- Email: [email protected]
New clinical sign for orthostatic tremor
social class, or, through physical activity, to dietary differences such as higher beer consumption, the OR would again be biased upwards. Third, several trades are linked with increased rates of lung cancer unrelated to asbestosfor instance, welding, foundry work, and chromium plating. A higher proportion of such trades among probablewould confound. occupations again exposure in with to Fourth, changes smoking habits, the cases respect on were average considerably older and had many more pack-years of smoking. But habits have changed towards filter-tips and low-tar, with probable reduction in risk per cigarette. Early pack-years would then bias the adjustment for smoking towards increasing the OR. Lastly, employment has changed. East London was devastated by bombing in World War II, and the first post-war decades involved much demolition and rebuilding. Employment then would have included more builders’ labourers and electricians, the groups contributing most to excess asbestos exposure, among the older cases. The post-war years have also seen the disappearance of shipyard and dockwork in east London, another apparent source of difference between cases and controls (table 2). These changes may again produce upward bias. These and yet other uncertainties prevent the article from making any useful contribution to the title question. The list of authors contains some distinguished names, but, as Horace (Ars Poetica, 359) reminded us 2000 years ago, Quandoque bonus dormitat Homerus-sometimes even great Homer dozes.
The suggestion that blocking out portions of films to ensure that the identity of cases and controls was hidden would prevent their proper classification is unlikely. Any such effect would tend to obscure differences not create them. We agree that except in textiles the risk of lung cancer from asbestos is mainly for workers with long and heavy exposure. We made no attempt to assess intensity-but for many of those with probable or definite exposure it was certainly long and may well have been heavy. Since our data gave no indication of fibre type or concentration it is not surprising that risk and duration of exposure were only loosely related. However, formal tests, the results of which were not reported, confirmed a statistically significant trend. With the limitations of a hospital-based case-control study, to which Weiss refers, no useful estimate could be made of population-attributable risk. Bearing in mind, however, that there are annually some 25 000 deaths in men from lung cancer and perhaps 1000 from mesothelioma, and that our study was in an area of London where work with asbestos was common, our findings on risk seem reasonable. With respect to Johnson’s two main areas of concern, our referent group consisted of patients representative of hospital admissions without lung cancer; we did not consider either the cardiac or the respiratory group as the more appropriate and so combined them. That masking lesions on the chest radiograph would interfere with radiological diagnosis was of course our intent: the ILO system calls for the objective reading of opacities and specifically avoids their use for diagnosis. His more detailed statistical speculations are not easy to follow, or interpret. We do not agree that the preponderance of published evidence on this important and difficult question is against our conclusions. Very few epidemiological studies have been made, none is perfect, and the results are about evenly divided. No single study can provide certain proof in questions of cause and effect, and account must also be taken of biological plausibility. We did not seek to prove a hypothesis, but to test one-namely, that the risk of lung from asbestos is confined to persons with cancer radiographic evidence of pulmonary fibrosis. We believe that our results provide sufficient evidence for rejecting or at least questioning the hypothesis that a cancer usually resulting from an interaction between asbestos fibres and cigarette smoke occurs only in the presence of small radiographic
Kevin Browne
opacities.
contributed, from five cohorts, to the powerful epidemiological evidence that quite heavy exposures are involved before the lung cancer standardised mortality ratio rises. And
have evidence from several UK cohorts that despite substantial mortality from mesotheliomas. The choice of referents introduces major problems of confounding. The first is exercise. The diagnoses suggest that many respiratory controls might have been chronically unfit for heavy physical work; similarly, the inverse relation between exercise and ischaemic heart disease suggests that sedentary jobs are over-represented among the cardiac controls. If the probable exposures included jobs involving a higher proportion of physically demanding work, the OR will be exaggerated. Second, diet is now considered an important risk factor for lung cancer. If the list is linked with lower rates
we
may remain normal
Leicester House, North Creake, Norfolk NR21 9JP, UK
reverse.
