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Tuberculous meningitis in the services
June 1954
126
Tuberculous Meningitis in the Services By K. B. TAYLOR
From the Military Hospital (Head Injuries), Wheatley, Oxon, and the Nuffield Department of Surgery, Oxford Between March 1947 and October i953, 60 proven cases of tuberculous meningitis have been admitted to the Military Hospital (Head Injuries), Wheatley, Oxon. O f these, 53 patients have completed all treatment, or died, and 7 are still in hospital. In addition, 7 patients have been fully treated for tuberculous meningitis, in spite of the absence ofbacterlological proof, but they are not included in this series, except where it is specifica!ly stated. The early results of treatment were reviewed in 1948 (Clarke, 1948 ) and in 195o (Richards, 195o ). The introduction of new therapeutic agents and the steady improvement in the results of treatment have prompted the writing of this paper. Since 1947, patients suffering from what had until then been considered a fatal disease, with rare exceptions (Hobson, 1936; Smith and Daniel, 1947) , have had a substantial hope of recovery. A great deal of this transformation can be ascribed directly to the work of the late Sir Hugh Cairns and his assistants, who have supervised all the patients treated at Wheatley since the introduction of streptomycin. Since their initial report (Smith, Vollum and Cairns, 1948 ) the expectation of recovery has increased markedly. Cairns and Taylor, in March 1949, concluded a review o f their cases with the following: 'At least 5 ° per cent of all cases treated are dying and there is ample room for improvement'. At that time the lesions they noted in their fatal cases included widespread meningitis, cerebral infarction, severe hydrocephalus of the communicating type and active tuberculosis in the lungs and elsewhere. Delay in initiation and prcnmture withdrawal of treatment were cited as the two main causes of failure. Wider experience has decreased the number of patients who relapse because they have been treated for too short a time. But while knowledge that the disease can
now be successfully treated has encouraged earlier diagnosis, delay in initiation of treatment is still the commonest cause of failure and in fact the proportion of advanced cases has changed very little. Although tuberculous meningitis has a so much longer course than the purulent meningitides, every hour gained in commencing treatment is as important for the patient as in the latter disease.
Diagnosis of Tuberculous Meningitis Age Incidence.--Tuberculous meningitis is predominantly a disease of young people. It seems likely that the age incidence has changed since the eighteenth century, when Robert W h y t t in his classical description of the disease, which he called 'acute hydrocephalus', defined the age incidence as between 2 and 16 years. Although the highest incidence is still in t h e first 25 years of life, there are numerous exceptions. O f the 60 patients treated at Wheatley, 9 were Over 25 years and I of these over 3o.When allowance is made for the selected population from which the Service cases were drawn, this is comparable to the experience of the Oxford Tuberculous Meningitis Unit where 33 out of 132 civilian patients were over 25. The great majority of cases of tuberculous meningitis occur in relation to the primary infection and it is reasonable to suppose that the delay in primary infection and tuberculin conversion observed in recent surveys (Daniels, 195 I) is the chief factor in determining the somewhat later age incidence. Seasonal Incidence.- Figures for the total number of deaths each month from untreated tul~erculous meningitis in England and Wales in 1945 to 1947, show the highest incidence between March and J u n e (Calnan, 1951 ). Hall (195o) gives the peak in the twentieth week of the year and states
June
1954
TABLE
TUBERCLE
I.- N U M B E R
OF OASES OF T U B E R C U L O U S THE YEARS J A N .
Month: Jan. No. of cases 4
F e b . Mar. 6 8
Apr. 7
May 7
that death occurs commonly in untreated cases at four months from the time of infection. This time-relationship cannot be accepted without reserve, b u t the argument that infectious contacts are most likely to be made over the Christmas season with its 'gathering of the clans', seems very reasonable. The Wheatley" figures for admission (Table I) show the highest numbers between the beginning of Fdbruary and the end of May, but the numbers are too small to be significant. Contacts.- The over-all number giving a history of contact is 14 out of a total of 43 patients whose past history has been properly elicited. These known contacts were almost all members of the patients' own families. This rate is very low by comparison with other series and it seems most likely that in the majority of cases the disease has been contracted in the Services. Clinical Findings. - Classically, the onset of the disease is insidious and measured in days, weeks or months. During this time fatigue, loss of or failure to gain weight, loss of TABLE
II.-
127
~[ENINGITIS A D M I T T E D
IN E A C H
I~,'[ONTH OF
1947--JAN. I 9 5 4 June 4
July 5
Aug. 4
Sept. 3
Oct. 3
Nov. 3
Dec. 6
appetite, irritability, constipation (especially in children), insomnia, nocturnal restlessness and an ill-defined malaise, may be noted. Importance may be attached to these prodromal symptoms only in retrospect and tuberculous infections elsewhere in the body, or some other chronic disease, may give rise to much the same picture. Neither is this picture invariable. Some patients present as cases of acute meningitis and others may develop a tuberculous meningitis during treatment for miliary tuberculosis, which masks the onset of the meningitis. Since the majority of patients under review were young adults, it was possible to obtain a fuller subjective history than in series consisting largely of young children. Table II shows the intervals between the first appearance of the main symptoms and signs of the disease and the establishment of diagnosis and treatment in 55 of the 60 patients. The diagnosis was established in the shortest time, though by no means in the earliest stages of the disease, when symptoms
TIME INTERVAL BE'I'~VEEN ONSET OF ~'IAIN SYMPTOMS AND SIGNS AND DIAGNOSIS
Days before diagnosis and beginning of therapy Symptonz or sign Coma
°-3
••
3
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128
TUBERCLE
and signs were dramatic. Among thcse wcrc fits, diplopia, paralysis and incontinence. No comatose patient remained undiagnoscd and untreated longer than two days. However, in two paticnts, ncck rigidity had been noted more than three weeks before diagnosis and, in one, photophobia had been present for over two months. Patients complaining of headache and fatigue, with persistent fever, w e r e in the main diagnosed late. Classification. - Rigid classification of cases according to the severity of their disease is clearly impracticable, b u t the practice at Wheatley is to divide patients into three broad clinical groups, after the fashion suggested by the Streptomycin Trials Committee of the M.R.C. (1948). The first group comprised those who were fully conscious and had no focal neurological signs; the third, those who were so stuporose as to be virtually inaccessible, or comatose, or had gross focal neurological signs. The second group embraced the rcmainder. This division, as will be shown, had great prognostic significance. There was no significant correlation be-" tween the average length of the prodromal phase and the clinical condition on a d - ' mission. This is shown in Table I I I (Grade I 21 "5 days. Grade II - 15.1 days. Grade III 17. 5 days). TABLE
III. -- S T A G E
OF
THE
DISEASE
ON
ADMISSION COMPARED %VITn DURATION OF PRESENTING SYMPTOMS
Grade I II III
Dqvs z-7 2 8 2
8-z4 3 zo 7
z5-22 2 3 3
22+ 4 8 3
Diagnostic Investigations Radiograpty.- A routine chest x-ray was taken on admission. In the 60 cases, I8 showcd miliary involvement of the lungs, 6 showcd a primary focus, 5 showed phthisis and 2, pleuraI effusions. Skull x-rays were taken as a routine, on admission, in case there was demonstrable evidence of in-
June 1954
creased intracranial pressure in children, or intracranial calcification in adults. Other examinations, such as straight x-rays of the abdomen, intravenous pyelography and xrays of the spine, were undertaken in selected cases. Confirmation of a diagnosis of Port's disease was obtained in 6 patients. Ventricular estimation, followed, if necessary, by the introduction of air, was done in cases where the diagnosis was in.doubt, or where the neurological findings suggested a tuberculoma or other space-occupying lesion (Cairns, i949). Mantoux Testing.- During the last three years, routine Mantoux tests have been done on admission. The initial test was performed with a 1/IO,OOO dilution of Old Tuberculin, followed by I/i,ooo if there was no response and i / I o o if there was no response again after forty-eight hours. A positive reaction is defined as an area o f o e d e m a of at least 8 ram. diameter present forty-eight hours after the injection. The results of 45 initial tests are available, of which 42 wcre positive to one of the standard dilutions. O n e patient died before the test could be read. These findings are in agreement with those of other series (M.R.C. trials, 1948; R u b i e and Mohun, I949; Debrd, 1953). Cerebrospinal Fluid. - L u m b a r puncture was done under conditions which allowed of careful recording of pressure and reliable examination of the cerebrospinal fluid for cells, protein, sugar and chlorides and also for organisms, by direct film, culture and guinea-pig inoculations. Appearance of Fluid. - With rare exceptions, the fluid obtained on admission was clear and colourless. The appearance of a spiderweb clot on standing was not a constant finding. Cell counts ranged from 35 to i,ooo and though a moderate predominance oflymphocytes was the usual finding, some fluids showed over 5 ° per cent of polymorphs. Protein.- The majority of fluids at initial punctures showed protein levels between 4o and ~oo mg. per lOO ml. three of the 6o cases showed levels over 500 rag. per ioo ml.
June
1954
TUBERCLE
Chlorides.- Normal or slightly reduced chloride levels were found and tile level was not of value in diagnosis. Sugar.- 15 cases (25 per cent) showed a sugar level of 5 ° mg. per Ioo ml. or above, on admission. These were considered to be in the normal range. The other 45 cases showed values between 35 and 45 mg. per Ioo ml. Direct Fihns. - In 34 cases, acid-fast bacilli were seen within seventy-two hours of admission, in 7 further cases within two weeks of admission and in 4 cases later than this. In 2 cases t h e organisms were found in ventricular fluid obtained when burr-holes were made and, in i of these, organisms were later seen in the lumbar fluid. In I other case, organisms were seen in a cisternal specimen sixteen days after commencement of'treatment, when lumbar fluids had been negative. Cultures. - In 44 of 57 cases (the results of 3 cases with positive films not yet being available), cultures were positive, using Kirschner and L6wenstein media. In 8 cases, cultures were positive when no acid-fast bacilli had been seen on examination of the direct films. In 9 cases, cultures of fluids were negative when acid-fast bacilli had been found microscopically. In 2 cases the diagnosis was made at post-mortem, when films and cultures had been negative throughout the course of the illness and, in 2 others, cercbeltar tuberculomata were removed at operation, films a n d cultures being negative before and after. In addition to the above investigations, every effort was made to reveal active tuberculosis elsewhere in the body. Six samples of sputum, when available, from each patient were examined for ~1I. tuberculosis by film and culture and, where sputum was not available, gastric washings were examined in a similar way. Three specimens of urine from each patient were examined for protein, cells and the presence of acid-fast bacilli and, in cases where tabes mesenterica was suspected, the stools also were examined for 31. tuberculosis.
