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The treatment of tuberculosis of bone and joint
ROYAL
SOCIETY
OF TROPICAL
Ordinary
MEDICINE
AND HYGIENE
Meeting
Manson House, Thursday, 19th May, 1977 The President: Dr. C. E. Gordon Smith, c.B., M.D., F.R.C.PATH.,in the Chair
Symposium
on surgical and medical treatment developing countries
The treatment
of tuberculosis
of tuberculosis
in
of bone and joint
D. LL. GRIFFITHS Chairman, Medical ReseatchCouncil’s Working Party on the Treatment of Tuberculosis of the Spine in Tropical Countries
The last 30 years have seen a remarkable fall in the incidence of tuberculosis of bone and joint in Britain and in the USA. This fall has not, however, occurred in any parallel degree in most of the ‘developing’ countries in the tropical or sub-tropical areas of the world, though the few tropical countries that can be regarded as ‘developed’ present a much better picture. There has been a very real fall in the incidence of this disease in the indigenous populations of Hong Kong and of Singapore, resembling in degree that seen in Western Europe although it occurred 20 years or so later. In India, tropical Africa and South America, however, the disease ranks with leprosy as one of the commonest serious orthopaedic problems, making great demands upon those countries’ limited surgical resources. One of the saddest features of this disease in tropical countries is the advanced state in which so many patients present for treatment. In Korea, by no means the worst country from this point of view, it is not uncommon to see spinal disease present with profound paraplegia or with sinuses. Disease of the hip still presents with a dislocated joint. Early diagnosis, so important if the value of chemotherapy is to be fully realized, is the exception. Treatment by unqualified practitioners consumes valuable time and often delays definitive surgical treatment, where this is indicated, by producing multiple septic areas in critical situations. Sites affected There are no useful figures about the total incidence of the disease in countries that cannot at present register even births and deaths, and we have no accurate information about the incidence of the disease in various parts of the body. It seems that tuberculosis of bone and joint in developing countries is dominated by disease of the spine. In the very selected clientele of certain Indian hospitals that can provide figures, about 60% of casesare reported to occur in the spine, some 15% in the hip, and all the other bones and joints account for the remaining 25 %.
Pathology The morbid anatomy of the disease was very well studied in Europe and in America in the days when it was common there and only a few new ideas about uathologv need be mentioned. These few, however, have-a bearing upon treatment. First, it is now apparent that in spinal disease a non-suppurative extra-dural granuloma can form around the dura mater and can constitute a cause of paraplegia not recognized by the earlier observers (ROM, 1956). Further, as has been shown by HODGSON and his associatesin Hong Kong (HODGSON et al., 1964), spinal disease can penetrate the dura mater more often than was thought. It may, in fact, produce a localized intra-dural abscess that can also constitute a hitherto overlooked cause of paraplegia, and earlier doubts of the existence of this possibility, including my own (GRIFFITHS et al., 1956) must be withdrawn. A third observation about pathology that has still to reach the text-books was made by KAUFMANN (1948). He showed that certain casesof tuberculosis of vertebral bodies are not, in fact, examples of blood-borne infection but are instances of direct invasion of the bodies from disease of overlying adjacent para-vertebral lymph-nodes. This pattern of infection explains the not infrequent examples of large psoas abscesses accompanying foci in the lumbar spine that are either very small or even totally unrecognizable in radiographs. The pathoiogy of paraplegia in spinal disease needs re-classification. We must now discard the time-honoured division of this, the most serious complication of spinal disease, into paraplegia of early onset and paraplegia of late onset. The real distinction between types of Pott’s paraplegia lies not in the time of onset of the paralysis, but in its causation. Nearly all casesof ‘early onset’ paraplegia and many cases-of ‘late onset’ paralysis are due-to pressure on the spinal cord from the materies morbi. These cases occur in circumstances in which the bony disease is still active, however long or short the history. Others, certainly the majority of cases
560
TREATMENTOF TUBERCULOSIS OF BONEAND JOINT
of ‘late’ onset, occur in spines in which the bony disease is inactive or healed, and often has been so for many years. The pathology of this group is obscure, but it is certainly not the same as that in cases in which the bony disease is still active. We should now speak of ‘Paraplegia with active disease’ and of ‘Paraplegia with healed disease’, thus making a much more valid distinction than one based upon time, and also making a distinction with therapeutic and prognostic significance. Early diagnosis Early diagnosis was important in the days when immobilization constituted the only effective method of treatment. Today, it is far more important. There is now abundant experience to show that a really early case of bone and joint tuberculosis, in anv part of the body, can be cured by chemotherapy without the old inevitable seauelae of deformitv in the spine and of ankylosis in ihe limb joints. Even if minor radiological changes have occurred, full restoration of function without deformity can be confidently expected if the diagnosis is made early enough. Simple survival of the patient in a moderately disabled condition is no longer our aim. Unfortunately, in tropical countries, this is too often still the best that can be obtained, for early diagnosis is exceptional. Early diagnosis must depend largely upon surgical exploration of lesions that could possibly be tuberculous. For example, any synovitis confined to one joint and without a clear history of an obvious cause, such as trauma, should be explored in order to establish a diagnosis before there is radiological evidence of erosion or of destruction of joint surfaces. This may, indeed, be the greatest contribution that surgery has to make to the management of this disease. Diagnostic problems In tropical countries where the disease is rife, the diagnostic problem in the spine is usually easy. In such countries, if a case looks like tuberculosis clinically and radiologically, it will almost certainly be one of tuberculosis. In the first series of trials of methods of treatment of the tuberculous spine, the Medical Research Council’s Working Party had a good check on the accuracy of diagnosis in the 213 patients submitted to open operation in Bulawayo and in Hong Kong. In 188 cases (88%) there was conclusive bacteriological or histological proof of the diagnosis and, though the remaining 12 y0 were inconclusive histologically and bacteriologically, in none was there evidence diagnostic of other disease. The bogy of non-tuberculous bacterial infection of the spine, a real problem in Britain, seemed relatively unimportant in those two places. Elsewhere, there may have been greater difficultv. Hydatid disease and brucellosis ao not confound the issue in Rhodesia and in Hong: Kong as thev do. for example, in North Africa. onexp&zted radio: logical manifestations may occur in the radiographs, however. It is not unknown for a confident diagnosis of metastatic malignancy to be followed by the discovery of tuberculous pus on exploration of the spine in question. In the spine, as in the limb joints,
early exploration of difficult should be almost a routine.
