å¡ CASE REPORT å¡ Leukoencephalopathy Induced by Tegafur: Serial Studies of Somatosensory Evoked Potentials and Cerebrospinal Fluid Ryoichi Hayashi, Norinao Hanyu and Akihiko Kitahara* A case of leukoencephalopathy induced by tegafur, an antineoplastic derivative of 5-FU, is reported. The patient received 600mg of tegafur p.o. for 16 days before excision of rectal cancer. After the operation, gait disturbance and mental abnormalities appeared. He became akinetic and mute within a few days following readministration of tegafur. Serial studies of brain CT, somatosensory evoked potentials (SEP) were made, and myelin basic proteins (MBP) in the cerebrospinal fluid were measured. The level of MBP was about twice the normal value and the central conduction time (CCT) of SEP was prolonged at admission. The value of MBP and CCTMedicine improved31: with recovery from akinetic mutism. (Internal 828-831, 1992) Key words: rectal cancer, antineoplastic derivative of 5-FU, myelin basic protein, central conduction time, akinetic mutism
Introduction Methotrexate is known to be neurotoxic and to cause subacute leukoencephalopathy (1-3). Several authors have reported that carmofur (l-hexylcarbamoyl-5 fluorouracil), a newly developed masked compound of 5-FU, causes the same effects as methotrexate (4, 5). Computerized tomography (CT) of the brain in patients with leukoencephalopathy revealed that the cerebral white matter shows diffuse hypodensity, which changes reversibly with the improvement of clinical symptoms (5). Recently, we encountered a patient with rectal cancer, who developed akinetic mutism after treatment with a 5-FU derivative. In thistegafur, paper, we describe the neurological symptoms and signs, and CT and magnetic resonance imaging (MRI) findings of tegafur-induced leukoencephalopathy, along with studies of somatosensory evoked potentials (SEP) and changes in myelin basic protein (MBP) in cerebrospinal fluid (CSF) during the recovery process. Case Report A 62-year-old man was diagnosed as having rectal cancer on November 6, 1989 after periodic appearance of bloody stool over a two-year period. Chemotherapy with tegafur was initiated at a daily oral dose of 600mg
for 16 days, followed by resection of the rectum on November 30, 1989. The patient was conscious that night. On the following morning, his systolic blood pressure decreased to 40mmHg and consciousness de creased for a short time; then vital signs and conscious ness level improved. Brain CT on December 1, 1989 (Fig. 1; la, lb) disclosed no abnormal mass, lesion or hypodensity of the white matter. The patient gradually developed gait disturbance, irritability and emotional instability. On December 15, 1989, tegafur was readmin istered at the same dosage. During the following 3 days, the patient could not walk and became akinetic and mute. Tegafur was continued for a total of seven days and then discontinued. The patient was admitted to our General physical examination and neurological exam neurological department on January 12, 1990.The patient ination of cranial nerves were unremarkable. was stuporous and did not respond to simple commands. His posture indicated decortication and the degree of opisthotonus increased with sound or touch stimulation. The muscles of the extremities were rigid and showed a paratonic rigidity. Deep tendon reflexes were slightly hyperactive, and the extensor plantar response was pos itive on the left side; snout, tonic plantar and grasp reflexes were positive. Laboratory data, including urinalysis, haematological findings, and hepatic and renal functions, were unre-
From the Department of Neurology and *the Department of Psychiatry, Nagano Red Cross Hospital, Nagano Received for publication March 14, 1991; Accepted for publication February 28, 1992 Reprint requests should be addressed to Dr. Ryoichi Hayashi, the Division of Clinical Neurophysiology, School of Allied Medical Scien Shinshu University, Matsumoto 390, Japan Internal
Medicine
Vol. 31, No. 6 (June
1992)
Tegafur-induced
Leukoencephalopathy
