- Email: [email protected]
Nerve growth factor in diabetic neuropathy
CORRESPONDENCE
3
patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum 1983; 26: 1346–53. Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981; 24: 1308–15.
1 2
3
4
Pulsating arm veins 5
Sir—M R Moawad and S D Blair’s Sept 26 case report (p 1030)1 was most informative. Usually, superior and inferior venae cavae have no valves and, therefore, a raised right atrial pressure is transmitted without any impediment to jugular vein and hepatic veins (having no venous values), which causes pulsation of jugular veins and the liver, respectively. Functional insufficiency of venous valves in the legs, whether of congenital origin or acquired after thrombophlebitis, causes varicosities. It is therefore understandable that in patients with tricuspid insufficiency pulsations of the veins of the legs have been reported early in patients with varicose veins.2 Veins do not have to be varicose to pulsate. Moreover, intracardiac pulsations may propagate not only to leg veins but also to arm veins,2 for example, tricuspid regurgitation in drug addicts who develop infective endocarditis on the tricuspid valve. The increased intravenous use of heroin has provided circumstances for thrombophlebitis of the arm veins and frequently during this process destruction of valves so that the arm veins would pulsate like right atrium and jugular veins. The reason why pulsating arm veins are not encountered as frequently as might be expected in drug addicts is that they usually have no patent arm veins left on account of phlebothrombosis and scarring from repeated intravenous injections of drugs. Moawad and Blair also discuss how raised right atrial pressure in tricuspid insufficiency can lead to pulsatile varicose veins. However, it should be noted that tricuspid insufficiency may be present without raised right atrial pressure. A normal right atrial pressure, both quantitatively and qualitatively, could not be relied upon to rule out tricuspid insufficiency.3 Just as a normal left atrial pressure may exist in the presence of severe mitral insufficiency, due to a dilated left atrium with increased compliance,4,5 so tricuspid insufficiency may exist without raised right atrial pressure. Tsung O Cheng Division of Cardiology, George Washington University Medical Centre, Washington, DC 20037, USA
THE LANCET • Vol 352 • November 14, 1998
Moawad MR, Blair SD. Pulsating varicose veins. Lancet 1998; 352: 1030. Ali N. Pulsations of arm veins in the absence of tricuspid insufficiency. Chest 1973; 63: 41–45. Cheng TO. Pulsations of arm veins in absence of tricuspid insufficiency. Chest 1974; 65: 235–36. Cheng TO, Bashour T, Lindsay J. Chronic mitral regurgitation resulting from ruptured chordae tendineae. Circulation 1971; 44: II–150. Braunwald E, Awe WC. The syndrome of severe mitral regurgitation with normal left atrial pressure. Circulation 1963; 27: 29–35.
Sir—I am surprised that M R Moawad and S D Blair1 searched for arteriovenous communications in a patient known to have mitral valve disease and with evidence of right-ventricular failure. Their case report reminded me of a patient I saw in the vein clinic at St Mary’s Hospital, London, in March, 1974. She was a 46-year-old Irish woman who complained of a hot, heavy aching right leg. She had had a mitral valvotomy for rheumatic valve disease in 1959 and gave a history of dyspnoea, tachycardia, and atrial fibrillation. In 1965, she had deep-vein thrombosis with pulmonary embolism. On examination, she had dilated veins and a raised pulsating jugular pulse. The lower right leg was pigmented and showed venous congestion; grossly dilated pulsating varicose veins were present on the right leg with distension of the whole saphenous system from groin to ankle with a pulsating anterolateral tributary. There were dilated collateral veins passing across the suprapubic region to the left groin. There was some congestion of the lower left leg but no significant varicose veins on this leg and no obvious pulsation. Ultrasound confirmed the gross pulsating incompetence in the right long saphenous vein system and an isotope venogram showed occlusion of the left common iliac vein with drainage of the left leg via the suprapubic collaterals, confirmed by bilateral femoral venography. The unilateral presentation could possibly have suggested an arteriovenous communication, but further investigations confirmed the presence of tricuspid incompetence, as in the case described by Moawad and Blair. The severe cramps and pain in the right leg on standing were not controlled by class II or III elastic stocking. A sapheno-femoral ligation was performed in June, 1975, with such relief of symptoms in the right leg that she needed only a light-weight class I stocking. I have detailed record cards of a personal series of 14 000 patients who
presented to vein clinics and have seen a second patient with pulsating varicose veins in both legs. My impression is that the history and obvious clinical findings are sufficient to relate pulsating varicose veins to rheumatic heart disease. I have not seen pulsating varicose veins in cases of acquired arteriovenous fistulae; these patients present with swollen, cyanosed, painful limbs which suggest post-thrombotic syndrome and in a few cases local pulsation could be seen on close careful inspection. These symptoms were relieved when the fistula was resected. In patients with extensive (up to 50% of body surface) congenital arteriovenous fistulae (Klippel Trenaunay syndrome) I have never seen pulsation. Pulsating varicose veins must have been more common in the past when untreated rheumatic heart disease was rife. John T Hobbs 4 Upper Wimpole Street, London W1M 7TD, UK 1
Moawad MR, Blair SD. Pulsating varicose veins. Lancet 1998; 352: 1030.
