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Encephalopathy with seizures after use of aluminium-containing bone cement
Encephalopathy with seizures after aluminium-containing bone cement
use
of
SiR-Renard and colleagues’ reported post-otoneurosurgery encephalopathy. We present our experience in 2
aluminium
patients undergoing the same procedure. A 29-year-old man (patient 1), with a history of lymphocytic meningitis more than 20 years earlier, underwent a right vestibular neurectomy for refractory Meniere’s disease. Bone cement (Ionocap LV, lonos, Germany, containing 1 g aluminium-calcium fluorosilicate glass, 318 mg polyalkenoic acid, 91 mg tartaric acid, 591 mg water, and preserved with benzoic acid) was used to bridge bone defects during the procedure. The patient presented two weeks later with postauricular accumulation of cerebrospinal fluid (CSF). On day 42, dizziness was noted, with right-sided paraesthesias and tonico-clonic seizures. Brain computed tomodensitometry and magnetic resonance imaging were uniformative. The patient was admitted 9 days later to the intensive care unit for status epilepticus. Despitethe administration of several manor anticonvulsant drugs, he died on day 143 from brain failure due to persistent convulsions. In a 54-year-old woman (patient 2), without previous medical history, the same operation was done with the use of the same cement. The immediate postoperative phase was complicated by CSF leakage with nasal fistula and left postauricular accumulation of fluid. On day 7 she developed confusion and alteration of consciousness. The fistula was closed on day 16 with the same cement. On day 36, leftsided tonico-clonic seizures evolved to grand mal seizures and refractory status epilepticus, leading to brain failure and death on day 80. In both patients, extensive investigations led us to exclude
postoperative meningitis then
encephalopathy. A toxicological suggested. In both patients, an or
hypothesis aluminium-containing cement had been used. The procedure was complicated by CSF postauricular was
in contact with the CSF. Aluminium concentrations were measured in the CSF, postauricular fluid, serum, and urine. The highest aluminium concentrations (tg/L) were 112 and 63 in CSF, 495 and 1440 in liquid from the fistula, and 4-4 and 4-3 in serum in patients 1 and 2, respectively (reference values for aluminium are usually less than 1 p.g/L in both serum and CSF). Aluminium renal excretion was also increased (up to 330 gg/g creatinine). In addition to cement removal and CSF drainage, desferrioxamine (1000 mg per day) was given for 10 days starting on days 61 and 50 for patients 1 and 2, respectively. This treatment led to an increased urinary excretion of aluminium but had no effect on aluminium concentration in serum and CSF. In patient 2, aluminium concentration in brain tissue obtained at necropsy was 2-5 pg/g (wet weight) versus 0-85 in a control cadaver. To confirm that aluminium could be leached from the cement, 0-2 g cement was incubated in the presence of CSF for 16 h at 37°C; at the end of the incubation period, aluminium concentration in the CSF was 2570 fig/L. These data suggest strongly that in both patients encephalopathy was caused by aluminium released from the cement. The clinical picture is similar to that in uraemic patients in whom an acute form of aluminium neurotoxicity has been described, in addition to the well known chronic presentation.2 Symptoms can also include agitation, confusion, myoclonic jerks, grand mal seizures, obtundation, coma, and death. Acute forms of aluminium neurotoxicity are uniformly fatal, irrespective of chelation therapy. Aluminium-containing cement should not be used where there is a risk of direct contact with CSF and possibly also
accumulation, and the bone
cement came
under circumstances (eg, renal insufficiency) in which the aluminium eluted from the cement cannot be rapidly eliminated by the renal route. Ph Hantson, P Mahieu, M Gersdorff, C J M
Sindic, R Lauwerys
Departments of Intensive Care and Neurology, and Industrial Toxicology and Occupational Medicine Unit, Cliniques Universitaires St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium
1
2
Renard JL, Felten D, Béquet D. Post-otoneurosurgery aluminium encephalopathy. Lancet 1994; 344: 63-64. Alfey AC. Aluminium toxicity in patients with chronic renal failure. Ther Drug Monit 1993; 15: 593-97.