Fig. 1. Brain CT and MRI. No abnormality is detected in brain CT done in December 1989 (la, lb). CT performed on January 13, 1990 shows very severe hypodensity of the entire cerebral white matter (2a, 2b). T2-weighted MRI (3a, 3b) on January 18, 1990 shows a high s intensity in the cerebral white matter (SE 1900/110). markable except for a slight decrease in red blood cells. CSF was normal in pressure, cell count, and protein and sugar content and no malignant cells were seen. There was no significant elevation of viral titers in CSF. The level of MBP in CSF was elevated to 8.9ng/ml (normal: less than 4ng/ml). EEG disclosed diffuse slow waves, and brain CT scan showed marked radiolucency of cerebral white matter on January 13, 1990 (Fig. 1; 2a, 2b). T2-weighted MRI on January 18, 1990 revealed these lesions as high inten sity (Fig. 1; 3a, 3b). Cerebellum and pons showed no abnormality By the middleinofMRI. February 1990, the patient was able to speak a few words, follow simple commands and sit in a wheel chair. Subsequently, his psychomotor functions continued to recover; however, he still had severe dementia. T2-weighted MRI on May 20, 1990 revealed the same changes in the intensity in cerebral white matter Serial auditory as thatstudies of MRIofon Januarybrain 18. stem response (ABR), SEP, MBP and brain CT were performed. ABR revealed Internal
Medicine
Vol. 31, No. 6 (June
1992)
0 5msec /D Fig. 2. Serial studies of sensory evoked response recorded at a somatic sensory area (C3') and at Erb point by stimulating the right median nerve. The latency of N9 with data obtained on 3 different days superimposed, shows a constant value. The latency of N20 shifts from long on January Calibration: 5 //V\25 to short on March 2, 1990. 829
Hayashi et al CT scan is routinely performed to detect metastatic brain tumors or to detect other abnormalities. In the present case, brain CT and MRI revealed diffuse and symmetrical attenuation of the cerebral white matter and no abnormal mass lesion. Our patient had no previous history of hypertension or CO intoxication, and had no medication of antineoplastic agents and had noofradiation therapy. There was no significant elevation viral titers in CSF. It is possible that short-term hypotension after operation could cause an anoxic encephalopathy or could exag gerate the brain damage. However, neurologic signs and symptoms developed after treatment with tegafur and were worsened by readministration. Based on the radio logical and laboratory findings during the clinical course, we concluded that the development of akinetic mutism was caused by the administration of tegafur. From the findings of ABR, N9 latency and MRI, it appeared that Tegafur is an antineoplastic derivative of 5-FU, as is the brain-stem and peripheral nerves were unaffected. carmofur. The first case of carmofur-induced leukoence phalopathy was reported in 1983 (6). Since then more than 40 cases of carmofur-induced or tegafur-induced leukoencephalopathy have been documented. Carmofur Fig. 3. Schematic drawing of clinical symptoms and signs with the and tegafur cause similar neurological disturbances, in latency of N20 and the level of MBP in CSF from the first day of the cluding unstable gait and mental deterioration as initial first administration of tegafur for 180 days. After discontinuation of tegafur, clinical improvement correlated well with the shorteningsigns. of Brain CT findings of leukoencephalopathy induced N20 and decrease in MBP. by either drug are similar (4, 5). Most patients recover gradually following discontinuation of these drugs, but a normal pattern with normal latency of the individual Neuropathological examination of die. carmofur-induced some remain severely disabled or peaks. SEPs were recorded by stimulating the median leukoencephalopathy revealed that the myelin sheath is lost in the gelatinous softened area of white matter; nerves. The active electrodes were put on C3' (2cm however, the axons are well preserved (7). These findings posterior to C3) and Erb point with a reference at Fz may concur with our observations of increased MBP in (international 10-20 system). The peak latency of N9 CSF and prolonged central conduction time of SEP in (at Erb point), of N20 (at C3' point) and the CCT (the the initial phase of illness. Tegafur crosses the blood difference between N9 and N20) were measured. The brain barrier and is distributed in the brain and CSF for a latency ofN9 was 9.2msec (normal value: 9.0 ± 0.5msec long period (8). Carmofur and its metabolite gradually in the age prolonged group) during observation (Fig. 2). Theappropriate N20 peak was to 20.0msec on January accumulate in the brain and are removed very slowly (9). 