664
intolerance
lactose
but
without tablet
underlying
of gastrointestinal disease, has 0-galactosidase derived from Aspergillus oryzae proved effective.15 These studies show the feasibility of enzyme replacement therapy. Whether the cost of this treatment compared with simple dietary exclusion will permit its general use is unclear, but in view of the frequency of symptoms, many practitioners will be tempted to try it. a
form
FJ. Primary adult lactose intolerance and the milking habit: a problem in biological and cultural interrelations. Am J Dig Dis 1970; 15:
1. Simoons
695-70.
Dahlqvist A, Borgström B. Digestion and absorption of disaccharides in man. Biochem J 1961; 81: 411-18. 3. Skovbjerg H, Sjöström H, Norén O. Purification and characterisation of amphiphilic lactase-phlorizin hydrolase from human small intestine. Eur J Biochem 1981; 114: 653-61. 4. Danielsen EM, Skovbjerg H, Norén O, Sjöstrom H. Biosynthesis of intestinal microvillar proteins. Intracellular processing of lactasephlorizin hydrolase. Biochem Biophys Res Commun 1984; 122: 82-90. 5. Mantei N, Villa M, Enzler T, et al. Complete primary structure of human and rabbit lactase-phlorizin hydrolase: implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J 1988; 7: 2.
2705-13. 6.
Freiburghaus AU, Schmitz J, Schindler M, et al. Protein patterns of brush disorder fragments in congenital lactose malabsorption and in specific hypolactasia of the adult. N Engl J Med 1976; 294: 1030-32. 7. Skovbjerg H, Gudman-Hoyer E, Fenger HJ. Immunoelectrophoretic studies on human small intestinal brush border proteins-amount of lactase in adult-type hypolactasia. Gut 1980; 21: 360-64. 8. Sterchi EE, Lentze MJ, Naim HY. Molecular aspects of disaccharide deficiencies. Baillière’s Clin Gastroenterol 1990; 4: 79-96. 9. Sebastio G, Villa M, Sartorio R, et al. Control of lactase in human adult-type hypolactasia and in weanling rabbits and rats. Am J Hum Genet 1989; 45: 489-97. 10. Nsi-Emvo J, Launay F, Raul F. Is adult-type hypolactasia in the intestine of mammals related to changes in the intracellular processing of lactose? Cell Mol Biol 1987; 33: 335-44. 11. Smith MV, James PS. Cellular origin of lactase decline in postweaned rats. Biochim Biophys Acta 1987; 707: 89-97. 12. King CE, Toskes PP. The use of breath tests in the study of malabsorption. Clin Gastroenterol 1983; 12: 591-610. 13. Newcomer AD, McGill DB, Thomas PJ, Hofmann AF. Prospective comparison of indirect methods for detecting lactase deficiency. N Engl
J Med 1975; 293: 1232-35. 14. Rosado JL, Solomons NW, Lisker R, et al. Enzyme replacement therapy for primary adult lactase deficiency. Gastroenterology 1984; 87: 1072-82. 15. Medow MS, Thek KD, Newman LJ, et al. &bgr;-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child 1990; 144: 1261-64.