129
Blood Picture.-Blood haemoglobin determinations were performed on admission in most cases, but the results were not consistently below the normal range. The white blood cell counts were undertaken on admission as a routine and showed a considerable variation, ranging from 4,4oo to 2o, Io% the abnormally high counts showing a relative polymorphonucleocytosis. There has been no evidence of leucopenia in those cases with miliary disease. Differential Diagnosis In the period under review a complete record of these patients, who were admitted as cases of tuberculous meningitis and found to be suffering from other diseases, is not available. They included cases of meningococcal and haemophilus meningitis, Weil's disease, general paralysis of the insane, lymphocytic meningitis of unknown aetiology, anterior poliomyelitis and brain abscess. Similarly, many of the 15atients who ultimately proved to have tuberculous meningitis were admitted with some other diagnosis than the correct one. The original diagnoses in these cases included, lymphocytic meningitis of unknown aetiology, anterior poliomyelitis, cerebral abscess, cerebral haemorrhage, Addison's disease, torulosis and pneumococcal meningitis. A case diagnosed as Fr6hlich's syndrome and treated by severe dieting and hormonal therapy, which produced a rather more dramatic loss of weight than was expected, is also to be found in this group. Apart from the investigations mentioned already, others were therefore undertaken in those cases where the clinical picture demanded them. These included W.R. and Kahn, Paul Bunnell, blood cultures, biochemical investigations, and serological tests to exclude leptospirosis. Treahnent Ghemotherapy.-Various preparations of streptomycin, by intramuscular and intrathecal injection, have formed the essential basis of treatment and this drug has not been superseded. The early preparations were
130
TUBERCLE
more irritant and toxic than the streptomycin sulphate, which has been used excluslvely during the last eighteen months. Its administration by intrathecal injection is considered to be the sine qua non of satisfactory therapy. The dose has been Ioo, ooo units daily in the adult, and 3o,ooo to 75,ooo units daily in children, according to age*. This dosage is continued without intermissions until the C.S.F. contents, especially protein, are returning steadily, without fluctuations, towards normal; until the patient's condition is satisfactory, without fever and with. steady gain in weight; or until eight weeks have passed since M. tuberculosis has been identified in the fluid; whichever of these i.s the longest. Where a spinal block develops the route of intrathecal therapy is changed to the cisterna magna or the lateral ventricles via bifrontal burr-holes. As soon as the block can be shown to have resolved the lumbar route is once more adopted. Where the ventricles are enlarged, as is so often the case, a n d easy to tap, ventricular injections are preferred to cisternal. They disturb the patient less, are technically somewhat easier, and the risk of streptomycin deafness developing would appear to be far less than when this drug is given into the cistern. There is, however, ahvays the risk of inducing a haemorrhage and, in a few cases, the ventricles may be hard to find. In these cases the cisternal route is obligatory. Intramuscular streptomycin is given in doses of x gramme b.d. to adults and on the basis of 2o mg. per pound body-weight to infants and young children. This treatment is continued without interruption for a total of six months or for two months after the cessation of intrathecal therapy in those cases in which no evidence of active systemic tuberculosis obtains at this time. Although intramuscular streptomycin produces a useful C.S.F. concentration o f the drug in the presence of meningitis and, indeed, some *Since October x953, the intrathecal and intramuscular dosages of streptomycin have been halved, in the hope that the incidence of deafness may be decreased.
June 1954
cures by this route of administration alone have been reported, its main function is to control systemic disease, which may or may not be demonstrable, but which must always be suspected. The persistence of evidence of systemic infection may demand prolongation of intramuscular treatment and other means of treating the condition. Adjuvant Chemotherapy.- Patients who had systemic lesions, in which the deyelopment of resistance of the M. tuberculosis to streptomycin was to be expected, were given paraamino-salicylic acid orally until recently. The development of resistance to streptomycin by the organism in the C.S.F. is exceedingly rare (Cairns et at., I95O) and PAS was never given as the adjuvant in the treatment of the meningitis itself. Its toxic side-effects, however, especially anorexia and vomiting, are highly undesirable and its use has now been superseded, in this series, by isonicotinic acid hydrazide. This "is given orally in doses of i5o mg. t.tt.s, in adults, and intrathecally in doses of 2o mg. daily. In children the dosage has been scaled down according to age and weight, infants receiving 5 ° mg. by mouth t.d.s, and I t mg. intrathecally. Other Treatment Sedation. - Since patients with tuberculous
meningitis show a tendency to cortical dysrhythmic attacks, they are sedated, the adults receiving phenobarbitone ½ grain t.d.s., and children a comparable dose. During the period of reaction to intrathecal P.P.D. an increase in sedation, either with barbiturates or paraldehyde, is sometimes found to be necessary. D i e t . - Every effort is made to check the almost invariable weight loss of these patients during the active phase of the disease and to produce gain in weight. Anorexia and vomiting may be troublesome and demand patience and nursing skill. Patients with bulimia are, unfortunately, rare. No satisfactory method of suppressing nausea and vomiting has been found. A normal diet, with high protein content, may suffice but tube feeding with milk, fortified
June 1954
TUBERCLE
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C i t ~ x I . - Cme~,D. A. (I%1) aged 18. Admitted,z4.6.53. Fourteen days' history of headache. Clinical Grade II. Continuous improvement from onset of treatment. No residua, apart from unsteadiness in dark. Note typical protein and weight curves.
132
TUBERCLE
with proteins and protein hydrolysates may be necessary in the seriously ill. This ensures as adequate an intake as possible and tends to obviate the risk of aspiration of food during ingestion. Where vomiting is a continuing feature, fluid balance charts and maintenance of fluid intake are essential. A full supplement of vitamins and iron by mouth are also given to every patient.
June 1954
amnesia and the disappearance of, or emergence of, new neurological signs is of the utmost importance. T h e blood is examined at least every month, the haemoglobin, white cell count and sedimentation rate being determined and the chest x-rayed as often. T h e possibility of urinary infection exists throughout treatment and the urine is therefore examined at least once a week for cells, casts, Blood Transfusion and protein and cultured for organisms. In patients who show a considerable anaemia Most patients remain critically ill for a blood transfusion of one or two pints has many weeks. They may be drowsy or stuporsometimes marked the beginning of a ose, internfittently or Continuously; they general improvement, both during the acute may develop further signs of neurological phase of the illness and in convalescence. involvement; and fever and loss of weight Nursing may continue for many weeks. This is onerous and demands experience and T h e cases under review fall into four an understanding of the patient. Special clinical groups. atterition to pressure points and turning In the first group, patients respond to every two hours, the maintenance of ade- treatment from the start. T h e fever settles, quate postural drainage to prevent bronchial drowsiness and mental confusion, meningism obstruction and collapse, keen observation and focal neurological signs disappear, of mental state and of sphincteric functions, appetite recovers and there is a gain iu and patience in feeding the anorexic are the weight, if not at once, at least after three to four weeks. most important features. T h e C.S.F. in these case's may show high l~ehaviour under Treatment initial 'activity', with spikes of cells and Charts.- T h e keeping of large charts on protein, the base-line values of which rise in squared paper has been found to be the only the first few weeks, tend to level out about satisfactory method of following the course the sixth week and then fall, steadily and of the disease (Smith, i952 ). On these charts without spiking, towards normal values. are recorded the presence or absence of i l l After cessation of therapy, follow-up shows tuberculosis in films and cultures, the daily no evidence of recrudescence (Chart I). level of cells and protein in the C.S.F., all The second group, a small one, comprises specific therapy, including P.P.D., daily those who respond well to treatment, but, C.S.F. pressures, daily m a x i m u m temperafollowing its cessation, relapse and require a tures and the patient's weight, taken wce "ldy. much more prolonged period of therapy. Some of these charts are reproduced in the They may die or recover. The initial relapse following section. can be ascribed to stopping treatment too In addition, four-hourly records oftempersoon and experience has diminished the ature, pulse and respiratory rates are kept incidence of this type of case (Chart II). rotitinely. T h e third course is of rapid downhill Clinical Assessment deterioration from the time of, or soon after, Full neurological and general clinical exami- admission and the beginning of treatment. nation of each patient is performed at least Death occurs between tile second and fifth once a week and more often if the patient's weeks, a picture very similar to that seen in condition demands it. Special attention is untreated cases. Many of these cases were paid to mental state, including the degree of admitted late in the coiarse of the disease, in
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CIIAI~T I I . - C a s e L . C. (F) aged 18. Admitted I6.7.48. Ten days' hkstory ofincreasing headache and neck stiffness. Lefthemiplegia. Clinical Grade III. Fourteen days intrathecal streptomycin only. Relapsed on 23.x 1.48. Irregular deterioration to death in coma on 27.8.49. Note positive cultures following cessation oflntrathecal streptomycin on t{vo occasions. Both courses too short.