*Corbett
McDonald, Anthony Newman Taylor
National Heart and
Lung Institute, London SW3 6LY, UK
Authors’
reply reply correspondents’ unexpected. The
on behalf of our colleagues to your criticism of our report, which is not classification of asbestos exposure that we used discriminated well between cases of mesothelioma and controls in the hands of four experienced groups of investigators from the USA, Netherlands, Canada, and the UK. We see no reason why it would have done less well in a study of lung cancer: certainly we know of no other classification system that has been better validated. Do our critics really believe that the ten occupations listed as having definite or probably asbestos exposure did not carry this level of risk? Was it really surprising, let alone arrogant or unscientific, that we should prefer a validated system to the notoriously unreliable opinion of industrial workers about the nature of the dusts to which they are exposed? The radiographic assessment was made by three experienced physicians, blind and independently, with remarkably little difference of opinion between them. We do not claim that small opacities on the chest radiograph necessarily implied fibrosis or, more importantly, the
SiR-We
306
New clinical
sign for orthostatic tremor
SIR—The description of a new clinical sign is an unusual event in medicine, and rarer still when its physiological basis is understood. Here I report a new diagnostic sign for primary orthostatic tremor. In this disorder a fine tremor in the muscles of the lower limbs leads to a striking sense of instability when standing.’ The frequency of the tremor is around 15 Hz, so that muscle contraction is partially fused and the tremor cannot be reliably seen or palpated by the examiner. The tremor disappears when not weight bearing or when walking. Given these factors the diagnosis is often missed, and hitherto has relied on electromyographic (EMG) recordings from the muscles of the legs during standing. The condition may be successfully treated with clonazepam and primidone.2 Auscultation with the diaphragm of a stethoscope over the muscles of the thigh and calf, particularly quadriceps and hamstrings, reveals a repetitive thumping sound, similar to the noise of a distant helicopter. This sound, like the tremor,
Ciprofloxacin for multiresistant
enteric fever
in pregnancy SiR-Multiresistant Salmonella typhi has caused several of typhoid fever in the Indian subcontinent in recent years,’1 and the fluoroquinolone antibiotic ciprofloxacin has become the main drug for management of the disease. Although the drug is not advised for patients younger than 18 years, it has also been used in children with enteric fever with reasonable safety; Karande and Kshirsagar2argued that its adverse effects profile is similar in adult and paediatric populations. Ciprofloxacin did not affect the physiological development of the fetus in cynomolgus monkeys when fed in doses up to 200 mg/kg and there was no increase in spontaneous abortions.3 Since the drug can cause arthropathy in juvenile animals, its use in pregnancy is recommended only if the potential benefits outweigh possible risks to the mother and the fetus. In the northern Indian state of Jammu and Kashmir, we have used ciprofloxacin in many patients with good safety and efficacy. During our 6 years of experience with the drug we had to use it for seven pregnant patients with multi-drugresistant enteric fever (MDREF). The patients (table) were admitted with pyrexia of varying duration that had not responded to antibiotics safe for use in pregnancy. Three women had anicteric hepatitis, one cholecystitis, and one pericardial effusion complicating the MDREF. In-vitro sensitivity patterns of the S typhi grown on blood culture showed to resistance co-trimoxazole, ampicillin, and with variable tetracycline chloramphenicol, sensitivity to cefotaxime (three), cefazolin (two), gentamicin (three), amikacin (six), and kanamycin (four). All the strains were sensitive to ciprofloxacin. Each patient received 5-7 days’ cefotaxime, to which there was no response. After we had explained the possible risks to the fetus and obtained consent, the patients started on ciprofloxacin 200 mg twice daily intravenously then switched to 500 mg twice daily by mouth on the 4th or 5th day. In all seven patients the fever resolved in 4-7 days (median 5). The drug was continued for 2 weeks in each case, with the dose halved after 8 days. The patients were followed up with weekly obstetric visits and regular ultrasonographic assessment. All the pregnancies carried to term and healthy babies were born spontaneously with vertex presentation. Apgar scores were all 8 or higher, and no congenital abnormalities were noted. Birthweight of the babies was within the 95th percentile.4 The infants were assessed every month for 6 months then every 3-4 months for at least 2 years. Two of the babies had long-term physiological jaundice and one had four episodes of respiratory infection during the first 8 months of life. Motor, adaptive, social, and language milestones in each baby were consistent with age, and no evidence of cartilage damage was found on regular clinical assessment up to 5 years. The manufacturers of ciprofloxacin (Bayer Pharmaceuticals) have received reports on 130 women who have received the drug during pregnancy, in most during the first trimester when they did not know they were pregnant. No baby born to these women had any congenital abnormalities
