Intensive Care Medicine
Intens. Care Med. 5, 5-9 (1979)
9 by Springer-Verlag1979
Review Article The Complications and Management of Meningococcal Meningitis J.M. Shneerson* and I.W. Fawcett** Whipps Cross Hospital, Leytonstone, London E. 11, England Summary. Twenty two cases of meningococcal meningitis admitted to a general hospital in London between 1970 and 1978 have been reviewed. Seven (32%) of the patients died. Unlike previous series, a high proportion of the deaths occured after a protracted illness. Adequate antibiotic treatment was started promptly after admission in almost every case and severely ill patients were admitted to the intensive therapy unit. Various features of the illness at presentation have been reviewed to identify the subjects with a poor prognosis. Neurological deterioration after admission and the development of severe disseminated intravascular coagulation were the best indicators. The modern management of the complications of meningococcal septicaemia has been discussed. It is possible that the late deaths in this series represent patients who would previously have died shortly after admission but whose lives were prolonged by intensive supportive treatment.
Introduction
Meningococcal meningitis and septicaemia is still a common problem in the United Kingdom. The number of reported cases increased annually from 1967 to a peak of 941 in 1974 but has since declined again steadily [3]. Local epidemics occasionally occur [5] in which the mortality may be high. In the tropics much larger epidemics of up to 160,000 cases sweep across from the Sudan to Guinea every 10-15 years [18]. We have reviewed the 22 cases notified between 1970 and 1978 from Whipps Cross Hospital, a 900 bed district general hospital in North East London serving a population of about 300,000. Thirteen of these patients were managed in the Intensive Therapy Unit because of the severity of their illness or its complications. The clinical problems encountered and their mangement have been reappraised in the light of modem supportive treatment. * Correspondence to Dr. J.M. Shneerson, Senior Medical Registrar, Westminster Hospital, Horseferry Road, London, S.W.1. ** Dr. LW. Fawcett at present Senior Medical Registrar, St. Bartholomew's Hospital, London
Ca~s
The complications of the 13 patients admitted to the Intensive Therapy Unit are summarised in Table 1. The case histories of five of these are presented below:
Case 1. C.T. aged 22 yrs. Admitted 30-8-72. She had suffered from fever and joint pains for 36 h before admission. On admission she had neck stiffness, a widespread petechial rash and swelling of the proximal interphalangeal finger joints. There was evidence of disseminated intravascular coagulation (D.I.C.). She was treated with benzylpenicillin, hydrocortisone and heparin intravenously. On the evening of admission she had a grand mal convulsion and became shocked. Artifical ventilation was required for 48 h. Acute renal failure was treated with peritoneal dialysis. Five days after admission a left third nerve palsy and left vitreous haemorrhage were noted. Six days later the skin rash, which was very extensive on admission, began to slough, with the loss of large areas of tissue down to the level of muscle (Fig. 1). Despite hyperbaric oxygen therapy, wound debridement and skin grafts, the skin did not heal and her general condition deteriorated with infection of the skin infarcts, marrow aplasia and a terminal bronchopneumonia. At autopsy examination the kidneys showed areas of cortical infarction.
Case 2. P.C. aged 1 year. Admitted 31-1-73. He had been febrile and increasingly drowsy for 12 h before admission. On examination he was unconscious but responsed to pain and had a stiff neck and positive Kernig's sign. There was a widespread petechial rash. He became shocked with no palpable pulse and was resuscitated with intravenous normal saline and hydrocortisone. Over the next six hours he had several fits, the purpura became widespread and he developed D.I.C. With intravenous benzylpenicillin and sulphadiazine, his rash faded over the next two days and his conscious level improved. Eleven
0342.4642[79/0005/0005/$ 01.00
6
J.M. Shneerson and l.W. Fawcett: Meningococcal Meningitis
Table 1. Complications o f 13 subjects admitted to Intensive Therapy Unit Case No.
Age (yrs)
Rash
DIC a
Deterioration o f conscious level after admission
Fits
Focal CNS Signs
Arthropathy (Early (E) o f late (L))
Other
Outcome
1
22
+
+
+
+
+
E
Skin infarction Renal failure
Died
2
1
+
+
-
+
-
-
Skin infarction Shock
Lived
Ruptured spleen
Died
3
18
+
+
+
+
4
1
+
-
+
.
5
52
+
.
6
72
+
+
7
13
+
+
8
2
+
.
.
.
E .
.
.
.
+
-
+
-
-
-
-
L
-
+
-
L
Died
.
