- Email: [email protected]
VITAMIN-B DEFICIENCY AND NERVOUS DISEASE
382
Letters
to
the Editor
VITAMIN-B DEFICIENCY AND NERVOUS DISEASE SIR,—In the interesting leader in your issue of Sept. 8 the conception of a " biochemical " as opposed to a " histologically demonstrable lesion is developed, and the reader might not unreasonably infer that this conception provides the complete solution of the problems involved in the pathogenesis of polyneuritis in general and of beriberi in particular. Nevertheless, the physician familiar with the clinical and pathological phenomena common to all aetiological varieties of polyneuritis will appreciate that between these phenomena and the proposed " biochemical lesion " there is a complete gap in our knowledge that this conception does nothing to fill. It may well be that thiamine is a catalyst in the absence of which nerve-cell metabolism in the brain breaks down at the stage of pyruvic-acid formation, that this substance then accumulates, and that in these circumstances there may be a failure to develop the full energy of carbohydrate which impairs the functions of the cells in question. Of the three items of this hypothesis, the first two cannot accurately be called novel, while the last is purely speculative. The notion of a breakdown in "
carbohydrate metabolism, when carbohydrates are taken without a due proportion of vitamin, is clearly implicit in the work of Braddon and Cooper, Funk, and other investigators of the period immediately preceding 1914, and summarising this evidence many years ago (Quart. J. Med. 1918, 11, 320.) I ventured to suggest
that some intermediate product of this arrested metabolism might be toxic for the nervous system, and thus act as the immediate factor in the’development of beriberi. It is only within the past decade that modern biochemists have tardily returned to this early conceptionin part, but without proceeding to ask whether the pyruvate that is reported to be present in excess in the blood and cerebrospinal fluid of beriberi patients may not be the toxic metabolite in question. But however this may be. the " biochemical lesion " as postulated in your article is clearly inadequate to account for the fact that the signs and symptoms of beriberi, as of other setiological varieties of polyneuritis, do not point to the nerve-cells of the brain as the seat of the relevant disorder of function, but point unequivocally to the peripheral nerve-fibres, that when lesions are histologically evident these also are predominant in. these nerves, and that whatever the functional activity of nerve-cells in the brain, this is not reflected in the clinical picture as an integral part of it. Something more is required to connect these two wholly disparate findings : the biochemical lesion in the brain on the one hand and the clinical signs and the lesions in peripheral nerves on the other, and until this " something more " has been found we cannot regard the .problem of polyneuritis as solved. It is not correct to say, therefore, that " we can easily explain " the occurrence of polyneuritis in the acute fevers, pregnancy, thyrotoxicosis, and] alcoholism. Indeed, there is no conclusive evidence that there is a polyneuritis of thyrotoxicosis, while the rare polyneuritis of pregnancy is a product of so many obscure factors that we may not even say that it is related to pregnancy per se. Brilliant as it is, the history of modern biochemistry reveals a persistent tendency to oversimplify the problems of polyneuritis, a very imperfect understanding of the many aspects of this malady, and a lack of historical sense which is seen as a disregard of the brilliant researches of the early workers prior to 1914 with a failure to appreciate the valuable lessons their work reveals. The truth surely is that to tackle the problems of polyneuritis with reasonable hope of success demands a comprehensive understanding of all its aspects, for we cannot expect to elucidate the factors operative in the production of a human disease without a sound grasp of its natural history, its forms and variations and its pathology, and some competence to view all these on
the
today,
general background of neuropathology. can
claim to have
experience
No-one,
of the full range of
the clinical and pathological manifestations of beriberi. Our only source of complete information is the vivid and complete account given by Hamilton Wright over forty years ago (Stud. Inst. med. Res. F.M.S. 1903, 3). I submit that no-one unfamiliar either with the disease or with this unequalled description can pretend to understand this illness. Divorced from this essential information, animal experiments inevitably wander from the realities of the problem they seek to solve. There is nothing new or revolutionary in this point of view. It has been cogently urged upon us by Sir Thomas Lewis and Mr. Wilfred Trotter in their pleas for a clinical science which shall attack medical problems by all necessary methods, clinical and experimental, and is to be pursued by workers ready and able to assess the whole field of relevant evidence. There could not be a problem calling more urgently for this comprehensive attack than that provided by polyneuritis. Only in this way shall we escape the departmentalism of thought and effort that has for so long kept us back from the successful elucidation of the pathogenesis of all forms of polyneuritis. Genius and industry have not been wanting in the attack upon the problem, but it cannot be denied that broadness of view and integration of thought and effort have not been present. That this is so, a historical survey of the history of beriberi research from the only too clear. One other comment upon the leader may be permitted. There seems implicit in it the assumption that in thiamine we have a potent and reliable remedy for polyneuritis, even though in chronic cases the results " may not be so spectacular " owing to the presence of structural lesions that require time to heal. It would be difficult to give a more misleading picture of the thera. peutic situation. Though I have sought it for over twenty years, I have yet to see the case of polyneuritis, acute or chronic, that gave a clear and striking response to the administration of the vitamin-B-complex or to thiamine, in whatever dosage and by whatever channel. In what we call febrile polyneuritis the ineffectiveness of these substances is quite painfully obvious, while I have never seen the severity or duration of a case of alcoholic polyneuritis mitigated by them. This, surely, is the common experience of those who like evidence upon which to base conclusions. In a controlled study of over 200 cases of polyneuritis in the Boston City Hospital, Brown (J. Amer. med. Ass. 1941, 116,1615) reports that thiamine administration was found to have no influence upon the behaviour or course of the malady. If, indeed, there be any conclusive evidence in a contrary sense, it is high time it was marshalled, and the medical profession presented with a body of documented and controlled observation, provided by workers in whose capacity to assess the progress of an organic nervous disease, and its response to treatment, we may have confidence. F. M. R. WALSHE. London, Wl.
