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PARAPLEGIA AFTER INTRATHECAL MITOZANTRONE
1393
evening. Focal seizure activity was observed on two occasions, consisting of tonic-clonic activity of his left arm and leg. On admission he had no evidence of focal neurological lesions and he withdrew to painful stimuli. Serum electrolytes, including calcium and magnesium, and blood glucose were normal. There were no changes in the blood cell count or liver function tests. A computerised tomographic scan of the head revealed mild atrophy without blood or mass lesions. A lumbar puncture revealed 1 white blood cell, no red blood cells, protein 45 mg/dl, and glucose 45 mg/dl. Serum and CSF cryptococcal antigen were negative. AZT was
stopped.
Over the next 24 h he became gradually more responsive. There were no further seizures or seizure-like activity. At 48 h he was alert and orientated, with no focal deficits and a normal EEG. He received occasional paracetamol for fever but no other medications. AZT was reintroduced at a dose of 200 mg every 4 h. 72 h after the reintroduction of the drug he complained of a slight headache, then quickly became increasingly confused, with aphasia, left-sided weakness, and intermittent twitching on the right side of his face, occasionally affecting the right arm and leg. Focal- seizures continued unabated for the next 12 h despite intravenous lorazepam and phenytoin. He had a respiratory arrest 36 h after the onset of neurological deterioration and was not resuscitated. This man with AIDS and multiple opportunistic infections had a headache and confusion progressing to unresponsiveness and focal seizures 48 h after beginning AZT. No structural or metabolic defect to explain this complication could be found. Withdrawal of AZT led to complete neurological recovery. Because of the possibility that multiple drug interactions at the initiation of therapy contributed to the presumed AZT neurotoxicity, AZT was reinstituted. Headache and confusion leading to focal status epilepticus unresponsive to anticonvulsants developed 72 h after rechallenge with AZT, and the patient died. We recommend that AZT be used with extreme caution in patients with late manifestations of AIDS, who may be more susceptible to toxic side-effects of AZT because of CNS infection with HIV or opportunistic pathogens and/or may have altered AZT metabolism due to liver disease caused by opportunistic infections or the drugs used in their treatment. Complaints of headache or confusion may be early manifestations of more severe neurotoxicity and may require AZT to be reduced in dose or stopped. Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA
DAN N. HAGLER PETER T. FRAME
response. In all he had ten intrathecal injections of methotrexate and
four of Ara-C. In February, 1986, he had a second CNS relapse which was treated effectively with nine doses of combination of intrathecal hydrocortisone, methotrexate, and Ara-C. In June, 1986, he presented with headaches, but no other neurological symptoms or signs. The CSF blast count was 670/pl. A brain computerised tomographic scan was normal. Since he had resistant CNS disease it was decided to treat him with intrathecal mitozantrone 2 mg weekly. After the second injection he had local pain and the third dose was reduced to 1 mg. Local pain again recurred, requiring relief by analgesia. 3-4 days later he had severe pain in his legs and paraplegia developed over a period of 2 weeks with absent leg reflexes but no sensory loss or alteration in bowel or bladder function. The CSF blast count fell to less than 1 /)il after the second injection. 4 months later he remains paraplegic and in chronic phase CGL. Intrathecal mitozantrone was effective in clearing blasts from the CSF in our patient, as in previous reports.1,2 The pain and paraplegia followed shortly after the third injection and since the patient had no previous neurological signs and no evidence of active CNS leukaemia we believe mitozantrone played a major part in its causation. A previous report’ described the development of paraplegia in a patient treated with intrathecal mitozantrone but this was thought to be related to disease, previous drugs, or mitozantrone. Mitozantrone does not cause significant neurological problems when given systemically.3 We conclude that intrathecal mitozantrone, although effective in treating resistant CNS disease in leukaemia, should be used with caution. A. ’1:T K. TLAKHANI A. G. ZUIABLE C. M. POLLARD A. MILNE Leukaemia Unit, J. TRELEAVEN Royal Marsden Hospital, R. L. POWLES Sutton, Surrey SM2 5PT .........