or atypical lesions
Bacteriology In tuberculosis of bone, as in visceral disease, absolute proof of diagnosis depends on the recovery of Mycobacterium tuberculosis from the lesion. This is not always possible even if one resorts to open exploration but it is much less likely if one does not. Collection of pus from a sinus, or aspiration of joint fluid or pus often fails to reveal the causal organism. In the cases at present being studied by the Medical Research Council’s Working Party, aspiration of large quantities of pus from psoas abscessesin even advanced casesproduced positive smears or cultures in less than 40 %. This is not surprising. Tuberculosis of parenchymatous organs, such as lungs, is associated with a high bacterial population;- tuberculosis of bone with a low one. DIBAUMONT (1966’1has shown that inoculation of Jensen tubes with ‘material derived directly from diseased vertebral bodies produces less than 50 colonies per tube in 85% of casesand under ten colonies per tube in 59 Oh.Positive sputum inoculated in a comparable manner produces 100,000 to 300,000 colonies per millilitre (BOQUET, 1938). DI?BAUMONTproduced further evidence that the total population of an infected spine may be fewer than one million bacteria. This explains why tuberculous pus arising from a bony lesion is so often reported to be sterile. It is also possible that this low bacterial population makes tuberculous bone particularly sensitive to chemotherapy, for the chance of the development of drug-resistant mutants is clearly much lower in a smaller population. Treatment The archaic attitude of standard text-books to the treatment of bone and joint tuberculosis is a reproach. They are still full of the shibboleths of pre-antibiotic treatment. Prolonged rest, plaster beds and frames, open air, vitamins, even cod-liver oil, are still praised without a scrap of evidence of their value. The operation of posterior fusion in spinal disease, useless if it fails and harmful if it succeeds, is still advocated and performed during the active phase of the disease, and its advocates are so satisfied in their prejudices that some of them refuse to put it to the test. The sad fact is that, with one exception, clinical trials have not been held and pre-antibiotic methods are still used with a regrettable lack of critical thought. In the caseof spinal disease,the Medical Research Council’s Working Party has produced some sound evidence of the efficacy of some methods of treatCOUNCIL, 1973a, 1973b, ment (~~JZDICALRESEARCH 1974a, 1974-b, 1976, 1977). It may be fair to base the treatment of the disease in other sites on this evidence, but this is perhaps speculative. What is certain, however, is that we have, at last, a sound basis for treatment of tuberculosis of the spine. A clinical trial The con&t of opinion about the treatment of spinal tuberculosis was represented at one extreme by the views of KONSTAM and his associates
561
D. LL. GRIFPITHS (KONSTAM & KONSTAM, 1958; KONSTAM & BLESOVSKY, 1962) in Nigeria. They claimed excellent
results, from the use of chemotherapy alone, in ambulant out-patients who received no other treatment, neither splintage, nor bed-rest, nor operations, At the other extreme, HODGSON and his colleagues (HODGSON & STOCK, 1956, 1960; HODGSON et al., 1967) in Hong Kong made equally strong claims for chemotherapy supplemented by a ‘radical’ operation, in which the affected vertebral bodies are resected, the considerable gap so produced being bridged by the insertion of autologous bone-grafts. Between these extremes, a wide variety of orthopaedic measures and of less radical operations were being performed and advocated. Among the latter was the operation of debridement of the focus, associated particularly with the work of PAUS (1964) in Korea, in which as much diseased material as possible is removed from the spinal lesion, but without deliberate resection of the affected bodies and without the use of any form of bone-grafting. It was this divergence of opinion and of practice that led the Medical Research Council to set up a series of controlled clinical trials. These trials were designed to investigate methods of treatment relevant to the resources of the countries in which they would take place. All patients admitted to this research had evidence of active tuberculosis of the thoracic or lumbar spine. All of them received, in the first series of trials. INAH and PAS (oaraaminosalicylic acid) for &ghteen months, and& all casesthe other methods of treatment employed were allocated by random allocation. All cases were studied prospectively. In Korea, in the cities of Masan and Pusan, surgical resources were very limited at the time of the start of the research. Conservative methods were therefore studied in those cities. In Masan, 100 out-patients received nothing but chemotherapy on an ambulant out-patient basis; 100 others were given, in addition, an initial period of six months’ bed-rest in hospital. In Pusan, 75 patients received only ambulant out-patient chemotherapy; 75 others also had their spines splinted in plaster-ofParis jackets for the first nine months of their out-patient chemotherapy. In Bulawayo, 65 patients were allocated at random to out-patient ambulant chemotherapy as in Korea, 65 to chemotherapy plus the performance of the debridement operation popularized by PAUS (1964). In Hong Kong, 75 patients were similarly allocated to dkbridement plus chemotherapy, 75 to the Hong Kong radical operation plus the same drug regimen. No attempt was made to study paraplegia in these four centres; patients unable to walk across a room were not admitted to the research. In Johannesburg and in Pretoria, where the work was started later, the studies made in Hong Kong were repeated and paraplegics were admitted to the trials. Isoniazid was given in doses of 10 mg/kg bodyweight and sodium PAS in doses of 200 mg/kg daily for 18 months in all centres to all patients. In addition, in Korea and in Bulawayo, but not in Hong Kong and South Africa, by a second random allocation, half the patients received streptomycin
sulphate in doses of 30 mg/kg daily (maximum daily dose 1 a0 gram) by intra-muscular injection for the first three months. In Hong Kong and in South Africa, all the patients received all three drugs in these dosages. Follow-up
In the four centres in which the work started, Masan, Pusan, Bulawayo and Hong Kong, we now have a five-year follow-up of 516 patients, and those in all centres except Bulawayo are being followed-up for at least ten years. The over-all follow-up rate in these four centres is 96.4 %. In the two Korean cities, only 2.3% of all cases have been lost to follow-up, a figure reflecting much credit on the field workers there. The death-rate in these four centres has been low. Only 0.8% of all the patients have died from or with active soinal tuberculosis. There have been a few deaths from other causes, including cancer, trauma and murder. In the casestreated conservatively in Masan and Pusan, only three of 350 have died with or from their disease. Results
