The treatment of tuberculous meningitis : a study of twenty-six cases

Abstract

Prior to the introduction of streptomycin a few years ago, tuberculous meningitis was a one hundred percent fatal disease. It is now justifiable to present a thesis on the treatment of this disease for streptomycin is the first therapeutic agent to be used extensively and successfully in the treatment of tuberculous meningitis. That fifty percent of the patients now live is a remarkable advance, but the fact that half the patients succumb serves to show that treatment is powerless to save those in whom the pathological changes are severe and . incompatible with recovery. Thus death is sometimes inevitable if the disease process is already advanced beyond the limits of the therapeutic power of streptomycin. The only certain preventative measure is earlier diagnosis of the disease. sobering feature of the conquest of this disease is that, though many may now live, some are unable to follow a full and happy life for treatment is not without its complications, some of which are permanent and disabling. It is the purpose of this thesis to describe the results of treatment of twenty -six cases of tuberculous meningitis in all stages and to present some of the factors which make this treatment unsuccessful or unsatisfactory.

The twenty-six cases to be studied in this thesis were admitted to Southfield SanatoriulL, Edinburgh between October 1948 and July 1951. The author has personally carried out the treatment of nine cases admitted after iiarch 195C and of five cases admitted prior to ìiarch 1950 but requiring treatment for varying periods thereafter. He has also been responsible for the follo1. -up and aftercare of all surviving patients including three in whom treatment was completed before 'kíarch 1950. The author was not_esponsible for the treatment of the remaining nine cases, all of whom were treated and died before _arch 1150. i em grateful to Professor Charles Cameron, i'iedical Superintendent, Southfield Sanatorium, Edinburgh, for permission to use the records of these nine cases.

1. The treatment of twenty -six cases of tuberculous meningitis has been described. It was found that the age group 10 - 20 years had the highest survival rate. The prognosis is unfavourable in children under 3 years of age.

2. The symptomatology of onset of the disease has been described. 7 cases presented with features of miliary tuberculosis, subsequently developing meningitis, while 19 cases presented with features of meningitis from the onset. In the former group a diagnosis of meningitis in an early stage was possible, and its onset varied between 3 - 13 weeks after the diagnosis of miliary disease was made. This earlier diagnosis does not universally lead to better results for the prognosis is less satisfactory when meningitis co- exists with miliary disease.

3. The results of treatment of the 26 cases are that 14 (54%) are alive and 12 (46%) are dead. Of the 14 survivors, 3 have been observed over 2 years, 8 over 12 - 24 months, and 3 continue to receive treatment. The highest survival rate occurred among the middle cases rather than the early eases because in the latter miliary disease largely influenced the outcome.

4. The tubercle bacillus isolated was of the human strain in 23 cases, and of the bovine strain in 1 case. The organism disappears early from the cerebro-spinal fluid following the introduction of intrathecal streptomycin.

5. The high fluctuating white cell count of the C.S.F., seen during the intrathecal administration of streptomycin, is not due entirely to the irritant action of the drug, but is probably the response of tuberculous meninges and tuberculous exudate to intrathecal streptomycin. As the meningitis subsides, the pleocytosis diminishes. Streptomycin leads to an increase in the polymorph-lymphocyte ratio of the C.S.F. The cells of the C.S.F. ha-:e never been found to return to normal so long as intrathecal streptomycin is administered. Even after discontinuation , many months elapse before a return to normal occurs.

6. the differential white cell count in the cerebrospinal fluid was described in detail. More satisfactory films were obtained using methyl alcohol to fix the film. The addition of protein to the C.S.F. during the preparation of a film reduced the disintegration of cells, especially polymorphs. It was thought that this method raised the osmotic pressure of the C.S.F. sufficiently to prevent such disintegration.

7. The causes of red blood cells in the C.S.F. have been discussed. As a consequence of streptomycin treatment, their occurrence is frequent and they have been found in more than half the specimens examined. On two occasions a subarachnoid haemorrhage has occurred. A high red cell count is the predominant response of the meninges to intrathecal tuberculin.

8. The protein content of the C.S.F. follows the pattern of the cell changes during the treatment of meningitis. A return to normal never occurs until after intrathecal streptomycin is withheld and it has usually been the last constituent of the C.S.F. to return to normal.

9. The sugar content of the C.S.F. has been found to be the most valuable in the early diagnosis and assessment of progress of tuberculous meningitis. The sugar value was below 50 mg.% at the time of diagnosis of all cases of meningitis. Higher levels were usually found in the earlier diagnosis of meningitis made in cases with miliary tuberculosis. With a satisfactory response to treatment, the sugar level gradually and consistently rose. It has been found that to discontinue treatment in a patient without symptoms and without clinical evidence of meningitis but with a C.S.F. sugar value below 50 mg.% leaves him in grave danger of a recrudescence of the disease.

