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
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
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
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
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
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
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.