The results of treatment have been classified thus : (i) ‘Favourable’, meaning that the patient is well, caoable of full ohvsical activity, with disease ra&ologically healed,‘abscessesand-sinuses (if any) healed, and that he is free from any disturbance of the central nervous system; (ii) ‘ Still not favourable’, implying the absence of palpable abscesses,the healing of sinuses (if any), but with persisting limitation of physical activity or without clear radiological evidence of healing of the bony focus ; and (iii) ‘Unfavourable’, indicating that abscessor sinus is still present, the disease unhealed radiologically, or that the patient has a persisting paraparesis or paraplegia, or is dead. Results
of conservative
treatment
In Korea, where no form of operative treatment was employed, the success-rate was high. In Masan, though only 61 y0 could be considered favourable at the end of 18 months (that is, at the end of their chemotherapy), 85% had become favourable at the end of the third year and, at the end of the fifth year, the figure was 90 %. The improvement between the 18th month and the end of the third year resulted from the delayed but progressive i&provement in most of the cases judged ‘still not favourable’ at the end of 18 months. In Pusan, the figures were much the same; 64% favourable at 18 months, 86% at three years and 87% at five. No statisticallv significant difference could be shown between thk results in those who had six months’ bed rest or nine months in a plaster jacket and the outcome in those who had neither. Moreover, no significant difference could be shown to result from the use of streptomycin. It therefore appears that, at least in cases without paraplegia, 90% of patients can be expected to respond well to treatment with the appropriate drugs and nothing else. --,”
~~~~
562
TREATMENT
OF TUBERCULOSIS
OF BONX AND
JOINT
Failures The fact that some 90% of patients do well unhappily implies that about 10y0 do not. We tried to determine any bad prognostic features that might be recognizable at the start of treatment, but we failed. Multiple regression analyses were performed on all groups, but no definite indication resulted. Surprisingly, there was no demonstrable difference in the prognosis for life and health between the mildly affected casesand the more severe ones, though deformity was much more marked in the latter group. We could show no prognostic significance in the number of vertebrae involved, in the presence of sequestra, abscessesor even sinuses. Most of the failures occurred in cases of thoracic rather than lumbar disease and there is some reason to believe that the initial response to treatment may have some limited prognostic significance, but the only certain reason for failure to respond to chemotherapy is failure of the patient to take the drugs.
and the dura mater posteriorly. Notches are then cut in the raw bony surfaces and up to three grafts, cut from the resected rib or from the ilium are wedged between them to bridge the gap. The wound is then closed. In Hong Kong, in the hands of its introducers, the claims made for this operation have been substantiated. Compared with a simple debridement performed by the same surgeons and accompanied in all cases by triple therapy, the ultimate results as regards preservation of life and health were much the same as those obtained by chemotherapy alone in Korea or by chemotherapy plus debridement in Bulawayo or Hong Kong. At three years in Hong Kong, 86% of those submitted to debridement had a favourable result, 87% of those undergoing the radical operation. At five years the figures were 88 % and 89 ‘$!,respectively. Patients undergoing the radical operation, however, reached a favourable status earlier, 89% at 18 months against 79% after debridement. Bony fusion also occurred earlier, though much of this particular advantage had disappeared by five years. There was less vertebral destruction in the radical series, despite the operative removal of bone and, probably the greatest advantage of this operation, the kyphosis did not increase. There was also earlier resolution of abscesses. The results in South Africa, though not yet published, support those obtained in Hong Kong in the patients without paraplegia. This is no operation for a surgeon who is not experienced in major spinal surgery. It demands resources seldom available in the tropics. It makes a much greater demand upon hospital beds than does out-patient chemotherapy and it remains to be seen if its outstanding advantage, the absence of increase in kyphosis, will be as obvious after ten years as it is after five in children, for they have a potential for correcting deformity by more rapid growth of vertebral bodies above and below the level of the lesion. At present, however, where circumstances permit its performance, it must be considered part of the treatment of choice in thoracic and lumbar disease.
The Hong Kong Operation The Hong Kong radical operation introduced a new concept. It was designed originally in the hope of producing more rapid cure in a country whose surgical resources were being strained by a massive inflow of refugees, many of whom had spinal tuberculosis. The operation is one of some severity. It calls for considerable surgical expertise and anaesthetic skill. The thorax is opened through the bed of a resected left rib or, in lumbar disease, the focus is exposed by an extra-peritoneal route. If necessary, the lung is separated from the paravertebral abscess, to which it may be adherent. The appropriate intercostal arteries are then divided and the aorta mobilized and retracted to the right. The abscessis then opened and a thorough debridement performed. The affected bodies are then resected, if necessary together with the intervertebral discs above and below the lesion, to expose healthy bleeding cancellous bone above and below
Paraplegia I have, so far, no new figures to offer about the treatment of the most important complication of spinal tuberculosis, namely paraplegia. My own practice has been to perform early decompression, preferably by means of the Hong Kong operation, on cases of paraplegia associated with active vertebral body disease. Resolution of the paralysis after decompression can be immediate, and patients should be relieved of paraplegia as a matter of some urgency. I have, however, no data from the Medical Research Council’s trials to support or to contest this opinion. In paraplegia associated with healed disease I can give no general advice, for we do not really understand the pathology of this type of paralysis. It appears, however, to depend upon severe kyphosis, and it may therefore be less likely to occur in patients whose kyphosis has been stabilized or reduced by the Hong Kong operation than in those treated by other methods.