Cochlear implants prove their worth There have been several important developments since
the
editoriah on cochlear consists of one or more implant implantation. electrodes in or adjacent to the cochlea; a receiverstimulator, usually in the mastoid process of the temporal bone; and an external speech processor. The trend away from single-channel devices towards multichannel implants has continued. The most commonly used prosthesis is the 22-channel ‘Nucleus’ (Cochlear Corporation), which uses digital signals. Another popular device is ’Ineraid’ (Richards Medical), a 6-channel implant which uses analogue signals. A comparative study of patients with these two types of implant carried out at the University of Iowa2 showed that the devices performed equally well when listening conditions were quiet but Ineraid was 1988
An
Lancet
better in background noise. The speech-processing strategy used for Nucleus was subsequently altered to overcome this deficiency. Research continues on new speech processing strategies; Wilson et al3 lately reported improved speech recognition with continuous interleaved sampling, in which the different electrodes are stimulated separately rather than simultaneously. What about complications? Cohen et al4 conducted a survey of one hundred and fifty-two American surgeons who were using the Nucleus implant. There were 55 reported complications associated with 459 operations, the overall complication rate being 11 8%. There were no deaths but meningitis developed in 1 patient. The 23 major complications included perilymph fistula (3), electrical problems (9), and severe facial nerve stimulation (1). The researchers felt that most of the complications were avoidable and recommended that would-be implant surgeons should attend training courses and practise the technique in a temporal bone laboratory before operating on patients. Webb and colleaguess reported the complications associated with the first 153 operations carried out in Hannover, Germany, and the first 100 in Melbourne, Australia; the Nucleus device was regularly used in both centres. Wound breakdown requiring removal of the implant occurred in 0-6% of cases in Hannover and 1% of cases in Melbourne. Other complications included wound infection, electrode tie erosion via the external auditory meatus, electrode slippage, persistent increase in tinnitus, and facial nerve stimulation. There were no cases of meningitis in either series. Webb et al emphasise the importance of care in the design and management of the skin flap raised at the time of surgery. Partial ossification of the cochlea was thought to be a relative contraindication to implantation. However, Balkany et al6have reported successful implants in 15 profoundly deaf patients with ossification of the basal turn of the cochlea. Some degree of speech discrimination subsequently developed in 9. Cochlear implantation for children remains controversial. Although one might think that children with prelingual profound deafness have most to gain from implantation, these patients are the most difficult to rehabilitate postoperatively because they have no previous experience of sound. In children with normal hearing speech develops during the first 5 years of life;7 it seems that after the age of 7 the central nervous system is no longer able readily to acquire speech perception. Experience with implants in prelingually deaf individuals lends support to this view, but it must be borne in mind that an implant does not give normal hearing and that the degree of acquisition of speech discrimination varies from patient to patient. Theoretically, however, the ideal time for implantation in childhood would be during the first 3 years of life. The drawbacks are the difficulty in establishing that a child of that age is deaf enough to be
665
candidate for implantation and the complexities of surgery in young children. There is additional uncertainty about the effects of growth on the long-term fate of the implant. Luxford et al8reported the outcome of implantation in a 2-year-old prelingually deaf child. Her behaviour improved after implantation and she was able to produce a few more intelligible words. With respect to implantation in elderly people, Horn et al9 reported a successful outcome in patients over 65 years. The results of their survey suggest that this group did just as well as younger adults. Thus, cochlear implants are now established as a recognised treatment for profound deafness and many more deaf people could benefit from them. In the UK the Government has agreed to fund implantation within the National Health Service; previously such operations had been financed by charitable donations. The existing implantation centres are to be funded and several additional centres are being established around the country. In other European countries and in North America, cochlear implantation has been well established for several years. a
1. Editorial. Cochlear implantation for the profoundly deaf. Lancet 1988; i: 686-87. 2. Gantz BJ, Tyler RS, Knutson JF, et al. Evaluation of 5 different cochlear implant designs: audiologic assessment and predictors of performance. Laryngoscope 1988; 98: 1100-06. 3. Wilson BS, Finley CC, Lawson DT, Wolford RD, Eddington D, Rabinowitz WM. Better speech recognition with cochlear implants. Nature 1991; 352: 236-38. 4. Cohen ML, Hoffman RA, Stronschen M. Medical or surgical complications related to the Nucleus multichannel cochlear implant. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 8-13. 5. Webb RL, Lenhardt E, Clark GM, et al. Surgical complications with the cochlear multiple-channel intracochlear implant. Ann Otol Rhinol Laryngol 1991; 100: 131-36. 6. Balkany T, Gantz B, Nadol JB. Multichannel cochlear implants in partially ossified cochleas. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 3-7. 7. McCormick B. Paediatric cochlear implantation in the UK-a delayed journey on a well marked route. Br J Audiol 1991; 25: 145-49. 8. Luxford WM, House WF, Hough JVD, et al. Experiences with the Nucleus multichannel cochlear implant in three young children. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 14-16. 9. Horn K, McMahon NB, Lewis JS, et al. Functional use of the Nucleus 22-channel cochlear implant in the elderly. Laryngoscope 1991; 101: 284-88.
