Folia Psychiatrica et Neurologica Japonica, Vol. 31, No. 2, 1977
An Autopsy Case of Cycloserine Poisoning Taihei Miyakawa, M.D., Takaaki Suzuki, M.D.,* Kiyoshi Nakamura, M.D. * * and Seijun Tatetsu, M.D. * * * Department of Neurology, Toxicology Institute Kitmarnoto University Medical School, Kutnutnoto * Iizuka Hospital, Fukiroka * * Sunpu Hospital, Shizuoka * * * Department of Neuropsychiatry, Kumamoto University Medical School. Kumantoto
INTRODUCTION
To patients with pulmonary tuberculosis, many antituberculous drugs, such as SM, INAH, PAS etc. have been used. However, cycloserine was administrated to some patients who did not respond to general antituberculous drugs. It is well known that cycloserine has side-effects. For this reason, it is not used today. Up to the present time histopathological changes of the autopsy case has not been reported. We had a chance to autopsy and examined the brain of a patient who showed several psychiatric and neurological symptoms caused by cycloserine poisoning. In this paper, we report the histopathological changes of this case. CASE REPORT Clinical History
T.Y., a girl aged 29, had nothing in her family history to suggest hereditary disease. When 19 years old, in 1955 she had pulmonary tuberculosis and entered a hospital. She had been trcated with many antituberculous drugs, such as PAS, SM, TH and INAH, but without responding to them. For Received for publication Oct. 7, 1976.
this reason, she was given cycloserine (CS) 0.5 g per day for 500 days (total dose 250 g). When she took CS for six months, on April 1964, she complained of headache, dizziness and difficulty in sleeping. She became irritable and her behavior was dull and slow. Her face was expressionless, hard, dull and empty. Neurologically, she was ataxic, had difficulty in speaking clearly and she had pyramidal signs, such as spasms in extremities, increase of tendon reflexes in all extremities with patellar clonus and pathologic reflex, such as Babinski sign. Subsequently, she fell into a manic state and sometimes seemed to be slightly unconscious. At this time, childish characters appeared. Following this, on January in 1965, gait disturbance and incontinentia urinae appeared. On February, extrapyramidal signs, such as muscle rigid, tremor, athetosis and disturbance of vegetative nerve, such as hyperidrosis, hypersalivation and dermatographism, appeared. Psychologically, hallucinatory-delusional state and dementia appeared, and then many pathologic reflexes, primitive reflexes, abnormal statue and hyperpathia appeared. She died on March 3, 1965 at the age of 29 about a year after treatment with CS. The clinical course of neurological symptoms induced by CS is shown in Fig. 1. On laboratory examination on February
236
T. Miyakawa et al.
Years
1964
Months
4
1965 11
1
Ataxia
Dysarthria Pyramidal sign fn
.-6
Gait disturbance
T!
lncontinentia urinae
J
Extrapyramidal sign
u)
22 0
Z
Disturbance of vegetative neve Primitive reflex Abnormal statue H yperpathia Complainments
E 8
Irritability
E
Manic state
.g
C haracter change
fn
+ .! c
*
0
Clouding of consciousness Hallucinatorydelusional states Dementia
Fig. 1 :
Clinical course of patients.
2
3
Cycloserine Poisoning
237
in 1965, blood, urine and routine tests were normal. Blood biochemical test; total protein, urea-N, Na, Ca, inorganic phosphorous, blood sugar, GOT, and GPT were all normal. Serological reaction for syphilis: WaR ( - 1. Ocular fundi: normal. EEG findings: basic pattern consisted of fast waves 20-50 Hz and 20-3OpV diffusely. RESULTS
Necropsy Fig. 2: Temporal cortex. Deletion of the nerve cells are diffusely observed, especially IIIrd layer. Nissl stain ( X40).
Fig. 3: Frontal cortex. Deletion of the nerve cells are diffusely observed in IIIrd layer. Nissl stain (X40).
The brain weighed 1,200 g and was optically normal. The basal arteries were slender.
Fig. 4: Hypothalamus. Small vessel is atrophic and deletion of the nerve cells are observed around it. Slight increase of glial cell is seen. Nissl stain (X82).
T. Miyakawa et al.
238
Fig. 5A: Subcortical white matter. Around the small vessel small myelin loss is observed. Sugatno myelin Ptain ( x 220).