Results of operative treatment In Bulawayo we were unable to show any advantage from the operation of debridement. A favourable status was reached in three years by 86% of those receiving out-patient ambulant chemotherapy and in 85% of those submitted to a dibridement in addition to their drugs. The results at five years showed no change. Operative debridement may have value in that it provides material for the establishment of the diagnosis, but it adds nothing to the patient’s chance of cure. It seems reasonable to believe that no lesser operation will do any more. There is one serious drawback to conservative treatment and also to debridement. The favourable results have been obtained, so far, at the expense of an increase in the angular deformity of the spine, the kyphosis. In Korean children this increase averaged about 15 degrees over three years, in Bulawayo about eight degrees in those treated without operation and about 12 degrees in those submitted to debridement. Unfortunately, the increases were greater in the patients less severely deformed on admission to the studies.
D. LL.
The place of surgery It is clear that the basis of the treatment of tuberculosis of bone and joint in any site and in any country must be chemotherapy. There seems as little indication for non-operative surgery, that is, for splintage, etc., as there is for sanatorium treatment in lung disease. The role of operative surgery has been much reduced and I expect to see further reduction. At present, the indications for operation may be regarded as absolute or relative. The first absolute indication is exploration to establish a diagnosis that is in any doubt. The word ‘exploration’ is used advisedly. ‘Biopsy’ is a word with too close an association with the removal of small fragments of tissue? often endoscopically, in the diagnosis of soft-ussue lesions. Such surgery is totally inadequate in bone and joint tuberculosis. The surgeon will want to seethe gross pathology of the lesion and it is essential to furnish the pathologist with a large piece of tissue if he is to be given a fair chance. Equally, because of the low bacterial population, the bacteriologist requires as much material as possible. The opening and suturing of an abscess that threatens to point, another absolute indication, should be undertaken in any abscessthat cannot be controlled by aspiration and chemotherapy alone. Equally, in the present state of our knowledge, I would regard paraplegia associated with active spinal disease as an absolute indication for operation. Among the relative indications for operation one would place circumstances permitting the performance of the Hong Kong operation in spinal disease. Regrettably, there is also a place for salvage procedures in destroyed joints in which early treatment has not been undertaken though, at least in the hip, there are grounds for hope that total replacement by low-friction arthroplasty will replace the classical operation of arthrodesis. The future The role of surgery may be further reduced if the newer drugs, which have been so efficacious in pulmonary disease, will prove capable of resolving bone and joint disease in shorter periods of time than the 18 months apparently required for PAS and INAH to be effective. We have no firm information about this yet. The Medical Research Council has, however, mounted a new series of studies in Korea, Hong Kong and Madras in which the effects of rifamoicin. ethambutol and PAS-INAH in short course-regimens are being compared with the results of standard 18 months’ PAS-INAH therapy. In Madras and in Hong Kong the radical operation reinforced by the newer drugs is also being studied. So far, 380 patients have been admitted to these new studies. If it proves possible to arrest this disease in six or in nine months instead of in 18, there will be fewer failures from default in drug-taking and less time for kyphosis to worsen. The more rapid cure and the avoidance of increase in deformity now associated with the Hong Kong radical operation may thus result from chemotherapy alone. The answer should be available in about three years’ time.
563
GRIPFITHS
References Boquet, A. (1938). Recherches sur la teneur des prod&s tuberculeux en en bacilles de Koch. Compte rendu des skances de la Societe de Biologie (Paris), 128, 473-483.
Dtbaumont, A. (1966). Bacteriologic de la tuberculose osteo-articulaire sous chimotherauie. Advances in Tuberculosis Research, 15, 125-188. Griffiths, D. Ll., Seddon, H. J. & Roaf, R. (1956). In: Pott’s Paraplegia. Oxford: Oxford University Press. Hodgson, A. R., Skisnes, 0. K. & Leong, C. Y. (1967). The pathogenesis of Pott’s Paraplegia. Journal of Bone and Joint Surgery, 49A, 114711%. ----_ Hodgson, A. R. & Stock, F. E. (1956). Anterior spinal fusion. British Journal of Surgery, 44, 266-275. Hodgson, A. R. & Stock, F. E. (1960). Anterior spinal fusion for the treatment of tuberculosis of the svine. Yournal of Bone and 7oint Suraerv, - -42A, 295-310: Hodgson, A. R., Yau, A., Kwon, J. S. & Kim, D. (19641. A clinical studv of 100 consecutive cases of P&t’s Paraplegia. klinical Orthopaedics, 36, 128-150. Kaufmann, R. (1948). Quinze observations d’attaque ganglionnaire dans le mal de Pott et autres localisations de la tuberculose. Memoires de l’dcademie
de Chirurgie,
74, 238-256.
Konstam, P. G. & Blesovsky, A. (1962). The ambulant treatment of spinal tuberculosis. British Journal of Surgery, 50,26-38. Konstam, P. G. & Konstam, S. T. (1958). Spinal tuberculosis in Southern Nigeria. Journal of Bone and Point Suroerv. 4OB. 26-32. Medical Research C&&l (1973a). A controlled trial of ambulant outpatient treatment and inpatient rest in bed in the management of tubercuolosis of the spine in patients on standard chemotherapy. Journal of Bone and Joint Surgery, - _. 55B, 678-697. Medical Research Council (1973b). A controlled trial of plaster-of-paris jackets in the management of ambulent outpatient treatment of tuberculosis of the spine in children on standard chemotherapy Tubercle, 54, 261-282.
Medical Research Council (1974a). A controlled trial of debridement and ambulatory treatment in the management of tuberculosis of the spine in patients on standard chemotherapy. Journal of Tropical Medicine and Hygiene, 77, 72-92.
Medical Research Council (1974b) A controlled trial of anterior spinal fusion and debridement in the surgical management of tuberculosis of the spine in patients on standard chemotherapy. British Journal of Surgery, 61, 853-866. Medical Research Council (1976). A five-year assessment of controlled trials of inpatient and outpatient treatment and of plaster-of-Paris jackets for tuberculosis of the spine in children on standard chemotherapy. Journal of Bone and Joint Surgery, 58B, 399-411. Medical Research Council (1978). Five-year assessments of controlled trials of ambulatory treatment, debridement and anterior spinal fusion in the management of tuberculosis of the spine. Journal of Bone and Joint Surgery, SOB, 161-177.