Lived Myoearditis
Died Lived
-
Lived
9
65
-
-
+
+
+
E
-
Died
10
13
+
-
+
-
+
-
-
Lived
11
15
-
+
-
+
-
-
12
49
-
+
-
-
-
13
35
+
-
+
+
-
L
10
5
9
6
5
6
Total
Shock
Died Died
-
Live d
aDIC defined a s t h e presence o f 3 or more o f the following: Platelet count 15 s., Kaolin partial thromboplastin time > 45 s., and fibrinogen titre 1/64 or less + = present; - = absent; no entry = not recorded
Fig. 1, Case 1 showing the ::,.~em, areas of skin necrosis d a y s a f t e r a d m i s s i o n his s k i n b e g a n t o s l o u g h a n d a f t e r a f u r t h e r 10 d a y s t h e r e was e x t e n s i v e skin n e c r o s i s . This h e a l e d c o m p l e t e l y over t h e n e x t t h r e e w e e k s . Case 7. C.P. aged 13 yrs. A d m i t t e d 12,2-76
She had a sore throat one month before admission. This w a s d i a g n o s e d as g l a n d u l a r fever. O n 12-2-76 s h e f e l t fev e r i s h , v o m i t e d several t i m e s , b e g a n t o c o u g h a n d c o m p l a i -
ned of calf pain. On admission she was drowsy with a stiff neck and a petechial rash was noted over her wrists, butt o c k s a n d legs. S h e h a d a t a c h y c a r d i a o f 1 2 0 / m i n u t e a n d a b l o o d p r e s s u r e o f 8 0 / 4 0 m m Hg. H e r r i g h t atrial p r e s s u r e w a s 14 c m H 2 0 a n d h e r E C G s h o w e d S T s e g m e n t d e p r e s sion. T h e f o l l o w i n g d a y a t h i r d h e a r t s o u n d b e c a m e audib l e a n d a d i a g n o s i s o f m y o c a r d i t i s w a s m a d e . D . I . C . developed. Despite intravenous benzylpenicillin and sulphadim i d i n e , h e r p u r p u r a i n c r e a s e d . O n 13-2-76 h e r a n k l e be-
J,M. Shneersonand I.W. Fawcett: MeningococcalMeningitis came swollen and tender. It required aspiration but no organisms were found. Her myocarditis gradually improved and she was f i t enough to play sport six weeks later.
Case 10. L.S. aged 13 yrs. Admitted 18-2-77 Following a sore throat, she developed a headache and temperature on the day before admission and woke at 2 a.m. delirious and vomiting. On admission she was responding to pain, was photophobic and had a stiff neck, positive Kernig's sign, bilateral upgoing plantar reflexes and purpura. She was given intravenous chlormethiazole and penicillin but remained the same until two days after admission. Her conscious level suddenly deteriorated and she showed Cheyne-Stokes respiration, flaccid limbs and absent plantar reflexes. She was given intravenous mannitol and dexamethasone, intubated and hyperventilated. She did not improve until 18 h later when, over a period of one hour, she became conscious and was extubated. She had residual weakness of her right arm and an upgoing right plantar reflex for two days.
Case 11. D.B. aged 15 yrs. Admitted 19-2-75 One week before admission she had a mild upper respiratory tract infection. She then developed a severe headache with vomiting and 12 h later had a series of grand mal fits and was admitted comatose. There was no fever or rash but her neck was slightly stiff. Within 2 h she developed a right third cranial nerve palsy with left sided upper motor neuron signs in the limbs. Despite intravenous mannitol and dexamethasone she became flaccid and apnoeic. She received intravenous benzylpenicillin and chloramphenicol and was intubated and ventilated. She died 14 h after admission, there being no evidence of cerebral activity.
Discussion
a. ) Diagnosis and Prognosis The diagnosis was confirmed by the isolation of Neisseria meningitidis in all 22 patients. It was found in the CSF in 21 subjects and grown from venous blood in nine. Seven (32%) of the patients died. This is rather higher than the figure of 9.2% of deaths recorded from 677 cases of acute bacterial meningitis occuring around North West London between t969 and 1973 by Goldacre [7]. Death in his series was particulary common in infants and within 12 h of hospital admission. In the present study the only child to die suffered from Down's syndrome and three of the seven deaths occurred between five days and seven weeks of a severe illness. Three of the early deaths were within 24 h of admission. Six of our deaths were in adults but this was not due to later diagnosis as the mean duration of illness before treatment was 28.4 h (~ = 10, S.D. = 20.7, range 12 - 72 h) compared with 36.0 h (r/= 12, S.D. = 25.8, range 12 - 84 h in the children. Blood cultures grew meningo-
cocci in five of the seven subjects who died. Once treatment was instituted, adequate doses of benzylpenlcillin (usually 24 mega units daily in theadults) were given to all the patients. 19 also received sulphadiazine or sulphadimidine and 9 chloramphenicol. The antibiotic regime was similar in the survivors and those who died. All 18 organisms that were tested were sensitive to penicillin and only one was resistant to sulphonamides. In view of the high mortality rate the complications of the patients admitted to the intensive therapy unit were analysed to see whether any of them provided an indicator of prognosis. The height of the fever on admission was similar in the survivors (mean = 39.0~ and non-survivors (mean = 38.2~ A petechial rash occurred in all the survivors and 57% of the fatalities. Arthropathy was present in half the survivors and 42% of those that died. The presence of DIC was not significant but the three patients with the most severe DIC all died. Epileptic fits were frequent in both groups. The development of focal neurological signs occurred in only 16% of the survivors but in 57% of the subjects who subsequently died. Meningism was present in all the subjects exept one. He was receiving steroids and eventually died. Two subjects suddenly lost consciousness, presumably due to cerebral coning, but were resuscitated by mannitol, dexamethasone and mechanical ventilation. In contrast to the patients managed in the intensive therapy unit, the only complication observed in the nine patients on the ordinary wards was a transient rash in two subjects. All nine survived their illness. There was correlation between the white cell count in the peripheral blood or CSF and survival. This may be an artefact due to the samples being obtained at different stages in the natural history of the infection in different patients. Stiehm and Damrosch [15] found that the absence of meningism, the presence of a petechial rash within 12 h of admission, a systolic blood pressure less than 70 mm Hg, a white cell count.less than 10,000//aL in peripheral blood, and an ESR less than 10 mm in the first hour, were all bad prognostic features. These findings indicate that an overwhelming meningococcaemia has a poor prognosis whereas a strong antibacterial reaction, which may result in markedly abnormal physical findings and investigations, is a favourable sign, However in our series none of these criteria was a useful prognostic indicator.
