuro-Behget's disease in relation to demyelinating disease and demyelinating encephalitis.
Acknowledgements. We wish to thank Miss Tsuyako Kito (Psychiatric Research Institute of Tokyo) for technical assistance.
REFERENCES Adams, R. D. : A comparison of the morphology of the human demyelinative disease and experimental allergic encephalomyelitis. In: "Allergic" encephalomyelitis (eds. M. S. Kics and E. C. Alvord, pp. 183-209. Springfield, Ill. : Ch. C. Thomas 1959 Alajouanine, Th., Castaigne, P., Lhermitte, F., Cambier, J., Gautier, J. C. : La meningoencephalite de la maladie de Behqet. Presse m6d. 69, 2579--2582 (1961) Alema, G., Bignami, A. : Involvement of the nervous system in Behget's disease. In: Behget's Disease (eds. M. Monacelli and P. Nazzaro), pp. 52--66. Basel-New York: Karger 1966 Beh~et, H. : fiber rezidivierende aphth6se, durch ein Virus verursachte Geschwtire am Mund, am Auge und an den Genitalien. Derm. Wschr. 105, 1152--1157 (1937) Berlin, C. : Behget's syndrome with involvement of the central nervous system. Arch. Derm. Syph. (Chic.) 49, 227--233 (1944) Cavara, V., D'Ermo, F. : XVII Concilium aphthalmologicum ACTA, vol. 3, p. 1489 (1954) Curth, H. O. : Behget syndrome (aphthosis). Arch. Derm. Syph. (Chic.) 66, 761 --762 (1952) Evans, A. D., Pallis, C. A., Spillane, J. D. : Involvement of the nervous system in Behget's syndrome. Lancet 1959 II, 349--353 Gray, G. S. : The tripe complex syndrome of Behget. Canad. med. Ass. J. 62, 597--599 (1950) Hartemann, P., Schnitt, J., Trison, P., Maken, J., Floquet, J., Guazzi, G. C. : Sur Ia signification des aspects de phlebite recidivante et granulomateuse dans les magnifications cerebrales de la maladie de Beh~et. Rev. neurol. 114, 33--42 (1966) Hashi, N , Tsutsumi, S., Nakata, K., Murakami, T. : Neuro-Beh~et's syndrome (Report of an autopsy case). Neurol. Psychiat. 67, 123--133 (1965) (Jap.) Hermann, C. : Involvement of the nervous system in relapsing uveitis with recurrent genital and oral ulcers (Behget's syndrome). Arch. Neurol. Psychiat. (Chic.) 69, 399--400 (1953) Kawakita, E., Nishimura, S.: An autopsy case of Beh~et's syndrome with neurologic signs. Advance Neurol. Sci. 10, 380 (1966) (Jap. abstract) Kurata, T., Ishiyama, F. : An autopsy case of Beh~et's Syndrome with diffuse demyelinated changes in cerebrospinalis. J. Path. 46, 427 (1957) (Jap. abstract) McMenemey, W.H., Lawrence, B. J. : Encephalomyelopathy in Behget's Disease. Report of necropsy findings in two cases. Lancet 1957 II, 353 358 Mii, T. : Neuro-Beh~et's Syndrome. An autopsy case of Neuro-Behqet's Syndrome and the patho-histological observations of the cases. Okayama reed. J. 73, 821--842 (1961) (Jap.)