SOCIETY
OF TROPICAL
Ordinary
MEDICINE
AND HYGIENE
Meeting
Manson House, Thursday, 19th May, 1977 The President: Dr. C. E. Gordon Smith, c.B., M.D., F.R.C.PATH.,in the Chair
Symposium
on surgical and medical treatment developing countries
The treatment
of tuberculosis
of tuberculosis
in
of bone and joint
D. LL. GRIFFITHS Chairman, Medical ReseatchCouncil’s Working Party on the Treatment of Tuberculosis of the Spine in Tropical Countries
The last 30 years have seen a remarkable fall in the incidence of tuberculosis of bone and joint in Britain and in the USA. This fall has not, however, occurred in any parallel degree in most of the ‘developing’ countries in the tropical or sub-tropical areas of the world, though the few tropical countries that can be regarded as ‘developed’ present a much better picture. There has been a very real fall in the incidence of this disease in the indigenous populations of Hong Kong and of Singapore, resembling in degree that seen in Western Europe although it occurred 20 years or so later. In India, tropical Africa and South America, however, the disease ranks with leprosy as one of the commonest serious orthopaedic problems, making great demands upon those countries’ limited surgical resources. One of the saddest features of this disease in tropical countries is the advanced state in which so many patients present for treatment. In Korea, by no means the worst country from this point of view, it is not uncommon to see spinal disease present with profound paraplegia or with sinuses. Disease of the hip still presents with a dislocated joint. Early diagnosis, so important if the value of chemotherapy is to be fully realized, is the exception. Treatment by unqualified practitioners consumes valuable time and often delays definitive surgical treatment, where this is indicated, by producing multiple septic areas in critical situations. Sites affected There are no useful figures about the total incidence of the disease in countries that cannot at present register even births and deaths, and we have no accurate information about the incidence of the disease in various parts of the body. It seems that tuberculosis of bone and joint in developing countries is dominated by disease of the spine. In the very selected clientele of certain Indian hospitals that can provide figures, about 60% of casesare reported to occur in the spine, some 15% in the hip, and all the other bones and joints account for the remaining 25 %.
Pathology The morbid anatomy of the disease was very well studied in Europe and in America in the days when it was common there and only a few new ideas about uathologv need be mentioned. These few, however, have-a bearing upon treatment. First, it is now apparent that in spinal disease a non-suppurative extra-dural granuloma can form around the dura mater and can constitute a cause of paraplegia not recognized by the earlier observers (ROM, 1956). Further, as has been shown by HODGSON and his associatesin Hong Kong (HODGSON et al., 1964), spinal disease can penetrate the dura mater more often than was thought. It may, in fact, produce a localized intra-dural abscess that can also constitute a hitherto overlooked cause of paraplegia, and earlier doubts of the existence of this possibility, including my own (GRIFFITHS et al., 1956) must be withdrawn. A third observation about pathology that has still to reach the text-books was made by KAUFMANN (1948). He showed that certain casesof tuberculosis of vertebral bodies are not, in fact, examples of blood-borne infection but are instances of direct invasion of the bodies from disease of overlying adjacent para-vertebral lymph-nodes. This pattern of infection explains the not infrequent examples of large psoas abscesses accompanying foci in the lumbar spine that are either very small or even totally unrecognizable in radiographs. The pathoiogy of paraplegia in spinal disease needs re-classification. We must now discard the time-honoured division of this, the most serious complication of spinal disease, into paraplegia of early onset and paraplegia of late onset. The real distinction between types of Pott’s paraplegia lies not in the time of onset of the paralysis, but in its causation. Nearly all casesof ‘early onset’ paraplegia and many cases-of ‘late onset’ paralysis are due-to pressure on the spinal cord from the materies morbi. These cases occur in circumstances in which the bony disease is still active, however long or short the history. Others, certainly the majority of cases
560
TREATMENTOF TUBERCULOSIS OF BONEAND JOINT
of ‘late’ onset, occur in spines in which the bony disease is inactive or healed, and often has been so for many years. The pathology of this group is obscure, but it is certainly not the same as that in cases in which the bony disease is still active. We should now speak of ‘Paraplegia with active disease’ and of ‘Paraplegia with healed disease’, thus making a much more valid distinction than one based upon time, and also making a distinction with therapeutic and prognostic significance. Early diagnosis Early diagnosis was important in the days when immobilization constituted the only effective method of treatment. Today, it is far more important. There is now abundant experience to show that a really early case of bone and joint tuberculosis, in anv part of the body, can be cured by chemotherapy without the old inevitable seauelae of deformitv in the spine and of ankylosis in ihe limb joints. Even if minor radiological changes have occurred, full restoration of function without deformity can be confidently expected if the diagnosis is made early enough. Simple survival of the patient in a moderately disabled condition is no longer our aim. Unfortunately, in tropical countries, this is too often still the best that can be obtained, for early diagnosis is exceptional. Early diagnosis must depend largely upon surgical exploration of lesions that could possibly be tuberculous. For example, any synovitis confined to one joint and without a clear history of an obvious cause, such as trauma, should be explored in order to establish a diagnosis before there is radiological evidence of erosion or of destruction of joint surfaces. This may, indeed, be the greatest contribution that surgery has to make to the management of this disease. Diagnostic problems In tropical countries where the disease is rife, the diagnostic problem in the spine is usually easy. In such countries, if a case looks like tuberculosis clinically and radiologically, it will almost certainly be one of tuberculosis. In the first series of trials of methods of treatment of the tuberculous spine, the Medical Research Council’s Working Party had a good check on the accuracy of diagnosis in the 213 patients submitted to open operation in Bulawayo and in Hong Kong. In 188 cases (88%) there was conclusive bacteriological or histological proof of the diagnosis and, though the remaining 12 y0 were inconclusive histologically and bacteriologically, in none was there evidence diagnostic of other disease. The bogy of non-tuberculous bacterial infection of the spine, a real problem in Britain, seemed relatively unimportant in those two places. Elsewhere, there may have been greater difficultv. Hydatid disease and brucellosis ao not confound the issue in Rhodesia and in Hong: Kong as thev do. for example, in North Africa. onexp&zted radio: logical manifestations may occur in the radiographs, however. It is not unknown for a confident diagnosis of metastatic malignancy to be followed by the discovery of tuberculous pus on exploration of the spine in question. In the spine, as in the limb joints,
early exploration of difficult should be almost a routine.
