Journal of the Royal Soc
t Medicfie lume 84 February 1991
63
Editorials
Prospects for the treatment of multiple sclerosis Recent epidemiological studies have shown prevalence rates of multiple sclerosis (MS) of one per thousand of the population in the UK and elsewhere, twice the figures we taught our students 10 years ago. The reason for the apparent increase is largely improved case ascertainment but partly increased longevity and possibly a small increase in incidence'. In theory every general practitioner in Britain should have two or three patients on his list and every British neurologist should be managing 300 patients. Since epidemiological studies have shown that the occurrence of MS is related to geographical and genetic, especially immunogenetic, factors, it was reasonable to propose that even if MS could not be cured, it might be prevented. If a viral, toxic or nutritional cause were proved, it should be possible to produce a vaccine, avoid the toxin or supplement the diet. For instance if measles had turned out to be the cause, the measles vaccination programme might eventually have been followed by a decrease in the incidence of MS. As more and more research fails to demonstrate a single viral cause or a single autoimmune response, such a simple solution is increasingly untenable. Guillain-Barre syndrome (GBS), an acute peripheral nervous system demyelinating disease, is triggered by several different viruses, bacteria and vaccines and is associated with autoantibodies and cell mediated responses to a wide variety of Schwann cell and axonal antigens2. The clinical and pathological heterogeneity of MS, even greater than that of GBS, suggests that the aetiology or pathogenesis are also heterogeneous and a single vaccine is not at present a reasonable goal. Short sharp courses of steroids are the only therapeutic tool of proven benefit. Intramuscular ACTH and intravenous methylprednisolone have both been shown in controlled trials to hasten recovery from an acute relapse more rapidly than placebo3'4. Intravenous methylprednisolone is no less effective than ACTH5 and is currently the most fashionable. It is probable that oral steroids would be as effective and dose-ranging studies and comparative trials are necessary. So far these have been considered too boring to design or too trivial to fund, but the benefit to the patient of not needing injections or hospital admission should not be underestimated. The savings in hospitalization costs would soon pay for the trials. The last 20 years have seen modest advances in symptomatic treatment of MS and further gradual progress in this direction may be expected. Carbamazepine is dramatically successful for paroxysmal symptoms including trigeminal neuralgia, brainstem paroxysms and Lhermitte's symptom. Derivatives of carbamazepine or other drugs may
be developed which do not cause dose-limiting drowsiness or dizziness. Management of urinary retention by intermittent self-catherization has been a real advance for patients who retain sufficient use of their hands. Further improvements in the understanding and delivery of bladder care are likely and will be of tremendous benefit. Modern anticholinergic drugs, such as terodiline, and oxybutinin have been more effective than their progenitors: the pharmacologist who develops a drug which dries the bladder and not the mouth will earn our gratitude. Spasticity can be reduced with drugs and better drugs are being developed: these should benefit the chairbound patient and avoid the need for more invasive treatments such as intrathecal baclofen6. However anti-spasticity drugs will remain of marginal benefit to the patient who relies on strong but spastic leg muscles to continue walking. Attempts to restore blocked nerve conduction with drugs such as 3,4-diaminopyridine7 are unlikely to offer more than minor temporary palliation unless the ongoing myelin and axonal damage can be prevented. Perhaps the most distressing symptom for the patient and the most difficult for the neurologist to treat isthe overwhelming tiredness: amitriptyline and other anti-depressants are of limited benefit. This problem is likely to persist until we can prevent the gradual accumulation of plaques in the cerebral white matter which have been highlighted by magnetic resonance imaging8. What patients really want when they ask about treatment is some means of preventing disease progression. The answer at present is a shame-faced admission that no agent has found widespread acceptance in this regard. Single