b) Management The clinical features, especially the petechial rash, often give an indication of the correct bacteriological diagnosis, but this should always be confirmed as soon as possible by CSF examination and blood cultures. Nose and throat swabs and aspiration of inflamed joints may also help. Typing of the organism is of no help in the individual case. An increasing percentage of meningococci are resistant to sulphonamides [3] although these drugs are effective alone if the organism is sensitive. Initially, however, intravenous
J.M. Shneersonand I.W.Fawcett: MeningococcalMeningitis benzylpenicillin 20 - 30 mega units daily should be given, although chloramphenicol orally or intravenously is effective if the patient is allergic to penicillin (Hillas Smith 1978, personal communication). Penicillin crosses the inflamed meninges easily and there is no indication for intrathecal penicillin in meningococcal meningitis. Throat swabs should be obtained from close contacts of the patient, including hospital staff in contact with him before and during the first 24 h of treatment. Those harbouring meningococci should receive sulphonamides if the organism is sensitive or minocycline or rifampicin if it is resistant. Penicillin is ineffective [2]. Admission of the subject to a high dependency area or intensive therapy unit is advisable if there is any neurological deterioration or other serious complication. Shock is a well-known accompaniment of meningococcal septicamia. It used to be thought that it was the result of adrenal haemorrhages causing an Addisonian crisis (Waterhouse-Friderichsen syndrome). Although these haemorrhages are sometimes seen, the cortisol levels do not correlate with the clinical picture or the presence of adrenal haemorrhages. The clinical picture is probably due to release of endotoxin, although myocarditis and disseminated intravascular coagulation (DIC) may also be present. Routine observations should include pulse rate and volume, blood pressure, core/toe temperature difference, urinary output, respiratory rate and ECG.monitoring. Assessment of acid/base status, urea and electrolytes and the urine/ plasma osmolality ratio are essential if shock is present. Right atrial pressure (RAP) monitoring is indicated in the presence of a diminishing pulse volume, persistent sinus tachycardia or other dysrhythrnia, or a core/toe temperature gradient of 4~ or greater. If the RAP is low and there is evidence of poor peripheral perfusion, plasma expanders, such as dextran 70 or haemaccel, are required. Methyl prednisolone (30 mgm/kgm body weight) should be given as a bolus for its protective effect against endotoxin if there is poor peripheral perfusion, oliguria, or severe metabolic acidosis which does not respond to volume replacement and correction of hypoxia. Myocarditis may produce the clinical picture of a low output state with a high RAP. Electrocardiographic changes have been detected in as many as 20 out of 112 cases [19] but the true frequency of myocarditis is unknown. Micro-abscesses may occur in the myocardium [13] but an allergic reaction to the meningococcus is probably more common. Occasionally large pericardial effusions containing meningococci occur [16] and relief of cardiac tamponade by pericardial aspiration may be necessary. The myocarditis may respond to digitalization if the cardiac output is poor. The deveopment of DIC may be diagnosed by the characteristic cold, cyanosed extremities, haemorrhages and single or multiple organ failure, particularly renal, pulmonary and hepatic [6]. The prothrombin time (PT), kaolin partial thromboplastin time (KPTT), fibrinogen titre, and platelet count are all abnormal in severe cases. These tests should be performed routinely. The presence of fibrin degradation products in the CSF is associated with a poor
prognosis [4]. Thrombocytopenia alone may be due to bone marrow suppression by the septicaemia. IfDIC is severe, replacement of clotting factores with fresh frozen plasma may be required although platelet transfusions are only indicated if haemorrhage occurs once clotting factors have been replaced or if the platelet count falls below 20,000//.tl or there is evidence of platelet dysfunction. The place of heparin is uncertain but, once started, it should be continued until the prothrombin time has been normal for three days. The characteristic petechial rash of meningococcaemia may occur without DIC. The skin lesions contain meningococci. A rash is a common finding and may reflect the severity of the septicaemia. The petechial rash commonly fades in a few days but may be succeeded about a week after the onset