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Reporting of suspect new variant Creutzfeldt-Jakob disease

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									                                                                                                                                   THE LANCET



 Research letters



Reporting of suspect new variant Creutzfeldt-Jakob disease
R G Will, R S G Knight, M Zeidler, G Stewart, J W Ironside, S N Cousens, P G Smith

The number of cases of Creutzfeldt-Jakob disease (CJD),                  reviewing a wide spectrum of clinical presentations in order
including the number of cases of new variant CJD (nvCJD),                to achieve a high degree of case ascertainment and also
is published monthly by the Department of Health. The                    reflects good cooperation with the referral process.
number of referrals of suspect cases to the CJD Surveillance                On current evidence, only a small proportion of referred
Unit is included but the number of referrals of suspect                  cases of suspect CJD aged less than 50 years old are
nvCJD is not listed separately and this has led to                       subsequently classified as nvCJD. Although this proportion
controversy.1 Reporting of numbers of suspect cases of                   may change, for example when necropsy results become
nvCJD might provide an early indication of likely future                 available, the number of referrals of CJD under the age of 50
numbers of actual cases if the clinical features of nvCJD were           years is a poor indicator of eventual numbers of cases of
relatively specific and if a large and consistent proportion of          nvCJD. Furthermore one case of classic CJD has been
cases referred were subsequently confirmed as nvCJD.                     identified from the younger referrals with clinical features
   On March 21, 1996, all neurologists in the UK were                    that were not clearly distinct from nvCJD. No validated
circulated with a description of the clinicopathological                 criteria have yet been established to classify referred cases as
features of nvCJD, based on details published in The Lancet              possible nvCJD and the difficulties of classifying cases in life
on April 6, 1996,2 and asked to refer any suspect cases to the           are underlined by the referred cases with clinical recovery.
CJD Surveillance Unit in Edinburgh. The young age of those                  Accurate reporting of confirmed or probable cases of
with nvCJD at death (currently mean 30 years, range 19–50                nvCJD is essential and will continue, but on current evidence
years) has been a characteristic of nvCJD and since March,               reporting of the numbers of referrals by age is unlikely to be
1996, there has been an increase in the number of referrals of           very informative.
cases of suspect CJD under the age of 50 years. Excluding
                                                                         1   Butler D. CJD variant stirs debate on release of data. Nature 1996;
familial and iatrogenic cases, up to Feb 28, 1997, 37 cases of               383: 658.
suspect CJD aged less than 50 years have been referred since             2   Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-
March, 1996, at a rate of 1–5 per month, with no increase in                 Jakob disease in the UK. Lancet 1996; 347: 921–25.
the rate of referral during this period. Neuropathological
examination is essential for the definite diagnosis of nvCJD.            CJD Surveillance Unit, Western General Hospital, Edinburgh EH4 2XU,
11 of the referred cases have died and necropsy has been                 UK (R G Will); and Department of Epidemiology and Population
                                                                         Sciences, London School of Hygiene and Tropical Medicine, London
done in nine. Of these nine, one has been confirmed as
nvCJD, one classic CJD, and three as other conditions. The
results of necropsy are awaited in four cases. In one patient
who died without necropsy, the diagnosis of nvCJD was
confirmed by brain biopsy and the one patient who died
without necropsy or brain biopsy has been classified as
probable nvCJD on the basis of clinical features and
investigations. The diagnosis of nvCJD has been confirmed                Diffusion-weighted magnetic
by brain biopsy in two patients who are still alive. Four of the
37 referred cases aged less than 50 years have been classified
                                                                         resonance imaging in Creutzfeldt-
as nvCJD and one as probable nvCJD (table).                              Jakob disease
   In the remaining 24 referred cases still alive (excluding the
two confirmed as nvCJD on brain biopsy), the diagnosis is                P Demaerel, A L Baert, L Vanopdenbosch, W Robberecht,
uncertain, although in the great majority nvCJD is very                  R Dom
unlikely because of alternative clinical diagnoses (12), clinical
                                                                         We report the magnetic resonance (MR) imaging findings in
recovery (3), clinical improvement (1), or lack of clinical
                                                                         a 68-year-old woman with histologically proven Creutzfeldt-
progression over several months (2). In two of the cases with
                                                                         Jakob disease (CJD). She developed a progressive dementia,
recovery, the initial clinical presentation was highly
                                                                         ataxia, and myoclonic jerks over 3 weeks. On admission she
suggestive of nvCJD. The diagnosis of nvCJD was confirmed
                                                                         had no spontaneous speech and could understand only
within 3 months of referral in the four neuropathologically
                                                                         simple instructions. Characteristic electroencephalogram
verified cases and 12 of the outstanding cases were referred
                                                                         changes consisting of periodic sharp waves were observed.
more than 4 months ago. The relatively low proportion of
                                                                         Brain MR imaging 4 weeks after onset of symptoms showed
cases diagnosed as nvCJD reflects the importance of
                                                                         subtle signal alterations in the left caudate and lentiform
                                                                         nucleus on T2-weighted imaging. Diffusion-weighted
Deaths      11              Necropsy 9      1 nvCJD                      imaging showed gross abnormalities involving most of the
                                            1 classic CJD                cortex of the left hemisphere (figure) and confirmed the
                                            3 other diagnoses
                                            4 results awaited
                                                                         abnormalities in the basal ganglia. 99mTc single-photon
                            No necropsy 2   1 nvCJD on brain biopsy      emission tomography (SPET) showed diminished perfusion
                                            1 probable nvCJD             in the left parietooccipital lobe and in both frontal lobes.
Alive       26                              2 nvCJD on brain biopsy      Follow-up MR imaging 4 weeks later showed progression of
                                            18 CJD clinically unlikely
                                            6 diagnosis uncertain
                                                                         the abnormalities in the basal ganglia but less conspicuous
                                                                         abnormalities in the cortex. The patient died 9 weeks after
Classification of suspected CJD referrals aged less than 50              onset of symptoms. The necropsy findings confirmed CJD.
years March 21, 1996, to Feb 28, 1997                                      Diffusion-weighted imaging detects tiny changes in water


Vol 349 • March 22, 1997                                                                                                                       847
THE LANCET