unconfirmed controlled trials suggest that very powerful immunosuppressive regimens arrest the progress of the disease for a year or two. However high dose intravenous cyclophosphamide causes total alopecia and carries the risk of bladder cancer9, total lymphoid irradiation causes amenorrhoea and has been too recently introduced for the risks to be known10"'1, and cyclosporin A causes a gradual rise in blood pressure and plasma creatininel2 3. Azathioprine, a less toxic immunosuppressive drug, had a marginal beneficial effect after three years on ambulation index in the largest controlled trial'4 and a meta-analysis of all trials showed a small but significant reduction in the number of relapses (Yudkin P and Hughes RAC, unpublished information). Unfortunately azathioprine cannot be tolerated by 10% of patients and carries a small increased risk of development of non-Hodgkin's lymphoma or skin cancer15. The evidence of efficacy of immunosuppressive treatments is now just sufficient to support an autoimmune component in the pathogenesis of MS and we may look forward to the development of immunosuppressive treatments which are better tolerated and not nephrotoxic. Unfortunately any broad spectrum immunosuppressive agent, even monoclonal antibodies directed against activated T cells alone16, is bound to carry
0141-0768/91/
020063-03/$02.00/0 © 1991 The Royal Society of Medicine
64
Journal of the Royal Society of Medicine Volume 84 February 1991
the risks of increased incidence of infection and probably neoplasia. Too little is made of physiotherapy. Uncontrolled observations suggest that experienced physiotherapists can reduce spasticity, improve gait patterns and increase functional independence. Little research has been devoted to the most effective types of physiotherapy or into the efficacy of regular long-term physiotherapeutic supervision. Benefits from physiotherapy, occupational therapy and appropriate aids are self-evident. What is needed as much as research is an improvement in the provision of these services to patients. Advances are being made in specific immunotherapy designed to remove or interfere with specific autoimmune responses. Examples include anti-idiotypic antibodies and production of anti-idiotypic T cells by vaccination. In experimental allergic encephalomyelitis depletion of T cells bearing a particular V beta T cell receptor gene eliminates all or most of the cells responding to myelin basic protein'7"8. Experimental allergic encephalomyelitis can also be inhibited by blockingthe major histocompatability class 2 molecule binding cleft with peptides which are recognized by the class 2 molecule but not the T cell receptor'9'20. If my gloomy hypothesis that MS has a multifactorial pathogenesis and aetiology is correct, this type of specific immunotherapy is unlikely to be successful. Whatever the aetiology and initial pathogenetic events in MS the final common pathway of immunologically mediated demyelination is macrophage stripping of myelin sheaths. In the peripheral nervous system model, experimental allergic neuritis, blocking macrophage function has been the most effective method of preventing or treating demyelination21. Large doses of steroids, known to be effective in MS, are one ofthe most effective ways of interferingwith macrophage function. It should be helpful to study the properties ofthe microglia/macrophages in CNS demyelinating lesions in the hope of identifying CNS specific biological properties which could be specifically inhibited. So long as the cause of MS remains undefined, efforts to improve treatment have to be divided between further empirical trials, study of the disease itself and research into the mechanisms of demyelination. The 1980s saw an increasing realization of the need to have trials with large enough numbers of patients to detect modest treatment effects22'23. One of the major endpoints in trials has been change on the Kurtzke disability scale which turns out not to change linearly with time12 and to have only limited reproducibility2" (Francis D, Bain P, Hughes RAC, in preparation). The development ofbetter scales of independent functions (disabilities) such as visual function, bulbar function, arm function and ambulation with non-ambiguous steps would improve the quality of future trials25. Development of new drugs to try will require continued interchange of ideas between laboratory and clinical scientist. All these programmes will require patience and perseverance from patient, researcher and grant-giving bodies.
