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Immunological Aspects of Carcinomatous Neuropathy
1112
Immunological Aspects of Carcinomatous Neuropathy ALTHOUGH a wide range of non-metastatic syndromes is known to affect the neuromuscular system in patients with malignant disease, the pathogenesis of these disorders remains totally obscure. New investigations have now raised the possibility that immunological mechanisms may play a part in the development of certain of these syndromes. Evidence is accumulating that tumours often differ antigenically from their parent tissue, and new antigenic substances may be produced by them which might be treated by the body as foreign. If determinants were shared between these tumour antigens and tissues such as brain or muscle, an immune reaction might be set up against the patient’s own neuromuscular system. Possibly, antigens in cells such as neurones are normally sequestered from contact with
immunologically competent cells. Damage to neurones from some other cause might result either in leak of these antigens or in modification of their determinant structure with the stimulation of
an immune response as a BURNET 1 has suggested that secondary phenomenon. somatic mutation of pathogenic cell clones is an operative factor both in autoimmune reactions and in cancer. Mutation of clones of immunologically competent cells reactive against neuromuscular antigens may be more likely to occur in certain types of malignant disease.
pointer to the relationship between malignancy, the system, and the immunologically competent cell came with the several descriptions of demyelinating encephalitis in association with neoplasms of the reticuloendothelial system discussed by CAVANAGH et a1.2 Although no immune mechanism was shown to operate in these cases, a recent report3 describes deficiencies in the serum level of immunoglobulins, particularly yA-globulin, with thymic abnormalities and malignant tumours of lymphoid tissue in ataxia-telangiectasia (a genetically determined syndrome consisting of progressive cerebellar ataxia with cutaneous telangiectasia and recurrent respiratory infection); and this again suggests an immunological connection between malignant A
nervous
and the nervous system. The earliest direct evidence of the presence of circulating antibody in carcinomatous neuromyopathy came in two reports of patients with carcinoma and dermatomyositis. It was shown, firstly in a case of breast tumour4 and later in a case of bronchial tumour,5 that the serum contained antibodies capable of transmitting skin sensitivity against the patient’s own tumour tissue to a normal individual as judged by the PrausnitzKustner reaction. Reaginic antibodies of this type might easily be overlooked, since they would not be detected by in-vitro laboratory tests. WILKINSONhas now detected complement-fixing antibodies against brain in patients
tumours
1.
2. 3. 4. 5.
6.
Burnet, F. M. The Clonal Selection Theory of Acquired Immunity. London, 1959. Cavanagh, J. B., Greenbaum, D., Marshall, A. H. E., Rubinstein, L. J. Lancet, 1959, ii, 524. Peterson, R. D. A., Kelly, W. D., Good, R. A. ibid. 1964, i, 1189. Grace, J. T., Dao, T. L. Cancer, N.Y. 1959, 12, 648. Curtis, A. C., Heckaman, J. H., Wheeler, A. H. J. Am. med. Ass. 1961, 178, 571. Wilkinson, P. C. Lancet, 1964, i, 1301.
with sensory carcinomatous neuropathy but not with other types of carcinomatous neuromyopathy. The suggestion that these antibodies were active against an antigen localised in neurones has been confirmed by WILKINSON and ZEROMSKI,7 who, using a fluorescent antibody technique, showed a reaction between sera from these patients and cytoplasmic granules present in neurones from all parts of the central nervous system and absent from other tissues. Though the finding of an antibody against neurones excites speculation that an immune mechanism may operate in these patients, circulating antibodies do not, by themselves, amount to an autoimmune disease. An important feature of diseases such as Hashimoto’s thyroiditis is local infiltration with lymphocytes and plasma cells and destruction of the normal thyroid architecture. Infiltration of the central nervous system and particularly of the dorsal-root ganglia with immunologically competent cells is seen in sensory neuropathy but is by no means always very striking.8 Destruction of neurones is also characteristic. Necropsy material, taken at the end of a disease, may not, however, reflect pathogenetic processes which took place many months earlier. HENSON et al. suggested9 on histological and clinical grounds that sensory neuropathy and the encephalo-
