- Email: [email protected]
Maternal 3-methylglutaconic aciduria associated with abnormalities in offspring
THE LANCET
Letters to the Editor
Premortem diagnosis of Creutzfeldt-Jakob disease by cerebrospinal fluid analysis
Maternal 3-methylglutaconic aciduria associated with abnormalities in offspring
SIR—The new variant of Creutzfeldt-Jakob disease (CJD)1 is remarkable because it affects younger individuals, presents with different symptoms, and has different pathological findings to sporadic CJD. There is a need to determine the epidemiology of this disease with a specific and sensitive premortem diagnostic test. Among tests available for the premortem diagnosis of CJD is determination of the presence of two low-abundance proteins, 130/131, reported to discriminate CJD from other causes of dementia when detected in the cerebrospinal fluid (CSF).2 In that previous report, all 21 patients with CJD had CSF proteins (p) 130/131, which were not present in the CSF of any of the 87 patients with other causes of dementia. This test for p 130/131 has not come into use in clinical laboratories because of its technical complexity. However, in collaboration with researchers at the National Institutes of Health, we have developed a simplified test based on the characterisation of these proteins3 that should lead to widespread use of these marker proteins in the routine diagnosis of CJD. Since our publication in 1986, we have studied over 500 samples from patients with dementia referred to us by clinicians. After p 130/131 testing, we were able to determine the necropsy diagnosis in 260 of these patients. Only two of the 260 patients had a misdiagnosis based on the p 130/131 test: one with primary central nervous system lymphoma was p 130/131 positive and one patient with CJD pathological findings had no p 130/131 detected at the time of examination. Of the remaining 258 patients, 48 were positive for p 130/131 and for CJD pathological findings and 210 were negative for p 130/131 and had no evidence of CJD. If we combine these previously unpublished results with those from the original publication,2 the p 130/131 test has a more than 98% sensitivity for CJD with a more than 99% specificity (table).
SIR—Maternal effects on fetal outcome in the pregnancies of women with various metabolic disorders have been recognised. Maternal phenylketonuria is one of the important metabolic disorders known to have teratogenic implications, including mental retardation and congenital microcephaly. We have analysed the plasma aminoacids and urine organic acids of 25 mothers with children with congenital microcephaly and severe psychomotor retardation of unknown cause. All women had normal head circumferences, normal intelligence, and uneventful medical histories. None of them had hyperphenylalaninaemia but six mothers were found to excrete 3-methylglutaconic acid (3-MGA) and 3methylglutaric acid, organic acids associated with the leucine degradative pathway. The mothers excreting 3-MGA did not show signs of a metabolic disorder. The range of excretion of 3-MGA in the six mothers was 19·3–40 mmol per mol creatinine (median 22·4) and for 3-methylglutaric acid it was 2·5–14·5 mmol per mol creatinine (median 4·9). The 3-hydroxyisovaleric acid excretions were normal. The clinical findings in the offspring of the women excreting 3-MGA are presented in the table. Patients two and three are brothers born to consanguineous parents. Consanguinity was present in one other family. Among the 19 mothers not excreting 3-MGA, in addition to a microcephalic child, several had normal children without microcephaly. None of the mothers with 3-MGA had normocephalic children or had children by other fathers. Controls for 3-MGA excretion were ten healthy mothers with normal offspring. The range of 3-MGA excretion was 0·6–4·5 mmol per mol creatinine (median 1·4), that of 3-methylglutaric acid excretion was 0–2·4 mmol per mol creatinine (median 0·8), and that of 3-hydroxyisovaleric acid excretion was 2·5–8·8 mmol per mol creatinine (median 4·4). 3-MGA aciduria has been observed in various clinical phenotypes, including retarded development of speech, Xlinked cardioskeletal myopathy with neutropenia, severe neurological dysfunction, Smith-Lemli-Opitz syndrome, and disturbed mitochondrial energy metabolism.1,2 Only 3-MGA aciduria type 1 (3-methylglutaconyl-CoA hydratase deficiency) is related to a defect in leucine catabolism and
No of patients with dementia Studied
Sensitivity
Specificity
1986 report This report
129 260
100% (21/21) >97% (48/49)
100% (87/87) >99% (210/211)
Total
389
>98% (69/70)
>99% (297/298)
Table: Sensitivity and specificity of 130/131 test for CJD
We are currently investigating at which stage of the disease the p 130/131 marker test becomes positive, the use of this marker in diagnosing new variant CJD, and for diagnosing transmissible spongiform encephalopathy in animals. Kelvin H Lee, *Michael G Harrington
Patient/sex
Microcephaly
Mental retardation
Seizures
Associated defects
MRI/CT brain defect
1/F
+
+
+
–
2/M
+
+
+
3/M
+
+
+
4/M
+
+
+
5/M 6/M 7/F
+ + +
+ + +
+ – +
Nystagmus, tetraplegia Nystagmus, tetraplegia VSD, hypotonia – – –
Cortical hypoplasia –
Biology 139-74, California Institute of Technology, Pasadena, CA 91125, USA
1 2
3
Will GR, Ironside JW, Zeidler M, et al. A new variant of CreutzfeldtJakob disease in the UK. Lancet 1996; 347: 921–25. Harrington MG, Merril CR, Asher DM, Gajdusek DC. Abnormal proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. N Engl J Med 1986; 315: 279–83. Hsich G, Kennedy K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 1996; 335: 924–30.