Histoputhological Findings
In the cortex of the brain, deletion of the nerve cells were diffusely observed except occipital lobes, especially in the IIIrd layer of the cortex and glial cells were slightly increased (Figs. 2 and 3). In the hypothalamus, around the small blood vessels, there were deletion of nerve cells and slight increase of glial elements (Fig. 4). By myelin stain, partially small myelin loss around the small vessels along the U fibres was observed (Fig. 5A) and patchy myelin loss around the small vessels in the subcortical white matter on the parietal lobe (Fig. 5B) was also noticed. In the internal capsules, some small vessels had plasma solution infiltrate around them, and near the
Fig. 5B: Parietal white matter. Small-patchy mvelin loss are observed. Woelcke myelin stain ( X 2 2 0 ) .
vessels some phagocytes existed that contained pigments. Remarkable changes were observed in the putamen and pallidum; some vessels were destroyed and small softenings were formed around them (Fig. 7). Some endothelial cells were destroyed, and there were deletion of nerve cells around the vessels (Fig. 8). In the ccrzbellum, Purkinje cells showed atrophic structure and Bergmann glia increase in thos? places, and Purkinje cells generally decrzased in number (Fig. 9). Midbrain, pons and medulla oblongata did not show any abnormal findings. Several stains, such as Holzer stain, sudan 111 and perdrau stain, were carried out. However, glial fibres, fat granule cells and increase of blood vessels were not observed.
Cycloserine Poisoning
Fig. 6: Internal capsule. Around the small blood vessel, plasma solutions infiltrate. Near from this place, phagocytes contained pigments exist. Nissl
239
Fig. 7: Lateral part of the left putamen. Vessel is destructed and formed small softening around it. H.-E stain ( X 125).
stain ( X l l O ) .
DISCUSSION Cycloserine (CS) was antibiotics with wide spectrum induced from streptomyces orchisaceus. Epstein et al. (1955)l reported that this drug had effect on the pulmonary tuberculosis. On the other hand, it was clarified that this drug clinically had side-effects to the central nervous s y ~ t e m .'~ - ~However, description of the histopathological changes has not yet been reported. The neuro-psychiatric symptoms of our present case were caused by cycloserine, because it is the same symptoms described by the above authors. Nakamura ( 1968)6 reported psychiatric and neurological symptoms caused by cy-
closerine poisoning. In the report, he examined 25 cases clinically. Our present case is one of them, and in that paper, Miyakawa described briefly that the histopathological change was caused by the change of the blood vessels (p. 52). As described above, the leading changes were found in diencephalon and characteristic change was the destruction of small blood vessels; many endothelial cells fell into necrosis and deletion of 'nerve cells were observed around them, mainly in the basal ganglia, then in white matter. In addition to this finding, the deletion of the nerve cells in the cortex of cerebrum and cerebellum was observed. This may be caused by disturbance of small vessels, because slight changes of the small vessels
240
T. Miyakawa
Fig. 8: Left pallidum. Small vessel is destructed and around this vessel, nerve cells decrease. Nissl stain ( ~ 8 2 ) .
et
al.
Fig. 9: Cerebellum. Purkinje cells decrease in number and many Purkinje cells are atrophic, with increase of Bergmann glia. Nissl stain (x36).
were also observed in the cortex. From this, we speculate that this drug is toxic against blood vessels and effects endothelial cells, especially the small blood vessels. Up to date, we had examined many brains with arteriosclerosis or disturbance of circulation. However, they were quite different from the present case. The present case had no arteriosclerosis and no changes caused by arteriosclerosis, such as granular atrophy, softenings etc. Recently, Wada et uf. ( 1975)O disclosed histopathological findings which might be due to cycloserine. In this abstract, 'they also pointed to the change of blood vessels. Finally, the present case showed severe neurological signs. However, histopathological changes were.not as severe as suggested
by the symptoms. This may be due not only to histopathological changes but also to disturbances of the nerve function of the CNS due to the effect of CS. SUMMARY Cycloserine was given to a 29-year-old girl with pulmonary tuberculosis for 500 days (total dose 250g). Following this treatment, she began to show several psychiatric and neurological symptoms and died. Histopathologically, deletion of the nerve cells in the cerebrum was diffusely observed, especially in the IIIrd layer of the frontal and temporal cortex and patchy demyelinations were found in the white matter of the
Cycloserine Poisoning parietal lobe. Characteristic findings were the change of small blood vessels and deletion of the nerve cell around the area of vessels in the hypothalamus, putamen and pallidum. The same changes of the blood vessels were found in the internal capsule. In the cerebellum, shrinkage of Purkinje cells and increase of Bergmann’s glia were observed.
