1481
monitoring aminoglycoside toxicity. We think that most evidence points to duration of exposure and therefore that trough concentration is more important.1,2 We agree that individualised dosage regimens are always better, as we repeatedly emphasise in our
report.
We agree with Rensma et al that our unqualified statement about the simplified equation described by Cockroft and Gault (CC-D) can be easily misinterpreted because many patients needing aminoglycosides may have weights of under 60 or over 90 kg. Khare comments on the limitations of estimated CLcr, which we also noted in our discussion. He implies that our statement "aminoglycosides and vancomycin are almost totally eliminated by the kidney" is a presumption; we believe this to be a fact. Nor did we imply that non-renal clearance is never affected by renal insufficiency. If non-renal clearance is abnormal, that too should be considered in the equation. We agree with Khare’s points about severe renal dysfunction and about children. Calculation of CLcr in children needs correction for weight and height, and we do not recommend the use of DREM in children.
development or trial. There is little reason to think that they would meningococcal meningitis, in which they would be unlikely to cross the blood-brain barrier in substantial amounts. Confusion between meningitis and septicaemia has arisen firstly since both were thought historically to be the same illnesscerebrospinal fever-and secondly, since septicaemia and meningitis may commonly co-exist in the same patient. It is thus clear that meningococcal septicaemia and meningococcal meningitis are very different diseases; with the rapid advances in understanding of the pathophysiology of severe infections, and consequent development of new therapeutic approaches, real dilemmas in clinical management have arisen; these can only be addressed if the two conditions are clearly be of value in
-
1. Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991; 35: 399-405. 2. Levison ME. New dosing regimens for aminoglycoside antibiotics. Ann Intern Med 1992; 117: 693-94. 3. Brook I, Craig WA, Drusano GL, et al. Continuous vs. intermittent infusion of beta-lactam antibiotics: a potential advance (Proceedings from a roundtable. Moellering RC, moderator). Infect Med 1992; 9B: 6-32.
differentiated and defined. A check of the 1991 Index Medicus under the heading meningococcal meningitis shows that about 70 % of articles actually deal with meningococcal septicaemia. Current terms used for epidemiology and data collection may thus be insufficiently precise for our changing ideas about pathophysiology and management; we need to differentiate clearly between those patients with meningitis alone, with a fairly good outlook, and those with septicaemia, with or without meningitis, in whom the outlook is poorer and management needs to be very different. Only meningococcal meningitis is a notifiable disease in the UK. This leads to a falsely high case-fatality ratio being cited because almost all deaths attributed to meningococcal meningitis are in fact due to meningococcal septicaemia. The presence of a purpuric rash could be regarded as evidence of systemic meningococcal illness and might be used as the primary feature differentiating septicaemia from meningitis. When both conditions co-exist this should be noted but the illness should be classified as "septicaemia"-as the more serious of the two ilnesses. Only when the two illnesses are perceived as different will we be able to understand each as a separate entity and to advance our understanding of them further.
Meningococcal meningitis septicaemia: plea for diagnostic clarity
Department of Paediatric Infectious Disease, University of Birmingham, East Birmingham Hospital, Birmingham B9 5ST, UK
Medical Research Laboratory, Antibiotic Management Program and Infectious Diseases Division, Department of Medicine and Drug Information Center,
Department of Pharmacy Services, Hospital, Hartford, Connecticut 06115, USA, Hartford
E. G. MADERAZO H. SUN G. T. JAY
and University of Connecticut Schools of Medicine and Pharmacy, Farmington and Storrs, Connecticut
or
a
SiR,—The term meningococcal meningitis is widely used both by lay individuals and by some health professionals to include both meningococcal meningitis and meningococcal septicaemia. This imprecision may not have mattered unduly in the past, but is causing increasing confusion as advances in pathophysiology and clinical management clearly separate them into different diseases. Meningococcal meningitis is a central nervous system infection with characteristic changes in the cerebrospinal fluid. In true meningococcal meningitis pathological changes are localised to the central nervous system and the mortality is 5% or less.1 Management is that of a bacterial infection of the central nervous system. Antibiotics are the mainstay of treatment. Fits can arise and associated cerebral oedema may lead to brain damage or death. Sensorineural deafness associated with cochlear inflammation is
a
major sequel. Adjunct therapy with steroids may be of value in shortening the course of the illness and improving prognosis.2 Meningococcal septicaemia, on the other hand, is a severe systemic illness in which the organism is disseminated throughout the body. Mortality is 15% or more, rising to over 80% in patients with severe shock.3 It is associated with the release into the circulation of endotoxin from the cell wall of Neisseria meningitidis; this initiates the release of large amounts of host cytokines, and leads to the clinical picture of gram-negative septic shock. Cytokine concentrations in the circulation in meningococcal septicaemia are many times higher than in most other types of gram-negative septic shock and the disease may progress very rapidly. Meningococcal septicaemia is not especially linked with the development of deafness, but unlike meningococcal meningitis, survivors often have severe vasculitic complications that may lead to the need for skin grafts or even the amputation of limbs. There is little evidence that steroids have a part to play in meningococcal septicaemia; indeed data for other forms of septic shock suggest that they may even worsen the prognosis. Systemic anti-endotoxin antibody is under trial in meningococcal septicaemia; other types of systemic immunotherapy are under
MICHAEL J. TARLOW ALASDAIR M. GEDDES
1. Anonymous. Defences against meningococcal infections. Lancet 1985; ii: 929-30. 2. Lebel MH, Freij BJ, Syrogiannopoulos GA, et al. Dexamethasone therapy for bacterial meningitis. N Engl J Med 1989; 319: 964-71. 3. Gedde-Dahl TW, Bjark P, Hølby A, Host JH, Bruun JN. Severity of meningococcal disease: assessment by factors and scores and implications for patient management. Rev Infect Dis 1990; 12: 973-92.