Vol 348 • September 28, 1996
– Cortical hypoplasia – Pachygyria –
VSD=ventricular septal defect, MRI=magnetic resonance imaging, CT=computed tomography. Patients 2 and 3 are brothers. +=present, –=absent.
Table: Clinical findings in children born to mothers with 3-methylglutaconic aciduria
887
THE LANCET
includes increased 3-hydroxyisovalerate excretion.3 In most patients with 3-MGA excretion no defect is detectable in the leucine degradative pathway. Inborn errors in several metabolic pathways may be hypothesised in these patients.1,2 The levels of 3-MGA excretion in the mothers ranged from 19·3–40 mmol per mol creatinine and are similar to values reported in some patients with 3-MGA excretion.4 Maternal 3-MGA aciduria may be secondary to a fundamental metabolic defect or a nonspecific indicator of metabolic disease in which the basic defect is not defined. Increased 3MGA excretion during pregnancy has been reported5 in two mothers with normal children. Urine organic acids in these reported mothers were analysed to detect risk factors for preeclampsia. Their paper suggests that not all cases of maternal 3-MGA excretion are related to birth defects. We suggest that, in addition to plasma aminoacids, urine should be tested for 3-MGA in mothers with children with congenital microcephaly and psychomotor retardation of unknown cause. *T J de Koning, M Duran, L Dorland, R Berger, B T Poll-The University Children’s Hospital ‘Het Wilhelmina Kinderziekenhuis’, Nieuwegracht 137, 3512 LK Utrecht, Netherlands
1
2 3
4
5
Gibson KM, Elpeleg ON, Jakobs C, Costeff H, Kelley RI. Multiple syndromes of 3-methylglutaconic aciduria. Pediatr Neurol 1993; 9: 120–23. Kelley RI, Kratz L. 3-methylglutaconic acidemia in Smith-Lemli-Opitz syndrome. Pediatr Res 1995; 37: 671–74. Duran M, Beemer FA, Tibosch AS, Bruinvis L, Ketting D, Wadman SK. Inherited 3-methylglutaconic aciduria in two brothers: another defect of leucine metabolism. J Pediatr 1982; 101: 551–54. Ogier de Baulny H, Wendel U, Saudubray JM. Branched-chain organic acidurias. In: Fernandes J, Saundubray JM, van den Berge G, eds. Inborn metabolic diseases: diagnosis and treatment, 2nd edn, Berlin: Springer-Verlag, 1995: 207–21. Kuhara T, Matsumoto I, Saiki K, Takabayashi H, Kuwabara S. 3-methylglutaconic aciduria in two adults. Clin chim Acta 1992; 207: 151–53.
