Bacterial meningitis 1940–79

Journal of Infectzon (1982) 5, 245--255

Bacterial

meningitis

194o-79

G. S a n g s t e r , J. M c C . M u r d o c h and J. A. Gray Department of Infectious Diseases, City Hospital, Greenbank Drive, Edinburgh E H I o 5SB Summary The treatment of 1871 episodes of bacterial meningitis (excluding leptospiral meningitis) affecting 1855 patients in the Infectious Diseases Unit of the City Hospital, Edinburgh, over the 4o-year period 194o-79 has been reviewed. There was a rapid reduction in mortality in the commoner forms of bacterial meningitis after sulphonamides were introduced and a further improvement following the introduction of penicillin and other antibiotics. Benzylpenicillin alone has given excellent results in meningococcal infections. Of the eight fatalities due to meningococcal infection in the past 2o years, seven were due to fulminant meningococcaemia. Likewise, benzylpenicillin alone has been valuable for pneumococcal meningitis, although it results in a lower cure rate than for meningococcal disease, especially in the very young and those over 55 years of age. Chloramphenicol alone has been the most effective drug for Haemophilus influenzae meningitis, especially since ampicillin resistance is increasing. No deaths from H. influenzae meningitis have occurred since 1943 and there have been few sequelae. Outside the neonatal period, a single antibacterial agent is advocated for most forms of bacterial meningitis, except tuberculous, with the use of corticosteroids and other supporting measures only when indicated.

Introduction F o r m a n y years some aspects of the m a n a g e m e n t of bacterial meningitis have been controversial and a variety of t r e a t m e n t schedules exists, not all of which are accepted in their e n t i r e t y ) , 2.3, 4 T h i s review was u n d e r t a k e n to assess the efficacy of our present t r e a t m e n t policy against a background of progress in changes in therapy. T h e period studied (i94o-79) encompasses the major chemotherapeutic advances following the era of serum t r e a t m e n t and starting after s u l p h o n a m i d e had become established. Before I938 serum t h e r a p y was the mainstay of the treatment of m e n i n g o coccal meningitis with a case fatality rate of 68-7 per cent in E d i n b u r g h and considerable m o r b i d i t y in m a n y of the survivors. F o r t u n a t e l y the use of sulphonamide, which became standard t r e a t m e n t in I938, was sufficiently established to influence the national epidemic of a meningococcal infection in 194o-42. T h e case fatality was r e d u c e d to 18 per cent in E d i n b u r g h 5and by 1943, even before the advent of penicillin, it had fallen to less t h a n IO per cent. T h e other types of septic meningitis which had been invariably fatal, sooner or later, showed a less dramatic response to the new era of chemotherapy.

Materials and methods A n analysis of the records of all the patients with a diagnosis of bacterial meningitis in the Infectious Diseases U n i t o f the E d i n b u r g h City Hospital was

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© 1982 The British Societyfor the Studyof Infection

246

G. S A N G S T E R , J. MCC. M U R D O C H

A N D J. A. G R A Y

made for the period 194o-79. As many of the patients with tuberculous meningitis completed their treatment outwith the unit, their records are necessarily incomplete and are therefore unsuitable for full comparison with the other varieties. T h e diagnosis of septic meningitis was made if the cerebrospinal fluid (CSF) showed a polymorphonuclear leucocytosis, a reduced glucose content and the presence of bacteria either by microscopy, culture or both. In the absence of bacteriological confirmation in the C S F , despite otherwise typical findings, a positive blood culture was regarded as satisfactory evidence of the causative organism. Where bacteriological confirmation was lacking in both C S F and blood but the other findings were compatible with a diagnosis of bacterial meningitis, the term 'non-specific' septic meningitis was used. In all, 1871 episodes of meningitis in 1855 patients were available for analysis of treatment methods, complications and outcome. Eleven patients had multiple attacks; these were not always with the same organism and not all of the episodes were treated in this unit. These episodes have been included in the total figures for the relevant type, except in two instances where the patients had eight and 3o episodes of 'non-specific' bacterial meningitis respectively; both have been regarded as single examples of 'non-specific' meningitis. Fifty examples of leptospiral meningitis which fell in the study period have not been included. T h e population of the catchment area of the Infectious Diseases U n i t of the E d i n b u r g h City Hospital has remained about 5oo ooo during the period under study. Some patients from the area with bacterial meningitis, especially neonates, were treated in other hospitals.