epidemics
U
0
1U
13
LU
3
Figure: EMG activity and sound from hamstrings patient with primary orthostatic tremor
in
standing
A=raw records of surface EMG and sound from hamstnngs. B=power spectrum of muscle sound from 0-25 Hz (and 0-300 Hz in inset). C=power spectrum of EMG. There is a clear peak at 15 Hz in spectra of sound and EMG. D=coherence between muscle sound and EMG. Horizontal line is level of 5% significance. There is striking coherence at around 15 Hz.
is
only present on standing. It is not heard when healthy subjects stand, and is due to the vibration set up by the rhythmic and synchronous contraction of muscle motor units in primary orthostatic tremor. The upper and lower traces in figure A show EMG activity and sound picked up by surface electrodes and microphone over hamstrings in a patient with this condition. The rhythmic grouped discharge of motor units occurs at about 15 Hz, with muscle sound paralleling this. The latter is confirmed in power spectra of the signals in B and C. Figure D shows that the microphone provides an exceptionally close translation of the muscle events, with coherence between EMG and muscle sound approaching unity in the frequency band of interest. It is this 15 Hz oscillation that is heard with the stethoscope, either at
this fundamental frequency or at harmonics thereof. Thus simple auscultation may identify the abnormal muscle activity in orthostatic tremor without recourse to EMG recordings. P Brown National Hospital for Neurology and Neurosurgery and MRC Human Movement and Balance Unit, Institute of Neurology, London WC1N 3BG, UK 1
2
Heilman KH. Orthostatic tremor. Arch Neurol 1984; 41: 880-81. Britton TC, Thompson PD, van der Kamp W, et al. Primary orthostatic tremor: further observations in six cases. JNeurol 1992; 239: 109-17.
Table: Clinical features of
seven
patients with MDREF 307
The suggestion that blocking out portions of films to ensure that the identity of cases and controls was hidden would prevent their proper classification is unlikely. Any such effect would tend to obscure differences not create them. We agree that except in textiles the risk of lung cancer from asbestos is mainly for workers with long and heavy exposure. We made no attempt to assess intensity-but for many of those with probable or definite exposure it was certainly long and may well have been heavy. Since our data gave no indication of fibre type or concentration it is not surprising that risk and duration of exposure were only loosely related. However, formal tests, the results of which were not reported, confirmed a statistically significant trend. With the limitations of a hospital-based case-control study, to which Weiss refers, no useful estimate could be made of population-attributable risk. Bearing in mind, however, that there are annually some 25 000 deaths in men from lung cancer and perhaps 1000 from mesothelioma, and that our study was in an area of London where work with asbestos was common, our findings on risk seem reasonable. With respect to Johnson’s two main areas of concern, our referent group consisted of patients representative of hospital admissions without lung cancer; we did not consider either the cardiac or the respiratory group as the more appropriate and so combined them. That masking lesions on the chest radiograph would interfere with radiological diagnosis was of course our intent: the ILO system calls for the objective reading of opacities and specifically avoids their use for diagnosis. His more detailed statistical speculations are not easy to follow, or interpret. We do not agree that the preponderance of published evidence on this important and difficult question is against our conclusions. Very few epidemiological studies have been made, none is perfect, and the results are about evenly divided. No single study can provide certain proof in questions of cause and effect, and account must also be taken of biological plausibility. We did not seek to prove a hypothesis, but to test one-namely, that the risk of lung from asbestos is confined to persons with cancer radiographic evidence of pulmonary fibrosis. We believe that our results provide sufficient evidence for rejecting or at least questioning the hypothesis that a cancer usually resulting from an interaction between asbestos fibres and cigarette smoke occurs only in the presence of small radiographic
Kevin Browne
opacities.