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Murofusi, K. : The studies on experimental demyelinating encephalomyelitis. Neurol. Psychiat. 60, 37--74 (1958) (Jap.) Nakamura, T., Ikui, H.: A case of Neuro-Beh~et's Disease. Advance Neurol. Sci. 6, 150--151 (1962) (Jap.) Nazzaro, P. : Cutaneous manifestation of Behget's Disease. Clinical and histopathological findings. In: Beh~et's Disease (eds. M. Monacelli and P. Nazzaro), pp. 15--41. Basel-New York: Karger ] 966 Pallis, C. A., Fudge, B. J. : The neurological complication of Behget's syndrome. Arch. Neurol. Psychiat. (Chic.) 75, 1--14 (1956) Roizin, L., Kolb, L. C. : Neuropathologic relationship of multiple sclerosis to experimental allergic encephalomyelitis. Neurol. Psychiat. 61, 483--540 (1959) Rubinstein, L. J., Urich, H. : Meningoencephalitis of Behget's disease; Case-report with pathological findings. Brain 86, 151--160 (1963) Schotland, D.L., Wolf, S.M., White, H . H . , Dubin, H. V. : Neurologic aspects of Behget's disease. Case report and review of the literature. Amer. J. Med. 34, 544--553 (1963) Sezer, N. : The isolation of a virus as the cause of Behget's disease. Amer. J. Ophthal. 36, 301--315 (1953) Shimizu, T., Kagami, T., Hara, T., Matsumoto, T., Matsumura, N. : Neurological disturbances of Beh~et's syndrome. Clin. Neurol. 3, 303 (1963) (Jap. abstract) Shiraki, H. : The present status of demyelinating encephalomyelitis of unknown origin from pathoanatomical viewpoint in Japan. Clin. Neurol. 1, 107-128 (1961) (Jap.) Silfverski61d, B. P. : Recurrent uveitis (Behqet's syndrome) and encephalomyelomeningitis. Acta psychiat. 26, 443--454 (1951) Strouth, J. C., Dyken, M. : Encephalopathy of Behqet's disease. Neurology (Minneap.) 14, 794--805 (1964) Swa, N., Iizuka, R., Takahata, N., Yamasaki, K., Watanabe, E. : Two autopsy cases of Neuro-Behqet's syndrome. Advance Neurol. Sci. 10, 801 (1966) (Jap. abstract) Swa, N., Sasano, N., Tachibana, Y. : An autopsy case of BehCet's disease. J. Path. 49, 789--790 (1960) (Jap. abstract) Totsuka, S. : Clinico-pathological studies on the two cases of neuromyelitis optica (D6vic disease) with a chronic clinical course.--With especial reference on its relationship to multiple sclerosis--Psychiat. Neurol. 64, 1149-- 1165 (1962) (Jap.) Totsuka, S., Matsumoto, Y., Tanikawa, K., Murakoshi, K., Takagi, Y.: An autopsy case of chronic disseminated encephalomyelitis with Behget's syndrome. With special reference to demyelinating disease. Psychiat. Neurol. 66, 883--892 (1964) (Jap.) Totsuka, S., Matsumoto, Y. : Clinico-pathological studies on demyeliuating encephalomyelitis. J. Chiba Med. 4, 333--360 (1966) (Jap.) Totsuka, S., Midorikawa, T., Matsumoto, Y. : Chronic disseminated encephalomyelitis in Behget's disease. A contribution to the pathology of so-called "Neuro-Behqet's Syndrome". Advance Neurol. Sci. 12, 1029--1045 (1968) (Jap.) Totsuka, S.: Some clinical and pathological problems in Neuro-Behqet's syndrome. Advance Neurol. Sci. 16, 186--189 (1972) (Jap.) Ulrich, J. : Nekrotisierende Encephalitis des Hirnstammes, unter dem Bild einer Multiplen Sklerose verlaufend (Behqet'sche Krankheit ?). Dtsch. Z. Nervenheilk. 186, 367--378 (1964) Received August 1, 1975; Accepted November 5, 1975 Prof. Dr. Taihei Miyakawa Department of Neurology, Toxicology Institute, Kumamoto University School of Medicine Honjo-Machi, Kumamoto Japan 8
Acta neuropa~h. (Berl.) Bd. 34
Acta Neuropathologica
9 by Springer-Verlag1976
Neuro-Behget's Disease Showing Severe Atrophy of the Cerebrum Taihei Miyakawa 1, Eiichi Murayama 1, Motonori Deshimaru 1, Isao Shikai 1, and Shiro K6zuma 2 1 Department of Neurology, Toxicology Institute, Kumamoto University School of Medicine, Kumamoto 2 Kozuma Hospital, Kumamoto
Summary. A 38-year-old female died 6 years after the onset of what was, clinically and histopathologically, consistent with Neuro-Beh~et's disease. Pathologically the cerebrum showed severe atrophy. The main changes were observed in the grey and white matter, the diencephalon and the basal ganglia by light microscopy. All these changes originated in softenings around blood vessels, especially small vessels or capillaries. These foci fused together to form large regions of softening. Gtial or mesenchymal reactions were minimal. In the white matter there was slight perivascular-infiltration, mainly consisting of lymphocytes. In view of these findings, it is suggested that these changes were caused by an allergic vasculitis. The present case of Neuro-Behget's disease is the first one showing general atrophy of the cerebrum. It is very important in relation to demyelinating encephalitis. Key words: Neuro-Beh~et's disease -- General atrophy of the cerebrum -Perivascular softenings. In 1937, Behget reported a syndrome which is characterised by relapsing iritis and recurrent ulceration in the mouth and on the genitalia (Beh~et's syndrome). Following this, some cases of Behget's syndrome accompanied by neuro-psychiatric signs were reported (Berlin, 1944; Hermann, ] 953) and Cavara (1954) gave the name "Neuro-Behget's syndrome" to such cases. Since then, many authors have used this title for cases of Behget's syndrome accompanied by neuro-psychiatric disorders. Up to the present, many cases of Neuro-Behget's syndrome have been reported clinically. Neuro-anatomical reports have however been few, so that the neuropathological entity of Neuro-Behget's syndrome has not yet been fully established. CASE R E P O R T
Clinical History Y. K., a woman aged 38, had nothing in her family history to suggest a similar disease or a hereditary disease. When 28 years old, in t959, she had had aphtosis in the mouth