Richard A C Hughes Department of Neurology United Medical and Dental Schools of Guy's and St Thomas's Hospitals Guys' Hospital London SEZ 9RT
References 1 Wynn DR, Rodriguez M, O'Fallon WM, Kurland LT. A reappraisal of the epidemiology of multiple sclerosis in Olmsted County, Minnesota. Neurology 1990;40:780-6 2 Hughes RAC. Guillain-Barre Syndrome. Heidelberg: Springer Verlag, 1990 3 Rose AS, Kuzma JW, Kurtzke JF, Namerow NS, Sibley WA, Tourtellotte WW. Cooperative study in the evaluation oftherapy in multiple sclerosis: ACTH versus placebo. Neurology (Minneap) 1970;20 (suppl):1-59 4 Milligan NM, Newcombe R, Compston DAS. A doubleblind controlled trial of high dose methylprednisolone in patients with multiple sclerosis. 1. Clinical effects. J Neurol Neurosurg Psychiatry 1987;50:511-16 5 Thompson AJ, Kennard C, Swash M, et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology 1989;39:969-71 6 Penn RD, Savoy SM, Corcos D, Latash M, Gottlieb G, Parke B, Kroin JS. Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989;320:1517-21 7 Bever CT Jr, Leslie J, Camenga DL, Panitch HS, Johnson KP. Preliminary trial of 3,4-diaminopyridine in patients with multiple sclerosis. Ann Neurol 1990; 27:421-7 8 Ormerod IEC, Miller DH, McDonald WI, et al. The role of NMR imaging in the assessment of MS and isolated neurological lesions. Brain 1987;110:1579-616 9 Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis: a randomised three-arm study of high dose intravenous cyclophosphamide, plasma exchange and ACTH. N Engl J Med 1983;308:173-80 10 Cook SD, Devereux C, Troiano R, et al. Effect of total lymphoid irradiation in chronic progressive multiple sclerosis. Lancet 1986;i:1405-8 11 Cook SD, Troiano R, Zito G, et al. Deaths after total lymphoid irradiation in multiple sclerosis. Lancet 1989; ii:277-8 12 The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: A randomized, double-blinded, placebocontrolled clinical trial. Ann Neurol 1990;27:591-605 13 Rudge P, Koetsier JC, Mertin J, Beyer JOM, van Walbeek HK, Clifford-Jones R, et al. Randomised double blind controlled trial of cyclosporin in multiple sclerosis. J Neurol Neurosurg Psychiatry 1989;52:559-65 14 British and Dutch Multiple Sclerosis Azathioprine Trial Group. Double-masked trial of azathioprine in multiple sclerosis. Lancet 1988;179-83 15 Kinlen LJ. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 1985;78 (suppl A): 44-9 16 Soulillou JP, Cantarovich D, Le MauffB, eta!. Randomizd controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal allografts. N Engi J Med 1990;322:1175-82 17 Heber-Katz E, Acha-Orbea H. The V-region hypothesis: evidence from autoimmune encephalomyelitis. Immunology Today 1989;10:164-9 18 Acha-Orbea H, Mitchell DJ, Timmermann L, et al. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 1988;54:263-73 19 Wraith DC, Smilek DE, Mitchell DJ, Steinman L, McDevitt HO. Antigen recognition in autoimmune encephalomyelitis and the potential for peptidemediated immunotherapy. Cell 1989;59:247-55 20 Urban JL, Horvath SJ, Hood L. Autoimmune T cells: immune recognition of normal and variant peptide epitopes and peptide-based therapy. Cell 1989;59:257-71 21 Hartung H-P, Schafer B, Heininger K, Stoll-G, Toyka KV. The role of macrophages and eicosanoids in the pathogenesis of experimental allergic neuritis. Brain 1988;111:1039-59
Journal of the Royal Society of Medicine Volume 84 February 1991 22 Brown JR, Beebe GW, Kurtzke JF, Loewenson RB, Silberberg DH, Tourtellotte WW. The design of clinical studies to assess therapeutic efficacy in multiple sclerosis. Neurology 1979;29:3-23 23 McKhann GM. The trials of clinical trials. Arch Neurol 1989;46:611-14 24 Noseworthy JH, Vandervoort MK, Wong CJ, Ebers GC.