contributed, from five cohorts, to the powerful epidemiological evidence that quite heavy exposures are involved before the lung cancer standardised mortality ratio rises. And
have evidence from several UK cohorts that despite substantial mortality from mesotheliomas. The choice of referents introduces major problems of confounding. The first is exercise. The diagnoses suggest that many respiratory controls might have been chronically unfit for heavy physical work; similarly, the inverse relation between exercise and ischaemic heart disease suggests that sedentary jobs are over-represented among the cardiac controls. If the probable exposures included jobs involving a higher proportion of physically demanding work, the OR will be exaggerated. Second, diet is now considered an important risk factor for lung cancer. If the list is linked with lower rates
we
may remain normal
Leicester House, North Creake, Norfolk NR21 9JP, UK
reverse.
*Corbett
McDonald, Anthony Newman Taylor
National Heart and
Lung Institute, London SW3 6LY, UK
Authors’
reply reply correspondents’ unexpected. The
on behalf of our colleagues to your criticism of our report, which is not classification of asbestos exposure that we used discriminated well between cases of mesothelioma and controls in the hands of four experienced groups of investigators from the USA, Netherlands, Canada, and the UK. We see no reason why it would have done less well in a study of lung cancer: certainly we know of no other classification system that has been better validated. Do our critics really believe that the ten occupations listed as having definite or probably asbestos exposure did not carry this level of risk? Was it really surprising, let alone arrogant or unscientific, that we should prefer a validated system to the notoriously unreliable opinion of industrial workers about the nature of the dusts to which they are exposed? The radiographic assessment was made by three experienced physicians, blind and independently, with remarkably little difference of opinion between them. We do not claim that small opacities on the chest radiograph necessarily implied fibrosis or, more importantly, the
SiR-We
306
New clinical
sign for orthostatic tremor
SIR—The description of a new clinical sign is an unusual event in medicine, and rarer still when its physiological basis is understood. Here I report a new diagnostic sign for primary orthostatic tremor. In this disorder a fine tremor in the muscles of the lower limbs leads to a striking sense of instability when standing.’ The frequency of the tremor is around 15 Hz, so that muscle contraction is partially fused and the tremor cannot be reliably seen or palpated by the examiner. The tremor disappears when not weight bearing or when walking. Given these factors the diagnosis is often missed, and hitherto has relied on electromyographic (EMG) recordings from the muscles of the legs during standing. The condition may be successfully treated with clonazepam and primidone.2 Auscultation with the diaphragm of a stethoscope over the muscles of the thigh and calf, particularly quadriceps and hamstrings, reveals a repetitive thumping sound, similar to the noise of a distant helicopter. This sound, like the tremor,
Ciprofloxacin for multiresistant
enteric fever
in pregnancy SiR-Multiresistant Salmonella typhi has caused several of typhoid fever in the Indian subcontinent in recent years,’1 and the fluoroquinolone antibiotic ciprofloxacin has become the main drug for management of the disease. Although the drug is not advised for patients younger than 18 years, it has also been used in children with enteric fever with reasonable safety; Karande and Kshirsagar2argued that its adverse effects profile is similar in adult and paediatric populations. Ciprofloxacin did not affect the physiological development of the fetus in cynomolgus monkeys when fed in doses up to 200 mg/kg and there was no increase in spontaneous abortions.3 Since the drug can cause arthropathy in juvenile animals, its use in pregnancy is recommended only if the potential benefits outweigh possible risks to the mother and the fetus. In the