Informed consent: how informed? Most activities carried out by doctors have a simple benevolent aim, even if the means of achieving it may be tortuous and the outcome sometimes questionable. Medical research shares this aim with one vital difference-the patient who participates in research may not benefit personally and may be inconvenienced or even harmed. If there are rewards to be reaped others may therefore reap them later. What motivates patients to participate in research? For some, participation is a purely philanthropic gesture; other reasons include direct financial inducements, a desire to oblige the doctor, or the hope of obtaining the latest treatment. For researchers the first motive is the ideal, but in the enterprise society
various
inducements
are
assuming
greater
importance. To avoid harming the participants, there have to be constraints-eg, ethical committee review. Another powerful constraint is telling the patient what he is volunteering to undergo. The Nuremberg War Crimes judges laid down ten basic principles, of which the first was that voluntary consent of the subject was essential. This consent requires that the subject should have sufficient knowledge and comprehension of what is proposed for him to make an "understanding and enlightened decision". Knowledge includes understanding the nature, purpose, and methods of the study, and the possible effects on the subject. The Declaration of Helsinki2
re-emphasised these fundamental obligations on medical researchers. Like other self-evident truths, the need for informed consent has not always been universally recognised, even after the Nuremberg judges stated it so plainly. The columns of the Lancet bear witness to "research by fraud"3 and research verging on "common assault",4in which patients participated in pure research disguised as clinical investigation or treatment. Pappworth,s5 in his celebrated polemic, described dental extractions in which cardiac catheterisation was carried out unknown to the patient. It is difficult not to sympathise with his conclusion that there was a fraudulent element in this research. Even more questionable was the attitude of the cardiologist with whom this work was discussed-he felt that it would be sufficient, to secure their consent, to tell patients that a small sample of blood was to be removed. Such happenings are far removed from the guidelines produced for the modem generation of clinical researchers.6,7 There are two reasons for a more
enlightened approach. First, cynical deception
seldom survives exposure even before formal mechanisms to correct abuses have been established. For this reason autocrats, whether medical or political, are well advised to avoid too much media exposure. Secondly and more creditably, medical practice has been increasingly concerned with respect for patients as autonomous beings whose needs include freedom to plan their own lives and happiness.8 Discussion may not be enough for patients to acquire sufficient knowledge to make informed decisions. The Royal College of Physicians recommends an information sheet, time to reflect, and (in most cases) a written consent form.6 The Association of the British Pharmaceutical Industry (ABPI) is less specific but also favours written consent and provision of all "pertinent information".But what is relevant/pertinent? Patients may have difficulty grasping concepts of probability and risk, especially of "minimal risk". Even the simple analogy of travelling as a scheduled passenger on an airline9 is likely to deter many potential recruits. A list of adverse effects may be factually correct but nevertheless present a bleak picture to the uninitiated.
intolerance
lactose
but
without tablet
underlying
of gastrointestinal disease, has 0-galactosidase derived from Aspergillus oryzae proved effective.15 These studies show the feasibility of enzyme replacement therapy. Whether the cost of this treatment compared with simple dietary exclusion will permit its general use is unclear, but in view of the frequency of symptoms, many practitioners will be tempted to try it. a
form
FJ. Primary adult lactose intolerance and the milking habit: a problem in biological and cultural interrelations. Am J Dig Dis 1970; 15:
1. Simoons
695-70.
Dahlqvist A, Borgström B. Digestion and absorption of disaccharides in man. Biochem J 1961; 81: 411-18. 3. Skovbjerg H, Sjöström H, Norén O. Purification and characterisation of amphiphilic lactase-phlorizin hydrolase from human small intestine. Eur J Biochem 1981; 114: 653-61. 4. Danielsen EM, Skovbjerg H, Norén O, Sjöstrom H. Biosynthesis of intestinal microvillar proteins. Intracellular processing of lactasephlorizin hydrolase. Biochem Biophys Res Commun 1984; 122: 82-90. 5. Mantei N, Villa M, Enzler T, et al. Complete primary structure of human and rabbit lactase-phlorizin hydrolase: implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J 1988; 7: 2.
2705-13. 6.
Freiburghaus AU, Schmitz J, Schindler M, et al. Protein patterns of brush disorder fragments in congenital lactose malabsorption and in specific hypolactasia of the adult. N Engl J Med 1976; 294: 1030-32. 7. Skovbjerg H, Gudman-Hoyer E, Fenger HJ. Immunoelectrophoretic studies on human small intestinal brush border proteins-amount of lactase in adult-type hypolactasia. Gut 1980; 21: 360-64. 8. Sterchi EE, Lentze MJ, Naim HY. Molecular aspects of disaccharide deficiencies. Baillière’s Clin Gastroenterol 1990; 4: 79-96. 9. Sebastio G, Villa M, Sartorio R, et al. Control of lactase in human adult-type hypolactasia and in weanling rabbits and rats. Am J Hum Genet 1989; 45: 489-97. 10. Nsi-Emvo J, Launay F, Raul F. Is adult-type hypolactasia in the intestine of mammals related to changes in the intracellular processing of lactose? Cell Mol Biol 1987; 33: 335-44. 11. Smith MV, James PS. Cellular origin of lactase decline in postweaned rats. Biochim Biophys Acta 1987; 707: 89-97. 12. King CE, Toskes PP. The use of breath tests in the study of malabsorption. Clin Gastroenterol 1983; 12: 591-610. 13. Newcomer AD, McGill DB, Thomas PJ, Hofmann AF. Prospective comparison of indirect methods for detecting lactase deficiency. N Engl
J Med 1975; 293: 1232-35. 14. Rosado JL, Solomons NW, Lisker R, et al. Enzyme replacement therapy for primary adult lactase deficiency. Gastroenterology 1984; 87: 1072-82. 15. Medow MS, Thek KD, Newman LJ, et al. &bgr;-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child 1990; 144: 1261-64.