Nerve growth factor in diabetic neuropathy Sir—Marilynn Larkin’s Sept 26 news item (p 1039)1 on the promise of recombinant human nerve growth factor (rhNGF) in diabetic neuropathy suggests that rhNGF will be most likely to be used in patients with signs and symptoms such as “loss of reflexes and vibratory sensation in the feet”. In fact, the known effects of rhNGF in patients with neuropathy and various preclinical studies indicate that rhNGF is not likely to affect these signs. NGF acts on unmyelinated sensory fibres and sympathetic nerve fibres that bear its receptor trkA, and would therefore ameliorate loss of temperature sensation, abnormal nociception, and autonomic dysfunction.2 We have proposed that it may provide prophylaxis for diabetic foot ulceration.3 It would therefore be important to identify for rhNGF treatment those patients with abnormalities on thermal threshold and cutaneous axon-reflex tests, that are not done routinely in clinical neurophysiology departments, particularly since these abnormalities usually precede loss of vibration and reflexes. A different member of the nerve growth factor family, neutrotrophin-3 (NT-3), and not nerve growth factor itself, is trophic to large sensory fibres, including muscle spindle afferents,
1629
CORRESPONDENCE
which are involved in loss of reflexes and vibration sensation. A cocktail of neurotrophic factors, including NGF and NT-3, may in the future be needed to rescue the full complement of sensory fibres. P Anand Academic Department of Neurology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London E1 1BB, UK 1 2
3
Larkin M. Nerve growth factor promising in diabetic neuropathy. Lancet 1998; 352: 1039. Anand P, Terenghi G, Warner G, Kopelman P, Sinicropi DV, Williams-Chestnut RE. The role of nerve growth factor in human diabetic neuropathy. Nat Med 1996; 2: 703–07. Anand P. Neurotrophins and peripheral neuropathy. Philos Trans R Soc Lond B Biol Sci 1996; 351: 449–54.
Late postnatal mother-tochild transmission of HIV-1 Sir—We are concerned that the takehome message of Valériane Leroy and colleagues’ meta-analysis (Aug 22, p 597)1 of late postnatal mother-tochild transmission of HIV-1 is misleading. The summary highlights that “if breastfeeding had stopped at age 4 months transmission would have occurred in no infants”. This finding could easily be interpreted to mean that there is no risk of HIV-1 transmission during the first 4 months of breastfeeding, but this is not supported by the study. According to the definition used by Leroy and colleagues, late postnatal transmission of HIV-1 was that occurring after age 2·5 months, so no cases by age 4 months actually means that in those studies no child was infected in the 6-week period between 2·5 and 4 months. Furthermore, children were included in the study only from the date of their first negative HIV-1 test. This test was at a median age of 5·8 months (range 2·5–15·7), so for fewer than half the children with information on timing of acquisition of HIV-1 infection were there any data before age 4 months. Finally, the timing of HIV-1 acquisition was estimated as the midpoint between the last negative and first positive test. We are not told the average interval between tests in the developing country studies. If follow-up was every 3 months as in the developed country cohorts, even for those children followed from age 2·5 months, it would be almost impossible for the estimated acquisition time to fall within the first 4 months of life. The casual reader of this study would conclude that breastfeeding for 4 months is safe. In fact, the report tells
1630
us very little about this early and crucial period. *Judith R Glynn, Laura Rodrigues Infectious Disease Epidemiology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK 1
Leroy V, Newell ML, Dabis F, et al, for the Ghent International Working Group on Mother-to-Child Transmission of HIV. International multicentre pooled analysis of late postnatal mother-to-child transmission of HIV-1 infection. Lancet 1998; 352: 597–600.