p53 protein associated with chemosensitivity in breast cancer specimens Mutant
SiR-The p53 tumour suppressor gene has a crucial role in the execution of some forms of apoptosis. Acquired mutations in the p53 gene have been associated with both treatment resistance and relapse in p53-expressing tumours in mice.’ In the clinical setting, one would expect that mutations in p53 might lead to resistance with chemotherapeutic agents. Patients with mutant p53 protein would therefore be more likely to express increased chemoresistance. Mutations in the p53 gene were detected in 58% of tumours of patients with a family history of breast cancer and in 13% with sporadic breast cancer. We investigated the correlation- between the concentration of mutant p53 protein and the in-vitro chemosensitivity of tumour specimens from 40 patients with primary untreated non-metastatic breast cancer. Mutant p53 protein was determined by ELISA with antibodies that only recognise mutant p53 protein.3 Chemosensitivity was tested with the adenosine triphosphate cell viability assay.4°5 The in-vitro assay has been shown to correlate with in-vitro chemosensitivity of breast cancer.4 CMF chemosensitivity (CMF=cyclophosphamide, methotrexate, and fluorouracil) was determined at six concentrations ranging from 0-125-4 X the reported peak plasma values.4 In our in-vitro assay, the active metabolite 4-hydroperoxycyclophosphamide was used for cyclophosphamide. The CMF chemosensitivity at 4 X peak plasma concentrations was compared with the amount of mutant p53 protein found in the same tumour specimens by linear regression for appropriately transformed data (figure). Our results suggest a significant correlation between the concentration of the mutant p53 protein and the in-vitro CMF chemosensitivity (r2=0’15, p=0018). . I
Mutant
p53 protein
Figure: Correlation of mutant p53 protein content with CMF chemosensitivity (survival fractions at 4 X peak plasma concentration) 1647
use
of
SiR-Renard and colleagues’ reported post-otoneurosurgery encephalopathy. We present our experience in 2
aluminium
patients undergoing the same procedure. A 29-year-old man (patient 1), with a history of lymphocytic meningitis more than 20 years earlier, underwent a right vestibular neurectomy for refractory Meniere’s disease. Bone cement (Ionocap LV, lonos, Germany, containing 1 g aluminium-calcium fluorosilicate glass, 318 mg polyalkenoic acid, 91 mg tartaric acid, 591 mg water, and preserved with benzoic acid) was used to bridge bone defects during the procedure. The patient presented two weeks later with postauricular accumulation of cerebrospinal fluid (CSF). On day 42, dizziness was noted, with right-sided paraesthesias and tonico-clonic seizures. Brain computed tomodensitometry and magnetic resonance imaging were uniformative. The patient was admitted 9 days later to the intensive care unit for status epilepticus. Despitethe administration of several manor anticonvulsant drugs, he died on day 143 from brain failure due to persistent convulsions. In a 54-year-old woman (patient 2), without previous medical history, the same operation was done with the use of the same cement. The immediate postoperative phase was complicated by CSF leakage with nasal fistula and left postauricular accumulation of fluid. On day 7 she developed confusion and alteration of consciousness. The fistula was closed on day 16 with the same cement. On day 36, leftsided tonico-clonic seizures evolved to grand mal seizures and refractory status epilepticus, leading to brain failure and death on day 80. In both patients, extensive investigations led us to exclude
postoperative meningitis then
encephalopathy. A toxicological suggested. In both patients, an or
hypothesis aluminium-containing cement had been used. The procedure was complicated by CSF postauricular was