myelitic form of carcinomatous neuropathy are variants of the same disease process. In the encephalomyelitic syndrome lymphocytic infiltration of the central nervous system is very striking. The site of the lesions and the course of the disease have led to the suggestion 10 that this is a virus infection, though no experimental evidence has yet come to light to support this hypothesis. Such a virus might be carried by the tumour cells themselves. Conceivably, a viral attack on the nervous system might stimulate an immune response against liberated or modified c.N.s. antigens. Alternatively virus-modified tumour cells may themselves act as antigens and excite the formation of antibodies which react against neurones. One histological finding which could point to a common factor (be it cell antigen, virus, or other) in tumours from these patients is the suggestive association noted by DAYAN et al." between the occurrence of the sensory and encephalomyelitic forms of neuropathy and bronchial carcinoma of the oat-cell type. The answers to many questions about carcinomatous neuropathy may lie in future studies of the antigenic and metabolic behaviour of these tumours. If tumour viruses or tumour antigens, for instance, are related to the lesions of neuropathy, then injection of tumour extracts in Freund’s complete adjuvant into laboratory animals might incite antibody formation or hypersensitivity reactions against brain tissue. If such an immune response to these tumours could be incited in animals, an autoimmune mechanism might be tested for by transfer of immunologically competent cells to normal animals. In other forms of carcinomatous neuromyopathy, 7. Wilkinson, P. C., Zeromski, J. Brain, 1965, 88, 529. 8. Croft, P. B., Henson, R. A., Urich, H., Wilkinson, P. C. ibid. p. 501. 9. Henson, R. A., Hoffman, H. L., Urich, H. ibid. p. 449. 10. Henson, R. A., Russell, D. S., Wilkinson, M. ibid, 1954, 77, 82. 11. Dayan, A. D., Croft, P. B., Wilkinson, M. ibid. 1965, 88, 435.
1113
scantier. The pathogenesis of subacute cerebellar degeneration, for example, is quite unknown, although BRAIN and WILKINSON 12 point to the resemblances between this disease and kuru, and they mention recent "speculations of BURNET 13 that kuru may be due to a persisting tolerated infection " with virus which occasionally produces a leak of cerebellar antigen, which in turn may stimulate the proliferation of pathogenic clones of immunocytes with the production of a subsequent vicious-circle autoimmune reaction. In the largest group of all numerically-those patients with carcinoma who present with predominantly motor symptoms-inflammatory lesions were found on muscle biopsy, although not more commonly so than in patients with " idiopathic myopathy" .14 Antibodies against muscle and brain have not been demonstrated in this group of patients, and the xtiology of the syndrome remains unknown.
suggestive findings
are
Drug
Addiction
THE Interdepartmental Committee on Drug Addiction had the misfortune to make its original report 15 in 1961, when there had been no increase in new addictions for three or four years. At that time the committee saw no necessity to recommend any positive action-neither registration of addicts nor their compulsory committal for treatment, nor special institutions for the purpose, nor special tribunals to investigate prescribing, nor further statutory controls of any kind. Only three years later, following suggestions 16 that all was not well, the committee was reconvened " to consider whether, in the light of recent experience, the advice they gave in 1961 in relation to the prescribing of addictive drugs by doctors needs revising and, if so, to make recommendations." " In only fifteen months the committee has now reversed 1 in almost every particular the advice that it previously took three years to offer, as well as adding some further, largely conservative recommendations. Though the report may receive a general welcome, it is inadequate in many ways. The positive proposals fall under four main headings: (a) compulsory " notification to a central authority (rather than " registration " with its connotation of acceptance) as in the case of certain infectious diseases, the analogy with which is appreciated 16 ; (b) the establishment of treatment centres especially in the London area, although it is suggested that each regional hospital board should designate such a centre of its own; (c) powers for compulsory detention of addicts, particularly during the withdrawal crisis; (d) the limitation to treatment-centre medical staff only of the right to prescribe heroin and cocaine for addicts; it would then be a statutory offence for other doctors to prescribe these drugs to an addict. The committee also recommends "
12. Brain, Wilkinson, M. ibid. p. 465. 13. Burnet, F. M. Lancet, 1965, i, 1141. 14. Shy, G. M., Silverstein, I. Brain, 1965, 88, 515. 15. Interdepartmental Committee on Drug Addiction: Report H.M. Stationery Office, 1961. 16. Lancet, 1964, i, 649. Chapple, P.A.L. 1964, ii, 649. 17. Interdepartmental Committee on Drug Addiction: Second H.M. Stationery Office, 1965.