25, 1990. The peak latency ofN20 decreased to 18.0msec The progression of leukoencephalopathy after discon on March 2 (normal 18.4 ± 0.9msec). The level of MBP tinuation of 5-FU derivatives may be explained by their in CSF decreased gradually; however, a transient increase metabolic characteristics (5). In the central nervous system was observed after 140 days of administration. In Fig. 3, (CNS), a myelin basic protein is the most characteristic the time courses of clinical symptoms and signs with protein specific to the myelin sheath (10, ll). The pres changes in N20 and MBP levels are summarized. ence of MBP in CSF appears to be characteristic of Discussion acute myelin sheath destruction in patients with such disorders as multiple sclerosis or cerebrovascular diseases The major findings of this case were the following: 1) (ll, 12). The level of MBP in CSF during acute attacks in patients with multiple sclerosis decreases to normal reversible development of clinical symptoms and signs values in less than 2 weeks (12). In patients with cerebro was observed to be tegafur-induced leukoencephalopathy; vascular diseases, MBP also normalized within 2 weeks and 2) after discontinuation of tegafur, clinical symptoms (data not shown). In the present patient with tegafur improved as well as the central conduction time of SEP induced leukoencephalopathy, the level of MBP in CSF and the level of MBP in CSF. or signs develop in When neurological symptoms decreased slowly and took more than 3 months to de cancer patients under treatment with chemotherapy, a crease to normal values. The reincrement of MBP was observed after 140 days of administration. From these 830 Internal
Medicine
Vol. 3JL, No. 6 (June
1992)
Tegafur-induced
Leukoencephalopathy
observations, we conclude that tegafur and its metab olites were deposited in CNS and were eliminated from CNS slowly in the same manner as carmofur. These agents may have destroyed the myelin sheath gradually. Demyelination may have caused the decrease in nerve conduction velocity and the prolongation of CCT in this patient. The improvement in CCT may imply the process of remyelination in CNS. In conclusion, 5-FU derivatives are potent neurotoxic agents which cause demyelination of the brain; this process continues acutely or subacutely after these drugs are discontinued. The process is reversible in some cases, but irreversible in others, leading to neurological dis ability. Effective therapy has not been established. Therefore, to prevent leukoencephalopathy, a careful
course of treatment with high-dose methotrexate. Cancer 53: 1849, 1984. Aoki N. Reversible leukoencephalopathy caused by 5-fluorouracil derivatives, presenting as akinetic mutism. Surg Neurol 25: 279, 1986. Kuzuhara S, Ohkoshi N, Kanemaru K, Hashimoto H, Nakanishi T, Toyokura Y. Subacute leucoencephalopathy induced by carmofur, a 5-fluorouracil derivative. J Neurol 234: 365, 1987. Ohkoshi N, Kanazawa I, Nakanishi T, Tohata K, Koizumi J. A case report of central nervous system damage due to an antitumor agent, carmofur. Clin Neurol (Tokyo) 23: 92, 1983 (in Japanese). Furuya A, Shiroyama H, Yano Y, Kishida S, Okeda R. Report on an autopsy of a cancer patient with carmofur (HCFU) leukoencephalopathy. Clin Neurol (Tokyo) 27: 1430, 1987 (abstract in English). Fujita H, Ogawa K, Akimoto K, et al. Distribution of FT-207 and its active substances into the brain and cerebrospinal fluid. Jpn J Cancer Chemother (Tokyo) 3: 551, 1976 (in Japanese). Yamamoto H, Kobari T, Kumakura M, et al. Absorption, distri neurological examination is essential and these drugs must bution and excretion of l-hexylcarbamoyl-5-fluorouracil (HCFU) be discontinued if any signs of neurotoxicity are found. in the rat. Yakuri To Chiryo (Tokyo) 8: 679, 1980 (in Japanese). Wolfgram F, Kotori K. The composition of the myelin proteins of References the central nervous system. J Neurochem 15: 1281, 1968. Whitaker JN. Myelin encephalitogenic protein fragments in cere Peylan-Ramu N, Poplack DG, Blei CL, Herdt JR, Vermess M, brospinal fluid of persons with multiple sclerosis. Neurology 27: Di Chiro G. Computer assisted tomography in methotrexate 911, 1977. Ohta M, Matsubara F, Konishi T, Nishitani H. Radioimmuno encephalopathy. J Comput Assist Tomogr 1: 216, 1977. Allen JC, Rosen G, Mehta BM, Horten B. Leukoencephalopathyassay of myelin basic protein in cerebrospinal fluid and its clinical following high-dose iv methotrexate chemotherapy with leucovorin application to patients with neurological diseases. Life Sci 27: rescue. Cancer Treat Rep 64: 1261, 1980. 1069, 1980. Fritsch G, Urban C. Transient encephalopathy during the late