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June 1954
TUBERCLE
coma or with gross neurological signs, but this is by no means invariable and Chart III, illustrating this type of course, is of a patient who, on admission, was almost fully alert and co-operative, with no marked neurological signs. T h e infection would appear to be overwhelming. T h e organisms have not been resistant to streptomycin, but their numbers and location have rendered therapy inadequate. The fourth group comprises a number of patients, who, regardless of the stage of the disease on admission, at first respond well, but then deteriorate between the second and fifth months of treatment (M.R.C. Trial, I948 ). During the first two years of experience' with streptomycin it was observed that most of these patients became decerebrate and died in coma, but, rarely, one might recover after a very stormy passage. Typically in these cases there was a decrease in cell content of the C.S.F. and an absence of spontaneous 'spikes' (Smith and Vollum, I95o ) and the protein would rise to high levels. During t h i s phase, spinal blocks might occur, necessitating the use of the ventricular route for therapy. Chart IV is of a patient who died after a course of this sort. Post-mortem examination of patients in both Groups III and I V revealed gross exudates round the base of the brain, ensheathing the brain-stem, with blocking of the cisterns and marked hydrocephalic changes and infarction of brain stem and cortex. A substance which would prevent the formation of, or help to disperse this exudate, was clearly demanded. Intrathecal tuberculin appears to meet these demands. Tuberculin.- A purified protein derivative of tuberculin (P.P.D.) is supplied by the Ministry of Agriculture and Fisheries Veterinary Laboratory, Weybridge. It possesses a high potency judged by its ability to produce the skin tuberculin reaction in sensitized humans and it has been used intrathecally since i949 iSmith and Vollum, 195o ). At first its use was confined to cases having a bad prognosis, as judged by the stage of the
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C~L~T III.- Case L,R. (M) aged 4½ years. Admitted 59.4.53. Fourteen days history.of listlessness, anorexia, headache and vomiting. O n admission, fully conscious, slight left facial weakness. Gradual deterioration to death on 17.5.53 in decerebrate state, after numerous decerebrate
attacks. (Positive C.S.F. culture, prior to admission,not ~hown on chart.)
1954
June
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136
TUBERCLE
dlsease and failure to respond to treatment, but now it is used in the large majority of Mantoux-positive patients. P.P.D. was first given intrathecally in tile human in the middle of I949, to a moribund patient whose condition had deteriorated in the manner described above. It was administered to test the theory that the spontaneous 'spikes' of cells and protein in the C.S.F. of patients treated with streptomycin alone were due to release of bacterial breakdown products, i.e. of tuberculoprotein, and that this produced an inflammatory reaction of meninges already sensitized to these products. The injection of P.P.D. produced identical cell and protein rises, with a rise also in C.S.F. pressure and a generalized systemic disturbance, marked by fever and tachycardia. There was also a temporary exacerbation of meningism and of the focal neurological signs. Later experimental work has shown that there is a rough correlation between the reaction to intrathccal and intradermal injections of tuberculin and there is now good evidence that the meningeal response is a true, specific tuberculin reaction (Swithinbank et al., I953). The remarkable finding was that the patient began to improve almost immediately and is now alive and well (Smith and Vollum, I95o ). This procedure was repeated in other cases and it was found that the use of P.P.D. intrathecally appeared to be a valuable factor in preventing deaths in this middle period already described. Even in those cases which died in spite of P.P.D. treatment, post-mortem findings showed a marked diminution or absence of that exudate seen in cases treated with streptomycin alone or untreated. The use of P.P.D. has now been carefully standardized. A positive Mantoux skin reaction seems to be essential. Bifrontal burr-holes are introduced in every case before the commencement of treatment, so that, should dangerous rises in the C.S.F. pressure occur, they can be relieved by vcntricular puncture. P.P.D. (Weybridge) is used in four
June 1954
concentrations: a standard solution, containing 0.0075 mg. per ml. and dilutions of I : io, i : I oo and I : i,ooo. It is injected intrathecally by the lumbar route at the same time as streptomycin is given, or, if a spinal block is present, into the cistern. It is also occasionally given into "the ventricles, but it is then desirable that the C.S.F. response should be followed by cisternal or lumbar tap, as the ependymal response is very small compared with that of the meninges. The initial dose is usually of the order of 0. 5 to I.o ml. of the standard/i,ooo dilution, depending on the intensity of the Mantoux reaction, and this is trebled up at three-day intervals until an adequate response is obtained, judged by the clinical picture of increased malaise and mental confusion, high fever, tachycardia, increased meningism and pre-existing focal neurological signs and by the C.S.F. changes. These consist of an acute rise in the cell count .with a relative rise in the polymorphonuclear count or a rise in the protein, or both, reaching a peak within twenty-four hours or forty-eight hours of injection. There may be a second spike of ceils, mainly lyrfiphocytes, and of protein between four to seven days after the injection (Swithinbank et al., I953). This reactive dose is then given at weekly or slightly longer intervals and is not changed unless the response diminishes or disappears. In these cases, the Mantoux test is repeated to ensure that the patient has not become desensitized. When the cells and protein do show a steady fall and the C.S.F. reactions tend to die away in spite of the persistence of a positive Mantoux, P.P.D. is stopped, while streptomycin therapy is continued according to the principles outlined above. Chart V is of a patient whose condition deteriorated during treatment with streptomycin alone, responded when intrathecal P.P.D. was given and recovered after a stormy passage. When the criteria for the stopping of intrathecal therapy are all satisfied, examinations of the cerebrospinal fluid are continued at regular intervals, at first twice a
June1954
T U BERC LE
I
137
INT'C~MU~CULA~ STF~J:~'O'.ttC~N ~\\~'~ I NTtRATHECAL
so
s t a e p t o ~ Yc I n , x X X X \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \
f\
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....................
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1,200 C.S.F. CELLS PER C . ~ I000
800
6OO
4~ °
° ",
,
[
2OO
I.S
P.PD. It.
~
o°
800
r I!,AHH.
I
s .
,
,
.
.
.
',SE PROTEIN MG.PERiO0~a._
600
200 IOC) C.SF. PRESSURE to2
TEMPERATURE "F
WEIGHT LBS
y ' ~ ' /
iIC
/ E.S.R.
/,O
DAYS
• [1~ '
=o
}"
40 '
50
I '0
7
"
J
~o
'
I00
! lO ' 12o 'I}O
"~
I$t
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170
180 '
,"
200
CIIART•r _ CaJ¢ R. B. (M) aged 18. Admitted on t3.8.5i. Clinical Grade II. Deteriorated on streptomycin alone. Persisting papilloedema and in a high pressure state. Marked improvement on P.P.D.
138
June 1954
TUBERCLE
week for the first month, then weekly, for six to eight weeks, then monthly and finally at three and six month intervals. Any rise in cells or protein during the initial follow-up period may be indicative of relapse, especially if there is recurrence of fever, or failure to gain weight. Some small fluctuations, especially in the protein levels, and the persistence of an abnormally high C.S.F. protein for months or even longer, are not, in themselves, necessarily of grave import, judged by our experience in this series.
20DE,4D
15
~o IO
pL',q/oa
Convalescence
Great importance is attached to this. T h e patient is not allowed out of bed until sufficienl~ time has elapsed after the stopping of intrathecal therapy to be sure that progress on intramugcular therapy is unipterrupted. Most Service cases in this series have convalesced, following discharge from Wheatley, at Headington Hill Hall, a special rehabilitation unit run by the Ministry of Pensions. This centre, within easy reach of Wheatley, has proved invaluable, in that admirable facilities for rehabilitation, including speech and physiotherapy, and thorough medical after-care are available at one and at the same time.
1"~'l'4t'/~ c
suRvtvA,a,~rc .~E~CENTAGE WITH P./~D.
1947-48
502
0.7
1949-50
1951-53
53Z
7_12'
,6 7/."
7,.7
*
•
Fio. i . - Results of treatment since 1947, showing the improvement since the introduction of intrathec-al purified protein derivative (P.P.D.).
intrathecal tuberculin, that during which its value was being determined, and that in which it has become more and more an established therapy. Table IV shows percentage survival in each clinical group during these three periods, and also the n6mber of eases in each group during these periods. It is apposite here to point out that in the i949-5o period it was the worst cases (i.e.
TABLE I V . - NUMBER OF CASES IN EACti CLINICAL GROUP AND PERCENTAGE SURVIVAL IN EACH GROUP, IN PERIODS DURING WHICH TREATMENT "~VAS COMMENCED
Clinical Group I II III
1947-48 Total No. Percentage of cases surviving 5 8o% 3 33% 4 25%
z949-5 ° Total .No. Percent.age of cases survzvzng 4 75% 8 37"5% 5 6o%
Results 32 patients have completed all treatment and have been followed up for periods longer than six months from the stopping of intrathecal therapy. 2z patients died during treatment, an over-all survival rate of 60 per cent. The histogram (fig. I) gives some indication of the improvement in results of treatment since I947, dividing the period into three stages: that prior to the use of
1951-53 Total No. Percentage of cases surviving 2 IOO% z5 8o% 7 43%
Group III) who were treated with intrathecal tuberculin, and it is in this group that the greatest improvement is seen, compared with z947-48. I n the I951-53 period, more and more Group II cases also received P.P.D. It is evident from Table IV that the improvement in results can clearly not be ascribed tO earlier diagnosis." Table V shows the incidence of coincident systemic infection and the outcome in these cases. It is clear that file presence of overt miliary spread or
June 1954
TABLE V . - R E C O V E R Y R A T E IN CASES COMPLICATED BY SYSTEMIC INFECTION
Systemic disease Miliary .... Phthisis .... Primary focus •• Pleural effusion .. Spinal caries . . . . Renal tuberculosis ..