that doctors should prescribe dangerous drugs in words and figures to reduce the risk of forgery, and that an advisory committee should be established to survey the whole field " of dangerous and dependency-inducing drugs with " authority to advise on corrective health and social measures ". Some will be unhappy about these proposals. Controls interfere with individual freedom: in this instance, perhaps even more with that of the doctor than with that of the addict. It certainly seems very hard that the whole profession should suffer this limitation on its professional judgment because " the major source of supply has been the activity of a very few doctors who have prescribed excessively for addicts ": in fact, not more than six doctors, one of whom prescribed nearly 6 kg. of heroin for addicts in 1962, or approximately 15% of the total heroin consumption in the United Kingdom in that year. If this judgment is fair, the conscience of the six must bear a heavy burden, even though they are found to have " acted within the law and according to their professional judgment". Nevertheless, the profession as a whole might be wise to accept the limitation, which is likely to save it much frustration in an area where therapy "
by non-specialists is virtually impossible. In fact, it can even be argued that the committee’s recommendations do not go far enough in this direction. For example, there are no longer any indications for the general use of cocaine, and its prescription should be prohibited. Less debatably, the prescription of any dangerous drug besides heroin and cocaine to an addict by any doctor not on the staff of a treatment centre might be prohibited. It is precisely here, otherwise, that history is in danger of repeating itself. Just as in 1961 the committee failed to see the significance of the sevenfold increase in seven years in addictions to heroin and cocaine against the apparently static total of all addictions, it has apparently again comforted itself with the belief that the extent of addiction to dangerous drugs other than heroin and cocaine remains " more or less the same ". This is demonstrably false, for although addiction to morphine is now apparently very slowly declining and addiction to methadone is now constant, even addiction to petliidine has increased by an average of almost 10% per annum since 1961, and the total number of addictions to manufactured drugs other than those already mentioned has more than doubled since 1961. For this, dextromonamide and dipipanone, both drugs not manufactured before 1959, are mainly responsible.17 About 1 in every 14 addicts known to the Home Office is taking one or other of these drugs: incidentally, the use of heroin itself, without cocaine, has also doubled in the past year. There seems little reason to think that doctors inexperienced in the recognition and handling of addicts will insist on retaining their freedom to withstand the increased demands made upon them, as addicts change their habits in order to avoid commission to the proposed treatment centres. "
(1961).
of a Report.
Treatment centre "
itself, in fact, seems something euphemism for "prescribing centre", although the
report
speaks
of
" provision
for research " and the
Immunological Aspects of Carcinomatous Neuropathy ALTHOUGH a wide range of non-metastatic syndromes is known to affect the neuromuscular system in patients with malignant disease, the pathogenesis of these disorders remains totally obscure. New investigations have now raised the possibility that immunological mechanisms may play a part in the development of certain of these syndromes. Evidence is accumulating that tumours often differ antigenically from their parent tissue, and new antigenic substances may be produced by them which might be treated by the body as foreign. If determinants were shared between these tumour antigens and tissues such as brain or muscle, an immune reaction might be set up against the patient’s own neuromuscular system. Possibly, antigens in cells such as neurones are normally sequestered from contact with
immunologically competent cells. Damage to neurones from some other cause might result either in leak of these antigens or in modification of their determinant structure with the stimulation of
an immune response as a BURNET 1 has suggested that secondary phenomenon. somatic mutation of pathogenic cell clones is an operative factor both in autoimmune reactions and in cancer. Mutation of clones of immunologically competent cells reactive against neuromuscular antigens may be more likely to occur in certain types of malignant disease.
pointer to the relationship between malignancy, the system, and the immunologically competent cell came with the several descriptions of demyelinating encephalitis in association with neoplasms of the reticuloendothelial system discussed by CAVANAGH et a1.2 Although no immune mechanism was shown to operate in these cases, a recent report3 describes deficiencies in the serum level of immunoglobulins, particularly yA-globulin, with thymic abnormalities and malignant tumours of lymphoid tissue in ataxia-telangiectasia (a genetically determined syndrome consisting of progressive cerebellar ataxia with cutaneous telangiectasia and recurrent respiratory infection); and this again suggests an immunological connection between malignant A
nervous
and the nervous system. The earliest direct evidence of the presence of circulating antibody in carcinomatous neuromyopathy came in two reports of patients with carcinoma and dermatomyositis. It was shown, firstly in a case of breast tumour4 and later in a case of bronchial tumour,5 that the serum contained antibodies capable of transmitting skin sensitivity against the patient’s own tumour tissue to a normal individual as judged by the PrausnitzKustner reaction. Reaginic antibodies of this type might easily be overlooked, since they would not be detected by in-vitro laboratory tests. WILKINSONhas now detected complement-fixing antibodies against brain in patients
tumours
1.