Actinobacillus suis infection after a pig bite SIR—A 37-year-old man farmer was bitten by a pig on his right knee. He was admitted to Albi hospital 24 hours later. His knee was extremely swollen and painful; there was a purulent discharge from the wound. Samples were taken for bacteriology and the wound was cleansed and drained. He was treated with co-amoxiclav (3 g daily) and recovered within 10 days. Characteristics of the infection were studied with API20E and API50CH systems (API-bioMérieux, La Balme-LesGrottes, France) and other conventional tests: the isolate was of non-motile gram-negative rods, facultatively anaerobic without gas. The culture was sticky (with a viscous growth in broth medium); haemolytic; positive for urease, βgalactosidase, nitrate reduction, and sensitivity to the vibriostatic agent (O/129); and negative for indole. The strain was identified as Actinobaccillus suis. It was susceptible to β-lactams (amoxycillin), tetracyclines, choramphenicol, and fluoroquinolones (pefloxacin) and intermediate to erythromycin using the disc diffusion method. Among members of the family Pasteurellaceae, the most important genes isolated in animal-wound infections are Pasteurella. 1,2 Actinobacillus, which are commensal oropharyngeal flora of many animals (cattle, sheep, horses, and rabbits), are rarely isolated from human beings.3–5 A retrospective study of Pasteurella and related bacteria from 1985 to 1994 found 1500 cases; Actinobacillus accounted for only 1·3%.1 This case illustrates that A suis can cause severe infections and suggests that in such infections swabs to
888
identify the microorganism must be taken. Amoxycillin plus clavulanate acid may be the antibiotic of choice for the treatment of infected animal bites. *F Escande, A Bailly, S Bone, J Lemozy *Laboratoire des Pasteurella, CIP, Institut Pasteur, F 75015 Paris, France; Laboratoire de Microbiologie; Chirurgie Orthopédique et Traumatologique, Centre Hospitalier Général, Albi; Laboratoire de Microbiologie, Centre Hospitalier Universitaire, Hôpital Purpan, Toulouse
1
2
3
4
5
Escande F, et le Groupe de Travail. Pasteurella et bactéries apparentées. Abstracts AT-7; 4éme Congrés de la Société Française de Microbiologie 1995, Tours, France. Scheftel JM, Rihn B, Metzger MP, et al. Infection d’une plaie par Pasteurella aerogenes chez un chasseur après blessure due à une charge de sanglier. Méd Mal Infect 1987; 5: 267–68. Benaoudia F, Escande F, Simonet M. Infection due to Actinobacillus lignieresii after a horse bite. Eur J Clin Microbiol Infect Dis 1994; 13: 439–40. Lemozy J, Simonet M, Vallée E, Escande F. Pasteurellaceae inhabituelles isolées après morsure animale. Abstract VE-72; 4éme Congrés de la Société Française de Microbiologie 1995, Tours, France. Peel MM, Hornidge KA, Luppino M, Stacpoole AM, Weaver RE. Actinobacillus spp and related bacteria in infected wounds of human bitten by horses and sheep. J Clin Microbiol 1991; 29: 2535–38.
Hydroxyurea for treatment of unresectable meningiomas SIR—According to the WHO grading system, most meningiomas are grade I (benign); grade II and III (malignant) account for about 7%.1 Complete surgical removal often fails because of invasive growth. Removal of meningiomas in the cavernous sinus, petrous apex, posterior fossa, and posterior sagittal sinus has a high morbidity and recurrence rate.2 The current treatment strategy aims at decompression, and fractioned radiotherapy in progressive tumours. Although radiotherapy only rarely causes a tumourmass reduction, it can delay regrowth or recurrence for a few years.3,4 We searched for other treatments, including chemotherapy. Hydroxyurea was chosen because it is well tolerated and side-effects are reversible even after years of treatment. Treatment of cultured meningioma cells with hydroxyurea resulted in decreased cell proliferation or blocked tumour-cell growth. DNA flow-cytometry showed 39% arrest of meningioma cells in the S-phase of the cell cycle. Electronmicroscopy of HU-treated meningioma cells showed ultrastructural features consistent with apoptosis. In all HU-treated nude mice meningioma transplants, DNA fragmentation was demonstrated by in-situ DNA-strandbreak labelling in distinct regions with alternate density. Hydroxyurea is a potent inhibitor of cultured human meningioma cells and nude mice meningioma transplants.5 We treated selected patients with hydroxyurea. All had had multiple resections and all except one had radiotherapy. Before hydroxyurea treatment, the tumours had been progressing for 6 to 12 months; none could have been removed completely at operation. Hydroxyurea was given in a daily dose of 1000 mg to 1500 mg day (about 20 mg kg–1 d–1). A 46-year-old man had a large meningioma (transitional; WHO, grade I) of the right sphenoid wing invading the cavernous sinus and the right temporal base. The intracranial mass reduced by 75% over 13 months’ treatment. A 47-year-old woman with a large ball-shaped meningioma (meningotheliomatous—angiomatous; WHO grade I) of the right sphenoid wing invading the cavernous sinus had a 73% decrease of the tumour volume within 10 months of treatment, shown by serial magnetic resonance images (MRI) (figure). The shrinkage of the tumour was
Vol 348 • September 28, 1996
Letters to the Editor
Premortem diagnosis of Creutzfeldt-Jakob disease by cerebrospinal fluid analysis