139
TUBERCLE'
Total No. of cases
Recovery
z7
i o*
5 7 z 6 I
4 2 o 4 I
"2 of these patients had spinal caries and renal tuberculosls, in addition to miliary, and x of them had phthMs as well. They are also included in the figures in these groups.
of chronic pulmonary phthisis, if treated energetically, need not have a marked effect on prognosis. Residual Disabilities. - Infants and children are not included in this assessment. Ataxia due to vestibular nerve damage due to streptomycin therapy has been a constant finding. All patients, however, have achieved a high degree of compensation and their only complaint at the end of convalescence is of some unsteadiness in the dark. Apart from this minor disability, I8 of a total of 28 patients are well, physically and mentally, and capable of full activities, 9 of these fell into the clinical Group I on admission and 8 into Group II. Only z patient in Group III escaped unscathed. T h e more serious residual disabilities fall into two classes: those caused by the disease and those caused by streptomycin therapy. The fact that deafness, d u e to eighth nerve damage, is almost always bilateral, irreversible and appears commonly when other neurological signs are receding, is in favour of this disability being due to therapy. Four of our patients are completely deaf and 3 have a partial deafness, still retaining a useful degree of auditory function. Disabilities in 3 patients are considered t o be due to the disease itself. One has a left hemiplegia which does not prevent his wor'Idng full-time as a clerk, another has a mild right hemiparesis which allows his earning his living making handicrafts and the third shows a fairly marked bitemporal hemianopia with adequate central vision.
Discussion
The number of cases rcvicwcd in this series is large enough to show some pointcis in diagnosis, treatment and prognosis. Both the speed and the clinical pattern of progression of the disease are extremely variable. It is these factors which make diagnosis so difficult and result in delay in treatment. Thus, a patient may be admitted in coma with only a few days' hist6ry of increasing headache and fever, or may develop mild neurological signs after a period of many weeks' mild and variable headache and associated fatigue and listlessBess. Not infrequently, however, the reason for delay would appear to be a failure to entertain the diagnosis at all. Headache, fatigue and continuing mild fever are evidently a combination, the significance of which may bc most easily overlooked. It is fair to suggest that any patient exhib!ting this triad, for which there is no obvious cause, should have a lumbar puncture and thorough examination of the C.S.F. within a week of the onset, of symptoms. Clinically, great importance attaches to the mental state of the patient. The degree of blunting of consciousness and amnesia is, in the majority of cases of tuberculous meningitis, greater in proportion to the degree of meningism than in the benign lymphocytic meningitides, the purulent meningitides and anterior poliomyelitis. The diminished mental awareness in the first contrasts sharply with the often agonizing mental clarity seen in the last (Lancet, Pers. Papers, i953). Examination of the C.S.F. may reveal acid-fast bacilli in about 5 ° per cent of cases within seventy-two hours of admission. This approximate figure takes into account the 7 patients, not included in this series, who were never proven bacteriologically, but who behaved, under treatment, as typical cases of tuberculous meningitis and had either miliary or clear evidcnce of other tuberculous infection. A moderately reduced sugar content and increased protein in the
140
TUBERCLE
C.S.F. are useful findings. T h e development o f other tests which may help to cstahlish the diagnosis, as quickly as possible, is an active field at the time. Certainly the demonstration of the increased amount of bromide which passes from the serum into the C.S.F. in cases of tuberculous meningitis (Taylor, Smith and Hunter, I954) has proved of great value in many of the cases in this series. There is ample justification for starting treatment of a patient in w h o m a diagnosis cannot be firmly established. Tubercle bacilli may be seen or cultured later and precious time and, very often, the patient's life, has been saved. There is no evidence to suggest that daily intrathecal therapy may prevent the return of the contents of the C.S.F. towards normal limits in these patients whose subsequent rapid recovery and the absence of positive cultures exclude the diagnosis of tuberculous meningitis. A twenty-eight-day course of streptomycin (until the first culture results are available) by lumbar route has in our experience never resulted in any toxic manifestation. Chart VI is of a patient treated thus, and also with penicillin, who was later shown serologically to have leptospiral meningitis. T h e establishment of a means of treating tuberculous meningitis satisfactorily, w i t h o u t intrathecal injections, is eagerly awaited. T h e recent reports of results with oral isonicotinic acid hydrazide alone (Kerr, i953) or in conjunction with intramuscular streptomycin (Torres-Gost, I953; Anderson et al., I953) or with A C T H (Bulkeley, I953) , have tended to b e incomplete and not wholly convincing. They are certainly not such as to permit at this stage a change from a tried regimen, which is producing good results by any standards. T h e statement (Douglass, i953) that 'the intrathecal administration of streptomycin has been abandoned by most physicians' (in the U.S.A.), is surprising, to say the least, and reports from that country are awaited with interest. Levinson (I949) stated that, in his experience, there was no place for intrathecal streptomycin therapy, but his
June 1954
1G.
S TP,EP.
0 . 0 5 G-
F////A L
150 MGM,
/./V~.
IO MGM,
t.T. i::::iiiii:;l
aoo
C S E CELLS per Crnrn.
3OO
2OO
300
CSF. PROTEIN
n~. per IOOrnl.
2OO
CllART "V[. Case D. 07. (M) aged x2. Treated fully as a case of tuberculous meningitis, until proven, serologically, as leptospirosis. - -
results showed a very high mortality rate. To sum up, the treatment of this disease is long and fraught with difficulties and dangers. If the best results arc to be obtained it should be undertaken, practically and not ideally speaking, in centres where the nursing staff is trained in the management of the patients, the clinical and laboratory medical staff constantly gaining in their experience of thedisease and where special methods of neurological investigation and facilities for "neurosurgical intervention are available. This is particularly so when intrathecal tuberculin is used. T h e behaviour of our patients under treatment has shown how difficult prognosis
June
TUBERCLE
1954
141
can be. Generally, the duration of non- is emphasized that certain clinical features, specific symptoms, such as headache and especially the mental state, are of considerfatigue, is a far less important factor in its able value. assessment than is the stage of the disease at It is not considered that the methods of which the patient is first diagnosed and treatment here described, with continuous treated. Debrd (I952) emphasizes this when intrathecal and intramuscular streptomycin he states that the state of consciousness of the and, more recently, intrathecal tuberculin patient is a better guide to prognosis than the and isonicotinic acid hydrazide intrathecally duration of symptoms. It is to be hoped that and by mouth, have yet been convincingly with earlier investigation of the non-specific superseded. symptoms mentioned above, more and more Acknowledgments patients Will be treated even before there is I am very grateful to Dr Honor Smith, under any definite blunting of consciousness. whose care these patients have been treated, A recent report on childhood tuberculosis for most helpful advice and criticism, and in Sheffield (I,orber, t953) , which shows a wish to express thanks to the Director75 per cent recovery from tuberculous General, Army Medical Services, for permeningitis in 18 Sheffield children, who mission to publish these cases. developed the disease while under observaReferences tion for primary tuberculosis, emphasizes the T., Kerr, M. R., and Landsman, J. B. (t953) impprtance of early diagnosis. The chances Anderson, Lancet, ix, 69 I. of survival of patients admitted with gross Bulkeley, W. C. M. 0953) Brit. Med. ft., it, Ii27. neurological signs and in stupor or coma are Cairns, H. (1949) Brit. ,lied. aT., z, 969 . Cairns, H., and Taylor, L. M. (t9.~9) Proc. R. Soc. Med., markedly reduced, and even when survival XLII, 155. H., Smith, H. V., and Vollum, R. L. 095 o) o7. takes place, the price paid, in terms of Cairns, Amer. ,lied. Ass., cxcxv, 92. residual disability, may be high. Cairns, H., and Smith, H. \z. 0952) Modern Practice in Tuberculosis. London, H, 374These residua may result partly from the Calnan, W. L. (x95I) BrR. 07. Tuberc., xnv, x53. prolongation of therapy required in the Clarke, E. S. (z948) 07. Royal Army ~lIedical Corps, xcH, 183. M. (I95~) Report on M.R.C. Tuberculin Surveys severe case, and this appliesparticularly to Daniels, x9 ~9-5 o, deafness; but it has been pointed out (Cairns Debrd, R. (x952) Amer. Rev. Tuberc., LXV, t68. R. (x953) Meningite Tuberculeuse et Tuberculose and Smith, i952 ) how important is the Dzbr6, Miliaire de l'enfant. Masson, Paris, p. 44. degree of involvement of blood vessels and Da'aglass, B. E. (1953) Proceedi,zgs of th ~.Staff Meetlngs of the ,'tla).J Clinic, xxvm, 38x. extent of infarctions in brain tissue before the Hall, S. (x95o) Tubercle, xxxh o4t. starting of treatment, in determining the Hob~on, F. G. (1936) Lancet, l, 933Kerr, J. G. 0953) Brit. Med. 07, n, x 13o. outcome. Lancet Personal Papers (1953) i, I x96.
Summary T h e diagnosis and treatment of 60 patients suffering from tuberculous meningitis are described. These were all proven bacteriologically and began treatment at every stage of the disease. 32 of these patients have survived and completed intrathecal treatment more than six months ago; 21 patients died during treatment, an over-all survival rate of 6o per cent. T h e results of treatment .have improved steadily since I947, when this series started. T h e only definite means of establishing diagnosis is by bacteriological proof, but it
Levinson, A. 09-t9) Amer. 07. Dis. Child., nxxvn, 7o9. Lorber, J. (z953) Brit. ,lied. 07, xx, x t22. Me:ileal Research Council. Streptomycin in Tuberculosis Trials Committee (t9~8) Lancet, t, 582. Richards, R. L. (x95o) 07. Ro'al Army ,lledical Corps, xctv, o_8t. Ruble, J., and Mohun, A. F. (t9~9) Brit. Med. 07, x, 338. Smith, H. V. 0952) University of Leeds ~lledical 07offrnal, I, 33. Smith, H. V., and Daniel, P. (x9~7) ~tbercle, xxwn, 64. Smith, H. V., Vollum, R. L., and Cairns, H. 0948) Lancet, t, 627. Smith, H. V., and Vollum, R. L. (I95o) La.tcet, Ix, 275. Swithinbank, J., Srriith, H. \r], and Vollum, R. L. (1953) 07. Path. Bact., Lxv, 585 . Taylor, L. M., Smith, H. V., and Hunter, G. (x954) Lancet, l, 700. Tnrres-Gost, J. (t953) Lancet, L 693~,Vtxytt, R. (x753) Obser~'ations on the Dropsy of" the Brain. Edinbargh, Balfour.