of the illness by a vesicular rash which often ulcerates. This appears to be due to an allergic vasculitis rather than direct infection [10]. In our series the skin of two patients sloughed off extensively and in one case required skin grafts. Hyperbaric oxygen in conjunction with skin grafting may encourage healing and reduce the incidence of secondary infection. It was used in one patient. Most patients with meningococcal meningitis are comatose or confused and lumbar puncture reveals a raised CSF pressure. Coning after lumbar puncture is very rare and its possibility should not delay the investigation. Observation of the level of consciousness, pupil size and reaction, and also pulse rate, blood pressure and respiratory rate will give warning of coning. If it does occur, up to 100 gm mannitol should be infused intravenously over 30 minutes and dexamethasone also given (initially 10 mg intravenously, then 5 mg 6 hourly). If there is further deterioration, intermittent positive pressure ventilation (IPPV) should be instituted with a high minute volume in order to decrease PaCO2 and intracranial pressure [ 1,14]. Coning may also occur spontaneously during the course of the illness. Two o f our patients suddenly deteriorated neurologically and one other developed central neurogenic hyperventflation. Mannitol, dexamethasone, and in two of the subjects IPPV, led to improvement. Coning is also likely to occur following epileptic fits, especially if status epilepticus develops. The temperature may rise, especially in children, and hypoxia is inevitable during the fits. Prompt treatment with a cooling blanket, mannitol, dexamethasone and a readiness to proceed to mechanical ventilation are necessary. Anti-epileptic drugs are also useful. The occurrence of fits later in the illness should suggest the possibility of a cerebral abscess, localized meningeal pus, or hydrocephalus due to obstruction of free CSF flow by meningeal adhesions. Three of our subjects complained of multiple joint pains early in their illness and three developed single swollen inflamed joints about a week after the onset of their illness. Whittle et al. [17] and Greenwood et al. [1 l] have elegantly shown that the former usually accompanies the acute septicaemia and that the latter is usually an allergic reaction in which antigen-antibody-complement complexes are deposited in the synovial membrane. The meningo-
J.M. Shneerson and I.W. Fawcett: Meningoeoccal Meningitis coccal antigen is probably a polysaccharide [9] and its presence is correlated with the development o f arthritis [ 12]. Serum C3 levels fall transiently at the time o f appearance o f the arthritis [8]. A secondary rise o f temperature m a y occur in the late type o f arthritis and suggest a relapse o f the infection, loculation o f pus, or antibiotic allergy. Aspiration and culture o f the synovial fluid is advisable b u t it is usually sterile.
Acknowledgements. We would like to thank Dr. Gillian C. Hanson for her help and encouragement, the consultant physicians in charge of the patients reported, and Mrs. R. Selby for typing the manuscript.
References 1. Alexander, S.C., Lassen, N.A.: Cerebral circulatory response to acute brain disease: implications for anaesthetic practice. Anesthesiology 32, 60 (1970) 2. Leading Article: Br. Med. J. 3,295 (1974) 3. Epidemology Br. Med. J. 1, 1671 (1977) 4. Brueton, M.J., Tugwell, P., Whittle, H.C., et al.: Fibrin degradation products in the serum and cerebrospinal fluid of patients with group A meningococcal meningitis. J. Clin. Path. 27,402 (1974) 5. Easton, D.M., Estcourt, P.G., Brimblecombe, F.S.W., Burgess, W., Hass, L. Kurtz, J.B.: Outbreak of meningococcal disease in Devon. Br. Med. J. 1,507 (1974) 6. Evans, R.W., Glick, Bo, Kimball, F., Lobell, M.: Fatal intravaseular consumption coagulopathy in meningococcal sepsis. Am. J. Med. 46,910 (1969) 7. Goldacre, M.J.: Acute bacterial meningitis: where do children die? Int. J. Epidemiol. 5,343 (1976)