beginning makes ’
INDEPENDENT RESEARCH SIR,—Stimulated by your leader and Prof. F. W. Twort’s admirable letter, I put forward the following considerations. In my view there are two grades of research : (1) the initiation of some original and fertile conception ; and (2) the elaboration of the processes required to make the new conception of practical value to man. Examples of class (1) are Becquerel’s discovery that electromagnetic waves emerge from pitchblende; Manson’s hypothesis that malaria was insect-borne ; and Fleming’s observation that the presence of a mould inhibited the growth of a coccal culture. The genius who evolves such a conception is almost always an independent worker, untrammelled by superior control, though rarely he may be a member of some team. Once the great and original idea is enunciated, then comes the value and the need of team-work. Thus the Curies and others elaborated Becquerel’s discovery; Ross worked out Manson’s idea ; and Florey and his co-workers brought Fleming’s original observation to fruition. Like Twort, I think excessive control will militate against class (1) research. No team of horses linked together could ever win the Derby. I have known of one who began research as a labour of love, and working freely and unpaid, with facilities
,
Letters
to
the Editor
VITAMIN-B DEFICIENCY AND NERVOUS DISEASE SIR,—In the interesting leader in your issue of Sept. 8 the conception of a " biochemical " as opposed to a " histologically demonstrable lesion is developed, and the reader might not unreasonably infer that this conception provides the complete solution of the problems involved in the pathogenesis of polyneuritis in general and of beriberi in particular. Nevertheless, the physician familiar with the clinical and pathological phenomena common to all aetiological varieties of polyneuritis will appreciate that between these phenomena and the proposed " biochemical lesion " there is a complete gap in our knowledge that this conception does nothing to fill. It may well be that thiamine is a catalyst in the absence of which nerve-cell metabolism in the brain breaks down at the stage of pyruvic-acid formation, that this substance then accumulates, and that in these circumstances there may be a failure to develop the full energy of carbohydrate which impairs the functions of the cells in question. Of the three items of this hypothesis, the first two cannot accurately be called novel, while the last is purely speculative. The notion of a breakdown in "
carbohydrate metabolism, when carbohydrates are taken without a due proportion of vitamin, is clearly implicit in the work of Braddon and Cooper, Funk, and other investigators of the period immediately preceding 1914, and summarising this evidence many years ago (Quart. J. Med. 1918, 11, 320.) I ventured to suggest
that some intermediate product of this arrested metabolism might be toxic for the nervous system, and thus act as the immediate factor in the’development of beriberi. It is only within the past decade that modern biochemists have tardily returned to this early conceptionin part, but without proceeding to ask whether the pyruvate that is reported to be present in excess in the blood and cerebrospinal fluid of beriberi patients may not be the toxic metabolite in question. But however this may be. the " biochemical lesion " as postulated in your article is clearly inadequate to account for the fact that the signs and symptoms of beriberi, as of other setiological varieties of polyneuritis, do not point to the nerve-cells of the brain as the seat of the relevant disorder of function, but point unequivocally to the peripheral nerve-fibres, that when lesions are histologically evident these also are predominant in. these nerves, and that whatever the functional activity of nerve-cells in the brain, this is not reflected in the clinical picture as an integral part of it. Something more is required to connect these two wholly disparate findings : the biochemical lesion in the brain on the one hand and the clinical signs and the lesions in peripheral nerves on the other, and until this " something more " has been found we cannot regard the .problem of polyneuritis as solved. It is not correct to say, therefore, that " we can easily explain " the occurrence of polyneuritis in the acute fevers, pregnancy, thyrotoxicosis, and] alcoholism. Indeed, there is no conclusive evidence that there is a polyneuritis of thyrotoxicosis, while the rare polyneuritis of pregnancy is a product of so many obscure factors that we may not even say that it is related to pregnancy per se. Brilliant as it is, the history of modern biochemistry reveals a persistent tendency to oversimplify the problems of polyneuritis, a very imperfect understanding of the many aspects of this malady, and a lack of historical sense which is seen as a disregard of the brilliant researches of the early workers prior to 1914 with a failure to appreciate the valuable lessons their work reveals. The truth surely is that to tackle the problems of polyneuritis with reasonable hope of success demands a comprehensive understanding of all its aspects, for we cannot expect to elucidate the factors operative in the production of a human disease without a sound grasp of its natural history, its forms and variations and its pathology, and some competence to view all these on