Cochlear implants prove their worth There have been several important developments since
the
editoriah on cochlear consists of one or more implant implantation. electrodes in or adjacent to the cochlea; a receiverstimulator, usually in the mastoid process of the temporal bone; and an external speech processor. The trend away from single-channel devices towards multichannel implants has continued. The most commonly used prosthesis is the 22-channel ‘Nucleus’ (Cochlear Corporation), which uses digital signals. Another popular device is ’Ineraid’ (Richards Medical), a 6-channel implant which uses analogue signals. A comparative study of patients with these two types of implant carried out at the University of Iowa2 showed that the devices performed equally well when listening conditions were quiet but Ineraid was 1988
An
Lancet
better in background noise. The speech-processing strategy used for Nucleus was subsequently altered to overcome this deficiency. Research continues on new speech processing strategies; Wilson et al3 lately reported improved speech recognition with continuous interleaved sampling, in which the different electrodes are stimulated separately rather than simultaneously. What about complications? Cohen et al4 conducted a survey of one hundred and fifty-two American surgeons who were using the Nucleus implant. There were 55 reported complications associated with 459 operations, the overall complication rate being 11 8%. There were no deaths but meningitis developed in 1 patient. The 23 major complications included perilymph fistula (3), electrical problems (9), and severe facial nerve stimulation (1). The researchers felt that most of the complications were avoidable and recommended that would-be implant surgeons should attend training courses and practise the technique in a temporal bone laboratory before operating on patients. Webb and colleaguess reported the complications associated with the first 153 operations carried out in Hannover, Germany, and the first 100 in Melbourne, Australia; the Nucleus device was regularly used in both centres. Wound breakdown requiring removal of the implant occurred in 0-6% of cases in Hannover and 1% of cases in Melbourne. Other complications included wound infection, electrode tie erosion via the external auditory meatus, electrode slippage, persistent increase in tinnitus, and facial nerve stimulation. There were no cases of meningitis in either series. Webb et al emphasise the importance of care in the design and management of the skin flap raised at the time of surgery. Partial ossification of the cochlea was thought to be a relative contraindication to implantation. However, Balkany et al6have reported successful implants in 15 profoundly deaf patients with ossification of the basal turn of the cochlea. Some degree of speech discrimination subsequently developed in 9. Cochlear implantation for children remains controversial. Although one might think that children with prelingual profound deafness have most to gain from implantation, these patients are the most difficult to rehabilitate postoperatively because they have no previous experience of sound. In children with normal hearing speech develops during the first 5 years of life;7 it seems that after the age of 7 the central nervous system is no longer able readily to acquire speech perception. Experience with implants in prelingually deaf individuals lends support to this view, but it must be borne in mind that an implant does not give normal hearing and that the degree of acquisition of speech discrimination varies from patient to patient. Theoretically, however, the ideal time for implantation in childhood would be during the first 3 years of life. The drawbacks are the difficulty in establishing that a child of that age is deaf enough to be
665
candidate for implantation and the complexities of surgery in young children. There is additional uncertainty about the effects of growth on the long-term fate of the implant. Luxford et al8reported the outcome of implantation in a 2-year-old prelingually deaf child. Her behaviour improved after implantation and she was able to produce a few more intelligible words. With respect to implantation in elderly people, Horn et al9 reported a successful outcome in patients over 65 years. The results of their survey suggest that this group did just as well as younger adults. Thus, cochlear implants are now established as a recognised treatment for profound deafness and many more deaf people could benefit from them. In the UK the Government has agreed to fund implantation within the National Health Service; previously such operations had been financed by charitable donations. The existing implantation centres are to be funded and several additional centres are being established around the country. In other European countries and in North America, cochlear implantation has been well established for several years. a