Authors’ reply Sir—We agree with Judith Glynn and Laura Rodrigues and indeed our report was not a plea for early cessation of breastfeeding. We would like to stress that our objective was to study the late postnatal transmission of HIV-1, but not to study early postnatal transmission which cannot be distinguished from transmission during delivery. To assess the risk of late postnatal transmission of HIV-1 we used all available information from the various studies in a pooled analysis. For this analysis we applied a standard definition of late postnatal transmission occurring as HIV-1 that was diagnosed after age 2·5 months. Thus, children were included in this analysis from the time of their first negative diagnosis (median age of 5·8 months). Children from developing countries’ studies were usually followed up every 3 months thereafter. As a first step, we decided that if the timing of infection was estimated as the midpoint between the last negative test and the first positive test, then no case was observed before 4 months of age. We suspected that this approach may lead to an overestimate of the benefit of early discontinuation of breastfeeding. Therefore, we repeated the analysis to take account of HIV-1 infection having occurred immediately after the last negative test (then just after 3 months for some children). In that analysis, two of the 20 children would have become infected before age 4 months. We clearly stated in the discussion that our estimation of the risk of late postnatal transmission of 3·2 per 100 child-years of breastfeeding follow-up underestimated the total risk of HIV-1 transmission through breastfeeding since we excluded transmission before age 2·5 months. This risk should be interpreted as an additional risk to the early postnatal risk that remains undefined and needs to be further explored. The take-home message of our multicentre pooled study is that the longer the duration of breastfeeding,
the higher is the cumulative risk of being infected through breastmilk. Finally, we reiterate that the risk of HIV-1 transmission through breastmilk should be balanced against the risk of neonatal mortality and morbidity, before stating that avoiding breastfeeding or early weaning is safe.1 *Valériane Leroy, Marie-Louise Newell, Francois Dabis, Catherine Peckham, Philippe Van de Perre, for the Ghent International Working Group on Motherto-child Transmission of HIV *Unité INSERM 330, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France; Institute of Child Health, London, UK; and Centre Muraz, Bobo-Dioulasso, Burkina Faso (e-mail: [email protected]) 1
Van de Perre P, Meda N, Cartoux M, Leroy V, Dabis F. Late postnatal transmission of HIV-1 and early weaning. Lancet 1997; 350: 221.
Appropriate technology for cataract surgery Sir—James Tielsch’s Sept 5 commentary1 only examines the role of posterior chamber lenses and makes no reference to the large randomised trial of anterior chamber lens implantation in Nepal published in The Lancet last year.2 Any decision on the most appropriate surgical treatment of cataract should be evidence-based and take account of the effective use of available resources, particularly in developing countries where highvolume, low-cost cataract surgery is usually required. The advantages of using anterior chamber lenses after intracapsular extraction include: less microsurgical technology; less retraining for existing intracapsular extraction surgeons; no posterior capsule left which may opacify at a later date; less expense and shorter time than the extracapsular with posterior chamber lens procedure. The disadvantages of intracapsular extraction include increased vitreousrelated problems, such as cystoid macula oedema and retinal detachment. The old anterior chamber lens prototypes caused corneal problems and uveitis, however, the Nepal study reported that the new open loupe anterior chamber lens has a low complication rate at 1 year, and the 2–5 year follow-up (currently being prepared for publication) confirms a low complication rate with no case of corneal decompensation. The advantages of having an intraocular lens implantation instead of spectacles, which can be lost or broken, are clearly shown. However, improvement in
THE LANCET • Vol 352 • November 14, 1998
3
patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum 1983; 26: 1346–53. Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981; 24: 1308–15.