Maternal 3-methylglutaconic aciduria associated with abnormalities in offspring
SIR—The new variant of Creutzfeldt-Jakob disease (CJD)1 is remarkable because it affects younger individuals, presents with different symptoms, and has different pathological findings to sporadic CJD. There is a need to determine the epidemiology of this disease with a specific and sensitive premortem diagnostic test. Among tests available for the premortem diagnosis of CJD is determination of the presence of two low-abundance proteins, 130/131, reported to discriminate CJD from other causes of dementia when detected in the cerebrospinal fluid (CSF).2 In that previous report, all 21 patients with CJD had CSF proteins (p) 130/131, which were not present in the CSF of any of the 87 patients with other causes of dementia. This test for p 130/131 has not come into use in clinical laboratories because of its technical complexity. However, in collaboration with researchers at the National Institutes of Health, we have developed a simplified test based on the characterisation of these proteins3 that should lead to widespread use of these marker proteins in the routine diagnosis of CJD. Since our publication in 1986, we have studied over 500 samples from patients with dementia referred to us by clinicians. After p 130/131 testing, we were able to determine the necropsy diagnosis in 260 of these patients. Only two of the 260 patients had a misdiagnosis based on the p 130/131 test: one with primary central nervous system lymphoma was p 130/131 positive and one patient with CJD pathological findings had no p 130/131 detected at the time of examination. Of the remaining 258 patients, 48 were positive for p 130/131 and for CJD pathological findings and 210 were negative for p 130/131 and had no evidence of CJD. If we combine these previously unpublished results with those from the original publication,2 the p 130/131 test has a more than 98% sensitivity for CJD with a more than 99% specificity (table).
SIR—Maternal effects on fetal outcome in the pregnancies of women with various metabolic disorders have been recognised. Maternal phenylketonuria is one of the important metabolic disorders known to have teratogenic implications, including mental retardation and congenital microcephaly. We have analysed the plasma aminoacids and urine organic acids of 25 mothers with children with congenital microcephaly and severe psychomotor retardation of unknown cause. All women had normal head circumferences, normal intelligence, and uneventful medical histories. None of them had hyperphenylalaninaemia but six mothers were found to excrete 3-methylglutaconic acid (3-MGA) and 3methylglutaric acid, organic acids associated with the leucine degradative pathway. The mothers excreting 3-MGA did not show signs of a metabolic disorder. The range of excretion of 3-MGA in the six mothers was 19·3–40 mmol per mol creatinine (median 22·4) and for 3-methylglutaric acid it was 2·5–14·5 mmol per mol creatinine (median 4·9). The 3-hydroxyisovaleric acid excretions were normal. The clinical findings in the offspring of the women excreting 3-MGA are presented in the table. Patients two and three are brothers born to consanguineous parents. Consanguinity was present in one other family. Among the 19 mothers not excreting 3-MGA, in addition to a microcephalic child, several had normal children without microcephaly. None of the mothers with 3-MGA had normocephalic children or had children by other fathers. Controls for 3-MGA excretion were ten healthy mothers with normal offspring. The range of 3-MGA excretion was 0·6–4·5 mmol per mol creatinine (median 1·4), that of 3-methylglutaric acid excretion was 0–2·4 mmol per mol creatinine (median 0·8), and that of 3-hydroxyisovaleric acid excretion was 2·5–8·8 mmol per mol creatinine (median 4·4). 3-MGA aciduria has been observed in various clinical phenotypes, including retarded development of speech, Xlinked cardioskeletal myopathy with neutropenia, severe neurological dysfunction, Smith-Lemli-Opitz syndrome, and disturbed mitochondrial energy metabolism.1,2 Only 3-MGA aciduria type 1 (3-methylglutaconyl-CoA hydratase deficiency) is related to a defect in leucine catabolism and
No of patients with dementia Studied
Sensitivity
Specificity
1986 report This report
129 260
100% (21/21) >97% (48/49)
100% (87/87) >99% (210/211)
Total
389
>98% (69/70)
>99% (297/298)
Table: Sensitivity and specificity of 130/131 test for CJD
We are currently investigating at which stage of the disease the p 130/131 marker test becomes positive, the use of this marker in diagnosing new variant CJD, and for diagnosing transmissible spongiform encephalopathy in animals. Kelvin H Lee, *Michael G Harrington
Patient/sex
Microcephaly
Mental retardation
Seizures
Associated defects
MRI/CT brain defect
1/F
+
+
+
–
2/M
+
+
+
3/M
+
+
+
4/M
+
+
+
5/M 6/M 7/F
+ + +
+ + +
+ – +
Nystagmus, tetraplegia Nystagmus, tetraplegia VSD, hypotonia – – –
Cortical hypoplasia –
Biology 139-74, California Institute of Technology, Pasadena, CA 91125, USA
1 2
3
Will GR, Ironside JW, Zeidler M, et al. A new variant of CreutzfeldtJakob disease in the UK. Lancet 1996; 347: 921–25. Harrington MG, Merril CR, Asher DM, Gajdusek DC. Abnormal proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. N Engl J Med 1986; 315: 279–83. Hsich G, Kennedy K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 1996; 335: 924–30.