How accurate is death certification of
multiple system atrophy? SiR,—1 in 4 patients with, at death, a diagnosis of idiopathic Parkinson’s disease do not have that condition,1,2 and the misdiagnosis rate earlier in the clinical course may approach 1 in 3. The commonest cause of erroneous diagnosis in life is probably multiple system atrophy (MSA).2,3 The proportion of MSA cases in parkinsonian brain banks varies from 5 to 22% (mean 8%). This frequency indicates a prevalence of 13 per 100 000, which would make MSA more common than, for example, Huntington’s disease. However, such "necroepidemiology" is subject to bias. Thus, the shorter life expectancy of MSA relative to that of Parkinson’s disease patients and the tendency for cases of atypical parkinsonism to be preferentially "recruited" into brain banks could inflate the frequency of MSA. The population prevalence of MSA has not been studied, but might a survey of death certification indicate its
frequency? We therefore examined the accuracy of death certification in MSA in two ways. First, we traced the death certificates of 36 patients diagnosed in life as MSA. 6 (17%) had a diagnosis of Parkinson’s disease alone on their death certificate; 4 of them had MSA confirmed by necropsy. In the other 30, MSA was mentioned in 15, Shy-Drager syndrome (SDS) in 5, both in 1, and striatonigral degeneration in 1 (table). Second, we looked at the death certificates of 30 cases of pathologically proven MSA (including 19 of the above cases). 4 of these 19 diagnosed as MSA in life nevertheless had only Parkinson’s disease on their death certificate. The remaining 11 had all continued to carry an erroneous clinical diagnosis of Parkinson’s
monitoring aminoglycoside toxicity. We think that most evidence points to duration of exposure and therefore that trough concentration is more important.1,2 We agree that individualised dosage regimens are always better, as we repeatedly emphasise in our
report.
We agree with Rensma et al that our unqualified statement about the simplified equation described by Cockroft and Gault (CC-D) can be easily misinterpreted because many patients needing aminoglycosides may have weights of under 60 or over 90 kg. Khare comments on the limitations of estimated CLcr, which we also noted in our discussion. He implies that our statement "aminoglycosides and vancomycin are almost totally eliminated by the kidney" is a presumption; we believe this to be a fact. Nor did we imply that non-renal clearance is never affected by renal insufficiency. If non-renal clearance is abnormal, that too should be considered in the equation. We agree with Khare’s points about severe renal dysfunction and about children. Calculation of CLcr in children needs correction for weight and height, and we do not recommend the use of DREM in children.
development or trial. There is little reason to think that they would meningococcal meningitis, in which they would be unlikely to cross the blood-brain barrier in substantial amounts. Confusion between meningitis and septicaemia has arisen firstly since both were thought historically to be the same illnesscerebrospinal fever-and secondly, since septicaemia and meningitis may commonly co-exist in the same patient. It is thus clear that meningococcal septicaemia and meningococcal meningitis are very different diseases; with the rapid advances in understanding of the pathophysiology of severe infections, and consequent development of new therapeutic approaches, real dilemmas in clinical management have arisen; these can only be addressed if the two conditions are clearly be of value in
-
1. Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991; 35: 399-405. 2. Levison ME. New dosing regimens for aminoglycoside antibiotics. Ann Intern Med 1992; 117: 693-94. 3. Brook I, Craig WA, Drusano GL, et al. Continuous vs. intermittent infusion of beta-lactam antibiotics: a potential advance (Proceedings from a roundtable. Moellering RC, moderator). Infect Med 1992; 9B: 6-32.
differentiated and defined. A check of the 1991 Index Medicus under the heading meningococcal meningitis shows that about 70 % of articles actually deal with meningococcal septicaemia. Current terms used for epidemiology and data collection may thus be insufficiently precise for our changing ideas about pathophysiology and management; we need to differentiate clearly between those patients with meningitis alone, with a fairly good outlook, and those with septicaemia, with or without meningitis, in whom the outlook is poorer and management needs to be very different. Only meningococcal meningitis is a notifiable disease in the UK. This leads to a falsely high case-fatality ratio being cited because almost all deaths attributed to meningococcal meningitis are in fact due to meningococcal septicaemia. The presence of a purpuric rash could be regarded as evidence of systemic meningococcal illness and might be used as the primary feature differentiating septicaemia from meningitis. When both conditions co-exist this should be noted but the illness should be classified as "septicaemia"-as the more serious of the two ilnesses. Only when the two illnesses are perceived as different will we be able to understand each as a separate entity and to advance our understanding of them further.