96 Table 1.
T. Miyakawa et al. Clinical course of patient
and erythema of the thigh. Next year, she began to have attacks of unconsciousness with generalized convulsions. F r o m 1962 to 1963, status epilepticus occasionally occurred. Following this, she gradually developed slurred speech and she was prone to speak and laugh. On her first admission (Sept. 30, 1963), her speech was slurred and her gait was unsteady. She had central paresis of the right facial nerve, slight hypertonic spasms of muscles in all extremities, increase of tendon reflexes in all extremities, with ankle clonus. She was ataxic, with dysdiadochokinesis and, primitive reflexes, such as grasp reflexes, support reactions and forced laughing-crying. Psychologically, she was flaccid and apathetic or euphoric and emotionally uncontrolled. Judgement, calculation and orientation were disturbed. On examination the optic discs showed papilloedema, but it disappeared in a few days. Electroencephalography showed diffuse slow a with 0 waves and in the frontal area 6 waves appeared. Five lumbar puncture were done: pressure 180--150mm, lymphocytes 58--21/mm 3, total protein 90 -- 60 mg/100 ml. Pneumoencephalography showed dilatation of the lateral ventricles and the III ventricle. Angiography showed no abnormality. Serum Wassermann reaction was negative. After admission, convulsive seizures were controlled with antiepileptic drugs, but in January, 1964, she sometimes lost consciousness. At that time she had furunculosis and ulceration of the skin. After readmission she was feverish, with erythema nodosum of the upper limbs, aphthosis in the mouth and she complained of pain in her joints. She showed
Neuro-Behqet's Disease
97
disorientation, forced laughing-crying and emotional incontinence. Intellectual functions, such as calculation, recent and remote memory were poor. Her neuro-psychiatric symptoms gradually progressed, with athetoid movement of the fingers, pathologic reflexes and severe ataxic gait. Since July, 1967, the patient became cachectic, and this state continued until she died on October 28, 1968, at the age of 38, 9 years after the first attack of the genito-oral aphthosis, 6 years after the appearance of neuropsychiatric symptoms.
RESULTS
Necropsy The brain weight weighed 920 g. The leptomeninges were slightly opaque and thick. The brain was generally shrunken with thin gyri. The basal arteries were slender. The right optic nerve and the white matter of the cerebrum were severely shrunken except the occipital lobe. The lateral and third ventricles showed marked dilatation. The cerebellum appeared normal and the brain stem was slightly small.