in contact with the CSF. Aluminium concentrations were measured in the CSF, postauricular fluid, serum, and urine. The highest aluminium concentrations (tg/L) were 112 and 63 in CSF, 495 and 1440 in liquid from the fistula, and 4-4 and 4-3 in serum in patients 1 and 2, respectively (reference values for aluminium are usually less than 1 p.g/L in both serum and CSF). Aluminium renal excretion was also increased (up to 330 gg/g creatinine). In addition to cement removal and CSF drainage, desferrioxamine (1000 mg per day) was given for 10 days starting on days 61 and 50 for patients 1 and 2, respectively. This treatment led to an increased urinary excretion of aluminium but had no effect on aluminium concentration in serum and CSF. In patient 2, aluminium concentration in brain tissue obtained at necropsy was 2-5 pg/g (wet weight) versus 0-85 in a control cadaver. To confirm that aluminium could be leached from the cement, 0-2 g cement was incubated in the presence of CSF for 16 h at 37°C; at the end of the incubation period, aluminium concentration in the CSF was 2570 fig/L. These data suggest strongly that in both patients encephalopathy was caused by aluminium released from the cement. The clinical picture is similar to that in uraemic patients in whom an acute form of aluminium neurotoxicity has been described, in addition to the well known chronic presentation.2 Symptoms can also include agitation, confusion, myoclonic jerks, grand mal seizures, obtundation, coma, and death. Acute forms of aluminium neurotoxicity are uniformly fatal, irrespective of chelation therapy. Aluminium-containing cement should not be used where there is a risk of direct contact with CSF and possibly also
accumulation, and the bone
cement came
under circumstances (eg, renal insufficiency) in which the aluminium eluted from the cement cannot be rapidly eliminated by the renal route. Ph Hantson, P Mahieu, M Gersdorff, C J M
Sindic, R Lauwerys
Departments of Intensive Care and Neurology, and Industrial Toxicology and Occupational Medicine Unit, Cliniques Universitaires St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium
1
2
Renard JL, Felten D, Béquet D. Post-otoneurosurgery aluminium encephalopathy. Lancet 1994; 344: 63-64. Alfey AC. Aluminium toxicity in patients with chronic renal failure. Ther Drug Monit 1993; 15: 593-97.
p53 protein associated with chemosensitivity in breast cancer specimens Mutant
SiR-The p53 tumour suppressor gene has a crucial role in the execution of some forms of apoptosis. Acquired mutations in the p53 gene have been associated with both treatment resistance and relapse in p53-expressing tumours in mice.’ In the clinical setting, one would expect that mutations in p53 might lead to resistance with chemotherapeutic agents. Patients with mutant p53 protein would therefore be more likely to express increased chemoresistance. Mutations in the p53 gene were detected in 58% of tumours of patients with a family history of breast cancer and in 13% with sporadic breast cancer. We investigated the correlation- between the concentration of mutant p53 protein and the in-vitro chemosensitivity of tumour specimens from 40 patients with primary untreated non-metastatic breast cancer. Mutant p53 protein was determined by ELISA with antibodies that only recognise mutant p53 protein.3 Chemosensitivity was tested with the adenosine triphosphate cell viability assay.4°5 The in-vitro assay has been shown to correlate with in-vitro chemosensitivity of breast cancer.4 CMF chemosensitivity (CMF=cyclophosphamide, methotrexate, and fluorouracil) was determined at six concentrations ranging from 0-125-4 X the reported peak plasma values.4 In our in-vitro assay, the active metabolite 4-hydroperoxycyclophosphamide was used for cyclophosphamide. The CMF chemosensitivity at 4 X peak plasma concentrations was compared with the amount of mutant p53 protein found in the same tumour specimens by linear regression for appropriately transformed data (figure). Our results suggest a significant correlation between the concentration of the mutant p53 protein and the in-vitro CMF chemosensitivity (r2=0’15, p=0018). . I
Mutant
p53 protein
Figure: Correlation of mutant p53 protein content with CMF chemosensitivity (survival fractions at 4 X peak plasma concentration) 1647