2. 3. 4. 5.
6.
Burnet, F. M. The Clonal Selection Theory of Acquired Immunity. London, 1959. Cavanagh, J. B., Greenbaum, D., Marshall, A. H. E., Rubinstein, L. J. Lancet, 1959, ii, 524. Peterson, R. D. A., Kelly, W. D., Good, R. A. ibid. 1964, i, 1189. Grace, J. T., Dao, T. L. Cancer, N.Y. 1959, 12, 648. Curtis, A. C., Heckaman, J. H., Wheeler, A. H. J. Am. med. Ass. 1961, 178, 571. Wilkinson, P. C. Lancet, 1964, i, 1301.
with sensory carcinomatous neuropathy but not with other types of carcinomatous neuromyopathy. The suggestion that these antibodies were active against an antigen localised in neurones has been confirmed by WILKINSON and ZEROMSKI,7 who, using a fluorescent antibody technique, showed a reaction between sera from these patients and cytoplasmic granules present in neurones from all parts of the central nervous system and absent from other tissues. Though the finding of an antibody against neurones excites speculation that an immune mechanism may operate in these patients, circulating antibodies do not, by themselves, amount to an autoimmune disease. An important feature of diseases such as Hashimoto’s thyroiditis is local infiltration with lymphocytes and plasma cells and destruction of the normal thyroid architecture. Infiltration of the central nervous system and particularly of the dorsal-root ganglia with immunologically competent cells is seen in sensory neuropathy but is by no means always very striking.8 Destruction of neurones is also characteristic. Necropsy material, taken at the end of a disease, may not, however, reflect pathogenetic processes which took place many months earlier. HENSON et al. suggested9 on histological and clinical grounds that sensory neuropathy and the encephalo-
myelitic form of carcinomatous neuropathy are variants of the same disease process. In the encephalomyelitic syndrome lymphocytic infiltration of the central nervous system is very striking. The site of the lesions and the course of the disease have led to the suggestion 10 that this is a virus infection, though no experimental evidence has yet come to light to support this hypothesis. Such a virus might be carried by the tumour cells themselves. Conceivably, a viral attack on the nervous system might stimulate an immune response against liberated or modified c.N.s. antigens. Alternatively virus-modified tumour cells may themselves act as antigens and excite the formation of antibodies which react against neurones. One histological finding which could point to a common factor (be it cell antigen, virus, or other) in tumours from these patients is the suggestive association noted by DAYAN et al." between the occurrence of the sensory and encephalomyelitic forms of neuropathy and bronchial carcinoma of the oat-cell type. The answers to many questions about carcinomatous neuropathy may lie in future studies of the antigenic and metabolic behaviour of these tumours. If tumour viruses or tumour antigens, for instance, are related to the lesions of neuropathy, then injection of tumour extracts in Freund’s complete adjuvant into laboratory animals might incite antibody formation or hypersensitivity reactions against brain tissue. If such an immune response to these tumours could be incited in animals, an autoimmune mechanism might be tested for by transfer of immunologically competent cells to normal animals. In other forms of carcinomatous neuromyopathy, 7. Wilkinson, P. C., Zeromski, J. Brain, 1965, 88, 529. 8. Croft, P. B., Henson, R. A., Urich, H., Wilkinson, P. C. ibid. p. 501. 9. Henson, R. A., Hoffman, H. L., Urich, H. ibid. p. 449. 10. Henson, R. A., Russell, D. S., Wilkinson, M. ibid, 1954, 77, 82. 11. Dayan, A. D., Croft, P. B., Wilkinson, M. ibid. 1965, 88, 435.
1113
scantier. The pathogenesis of subacute cerebellar degeneration, for example, is quite unknown, although BRAIN and WILKINSON 12 point to the resemblances between this disease and kuru, and they mention recent "speculations of BURNET 13 that kuru may be due to a persisting tolerated infection " with virus which occasionally produces a leak of cerebellar antigen, which in turn may stimulate the proliferation of pathogenic clones of immunocytes with the production of a subsequent vicious-circle autoimmune reaction. In the largest group of all numerically-those patients with carcinoma who present with predominantly motor symptoms-inflammatory lesions were found on muscle biopsy, although not more commonly so than in patients with " idiopathic myopathy" .14 Antibodies against muscle and brain have not been demonstrated in this group of patients, and the xtiology of the syndrome remains unknown.