REFERENCES Epstein, I. G., Nair, K. G. S. and Boyd, L. J.: Cycloserine, a new antibiotic, in the treatment of human pulmonary tuberculosis: A preliminary report, Antibiot Med, 1: 80-93, 1955. Epstein, I. G., Nair, K. G. S. and Boyd, L. J.: The treatment of human pulmonary tuberculosis with cycloserine: Progress report, Dis chest, 29: 241-257, 1956. Levi-Valensi: Neuropsychiatrische Komplikationen bei Cycloserine-behandlung
24 1
Tuberkuloser (abstr.), Tbk arzt, 13: 142, 1959. 4 Levis, W. C., Calden, G., Thurson, J. R.,
5
6
7
8
Gilson, W. E.: Psychiatric and neurological reactions to cycloserine in the treatment of tuberculosis, Dis chest, 32: 172-1 82, 1957. Naka, K., Hayashi, A., Hikiji, A. and Yamamoto, M.: Psychiatric disturbance caused by cycloserine (abstr.), Psychiatr Neurol, 67: 389, 1965 (in Japanese). Nakamura, K. : Psychiatric and neurological symptoms caused by cycloserine poisoning, Psychiatr Neurol Japonica, 70: 503-602, 1968 (in Japanese). Shita, S.: Atypical psychosis and cycloserine poisoning, Commemorative Article of Prof. T. Miura’s Retirement, Depart Neurology, Keio University Medical School, Tokyo, p 259-265, 1963. U.S. Public Health Service Cooperative Clinical Investigation: A pilot study of cycloserine toxicity, Am Rev Tuberc, 74: 196-209, 1956.
9 Wada, T., Yano, K., Moro, K.: Neuropathological examination on patients who may be thought as cycloserine poi-oning, Jap Neuropath Program (abstr.) , 1975.
An Autopsy Case of Cycloserine Poisoning Taihei Miyakawa, M.D., Takaaki Suzuki, M.D.,* Kiyoshi Nakamura, M.D. * * and Seijun Tatetsu, M.D. * * * Department of Neurology, Toxicology Institute Kitmarnoto University Medical School, Kutnutnoto * Iizuka Hospital, Fukiroka * * Sunpu Hospital, Shizuoka * * * Department of Neuropsychiatry, Kumamoto University Medical School. Kumantoto
INTRODUCTION
To patients with pulmonary tuberculosis, many antituberculous drugs, such as SM, INAH, PAS etc. have been used. However, cycloserine was administrated to some patients who did not respond to general antituberculous drugs. It is well known that cycloserine has side-effects. For this reason, it is not used today. Up to the present time histopathological changes of the autopsy case has not been reported. We had a chance to autopsy and examined the brain of a patient who showed several psychiatric and neurological symptoms caused by cycloserine poisoning. In this paper, we report the histopathological changes of this case. CASE REPORT Clinical History
T.Y., a girl aged 29, had nothing in her family history to suggest hereditary disease. When 19 years old, in 1955 she had pulmonary tuberculosis and entered a hospital. She had been trcated with many antituberculous drugs, such as PAS, SM, TH and INAH, but without responding to them. For Received for publication Oct. 7, 1976.
this reason, she was given cycloserine (CS) 0.5 g per day for 500 days (total dose 250 g). When she took CS for six months, on April 1964, she complained of headache, dizziness and difficulty in sleeping. She became irritable and her behavior was dull and slow. Her face was expressionless, hard, dull and empty. Neurologically, she was ataxic, had difficulty in speaking clearly and she had pyramidal signs, such as spasms in extremities, increase of tendon reflexes in all extremities with patellar clonus and pathologic reflex, such as Babinski sign. Subsequently, she fell into a manic state and sometimes seemed to be slightly unconscious. At this time, childish characters appeared. Following this, on January in 1965, gait disturbance and incontinentia urinae appeared. On February, extrapyramidal signs, such as muscle rigid, tremor, athetosis and disturbance of vegetative nerve, such as hyperidrosis, hypersalivation and dermatographism, appeared. Psychologically, hallucinatory-delusional state and dementia appeared, and then many pathologic reflexes, primitive reflexes, abnormal statue and hyperpathia appeared. She died on March 3, 1965 at the age of 29 about a year after treatment with CS. The clinical course of neurological symptoms induced by CS is shown in Fig. 1. On laboratory examination on February
236
T. Miyakawa et al.
Years
1964
Months
4
1965 11
1
Ataxia
Dysarthria Pyramidal sign fn
.-6
Gait disturbance
T!