or atypical lesions
Bacteriology In tuberculosis of bone, as in visceral disease, absolute proof of diagnosis depends on the recovery of Mycobacterium tuberculosis from the lesion. This is not always possible even if one resorts to open exploration but it is much less likely if one does not. Collection of pus from a sinus, or aspiration of joint fluid or pus often fails to reveal the causal organism. In the cases at present being studied by the Medical Research Council’s Working Party, aspiration of large quantities of pus from psoas abscessesin even advanced casesproduced positive smears or cultures in less than 40 %. This is not surprising. Tuberculosis of parenchymatous organs, such as lungs, is associated with a high bacterial population;- tuberculosis of bone with a low one. DIBAUMONT (1966’1has shown that inoculation of Jensen tubes with ‘material derived directly from diseased vertebral bodies produces less than 50 colonies per tube in 85% of casesand under ten colonies per tube in 59 Oh.Positive sputum inoculated in a comparable manner produces 100,000 to 300,000 colonies per millilitre (BOQUET, 1938). DI?BAUMONTproduced further evidence that the total population of an infected spine may be fewer than one million bacteria. This explains why tuberculous pus arising from a bony lesion is so often reported to be sterile. It is also possible that this low bacterial population makes tuberculous bone particularly sensitive to chemotherapy, for the chance of the development of drug-resistant mutants is clearly much lower in a smaller population. Treatment The archaic attitude of standard text-books to the treatment of bone and joint tuberculosis is a reproach. They are still full of the shibboleths of pre-antibiotic treatment. Prolonged rest, plaster beds and frames, open air, vitamins, even cod-liver oil, are still praised without a scrap of evidence of their value. The operation of posterior fusion in spinal disease, useless if it fails and harmful if it succeeds, is still advocated and performed during the active phase of the disease, and its advocates are so satisfied in their prejudices that some of them refuse to put it to the test. The sad fact is that, with one exception, clinical trials have not been held and pre-antibiotic methods are still used with a regrettable lack of critical thought. In the caseof spinal disease,the Medical Research Council’s Working Party has produced some sound evidence of the efficacy of some methods of treatCOUNCIL, 1973a, 1973b, ment (~~JZDICALRESEARCH 1974a, 1974-b, 1976, 1977). It may be fair to base the treatment of the disease in other sites on this evidence, but this is perhaps speculative. What is certain, however, is that we have, at last, a sound basis for treatment of tuberculosis of the spine. A clinical trial The con&t of opinion about the treatment of spinal tuberculosis was represented at one extreme by the views of KONSTAM and his associates
561
D. LL. GRIFPITHS (KONSTAM & KONSTAM, 1958; KONSTAM & BLESOVSKY, 1962) in Nigeria. They claimed excellent
results, from the use of chemotherapy alone, in ambulant out-patients who received no other treatment, neither splintage, nor bed-rest, nor operations, At the other extreme, HODGSON and his colleagues (HODGSON & STOCK, 1956, 1960; HODGSON et al., 1967) in Hong Kong made equally strong claims for chemotherapy supplemented by a ‘radical’ operation, in which the affected vertebral bodies are resected, the considerable gap so produced being bridged by the insertion of autologous bone-grafts. Between these extremes, a wide variety of orthopaedic measures and of less radical operations were being performed and advocated. Among the latter was the operation of debridement of the focus, associated particularly with the work of PAUS (1964) in Korea, in which as much diseased material as possible is removed from the spinal lesion, but without deliberate resection of the affected bodies and without the use of any form of bone-grafting. It was this divergence of opinion and of practice that led the Medical Research Council to set up a series of controlled clinical trials. These trials were designed to investigate methods of treatment relevant to the resources of the countries in which they would take place. All patients admitted to this research had evidence of active tuberculosis of the thoracic or lumbar spine. All of them received, in the first series of trials. INAH and PAS (oaraaminosalicylic acid) for &ghteen months, and& all casesthe other methods of treatment employed were allocated by random allocation. All cases were studied prospectively. In Korea, in the cities of Masan and Pusan, surgical resources were very limited at the time of the start of the research. Conservative methods were therefore studied in those cities. In Masan, 100 out-patients received nothing but chemotherapy on an ambulant out-patient basis; 100 others were given, in addition, an initial period of six months’ bed-rest in hospital. In Pusan, 75 patients received only ambulant out-patient chemotherapy; 75 others also had their spines splinted in plaster-ofParis jackets for the first nine months of their out-patient chemotherapy. In Bulawayo, 65 patients were allocated at random to out-patient ambulant chemotherapy as in Korea, 65 to chemotherapy plus the performance of the debridement operation popularized by PAUS (1964). In Hong Kong, 75 patients were similarly allocated to dkbridement plus chemotherapy, 75 to the Hong Kong radical operation plus the same drug regimen. No attempt was made to study paraplegia in these four centres; patients unable to walk across a room were not admitted to the research. In Johannesburg and in Pretoria, where the work was started later, the studies made in Hong Kong were repeated and paraplegics were admitted to the trials. Isoniazid was given in doses of 10 mg/kg bodyweight and sodium PAS in doses of 200 mg/kg daily for 18 months in all centres to all patients. In addition, in Korea and in Bulawayo, but not in Hong Kong and South Africa, by a second random allocation, half the patients received streptomycin
sulphate in doses of 30 mg/kg daily (maximum daily dose 1 a0 gram) by intra-muscular injection for the first three months. In Hong Kong and in South Africa, all the patients received all three drugs in these dosages. Follow-up
In the four centres in which the work started, Masan, Pusan, Bulawayo and Hong Kong, we now have a five-year follow-up of 516 patients, and those in all centres except Bulawayo are being followed-up for at least ten years. The over-all follow-up rate in these four centres is 96.4 %. In the two Korean cities, only 2.3% of all cases have been lost to follow-up, a figure reflecting much credit on the field workers there. The death-rate in these four centres has been low. Only 0.8% of all the patients have died from or with active soinal tuberculosis. There have been a few deaths from other causes, including cancer, trauma and murder. In the casestreated conservatively in Masan and Pusan, only three of 350 have died with or from their disease. Results