northern Indian state of Jammu and Kashmir, we have used ciprofloxacin in many patients with good safety and efficacy. During our 6 years of experience with the drug we had to use it for seven pregnant patients with multi-drugresistant enteric fever (MDREF). The patients (table) were admitted with pyrexia of varying duration that had not responded to antibiotics safe for use in pregnancy. Three women had anicteric hepatitis, one cholecystitis, and one pericardial effusion complicating the MDREF. In-vitro sensitivity patterns of the S typhi grown on blood culture showed to resistance co-trimoxazole, ampicillin, and with variable tetracycline chloramphenicol, sensitivity to cefotaxime (three), cefazolin (two), gentamicin (three), amikacin (six), and kanamycin (four). All the strains were sensitive to ciprofloxacin. Each patient received 5-7 days’ cefotaxime, to which there was no response. After we had explained the possible risks to the fetus and obtained consent, the patients started on ciprofloxacin 200 mg twice daily intravenously then switched to 500 mg twice daily by mouth on the 4th or 5th day. In all seven patients the fever resolved in 4-7 days (median 5). The drug was continued for 2 weeks in each case, with the dose halved after 8 days. The patients were followed up with weekly obstetric visits and regular ultrasonographic assessment. All the pregnancies carried to term and healthy babies were born spontaneously with vertex presentation. Apgar scores were all 8 or higher, and no congenital abnormalities were noted. Birthweight of the babies was within the 95th percentile.4 The infants were assessed every month for 6 months then every 3-4 months for at least 2 years. Two of the babies had long-term physiological jaundice and one had four episodes of respiratory infection during the first 8 months of life. Motor, adaptive, social, and language milestones in each baby were consistent with age, and no evidence of cartilage damage was found on regular clinical assessment up to 5 years. The manufacturers of ciprofloxacin (Bayer Pharmaceuticals) have received reports on 130 women who have received the drug during pregnancy, in most during the first trimester when they did not know they were pregnant. No baby born to these women had any congenital abnormalities
epidemics
U
0
1U
13
LU
3
Figure: EMG activity and sound from hamstrings patient with primary orthostatic tremor
in
standing
A=raw records of surface EMG and sound from hamstnngs. B=power spectrum of muscle sound from 0-25 Hz (and 0-300 Hz in inset). C=power spectrum of EMG. There is a clear peak at 15 Hz in spectra of sound and EMG. D=coherence between muscle sound and EMG. Horizontal line is level of 5% significance. There is striking coherence at around 15 Hz.
is
only present on standing. It is not heard when healthy subjects stand, and is due to the vibration set up by the rhythmic and synchronous contraction of muscle motor units in primary orthostatic tremor. The upper and lower traces in figure A show EMG activity and sound picked up by surface electrodes and microphone over hamstrings in a patient with this condition. The rhythmic grouped discharge of motor units occurs at about 15 Hz, with muscle sound paralleling this. The latter is confirmed in power spectra of the signals in B and C. Figure D shows that the microphone provides an exceptionally close translation of the muscle events, with coherence between EMG and muscle sound approaching unity in the frequency band of interest. It is this 15 Hz oscillation that is heard with the stethoscope, either at
this fundamental frequency or at harmonics thereof. Thus simple auscultation may identify the abnormal muscle activity in orthostatic tremor without recourse to EMG recordings. P Brown National Hospital for Neurology and Neurosurgery and MRC Human Movement and Balance Unit, Institute of Neurology, London WC1N 3BG, UK 1
2
Heilman KH. Orthostatic tremor. Arch Neurol 1984; 41: 880-81. Britton TC, Thompson PD, van der Kamp W, et al. Primary orthostatic tremor: further observations in six cases. JNeurol 1992; 239: 109-17.
Table: Clinical features of
seven
patients with MDREF 307