The estimation of the sugar content of the C.S.F. at variable periods after the fluid has been withdrawn has been discussed. It was found that the fall in the value depended upon the leucocytosis of the C.S.F. present. An insignificant fall occurred 48 hours after the withdrawal of the fluid if the cell count was normal. The addition of sodium fluoride to the specimen enabled dependable results to be obtained in the presence of a leucocytosis.

10. It was found that the chloride content of the C.S.F. was not of reliable diagnostic or prognostic significance.

11. The C.S.F. graphs of each case in the appendix reveal that in the case showing a satisfactory response to treatment the sugar- chloride curves diverge from the protein -cell curves, while in the unsuccessful cases these curves converge.

12. The C.S.F. of the 14 survivors has been analysed. Long after the cessation of treatment, the majority cannot be regarded as having a normal C.S.F. on account of the slightly raised cell and protein contents. Apart from this, the sugar and chloride contents of all those, in whom the disease is thought to be arrested, are normal.

13. 10 of the 26 cases of meningitis were accompanied by miliary tuberculosis. 5 (50%) are alive. The results are only slightly inferior to those in the treatment of uncomplicated meningitis (56%). This was due to the fact that 7 of the 10 miliary cases were already in hospital receiving streptomycin for that condition when the meningitis supervened. In few cases of uncomplicated meningitis could treatment be instituted so quickly. A high percentage of cases of miliary tuberculosis develop meningitis during treatment and streptomycin affords no protection. For this reason regular examination of the C.S.F. is necessary.

14. Choroidal tubercles were found in 7 (70%) of the 10 cases of miliary tuberculosis but none were found in the cases of meningitis without miliary disease. It was stated that when additional choroidal tubercles were found during the course of the illness, they were more likely to have been missed on previous examinations than to have developed during the course of streptomycin treatment. They were an indication of the severity of dissemination of the disease.

15. The systemic administration of streptomycin was discussed. At present adults receive 1 gm. daily and children 0.5 - 1 gm. The original plan was that it should be given continuously for 6 months. The commonest cause of cessation of this plan was death. In general the smallest amounts of streptomycin were received by those who died. In the 10 cases alive and well who have completed treatment, the average duration of systemic streptomycin was 6 months and 5 days. Only 2 of the 12 dead received a treatment of similar duration.

16. Intrathecal streptomycin has been given to all cases in interrupted courses. The adult dose was 100 mg. and for a child was 50 mg. The planned intrathecal course resulted in 120 intrathecal injections being given during the 6 months' course of systemic streptomycin. The average number received by the 10: survivors was 136 and the averge amount was 7.6 gm. This meant that intrathecal streptomycin was given on 75% of the days on which intramuscular streptomycin was given. In no case that died did the number of intrathecal injections exceed the average number given to the survivors. It has been concluded that it is unsafe to give a less intensive intrathecal course than this.

17. The main criterion for stopping all streptomycin treatment was usually the state of the C.S.F. The clinical condition seldom required consideration for at this stage it was always very satisfactory and physical signs of meningitis had long since disappeared.

18. The administration of intrathecal streptomycin presented no serious problems. The co-operation of patients, old and young alike, is readily attained and local anaesthesia is not required. Streptomycin injected into the cisterna magna, in cases of spinal block, caused toxic features not seen when the lumbar route was used. The commonest features were drowsiness and marked nystagmus.

19. There were two phases of response to treatment. There was first the clinical improvement and gradual disappearance of all physical signs of meningitis. The persistence of a positive Kernig's sign for a long time was thought to be the result of prolonged spasm during the acute stage. The second response was that shown by the C.S.F. which occurs more slowly and requires longer than the first response. Even though the clinical response is encouraging, it is the C.S.F. picture alone which most accurately portrays the state of disease within the central nervous system.

20. In the survivors, residual complications of the disease itself are noticeably absent. The important disabilities (deafness, ataxia) have resulted from the drug used in its treatment.

21. No case of relapse has occurred in the 10 patients apparently cured. A recrudescence occurred in 3 patients in whom persisting abnormality of the C.S.I. was a constant feature.

22. The obstructions of the cerebrospinal fluid pathways have been discussed. Partial spinal block has been a common occurrence. The relationship of this to the administration of intrathecal streptomycin has been suggested because spinal block was found to resolve rapidly when streptomycin injected into the lumbar theca was withheld. The form in which the Queckenstedt test becomes modified has been described, and better results have been obtained by performing this test with light pressure to both jugular veins simultaneously.

23. The important neurotoxic manifestations of streptomycin have been described. No serious residual vestibular disturbances have been seen. 3 cases have developed complete deafness after being treated with dihydrostreptomycin and all the others receiving this preparation at some time or other during the course of their treatment show some auditory impairment. Deafness has never been encountered with the calcium chloride complex of streptomycin. For this reason dihydrostreptomycin is no longer used in the treatment of tuberculous meningitis.

24. Adjuvant forms of therapy played little part in the treatment of these cases.

25. The post-mortem findings in 8 of the 12 deaths were variable. It was evident that fibrosis of tuberculous exudate does occur as a result of streptomycin treatment but that acute meningitis was often present in adjacent areas relatively unaffected by treatment.