                                                                          affected mother (I-2) had a large right tumour removed at
                                                                          age 76 but died from metastatic disease. She had eight
                                                                          children. One son (II-3) had a 7 cm left tumour at age 56.
                                                                          One daughter (II-6) was found to have idiopathic
                                                                          thrombocytosis and was entered into an interferon A trial at
                                                                          the age of 53. A computed tomograph scan of the abdomen
                                                                          revealed a 3 cm diameter tumour in her left kidney. Two
                                                                          other sons, aged 62 (II-1) and 55 (II-5) who were otherwise
                                                                          in good health underwent screening which revealed a solitary
                                                                          renal tumour in both cases. The screenings of three other
                                                                          children were normal. All tumours in the children were
                                                                          confined to the kidney and were excised; all tumours showed
Axial diffusion-weighted MR images of cerebral hemispheres
Note diffuse involvement of cortex of left hemisphere (arrowhead).
                                                                          a non-papillary pattern constituting entirely clear cells.
                                                                             Family FR002 is white and living in France (figure). The
mobility, resulting in ultra-rapid detection of a disturbed               proband (III-3) had a 5 cm right renal tumour removed at
cellular homoeostasis, when cell damage and a shift from                  age 32 and was found to have metastatic disease at age 36.
extracellular to intracellular space occurs. The examination              The father (II-3) had a 6 cm tumour removed at age 54, and
time is of the order of 4 seconds. It is well-known that the              at age 71 renal cysts from the left kidney were removed but
sensitivity of diffusion-weighted imaging to detect ischaemia             no evidence of cancer was found. One of the proband’s aunts
exceeds by far the sensitivity of any other imaging technique.1           (II-4) had a left localised 6 cm tumour excised at age 61. The
Recently the MR imaging appearances of CJD have been                      grandmother (I-2) had a nephrectomy for a 10 cm tumour at
reviewed.2 Abnormalities were seen in the basal ganglia in                age 58 and died from metastatic disease in her 70s. The
79% of the patients, but no abnormalities were seen in the                histopathology of all four tumours of the family showed
remaining 21%. Spongiform degeneration, astrocytic gliosis,               predominantly clear cells with some foci of acidophilic cells.
and neuronal loss are characteristic neuropathological                       All participating living members were screened for other
findings. On routine MR images, these changes are more                    VHL-related tumours with normal findings. Karyotype
difficult to appreciate in the cortex than in the basal ganglia,          analysis in three affected cases from each family did not show
which are surrounded by unaffected white matter. Positron                 any cytogenetic abnormalities. Mutation analysis with direct
emission tomography and 99mTc-SPET have shown metabolic                   sequencing of the VHL gene was carried out2 on all living
and blood flow changes in CJD but sensitivity and specificity             members of both families together with four VHL patients as
of these examinations have not yet been determined.3 Up to                controls. VHL mutations were identified in all four controls
now there have been no comparisons between these                          but not in any of the family members. Linkage analysis with
functional studies and diffusion-weighted imaging.
Advantages of diffusion-weighted imaging are low cost, as it              Family FR001                                   1 2                          3       3
can be implemented on existing MR scanners, better
                                                                                                                         5 1                          2       3
anatomical resolution, absence of radiation exposure, and                                 I                                              1        2
extremely short examination time.                                                                                        2 2                          1       1
   We call for the use of diffusion-weighted imaging in                                                                  1 2                          2       3
suspected cases of CJD which will be followed up to
necropsy so as to build up definitive evidence of the potential                           II       1         2               3           4            5           6               7   8
of this technique to substantiate the diagnosis of CJD.                         D3S1537        3   1    3    1       3       2       3   2   3        1   3       1       3       2

                                                                                D3S1304        2   5    2    5       3       1       2   1   2        5   3       5       3       1
1   Sorensen AG, Buonanno FS, Gonzalez RG, et al. Hyperacute stroke:      VHL
                                                                                D3S1317        1   2    1    2       1       2       1   2   1        2   1       2       1       2
    evaluation with combined diffusion-weighted and hemodynamically
    weighted echo-planar MR imaging. Radiology 1996; 199: 391–401.              D3S1038        2   1    2    1       3       2       2   2   2        1   2       1       3       2
2   Finkenstaedt M, Szudra A, Zeer I, et al. MR imaging of Creutzfeldt-
    Jakob disease. Radiology 1996; 199: 793–98.
3   Grunwald F, Pohl C, Bender H, et al. 18F-fluorodeoxyglucose-PET
    and 99mTc-bicisate SPECT in Creutzfeldt-Jakob disease. Ann Nucl Med
    1996; 10: 131–34.                                                     Family FR002                                   1       2                    1       2

                                                                                                                         1       3                    1       2
Departments of Radiology (P Demaerel) and Neurology, University                           I                                              1        2
Hospitals, B-3000 Leuven, Belgium                                                                                        4       2                    1       3

                                                                                                                         2       2                    2       2


                                                                                          II       1             2               3           7                4               5       6
Familial non-VHL non--papillary
                                                                                               1   2     1       1       1       2       2   2        2       1       1       2
clear-cell renal cancer                                                                        1   2     1       1       1       2       1   2        3       1       1       2
Bin Tean Teh, Sophie Giraud, Nora Fatiha Sari, Su Ing Hii,
                                                                                               4   3     4       1       4       3       3   3        2       1       2       3
Jean Pierre Bergerat, Catharina Larsson, Jean Marc Limacher,
David Nicol                                                                                    2   2     2       2       2       2       1   1        2       2       2       2


Familial renal cancers include von Hippel-Lindau disease                                  III                        1                   2                3

(VHL), familial cancer associated with t(3;8)(p14;q24), and                                    D3S1537       2       2               2   2        2       2
familial papillary renal-cell cancers.1 VHL is characterised by                                D3S1304       2       2               2   1        2       2
haemangioblastoma, non-papillary clear-cell renal cancer,                           VHL
                                                                                               D3S1317       3       3               3   3        3       3
and phaeochromocytoma and its gene in 3p25-p26 was
recently cloned. We described here two families with nine                                      D3S651        2       1               2   1        2       1
cases of non-VHL non-papillary clear-cell renal cancers.                  Pedigrees showing VHL haplotypes
  Family FR001 is white and living in Australia (figure). The             The bracketed haplotypes represent the haplotyping of the children.