Advanced medical courses at the Royal Society of Medicine Since January 1990 the Royal Society of Medicine, the British Postgraduate Medical Federation and the British Journal of Hospital Medicine have been working together to produce revision programmes, specialist short courses and postgraduate workshops. The first courses to be started are those relating to higher medical training and are geared towards MRCP part I and part II. There is also a one day cardiorespiratory course for those preparing the FCAnaes part III clinical section. The part I MRCP(UK) examination is usually taken about 2 years after qualification and comprises a multiple choice examination of 60 questions set from a bank of about 4000 questions. No syllabus is published but the Colleges have recently increased the emphasis on basic sciences which may now comprise up to 30% of the examination. Questions are set across the whole width of the medical specialties. The examination is essentially competitive with about the top 30% of candidates passing each time. Thus, the exact pass mark is variable and the successful candidate must perform better than his or her colleagues. Achieving this requires a sound knowledge of medicine and basic science; practising multiple choice question technique is also important as there is a penalty for each incorrect answer. There is a temptation for candidates to try and revise by obtaining as many multiple choice questions as possible (either from books available from medical publishers, or from MCQ banks within medical schools, or from previous candidates) in the hope that this will see them through the examination. This approach is quite rightly frowned upon by the Colleges as it does not improve understanding of the basic principles of the practice of medicine. The part II MRCP (UK) examination is taken a year or so after part I, when the cendidate has obtained at least a minimum of clinical experience in approved posts. This examination takes the form of a written paper with clinical spot slides and grey cases. Candidates who pass this (or only barely fail) are invited to take the clinical and viva sections. Revision for the clinical examination is more difficult as it is aimed at examining clinical expertise and judgement, rather than just factual 'book' knowledge. Unsuccessful candidates in either part are offered counselling and advice by the local College tutor. The problems of postgraduate training for hospital physicians are well known. Senior house officers are
65
Canadian Cooperative MS Study Group. Interrater variability with the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. Neurology 1990;40:971-5 25 Willoughby EW, Paty DW. Scales for rating impairment in multiple sclerosis: A critique. Neurology 1988;38:1793-8
in busy, short-term posts which offer little spare time for reading. Few receive formal teaching from their consultants or registrars and it seems that they are expected to learn by osmosis and experience. This process may well be good enough in the particular specialties in which the senior house officer works, but it is unlikely that any young doctor will have been exposed to all of the medical specialties by the time he or she takes part II, let alone part I of the MRCP. It is for this reason that we believe that courses are necessary to widen the candidate's exposure and understanding of medical specialties in which he or she has not held a specific appointment. Thus, the primary aim of our current courses is to increase the participants' awareness of specialties in which they have had little or no first hand experience or which have been badly taught at medical school; the secondary aim is to help candidates to obtain, by training, a few of the valuable extra percentage points which are so important in this competitive examination. Furthermore, it is essential that the candidates are brought up-to-date with recent advances in each specialty for there would otherwise be a requirement for a wide reading of specialist journals for which candidates simply do not have the time.