Internal
Medicine
Vol. 31, No. 6 (June
1992)
831
Introduction Methotrexate is known to be neurotoxic and to cause subacute leukoencephalopathy (1-3). Several authors have reported that carmofur (l-hexylcarbamoyl-5 fluorouracil), a newly developed masked compound of 5-FU, causes the same effects as methotrexate (4, 5). Computerized tomography (CT) of the brain in patients with leukoencephalopathy revealed that the cerebral white matter shows diffuse hypodensity, which changes reversibly with the improvement of clinical symptoms (5). Recently, we encountered a patient with rectal cancer, who developed akinetic mutism after treatment with a 5-FU derivative. In thistegafur, paper, we describe the neurological symptoms and signs, and CT and magnetic resonance imaging (MRI) findings of tegafur-induced leukoencephalopathy, along with studies of somatosensory evoked potentials (SEP) and changes in myelin basic protein (MBP) in cerebrospinal fluid (CSF) during the recovery process. Case Report A 62-year-old man was diagnosed as having rectal cancer on November 6, 1989 after periodic appearance of bloody stool over a two-year period. Chemotherapy with tegafur was initiated at a daily oral dose of 600mg
for 16 days, followed by resection of the rectum on November 30, 1989. The patient was conscious that night. On the following morning, his systolic blood pressure decreased to 40mmHg and consciousness de creased for a short time; then vital signs and conscious ness level improved. Brain CT on December 1, 1989 (Fig. 1; la, lb) disclosed no abnormal mass, lesion or hypodensity of the white matter. The patient gradually developed gait disturbance, irritability and emotional instability. On December 15, 1989, tegafur was readmin istered at the same dosage. During the following 3 days, the patient could not walk and became akinetic and mute. Tegafur was continued for a total of seven days and then discontinued. The patient was admitted to our General physical examination and neurological exam neurological department on January 12, 1990.The patient ination of cranial nerves were unremarkable. was stuporous and did not respond to simple commands. His posture indicated decortication and the degree of opisthotonus increased with sound or touch stimulation. The muscles of the extremities were rigid and showed a paratonic rigidity. Deep tendon reflexes were slightly hyperactive, and the extensor plantar response was pos itive on the left side; snout, tonic plantar and grasp reflexes were positive. Laboratory data, including urinalysis, haematological findings, and hepatic and renal functions, were unre-
From the Department of Neurology and *the Department of Psychiatry, Nagano Red Cross Hospital, Nagano Received for publication March 14, 1991; Accepted for publication February 28, 1992 Reprint requests should be addressed to Dr. Ryoichi Hayashi, the Division of Clinical Neurophysiology, School of Allied Medical Scien Shinshu University, Matsumoto 390, Japan Internal
Medicine
Vol. 31, No. 6 (June
1992)
Tegafur-induced
Leukoencephalopathy
Fig. 1. Brain CT and MRI. No abnormality is detected in brain CT done in December 1989 (la, lb). CT performed on January 13, 1990 shows very severe hypodensity of the entire cerebral white matter (2a, 2b). T2-weighted MRI (3a, 3b) on January 18, 1990 shows a high s intensity in the cerebral white matter (SE 1900/110). markable except for a slight decrease in red blood cells. CSF was normal in pressure, cell count, and protein and sugar content and no malignant cells were seen. There was no significant elevation of viral titers in CSF. The level of MBP in CSF was elevated to 8.9ng/ml (normal: less than 4ng/ml). EEG disclosed diffuse slow waves, and brain CT scan showed marked radiolucency of cerebral white matter on January 13, 1990 (Fig. 1; 2a, 2b). T2-weighted MRI on January 18, 1990 revealed these lesions as high inten sity (Fig. 1; 3a, 3b). Cerebellum and pons showed no abnormality By the middleinofMRI. February 1990, the patient was able to speak a few words, follow simple commands and sit in a wheel chair. Subsequently, his psychomotor functions continued to recover; however, he still had severe dementia. T2-weighted MRI on May 20, 1990 revealed the same changes in the intensity in cerebral white matter Serial auditory as thatstudies of MRIofon Januarybrain 18. stem response (ABR), SEP, MBP and brain CT were performed. ABR revealed Internal