8. Greenwood, B.M., Onyewotu, II, Whittle, H.C.: Complement and meningococcal infection. Br. Med. J. 1,797 (1976) 9. Greewood, B.M., Whittle, H.C.: Nature of the antigen present in the cerebrospinal fluid and serum of patients with Group A meningococcal meningitis. Clin. Exp. Immunol. 16, 413 (1974) 10. Greenwood, B.M., Whittle, H.C. Infection and immunology in rheumatic diseases. Dumonde, P., (ed.), p. 119. Oxford: Blackwell 1976 11. Greenwood, B.M., Whittle, I-I.C., Bryceson, A.D.M.: Allergic complications of meningococcal disease. II. Immunological investigations. Br. Med. J. 2, 737 (1973) 12. Greenwood, B.M., Whittle, H.C., Dominic-Rajkovic, O.: Counter- Current Immunoelectrophoresis in the diagnosis of meningococcat infections. Lancet 2, 519 (1971) 13. Korczyn, A.D., Kessler, E., Bornstein, B.: Meningococcal disease with cardiac death. Confin. Neurol. 33, 271 (1971) 14. Lundberg, N., Kj~llquist, A., Bien, C.: Reduction of increased intracranial pressure by hypeiventilation. Acta Psychiatr. Neurol. Scand. 34, Suppl. 139 (1959) 15. Stiehm, E.R., Damrosch, D.S.: Factors in the prognosis of meningococcal infection. J. Pediatr. 68. 457 (1966) 16. Thompson, D.G., Pease, C.T., Howard, A.J.: Meningococcal pericarditis without meningitis. Br. Med. J. 2, 1330 (1977) 17. Whittle, H.C., Abdullahi, M.T., Fakunle, F.A., Greenwood, B.M., Bryceson, A.D.M., Parry, E.H.O., Turk, J.L.: Allergic complications of meningococcal disease. I - Clinical aspects. Br. Med. J. 2, 733 (1973) 18. Whittle, H.C. Greenwood, B.M.: Meningococcal meningitis in the northern savanna of Africa. Trop. Doer. 6, 99 (1976) 19. Wolf, R.E.: Unusual electrocardiogram in meningococcal disease. Am. Heart J. 76,293 (1968) Dr. J.M. Shneerson Senior Medical Registrar Westminster Hospital London SW1 England
Intens. Care Med. 5, 5-9 (1979)
9 by Springer-Verlag1979
Review Article The Complications and Management of Meningococcal Meningitis J.M. Shneerson* and I.W. Fawcett** Whipps Cross Hospital, Leytonstone, London E. 11, England Summary. Twenty two cases of meningococcal meningitis admitted to a general hospital in London between 1970 and 1978 have been reviewed. Seven (32%) of the patients died. Unlike previous series, a high proportion of the deaths occured after a protracted illness. Adequate antibiotic treatment was started promptly after admission in almost every case and severely ill patients were admitted to the intensive therapy unit. Various features of the illness at presentation have been reviewed to identify the subjects with a poor prognosis. Neurological deterioration after admission and the development of severe disseminated intravascular coagulation were the best indicators. The modern management of the complications of meningococcal septicaemia has been discussed. It is possible that the late deaths in this series represent patients who would previously have died shortly after admission but whose lives were prolonged by intensive supportive treatment.
Introduction
Meningococcal meningitis and septicaemia is still a common problem in the United Kingdom. The number of reported cases increased annually from 1967 to a peak of 941 in 1974 but has since declined again steadily [3]. Local epidemics occasionally occur [5] in which the mortality may be high. In the tropics much larger epidemics of up to 160,000 cases sweep across from the Sudan to Guinea every 10-15 years [18]. We have reviewed the 22 cases notified between 1970 and 1978 from Whipps Cross Hospital, a 900 bed district general hospital in North East London serving a population of about 300,000. Thirteen of these patients were managed in the Intensive Therapy Unit because of the severity of their illness or its complications. The clinical problems encountered and their mangement have been reappraised in the light of modem supportive treatment. * Correspondence to Dr. J.M. Shneerson, Senior Medical Registrar, Westminster Hospital, Horseferry Road, London, S.W.1. ** Dr. LW. Fawcett at present Senior Medical Registrar, St. Bartholomew's Hospital, London
Ca~s
The complications of the 13 patients admitted to the Intensive Therapy Unit are summarised in Table 1. The case histories of five of these are presented below:
Case 1. C.T. aged 22 yrs. Admitted 30-8-72. She had suffered from fever and joint pains for 36 h before admission. On admission she had neck stiffness, a widespread petechial rash and swelling of the proximal interphalangeal finger joints. There was evidence of disseminated intravascular coagulation (D.I.C.). She was treated with benzylpenicillin, hydrocortisone and heparin intravenously. On the evening of admission she had a grand mal convulsion and became shocked. Artifical ventilation was required for 48 h. Acute renal failure was treated with peritoneal dialysis. Five days after admission a left third nerve palsy and left vitreous haemorrhage were noted. Six days later the skin rash, which was very extensive on admission, began to slough, with the loss of large areas of tissue down to the level of muscle (Fig. 1). Despite hyperbaric oxygen therapy, wound debridement and skin grafts, the skin did not heal and her general condition deteriorated with infection of the skin infarcts, marrow aplasia and a terminal bronchopneumonia. At autopsy examination the kidneys showed areas of cortical infarction.