126
Tuberculous Meningitis in the Services By K. B. TAYLOR
From the Military Hospital (Head Injuries), Wheatley, Oxon, and the Nuffield Department of Surgery, Oxford Between March 1947 and October i953, 60 proven cases of tuberculous meningitis have been admitted to the Military Hospital (Head Injuries), Wheatley, Oxon. O f these, 53 patients have completed all treatment, or died, and 7 are still in hospital. In addition, 7 patients have been fully treated for tuberculous meningitis, in spite of the absence ofbacterlological proof, but they are not included in this series, except where it is specifica!ly stated. The early results of treatment were reviewed in 1948 (Clarke, 1948 ) and in 195o (Richards, 195o ). The introduction of new therapeutic agents and the steady improvement in the results of treatment have prompted the writing of this paper. Since 1947, patients suffering from what had until then been considered a fatal disease, with rare exceptions (Hobson, 1936; Smith and Daniel, 1947) , have had a substantial hope of recovery. A great deal of this transformation can be ascribed directly to the work of the late Sir Hugh Cairns and his assistants, who have supervised all the patients treated at Wheatley since the introduction of streptomycin. Since their initial report (Smith, Vollum and Cairns, 1948 ) the expectation of recovery has increased markedly. Cairns and Taylor, in March 1949, concluded a review o f their cases with the following: 'At least 5 ° per cent of all cases treated are dying and there is ample room for improvement'. At that time the lesions they noted in their fatal cases included widespread meningitis, cerebral infarction, severe hydrocephalus of the communicating type and active tuberculosis in the lungs and elsewhere. Delay in initiation and prcnmture withdrawal of treatment were cited as the two main causes of failure. Wider experience has decreased the number of patients who relapse because they have been treated for too short a time. But while knowledge that the disease can
now be successfully treated has encouraged earlier diagnosis, delay in initiation of treatment is still the commonest cause of failure and in fact the proportion of advanced cases has changed very little. Although tuberculous meningitis has a so much longer course than the purulent meningitides, every hour gained in commencing treatment is as important for the patient as in the latter disease.
Diagnosis of Tuberculous Meningitis Age Incidence.--Tuberculous meningitis is predominantly a disease of young people. It seems likely that the age incidence has changed since the eighteenth century, when Robert W h y t t in his classical description of the disease, which he called 'acute hydrocephalus', defined the age incidence as between 2 and 16 years. Although the highest incidence is still in t h e first 25 years of life, there are numerous exceptions. O f the 60 patients treated at Wheatley, 9 were Over 25 years and I of these over 3o.When allowance is made for the selected population from which the Service cases were drawn, this is comparable to the experience of the Oxford Tuberculous Meningitis Unit where 33 out of 132 civilian patients were over 25. The great majority of cases of tuberculous meningitis occur in relation to the primary infection and it is reasonable to suppose that the delay in primary infection and tuberculin conversion observed in recent surveys (Daniels, 195 I) is the chief factor in determining the somewhat later age incidence. Seasonal Incidence.- Figures for the total number of deaths each month from untreated tul~erculous meningitis in England and Wales in 1945 to 1947, show the highest incidence between March and J u n e (Calnan, 1951 ). Hall (195o) gives the peak in the twentieth week of the year and states
June
1954
TABLE
TUBERCLE
I.- N U M B E R
OF OASES OF T U B E R C U L O U S THE YEARS J A N .
Month: Jan. No. of cases 4
F e b . Mar. 6 8
Apr. 7
May 7
that death occurs commonly in untreated cases at four months from the time of infection. This time-relationship cannot be accepted without reserve, b u t the argument that infectious contacts are most likely to be made over the Christmas season with its 'gathering of the clans', seems very reasonable. The Wheatley" figures for admission (Table I) show the highest numbers between the beginning of Fdbruary and the end of May, but the numbers are too small to be significant. Contacts.- The over-all number giving a history of contact is 14 out of a total of 43 patients whose past history has been properly elicited. These known contacts were almost all members of the patients' own families. This rate is very low by comparison with other series and it seems most likely that in the majority of cases the disease has been contracted in the Services. Clinical Findings. - Classically, the onset of the disease is insidious and measured in days, weeks or months. During this time fatigue, loss of or failure to gain weight, loss of TABLE
II.-
127
~[ENINGITIS A D M I T T E D
IN E A C H
I~,'[ONTH OF
1947--JAN. I 9 5 4 June 4
July 5
Aug. 4
Sept. 3
Oct. 3
Nov. 3
Dec. 6
appetite, irritability, constipation (especially in children), insomnia, nocturnal restlessness and an ill-defined malaise, may be noted. Importance may be attached to these prodromal symptoms only in retrospect and tuberculous infections elsewhere in the body, or some other chronic disease, may give rise to much the same picture. Neither is this picture invariable. Some patients present as cases of acute meningitis and others may develop a tuberculous meningitis during treatment for miliary tuberculosis, which masks the onset of the meningitis. Since the majority of patients under review were young adults, it was possible to obtain a fuller subjective history than in series consisting largely of young children. Table II shows the intervals between the first appearance of the main symptoms and signs of the disease and the establishment of diagnosis and treatment in 55 of the 60 patients. The diagnosis was established in the shortest time, though by no means in the earliest stages of the disease, when symptoms
TIME INTERVAL BE'I'~VEEN ONSET OF ~'IAIN SYMPTOMS AND SIGNS AND DIAGNOSIS
Days before diagnosis and beginning of therapy Symptonz or sign Coma
°-3
••
3
Delirium .. Incontinence Diplopia • • Paralysis .. Fits• • Drowsiness and confusion . . Vomiting .. Abdominal pain .. Irritability. Neck rigidity Fever •• Fatigue .. Fhotophobia Headache ..
~
5 5 5 12
~
2
4.a
O
~
.a E ~
4-7
8-II
iy-i 5 i6-9o 21-3o 3I-4 o 41-5 ° 5I-6o 71-6o 7 0 +
3 2 2 I
0
I
0
2
0
I
I 2
7
5
x
11
7
5
o
2
2
I
O
0
I
I
3
2
3
o
0
IS 5 2
4 8 3
3 6 I
o
o 1
0
I
5 I
3
I
2
o
2
I
2 8
2 II
I 8
0 3
O 5
0
0
0
3
0
I I
5
26 5 o 2 2
I 4 I
I I
128
TUBERCLE
and signs were dramatic. Among thcse wcrc fits, diplopia, paralysis and incontinence. No comatose patient remained undiagnoscd and untreated longer than two days. However, in two paticnts, ncck rigidity had been noted more than three weeks before diagnosis and, in one, photophobia had been present for over two months. Patients complaining of headache and fatigue, with persistent fever, w e r e in the main diagnosed late. Classification. - Rigid classification of cases according to the severity of their disease is clearly impracticable, b u t the practice at Wheatley is to divide patients into three broad clinical groups, after the fashion suggested by the Streptomycin Trials Committee of the M.R.C. (1948). The first group comprised those who were fully conscious and had no focal neurological signs; the third, those who were so stuporose as to be virtually inaccessible, or comatose, or had gross focal neurological signs. The second group embraced the rcmainder. This division, as will be shown, had great prognostic significance. There was no significant correlation be-" tween the average length of the prodromal phase and the clinical condition on a d - ' mission. This is shown in Table I I I (Grade I 21 "5 days. Grade II - 15.1 days. Grade III 17. 5 days). TABLE
III. -- S T A G E
OF
THE
DISEASE
ON
ADMISSION COMPARED %VITn DURATION OF PRESENTING SYMPTOMS
Grade I II III
Dqvs z-7 2 8 2
8-z4 3 zo 7
z5-22 2 3 3
22+ 4 8 3
Diagnostic Investigations Radiograpty.- A routine chest x-ray was taken on admission. In the 60 cases, I8 showcd miliary involvement of the lungs, 6 showcd a primary focus, 5 showed phthisis and 2, pleuraI effusions. Skull x-rays were taken as a routine, on admission, in case there was demonstrable evidence of in-
June 1954
creased intracranial pressure in children, or intracranial calcification in adults. Other examinations, such as straight x-rays of the abdomen, intravenous pyelography and xrays of the spine, were undertaken in selected cases. Confirmation of a diagnosis of Port's disease was obtained in 6 patients. Ventricular estimation, followed, if necessary, by the introduction of air, was done in cases where the diagnosis was in.doubt, or where the neurological findings suggested a tuberculoma or other space-occupying lesion (Cairns, i949). Mantoux Testing.- During the last three years, routine Mantoux tests have been done on admission. The initial test was performed with a 1/IO,OOO dilution of Old Tuberculin, followed by I/i,ooo if there was no response and i / I o o if there was no response again after forty-eight hours. A positive reaction is defined as an area o f o e d e m a of at least 8 ram. diameter present forty-eight hours after the injection. The results of 45 initial tests are available, of which 42 wcre positive to one of the standard dilutions. O n e patient died before the test could be read. These findings are in agreement with those of other series (M.R.C. trials, 1948; R u b i e and Mohun, I949; Debrd, 1953). Cerebrospinal Fluid. - L u m b a r puncture was done under conditions which allowed of careful recording of pressure and reliable examination of the cerebrospinal fluid for cells, protein, sugar and chlorides and also for organisms, by direct film, culture and guinea-pig inoculations. Appearance of Fluid. - With rare exceptions, the fluid obtained on admission was clear and colourless. The appearance of a spiderweb clot on standing was not a constant finding. Cell counts ranged from 35 to i,ooo and though a moderate predominance oflymphocytes was the usual finding, some fluids showed over 5 ° per cent of polymorphs. Protein.- The majority of fluids at initial punctures showed protein levels between 4o and ~oo mg. per lOO ml. three of the 6o cases showed levels over 500 rag. per ioo ml.