Our part I MRCP course is run three times each year and comprises 20 2-h sessions held at the Royal Society of Medicine from 6.30 pm to 8.30 pm over a period of 5 weeks. Each evening the tutors address a single specialist topic. The majority of sessions are woven around carefully chosen MCQ questions which have been written by the lecturer and updated for each course so that the basic scientific principles of the chosen subject can be dealt with in one or, at the most two sessions. The speakers use slides to illustrate their lectures and provide answers to the questions. The questions are provided in advance of each session so that candidates can work through them by way of preparation. In this way it is hoped that the participants will be aware oftheir areas of ignorance before arriving and will be receptive to the lecture. The lectures are interactive so that, during each session, the participants can clarify areas of uncertainty. For candidates who find it difficult to attend the evening course we also run a weekend condensed course which provides a total of eight 90 min specialist sessions. The part II course is a lecture and slide study built around grey cases which have been described in a precirculated book. In discussing carefully selected grey cases it is possible to cover large areas of clinical medicine in a way that is of value not only in the written section, but also in the viva, and even in the clinical part of the examination. The course comprises
0141-0768/91/ 020065-02/$02.00/0 © 1991
The Royal Society of Medicine
t Medicfie lume 84 February 1991
63
Editorials
Prospects for the treatment of multiple sclerosis Recent epidemiological studies have shown prevalence rates of multiple sclerosis (MS) of one per thousand of the population in the UK and elsewhere, twice the figures we taught our students 10 years ago. The reason for the apparent increase is largely improved case ascertainment but partly increased longevity and possibly a small increase in incidence'. In theory every general practitioner in Britain should have two or three patients on his list and every British neurologist should be managing 300 patients. Since epidemiological studies have shown that the occurrence of MS is related to geographical and genetic, especially immunogenetic, factors, it was reasonable to propose that even if MS could not be cured, it might be prevented. If a viral, toxic or nutritional cause were proved, it should be possible to produce a vaccine, avoid the toxin or supplement the diet. For instance if measles had turned out to be the cause, the measles vaccination programme might eventually have been followed by a decrease in the incidence of MS. As more and more research fails to demonstrate a single viral cause or a single autoimmune response, such a simple solution is increasingly untenable. Guillain-Barre syndrome (GBS), an acute peripheral nervous system demyelinating disease, is triggered by several different viruses, bacteria and vaccines and is associated with autoantibodies and cell mediated responses to a wide variety of Schwann cell and axonal antigens2. The clinical and pathological heterogeneity of MS, even greater than that of GBS, suggests that the aetiology or pathogenesis are also heterogeneous and a single vaccine is not at present a reasonable goal. Short sharp courses of steroids are the only therapeutic tool of proven benefit. Intramuscular ACTH and intravenous methylprednisolone have both been shown in controlled trials to hasten recovery from an acute relapse more rapidly than placebo3'4. Intravenous methylprednisolone is no less effective than ACTH5 and is currently the most fashionable. It is probable that oral steroids would be as effective and dose-ranging studies and comparative trials are necessary. So far these have been considered too boring to design or too trivial to fund, but the benefit to the patient of not needing injections or hospital admission should not be underestimated. The savings in hospitalization costs would soon pay for the trials. The last 20 years have seen modest advances in symptomatic treatment of MS and further gradual progress in this direction may be expected. Carbamazepine is dramatically successful for paroxysmal symptoms including trigeminal neuralgia, brainstem paroxysms and Lhermitte's symptom. Derivatives of carbamazepine or other drugs may
be developed which do not cause dose-limiting drowsiness or dizziness. Management of urinary retention by intermittent self-catherization has been a real advance for patients who retain sufficient use of their hands. Further improvements in the understanding and delivery of bladder care are likely and will be of tremendous benefit. Modern anticholinergic drugs, such as terodiline, and oxybutinin have been more effective than their progenitors: the pharmacologist who develops a drug which dries the bladder and not the mouth will earn our gratitude. Spasticity can be reduced with drugs and better drugs are being developed: these should benefit the chairbound patient and avoid the need for more invasive treatments such as intrathecal baclofen6. However anti-spasticity drugs will remain of marginal benefit to the patient who relies on strong but spastic leg muscles to continue walking. Attempts to restore blocked nerve conduction