Histopathological Findings The primary changes were found in the cortex and white matter of the cerebrum, the diencephalon and the basal ganglia. The secondary change was observed in the brain stem. In the cerebral hemisphere through the chiasm, demyelination was observed diffusely in the white matter and the basal ganglia, especially from the lateral ventricles to the centre of the white matter. The right optic nerve was completely without myelin (Fig. 1 a). Glial fibres were increased in all the white matter and the optic nerves, but fibre formation was slight in the serverely demyelinated area, whilst marked gliosis was observed in the relatively slightly demyelinated area (Fig. 1 b). In the parts with severe demyelination, nerve fibres were also deleted. In the occipital lobes, only slight demyelination and slight glial fibre-formation were found. The cerebellum did not show any change. In the brain stem, slight demyelination and glial fibre formation were found at the
b Fig. 1. (a) Coronal section through posterior part of anterior comissure. Confluent foci of myelin loss in white matter, especially adjacent to lateral ventricles and right optic nerve (Woelcke myelin stain). (b) Section close to l a . Gliosis corresponds with loci of myelin loss, especially where slight, such as in temporal lobes and left optic nerve (Holzer stain)
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Fig.2. (a) Transverse section of left midbrain. Slight myelin loss from the corticospinal tract and superficial pontine fibres (arrow) (Woelcke myelin stain). • 1.9. (b) Midbrain at the same transverse section to 2 a. Slight gliosis at the cortico-spinal tract,a part of superficial pontine fibres and from the part of nigra to tegmentum. • 1.9 Fig.3. (a) Transverse section of pons. Myelin loss from the cortico-spinal tracts and deep pontine fibres (Sugamo myelin stain). • 1.5. (b) Ports at the same transverse section to 3a. Gliosis corresponds with foci of myelin loss (Holzer stain). • 1.5 Fig.4. (a) Transverse section of medulla oblongata. Atrophic cortico-spinal tracts and slight myelin loss from the cortico-spinal tract (Woelcke myelin stain). • 1.8. (b)Medulla oblongata at the same transverse section to 4a. Slight gliosis in cortico-spinal tracts and white matter around olivary nucleus (Holzer stain). • 1.8
cortico-spinal tracts and the superficial pontine tracts in the midbrain (Fig.2a, b), the pyramidal tracts in the pons (Fig. 3 a, b) and a part of the pyramidal tracts in the medulla oblongata (Fig.4a, b). Both cortex and white matter contained innumerable small softenings around small vessels (Fig. 5). Small softenings gradually fused with each other into large loci. Glial and mesenchymal reactions were scarcely observed, except for slight gliaI-fibre formation (Fig. 6), There were slight perivascular infiltrations in the white matter. The investing cells were mostly lymphocytes (Fig.7). In the damaged regions of the white matter, foci of myelin loss began around the blood vessels and gradually fused with each other to form large foci of myelin loss (Fig. 8). In addition to these changes, chronic nerve cell change was found in a part of the frontal, parietal and temporal cortex and deletion of pyramidal cells from the hippocampal formation, especially in Sommer's sector was
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found. In the leptomeninges of the right optic nerve, which showed complete loss of myelin, innumerable cells, such as lymphocytes and histiocytes, were found. In the diencephalon and basal ganglia, the same changes were observed as in the cerebrum. In the brain stem, slight secondary degeneration was observed. Fat granule cells were not found in the softenings on the perivascular spaces. Glial cell nodules and inclusion bodies were not found. Several parts of the brain were examined by the electron microscope, but virus-like particles were not found.
DISCUSSION The present case presented recurrent aphthosis in the mouth and on the genitalia in the course of the disease. Although papilloedema and opacity of the vitreous body were observed, uveitis did not appear. However, Curth (1952) insisted that Behget's syndrome could be diagnosed if two symtoms appeared. For this reason, a clinical diagnosis of Behget's disease could be made. There are various neuropsychiatric symptoms in Neuro-Behget's disease. According to Schotland (1963), cranial nerve signs, convulsions, hemi or tetraparesis and pseudobulbar signs are the most common manifestations of Neuro-Behget's disease. This is understandable because many cases of Neuro-Behget's disease have predominantly brain stem involvement. In this case, there were cerebral symptoms, such as severe dementia, epileptic convulsions, emotional incontinence, forced laughing-crying, primitive reflexes and clouding of consciousness were remarkable. This is different from many cases reported to date. Pallis et aI. (1956) divided the involvement of the nervous system into following three types: (a) a brain stem syndrome (b) a meningomyelitic syndrome (c) an organic confusional syndrome (possibly encephalitis). According to this classification, this case belongs to an organic confusional syndrome. Regarding laboratory findings, the cerebrospinal fluid shows pleocytosis (above 60 mm a in 81%) and increase of protein (above 50 rag- % in 65 %) of cases of Neuro-Behget's disease (Schotland et al., 1963). Similar findings were present in this case. Pathologically the characteristic findings of this case can be