Results T h e results of the survey are categorised under the infecting organism. Details of the outcome, complications and sequelae, associated factors and treatment given are recorded in Tables I - I V , respectively. T h e high incidence of meningitis in the first decade of the survey coincided with the epidemic of meningococcal infection in the early stages of World War II, since when there has been a gradual decline. Similarly the fall in the incidence of tuberculous meningitis is striking, but the other types show only a little variation over the years (Table I).

Meningocoecal meningitis Of I279 patients in this group, 702 were male and 577 female; most were under 3o years of age. D u r i n g the epidemic in the early I94OS a higher proportion of females died, but subsequently, when there were fewer cases and deaths, male deaths exceeded those of females (except in 1965 when all the patients were female and three died). A purpuric rash was seen in 178 patients of both sexes (29 per cent) during the first decade, whereas over the next 3o years only 15 per cent showed this feature. T h e commonest complication, excluding the Waterhouse-Friderichsen syndrome which was seen in most of the fatal cases, was arthropathy, often involving several large joints. T h r o u g h o u t the first decade the occurrence rate

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was relatively c o n s t a n t - I'5-3"5 per cent, except in I944 when I I.Z per cent showed this complication (Table II). Eighth nerve deafness was the next most common sequel, particularly during the first decade. Other important neurological complications were uncommon, relatively few patients showing delayed resolution or the presence of subdural effusions. D r u g rashes were frequent during the early part of the study when sulphonamides were the only treatment. Few associated and predisposing factors or relapses were found (Tables II and III). From 194o-I 944 sulphonamides were given routinely in an initial parenteral dose of 0"5-2 g, according to age, followed by I-4 g per day orally for seven to io days, with a high fluid intake to prevent renal crystallisation by the earlier preparations. Sulphapyridine, introduced in I938, was followed by sulphathiazole early in the first decade and later by sulphadiazine and sulphamerazine. From late I944 when benzylpenicillin became available, there was a further drop in mortality to under Io per cent. In the second decade, sulphonamides alone or in combination with penicillin remained the standard treatment and the case fatality fell to 4"7 per cent. From I96O, however, sulphonamides were used less frequently and reliance was made on penicillin alone, in those days rarely intravenously but often intrathecally on at least one occasion. T h e usual dose was o'5-2 mega units daily (and sometimes I o 000-20 ooo units intrathecally), according to age, the course lasting Io days on average. With this regime the results were satisfactory, although the case fatality rate remained just over four per cent for the decade. All the deaths on this regime and most during the previous decade, however, resulted from fulminating meningococcaemia. Apart from two patients whose deterioration and death was a late event in established meningitis, the remainder survived less than I2 hours after admission. During the fourth decade a mortality of five per cent has persisted; fulminant infections in the young, with minimal evidence of meningitis, account for all the deaths except one, an 8o-year-old woman who also suffered cerebral thrombosis.

Non-speeifie meningitis Predisposing conditions of a neurological or parameningeal nature were present in six per cent of this group. One child survived eight attacks, the first strongly resembling pyogenic meningitis (CSF 2800 leucocytes x io6/1; polymorphonuclear cells 90 per cent) and was ultimately found to have a leaking epidermoid cyst of the conus medullaris, without evidence of infection. Two of the four fatal cases suffered recurrent attacks, one dying after his 3oth episode. Up to I945 all were treated with sulphonamide only and made a good recovery. For the next five years the standard treatment was penicillin plus sulphonamide, which also gave good results; the only fatality occurred in a child whose meningitis had responded well to penicillin but in whom gastroenteritis supervened. Over the last three decades chloramphenicol has been the initial and usually the only antibiotic treatment. During this period there were three deaths, one related to otitis media, another to sinusitis, and the third to coning.