1 2
3
4
Pulsating arm veins 5
Sir—M R Moawad and S D Blair’s Sept 26 case report (p 1030)1 was most informative. Usually, superior and inferior venae cavae have no valves and, therefore, a raised right atrial pressure is transmitted without any impediment to jugular vein and hepatic veins (having no venous values), which causes pulsation of jugular veins and the liver, respectively. Functional insufficiency of venous valves in the legs, whether of congenital origin or acquired after thrombophlebitis, causes varicosities. It is therefore understandable that in patients with tricuspid insufficiency pulsations of the veins of the legs have been reported early in patients with varicose veins.2 Veins do not have to be varicose to pulsate. Moreover, intracardiac pulsations may propagate not only to leg veins but also to arm veins,2 for example, tricuspid regurgitation in drug addicts who develop infective endocarditis on the tricuspid valve. The increased intravenous use of heroin has provided circumstances for thrombophlebitis of the arm veins and frequently during this process destruction of valves so that the arm veins would pulsate like right atrium and jugular veins. The reason why pulsating arm veins are not encountered as frequently as might be expected in drug addicts is that they usually have no patent arm veins left on account of phlebothrombosis and scarring from repeated intravenous injections of drugs. Moawad and Blair also discuss how raised right atrial pressure in tricuspid insufficiency can lead to pulsatile varicose veins. However, it should be noted that tricuspid insufficiency may be present without raised right atrial pressure. A normal right atrial pressure, both quantitatively and qualitatively, could not be relied upon to rule out tricuspid insufficiency.3 Just as a normal left atrial pressure may exist in the presence of severe mitral insufficiency, due to a dilated left atrium with increased compliance,4,5 so tricuspid insufficiency may exist without raised right atrial pressure. Tsung O Cheng Division of Cardiology, George Washington University Medical Centre, Washington, DC 20037, USA
THE LANCET • Vol 352 • November 14, 1998
Moawad MR, Blair SD. Pulsating varicose veins. Lancet 1998; 352: 1030. Ali N. Pulsations of arm veins in the absence of tricuspid insufficiency. Chest 1973; 63: 41–45. Cheng TO. Pulsations of arm veins in absence of tricuspid insufficiency. Chest 1974; 65: 235–36. Cheng TO, Bashour T, Lindsay J. Chronic mitral regurgitation resulting from ruptured chordae tendineae. Circulation 1971; 44: II–150. Braunwald E, Awe WC. The syndrome of severe mitral regurgitation with normal left atrial pressure. Circulation 1963; 27: 29–35.
Sir—I am surprised that M R Moawad and S D Blair1 searched for arteriovenous communications in a patient known to have mitral valve disease and with evidence of right-ventricular failure. Their case report reminded me of a patient I saw in the vein clinic at St Mary’s Hospital, London, in March, 1974. She was a 46-year-old Irish woman who complained of a hot, heavy aching right leg. She had had a mitral valvotomy for rheumatic valve disease in 1959 and gave a history of dyspnoea, tachycardia, and atrial fibrillation. In 1965, she had deep-vein thrombosis with pulmonary embolism. On examination, she had dilated veins and a raised pulsating jugular pulse. The lower right leg was pigmented and showed venous congestion; grossly dilated pulsating varicose veins were present on the right leg with distension of the whole saphenous system from groin to ankle with a pulsating anterolateral tributary. There were dilated collateral veins passing across the suprapubic region to the left groin. There was some congestion of the lower left leg but no significant varicose veins on this leg and no obvious pulsation. Ultrasound confirmed the gross pulsating incompetence in the right long saphenous vein system and an isotope venogram showed occlusion of the left common iliac vein with drainage of the left leg via the suprapubic collaterals, confirmed by bilateral femoral venography. The unilateral presentation could possibly have suggested an arteriovenous communication, but further investigations confirmed the presence of tricuspid incompetence, as in the case described by Moawad and Blair. The severe cramps and pain in the right leg on standing were not controlled by class II or III elastic stocking. A sapheno-femoral ligation was performed in June, 1975, with such relief of symptoms in the right leg that she needed only a light-weight class I stocking. I have detailed record cards of a personal series of 14 000 patients who
presented to vein clinics and have seen a second patient with pulsating varicose veins in both legs. My impression is that the history and obvious clinical findings are sufficient to relate pulsating varicose veins to rheumatic heart disease. I have not seen pulsating varicose veins in cases of acquired arteriovenous fistulae; these patients present with swollen, cyanosed, painful limbs which suggest post-thrombotic syndrome and in a few cases local pulsation could be seen on close careful inspection. These symptoms were relieved when the fistula was resected. In patients with extensive (up to 50% of body surface) congenital arteriovenous fistulae (Klippel Trenaunay syndrome) I have never seen pulsation. Pulsating varicose veins must have been more common in the past when untreated rheumatic heart disease was rife. John T Hobbs 4 Upper Wimpole Street, London W1M 7TD, UK 1
Moawad MR, Blair SD. Pulsating varicose veins. Lancet 1998; 352: 1030.