summarized as follows: (1) general atrophy of the cerebrum (2) perivascular softenings in all part of cerebral cortex and white matter. The foci fused with each other into large foci (3) perivascular infiltration in the white matter (4) all loci were free from glial or mesenchymal reactions. Regarding the foci, the question is whether the perivascular changes are softenings or demyelination. In the lesions, there were various grades from myelin loss with destruction and deletion of nerve fibres to foei without severe deletion of nerve fibres. There were thus various grades of changes from demyelinating change to softenings. Perivascular infiltration was slight in the white matter without softenings, whilst it was not found in the blood vessels surrounded by softenings. From this perivascular infiltration might be a primary change and slight infiltration might be the reason for the long duration of the clinical course of the disease. Up to date only a few cases of Neuro-Behget's disease have been examined histopathologically, and predominant brain stem involvement has been reported
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in many of them (Berlin, 1944; Silfverski61d, 1951 ; Kurata et al., 1957; Mii, 1961 ; Nakamura et al., 1962; Totsuka et al., 1968, 1972). In the previous reports, some cases which also involved the cerebrum have been described (McMenemey et al., 1957; Kurata et al., 1957; Swa et al., 1960; Alajouanine et al., 1961; Mii, 1961; Nakamura et al., 1962; Shimizu et al., 1963; Strouth, 1964; Hashi et al., 1965; Swa et al., 1966; Hartemann et al., 1966; Kawakita et al., 1966). Hashi et al. (1965) described the pathoanatomical findings in his case and noted that the gyri of the cerebrum were slightly atrophied and contained small softenings in the cortex. McMenemey et al. (1957) found innumerable small softenings in the cortex and white matter. However, there is no case which showed severe atrophy of the cerebrum, and contained innumerable softenings both in the cortex and white matter, as it was found in this case. The changes must be considered in relation to multiple sclerosis (M S). In our case, large foci with demyelination, especially surrounding the ventricles, were observed. This is similar to the findings in M S However. the boundaries of the demyelination are not clear and there is no active reaction of glial and mesenchymal elements to the lesions. In M S the boundaries of demyelination are extremely clearly delineated and an increase of phagocytes and gliosis are observed. However, Shiraki (1961) pointed out that demyelinating disease in Japan has a tendency towards tissue's necrosis and Totsuka et al. (1962, 1966) also had the same opinion in the previous reports. This problem must be carefully examined in the future. The histopathological diagnosis in Neuro-Beh~et's disease is not the same in all cases. It has been called encephalopathy (McMenemey et al., 1957), meningoencephalitis (Rubinstein et al., 1963), Nekrotisierende Encephalitis (Ulrich, 1964), demyelinated encephalomyelitis (Swa et al., 1960), Pan-meningoencephalitis disseminata chronica (Mii, 1961; Hashi et al., 1965) and chronic disseminated encephalomyelitis (Totsuka et al., 1964). This may be because autopsy examination of Neuro-Behget's disease has not been done in many cases. However, these various features in Neuro-Behget's disease might be caused by the variation in the reaction of the living body against a single noxus, rather than a number of noxae.
Regarding the etiology of Neuro-Behr disease, various theories have been proposed, especially virus (Sezer et al., 1956; Evans et al., 1959; Alema et al., 1966), allergy (McMenemey et al., 1957; Hashi et al., 1965; Nazzaro, 1966; Totsuka et al., 1972) and circulatory disturbances (Adams, 1959; Totsuka et al., 1968).
Fig. 5. Parietal cortex. Perivascular softenings in the IlI--Vth layer. Glial or mesenchymal reactions are not visible (H.-E. stain). • 230 Fig. 6. Parietal cortex. Large foci around the blood vessel. Active reactions of glial and mesenchymal elements are not found (H.-E. stain). • 230 Fig. 7. White matter in gyrus cingli. Perivascular infiltration, mostly consisted of lymphocytes. The parenchyma around this vessel is compressed by some substance (H.-E. stain). • 250 Fig. 8. White matter of internal capsule. Perivascular myelin loss gradually extends to fuse each other (Woelcke myelin stain). • 45
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Histopathologically, the findings observed in our case have some similarity to experimental allergic encephalomyelitis which is characterized by previous inflammatory reaction in the white matter (Roizin et al., 1959; Murofushi, 1958). We could not find glial nodules, thrombosis in vessels and inclusion bodies and virus-like particles by means of electronmicroscopy. At present, the etiology of some encephalitides, such as postinfectious encephalitis, serum encephalitis, postvaccinal encephalitis and acute disseminated encephalitis and acute multiple sclerosis is also t h o u g h t to be due to an allergic reaction, but more advanced researches must be done to decide the cause o f them in the future. The present case is of importance concerning the etiology of Neuro-Behget's disease in relation to demyelinating disease and demyelinating encephalitis.
Acknowledgements. We wish to thank Miss Tsuyako Kito (Psychiatric Research Institute of Tokyo) for technical assistance.
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Acta neuropa~h. (Berl.) Bd. 34