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Pneumococcal meningitis Predisposing factors and serious neurological complications were common in the I5O patients with pneumococcal meningitis (Tables II and III). Another indication of severity was the occurrence of stress gastric ulceration in two patients, one of whom, an infant of 20 months, died of peritonitis within 24 hours of admission. T h e other, a boy of Io years, survived his perforation and peritonitis and made a good recovery, although he claimed to have auditory hallucinations subsequently. This complication may have been due to meningitis or a pre-operative cardiac arrest. T h e average case fatality over the four decades was 25 per cent. T h e first ever recovery from this type of meningitis in this unit was recorded in I938 following treatment with sulphonamide. While the addition of penicillin led to some improvement in the situation late in the first decade, it was not until I956 that there was a more acceptable recovery rate. T h e usual schedule included sulphonamide and penicillin, with daily intrathecal penicillin for five to seven days. Because of the relatively poor results, other antibiotics were tried as they became available, in the hope of resolving the meningitis and also of dealing with underlying conditions which were common in this variety and often involved bone (Table III). Chloramphenicol was used in some cases singly or in combination with or following penicillin and sulphonamide during the second decade. In I964 and for a short period, parenteral cephaloridine, including intrathecal therapy, was used with limited success. Between 1965 and i971 lincomycin cured two out of three patients when used alone. In the last decade equally good results were obtained with high doses of benzylpenicillin (8-i2 mega units intravenously daily for adults) for a week on average, and followed by oral penicillin. In the more severe cases, dexamethasone appeared to exert a favourable effect on the course of the illness.

Haemophilus influenzae meningitis O f the Io9 patients with this infection, IO5 were children, all under five years except two aged seven and eight years. T h e series includes four adults aged 4o, 49, 67 and 72 years. T h e youngest of these developed his infection soon after oesophagoscopy, but predisposing factors were fewer than in the pneumococcal group. Serious complications were rare but a slower than expected response to treatment, with the possibility of subdural effusion, was commoner than with the other types of meningitis (Table II). T h e first recoveries from H. influenzae meningitis were recorded in I94I, and since I944 no deaths have occurred. Combined sulphonamide and penicillin, including intrathecal penicillin therapy (usually three to five daily doses of ioooo units), was giving excellent results, but when chloramphenicol became available in I95o , it became standard treatment from the third decade onwards, apart from a period of six years (I966-72) when high doses of ampicillin were given with success in I5 patients. In five others, it was used additionally to other antibiotics when more prolonged treatment was thought desirable. Ampicillin was given intravenously for at least 48 hours, then intramuscularly for another five days on average, and orally for a further five to seven days.

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Most patients improved rapidly and few complications were seen. Because of the increasing chance of ampicillin resistance late in the fourth decade, chloramphenicol was reinstated as first-line treatment. Where progress appeared to be slow in a few cases, dexamethasone was added for a limited period. Complications and sequelae were uncommon.

Staphylococcal meningitis Only four patients had this infection. In the two fatal cases, Down's syndrome and a meningocele were complicating factors. A 67-year-old diabetic lady responded well to quinacillin but subsequently developed diabetes insipidus. T h e other patient who recovered was an eight-and-a-half-year-old boy who had penicillin encephalopathy as a result of excessive intrathecal administration elsewhere; he responded successfully to chloramphenicol.

Streptococcal meningitis This was most common in the first decade. T h e first two recoveries were recorded in I949, since when only one death (a neonate in I952) has occurred from infection with haemolytic streptococci. Three patients had associated endocarditis and one other, a cerebral abscess due to anaerobic streptococci. Interestingly, an exploratory ear, nose and throat examination under general anaesthesia in an adult was followed within 24 hours by an attack.