June
1954
TUBERCLE
Chlorides.- Normal or slightly reduced chloride levels were found and tile level was not of value in diagnosis. Sugar.- 15 cases (25 per cent) showed a sugar level of 5 ° mg. per Ioo ml. or above, on admission. These were considered to be in the normal range. The other 45 cases showed values between 35 and 45 mg. per Ioo ml. Direct Fihns. - In 34 cases, acid-fast bacilli were seen within seventy-two hours of admission, in 7 further cases within two weeks of admission and in 4 cases later than this. In 2 cases t h e organisms were found in ventricular fluid obtained when burr-holes were made and, in i of these, organisms were later seen in the lumbar fluid. In I other case, organisms were seen in a cisternal specimen sixteen days after commencement of'treatment, when lumbar fluids had been negative. Cultures. - In 44 of 57 cases (the results of 3 cases with positive films not yet being available), cultures were positive, using Kirschner and L6wenstein media. In 8 cases, cultures were positive when no acid-fast bacilli had been seen on examination of the direct films. In 9 cases, cultures of fluids were negative when acid-fast bacilli had been found microscopically. In 2 cases the diagnosis was made at post-mortem, when films and cultures had been negative throughout the course of the illness and, in 2 others, cercbeltar tuberculomata were removed at operation, films a n d cultures being negative before and after. In addition to the above investigations, every effort was made to reveal active tuberculosis elsewhere in the body. Six samples of sputum, when available, from each patient were examined for ~1I. tuberculosis by film and culture and, where sputum was not available, gastric washings were examined in a similar way. Three specimens of urine from each patient were examined for protein, cells and the presence of acid-fast bacilli and, in cases where tabes mesenterica was suspected, the stools also were examined for 31. tuberculosis.
129
Blood Picture.-Blood haemoglobin determinations were performed on admission in most cases, but the results were not consistently below the normal range. The white blood cell counts were undertaken on admission as a routine and showed a considerable variation, ranging from 4,4oo to 2o, Io% the abnormally high counts showing a relative polymorphonucleocytosis. There has been no evidence of leucopenia in those cases with miliary disease. Differential Diagnosis In the period under review a complete record of these patients, who were admitted as cases of tuberculous meningitis and found to be suffering from other diseases, is not available. They included cases of meningococcal and haemophilus meningitis, Weil's disease, general paralysis of the insane, lymphocytic meningitis of unknown aetiology, anterior poliomyelitis and brain abscess. Similarly, many of the 15atients who ultimately proved to have tuberculous meningitis were admitted with some other diagnosis than the correct one. The original diagnoses in these cases included, lymphocytic meningitis of unknown aetiology, anterior poliomyelitis, cerebral abscess, cerebral haemorrhage, Addison's disease, torulosis and pneumococcal meningitis. A case diagnosed as Fr6hlich's syndrome and treated by severe dieting and hormonal therapy, which produced a rather more dramatic loss of weight than was expected, is also to be found in this group. Apart from the investigations mentioned already, others were therefore undertaken in those cases where the clinical picture demanded them. These included W.R. and Kahn, Paul Bunnell, blood cultures, biochemical investigations, and serological tests to exclude leptospirosis. Treahnent Ghemotherapy.-Various preparations of streptomycin, by intramuscular and intrathecal injection, have formed the essential basis of treatment and this drug has not been superseded. The early preparations were
130
TUBERCLE
more irritant and toxic than the streptomycin sulphate, which has been used excluslvely during the last eighteen months. Its administration by intrathecal injection is considered to be the sine qua non of satisfactory therapy. The dose has been Ioo, ooo units daily in the adult, and 3o,ooo to 75,ooo units daily in children, according to age*. This dosage is continued without intermissions until the C.S.F. contents, especially protein, are returning steadily, without fluctuations, towards normal; until the patient's condition is satisfactory, without fever and with. steady gain in weight; or until eight weeks have passed since M. tuberculosis has been identified in the fluid; whichever of these i.s the longest. Where a spinal block develops the route of intrathecal therapy is changed to the cisterna magna or the lateral ventricles via bifrontal burr-holes. As soon as the block can be shown to have resolved the lumbar route is once more adopted. Where the ventricles are enlarged, as is so often the case, a n d easy to tap, ventricular injections are preferred to cisternal. They disturb the patient less, are technically somewhat easier, and the risk of streptomycin deafness developing would appear to be far less than when this drug is given into the cistern. There is, however, ahvays the risk of inducing a haemorrhage and, in a few cases, the ventricles may be hard to find. In these cases the cisternal route is obligatory. Intramuscular streptomycin is given in doses of x gramme b.d. to adults and on the basis of 2o mg. per pound body-weight to infants and young children. This treatment is continued without interruption for a total of six months or for two months after the cessation of intrathecal therapy in those cases in which no evidence of active systemic tuberculosis obtains at this time. Although intramuscular streptomycin produces a useful C.S.F. concentration o f the drug in the presence of meningitis and, indeed, some *Since October x953, the intrathecal and intramuscular dosages of streptomycin have been halved, in the hope that the incidence of deafness may be decreased.
June 1954
cures by this route of administration alone have been reported, its main function is to control systemic disease, which may or may not be demonstrable, but which must always be suspected. The persistence of evidence of systemic infection may demand prolongation of intramuscular treatment and other means of treating the condition. Adjuvant Chemotherapy.- Patients who had systemic lesions, in which the deyelopment of resistance of the M. tuberculosis to streptomycin was to be expected, were given paraamino-salicylic acid orally until recently. The development of resistance to streptomycin by the organism in the C.S.F. is exceedingly rare (Cairns et at., I95O) and PAS was never given as the adjuvant in the treatment of the meningitis itself. Its toxic side-effects, however, especially anorexia and vomiting, are highly undesirable and its use has now been superseded, in this series, by isonicotinic acid hydrazide. This "is given orally in doses of i5o mg. t.tt.s, in adults, and intrathecally in doses of 2o mg. daily. In children the dosage has been scaled down according to age and weight, infants receiving 5 ° mg. by mouth t.d.s, and I t mg. intrathecally. Other Treatment Sedation. - Since patients with tuberculous
meningitis show a tendency to cortical dysrhythmic attacks, they are sedated, the adults receiving phenobarbitone ½ grain t.d.s., and children a comparable dose. During the period of reaction to intrathecal P.P.D. an increase in sedation, either with barbiturates or paraldehyde, is sometimes found to be necessary. D i e t . - Every effort is made to check the almost invariable weight loss of these patients during the active phase of the disease and to produce gain in weight. Anorexia and vomiting may be troublesome and demand patience and nursing skill. Patients with bulimia are, unfortunately, rare. No satisfactory method of suppressing nausea and vomiting has been found. A normal diet, with high protein content, may suffice but tube feeding with milk, fortified
June 1954
TUBERCLE
131
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C i t ~ x I . - Cme~,D. A. (I%1) aged 18. Admitted,z4.6.53. Fourteen days' history of headache. Clinical Grade II. Continuous improvement from onset of treatment. No residua, apart from unsteadiness in dark. Note typical protein and weight curves.
132
TUBERCLE
with proteins and protein hydrolysates may be necessary in the seriously ill. This ensures as adequate an intake as possible and tends to obviate the risk of aspiration of food during ingestion. Where vomiting is a continuing feature, fluid balance charts and maintenance of fluid intake are essential. A full supplement of vitamins and iron by mouth are also given to every patient.
June 1954
amnesia and the disappearance of, or emergence of, new neurological signs is of the utmost importance. T h e blood is examined at least every month, the haemoglobin, white cell count and sedimentation rate being determined and the chest x-rayed as often. T h e possibility of urinary infection exists throughout treatment and the urine is therefore examined at least once a week for cells, casts, Blood Transfusion and protein and cultured for organisms. In patients who show a considerable anaemia Most patients remain critically ill for a blood transfusion of one or two pints has many weeks. They may be drowsy or stuporsometimes marked the beginning of a ose, internfittently or Continuously; they general improvement, both during the acute may develop further signs of neurological phase of the illness and in convalescence. involvement; and fever and loss of weight Nursing may continue for many weeks. This is onerous and demands experience and T h e cases under review fall into four an understanding of the patient. Special clinical groups. atterition to pressure points and turning In the first group, patients respond to every two hours, the maintenance of ade- treatment from the start. T h e fever settles, quate postural drainage to prevent bronchial drowsiness and mental confusion, meningism obstruction and collapse, keen observation and focal neurological signs disappear, of mental state and of sphincteric functions, appetite recovers and there is a gain iu and patience in feeding the anorexic are the weight, if not at once, at least after three to four weeks. most important features. T h e C.S.F. in these case's may show high l~ehaviour under Treatment initial 'activity', with spikes of cells and Charts.- T h e keeping of large charts on protein, the base-line values of which rise in squared paper has been found to be the only the first few weeks, tend to level out about satisfactory method of following the course the sixth week and then fall, steadily and of the disease (Smith, i952 ). On these charts without spiking, towards normal values. are recorded the presence or absence of i l l After cessation of therapy, follow-up shows tuberculosis in films and cultures, the daily no evidence of recrudescence (Chart I). level of cells and protein in the C.S.F., all The second group, a small one, comprises specific therapy, including P.P.D., daily those who respond well to treatment, but, C.S.F. pressures, daily m a x i m u m temperafollowing its cessation, relapse and require a tures and the patient's weight, taken wce "ldy. much more prolonged period of therapy. Some of these charts are reproduced in the They may die or recover. The initial relapse following section. can be ascribed to stopping treatment too In addition, four-hourly records oftempersoon and experience has diminished the ature, pulse and respiratory rates are kept incidence of this type of case (Chart II). rotitinely. T h e third course is of rapid downhill Clinical Assessment deterioration from the time of, or soon after, Full neurological and general clinical exami- admission and the beginning of treatment. nation of each patient is performed at least Death occurs between tile second and fifth once a week and more often if the patient's weeks, a picture very similar to that seen in condition demands it. Special attention is untreated cases. Many of these cases were paid to mental state, including the degree of admitted late in the coiarse of the disease, in
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CIIAI~T I I . - C a s e L . C. (F) aged 18. Admitted I6.7.48. Ten days' hkstory ofincreasing headache and neck stiffness. Lefthemiplegia. Clinical Grade III. Fourteen days intrathecal streptomycin only. Relapsed on 23.x 1.48. Irregular deterioration to death in coma on 27.8.49. Note positive cultures following cessation oflntrathecal streptomycin on t{vo occasions. Both courses too short.