Case 2. P.C. aged 1 year. Admitted 31-1-73. He had been febrile and increasingly drowsy for 12 h before admission. On examination he was unconscious but responsed to pain and had a stiff neck and positive Kernig's sign. There was a widespread petechial rash. He became shocked with no palpable pulse and was resuscitated with intravenous normal saline and hydrocortisone. Over the next six hours he had several fits, the purpura became widespread and he developed D.I.C. With intravenous benzylpenicillin and sulphadiazine, his rash faded over the next two days and his conscious level improved. Eleven
0342.4642[79/0005/0005/$ 01.00
6
J.M. Shneerson and l.W. Fawcett: Meningococcal Meningitis
Table 1. Complications o f 13 subjects admitted to Intensive Therapy Unit Case No.
Age (yrs)
Rash
DIC a
Deterioration o f conscious level after admission
Fits
Focal CNS Signs
Arthropathy (Early (E) o f late (L))
Other
Outcome
1
22
+
+
+
+
+
E
Skin infarction Renal failure
Died
2
1
+
+
-
+
-
-
Skin infarction Shock
Lived
Ruptured spleen
Died
3
18
+
+
+
+
4
1
+
-
+
.
5
52
+
.
6
72
+
+
7
13
+
+
8
2
+
.
.
.
E .
.
.
.
+
-
+
-
-
-
-
L
-
+
-
L
Died
.
Lived Myoearditis
Died Lived
-
Lived
9
65
-
-
+
+
+
E
-
Died
10
13
+
-
+
-
+
-
-
Lived
11
15
-
+
-
+
-
-
12
49
-
+
-
-
-
13
35
+
-
+
+
-
L
10
5
9
6
5
6
Total
Shock
Died Died
-
Live d
aDIC defined a s t h e presence o f 3 or more o f the following: Platelet count 15 s., Kaolin partial thromboplastin time > 45 s., and fibrinogen titre 1/64 or less + = present; - = absent; no entry = not recorded
Fig. 1, Case 1 showing the ::,.~em, areas of skin necrosis d a y s a f t e r a d m i s s i o n his s k i n b e g a n t o s l o u g h a n d a f t e r a f u r t h e r 10 d a y s t h e r e was e x t e n s i v e skin n e c r o s i s . This h e a l e d c o m p l e t e l y over t h e n e x t t h r e e w e e k s . Case 7. C.P. aged 13 yrs. A d m i t t e d 12,2-76
She had a sore throat one month before admission. This w a s d i a g n o s e d as g l a n d u l a r fever. O n 12-2-76 s h e f e l t fev e r i s h , v o m i t e d several t i m e s , b e g a n t o c o u g h a n d c o m p l a i -
ned of calf pain. On admission she was drowsy with a stiff neck and a petechial rash was noted over her wrists, butt o c k s a n d legs. S h e h a d a t a c h y c a r d i a o f 1 2 0 / m i n u t e a n d a b l o o d p r e s s u r e o f 8 0 / 4 0 m m Hg. H e r r i g h t atrial p r e s s u r e w a s 14 c m H 2 0 a n d h e r E C G s h o w e d S T s e g m e n t d e p r e s sion. T h e f o l l o w i n g d a y a t h i r d h e a r t s o u n d b e c a m e audib l e a n d a d i a g n o s i s o f m y o c a r d i t i s w a s m a d e . D . I . C . developed. Despite intravenous benzylpenicillin and sulphadim i d i n e , h e r p u r p u r a i n c r e a s e d . O n 13-2-76 h e r a n k l e be-
J,M. Shneersonand I.W. Fawcett: MeningococcalMeningitis came swollen and tender. It required aspiration but no organisms were found. Her myocarditis gradually improved and she was f i t enough to play sport six weeks later.
Case 10. L.S. aged 13 yrs. Admitted 18-2-77 Following a sore throat, she developed a headache and temperature on the day before admission and woke at 2 a.m. delirious and vomiting. On admission she was responding to pain, was photophobic and had a stiff neck, positive Kernig's sign, bilateral upgoing plantar reflexes and purpura. She was given intravenous chlormethiazole and penicillin but remained the same until two days after admission. Her conscious level suddenly deteriorated and she showed Cheyne-Stokes respiration, flaccid limbs and absent plantar reflexes. She was given intravenous mannitol and dexamethasone, intubated and hyperventilated. She did not improve until 18 h later when, over a period of one hour, she became conscious and was extubated. She had residual weakness of her right arm and an upgoing right plantar reflex for two days.
Case 11. D.B. aged 15 yrs. Admitted 19-2-75 One week before admission she had a mild upper respiratory tract infection. She then developed a severe headache with vomiting and 12 h later had a series of grand mal fits and was admitted comatose. There was no fever or rash but her neck was slightly stiff. Within 2 h she developed a right third cranial nerve palsy with left sided upper motor neuron signs in the limbs. Despite intravenous mannitol and dexamethasone she became flaccid and apnoeic. She received intravenous benzylpenicillin and chloramphenicol and was intubated and ventilated. She died 14 h after admission, there being no evidence of cerebral activity.