Coliform and salmonella meningitis T h e r e were only three patients with Escherichia coli and one with salmonella meningitis. T h e child with salmonella meningitis, which was complicated by subdural effusions, made a full recovery, as did a two-and-a-half-year-old child with Esch. coli meningitis. T h e two deaths from Esch. coli meningitis occurred in a seven-day-old infant on the day of admission and a child of six months with a meningocele.

Listerial meningitis T h e two patients with Listeria monocytogenes meningitis presented in the second half of I977. Both were males, aged 37 and 62 years, with no obvious underlying disease. One received benzylpenicillin intravenously and the other chloramphenicol on account of penicillin allergy. Both responded well but slowly to treatment and no complication or sequela occurred.

Tuberculous meningitis T h e first cures of this previously lethal type of meningitis were seen in I948 following the introduction of streptomycin. During the second decade fewer patients were admitted and subsequently the diagnosis was made infrequently. Since many of the earlier patients with tuberculous meningitis were transferred to special units and were lost to follow-up, this group has been omitted from Tables II, III and IV.

254

G. S A N G S T E R , J. MCC. M U R D O C H

A N D .]'. A. G R A Y

Discussion

Although most patients with bacterial meningitis died in the pre-sulphonamide era, approximately 30 per cent of those with meningococcal infection did survive, some even without the benefit of intrathecal a n t i s e r u m ) T h e introduction of sulphonamides led to a striking improvement in the outcome of most types of bacterial meningitis (excluding tuberculous). T h e availability of antibiotics after I944 altered the overall picture dramatically (Table I). In the first half of the survey few chemotherapeutic agents were available, while in the second half use was made of the widening spectrum of antibiotics (Table IV). Nevertheless three drugs stand o u t - sulphonamides, penicillin and chloramphenicol - and remain prominent in the second half of the study, although sulphonamide showed a decline in favour of penicillin for meningococcal infection and ampicillin temporarily ousted chloramphenicol in haemophilus meningitis. During the first two decades, 996 incidents (73"5 per cent) were treated with only one drug and in the second two decades 390 (80 per cent). In the first four years of the study there was, of course, no choice other than that of sulphonamide. A combination of sulphonamide and penicillin was used extensively in meningococcal, non-specific, pneumococcal and haemophilus meningitis but, after the introduction of chloramphenicol, this combination was used less for non-specific and haemophilus infections. Other combinations were used in only 34 patients. Surprisingly, erythromycin and lincomycin were successful in a small number of patients. When cerebral oedema or raised intracranial pressure occurred, mannitol a n d / o r dexamethasone were used. Likewise, in a few patients who were slow to respond, mainly those with pneumococcal and haemophilus infections, corticosteroids were given with some benefit. T h e recent results of the therapy of meningococcal infection with penicillin alone are extremely good - with the notable exception of fulminating infections, which are fortunately uncommon. Similarly the treatment of Haemophilus influenzae meningitis has been satisfactory, although more often resulting in complications. A possible reason for this may be that treatment is delayed because, with the common subacute onset, central nervous system involvement may not be detected as early as in other forms of septic meningitis. T h e prior use of antibiotics plays little or no part in obscuring the diagnosis in this or any other variety of meningitis. 6 T h e poorest results are in the pneumococcal group in which the mean age is higher and there are more associated and predisposing factors. In most series the mortality rises steeply with advancing a g e - especially in those over 50 years. 7' 8, 9 Head injury and parameningeal infection are important predisposing factors. Arthropathy and eighth nerve deafness were the outstanding complications of meningococcal infection (Table II), as has been seen in other studies, a, ~ Neurological complications were most frequent in the pneumococcal group, again showing similarities to previous reports. 4Most of the drug hypersensitivity reactions reported in the meningococcal group resulted from sulphonamide therapy during the first decade of the study. Rashes, except those due to drug sensitivity, were uncommon in non-meningococcal infections. While these may help in diagnosis, additional tools should not be overlooked, namely blood