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June 1954
TUBERCLE
coma or with gross neurological signs, but this is by no means invariable and Chart III, illustrating this type of course, is of a patient who, on admission, was almost fully alert and co-operative, with no marked neurological signs. T h e infection would appear to be overwhelming. T h e organisms have not been resistant to streptomycin, but their numbers and location have rendered therapy inadequate. The fourth group comprises a number of patients, who, regardless of the stage of the disease on admission, at first respond well, but then deteriorate between the second and fifth months of treatment (M.R.C. Trial, I948 ). During the first two years of experience' with streptomycin it was observed that most of these patients became decerebrate and died in coma, but, rarely, one might recover after a very stormy passage. Typically in these cases there was a decrease in cell content of the C.S.F. and an absence of spontaneous 'spikes' (Smith and Vollum, I95o ) and the protein would rise to high levels. During t h i s phase, spinal blocks might occur, necessitating the use of the ventricular route for therapy. Chart IV is of a patient who died after a course of this sort. Post-mortem examination of patients in both Groups III and I V revealed gross exudates round the base of the brain, ensheathing the brain-stem, with blocking of the cisterns and marked hydrocephalic changes and infarction of brain stem and cortex. A substance which would prevent the formation of, or help to disperse this exudate, was clearly demanded. Intrathecal tuberculin appears to meet these demands. Tuberculin.- A purified protein derivative of tuberculin (P.P.D.) is supplied by the Ministry of Agriculture and Fisheries Veterinary Laboratory, Weybridge. It possesses a high potency judged by its ability to produce the skin tuberculin reaction in sensitized humans and it has been used intrathecally since i949 iSmith and Vollum, 195o ). At first its use was confined to cases having a bad prognosis, as judged by the stage of the
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C~L~T III.- Case L,R. (M) aged 4½ years. Admitted 59.4.53. Fourteen days history.of listlessness, anorexia, headache and vomiting. O n admission, fully conscious, slight left facial weakness. Gradual deterioration to death on 17.5.53 in decerebrate state, after numerous decerebrate
attacks. (Positive C.S.F. culture, prior to admission,not ~hown on chart.)
1954
June
TUBERCLE STREPTOMYCIN
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Admitted 27-3.47- Five weeks' history. Clinical Grade II. Treated Gradual deterioration to death in third month of illne~,
136
TUBERCLE
dlsease and failure to respond to treatment, but now it is used in the large majority of Mantoux-positive patients. P.P.D. was first given intrathecally in tile human in the middle of I949, to a moribund patient whose condition had deteriorated in the manner described above. It was administered to test the theory that the spontaneous 'spikes' of cells and protein in the C.S.F. of patients treated with streptomycin alone were due to release of bacterial breakdown products, i.e. of tuberculoprotein, and that this produced an inflammatory reaction of meninges already sensitized to these products. The injection of P.P.D. produced identical cell and protein rises, with a rise also in C.S.F. pressure and a generalized systemic disturbance, marked by fever and tachycardia. There was also a temporary exacerbation of meningism and of the focal neurological signs. Later experimental work has shown that there is a rough correlation between the reaction to intrathccal and intradermal injections of tuberculin and there is now good evidence that the meningeal response is a true, specific tuberculin reaction (Swithinbank et al., I953). The remarkable finding was that the patient began to improve almost immediately and is now alive and well (Smith and Vollum, I95o ). This procedure was repeated in other cases and it was found that the use of P.P.D. intrathecally appeared to be a valuable factor in preventing deaths in this middle period already described. Even in those cases which died in spite of P.P.D. treatment, post-mortem findings showed a marked diminution or absence of that exudate seen in cases treated with streptomycin alone or untreated. The use of P.P.D. has now been carefully standardized. A positive Mantoux skin reaction seems to be essential. Bifrontal burr-holes are introduced in every case before the commencement of treatment, so that, should dangerous rises in the C.S.F. pressure occur, they can be relieved by vcntricular puncture. P.P.D. (Weybridge) is used in four
June 1954
concentrations: a standard solution, containing 0.0075 mg. per ml. and dilutions of I : io, i : I oo and I : i,ooo. It is injected intrathecally by the lumbar route at the same time as streptomycin is given, or, if a spinal block is present, into the cistern. It is also occasionally given into "the ventricles, but it is then desirable that the C.S.F. response should be followed by cisternal or lumbar tap, as the ependymal response is very small compared with that of the meninges. The initial dose is usually of the order of 0. 5 to I.o ml. of the standard/i,ooo dilution, depending on the intensity of the Mantoux reaction, and this is trebled up at three-day intervals until an adequate response is obtained, judged by the clinical picture of increased malaise and mental confusion, high fever, tachycardia, increased meningism and pre-existing focal neurological signs and by the C.S.F. changes. These consist of an acute rise in the cell count .with a relative rise in the polymorphonuclear count or a rise in the protein, or both, reaching a peak within twenty-four hours or forty-eight hours of injection. There may be a second spike of ceils, mainly lyrfiphocytes, and of protein between four to seven days after the injection (Swithinbank et al., I953). This reactive dose is then given at weekly or slightly longer intervals and is not changed unless the response diminishes or disappears. In these cases, the Mantoux test is repeated to ensure that the patient has not become desensitized. When the cells and protein do show a steady fall and the C.S.F. reactions tend to die away in spite of the persistence of a positive Mantoux, P.P.D. is stopped, while streptomycin therapy is continued according to the principles outlined above. Chart V is of a patient whose condition deteriorated during treatment with streptomycin alone, responded when intrathecal P.P.D. was given and recovered after a stormy passage. When the criteria for the stopping of intrathecal therapy are all satisfied, examinations of the cerebrospinal fluid are continued at regular intervals, at first twice a
June1954
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CIIART•r _ CaJ¢ R. B. (M) aged 18. Admitted on t3.8.5i. Clinical Grade II. Deteriorated on streptomycin alone. Persisting papilloedema and in a high pressure state. Marked improvement on P.P.D.
138
June 1954
TUBERCLE
week for the first month, then weekly, for six to eight weeks, then monthly and finally at three and six month intervals. Any rise in cells or protein during the initial follow-up period may be indicative of relapse, especially if there is recurrence of fever, or failure to gain weight. Some small fluctuations, especially in the protein levels, and the persistence of an abnormally high C.S.F. protein for months or even longer, are not, in themselves, necessarily of grave import, judged by our experience in this series.
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Convalescence
Great importance is attached to this. T h e patient is not allowed out of bed until sufficienl~ time has elapsed after the stopping of intrathecal therapy to be sure that progress on intramugcular therapy is unipterrupted. Most Service cases in this series have convalesced, following discharge from Wheatley, at Headington Hill Hall, a special rehabilitation unit run by the Ministry of Pensions. This centre, within easy reach of Wheatley, has proved invaluable, in that admirable facilities for rehabilitation, including speech and physiotherapy, and thorough medical after-care are available at one and at the same time.
1"~'l'4t'/~ c
suRvtvA,a,~rc .~E~CENTAGE WITH P./~D.
1947-48
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1949-50
1951-53
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intrathecal tuberculin, that during which its value was being determined, and that in which it has become more and more an established therapy. Table IV shows percentage survival in each clinical group during these three periods, and also the n6mber of eases in each group during these periods. It is apposite here to point out that in the i949-5o period it was the worst cases (i.e.
TABLE I V . - NUMBER OF CASES IN EACti CLINICAL GROUP AND PERCENTAGE SURVIVAL IN EACH GROUP, IN PERIODS DURING WHICH TREATMENT "~VAS COMMENCED
Clinical Group I II III
1947-48 Total No. Percentage of cases surviving 5 8o% 3 33% 4 25%
z949-5 ° Total .No. Percent.age of cases survzvzng 4 75% 8 37"5% 5 6o%
Results 32 patients have completed all treatment and have been followed up for periods longer than six months from the stopping of intrathecal therapy. 2z patients died during treatment, an over-all survival rate of 60 per cent. The histogram (fig. I) gives some indication of the improvement in results of treatment since I947, dividing the period into three stages: that prior to the use of
1951-53 Total No. Percentage of cases surviving 2 IOO% z5 8o% 7 43%
Group III) who were treated with intrathecal tuberculin, and it is in this group that the greatest improvement is seen, compared with z947-48. I n the I951-53 period, more and more Group II cases also received P.P.D. It is evident from Table IV that the improvement in results can clearly not be ascribed tO earlier diagnosis." Table V shows the incidence of coincident systemic infection and the outcome in these cases. It is clear that file presence of overt miliary spread or
June 1954
TABLE V . - R E C O V E R Y R A T E IN CASES COMPLICATED BY SYSTEMIC INFECTION
Systemic disease Miliary .... Phthisis .... Primary focus •• Pleural effusion .. Spinal caries . . . . Renal tuberculosis ..
