expected in neuronal and glial cells because of generation of H2O2 and neurocytotoxic hydroxyl radicals via MAO-A or MAO-B or both. Miller and colleagues5 have shown in an in-vitro model of catecholamine auto-oxidation that replacement of dopamine and levodopa by their O-methylated metabolites 3-OMD and 3-OMDA significantly decreases the rate of oxidation.5 Thus, O-methylation might be of physiological importance in the brain’s antioxidant defence against catecholamine auto-oxidation. Central COMT-inhibition could induce neurotoxicity in patients with Parkinson’s disease. However, experimental and clinical data on longterm effects are lacking. *Wilfried Kuhn, Dirk Woitalla, Manfred Gerlach, Hermann Russ, Thomas Müller *Department of Neurology, University of Bochum, St Josef-Hospital, 44791 Bochum, Germany; Department of Neurochemistry, University of Würzburg, Würzburg; and Department of Neurology, University of Regensburg, Regensburg 1
Xie T, Ho SL, Ramsden D. Catechol-Omethyltransferase inhibitors in Parkinson’s disease. Lancet 1998; 351: 1966. Da Prada M, Borgulya J, Napolitano A, et al. Improved therapy of Parkinson’s disease with Tolcapone, a central and peripheral COMT Inhibitor with an S-Adenosyl-L-Methioninesparing effect. Clin Neuropharmacol 1994; 17 (suppl 3): S26–S37. Charlton CG, Mack J. Substantia nigra degeneration and tyrosine hydroxylase depletion caused by excess S-adenosylmethionine in the rat brain. Mol Neurobiol 1994; 9: 149–61. Zürcher G, Dingemanse J, Da Prada M. Ro 40-7592, a potent inhibitor of extracerebral and brain Catechol-Omethyltransferase: preclinical and clinical findings. In: Agnoli A, Campanella G, eds. New developments in therapy of Parkinson’s disease. Rome: John Libbey, 1991: 37–43. Miller JW, Selhub J, Joseph JA. Oxidative damage caused by free radicals produced during catecholamine autoxidation: protective effects of O-methylation and melatonin. Free Radic Biol Med 1996; 21: 241–49.
Chronic obstructive pulmonary disease Sir—Mark Madison and Richard Irwin (Aug 8, p 467)1 state that the pathogenesis of pulmonary emphysema remains enigmatic. In 1964 I reported a case2—later confirmed pathologically— in which cough could be incriminated as an important causal factor. The patient had severe pulmonary disease at the age of 70. On advice she refrained from coughing and lived another 19 years with a resting respiratory rate of 30 breaths per min, the same as at age 70. A puzzling feature of common emphysema is selective involvement of
the upper lung fields rather than the bases. In pulmonary tuberculosis a slight cough during chest fluoroscopy caused the apices to light up as they momentarily became distended with air. Intrathoracic expiratory air pressure is not distributed uniformly during coughing. The higher compressive forces at the lung bases drive air into the lower-pressure apices. When lipiodol was used in X-ray examination of the bronchial tree, patients who coughed after the procedure showed lipiodol scattered in the upper parts of the lungs, whereas the apices of patients who refrained from coughing remained free of lipiodol. Dynamic forces during coughing can be damaging to the apica and alveoli. Many years of coughing may be tolerated, but with the enlargement of the damaged alveoli and increased area of the wall, the force on the walls increases for the same pressure (PxA=F) and progression accelerates. I have closely observed several patients who were healthy coughing cigarette smokers at the age of 40 until they became pulmonary invalids and died in their 60s. On the other hand I am following a patient with severe asthma of 53 years’ duration who had taken the advice not to cough and still has a normal forced expiratory volume. Obstruction as the primary mechanism of emphysema has not been validated. Coughing warrants further consideration. C Miller Fisher Neurology Service, Massachusetts General Hospital, Boston, MA 02114, USA 1
Madison JM, Irwin RS. Chronic obstructive pulmonary disease. Lancet 1998; 352: 467–73. Fisher CM. The possible role of coughing in the pathogenesis of pulmonary emphysema. Canad Med Assoc J 1964; 91: 351–52.
Authors’ reply Sir—The idea that chronic cough or other mechanical factors could explain the development of emphysema dates back to at least the mid-nineteenth century.1 Laennec postulated that emphysema was caused by high pulmonary pressures generated during chronic coughing. The upper lobe predominance for emphysema in smokers was attributed by some to the forcing of air into the upper lobes during coughing. Variations on this hypothesis emphasised obstruction of airways with consequent trapping of air and overdistention of alveoli as the primary cause of progressive alveolar damage. All these hypotheses received much attention during the 19th and early 20th century but were not supported. Many
laboratory attempts to cause emphysema by overdistention of the lungs of animals did not cause the mechanical, histological, and gas exchange abnormalities characteristic of emphysema.2 The newer and still evolving notion, which stemmed from the pioneering observations of Laurell and Eriksson and colleagues,3 and that of Gross and colleagues,4 is that pulmonary emphysema is caused by imbalances between protease and antiprotease activity in the lungs. Cough does generate intrathoracic pressures as high as 300 mm Hg.5 This very high pressure can lead to various complications, which include rupture of an airway and the development of so-called pulmonary interstitial emphysema.5 This interstitial air might dissect along the pulmonary interstitium and result in pneumothorax, pneumomediastinum, pneumoperitoneum, and subcutaneous emphysema. However, these complications of cough have a pathology that is distinct from that of the centrilobular emphysema in smokers.1 We agree that much can still be learned about the details of the pathogenesis of pulmonary emphysema. Improved understanding of the molecular and cellular events in pulmonary emphysema could raise new and interesting questions about the potential role of chronic cough and other mechanical factors. However, on the basis of our experience of prospective and rigorous evaluation of more than 300 patients with coughing for an average of about 5 years (in some cases as long as 40–50 years), neither progressive airway obstruction nor emphysema have been complications that can be attributed to chronic coughing.5 There is no compelling evidence that chronic cough per se is a primary factor in the pathogenesis of pulmonary emphysema. J Mark Madison, Richard S Irwin Division of Pulmonary, Allergy, and Critical Care Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA 1
Snider GL. Emphysema: the first two centuries—and beyond. Am Rev Respir Dis 1992; 146: 1334–44 and 1615–22. Karlinsky JB, Snider GL. Animal models of emphysema. Am Rev Respir Dis 1978; 117: 1109–33. Laurell CB, Eriksson S. The electropheretic alpha-1-globulin pattern of serum in alpha-1antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15: 132–40. Gross P, Babyak MA, Tolker E, Kaschak M. Enzymatically produced pulmonary emphysema: a preliminary report. J Occup Med 1964; 6: 481–84. Irwins RS. Cough. In: Irwin RS, Curley FJ, Grossman RF, eds. Diagnosis and treatment of symptoms of the respiratory tract. Armonk, NY: Futura Publishing 1997: 1–54.
THE LANCET • Vol 352 • October 17, 1998