B a c t e r i a l meningitis I94O-79

255

cultures, wh ic h m a y p r o v i d e the only exact bacterial confi rm at i on and m o d i f y t r e a t m e n t w h e n the organisms c a n n o t be identified in the C S F . C o u n t e r c u r r e n t i m m u n o e l e c t r o p h o r e s i s m a y be helpful in det ect i ng bacterial antigens; this test was n o t available until the last few years o f the st udy period. T h e d e v e l o p m e n t o f resistance m a y restrict t he use o f available antibiotics especially in the t r e a t m e n t o f h a e m o p h i l u s meningitis. Just as increasing s u l p h o n a m i d e resistance has gradually r e d u c e d the effectiveness o f these drugs for m e n i n g o c o c c a l infection - in Scot l and in r 979 17"5 p e r cent o f isolates were resistant and 61 "7 p e r cent partially resistant 1° - so the appearance o f a m p i c i l l i n resistant h a e m o p h i l u s species has also led to a revision o f t r e a t m e n t . T h e findings in this series confirm the p a t t e r n o f bacterial meningitis as seen in d e v e l o p e d countries in r e c e n t times - the satisfactory t r e a t m e n t o f e n d e m i c m e n i n g o c o c c a l and m o s t o t h e r varieties o f meningitis except p n e u m o c o c c a l 2 G o o d results can be o b t a i n e d using a single antibiotic even w h e n t he precise bacteriological diagnosis is n o t available. In essence, m o s t cases can be m a n a g e d b y one o f two a n t i b i o t i c s - benzylpenicillin or c h l o r a m p h e n i c o l w h i c h cover the e x p e c t e d a nd usual range o f causative organisms. F o r special situations in c l udi ng ne ona t a l infections, o t h e r antibiotics are available either as alternatives or as additional support. Indications for intrathecal a d m i n i stration are n o w e x t r e m e l y rare, a nd d e p e n d on the inability o f an antibiotic to cross the b l o o d / b r a i n barrier. I m p r o v e m e n t in t he m a n a g e m e n t o f p n e u m o coccal meningitis is hi ghl y desirable and the p r o m p t use of m o d e r n diagnostic aids, e.g. C A T scan, s h o u l d be c o n s i d e r e d if response to a p p r o p r i a t e antibiotic t r e a t m e n t is n o t rapid. (Our thanks are due to the many members of the laboratory staff for the bacteriological results, as well as to the junior clinical staff and nursing staff over the years.) We regret to record the death of George Sangster on 19 July I982. )

References

I. Leading Article. Meningitis in infancy and children. Br MedJ. I965; x: 537-538. 2. Hambleton G, Davies PA. Diagnosis and management of bacterial meningitis. Drugs r974; 8: I5-53. 3. Overturf GD, Wehrle PF. Bacterial meningitis: which regimen? Drugs I979; xS: 65-73. 4. Christie AB. Infectious Diseases : Epidemiology and Clinical Practice, 3rd ed. Edinburgh, London, Melbourne and New York: Churchill Livingstone, I98o: 622-628. 5. Joe A. The treatment of cerebro-spinal fever by sulphapyridine. Edin Med ff 1942; 49: 628--642. 6. Pickens S, Sangster G, Gray JA, Murdoch JMcC. The effects of pre-admission antibiotics in the bacteriological diagnosis ofpyogenic meningitis. ScandJInfect Dis I978; xo: I83-t85. 7. Carpenter RR, Petersdorf RG. The clinical spectrum of bacterial meningitis. Am ff Med I962; 33: 262--2758. Finland M, Barnes MW. Acute bacterial meningitis at Boston City Hospital during i2 selected years, I935-1972. J Infect Dis 1977; x36: 4oo--415. 9. Lambert HP. Use of antibiotics: meningitis. Br M e d J r978; z: 259-26I. Io. Fallon RJ. Meningococcal infections in Scotland 1979. Commun Dis (Scotland) wkly Rep 198o; 9: PP- vii-xii.