848                                                                                                                                              Vol 349 • March 22, 1997
                                                                                                                                               THE LANCET


the markers D3S1537, D3S1304, D3S1317, D3S1038, and                                 3   p=0·009              100       p=0·16           100        p=0·84
D3S651 for VHL and D3S1289, D3S1766, D3S1300,
D3S1312, and D3S1285 for 3p14.2 was carried out.3,4
Combined lod scores of less than 2 were obtained for two                                                          75                          75
flanking markers of VHL (D3S1304 and D3S1317) and                                   2




                                                                                                         Ki67 %
3p14.2 (D3S1766 and D3S1312) excluding linkage to the




                                                                                                                                    Bcl-2 %
                                                                             AI %
VHL gene and the 3p14.2 region. These results are further                                                         50                          50
confirmed by haplotype analysis.
   The disease is transmitted in an autosomal dominant                              1
pattern with no difference in sex ratio. In all except one case,                                                  25                          25
the affected members were over 50 years of age at diagnosis,
which is relatively later than VHL. All cases had unilateral
                                                                                    0                 0                     0
solitary tumours in contrast with other familial renal cancers                      Pre Post              Pre Post               Pre Post
which are commonly bilateral and multifocal. Smoking can                     Changes in AI, Ki67 score, and Bcl-2 expression before (pre)
not account for the disease in these families, since three                   and 24 h after (post) chemotherapy
affected cases are non-smokers and none of them are known                    Wilcoxon signed-rank test; p=0·009.
to have been exposed to any carcinogenic hazards.
We thank Bert Zbar.
                                                                             scored blind to patient data. The percentage of positively
                                                                             stained tumour cells to total number of tumour cells was
1   Berton Zbar. Genetic techniques in the diagnosis of carcinomas of the    determined by counting 3000 cells in ten high-power fields
    kidney. Semim Nephrol 1995; 15: 50–56.                                   spread randomly through the section.
2   Crossey PA, Richards FM, Foster K, et al. Identification of intragenic      Ten patients (59%) showed more than 50% increase in AI
    mutations in the Von Hippel-Lindau disease tumour suppressor gene
    and correlation with disease phenotype. Hum Mol Genet 1994; 3:           24 h following chemotherapy, five showed less than 50%
    1303–08.                                                                 change and were considered unchanged, and two decreased by
3   Olschwang S, Boisson C, Richard S, Resche F, Thomas G. DNA-              more than 50%. Median AIs before and after treatment were
    based presymptomatic diagnosis for the von Hippel-Lindau disease by      0·47% (range 0·07–2·3%) and 1·02% (0·11–2·91%),
    linkage analysis. Eur J Hum Genet 1995; 3: 108–15.
                                                                             respectively. Overall there was a significant increase in
4   Druck T, Kastury K, Hadaczek P, et al. Loss of heterozygosity at the
    familial RCC t(3;8) locus in most clear cell renal carcinomas.           apoptosis in the 24-h biopsy samples (p=0·009) (figure).
    Cancer Res 1995; 55: 5348–53.                                            Median Ki67 scores before and after treatment were 19·2%
                                                                             (1·1–83%) and 15·75% (1·1–87·7%), respectively, with no
Department of Urology, Princess Alexandra Hospital, Brisbane 4102,           significant difference between the two groups (p=0·16). There
Australia (D Nicol); Department of Molecular Medicine, Karolinska            was no significant change in Bcl-2 (median Bcl-2 before
Hospital, Stockholm, Sweden; Department of Genetics, Edouard Herriot
Hospital, Lyon, France; and Service D’Oncologie Les Hopitaux                 treatment 60%; median Bcl-2 after treatment 72%) (p=0·84).
Universitaires de Strasbourg, 67091 Strasbourg, France                       17 patients were assessable for clinical response. Nine of 13
                                                                             clinical responders (69%) showed a greater than 50% increase
                                                                             in AI, whereas three of four non-responders (75%) showed no
Preoperative chemotherapy induces                                            significant change in AI (p=0·22).
                                                                                To our knowledge this is the first clinical demonstration of
apoptosis in early breast cancer                                             chemotherapy-induced apoptosis in human solid tumours. It
                                                                             confirms in-vitro and animal work on the early induction of
P A Ellis, I E Smith, K McCarthy, S Detre, J Salter, M Dowsett
                                                                             apoptosis after treatment.5 Although preliminary, these results
Laboratory studies have shown that many anti-cancer agents                   are potentially important in translating proven laboratory data
with differing modes of action achieve their cytotoxic effect by             into clinically relevant findings that may influence therapy.
inducing apoptosis.1 So far there have been no corresponding                 The data relating change in apoptosis and clinical response
studies in patients with solid tumours. The use of primary                   require larger numbers and further follow-up to draw firm
(preoperative) chemotherapy in operable breast cancer2 offers                conclusions. However, if the trend suggesting an intact
the opportunity to test the clinical relevance of these                      apoptotic response after treatment is associated with clinical
observations, with the tumour remaining in situ throughout                   response is confirmed, then it may be possible to predict
treatment as an in-vivo measure of response. Here we present                 patients’ subsequent clinical outcome shortly after starting
a study designed to determine whether preoperative                           therapy and to modify treatment accordingly.
chemotherapy induces apoptosis in human breast cancer.                         We thank Michael Baum, Academic Department of Surgery, Royal
                                                                             Marsden Hospital, and Steve Ebbs, Department of Surgery, Mayday
   27 patients with operable breast cancer (>3 cm) entered
                                                                             University Hospital, for their collaboration and support.
into a randomised trial of preoperative chemotherapy
(comparing six cycles of epirubicin, cisplatin, and fluorouracil
with six cycles of doxorubicin and cyclophosphamide)                         1      Hickman JA. Apoptosis induced by anticancer drugs. Cancer Metastasis
consented to be part of this study. Sequential Tru-cut biopsies                     Rev 1992; 11: 121–39.
                                                                             2      Smith IE, Walsh G, Prendiville J, et al. High complete remissions with
were done 7 days before chemotherapy and again                                      primary infusional chemotherapy for large early breast cancer. J Clin
24 h after commencing treatment, and immediately fixed in                           Oncol 1995; 13: 424–29.
formalin and paraffin-embedded. Tumour size was assessed                     3      Wijsman JH, Jonker R, Keijzer R, Van De Velde CJH, Cornelisse CJ,
bi-dimensionally and clinical response determined (according                        Van Dierendonck JH. A new method to detect apoptosis in paraffin
to standard UICC criteria) before each cycle. 19 patients had                       sections: in situ end-labelling of fragmented DNA. J Histochem Cytochem
                                                                                    1993; 41: 7–12.
sufficient tissue available in both specimens to accurately                  4      Hsu SM, Raine L, Fanger H. Use of the avidin-biotin-peroxidase
assess apoptotic index (AI), proliferation (Ki67 nuclear                            complex (ABC) and unlabelled antibody (PAP) procedure. J Histochem
antigen), and Bcl-2 protein expression. AI was determined                           Cytochem 1981; 29: 577–80.
with the in-situ end-labelling assay.3 Ki67 (MIB-1 monoclonal                5      Meyn RE, Stephens LC, Hunter NR, Milas L. Induction of apoptosis in
antibody, DAKO) and Bcl-2 (BCL-124 antibody, DAKO)                                  murine tumours by cyclophosphamide. Cancer Res 1994; 33: 410–14.
were assessed with standard immunohistochemical assays
                                                                             Departments of Medicine (P A Ellis), Academic Biochemistry, and
using antigen retrieval by microwave treatment and detection                 Pathology, and The Breast Unit, Royal Marsden Hospital,
with the Avidin-Biotin-Complex method.4 Sections were                        London SW3 6JJ, UK