with drugs such as 3,4-diaminopyridine7 are unlikely to offer more than minor temporary palliation unless the ongoing myelin and axonal damage can be prevented. Perhaps the most distressing symptom for the patient and the most difficult for the neurologist to treat isthe overwhelming tiredness: amitriptyline and other anti-depressants are of limited benefit. This problem is likely to persist until we can prevent the gradual accumulation of plaques in the cerebral white matter which have been highlighted by magnetic resonance imaging8. What patients really want when they ask about treatment is some means of preventing disease progression. The answer at present is a shame-faced admission that no agent has found widespread acceptance in this regard. Single unconfirmed controlled trials suggest that very powerful immunosuppressive regimens arrest the progress of the disease for a year or two. However high dose intravenous cyclophosphamide causes total alopecia and carries the risk of bladder cancer9, total lymphoid irradiation causes amenorrhoea and has been too recently introduced for the risks to be known10"'1, and cyclosporin A causes a gradual rise in blood pressure and plasma creatininel2 3. Azathioprine, a less toxic immunosuppressive drug, had a marginal beneficial effect after three years on ambulation index in the largest controlled trial'4 and a meta-analysis of all trials showed a small but significant reduction in the number of relapses (Yudkin P and Hughes RAC, unpublished information). Unfortunately azathioprine cannot be tolerated by 10% of patients and carries a small increased risk of development of non-Hodgkin's lymphoma or skin cancer15. The evidence of efficacy of immunosuppressive treatments is now just sufficient to support an autoimmune component in the pathogenesis of MS and we may look forward to the development of immunosuppressive treatments which are better tolerated and not nephrotoxic. Unfortunately any broad spectrum immunosuppressive agent, even monoclonal antibodies directed against activated T cells alone16, is bound to carry
0141-0768/91/
020063-03/$02.00/0 © 1991 The Royal Society of Medicine
64
Journal of the Royal Society of Medicine Volume 84 February 1991
the risks of increased incidence of infection and probably neoplasia. Too little is made of physiotherapy. Uncontrolled observations suggest that experienced physiotherapists can reduce spasticity, improve gait patterns and increase functional independence. Little research has been devoted to the most effective types of physiotherapy or into the efficacy of regular long-term physiotherapeutic supervision. Benefits from physiotherapy, occupational therapy and appropriate aids are self-evident. What is needed as much as research is an improvement in the provision of these services to patients. Advances are being made in specific immunotherapy designed to remove or interfere with specific autoimmune responses. Examples include anti-idiotypic antibodies and production of anti-idiotypic T cells by vaccination. In experimental allergic encephalomyelitis depletion of T cells bearing a particular V beta T cell receptor gene eliminates all or most of the cells responding to myelin basic protein'7"8. Experimental allergic encephalomyelitis can also be inhibited by blockingthe major histocompatability class 2 molecule binding cleft with peptides which are recognized by the class 2 molecule but not the T cell receptor'9'20. If my gloomy hypothesis that MS has a multifactorial pathogenesis and aetiology is correct, this type of specific immunotherapy is unlikely to be successful. Whatever the aetiology and initial pathogenetic events in MS the final common pathway of immunologically mediated demyelination is macrophage stripping of myelin sheaths. In the peripheral nervous system model, experimental allergic neuritis, blocking macrophage function has been the most effective method of preventing or treating demyelination21. Large doses of steroids, known to be effective in MS, are one ofthe most effective ways of interferingwith macrophage function. It should be helpful to study the properties ofthe microglia/macrophages in CNS demyelinating lesions in the hope of identifying CNS specific biological properties which could be specifically inhibited. So long as the cause of MS remains undefined, efforts to improve treatment have to be divided between further empirical trials, study of the disease itself and research into the mechanisms of demyelination. The 1980s saw an increasing realization of the need to have trials with large enough numbers of patients to detect modest treatment effects22'23. One of the major endpoints in trials has been change on the Kurtzke disability scale which turns out not to change linearly with time12 and to have only limited reproducibility2" (Francis D, Bain P, Hughes RAC, in preparation). The development ofbetter scales of independent functions (disabilities) such as visual function, bulbar function, arm function and ambulation with non-ambiguous steps would improve the quality of future trials25. Development of new drugs to try will require continued interchange of ideas between laboratory and clinical scientist. All these programmes will require patience and perseverance from patient, researcher and grant-giving bodies.