Discussion
a. ) Diagnosis and Prognosis The diagnosis was confirmed by the isolation of Neisseria meningitidis in all 22 patients. It was found in the CSF in 21 subjects and grown from venous blood in nine. Seven (32%) of the patients died. This is rather higher than the figure of 9.2% of deaths recorded from 677 cases of acute bacterial meningitis occuring around North West London between t969 and 1973 by Goldacre [7]. Death in his series was particulary common in infants and within 12 h of hospital admission. In the present study the only child to die suffered from Down's syndrome and three of the seven deaths occurred between five days and seven weeks of a severe illness. Three of the early deaths were within 24 h of admission. Six of our deaths were in adults but this was not due to later diagnosis as the mean duration of illness before treatment was 28.4 h (~ = 10, S.D. = 20.7, range 12 - 72 h) compared with 36.0 h (r/= 12, S.D. = 25.8, range 12 - 84 h in the children. Blood cultures grew meningo-
cocci in five of the seven subjects who died. Once treatment was instituted, adequate doses of benzylpenlcillin (usually 24 mega units daily in theadults) were given to all the patients. 19 also received sulphadiazine or sulphadimidine and 9 chloramphenicol. The antibiotic regime was similar in the survivors and those who died. All 18 organisms that were tested were sensitive to penicillin and only one was resistant to sulphonamides. In view of the high mortality rate the complications of the patients admitted to the intensive therapy unit were analysed to see whether any of them provided an indicator of prognosis. The height of the fever on admission was similar in the survivors (mean = 39.0~ and non-survivors (mean = 38.2~ A petechial rash occurred in all the survivors and 57% of the fatalities. Arthropathy was present in half the survivors and 42% of those that died. The presence of DIC was not significant but the three patients with the most severe DIC all died. Epileptic fits were frequent in both groups. The development of focal neurological signs occurred in only 16% of the survivors but in 57% of the subjects who subsequently died. Meningism was present in all the subjects exept one. He was receiving steroids and eventually died. Two subjects suddenly lost consciousness, presumably due to cerebral coning, but were resuscitated by mannitol, dexamethasone and mechanical ventilation. In contrast to the patients managed in the intensive therapy unit, the only complication observed in the nine patients on the ordinary wards was a transient rash in two subjects. All nine survived their illness. There was correlation between the white cell count in the peripheral blood or CSF and survival. This may be an artefact due to the samples being obtained at different stages in the natural history of the infection in different patients. Stiehm and Damrosch [15] found that the absence of meningism, the presence of a petechial rash within 12 h of admission, a systolic blood pressure less than 70 mm Hg, a white cell count.less than 10,000//aL in peripheral blood, and an ESR less than 10 mm in the first hour, were all bad prognostic features. These findings indicate that an overwhelming meningococcaemia has a poor prognosis whereas a strong antibacterial reaction, which may result in markedly abnormal physical findings and investigations, is a favourable sign, However in our series none of these criteria was a useful prognostic indicator.
b) Management The clinical features, especially the petechial rash, often give an indication of the correct bacteriological diagnosis, but this should always be confirmed as soon as possible by CSF examination and blood cultures. Nose and throat swabs and aspiration of inflamed joints may also help. Typing of the organism is of no help in the individual case. An increasing percentage of meningococci are resistant to sulphonamides [3] although these drugs are effective alone if the organism is sensitive. Initially, however, intravenous
J.M. Shneersonand I.W.Fawcett: MeningococcalMeningitis benzylpenicillin 20 - 30 mega units daily should be given, although chloramphenicol orally or intravenously is effective if the patient is allergic to penicillin (Hillas Smith 1978, personal communication). Penicillin crosses the inflamed meninges easily and there is no indication for intrathecal penicillin in meningococcal meningitis. Throat swabs should be obtained from close contacts of the patient, including hospital staff in contact with him before and during the first 24 h of treatment. Those harbouring meningococci should receive sulphonamides if the organism is sensitive or minocycline or rifampicin if it is resistant. Penicillin is ineffective [2]. Admission of the subject to a high dependency area or intensive therapy unit is advisable if there is any neurological deterioration or other serious complication. Shock is a well-known accompaniment of meningococcal septicamia. It used to be thought that it was the result of adrenal haemorrhages causing an Addisonian crisis (Waterhouse-Friderichsen syndrome). Although these haemorrhages are sometimes seen, the cortisol levels do not correlate with the clinical picture or the presence of adrenal haemorrhages. The clinical picture is probably due to release of endotoxin, although myocarditis and disseminated intravascular coagulation (DIC) may also be present. Routine observations should include pulse rate and volume, blood pressure, core/toe temperature difference, urinary output, respiratory rate and ECG.monitoring. Assessment of acid/base status, urea and electrolytes and the urine/ plasma osmolality