lncontinentia urinae
J
Extrapyramidal sign
u)
22 0
Z
Disturbance of vegetative neve Primitive reflex Abnormal statue H yperpathia Complainments
E 8
Irritability
E
Manic state
.g
C haracter change
fn
+ .! c
*
0
Clouding of consciousness Hallucinatorydelusional states Dementia
Fig. 1 :
Clinical course of patients.
2
3
Cycloserine Poisoning
237
in 1965, blood, urine and routine tests were normal. Blood biochemical test; total protein, urea-N, Na, Ca, inorganic phosphorous, blood sugar, GOT, and GPT were all normal. Serological reaction for syphilis: WaR ( - 1. Ocular fundi: normal. EEG findings: basic pattern consisted of fast waves 20-50 Hz and 20-3OpV diffusely. RESULTS
Necropsy Fig. 2: Temporal cortex. Deletion of the nerve cells are diffusely observed, especially IIIrd layer. Nissl stain ( X40).
Fig. 3: Frontal cortex. Deletion of the nerve cells are diffusely observed in IIIrd layer. Nissl stain (X40).
The brain weighed 1,200 g and was optically normal. The basal arteries were slender.
Fig. 4: Hypothalamus. Small vessel is atrophic and deletion of the nerve cells are observed around it. Slight increase of glial cell is seen. Nissl stain (X82).
T. Miyakawa et al.
238
Fig. 5A: Subcortical white matter. Around the small vessel small myelin loss is observed. Sugatno myelin Ptain ( x 220).
Histoputhological Findings
In the cortex of the brain, deletion of the nerve cells were diffusely observed except occipital lobes, especially in the IIIrd layer of the cortex and glial cells were slightly increased (Figs. 2 and 3). In the hypothalamus, around the small blood vessels, there were deletion of nerve cells and slight increase of glial elements (Fig. 4). By myelin stain, partially small myelin loss around the small vessels along the U fibres was observed (Fig. 5A) and patchy myelin loss around the small vessels in the subcortical white matter on the parietal lobe (Fig. 5B) was also noticed. In the internal capsules, some small vessels had plasma solution infiltrate around them, and near the
Fig. 5B: Parietal white matter. Small-patchy mvelin loss are observed. Woelcke myelin stain ( X 2 2 0 ) .
vessels some phagocytes existed that contained pigments. Remarkable changes were observed in the putamen and pallidum; some vessels were destroyed and small softenings were formed around them (Fig. 7). Some endothelial cells were destroyed, and there were deletion of nerve cells around the vessels (Fig. 8). In the ccrzbellum, Purkinje cells showed atrophic structure and Bergmann glia increase in thos? places, and Purkinje cells generally decrzased in number (Fig. 9). Midbrain, pons and medulla oblongata did not show any abnormal findings. Several stains, such as Holzer stain, sudan 111 and perdrau stain, were carried out. However, glial fibres, fat granule cells and increase of blood vessels were not observed.
Cycloserine Poisoning
Fig. 6: Internal capsule. Around the small blood vessel, plasma solutions infiltrate. Near from this place, phagocytes contained pigments exist. Nissl
239
Fig. 7: Lateral part of the left putamen. Vessel is destructed and formed small softening around it. H.-E stain ( X 125).
stain ( X l l O ) .