Vol 349 • March 22, 1997                                                                                                                                    849
THE LANCET


2·5 year remission of AIDS-                                         of aphasia and right arm weakness was not due to PML, but
                                                                    to an unusual manifestation of HIV. In previously reported
associated progressive multifocal                                   cases, either the original symptoms were less severe or the
                                                                    resolution of neurological deficits was not as complete. Our
leukoencephalopathy with                                            patient has survived beyond the mean (over 2 years from the
                                                                    onset of symptoms) and has regained over 95% of his original
combined antiretroviral therapy                                     function. This remission has been associated with
Bethany Elliot, Ireene Aromin, Richard Gold, Timothy Flanigan,      improvement in immune function, evident by the rise in
Maria Mileno                                                        CD4 count. As more effective antiretroviral regimens
                                                                    become available, there may be more frequent remissions in
Progressive multifocal leukoencephalopathy (PML) results            persons with PML.
from infection of the central nervous system with JC virus, a
papovavirus, which causes demyelination in the white matter         1   Walker DL. Progressive multifocal leukoencephalopathy.
of the brain.1 Long-term survival in AIDS patients with PML             In: Vinken PJ, Bruyn GW, Klawans HL, eds. Demyelinating diseases.
is rare.2,3 There is no consistently effective treatment although       Handbook of clinical neurology. Vol 47. Amsterdam: Elsevier Science,
cytarabine, interferon, and zidovudine (AZT) may                        1985: 503–24.
occasionally result in regression.4,5 We report remission of        2   Berger JR, Mucke L. Prolonged survival and partial recovery in AIDS-
                                                                        associated progressive multifocal leukoencephalopathy. Neurology
PML-associated hemiparesis for 104 weeks during                         1988; 38: 1060–65.
combination antiretroviral therapy including a protease             3   Lortholary O, Pialoux G, Dupont B, et al. Prolonged survival of a
inhibitor.                                                              patient with AIDS and progressive multifocal leukoencephalopathy.
   A 35-year-old man and previous intravenous drug user,                Clin Infect Dis 1994; 18: 826–27.
was admitted due to worsening neurological symptoms,                4   Steiger MJ, Tarnesby G, Gabe S, Mclaughlin J, Schapira AH.
                                                                        Successful outcome of progressive multifocal leukoencephalopathy
including dysarthria, aphasia, a right-sided facial droop, right        with cytarabine and interferon. Ann Neurol 1993; 33: 407–10.
arm weakness, and a walk that listed to the right. A T2-            5   Singer EJ, Stoner GL, Singer P, et al. AIDS presenting as progressive
weighted MRI scan showed confluent high signal intensity in             multifocal leukoencephalopathy with clinical response to zidovudine.
the left centrum semiovale, left corona radiata with extension          Acta Neurol Scand 1994; 90: 443–47.
into the left internal capsule, left cerebral peduncle, and the
                                                                    Immunology Center (M Mileno) and Radiology Department,
pontine cortical spinal tracts (left figure). There was faint       Miriam Hospital, Brown University, Providence, RI 02906, USA
enhancement without mass effect. The MRI findings were
characteristic of those observed with PML. No brain biopsy
was done. Laboratory studies (ELISA and western blot)
established the diagnosis of HIV infection. The CD4 count           Natural conception in HIV-negative
was 30 cells/µL and his HIV viral load was 189 900                  women with HIV-infected partners
copies/mL. He began zidovudine 200 mg three times daily and
didanosine 200 mg twice daily as part of a controlled trial.        L Mandelbrot, I Heard, E Henrion-Géant, R Henrion
   Over the next 2–4 weeks the patient’s ability to convey
thoughts quickly and to speak clearly improved. By the 10th         An increasing number of couples in which the man is HIV
week of antiretroviral therapy, he began an exercise regimen        positive and the woman HIV negative want children.
which included weight-lifting and aerobic activity and, by          Insemination with sperm from seronegative donors is the
week 12, he was able to return to work as a fisherman. At           only safe option, yet most couples wish to have a child who is
week 24, indinavir, a protease inhibitor, was added (600 mg         biologically theirs. We report a 10-year experience of
every 6 hours) to the anti-HIV regimen. By week 44, the             pregnancies following natural conception.
                                                                       Between 1986 and 1996, we followed 104 consecutive
CD4 count had increased to 230 cells/µL and the viral load
                                                                    pregnancies in 92 HIV-negative women with HIV-positive
was 240 copies/mL. A repeat MRI scan, 16 months after the
                                                                    partners. All were singleton pregnancies, conceived without
first, demonstrated improvement in the extent of the T2
                                                                    the use of assisted reproduction techniques. Most couples
abnormalities (right figure).
                                                                    had received non-directive pre-conceptual counselling on the
   In none of the reported cases of long-term survival of
                                                                    risks of heterosexual HIV transmission. Most of the men
patients treated with zidovudine or cytarabine was the
                                                                    were symptom-free, 14 (13%) had HIV-related symptoms,
remission as complete as the one cited here, although, since a
                                                                    and one died of AIDS during the pregnancy. CD4 counts
biopsy was not done, it is possible that the initial presentation
                                                                    were available for 60 men; the mean was 548/ L (range
                                                                    7–1273), and 3 were below 200/ L. 21 men were receiving
                                                                    antiretroviral therapy at the time of conception. Genital
                                                                    infections were diagnosed and treated, a basic fertility work-
                                                                    up was offered where appropriate, and couples were advised
                                                                    to pinpoint ovulation in order to reduce possible exposure.
                                                                    One-third reported inconsistent or no condom use; in 68
                                                                    pregnancies conception resulted from unprotected
                                                                    intercourse during ovulation, only after one episode of
                                                                    intercourse in 17 of these cases. After conception, couples
                                                                    were advised to use condoms, and women were tested
                                                                    monthly for HIV antibodies and p24 antigen. Follow-up was
                                                                    3 months in all cases and more than 6 months in 95 cases.
                                                                    There were 92 deliveries, four abortions, six miscarriages,
                                                                    and two lost to follow-up in the second trimester. No
                                                                    seronconversions occurred within the first 3 months
                                                                    following conception. Seroconversion was observed in two
MRI scans with PML lesions at diagnosis (left) and 16 months        women at 7 months of pregnancy and in two others post-
later, on combined antiretroviral therapy (right) with atrophy      partum; all such cases arose in couples reporting inconsistent
shown by the increased size of left central sulcus (arrow)          condom use.