The results of treatment have been classified thus : (i) ‘Favourable’, meaning that the patient is well, caoable of full ohvsical activity, with disease ra&ologically healed,‘abscessesand-sinuses (if any) healed, and that he is free from any disturbance of the central nervous system; (ii) ‘ Still not favourable’, implying the absence of palpable abscesses,the healing of sinuses (if any), but with persisting limitation of physical activity or without clear radiological evidence of healing of the bony focus ; and (iii) ‘Unfavourable’, indicating that abscessor sinus is still present, the disease unhealed radiologically, or that the patient has a persisting paraparesis or paraplegia, or is dead. Results
of conservative
treatment
In Korea, where no form of operative treatment was employed, the success-rate was high. In Masan, though only 61 y0 could be considered favourable at the end of 18 months (that is, at the end of their chemotherapy), 85% had become favourable at the end of the third year and, at the end of the fifth year, the figure was 90 %. The improvement between the 18th month and the end of the third year resulted from the delayed but progressive i&provement in most of the cases judged ‘still not favourable’ at the end of 18 months. In Pusan, the figures were much the same; 64% favourable at 18 months, 86% at three years and 87% at five. No statisticallv significant difference could be shown between thk results in those who had six months’ bed rest or nine months in a plaster jacket and the outcome in those who had neither. Moreover, no significant difference could be shown to result from the use of streptomycin. It therefore appears that, at least in cases without paraplegia, 90% of patients can be expected to respond well to treatment with the appropriate drugs and nothing else. --,”
~~~~
562
TREATMENT
OF TUBERCULOSIS
OF BONX AND
JOINT
Failures The fact that some 90% of patients do well unhappily implies that about 10y0 do not. We tried to determine any bad prognostic features that might be recognizable at the start of treatment, but we failed. Multiple regression analyses were performed on all groups, but no definite indication resulted. Surprisingly, there was no demonstrable difference in the prognosis for life and health between the mildly affected casesand the more severe ones, though deformity was much more marked in the latter group. We could show no prognostic significance in the number of vertebrae involved, in the presence of sequestra, abscessesor even sinuses. Most of the failures occurred in cases of thoracic rather than lumbar disease and there is some reason to believe that the initial response to treatment may have some limited prognostic significance, but the only certain reason for failure to respond to chemotherapy is failure of the patient to take the drugs.
and the dura mater posteriorly. Notches are then cut in the raw bony surfaces and up to three grafts, cut from the resected rib or from the ilium are wedged between them to bridge the gap. The wound is then closed. In Hong Kong, in the hands of its introducers, the claims made for this operation have been substantiated. Compared with a simple debridement performed by the same surgeons and accompanied in all cases by triple therapy, the ultimate results as regards preservation of life and health were much the same as those obtained by chemotherapy alone in Korea or by chemotherapy plus debridement in Bulawayo or Hong Kong. At three years in Hong Kong, 86% of those submitted to debridement had a favourable result, 87% of those undergoing the radical operation. At five years the figures were 88 % and 89 ‘$!,respectively. Patients undergoing the radical operation, however, reached a favourable status earlier, 89% at 18 months against 79% after debridement. Bony fusion also occurred earlier, though much of this particular advantage had disappeared by five years. There was less vertebral destruction in the radical series, despite the operative removal of bone and, probably the greatest advantage of this operation, the kyphosis did not increase. There was also earlier resolution of abscesses. The results in South Africa, though not yet published, support those obtained in Hong Kong in the patients without paraplegia. This is no operation for a surgeon who is not experienced in major spinal surgery. It demands resources seldom available in the tropics. It makes a much greater demand upon hospital beds than does out-patient chemotherapy and it remains to be seen if its outstanding advantage, the absence of increase in kyphosis, will be as obvious after ten years as it is after five in children, for they have a potential for correcting deformity by more rapid growth of vertebral bodies above and below the level of the lesion. At present, however, where circumstances permit its performance, it must be considered part of the treatment of choice in thoracic and lumbar disease.
The Hong Kong Operation The Hong Kong radical operation introduced a new concept. It was designed originally in the hope of producing more rapid cure in a country whose surgical resources were being strained by a massive inflow of refugees, many of whom had spinal tuberculosis. The operation is one of some severity. It calls for considerable surgical expertise and anaesthetic skill. The thorax is opened through the bed of a resected left rib or, in lumbar disease, the focus is exposed by an extra-peritoneal route. If necessary, the lung is separated from the paravertebral abscess, to which it may be adherent. The appropriate intercostal arteries are then divided and the aorta mobilized and retracted to the right. The abscessis then opened and a thorough debridement performed. The affected bodies are then resected, if necessary together with the intervertebral discs above and below the lesion, to expose healthy bleeding cancellous bone above and below
Paraplegia I have, so far, no new figures to offer about the treatment of the most important complication of spinal tuberculosis, namely paraplegia. My own practice has been to perform early decompression, preferably by means of the Hong Kong operation, on cases of paraplegia associated with active vertebral body disease. Resolution of the paralysis after decompression can be immediate, and patients should be relieved of paraplegia as a matter of some urgency. I have, however, no data from the Medical Research Council’s trials to support or to contest this opinion. In paraplegia associated with healed disease I can give no general advice, for we do not really understand the pathology of this type of paralysis. It appears, however, to depend upon severe kyphosis, and it may therefore be less likely to occur in patients whose kyphosis has been stabilized or reduced by the Hong Kong operation than in those treated by other methods.