the
today,
general background of neuropathology. can
claim to have
experience
No-one,
of the full range of
the clinical and pathological manifestations of beriberi. Our only source of complete information is the vivid and complete account given by Hamilton Wright over forty years ago (Stud. Inst. med. Res. F.M.S. 1903, 3). I submit that no-one unfamiliar either with the disease or with this unequalled description can pretend to understand this illness. Divorced from this essential information, animal experiments inevitably wander from the realities of the problem they seek to solve. There is nothing new or revolutionary in this point of view. It has been cogently urged upon us by Sir Thomas Lewis and Mr. Wilfred Trotter in their pleas for a clinical science which shall attack medical problems by all necessary methods, clinical and experimental, and is to be pursued by workers ready and able to assess the whole field of relevant evidence. There could not be a problem calling more urgently for this comprehensive attack than that provided by polyneuritis. Only in this way shall we escape the departmentalism of thought and effort that has for so long kept us back from the successful elucidation of the pathogenesis of all forms of polyneuritis. Genius and industry have not been wanting in the attack upon the problem, but it cannot be denied that broadness of view and integration of thought and effort have not been present. That this is so, a historical survey of the history of beriberi research from the only too clear. One other comment upon the leader may be permitted. There seems implicit in it the assumption that in thiamine we have a potent and reliable remedy for polyneuritis, even though in chronic cases the results " may not be so spectacular " owing to the presence of structural lesions that require time to heal. It would be difficult to give a more misleading picture of the thera. peutic situation. Though I have sought it for over twenty years, I have yet to see the case of polyneuritis, acute or chronic, that gave a clear and striking response to the administration of the vitamin-B-complex or to thiamine, in whatever dosage and by whatever channel. In what we call febrile polyneuritis the ineffectiveness of these substances is quite painfully obvious, while I have never seen the severity or duration of a case of alcoholic polyneuritis mitigated by them. This, surely, is the common experience of those who like evidence upon which to base conclusions. In a controlled study of over 200 cases of polyneuritis in the Boston City Hospital, Brown (J. Amer. med. Ass. 1941, 116,1615) reports that thiamine administration was found to have no influence upon the behaviour or course of the malady. If, indeed, there be any conclusive evidence in a contrary sense, it is high time it was marshalled, and the medical profession presented with a body of documented and controlled observation, provided by workers in whose capacity to assess the progress of an organic nervous disease, and its response to treatment, we may have confidence. F. M. R. WALSHE. London, Wl.
beginning makes ’
INDEPENDENT RESEARCH SIR,—Stimulated by your leader and Prof. F. W. Twort’s admirable letter, I put forward the following considerations. In my view there are two grades of research : (1) the initiation of some original and fertile conception ; and (2) the elaboration of the processes required to make the new conception of practical value to man. Examples of class (1) are Becquerel’s discovery that electromagnetic waves emerge from pitchblende; Manson’s hypothesis that malaria was insect-borne ; and Fleming’s observation that the presence of a mould inhibited the growth of a coccal culture. The genius who evolves such a conception is almost always an independent worker, untrammelled by superior control, though rarely he may be a member of some team. Once the great and original idea is enunciated, then comes the value and the need of team-work. Thus the Curies and others elaborated Becquerel’s discovery; Ross worked out Manson’s idea ; and Florey and his co-workers brought Fleming’s original observation to fruition. Like Twort, I think excessive control will militate against class (1) research. No team of horses linked together could ever win the Derby. I have known of one who began research as a labour of love, and working freely and unpaid, with facilities
,