850                                                                                                                Vol 349 • March 22, 1997
                                                                                                                                    THE LANCET


   Our experience suggests that male-to-female transmission                                100
of HIV is infrequent during natural conception.
Seroconversion occurring up to 3 months post-conception
                                                                                            80
may be attributed to exposure up to the time of conception;
no cases were observed. Counselling may help to reduce the




                                                                            % protection
risk of transmission, but this cannot be established from the                               60
number of couples followed in this study. It has been shown                                                                            p<0·005
that there is a poor relationship between the number of acts
                                                                                            40
of intercourse and the probability of transmission,1 indicating
a great heterogeneity in infectivity. Our data may be biased                                                                           p<0·025
being based on voluntary follow-up, and not a protocol.                                     20       Paraoxonase AA (n=9)
Some couples who did not return may have attempted to                                                AB (n=13)
conceive unsuccessfully, and may not have reported                                                   BB (n=6)
                                                                                             0
seroconversions. Our findings are compatible with
seroconversion rates in the order of 1 per 1000 episodes of                                      1       2                  4                 6
unprotected intercourse reported in longitudinal studies of
stable heterosexual couples,2 as well as in studies of                                                             Time (h)
transmission through artificial insemination.3 Some authors
advocate intrauterine insemination with semen from the                      Protection of LDL against the accumulation of lipid-peroxides
HIV-infected man,4 but the risk of this must be measured                    by HDL containing different paraoxonase alloenzymes
against the low background risk of natural conception.                      LDL and autologous HDL prepared by ultracentrifugation were
Stringent standards of safety must be required before                       co-incubated at 37°C in the presence of 5 µmol/L Cu2+. Lipid peroxides
                                                                            on LDL were analysed as described.2,5 Under the ultracentrifugal
inseminating potentially infective semen.5 Longitudinal                     conditions employed to isolate HDL, 70–80% of serum paraoxonase
virological studies are needed to evaluate whether                          remained associated with the HDL fraction and no differences between
interventions, including semen preparation, or antiretroviral               the recovery of A and B alloenzymes in HDL were seen. Points are
therapies, can effectively clear cell-associated and cell-free              median values. % Protection is defined as the amount of lipid-peroxides
                                                                            present in LDL incubated in the presence of HDL subtracted from the
virus from semen, thereby offering real hope for risk-free                  amount of lipid-peroxide in LDL incubated in the absence of HDL
reproduction in “sero-different” couples.                                   multiplied by 100.

1   Downs AM, de Vincenzi I. European study group on heterosexual
    transmission of HIV. Probability of heterosexual transmission of HIV:   192, which defines its activity towards paraoxon which is
    relationship to the number of unprotected sexual contacts.              hydrolysed at a higher rate by the B-alloenzyme than the A-
    J Acquir Immune Defic Syndr Human Retrovirol 1996; 11: 388–95.          alloenzyme.3 However, the alloenzymes have similar activity
2   de Vincenzi I. European study group on heterosexual transmission of
    HIV. A longitudinal study of human immunodeficiency virus
                                                                            towards other substrates, such as phenylacetate; and other
    transmission by heterosexual partners. N Engl J Med 1994; 331:          substrates, such as diazoxon, are hydrolysed faster by the A-
    341–46.                                                                 alloenzyme.4 We considered the possibility that recent
3   Chiasson MA, Stoneburner RL, Joseph SC. Human                           epidemiological evidence suggesting the paraoxonase 192 B-
    immunodeficiency virus transmission through artificial insemination.    allele to be an independent risk factor for coronary heart
    J Acquir Immun Defic Syndr Hum Retrovirol 1990; 3: 69–72.
4   Semprini AE, Levi-Setti P, Bozzo M, et al. Insemination of HIV-
                                                                            disease (reviewed in 3) might be due to a difference in the
    negative women with processed semen of HIV-positive partners. Lancet    ability of the two alloenzymes to prevent the accumulation of
    1992; 340: 1317–19.                                                     lipid-peroxides on LDL.
5   Mostad SB, Kreiss JK. Shedding of HIV-1 in the genital tract. AIDS         HDL was isolated from the plasma of 28 normolipidaemic
    1996; 10: 1305–15.                                                      people; nine were homozygous for the A alloenzyme (Glu at
                                                                            192), 13 were heterozygotes, and six were homozygous for
Service de Gynécologie-Obstétrique I, Hûpital Cochin-Port Royal,
75014 Paris, France (L Mandelbrot)                                          the B alloenzyme (Arg at 192). The HDL from all three
                                                                            groups lost its ability to protect LDL from Cu2+-induced
                                                                            oxidative modification as the duration of their co-incubation
                                                                            progressed (figure). Although the protection against LDL
                                                                            lipid-peroxidation by paraoxonase-BB HDL was higher in
                                                                            the first 2 h of incubation, after 6 h, paraoxonase AA HDL
Alloenzymes of paraoxonase and                                              retained median 40·0 (95% CI 11·0–58·6)% of its
effectiveness of high-density                                               original ability to protect LDL and paraoxonase-AB HDL
                                                                            23·0 (14·8–49·8)%. However, the paraoxonase-BB HDL
lipoproteins in protecting low-                                             retained only 0·75 ( 3·8 to 14·5)% of its ability to protect
                                                                            LDL (significantly different from paraoxonase AA HDL,
density lipoprotein against lipid                                           p=0·0033, and from paraoxonase-AB HDL, p=0·025). The
                                                                            loss of protection by HDL containing the paraoxonase-B
peroxidation                                                                alloenzyme was greater at 4 and 6 hours being 43·2%
Michael I Mackness, Sharon Arrol, Bharti Mackness,                          (16·9–71·0) and 40·0% (11–58·6) respectively for
Paul N Durrington                                                           paraoxonase AA HDL and 31·0% (22·2–42·8) and 9·0%
                                                                            (10·7–36·9) respectively for paraoxonase AB+BB HDL
The peroxidation of low-density lipoprotein (LDL) lipids is                 (p<0·005).
central to atherogenesis.1 In-vitro high-density lipoprotein                   Large variations in the ability of HDL from different
(HDL) can protect LDL against the accumulation of lipid                     individuals to protect LDL against oxidative modification
peroxides under oxidising conditions. Serum paraoxonase,                    have been reported.5 Paraoxonase may act in tandem with
previously known for its ability to detoxify organophosphorus               another HDL-associated enzyme, PAF-acetylhydrolase, to
nerve gases and insecticides, is associated with HDL. It was                prevent LDL lipid-peroxidation.3 However, PAF-
first shown by us to protect LDL against oxidative                          acetylhydrolase activity was not found to vary between HDL
modification in vitro.2 Paraoxonase has a genetic                           preparations from different individuals.
polymorphism due to an aminoacid substitution at position                      Our results indicate that under the experimental