Results of operative treatment In Bulawayo we were unable to show any advantage from the operation of debridement. A favourable status was reached in three years by 86% of those receiving out-patient ambulant chemotherapy and in 85% of those submitted to a dibridement in addition to their drugs. The results at five years showed no change. Operative debridement may have value in that it provides material for the establishment of the diagnosis, but it adds nothing to the patient’s chance of cure. It seems reasonable to believe that no lesser operation will do any more. There is one serious drawback to conservative treatment and also to debridement. The favourable results have been obtained, so far, at the expense of an increase in the angular deformity of the spine, the kyphosis. In Korean children this increase averaged about 15 degrees over three years, in Bulawayo about eight degrees in those treated without operation and about 12 degrees in those submitted to debridement. Unfortunately, the increases were greater in the patients less severely deformed on admission to the studies.
D. LL.
The place of surgery It is clear that the basis of the treatment of tuberculosis of bone and joint in any site and in any country must be chemotherapy. There seems as little indication for non-operative surgery, that is, for splintage, etc., as there is for sanatorium treatment in lung disease. The role of operative surgery has been much reduced and I expect to see further reduction. At present, the indications for operation may be regarded as absolute or relative. The first absolute indication is exploration to establish a diagnosis that is in any doubt. The word ‘exploration’ is used advisedly. ‘Biopsy’ is a word with too close an association with the removal of small fragments of tissue? often endoscopically, in the diagnosis of soft-ussue lesions. Such surgery is totally inadequate in bone and joint tuberculosis. The surgeon will want to seethe gross pathology of the lesion and it is essential to furnish the pathologist with a large piece of tissue if he is to be given a fair chance. Equally, because of the low bacterial population, the bacteriologist requires as much material as possible. The opening and suturing of an abscess that threatens to point, another absolute indication, should be undertaken in any abscessthat cannot be controlled by aspiration and chemotherapy alone. Equally, in the present state of our knowledge, I would regard paraplegia associated with active spinal disease as an absolute indication for operation. Among the relative indications for operation one would place circumstances permitting the performance of the Hong Kong operation in spinal disease. Regrettably, there is also a place for salvage procedures in destroyed joints in which early treatment has not been undertaken though, at least in the hip, there are grounds for hope that total replacement by low-friction arthroplasty will replace the classical operation of arthrodesis. The future The role of surgery may be further reduced if the newer drugs, which have been so efficacious in pulmonary disease, will prove capable of resolving bone and joint disease in shorter periods of time than the 18 months apparently required for PAS and INAH to be effective. We have no firm information about this yet. The Medical Research Council has, however, mounted a new series of studies in Korea, Hong Kong and Madras in which the effects of rifamoicin. ethambutol and PAS-INAH in short course-regimens are being compared with the results of standard 18 months’ PAS-INAH therapy. In Madras and in Hong Kong the radical operation reinforced by the newer drugs is also being studied. So far, 380 patients have been admitted to these new studies. If it proves possible to arrest this disease in six or in nine months instead of in 18, there will be fewer failures from default in drug-taking and less time for kyphosis to worsen. The more rapid cure and the avoidance of increase in deformity now associated with the Hong Kong radical operation may thus result from chemotherapy alone. The answer should be available in about three years’ time.
563
GRIPFITHS
References Boquet, A. (1938). Recherches sur la teneur des prod&s tuberculeux en en bacilles de Koch. Compte rendu des skances de la Societe de Biologie (Paris), 128, 473-483.
Dtbaumont, A. (1966). Bacteriologic de la tuberculose osteo-articulaire sous chimotherauie. Advances in Tuberculosis Research, 15, 125-188. Griffiths, D. Ll., Seddon, H. J. & Roaf, R. (1956). In: Pott’s Paraplegia. Oxford: Oxford University Press. Hodgson, A. R., Skisnes, 0. K. & Leong, C. Y. (1967). The pathogenesis of Pott’s Paraplegia. Journal of Bone and Joint Surgery, 49A, 114711%. ----_ Hodgson, A. R. & Stock, F. E. (1956). Anterior spinal fusion. British Journal of Surgery, 44, 266-275. Hodgson, A. R. & Stock, F. E. (1960). Anterior spinal fusion for the treatment of tuberculosis of the svine. Yournal of Bone and 7oint Suraerv, - -42A, 295-310: Hodgson, A. R., Yau, A., Kwon, J. S. & Kim, D. (19641. A clinical studv of 100 consecutive cases of P&t’s Paraplegia. klinical Orthopaedics, 36, 128-150. Kaufmann, R. (1948). Quinze observations d’attaque ganglionnaire dans le mal de Pott et autres localisations de la tuberculose. Memoires de l’dcademie
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Konstam, P. G. & Blesovsky, A. (1962). The ambulant treatment of spinal tuberculosis. British Journal of Surgery, 50,26-38. Konstam, P. G. & Konstam, S. T. (1958). Spinal tuberculosis in Southern Nigeria. Journal of Bone and Point Suroerv. 4OB. 26-32. Medical Research C&&l (1973a). A controlled trial of ambulant outpatient treatment and inpatient rest in bed in the management of tubercuolosis of the spine in patients on standard chemotherapy. Journal of Bone and Joint Surgery, - _. 55B, 678-697. Medical Research Council (1973b). A controlled trial of plaster-of-paris jackets in the management of ambulent outpatient treatment of tuberculosis of the spine in children on standard chemotherapy Tubercle, 54, 261-282.
Medical Research Council (1974a). A controlled trial of debridement and ambulatory treatment in the management of tuberculosis of the spine in patients on standard chemotherapy. Journal of Tropical Medicine and Hygiene, 77, 72-92.
Medical Research Council (1974b) A controlled trial of anterior spinal fusion and debridement in the surgical management of tuberculosis of the spine in patients on standard chemotherapy. British Journal of Surgery, 61, 853-866. Medical Research Council (1976). A five-year assessment of controlled trials of inpatient and outpatient treatment and of plaster-of-Paris jackets for tuberculosis of the spine in children on standard chemotherapy. Journal of Bone and Joint Surgery, 58B, 399-411. Medical Research Council (1978). Five-year assessments of controlled trials of ambulatory treatment, debridement and anterior spinal fusion in the management of tuberculosis of the spine. Journal of Bone and Joint Surgery, SOB, 161-177.