Medicine
Vol. 31, No. 6 (June
1992)
0 5msec /D Fig. 2. Serial studies of sensory evoked response recorded at a somatic sensory area (C3') and at Erb point by stimulating the right median nerve. The latency of N9 with data obtained on 3 different days superimposed, shows a constant value. The latency of N20 shifts from long on January Calibration: 5 //V\25 to short on March 2, 1990. 829
Hayashi et al CT scan is routinely performed to detect metastatic brain tumors or to detect other abnormalities. In the present case, brain CT and MRI revealed diffuse and symmetrical attenuation of the cerebral white matter and no abnormal mass lesion. Our patient had no previous history of hypertension or CO intoxication, and had no medication of antineoplastic agents and had noofradiation therapy. There was no significant elevation viral titers in CSF. It is possible that short-term hypotension after operation could cause an anoxic encephalopathy or could exag gerate the brain damage. However, neurologic signs and symptoms developed after treatment with tegafur and were worsened by readministration. Based on the radio logical and laboratory findings during the clinical course, we concluded that the development of akinetic mutism was caused by the administration of tegafur. From the findings of ABR, N9 latency and MRI, it appeared that Tegafur is an antineoplastic derivative of 5-FU, as is the brain-stem and peripheral nerves were unaffected. carmofur. The first case of carmofur-induced leukoence phalopathy was reported in 1983 (6). Since then more than 40 cases of carmofur-induced or tegafur-induced leukoencephalopathy have been documented. Carmofur Fig. 3. Schematic drawing of clinical symptoms and signs with the and tegafur cause similar neurological disturbances, in latency of N20 and the level of MBP in CSF from the first day of the cluding unstable gait and mental deterioration as initial first administration of tegafur for 180 days. After discontinuation of tegafur, clinical improvement correlated well with the shorteningsigns. of Brain CT findings of leukoencephalopathy induced N20 and decrease in MBP. by either drug are similar (4, 5). Most patients recover gradually following discontinuation of these drugs, but a normal pattern with normal latency of the individual Neuropathological examination of die. carmofur-induced some remain severely disabled or peaks. SEPs were recorded by stimulating the median leukoencephalopathy revealed that the myelin sheath is lost in the gelatinous softened area of white matter; nerves. The active electrodes were put on C3' (2cm however, the axons are well preserved (7). These findings posterior to C3) and Erb point with a reference at Fz may concur with our observations of increased MBP in (international 10-20 system). The peak latency of N9 CSF and prolonged central conduction time of SEP in (at Erb point), of N20 (at C3' point) and the CCT (the the initial phase of illness. Tegafur crosses the blood difference between N9 and N20) were measured. The brain barrier and is distributed in the brain and CSF for a latency ofN9 was 9.2msec (normal value: 9.0 ± 0.5msec long period (8). Carmofur and its metabolite gradually in the age prolonged group) during observation (Fig. 2). Theappropriate N20 peak was to 20.0msec on January accumulate in the brain and are removed very slowly (9). 