Godefroy W, Vemey A, Gorin WC, Nalman A, Duhamel G. Intrathecal mitozantrone. Lancet 1985, ii. 160. 2 Zuiable AG, Maitland J, Nandi A, Clink HM, Powels RL. Intrathecal mitozantrone for resistant leukaemia. Lancet 1985; ii. 1061. 3. Anderson KL, et al. Phase 1 trial of mitozantrone by 24 hours continuous infusions. Cancer Treat Rep 1983; 67: 435-38. 1. La Porte JP,
HYPERCHOLESTEROLAEMIA AFTER ADMINISTRATION OF NICOTINE CHEWING GUM
SIR,-Increased cholesterol levels and coronary heart disease2 observed in cigarette smokers. However, because tobacco smoke contains many constituents, it has been difficult to uncover the factor(s) responsible for these increases. It seemed important to find out whether regular administration of nicotine, a constituent of tobacco that is commonly used by people trying to give up smoking, produces a cardiovascular risk. In a 29-year-old man increases in serum triglycerides and are
1. Yarchoan
R,
et
al. Administration of
HTLV-III/LAV replication,
to
3’-azido-3’-deoxymaymidine, an inhibitor of patients with AIDS or AIDS-related complex.
Lancet 1986; i: 575-80. Azidothymidine for AIDS. Med Letter 1986; 28: 107-09.
2. Anon.
PARAPLEGIA AFTER INTRATHECAL MITOZANTRONE
SIR,-Mitozantrone has been used intrathecally to treat resistant central nervous system (CNS) disease in lymphomal and leukaemia.2 We report a patient who became paraplegic after intrathecal mitozantrone for resistant CNS leukaemia. A 38-year-old man presented with Philadelphia chromosome positive (ph+) acute lymphoblastic leukaemia in July, 1982. Remission was obtained with MRC Leukaemia Working Party UKALL IX protocol. CNS disease was absent and he received intrathecal methotrexate and 18 Gy cranial irradiation as prophylaxis. Maintenance treatment was with oral 6mercaptopurine and methotrexate. In March, 1984, he was found to be in the chronic phase of Ph- chronic granulocytic leukaemia (CGL), which required treatment with busulphan and
hydroxyurea. In May, 1984, testicular swelling developed, which contained lymphoblasts, but the bone marrow remained in chronic phase CGL. He received further UKALL X induction chemotherapy with intensification and 24 Gy testicular irradiation. In September, 1985, CNS relapse was diagnosed. Intrathecal methotrexate failed to clear the cerebrospinal fluid of blast cells but the addition of intrathecal cytosine arabinoside (Ara-C.) produced a
cholesterol were observed after he had been taking nicotine chewing gum (20 mg nicotine daily) for withdrawal of tobacco smoking. The cholesterol increase was mainly in the low density lipoprotein (LDL) fraction and the high density lipoprotein (HDL) cholesterol to LDL + very low density lipoprotein (VLDL) cholesterol ratio fell. Apoprotein B rose from 1 -30 to 1 84 g/l, mainly in apo-B100’
indicating a hepatic origin. After the chewing gum was stopped the triglyceride, cholesterol, LDL cholesterol, and apo-B levels fell towards baseline values (figure). No hypolipidaemic agents were administered. Triglyceride, cholesterol, LDL cholesterol, and apo-B levels rose again when the chewing gum was reintroduced and fell when the man again stopped using the gum. Short-term experiments in rabbits3 and man4 have shown that nicotine by mouth raises total and LDL cholesterol and lowers HDL cholesterol. Cluette-Brown et als found that long-term consumption of oral nicotine increased total and LDL cholesterol and decreased HDL cholesterol/total cholesterol ratio by enhancing lipolytic conversion of VLDL to LDL in squirrel monkeys. Nicotine also increases the circulating pool ofatherogenic LDL via accelerated transfer of lipid from HDL and impaired clearance of
evening. Focal seizure activity was observed on two occasions, consisting of tonic-clonic activity of his left arm and leg. On admission he had no evidence of focal neurological lesions and he withdrew to painful stimuli. Serum electrolytes, including calcium and magnesium, and blood glucose were normal. There were no changes in the blood cell count or liver function tests. A computerised tomographic scan of the head revealed mild atrophy without blood or mass lesions. A lumbar puncture revealed 1 white blood cell, no red blood cells, protein 45 mg/dl, and glucose 45 mg/dl. Serum and CSF cryptococcal antigen were negative. AZT was
stopped.