Vol 349 • March 22, 1997                                                                                                                       851
THE LANCET


conditions employed the paraoxonase alloenzymes were the                                                      15   APSA-ARE-CAT
major determinant of individual variation in the ability of                                                        wild type AR
HDL to protect LDL against oxidative modification. Our
observations may also explain recent epidemiological studies
that report an association between paraoxonase B genotype
and coronary heart disease, because it is this alloenzyme
                                                                                                              10
which confers least ability to HDL to prevent accumulation
of lipid peroxides on LDL.
  This work was supported by grants from the Medical Research Council,
UK, and the British Heart Foundation.

                                                                                                               5
1   Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.
    Beyond cholesterol modifications of low-density lipoprotein that
    increase its atherogenicity. New Engl J Med 1989; 320: 915–24.
2   Mackness MI, Arrol S, Abbott CA, Durrington PN. Protection of low-
    density lipoprotein against oxidative modification by high-density
    lipoprotein associated paraoxonase. Atherosclerosis 1993; 104: 129–35.
3   Mackness MI, Mackness B, Durrington PN, Connelly PW,                                                       0
    Hegele RA. Paraoxonase: biochemistry, genetics and relationship to                                        15
    plasma lipoproteins. Curr Opin Lipidol 1996; 7: 69–76.
                                                                                                                   BMMTV-ARE-CAT
4   Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J,
                                                                                                                   wild type AR
    Furlong CE. The effect of the human serum paraoxonase
    polymorphism is reversed with diazoxon, soman and sarin. Nat Genet



                                                                               Relative CAT activity (fold)
    1996; 14: 334–36.
5   Mackness MI, Abbott CA, Arrol S, Durrington PN. The role of high
    density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting                                  10
    low-density lipoprotein oxidation. Biochem J 1993; 294: 829–35.

University Department of Medicine, Manchester Royal Infirmary,
Manchester M3 9WL, UK (M I Mackness)

                                                                                                               5


Hydroxyflutamide may not always be
a pure antiandrogen
Shuyuan Yeh, Hiroshi Miyamoto, Chawnshang Chang                                                                0
                                                                                                              15   CMMTV-ARE-CAT
Prostate cancer has become the most commonly diagnosed                                                             mutant AR877
cancer in US men.1 Today most prostate cancers from patients
treated with androgen ablation progress from an androgen-
dependent to an androgen-independent state. With the
cloning of the androgen receptor cDNA2 and the discovery                                                      10
that some mutant androgen receptors may be able to change
steroid and antiandrogen specificity,3 the hypothesis that
mutations in androgen receptors may be the reason why
hydroxyflutamide, the active metabolite of flutamide, can
activate androgen receptor target genes and stimulate (rather
than inhibit) prostate cancer growth, is becoming widely                                                       5
accepted. The same mechanism has been used to explain the
flutamide withdrawal syndrome, in which patients who
experience an increase in prostate-specific antigen (PSA) while
taking flutamide, have a decrease in PSA after withdrawal of
treatment. Since this syndrome often heralds the failure of                                                    0
                                                                                                                     1   2    3 4         5 6     7    8
androgen-ablative therapy, elucidating the mechanism by
                                                                                                                              Hydroxyflutamide
which hydroxyflutamide increases the expression of PSA may
provide a new approach to delaying or reversing the emergence                                                        0 10-7 10-6 10-5    0 10-7 10-6 10-5
of androgen independence.
   The discovery of ARA70, the first co-activator for androgen                                                           -ARA70             +ARA70
receptor, and the observation that higher concentrations of
hydroxyflutamide may have weak agonistic activity in the                       ARA70 and androgenic activity of hydroxyflutamide
                                                                               A and B: 1·5 µg wild-type hAR alone (columns 1, 2, 3, and 4) and co-
presence of ARA70,4 has allowed us to investigate this                         transfected with 4·5 µg ARA70 (5, 6, 7, and 8) in the absence or
phenomenon further. We present evidence that                                   presence of 10–7, 10–6, 10–5 mol/L of hydroxyflutamide. C the mutant
hydroxyflutamide can activate androgen receptor target genes,                  AR877 was used to replace the wild-type AR to perform the same
such as PSA and MMTV-LTR, in the presence of ARA70.                            experiment on panel B. All experiments were performed in human
                                                                               prostate cancer DU145 cells cultured in DMEM with 5% charcoal-
While AR877 mutation may increase potency of                                   stripped fetal calf serum. In each transfection, 3·5 µg of PSA-ARE CAT
hydroxyflutamide (figure, B, 7; C, 7), a mutated androgen                      (A) or MMTV-ARE CAT (B and C) were used as a reporter. The mock
receptor alone has only a small capacity to mediate                            treatment of lane 1 was counted as standard one-fold. Relative CAT
hydroxyflutamide induction of PSA in DU145 cells (figure, C,                   activity was calculated by the quantitation of phosphorimager. Data
                                                                               represent an average of at least three experiments.
1–4). Our data suggest that in the absence of androgens, a
condition similar to some of the later stages of prostate cancer               may become an agonist by inducing PSA in the presence of
under maximal androgen ablative therapy, hydroxyflutamide                      ARA70 and normal/mutant androgen receptor. This suggests