ratio are essential if shock is present. Right atrial pressure (RAP) monitoring is indicated in the presence of a diminishing pulse volume, persistent sinus tachycardia or other dysrhythrnia, or a core/toe temperature gradient of 4~ or greater. If the RAP is low and there is evidence of poor peripheral perfusion, plasma expanders, such as dextran 70 or haemaccel, are required. Methyl prednisolone (30 mgm/kgm body weight) should be given as a bolus for its protective effect against endotoxin if there is poor peripheral perfusion, oliguria, or severe metabolic acidosis which does not respond to volume replacement and correction of hypoxia. Myocarditis may produce the clinical picture of a low output state with a high RAP. Electrocardiographic changes have been detected in as many as 20 out of 112 cases [19] but the true frequency of myocarditis is unknown. Micro-abscesses may occur in the myocardium [13] but an allergic reaction to the meningococcus is probably more common. Occasionally large pericardial effusions containing meningococci occur [16] and relief of cardiac tamponade by pericardial aspiration may be necessary. The myocarditis may respond to digitalization if the cardiac output is poor. The deveopment of DIC may be diagnosed by the characteristic cold, cyanosed extremities, haemorrhages and single or multiple organ failure, particularly renal, pulmonary and hepatic [6]. The prothrombin time (PT), kaolin partial thromboplastin time (KPTT), fibrinogen titre, and platelet count are all abnormal in severe cases. These tests should be performed routinely. The presence of fibrin degradation products in the CSF is associated with a poor
prognosis [4]. Thrombocytopenia alone may be due to bone marrow suppression by the septicaemia. IfDIC is severe, replacement of clotting factores with fresh frozen plasma may be required although platelet transfusions are only indicated if haemorrhage occurs once clotting factors have been replaced or if the platelet count falls below 20,000//.tl or there is evidence of platelet dysfunction. The place of heparin is uncertain but, once started, it should be continued until the prothrombin time has been normal for three days. The characteristic petechial rash of meningococcaemia may occur without DIC. The skin lesions contain meningococci. A rash is a common finding and may reflect the severity of the septicaemia. The petechial rash commonly fades in a few days but may be succeeded about a week after the onset of the illness by a vesicular rash which often ulcerates. This appears to be due to an allergic vasculitis rather than direct infection [10]. In our series the skin of two patients sloughed off extensively and in one case required skin grafts. Hyperbaric oxygen in conjunction with skin grafting may encourage healing and reduce the incidence of secondary infection. It was used in one patient. Most patients with meningococcal meningitis are comatose or confused and lumbar puncture reveals a raised CSF pressure. Coning after lumbar puncture is very rare and its possibility should not delay the investigation. Observation of the level of consciousness, pupil size and reaction, and also pulse rate, blood pressure and respiratory rate will give warning of coning. If it does occur, up to 100 gm mannitol should be infused intravenously over 30 minutes and dexamethasone also given (initially 10 mg intravenously, then 5 mg 6 hourly). If there is further deterioration, intermittent positive pressure ventilation (IPPV) should be instituted with a high minute volume in order to decrease PaCO2 and intracranial pressure [ 1,14]. Coning may also occur spontaneously during the course of the illness. Two o f our patients suddenly deteriorated neurologically and one other developed central neurogenic hyperventflation. Mannitol, dexamethasone, and in two of the subjects IPPV, led to improvement. Coning is also likely to occur following epileptic fits, especially if status epilepticus develops. The temperature may rise, especially in children, and hypoxia is inevitable during the fits. Prompt treatment with a cooling blanket, mannitol, dexamethasone and a readiness to proceed to mechanical ventilation are necessary. Anti-epileptic drugs are also useful. The occurrence of fits later in the illness should suggest the possibility of a cerebral abscess, localized meningeal pus, or hydrocephalus due to obstruction of free CSF flow by meningeal adhesions. Three of our subjects complained of multiple joint pains early in their illness and three developed single swollen inflamed joints about a week after the onset of their illness. Whittle et al. [17] and Greenwood et al. [1 l] have elegantly shown that the former usually accompanies the acute septicaemia and that the latter is usually an allergic reaction in which antigen-antibody-complement complexes are deposited in the synovial membrane. The meningo-
J.M. Shneerson and I.W. Fawcett: Meningoeoccal Meningitis coccal antigen is probably a polysaccharide [9] and its presence is correlated with the development o f arthritis [ 12]. Serum C3 levels fall transiently at the time o f appearance o f the arthritis [8]. A secondary rise o f temperature m a y occur in the late type o f arthritis and suggest a relapse o f the infection, loculation o f pus, or antibiotic allergy. Aspiration and culture o f the synovial fluid is advisable b u t it is usually sterile.
Acknowledgements. We would like to thank Dr. Gillian C. Hanson for her help and encouragement, the consultant physicians in charge of the patients reported, and Mrs. R. Selby for typing the manuscript.
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