Richard A C Hughes Department of Neurology United Medical and Dental Schools of Guy's and St Thomas's Hospitals Guys' Hospital London SEZ 9RT
References 1 Wynn DR, Rodriguez M, O'Fallon WM, Kurland LT. A reappraisal of the epidemiology of multiple sclerosis in Olmsted County, Minnesota. Neurology 1990;40:780-6 2 Hughes RAC. Guillain-Barre Syndrome. Heidelberg: Springer Verlag, 1990 3 Rose AS, Kuzma JW, Kurtzke JF, Namerow NS, Sibley WA, Tourtellotte WW. Cooperative study in the evaluation oftherapy in multiple sclerosis: ACTH versus placebo. Neurology (Minneap) 1970;20 (suppl):1-59 4 Milligan NM, Newcombe R, Compston DAS. A doubleblind controlled trial of high dose methylprednisolone in patients with multiple sclerosis. 1. Clinical effects. J Neurol Neurosurg Psychiatry 1987;50:511-16 5 Thompson AJ, Kennard C, Swash M, et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology 1989;39:969-71 6 Penn RD, Savoy SM, Corcos D, Latash M, Gottlieb G, Parke B, Kroin JS. Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989;320:1517-21 7 Bever CT Jr, Leslie J, Camenga DL, Panitch HS, Johnson KP. Preliminary trial of 3,4-diaminopyridine in patients with multiple sclerosis. Ann Neurol 1990; 27:421-7 8 Ormerod IEC, Miller DH, McDonald WI, et al. The role of NMR imaging in the assessment of MS and isolated neurological lesions. Brain 1987;110:1579-616 9 Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis: a randomised three-arm study of high dose intravenous cyclophosphamide, plasma exchange and ACTH. N Engl J Med 1983;308:173-80 10 Cook SD, Devereux C, Troiano R, et al. Effect of total lymphoid irradiation in chronic progressive multiple sclerosis. Lancet 1986;i:1405-8 11 Cook SD, Troiano R, Zito G, et al. Deaths after total lymphoid irradiation in multiple sclerosis. Lancet 1989; ii:277-8 12 The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: A randomized, double-blinded, placebocontrolled clinical trial. Ann Neurol 1990;27:591-605 13 Rudge P, Koetsier JC, Mertin J, Beyer JOM, van Walbeek HK, Clifford-Jones R, et al. Randomised double blind controlled trial of cyclosporin in multiple sclerosis. J Neurol Neurosurg Psychiatry 1989;52:559-65 14 British and Dutch Multiple Sclerosis Azathioprine Trial Group. Double-masked trial of azathioprine in multiple sclerosis. Lancet 1988;179-83 15 Kinlen LJ. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 1985;78 (suppl A): 44-9 16 Soulillou JP, Cantarovich D, Le MauffB, eta!. Randomizd controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal allografts. N Engi J Med 1990;322:1175-82 17 Heber-Katz E, Acha-Orbea H. The V-region hypothesis: evidence from autoimmune encephalomyelitis. Immunology Today 1989;10:164-9 18 Acha-Orbea H, Mitchell DJ, Timmermann L, et al. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 1988;54:263-73 19 Wraith DC, Smilek DE, Mitchell DJ, Steinman L, McDevitt HO. Antigen recognition in autoimmune encephalomyelitis and the potential for peptidemediated immunotherapy. Cell 1989;59:247-55 20 Urban JL, Horvath SJ, Hood L. Autoimmune T cells: immune recognition of normal and variant peptide epitopes and peptide-based therapy. Cell 1989;59:257-71 21 Hartung H-P, Schafer B, Heininger K, Stoll-G, Toyka KV. The role of macrophages and eicosanoids in the pathogenesis of experimental allergic neuritis. Brain 1988;111:1039-59
Journal of the Royal Society of Medicine Volume 84 February 1991 22 Brown JR, Beebe GW, Kurtzke JF, Loewenson RB, Silberberg DH, Tourtellotte WW. The design of clinical studies to assess therapeutic efficacy in multiple sclerosis. Neurology 1979;29:3-23 23 McKhann GM. The trials of clinical trials. Arch Neurol 1989;46:611-14 24 Noseworthy JH, Vandervoort MK, Wong CJ, Ebers GC.