852                                                                                                                                        Vol 349 • March 22, 1997
                                                                                                                                          THE LANCET


that in addition to the androgen receptor, another factor,                    for a minor urological procedure. While awaiting surgery, the
ARA70, may be required to enhance the agonistic activity of                   decision was made to administer her scheduled gold therapy.
hydroxyflutamide.                                                             The patient related during the admission history that she had
   These findings may raise some concerns about treatment of                  experienced a reaction to gold, but did not elaborate on its
prostate cancer with supposedly pure antiandrogens in                         severity or relation to a particular gold preparation. As
maximal androgen ablative therapy.5 Finding molecules that                    aurothioglucose was not on the hospital formulary, sodium
interfere with the interaction between the androgen receptor                  aurothiomalate was substituted by the pharmacy. 30 min after
and ARA70 may be valuable in delaying the emergence of                        administration, she became confused, diaphoretic, and pallid,
androgen resistance.                                                          with a blood pressure of 60/40 mm Hg. Shortly thereafter she
                                                                              became unconsciousness and developed respiratory
1   Boring CC, Squires TS, Tong T. Cancer statistics, 1992.                   insufficiency. Computed axial tomographic imaging of the
    CA-Cancer J Clin 1992; 42: 19–38.                                         brain demonstrated ischaemic changes. She never regained
2   Chang CS, Kokontis J, Liao ST. Molecular cloning of human and rat         consciousness, and subsequently died.
    complementary DNA encoding androgen receptors. Science 1988; 240:            Vasomotor symptoms have been reported as
    324–26.
3   Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-
                                                                              experienced by 5–10% of patients receiving thiomalate.3 They
    receptor gene in metastatic androgen-independent prostate cancer.         may appear at any point in therapy, but may be more common
    N Engl J Med 1995; 332: 1393–98.                                          when ACE inhibitors are concurrently administered.4 Reports
4   Yeh S, Chang C. Cloning and characterization of a specific coactivator,   of acute hypoxic neurological injury attendant to such an
    ARA70, for the androgen receptor in human prostate cells. Proc Natl       episode are rare.5 On the other hand, cerebral ischaemia may
    Acad Sci USA 1996; 93: 5517–21.
5   Chang A, Yeap B, Davis T, et al. Double-blind, randomized study of
                                                                              occur after even a brief episode of relative hypotension, in an
    primary hormonal treatment of stage D2 prostate carcinoma—flutamide       elderly individual, with long-standing hypertension and
    versus diethylstilbestrol. J Clin Oncol 1996; 14: 2250–57.                cerebrovascular disease. We suggest that elderly individuals,
                                                                              especially those in whom sensitivity to sodium aurothiomalate
UWCCC and Department of Medicine, University of Wisconsin-Madison,            has been demonstrated, or those on ACE inhibitor therapy,
Madison, Wisconsin 53792, USA (C Chang)
                                                                              would be better served by aurothioglucose, or auranofin, an
                                                                              orally effective gold preparation. Parenteral gold preparations
                                                                              differ in their suspensory vehicles and bioavailability, and
Adverse reactions to parenteral gold                                          should not be considered generic equivalents.
salts                                                                         1   Gumpel JM. Deaths associated with gold treatment: a reassessment.
                                                                                  BMJ 1978; 1: 215–16.
John A Tilelli, Michael M Heinrichs
                                                                              2   Tozman EC, Gottlieb NL. Adverse reactions with oral and parenteral
                                                                                  gold preparations. Med Toxicol 1987; 2: 177–89.
Gold salts continue to serve an important role in the therapy of              3   Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and
rheumatoid arthritis. Despite their characterisation as highly                    toxicity of second-line drugs in rheumatoid arthritis. Arthritis Rheum
dangerous, life-threatening reactions are unusual.1 Parenteral                    1990; 33: 1449–61.
gold preparations are available as sodium aurothiomalate and                  4   Healy LA, Backes MB. Nitritoid reactions and angiotensin-converting
                                                                                  enzyme inhibitors. N Engl J Med 1989; 321: 763.
aurothioglucose. The former, which is prepared in aqueous
                                                                              5   Hill C, Pile K, Henderson D, Kirkham B. Neurological side effects in
solution is occasionally associated with hypotensive episodes                     two patients receiving gold injections for rheumatoid arthritis. Br J
after administration, whereas the latter, suspended in sesame                     Rheumatol 1995; 34: 989–90.
oil, is not. These, so-called “nitritoid” reactions have been
described as frightening but transient2 and have been                         Orlando Regional Healthcare System, Orlando, Florida, USA (J A Tilelli)
attributed to the more rapid absorption of the aqueous
preparation. Severe acute reactions, including myocardial
infarction and angina, have been reported after sodium                        Implantation of an arrhythmia
aurothiomalate injection.1 We report cerebral ischaemia and
death following a nitritoid reaction.                                         management system for
   A 71-year-old woman undergoing therapy for rheumatoid
arthritis was initiated on gold salts, having had a poor response
                                                                              ventricular and supraventricular
to non-steroidal agents and sulphasalazine. At the time that                  tachyarrhythmias
gold therapy was initiated, her therapeutic regimen consisted
of prednisone, 10 mg orally once daily. Sodium                                Werner Jung, Berndt Lüderitz
aurothiomalate was administered, 25 mg intramuscularly,                       A 61-year-old woman with coronary artery disease was
once a week, and increased 2 weeks later to 50 mg weekly.                     admitted to the Department of Cardiology at the University
Other medical problems included hypertension, which was                       Hospital of Bonn for evaluation of multiple shocks delivered
being treated with the angiotensin-converting enzyme (ACE)                    by her implantable cardioverter-defibrillator (ICD), which she
inhibitor, captopril, and cerebrovascular disease. She had                    had had since 1991 because of drug-resistant ventricular
experienced a cerebrovascular accident, leaving her with a                    tachyarrhythmias. Despite concomitant antiarrhythmic
facial palsy and unilateral weakness. Her response to gold was                drugs she had experienced several appropriate as well as
satisfactory, and therapy was continued for a period of 31                    inappropriate ICD shocks caused by ventricular and
weeks. Moments after her routine gold injection, and without                  supraventricular tachycardias including atrial fibrillation and
apparent change in any clinical condition, she experienced                    flutter, respectively. Electrocardiograms stored by the ICD
nausea, vomiting, diaphoresis, and a feeling of impending                     revealed that she had had 30 inappropriate shocks triggered by
doom. Her blood pressure at the time was 85/50 mm Hg. She                     supraventricular tachycardias within the past 3 days. Resolving
was treated with diphenhydramine and epinephrine with                         the problem would require a device that would not only
prompt clinical response and was discharged.                                  discriminate between ventricular and supraventricular
   2 weeks later, gold therapy was resumed in the form of                     tachycardias, but that would also be able to terminate these
aurothioglucose 50 mg intramuscularly, which was well                         arrhythmias.
tolerated, without hypotension or other side-effects. After 14                   On Jan 10, 1997, she received a multiprogrammable dual-
weeks of further therapy, the patient was admitted to hospital                chamber implantable defibrillator (model 7250, Arrhythmia