Vol 348 • September 28, 1996
– Cortical hypoplasia – Pachygyria –
VSD=ventricular septal defect, MRI=magnetic resonance imaging, CT=computed tomography. Patients 2 and 3 are brothers. +=present, –=absent.
Table: Clinical findings in children born to mothers with 3-methylglutaconic aciduria
887
THE LANCET
includes increased 3-hydroxyisovalerate excretion.3 In most patients with 3-MGA excretion no defect is detectable in the leucine degradative pathway. Inborn errors in several metabolic pathways may be hypothesised in these patients.1,2 The levels of 3-MGA excretion in the mothers ranged from 19·3–40 mmol per mol creatinine and are similar to values reported in some patients with 3-MGA excretion.4 Maternal 3-MGA aciduria may be secondary to a fundamental metabolic defect or a nonspecific indicator of metabolic disease in which the basic defect is not defined. Increased 3MGA excretion during pregnancy has been reported5 in two mothers with normal children. Urine organic acids in these reported mothers were analysed to detect risk factors for preeclampsia. Their paper suggests that not all cases of maternal 3-MGA excretion are related to birth defects. We suggest that, in addition to plasma aminoacids, urine should be tested for 3-MGA in mothers with children with congenital microcephaly and psychomotor retardation of unknown cause. *T J de Koning, M Duran, L Dorland, R Berger, B T Poll-The University Children’s Hospital ‘Het Wilhelmina Kinderziekenhuis’, Nieuwegracht 137, 3512 LK Utrecht, Netherlands
1
2 3
4
5
Gibson KM, Elpeleg ON, Jakobs C, Costeff H, Kelley RI. Multiple syndromes of 3-methylglutaconic aciduria. Pediatr Neurol 1993; 9: 120–23. Kelley RI, Kratz L. 3-methylglutaconic acidemia in Smith-Lemli-Opitz syndrome. Pediatr Res 1995; 37: 671–74. Duran M, Beemer FA, Tibosch AS, Bruinvis L, Ketting D, Wadman SK. Inherited 3-methylglutaconic aciduria in two brothers: another defect of leucine metabolism. J Pediatr 1982; 101: 551–54. Ogier de Baulny H, Wendel U, Saudubray JM. Branched-chain organic acidurias. In: Fernandes J, Saundubray JM, van den Berge G, eds. Inborn metabolic diseases: diagnosis and treatment, 2nd edn, Berlin: Springer-Verlag, 1995: 207–21. Kuhara T, Matsumoto I, Saiki K, Takabayashi H, Kuwabara S. 3-methylglutaconic aciduria in two adults. Clin chim Acta 1992; 207: 151–53.