Advanced medical courses at the Royal Society of Medicine Since January 1990 the Royal Society of Medicine, the British Postgraduate Medical Federation and the British Journal of Hospital Medicine have been working together to produce revision programmes, specialist short courses and postgraduate workshops. The first courses to be started are those relating to higher medical training and are geared towards MRCP part I and part II. There is also a one day cardiorespiratory course for those preparing the FCAnaes part III clinical section. The part I MRCP(UK) examination is usually taken about 2 years after qualification and comprises a multiple choice examination of 60 questions set from a bank of about 4000 questions. No syllabus is published but the Colleges have recently increased the emphasis on basic sciences which may now comprise up to 30% of the examination. Questions are set across the whole width of the medical specialties. The examination is essentially competitive with about the top 30% of candidates passing each time. Thus, the exact pass mark is variable and the successful candidate must perform better than his or her colleagues. Achieving this requires a sound knowledge of medicine and basic science; practising multiple choice question technique is also important as there is a penalty for each incorrect answer. There is a temptation for candidates to try and revise by obtaining as many multiple choice questions as possible (either from books available from medical publishers, or from MCQ banks within medical schools, or from previous candidates) in the hope that this will see them through the examination. This approach is quite rightly frowned upon by the Colleges as it does not improve understanding of the basic principles of the practice of medicine. The part II MRCP (UK) examination is taken a year or so after part I, when the cendidate has obtained at least a minimum of clinical experience in approved posts. This examination takes the form of a written paper with clinical spot slides and grey cases. Candidates who pass this (or only barely fail) are invited to take the clinical and viva sections. Revision for the clinical examination is more difficult as it is aimed at examining clinical expertise and judgement, rather than just factual 'book' knowledge. Unsuccessful candidates in either part are offered counselling and advice by the local College tutor. The problems of postgraduate training for hospital physicians are well known. Senior house officers are
65
Canadian Cooperative MS Study Group. Interrater variability with the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. Neurology 1990;40:971-5 25 Willoughby EW, Paty DW. Scales for rating impairment in multiple sclerosis: A critique. Neurology 1988;38:1793-8
in busy, short-term posts which offer little spare time for reading. Few receive formal teaching from their consultants or registrars and it seems that they are expected to learn by osmosis and experience. This process may well be good enough in the particular specialties in which the senior house officer works, but it is unlikely that any young doctor will have been exposed to all of the medical specialties by the time he or she takes part II, let alone part I of the MRCP. It is for this reason that we believe that courses are necessary to widen the candidate's exposure and understanding of medical specialties in which he or she has not held a specific appointment. Thus, the primary aim of our current courses is to increase the participants' awareness of specialties in which they have had little or no first hand experience or which have been badly taught at medical school; the secondary aim is to help candidates to obtain, by training, a few of the valuable extra percentage points which are so important in this competitive examination. Furthermore, it is essential that the candidates are brought up-to-date with recent advances in each specialty for there would otherwise be a requirement for a wide reading of specialist journals for which candidates simply do not have the time.
Our part I MRCP course is run three times each year and comprises 20 2-h sessions held at the Royal Society of Medicine from 6.30 pm to 8.30 pm over a period of 5 weeks. Each evening the tutors address a single specialist topic. The majority of sessions are woven around carefully chosen MCQ questions which have been written by the lecturer and updated for each course so that the basic scientific principles of the chosen subject can be dealt with in one or, at the most two sessions. The speakers use slides to illustrate their lectures and provide answers to the questions. The questions are provided in advance of each session so that candidates can work through them by way of preparation. In this way it is hoped that the participants will be aware oftheir areas of ignorance before arriving and will be receptive to the lecture. The lectures are interactive so that, during each session, the participants can clarify areas of uncertainty. For candidates who find it difficult to attend the evening course we also run a weekend condensed course which provides a total of eight 90 min specialist sessions. The part II course is a lecture and slide study built around grey cases which have been described in a precirculated book. In discussing carefully selected grey cases it is possible to cover large areas of clinical medicine in a way that is of value not only in the written section, but also in the viva, and even in the clinical part of the examination. The course comprises
0141-0768/91/ 020065-02/$02.00/0 © 1991
The Royal Society of Medicine