Nerve growth factor in diabetic neuropathy Sir—Marilynn Larkin’s Sept 26 news item (p 1039)1 on the promise of recombinant human nerve growth factor (rhNGF) in diabetic neuropathy suggests that rhNGF will be most likely to be used in patients with signs and symptoms such as “loss of reflexes and vibratory sensation in the feet”. In fact, the known effects of rhNGF in patients with neuropathy and various preclinical studies indicate that rhNGF is not likely to affect these signs. NGF acts on unmyelinated sensory fibres and sympathetic nerve fibres that bear its receptor trkA, and would therefore ameliorate loss of temperature sensation, abnormal nociception, and autonomic dysfunction.2 We have proposed that it may provide prophylaxis for diabetic foot ulceration.3 It would therefore be important to identify for rhNGF treatment those patients with abnormalities on thermal threshold and cutaneous axon-reflex tests, that are not done routinely in clinical neurophysiology departments, particularly since these abnormalities usually precede loss of vibration and reflexes. A different member of the nerve growth factor family, neutrotrophin-3 (NT-3), and not nerve growth factor itself, is trophic to large sensory fibres, including muscle spindle afferents,
1629
CORRESPONDENCE
which are involved in loss of reflexes and vibration sensation. A cocktail of neurotrophic factors, including NGF and NT-3, may in the future be needed to rescue the full complement of sensory fibres. P Anand Academic Department of Neurology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London E1 1BB, UK 1 2
3
Larkin M. Nerve growth factor promising in diabetic neuropathy. Lancet 1998; 352: 1039. Anand P, Terenghi G, Warner G, Kopelman P, Sinicropi DV, Williams-Chestnut RE. The role of nerve growth factor in human diabetic neuropathy. Nat Med 1996; 2: 703–07. Anand P. Neurotrophins and peripheral neuropathy. Philos Trans R Soc Lond B Biol Sci 1996; 351: 449–54.
Late postnatal mother-tochild transmission of HIV-1 Sir—We are concerned that the takehome message of Valériane Leroy and colleagues’ meta-analysis (Aug 22, p 597)1 of late postnatal mother-tochild transmission of HIV-1 is misleading. The summary highlights that “if breastfeeding had stopped at age 4 months transmission would have occurred in no infants”. This finding could easily be interpreted to mean that there is no risk of HIV-1 transmission during the first 4 months of breastfeeding, but this is not supported by the study. According to the definition used by Leroy and colleagues, late postnatal transmission of HIV-1 was that occurring after age 2·5 months, so no cases by age 4 months actually means that in those studies no child was infected in the 6-week period between 2·5 and 4 months. Furthermore, children were included in the study only from the date of their first negative HIV-1 test. This test was at a median age of 5·8 months (range 2·5–15·7), so for fewer than half the children with information on timing of acquisition of HIV-1 infection were there any data before age 4 months. Finally, the timing of HIV-1 acquisition was estimated as the midpoint between the last negative and first positive test. We are not told the average interval between tests in the developing country studies. If follow-up was every 3 months as in the developed country cohorts, even for those children followed from age 2·5 months, it would be almost impossible for the estimated acquisition time to fall within the first 4 months of life. The casual reader of this study would conclude that breastfeeding for 4 months is safe. In fact, the report tells
1630
us very little about this early and crucial period. *Judith R Glynn, Laura Rodrigues Infectious Disease Epidemiology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK 1
Leroy V, Newell ML, Dabis F, et al, for the Ghent International Working Group on Mother-to-Child Transmission of HIV. International multicentre pooled analysis of late postnatal mother-to-child transmission of HIV-1 infection. Lancet 1998; 352: 597–600.