Over the next 24 h he became gradually more responsive. There were no further seizures or seizure-like activity. At 48 h he was alert and orientated, with no focal deficits and a normal EEG. He received occasional paracetamol for fever but no other medications. AZT was reintroduced at a dose of 200 mg every 4 h. 72 h after the reintroduction of the drug he complained of a slight headache, then quickly became increasingly confused, with aphasia, left-sided weakness, and intermittent twitching on the right side of his face, occasionally affecting the right arm and leg. Focal- seizures continued unabated for the next 12 h despite intravenous lorazepam and phenytoin. He had a respiratory arrest 36 h after the onset of neurological deterioration and was not resuscitated. This man with AIDS and multiple opportunistic infections had a headache and confusion progressing to unresponsiveness and focal seizures 48 h after beginning AZT. No structural or metabolic defect to explain this complication could be found. Withdrawal of AZT led to complete neurological recovery. Because of the possibility that multiple drug interactions at the initiation of therapy contributed to the presumed AZT neurotoxicity, AZT was reinstituted. Headache and confusion leading to focal status epilepticus unresponsive to anticonvulsants developed 72 h after rechallenge with AZT, and the patient died. We recommend that AZT be used with extreme caution in patients with late manifestations of AIDS, who may be more susceptible to toxic side-effects of AZT because of CNS infection with HIV or opportunistic pathogens and/or may have altered AZT metabolism due to liver disease caused by opportunistic infections or the drugs used in their treatment. Complaints of headache or confusion may be early manifestations of more severe neurotoxicity and may require AZT to be reduced in dose or stopped. Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA
DAN N. HAGLER PETER T. FRAME
response. In all he had ten intrathecal injections of methotrexate and
four of Ara-C. In February, 1986, he had a second CNS relapse which was treated effectively with nine doses of combination of intrathecal hydrocortisone, methotrexate, and Ara-C. In June, 1986, he presented with headaches, but no other neurological symptoms or signs. The CSF blast count was 670/pl. A brain computerised tomographic scan was normal. Since he had resistant CNS disease it was decided to treat him with intrathecal mitozantrone 2 mg weekly. After the second injection he had local pain and the third dose was reduced to 1 mg. Local pain again recurred, requiring relief by analgesia. 3-4 days later he had severe pain in his legs and paraplegia developed over a period of 2 weeks with absent leg reflexes but no sensory loss or alteration in bowel or bladder function. The CSF blast count fell to less than 1 /)il after the second injection. 4 months later he remains paraplegic and in chronic phase CGL. Intrathecal mitozantrone was effective in clearing blasts from the CSF in our patient, as in previous reports.1,2 The pain and paraplegia followed shortly after the third injection and since the patient had no previous neurological signs and no evidence of active CNS leukaemia we believe mitozantrone played a major part in its causation. A previous report’ described the development of paraplegia in a patient treated with intrathecal mitozantrone but this was thought to be related to disease, previous drugs, or mitozantrone. Mitozantrone does not cause significant neurological problems when given systemically.3 We conclude that intrathecal mitozantrone, although effective in treating resistant CNS disease in leukaemia, should be used with caution. A. ’1:T K. TLAKHANI A. G. ZUIABLE C. M. POLLARD A. MILNE Leukaemia Unit, J. TRELEAVEN Royal Marsden Hospital, R. L. POWLES Sutton, Surrey SM2 5PT .........