suggestive findings
are
Drug
Addiction
THE Interdepartmental Committee on Drug Addiction had the misfortune to make its original report 15 in 1961, when there had been no increase in new addictions for three or four years. At that time the committee saw no necessity to recommend any positive action-neither registration of addicts nor their compulsory committal for treatment, nor special institutions for the purpose, nor special tribunals to investigate prescribing, nor further statutory controls of any kind. Only three years later, following suggestions 16 that all was not well, the committee was reconvened " to consider whether, in the light of recent experience, the advice they gave in 1961 in relation to the prescribing of addictive drugs by doctors needs revising and, if so, to make recommendations." " In only fifteen months the committee has now reversed 1 in almost every particular the advice that it previously took three years to offer, as well as adding some further, largely conservative recommendations. Though the report may receive a general welcome, it is inadequate in many ways. The positive proposals fall under four main headings: (a) compulsory " notification to a central authority (rather than " registration " with its connotation of acceptance) as in the case of certain infectious diseases, the analogy with which is appreciated 16 ; (b) the establishment of treatment centres especially in the London area, although it is suggested that each regional hospital board should designate such a centre of its own; (c) powers for compulsory detention of addicts, particularly during the withdrawal crisis; (d) the limitation to treatment-centre medical staff only of the right to prescribe heroin and cocaine for addicts; it would then be a statutory offence for other doctors to prescribe these drugs to an addict. The committee also recommends "
12. Brain, Wilkinson, M. ibid. p. 465. 13. Burnet, F. M. Lancet, 1965, i, 1141. 14. Shy, G. M., Silverstein, I. Brain, 1965, 88, 515. 15. Interdepartmental Committee on Drug Addiction: Report H.M. Stationery Office, 1961. 16. Lancet, 1964, i, 649. Chapple, P.A.L. 1964, ii, 649. 17. Interdepartmental Committee on Drug Addiction: Second H.M. Stationery Office, 1965.
that doctors should prescribe dangerous drugs in words and figures to reduce the risk of forgery, and that an advisory committee should be established to survey the whole field " of dangerous and dependency-inducing drugs with " authority to advise on corrective health and social measures ". Some will be unhappy about these proposals. Controls interfere with individual freedom: in this instance, perhaps even more with that of the doctor than with that of the addict. It certainly seems very hard that the whole profession should suffer this limitation on its professional judgment because " the major source of supply has been the activity of a very few doctors who have prescribed excessively for addicts ": in fact, not more than six doctors, one of whom prescribed nearly 6 kg. of heroin for addicts in 1962, or approximately 15% of the total heroin consumption in the United Kingdom in that year. If this judgment is fair, the conscience of the six must bear a heavy burden, even though they are found to have " acted within the law and according to their professional judgment". Nevertheless, the profession as a whole might be wise to accept the limitation, which is likely to save it much frustration in an area where therapy "
by non-specialists is virtually impossible. In fact, it can even be argued that the committee’s recommendations do not go far enough in this direction. For example, there are no longer any indications for the general use of cocaine, and its prescription should be prohibited. Less debatably, the prescription of any dangerous drug besides heroin and cocaine to an addict by any doctor not on the staff of a treatment centre might be prohibited. It is precisely here, otherwise, that history is in danger of repeating itself. Just as in 1961 the committee failed to see the significance of the sevenfold increase in seven years in addictions to heroin and cocaine against the apparently static total of all addictions, it has apparently again comforted itself with the belief that the extent of addiction to dangerous drugs other than heroin and cocaine remains " more or less the same ". This is demonstrably false, for although addiction to morphine is now apparently very slowly declining and addiction to methadone is now constant, even addiction to petliidine has increased by an average of almost 10% per annum since 1961, and the total number of addictions to manufactured drugs other than those already mentioned has more than doubled since 1961. For this, dextromonamide and dipipanone, both drugs not manufactured before 1959, are mainly responsible.17 About 1 in every 14 addicts known to the Home Office is taking one or other of these drugs: incidentally, the use of heroin itself, without cocaine, has also doubled in the past year. There seems little reason to think that doctors inexperienced in the recognition and handling of addicts will insist on retaining their freedom to withstand the increased demands made upon them, as addicts change their habits in order to avoid commission to the proposed treatment centres. "
(1961).
of a Report.
Treatment centre "
itself, in fact, seems something euphemism for "prescribing centre", although the
report
speaks
of
" provision
for research " and the