Authors’ reply Sir—We agree with Judith Glynn and Laura Rodrigues and indeed our report was not a plea for early cessation of breastfeeding. We would like to stress that our objective was to study the late postnatal transmission of HIV-1, but not to study early postnatal transmission which cannot be distinguished from transmission during delivery. To assess the risk of late postnatal transmission of HIV-1 we used all available information from the various studies in a pooled analysis. For this analysis we applied a standard definition of late postnatal transmission occurring as HIV-1 that was diagnosed after age 2·5 months. Thus, children were included in this analysis from the time of their first negative diagnosis (median age of 5·8 months). Children from developing countries’ studies were usually followed up every 3 months thereafter. As a first step, we decided that if the timing of infection was estimated as the midpoint between the last negative test and the first positive test, then no case was observed before 4 months of age. We suspected that this approach may lead to an overestimate of the benefit of early discontinuation of breastfeeding. Therefore, we repeated the analysis to take account of HIV-1 infection having occurred immediately after the last negative test (then just after 3 months for some children). In that analysis, two of the 20 children would have become infected before age 4 months. We clearly stated in the discussion that our estimation of the risk of late postnatal transmission of 3·2 per 100 child-years of breastfeeding follow-up underestimated the total risk of HIV-1 transmission through breastfeeding since we excluded transmission before age 2·5 months. This risk should be interpreted as an additional risk to the early postnatal risk that remains undefined and needs to be further explored. The take-home message of our multicentre pooled study is that the longer the duration of breastfeeding,
the higher is the cumulative risk of being infected through breastmilk. Finally, we reiterate that the risk of HIV-1 transmission through breastmilk should be balanced against the risk of neonatal mortality and morbidity, before stating that avoiding breastfeeding or early weaning is safe.1 *Valériane Leroy, Marie-Louise Newell, Francois Dabis, Catherine Peckham, Philippe Van de Perre, for the Ghent International Working Group on Motherto-child Transmission of HIV *Unité INSERM 330, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France; Institute of Child Health, London, UK; and Centre Muraz, Bobo-Dioulasso, Burkina Faso (e-mail: [email protected]) 1
Van de Perre P, Meda N, Cartoux M, Leroy V, Dabis F. Late postnatal transmission of HIV-1 and early weaning. Lancet 1997; 350: 221.
Appropriate technology for cataract surgery Sir—James Tielsch’s Sept 5 commentary1 only examines the role of posterior chamber lenses and makes no reference to the large randomised trial of anterior chamber lens implantation in Nepal published in The Lancet last year.2 Any decision on the most appropriate surgical treatment of cataract should be evidence-based and take account of the effective use of available resources, particularly in developing countries where highvolume, low-cost cataract surgery is usually required. The advantages of using anterior chamber lenses after intracapsular extraction include: less microsurgical technology; less retraining for existing intracapsular extraction surgeons; no posterior capsule left which may opacify at a later date; less expense and shorter time than the extracapsular with posterior chamber lens procedure. The disadvantages of intracapsular extraction include increased vitreousrelated problems, such as cystoid macula oedema and retinal detachment. The old anterior chamber lens prototypes caused corneal problems and uveitis, however, the Nepal study reported that the new open loupe anterior chamber lens has a low complication rate at 1 year, and the 2–5 year follow-up (currently being prepared for publication) confirms a low complication rate with no case of corneal decompensation. The advantages of having an intraocular lens implantation instead of spectacles, which can be lost or broken, are clearly shown. However, improvement in
THE LANCET • Vol 352 • November 14, 1998