25, 1990. The peak latency ofN20 decreased to 18.0msec The progression of leukoencephalopathy after discon on March 2 (normal 18.4 ± 0.9msec). The level of MBP tinuation of 5-FU derivatives may be explained by their in CSF decreased gradually; however, a transient increase metabolic characteristics (5). In the central nervous system was observed after 140 days of administration. In Fig. 3, (CNS), a myelin basic protein is the most characteristic the time courses of clinical symptoms and signs with protein specific to the myelin sheath (10, ll). The pres changes in N20 and MBP levels are summarized. ence of MBP in CSF appears to be characteristic of Discussion acute myelin sheath destruction in patients with such disorders as multiple sclerosis or cerebrovascular diseases The major findings of this case were the following: 1) (ll, 12). The level of MBP in CSF during acute attacks in patients with multiple sclerosis decreases to normal reversible development of clinical symptoms and signs values in less than 2 weeks (12). In patients with cerebro was observed to be tegafur-induced leukoencephalopathy; vascular diseases, MBP also normalized within 2 weeks and 2) after discontinuation of tegafur, clinical symptoms (data not shown). In the present patient with tegafur improved as well as the central conduction time of SEP induced leukoencephalopathy, the level of MBP in CSF and the level of MBP in CSF. or signs develop in When neurological symptoms decreased slowly and took more than 3 months to de cancer patients under treatment with chemotherapy, a crease to normal values. The reincrement of MBP was observed after 140 days of administration. From these 830 Internal
Medicine
Vol. 3JL, No. 6 (June
1992)
Tegafur-induced
Leukoencephalopathy
observations, we conclude that tegafur and its metab olites were deposited in CNS and were eliminated from CNS slowly in the same manner as carmofur. These agents may have destroyed the myelin sheath gradually. Demyelination may have caused the decrease in nerve conduction velocity and the prolongation of CCT in this patient. The improvement in CCT may imply the process of remyelination in CNS. In conclusion, 5-FU derivatives are potent neurotoxic agents which cause demyelination of the brain; this process continues acutely or subacutely after these drugs are discontinued. The process is reversible in some cases, but irreversible in others, leading to neurological dis ability. Effective therapy has not been established. Therefore, to prevent leukoencephalopathy, a careful
course of treatment with high-dose methotrexate. Cancer 53: 1849, 1984. Aoki N. Reversible leukoencephalopathy caused by 5-fluorouracil derivatives, presenting as akinetic mutism. Surg Neurol 25: 279, 1986. Kuzuhara S, Ohkoshi N, Kanemaru K, Hashimoto H, Nakanishi T, Toyokura Y. Subacute leucoencephalopathy induced by carmofur, a 5-fluorouracil derivative. J Neurol 234: 365, 1987. Ohkoshi N, Kanazawa I, Nakanishi T, Tohata K, Koizumi J. A case report of central nervous system damage due to an antitumor agent, carmofur. Clin Neurol (Tokyo) 23: 92, 1983 (in Japanese). Furuya A, Shiroyama H, Yano Y, Kishida S, Okeda R. Report on an autopsy of a cancer patient with carmofur (HCFU) leukoencephalopathy. Clin Neurol (Tokyo) 27: 1430, 1987 (abstract in English). Fujita H, Ogawa K, Akimoto K, et al. Distribution of FT-207 and its active substances into the brain and cerebrospinal fluid. Jpn J Cancer Chemother (Tokyo) 3: 551, 1976 (in Japanese). Yamamoto H, Kobari T, Kumakura M, et al. Absorption, distri neurological examination is essential and these drugs must bution and excretion of l-hexylcarbamoyl-5-fluorouracil (HCFU) be discontinued if any signs of neurotoxicity are found. in the rat. Yakuri To Chiryo (Tokyo) 8: 679, 1980 (in Japanese). Wolfgram F, Kotori K. The composition of the myelin proteins of References the central nervous system. J Neurochem 15: 1281, 1968. Whitaker JN. Myelin encephalitogenic protein fragments in cere Peylan-Ramu N, Poplack DG, Blei CL, Herdt JR, Vermess M, brospinal fluid of persons with multiple sclerosis. Neurology 27: Di Chiro G. Computer assisted tomography in methotrexate 911, 1977. Ohta M, Matsubara F, Konishi T, Nishitani H. Radioimmuno encephalopathy. J Comput Assist Tomogr 1: 216, 1977. Allen JC, Rosen G, Mehta BM, Horten B. Leukoencephalopathyassay of myelin basic protein in cerebrospinal fluid and its clinical following high-dose iv methotrexate chemotherapy with leucovorin application to patients with neurological diseases. Life Sci 27: rescue. Cancer Treat Rep 64: 1261, 1980. 1069, 1980. Fritsch G, Urban C. Transient encephalopathy during the late
Internal
Medicine
Vol. 31, No. 6 (June
1992)
831