DISCUSSION Cycloserine (CS) was antibiotics with wide spectrum induced from streptomyces orchisaceus. Epstein et al. (1955)l reported that this drug had effect on the pulmonary tuberculosis. On the other hand, it was clarified that this drug clinically had side-effects to the central nervous s y ~ t e m .'~ - ~However, description of the histopathological changes has not yet been reported. The neuro-psychiatric symptoms of our present case were caused by cycloserine, because it is the same symptoms described by the above authors. Nakamura ( 1968)6 reported psychiatric and neurological symptoms caused by cy-
closerine poisoning. In the report, he examined 25 cases clinically. Our present case is one of them, and in that paper, Miyakawa described briefly that the histopathological change was caused by the change of the blood vessels (p. 52). As described above, the leading changes were found in diencephalon and characteristic change was the destruction of small blood vessels; many endothelial cells fell into necrosis and deletion of 'nerve cells were observed around them, mainly in the basal ganglia, then in white matter. In addition to this finding, the deletion of the nerve cells in the cortex of cerebrum and cerebellum was observed. This may be caused by disturbance of small vessels, because slight changes of the small vessels
240
T. Miyakawa
Fig. 8: Left pallidum. Small vessel is destructed and around this vessel, nerve cells decrease. Nissl stain ( ~ 8 2 ) .
et
al.
Fig. 9: Cerebellum. Purkinje cells decrease in number and many Purkinje cells are atrophic, with increase of Bergmann glia. Nissl stain (x36).
were also observed in the cortex. From this, we speculate that this drug is toxic against blood vessels and effects endothelial cells, especially the small blood vessels. Up to date, we had examined many brains with arteriosclerosis or disturbance of circulation. However, they were quite different from the present case. The present case had no arteriosclerosis and no changes caused by arteriosclerosis, such as granular atrophy, softenings etc. Recently, Wada et uf. ( 1975)O disclosed histopathological findings which might be due to cycloserine. In this abstract, 'they also pointed to the change of blood vessels. Finally, the present case showed severe neurological signs. However, histopathological changes were.not as severe as suggested
by the symptoms. This may be due not only to histopathological changes but also to disturbances of the nerve function of the CNS due to the effect of CS. SUMMARY Cycloserine was given to a 29-year-old girl with pulmonary tuberculosis for 500 days (total dose 250g). Following this treatment, she began to show several psychiatric and neurological symptoms and died. Histopathologically, deletion of the nerve cells in the cerebrum was diffusely observed, especially in the IIIrd layer of the frontal and temporal cortex and patchy demyelinations were found in the white matter of the
Cycloserine Poisoning parietal lobe. Characteristic findings were the change of small blood vessels and deletion of the nerve cell around the area of vessels in the hypothalamus, putamen and pallidum. The same changes of the blood vessels were found in the internal capsule. In the cerebellum, shrinkage of Purkinje cells and increase of Bergmann’s glia were observed.
REFERENCES Epstein, I. G., Nair, K. G. S. and Boyd, L. J.: Cycloserine, a new antibiotic, in the treatment of human pulmonary tuberculosis: A preliminary report, Antibiot Med, 1: 80-93, 1955. Epstein, I. G., Nair, K. G. S. and Boyd, L. J.: The treatment of human pulmonary tuberculosis with cycloserine: Progress report, Dis chest, 29: 241-257, 1956. Levi-Valensi: Neuropsychiatrische Komplikationen bei Cycloserine-behandlung
24 1
Tuberkuloser (abstr.), Tbk arzt, 13: 142, 1959. 4 Levis, W. C., Calden, G., Thurson, J. R.,
5
6
7
8
Gilson, W. E.: Psychiatric and neurological reactions to cycloserine in the treatment of tuberculosis, Dis chest, 32: 172-1 82, 1957. Naka, K., Hayashi, A., Hikiji, A. and Yamamoto, M.: Psychiatric disturbance caused by cycloserine (abstr.), Psychiatr Neurol, 67: 389, 1965 (in Japanese). Nakamura, K. : Psychiatric and neurological symptoms caused by cycloserine poisoning, Psychiatr Neurol Japonica, 70: 503-602, 1968 (in Japanese). Shita, S.: Atypical psychosis and cycloserine poisoning, Commemorative Article of Prof. T. Miura’s Retirement, Depart Neurology, Keio University Medical School, Tokyo, p 259-265, 1963. U.S. Public Health Service Cooperative Clinical Investigation: A pilot study of cycloserine toxicity, Am Rev Tuberc, 74: 196-209, 1956.
9 Wada, T., Yano, K., Moro, K.: Neuropathological examination on patients who may be thought as cycloserine poi-oning, Jap Neuropath Program (abstr.) , 1975.