Godefroy W, Vemey A, Gorin WC, Nalman A, Duhamel G. Intrathecal mitozantrone. Lancet 1985, ii. 160. 2 Zuiable AG, Maitland J, Nandi A, Clink HM, Powels RL. Intrathecal mitozantrone for resistant leukaemia. Lancet 1985; ii. 1061. 3. Anderson KL, et al. Phase 1 trial of mitozantrone by 24 hours continuous infusions. Cancer Treat Rep 1983; 67: 435-38. 1. La Porte JP,
HYPERCHOLESTEROLAEMIA AFTER ADMINISTRATION OF NICOTINE CHEWING GUM
SIR,-Increased cholesterol levels and coronary heart disease2 observed in cigarette smokers. However, because tobacco smoke contains many constituents, it has been difficult to uncover the factor(s) responsible for these increases. It seemed important to find out whether regular administration of nicotine, a constituent of tobacco that is commonly used by people trying to give up smoking, produces a cardiovascular risk. In a 29-year-old man increases in serum triglycerides and are
1. Yarchoan
R,
et
al. Administration of
HTLV-III/LAV replication,
to
3’-azido-3’-deoxymaymidine, an inhibitor of patients with AIDS or AIDS-related complex.
Lancet 1986; i: 575-80. Azidothymidine for AIDS. Med Letter 1986; 28: 107-09.
2. Anon.
PARAPLEGIA AFTER INTRATHECAL MITOZANTRONE
SIR,-Mitozantrone has been used intrathecally to treat resistant central nervous system (CNS) disease in lymphomal and leukaemia.2 We report a patient who became paraplegic after intrathecal mitozantrone for resistant CNS leukaemia. A 38-year-old man presented with Philadelphia chromosome positive (ph+) acute lymphoblastic leukaemia in July, 1982. Remission was obtained with MRC Leukaemia Working Party UKALL IX protocol. CNS disease was absent and he received intrathecal methotrexate and 18 Gy cranial irradiation as prophylaxis. Maintenance treatment was with oral 6mercaptopurine and methotrexate. In March, 1984, he was found to be in the chronic phase of Ph- chronic granulocytic leukaemia (CGL), which required treatment with busulphan and
hydroxyurea. In May, 1984, testicular swelling developed, which contained lymphoblasts, but the bone marrow remained in chronic phase CGL. He received further UKALL X induction chemotherapy with intensification and 24 Gy testicular irradiation. In September, 1985, CNS relapse was diagnosed. Intrathecal methotrexate failed to clear the cerebrospinal fluid of blast cells but the addition of intrathecal cytosine arabinoside (Ara-C.) produced a
cholesterol were observed after he had been taking nicotine chewing gum (20 mg nicotine daily) for withdrawal of tobacco smoking. The cholesterol increase was mainly in the low density lipoprotein (LDL) fraction and the high density lipoprotein (HDL) cholesterol to LDL + very low density lipoprotein (VLDL) cholesterol ratio fell. Apoprotein B rose from 1 -30 to 1 84 g/l, mainly in apo-B100’
indicating a hepatic origin. After the chewing gum was stopped the triglyceride, cholesterol, LDL cholesterol, and apo-B levels fell towards baseline values (figure). No hypolipidaemic agents were administered. Triglyceride, cholesterol, LDL cholesterol, and apo-B levels rose again when the chewing gum was reintroduced and fell when the man again stopped using the gum. Short-term experiments in rabbits3 and man4 have shown that nicotine by mouth raises total and LDL cholesterol and lowers HDL cholesterol. Cluette-Brown et als found that long-term consumption of oral nicotine increased total and LDL cholesterol and decreased HDL cholesterol/total cholesterol ratio by enhancing lipolytic conversion of VLDL to LDL in squirrel monkeys. Nicotine also increases the circulating pool ofatherogenic LDL via accelerated transfer of lipid from HDL and impaired clearance of