1. Editorial. Cochlear implantation for the profoundly deaf. Lancet 1988; i: 686-87. 2. Gantz BJ, Tyler RS, Knutson JF, et al. Evaluation of 5 different cochlear implant designs: audiologic assessment and predictors of performance. Laryngoscope 1988; 98: 1100-06. 3. Wilson BS, Finley CC, Lawson DT, Wolford RD, Eddington D, Rabinowitz WM. Better speech recognition with cochlear implants. Nature 1991; 352: 236-38. 4. Cohen ML, Hoffman RA, Stronschen M. Medical or surgical complications related to the Nucleus multichannel cochlear implant. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 8-13. 5. Webb RL, Lenhardt E, Clark GM, et al. Surgical complications with the cochlear multiple-channel intracochlear implant. Ann Otol Rhinol Laryngol 1991; 100: 131-36. 6. Balkany T, Gantz B, Nadol JB. Multichannel cochlear implants in partially ossified cochleas. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 3-7. 7. McCormick B. Paediatric cochlear implantation in the UK-a delayed journey on a well marked route. Br J Audiol 1991; 25: 145-49. 8. Luxford WM, House WF, Hough JVD, et al. Experiences with the Nucleus multichannel cochlear implant in three young children. Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 14-16. 9. Horn K, McMahon NB, Lewis JS, et al. Functional use of the Nucleus 22-channel cochlear implant in the elderly. Laryngoscope 1991; 101: 284-88.
Informed consent: how informed? Most activities carried out by doctors have a simple benevolent aim, even if the means of achieving it may be tortuous and the outcome sometimes questionable. Medical research shares this aim with one vital difference-the patient who participates in research may not benefit personally and may be inconvenienced or even harmed. If there are rewards to be reaped others may therefore reap them later. What motivates patients to participate in research? For some, participation is a purely philanthropic gesture; other reasons include direct financial inducements, a desire to oblige the doctor, or the hope of obtaining the latest treatment. For researchers the first motive is the ideal, but in the enterprise society
various
inducements
are
assuming
greater
importance. To avoid harming the participants, there have to be constraints-eg, ethical committee review. Another powerful constraint is telling the patient what he is volunteering to undergo. The Nuremberg War Crimes judges laid down ten basic principles, of which the first was that voluntary consent of the subject was essential. This consent requires that the subject should have sufficient knowledge and comprehension of what is proposed for him to make an "understanding and enlightened decision". Knowledge includes understanding the nature, purpose, and methods of the study, and the possible effects on the subject. The Declaration of Helsinki2
re-emphasised these fundamental obligations on medical researchers. Like other self-evident truths, the need for informed consent has not always been universally recognised, even after the Nuremberg judges stated it so plainly. The columns of the Lancet bear witness to "research by fraud"3 and research verging on "common assault",4in which patients participated in pure research disguised as clinical investigation or treatment. Pappworth,s5 in his celebrated polemic, described dental extractions in which cardiac catheterisation was carried out unknown to the patient. It is difficult not to sympathise with his conclusion that there was a fraudulent element in this research. Even more questionable was the attitude of the cardiologist with whom this work was discussed-he felt that it would be sufficient, to secure their consent, to tell patients that a small sample of blood was to be removed. Such happenings are far removed from the guidelines produced for the modem generation of clinical researchers.6,7 There are two reasons for a more
enlightened approach. First, cynical deception
seldom survives exposure even before formal mechanisms to correct abuses have been established. For this reason autocrats, whether medical or political, are well advised to avoid too much media exposure. Secondly and more creditably, medical practice has been increasingly concerned with respect for patients as autonomous beings whose needs include freedom to plan their own lives and happiness.8 Discussion may not be enough for patients to acquire sufficient knowledge to make informed decisions. The Royal College of Physicians recommends an information sheet, time to reflect, and (in most cases) a written consent form.6 The Association of the British Pharmaceutical Industry (ABPI) is less specific but also favours written consent and provision of all "pertinent information".But what is relevant/pertinent? Patients may have difficulty grasping concepts of probability and risk, especially of "minimal risk". Even the simple analogy of travelling as a scheduled passenger on an airline9 is likely to deter many potential recruits. A list of adverse effects may be factually correct but nevertheless present a bleak picture to the uninitiated.