Meningococcal meningitis septicaemia: plea for diagnostic clarity
Department of Paediatric Infectious Disease, University of Birmingham, East Birmingham Hospital, Birmingham B9 5ST, UK
Medical Research Laboratory, Antibiotic Management Program and Infectious Diseases Division, Department of Medicine and Drug Information Center,
Department of Pharmacy Services, Hospital, Hartford, Connecticut 06115, USA, Hartford
E. G. MADERAZO H. SUN G. T. JAY
and University of Connecticut Schools of Medicine and Pharmacy, Farmington and Storrs, Connecticut
or
a
SiR,—The term meningococcal meningitis is widely used both by lay individuals and by some health professionals to include both meningococcal meningitis and meningococcal septicaemia. This imprecision may not have mattered unduly in the past, but is causing increasing confusion as advances in pathophysiology and clinical management clearly separate them into different diseases. Meningococcal meningitis is a central nervous system infection with characteristic changes in the cerebrospinal fluid. In true meningococcal meningitis pathological changes are localised to the central nervous system and the mortality is 5% or less.1 Management is that of a bacterial infection of the central nervous system. Antibiotics are the mainstay of treatment. Fits can arise and associated cerebral oedema may lead to brain damage or death. Sensorineural deafness associated with cochlear inflammation is
a
major sequel. Adjunct therapy with steroids may be of value in shortening the course of the illness and improving prognosis.2 Meningococcal septicaemia, on the other hand, is a severe systemic illness in which the organism is disseminated throughout the body. Mortality is 15% or more, rising to over 80% in patients with severe shock.3 It is associated with the release into the circulation of endotoxin from the cell wall of Neisseria meningitidis; this initiates the release of large amounts of host cytokines, and leads to the clinical picture of gram-negative septic shock. Cytokine concentrations in the circulation in meningococcal septicaemia are many times higher than in most other types of gram-negative septic shock and the disease may progress very rapidly. Meningococcal septicaemia is not especially linked with the development of deafness, but unlike meningococcal meningitis, survivors often have severe vasculitic complications that may lead to the need for skin grafts or even the amputation of limbs. There is little evidence that steroids have a part to play in meningococcal septicaemia; indeed data for other forms of septic shock suggest that they may even worsen the prognosis. Systemic anti-endotoxin antibody is under trial in meningococcal septicaemia; other types of systemic immunotherapy are under
MICHAEL J. TARLOW ALASDAIR M. GEDDES
1. Anonymous. Defences against meningococcal infections. Lancet 1985; ii: 929-30. 2. Lebel MH, Freij BJ, Syrogiannopoulos GA, et al. Dexamethasone therapy for bacterial meningitis. N Engl J Med 1989; 319: 964-71. 3. Gedde-Dahl TW, Bjark P, Hølby A, Host JH, Bruun JN. Severity of meningococcal disease: assessment by factors and scores and implications for patient management. Rev Infect Dis 1990; 12: 973-92.
How accurate is death certification of
multiple system atrophy? SiR,—1 in 4 patients with, at death, a diagnosis of idiopathic Parkinson’s disease do not have that condition,1,2 and the misdiagnosis rate earlier in the clinical course may approach 1 in 3. The commonest cause of erroneous diagnosis in life is probably multiple system atrophy (MSA).2,3 The proportion of MSA cases in parkinsonian brain banks varies from 5 to 22% (mean 8%). This frequency indicates a prevalence of 13 per 100 000, which would make MSA more common than, for example, Huntington’s disease. However, such "necroepidemiology" is subject to bias. Thus, the shorter life expectancy of MSA relative to that of Parkinson’s disease patients and the tendency for cases of atypical parkinsonism to be preferentially "recruited" into brain banks could inflate the frequency of MSA. The population prevalence of MSA has not been studied, but might a survey of death certification indicate its
frequency? We therefore examined the accuracy of death certification in MSA in two ways. First, we traced the death certificates of 36 patients diagnosed in life as MSA. 6 (17%) had a diagnosis of Parkinson’s disease alone on their death certificate; 4 of them had MSA confirmed by necropsy. In the other 30, MSA was mentioned in 15, Shy-Drager syndrome (SDS) in 5, both in 1, and striatonigral degeneration in 1 (table). Second, we looked at the death certificates of 30 cases of pathologically proven MSA (including 19 of the above cases). 4 of these 19 diagnosed as MSA in life nevertheless had only Parkinson’s disease on their death certificate. The remaining 11 had all continued to carry an erroneous clinical diagnosis of Parkinson’s