139
TUBERCLE'
Total No. of cases
Recovery
z7
i o*
5 7 z 6 I
4 2 o 4 I
"2 of these patients had spinal caries and renal tuberculosls, in addition to miliary, and x of them had phthMs as well. They are also included in the figures in these groups.
of chronic pulmonary phthisis, if treated energetically, need not have a marked effect on prognosis. Residual Disabilities. - Infants and children are not included in this assessment. Ataxia due to vestibular nerve damage due to streptomycin therapy has been a constant finding. All patients, however, have achieved a high degree of compensation and their only complaint at the end of convalescence is of some unsteadiness in the dark. Apart from this minor disability, I8 of a total of 28 patients are well, physically and mentally, and capable of full activities, 9 of these fell into the clinical Group I on admission and 8 into Group II. Only z patient in Group III escaped unscathed. T h e more serious residual disabilities fall into two classes: those caused by the disease and those caused by streptomycin therapy. The fact that deafness, d u e to eighth nerve damage, is almost always bilateral, irreversible and appears commonly when other neurological signs are receding, is in favour of this disability being due to therapy. Four of our patients are completely deaf and 3 have a partial deafness, still retaining a useful degree of auditory function. Disabilities in 3 patients are considered t o be due to the disease itself. One has a left hemiplegia which does not prevent his wor'Idng full-time as a clerk, another has a mild right hemiparesis which allows his earning his living making handicrafts and the third shows a fairly marked bitemporal hemianopia with adequate central vision.
Discussion
The number of cases rcvicwcd in this series is large enough to show some pointcis in diagnosis, treatment and prognosis. Both the speed and the clinical pattern of progression of the disease are extremely variable. It is these factors which make diagnosis so difficult and result in delay in treatment. Thus, a patient may be admitted in coma with only a few days' hist6ry of increasing headache and fever, or may develop mild neurological signs after a period of many weeks' mild and variable headache and associated fatigue and listlessBess. Not infrequently, however, the reason for delay would appear to be a failure to entertain the diagnosis at all. Headache, fatigue and continuing mild fever are evidently a combination, the significance of which may bc most easily overlooked. It is fair to suggest that any patient exhib!ting this triad, for which there is no obvious cause, should have a lumbar puncture and thorough examination of the C.S.F. within a week of the onset, of symptoms. Clinically, great importance attaches to the mental state of the patient. The degree of blunting of consciousness and amnesia is, in the majority of cases of tuberculous meningitis, greater in proportion to the degree of meningism than in the benign lymphocytic meningitides, the purulent meningitides and anterior poliomyelitis. The diminished mental awareness in the first contrasts sharply with the often agonizing mental clarity seen in the last (Lancet, Pers. Papers, i953). Examination of the C.S.F. may reveal acid-fast bacilli in about 5 ° per cent of cases within seventy-two hours of admission. This approximate figure takes into account the 7 patients, not included in this series, who were never proven bacteriologically, but who behaved, under treatment, as typical cases of tuberculous meningitis and had either miliary or clear evidcnce of other tuberculous infection. A moderately reduced sugar content and increased protein in the
140
TUBERCLE
C.S.F. are useful findings. T h e development o f other tests which may help to cstahlish the diagnosis, as quickly as possible, is an active field at the time. Certainly the demonstration of the increased amount of bromide which passes from the serum into the C.S.F. in cases of tuberculous meningitis (Taylor, Smith and Hunter, I954) has proved of great value in many of the cases in this series. There is ample justification for starting treatment of a patient in w h o m a diagnosis cannot be firmly established. Tubercle bacilli may be seen or cultured later and precious time and, very often, the patient's life, has been saved. There is no evidence to suggest that daily intrathecal therapy may prevent the return of the contents of the C.S.F. towards normal limits in these patients whose subsequent rapid recovery and the absence of positive cultures exclude the diagnosis of tuberculous meningitis. A twenty-eight-day course of streptomycin (until the first culture results are available) by lumbar route has in our experience never resulted in any toxic manifestation. Chart VI is of a patient treated thus, and also with penicillin, who was later shown serologically to have leptospiral meningitis. T h e establishment of a means of treating tuberculous meningitis satisfactorily, w i t h o u t intrathecal injections, is eagerly awaited. T h e recent reports of results with oral isonicotinic acid hydrazide alone (Kerr, i953) or in conjunction with intramuscular streptomycin (Torres-Gost, I953; Anderson et al., I953) or with A C T H (Bulkeley, I953) , have tended to b e incomplete and not wholly convincing. They are certainly not such as to permit at this stage a change from a tried regimen, which is producing good results by any standards. T h e statement (Douglass, i953) that 'the intrathecal administration of streptomycin has been abandoned by most physicians' (in the U.S.A.), is surprising, to say the least, and reports from that country are awaited with interest. Levinson (I949) stated that, in his experience, there was no place for intrathecal streptomycin therapy, but his
June 1954
1G.
S TP,EP.
0 . 0 5 G-
F////A L
150 MGM,
/./V~.
IO MGM,
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aoo
C S E CELLS per Crnrn.
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300
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CllART "V[. Case D. 07. (M) aged x2. Treated fully as a case of tuberculous meningitis, until proven, serologically, as leptospirosis. - -
results showed a very high mortality rate. To sum up, the treatment of this disease is long and fraught with difficulties and dangers. If the best results arc to be obtained it should be undertaken, practically and not ideally speaking, in centres where the nursing staff is trained in the management of the patients, the clinical and laboratory medical staff constantly gaining in their experience of thedisease and where special methods of neurological investigation and facilities for "neurosurgical intervention are available. This is particularly so when intrathecal tuberculin is used. T h e behaviour of our patients under treatment has shown how difficult prognosis
June
TUBERCLE
1954
141
can be. Generally, the duration of non- is emphasized that certain clinical features, specific symptoms, such as headache and especially the mental state, are of considerfatigue, is a far less important factor in its able value. assessment than is the stage of the disease at It is not considered that the methods of which the patient is first diagnosed and treatment here described, with continuous treated. Debrd (I952) emphasizes this when intrathecal and intramuscular streptomycin he states that the state of consciousness of the and, more recently, intrathecal tuberculin patient is a better guide to prognosis than the and isonicotinic acid hydrazide intrathecally duration of symptoms. It is to be hoped that and by mouth, have yet been convincingly with earlier investigation of the non-specific superseded. symptoms mentioned above, more and more Acknowledgments patients Will be treated even before there is I am very grateful to Dr Honor Smith, under any definite blunting of consciousness. whose care these patients have been treated, A recent report on childhood tuberculosis for most helpful advice and criticism, and in Sheffield (I,orber, t953) , which shows a wish to express thanks to the Director75 per cent recovery from tuberculous General, Army Medical Services, for permeningitis in 18 Sheffield children, who mission to publish these cases. developed the disease while under observaReferences tion for primary tuberculosis, emphasizes the T., Kerr, M. R., and Landsman, J. B. (t953) impprtance of early diagnosis. The chances Anderson, Lancet, ix, 69 I. of survival of patients admitted with gross Bulkeley, W. C. M. 0953) Brit. Med. ft., it, Ii27. neurological signs and in stupor or coma are Cairns, H. (1949) Brit. ,lied. aT., z, 969 . Cairns, H., and Taylor, L. M. (t9.~9) Proc. R. Soc. Med., markedly reduced, and even when survival XLII, 155. H., Smith, H. V., and Vollum, R. L. 095 o) o7. takes place, the price paid, in terms of Cairns, Amer. ,lied. Ass., cxcxv, 92. residual disability, may be high. Cairns, H., and Smith, H. \z. 0952) Modern Practice in Tuberculosis. London, H, 374These residua may result partly from the Calnan, W. L. (x95I) BrR. 07. Tuberc., xnv, x53. prolongation of therapy required in the Clarke, E. S. (z948) 07. Royal Army ~lIedical Corps, xcH, 183. M. (I95~) Report on M.R.C. Tuberculin Surveys severe case, and this appliesparticularly to Daniels, x9 ~9-5 o, deafness; but it has been pointed out (Cairns Debrd, R. (x952) Amer. Rev. Tuberc., LXV, t68. R. (x953) Meningite Tuberculeuse et Tuberculose and Smith, i952 ) how important is the Dzbr6, Miliaire de l'enfant. Masson, Paris, p. 44. degree of involvement of blood vessels and Da'aglass, B. E. (1953) Proceedi,zgs of th ~.Staff Meetlngs of the ,'tla).J Clinic, xxvm, 38x. extent of infarctions in brain tissue before the Hall, S. (x95o) Tubercle, xxxh o4t. starting of treatment, in determining the Hob~on, F. G. (1936) Lancet, l, 933Kerr, J. G. 0953) Brit. Med. 07, n, x 13o. outcome. Lancet Personal Papers (1953) i, I x96.
Summary T h e diagnosis and treatment of 60 patients suffering from tuberculous meningitis are described. These were all proven bacteriologically and began treatment at every stage of the disease. 32 of these patients have survived and completed intrathecal treatment more than six months ago; 21 patients died during treatment, an over-all survival rate of 6o per cent. T h e results of treatment .have improved steadily since I947, when this series started. T h e only definite means of establishing diagnosis is by bacteriological proof, but it
Levinson, A. 09-t9) Amer. 07. Dis. Child., nxxvn, 7o9. Lorber, J. (z953) Brit. ,lied. 07, xx, x t22. Me:ileal Research Council. Streptomycin in Tuberculosis Trials Committee (t9~8) Lancet, t, 582. Richards, R. L. (x95o) 07. Ro'al Army ,lledical Corps, xctv, o_8t. Ruble, J., and Mohun, A. F. (t9~9) Brit. Med. 07, x, 338. Smith, H. V. 0952) University of Leeds ~lledical 07offrnal, I, 33. Smith, H. V., and Daniel, P. (x9~7) ~tbercle, xxwn, 64. Smith, H. V., Vollum, R. L., and Cairns, H. 0948) Lancet, t, 627. Smith, H. V., and Vollum, R. L. (I95o) La.tcet, Ix, 275. Swithinbank, J., Srriith, H. \r], and Vollum, R. L. (1953) 07. Path. Bact., Lxv, 585 . Taylor, L. M., Smith, H. V., and Hunter, G. (x954) Lancet, l, 700. Tnrres-Gost, J. (t953) Lancet, L 693~,Vtxytt, R. (x753) Obser~'ations on the Dropsy of" the Brain. Edinbargh, Balfour.