Vol 349 • March 22, 1997                                                                                                                             853
THE LANCET


Management Device, AMD, Medtronic Inc, Minneapolis,
MN, USA) which had not been used before. The device, with
a weight of 93 g and a volume of 55 mL, was implanted in the
left pectoral region and connected with transvenous
defibrillation leads placed in the apex of the right ventricle and
in the appendage of the right atrium. This defibrillator offers a
tiered-therapy approach to patients with supraventricular and
ventricular tachycardias. It combines atrial and ventricular
detection and treatment modalities in a single unit and
provides a new algorithm (atrial rate stabilisation) for
prevention of atrial arrhythmias. A dual-chamber detection
algorithm is used to improve discrimination of ventricular
tachycardia from supraventricular tachycardia by applying
pattern-recognition methods based on different P wave
positions within RR sequences. The detection algorithm can
be used to withhold inappropriate ventricular therapies for
atrial tachycardias, atrial fibrillation, sinus tachycardia, 1:1
supraventricular tachycardias, or any combination of these.
The first day after implantation of the new defibrillator, three
sustained episodes of atrial fibrillation occurred which were all
successfully treated by high-frequency burst pacing, a new
option, which allows painless termination of recent onset atrial
tachycardias. None of these arrhythmias were inappropriately
detected or treated as ventricular episodes.
   Single-chamber ventricular defibrillator implantation has
been shown to be an effective and safe treatment for patients
with malignant ventricular tachyarrhythmias and to                              There is good callus formation at the fracture site
significantly reduce the incidence of sudden cardiac death.1
However, the high incidence of inappropriate ICD therapy
due to supraventricular tachycardias is a major challenge and                   Radiographs of her left tibia and fibula showed a faint but
has been reported to affect up to 25% of patients.2 Recently, a                 definite periosteal reaction at the proximal tibial
stand-alone implantable atrial defibrillator has entered clinical               metaphysis. Re-examination showed no tenderness at this
evaluation in patients suffering exclusively from drug-                         site. An isotope bone scan on July 4 showed “intense
refractory atrial fibrillation.3                                                increased uptake in the proximal third of the left tibia”
   Our report suggests that dual-chamber arrhythmia                             which, taken with the periosteal reaction, is typical of a
management systems may be an improvement in the                                 stress fracture. By Aug 21, there was mature callus
management of patients with both supraventricular and                           formation at the fracture site (figure). By Oct 24 she had
ventricular tachyarrhythmias.                                                   no localised tenderness, but was still limping at times
                                                                                although extremely active; repeat radiographs showed
1   Winkle RA, Mead RH, Ruder MA, et al. Long-term outcome with the             remodelling of the previous stress fracture; quite
    automatic implantable cardioverter-defibrillator. J Am Coll Cardiol 1989;   unexpectedly there was a new healing fracture of the
    13: 1353–61.                                                                proximal third of the left fibula surrounded by callus.
2   Hook BG, Marchlinksi FE. Value of ventricular electrogram in the
    diagnosis of arrhythmias precipitating electrical device therapy.
                                                                                   Stress fractures in children are uncommon especially
    J Am Coll Cardiol 1991; 17: 985–90.                                         under 5 years;1 fractures of the tibia are commonest, the
3   Jung W, Kirchoff PG, Lau CP, Tse HF, Lüderitz B, for the Metrix             usual site being the proximal followed by the distal shaft, 2
    System Clinical Investigational Group. Therapy delivery with the            followed by the fibula. Hitchens and Lyons 3 noted a fatigue
    METRIX automatic atrial defibrillation sytem: threshold stability and       fracture of the medial malleolus in a 9-year-old female
    shock safety. J Am Coll Cardiol 1997; 29 (suppl A): 78A (abstr).
                                                                                roller skater. Sheehan et al4 reported bilateral fibular stress
Department of Medicine-Cardiology, University of Bonn,                          fractures in a 10-month-old girl due to use of an infant
53105 Bonn, Germany (W Jung)                                                    walker; it was thought that repeated sub-acute trauma due
                                                                                to banging her walker into the kitchen cabinets, with
                                                                                consequent transfer of energy to the crossbar and thence to
                                                                                each fibula, was the mechanism. The common factor
                                                                                appears to be continued sudden violent repetitive activity.
Stress fractures in a hyperactive                                               No such predisposing factors could be found in this
3-year-old girl                                                                 patient, apart from her unusual activity.
                                                                                  We thank the staff of the Radiography Department, St Mary’s
E S Mucklow, G Evans                                                            Hospital, for the radiographs and Sandra Chaplow, for typing this
                                                                                manuscript. We are grateful to Robert Wardle, for locating references.
A 3-year-old girl was admitted to hospital on June 28,
1996, after a week’s pain in the left leg and a limp. She was                   1   Devas MB. Stress fractures in children. J Bone Jt Surg 1963; 45:
not feverish. There was no history of trauma nor of family                          528-41.
                                                                                2   Kozlowski K, Azouz M, Barrett IR, Hoff D, Scougall JS. Midshaft
history of joint disease or bleeding disorder. She was
                                                                                    tibial stress fractures in children: report of 4 cases. Austr Radiology
unusually active, being on the move all the time.                                   1992; 36: 131–34.
Examination was inconclusive as she was uncooperative,                          3   Hitchens PR, Lyons WJ. Fatigue fracture of the medial malleolus in
but she had no restriction of joint movements, although it                          a junior roller skater. Austr Nz J Surg 1996; 66: 265–66.
was clear that her left leg was giving way when she walked.                     4   Sheehan KM, Gordon S, Tanz RR. Bilateral fibula fractures from
                                                                                    infant walker use. Ped Emerg Care 1995; 11: 27–29.
Her limp became steadily worse over the next week.
  Investigations showed a normal white blood count and                          Departments of Paediatrics (E S Mucklow) and Orthopaedics,
an erythrocyte sedimentation rate of 10 mm/h.                                   St Mary’s Hospital, Newport, Isle of Wight PO30 5TG, UK



854                                                                                                                              Vol 349 • March 22, 1997

								
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