Actinobacillus suis infection after a pig bite SIR—A 37-year-old man farmer was bitten by a pig on his right knee. He was admitted to Albi hospital 24 hours later. His knee was extremely swollen and painful; there was a purulent discharge from the wound. Samples were taken for bacteriology and the wound was cleansed and drained. He was treated with co-amoxiclav (3 g daily) and recovered within 10 days. Characteristics of the infection were studied with API20E and API50CH systems (API-bioMérieux, La Balme-LesGrottes, France) and other conventional tests: the isolate was of non-motile gram-negative rods, facultatively anaerobic without gas. The culture was sticky (with a viscous growth in broth medium); haemolytic; positive for urease, βgalactosidase, nitrate reduction, and sensitivity to the vibriostatic agent (O/129); and negative for indole. The strain was identified as Actinobaccillus suis. It was susceptible to β-lactams (amoxycillin), tetracyclines, choramphenicol, and fluoroquinolones (pefloxacin) and intermediate to erythromycin using the disc diffusion method. Among members of the family Pasteurellaceae, the most important genes isolated in animal-wound infections are Pasteurella. 1,2 Actinobacillus, which are commensal oropharyngeal flora of many animals (cattle, sheep, horses, and rabbits), are rarely isolated from human beings.3–5 A retrospective study of Pasteurella and related bacteria from 1985 to 1994 found 1500 cases; Actinobacillus accounted for only 1·3%.1 This case illustrates that A suis can cause severe infections and suggests that in such infections swabs to
888
identify the microorganism must be taken. Amoxycillin plus clavulanate acid may be the antibiotic of choice for the treatment of infected animal bites. *F Escande, A Bailly, S Bone, J Lemozy *Laboratoire des Pasteurella, CIP, Institut Pasteur, F 75015 Paris, France; Laboratoire de Microbiologie; Chirurgie Orthopédique et Traumatologique, Centre Hospitalier Général, Albi; Laboratoire de Microbiologie, Centre Hospitalier Universitaire, Hôpital Purpan, Toulouse
1
2
3
4
5
Escande F, et le Groupe de Travail. Pasteurella et bactéries apparentées. Abstracts AT-7; 4éme Congrés de la Société Française de Microbiologie 1995, Tours, France. Scheftel JM, Rihn B, Metzger MP, et al. Infection d’une plaie par Pasteurella aerogenes chez un chasseur après blessure due à une charge de sanglier. Méd Mal Infect 1987; 5: 267–68. Benaoudia F, Escande F, Simonet M. Infection due to Actinobacillus lignieresii after a horse bite. Eur J Clin Microbiol Infect Dis 1994; 13: 439–40. Lemozy J, Simonet M, Vallée E, Escande F. Pasteurellaceae inhabituelles isolées après morsure animale. Abstract VE-72; 4éme Congrés de la Société Française de Microbiologie 1995, Tours, France. Peel MM, Hornidge KA, Luppino M, Stacpoole AM, Weaver RE. Actinobacillus spp and related bacteria in infected wounds of human bitten by horses and sheep. J Clin Microbiol 1991; 29: 2535–38.
Hydroxyurea for treatment of unresectable meningiomas SIR—According to the WHO grading system, most meningiomas are grade I (benign); grade II and III (malignant) account for about 7%.1 Complete surgical removal often fails because of invasive growth. Removal of meningiomas in the cavernous sinus, petrous apex, posterior fossa, and posterior sagittal sinus has a high morbidity and recurrence rate.2 The current treatment strategy aims at decompression, and fractioned radiotherapy in progressive tumours. Although radiotherapy only rarely causes a tumourmass reduction, it can delay regrowth or recurrence for a few years.3,4 We searched for other treatments, including chemotherapy. Hydroxyurea was chosen because it is well tolerated and side-effects are reversible even after years of treatment. Treatment of cultured meningioma cells with hydroxyurea resulted in decreased cell proliferation or blocked tumour-cell growth. DNA flow-cytometry showed 39% arrest of meningioma cells in the S-phase of the cell cycle. Electronmicroscopy of HU-treated meningioma cells showed ultrastructural features consistent with apoptosis. In all HU-treated nude mice meningioma transplants, DNA fragmentation was demonstrated by in-situ DNA-strandbreak labelling in distinct regions with alternate density. Hydroxyurea is a potent inhibitor of cultured human meningioma cells and nude mice meningioma transplants.5 We treated selected patients with hydroxyurea. All had had multiple resections and all except one had radiotherapy. Before hydroxyurea treatment, the tumours had been progressing for 6 to 12 months; none could have been removed completely at operation. Hydroxyurea was given in a daily dose of 1000 mg to 1500 mg day (about 20 mg kg–1 d–1). A 46-year-old man had a large meningioma (transitional; WHO, grade I) of the right sphenoid wing invading the cavernous sinus and the right temporal base. The intracranial mass reduced by 75% over 13 months’ treatment. A 47-year-old woman with a large ball-shaped meningioma (meningotheliomatous—angiomatous; WHO grade I) of the right sphenoid wing invading the cavernous sinus had a 73% decrease of the tumour volume within 10 months of treatment, shown by serial magnetic resonance images (MRI) (figure). The shrinkage of the tumour was
Vol 348 • September 28, 1996