Brain, Vol. 126, No. 5, 1015-1025,
May 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg113
Pneumococcal meningitis in adults
Spectrum of complications and prognostic factors in a series of 87 cases
Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany
Correspondence to: Stefan Kastenbauer, MD, Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians University, Marchioninistrasse 15, 81377 Munich, Germany E-mail: stefan{at}kastenbauer.de
Received August 29, 2002. Revised November 25, 2002. Accepted December 16, 2002.
 |
Summary |
|---|
 Top Summary IntroductionPatients and methodsResultsDiscussionReferences |
|---|
Studies on the incidence and spectrum of complications and prognostic factors in adults with pneumococcal meningitis are scarce. Therefore, we analysed 87 consecutive cases who were treated in our department between 1984 and 2002. Meningitis-associated intracranial complications developed in 74.7% and systemic complications in 37.9% of cases. Diffuse brain oedema (28.7%) and hydrocephalus (16.1%) developed more frequently than previously reported. The incidences of arterial (21.8%) and venous (9.2%) cerebrovascular complications were also very high. Furthermore, 9.2% of cases developed spontaneous intracranial haemorrhages (two patients with subarachnoid and two with subarachnoid and intracerebral bleedings, all in association with vasculitis; one subject with intracerebral haemorrhage due to sinus thrombosis; and three cases with intracerebral bleedings of unknown aetiology). Other new findings were the incidence of acute spinal cord dysfunction due to myelitis (2.3%) and that of hearing loss (19.5% of all patients and 25.8% of survivors). The in-hospital mortality was 24.1%. Only 48.3% of the patients had a good outcome at discharge [Glasgow Outcome Scale Score (GOS) = 5]. Outcome did not change during the study period, as mortality and GOS were similar for patients treated between 1984 and 1992 and for those treated between 1993 and 2002. Factors associated with a bad outcome (GOS
4) were chronic debilitating diseases, low Glasgow Coma Scale Score and focal neurological deficits on admission, low CSF leucocyte counts, pneumonia, bacteraemia and meningitis-associated intracranial and systemic complications. Low CSF leucocyte counts were also associated with the development of meningitis-associated intracranial complications. Age 
60 years was associated with a higher mortality (36.7 versus 17.5%), but the GOS of the survivors was comparable to that of the surviving younger patients. The causes of death were mostly systemic complications in the elderly and cerebral complications in the younger patients. A haematogenous pathogenesis seemed likely in asplenic patients, while contiguous spread from sinusitis or otitis was the major cause of meningitis in non-asplenic individuals. Furthermore, asplenic patients had a raised incidence of meningitis-associated intracranial complications, but their outcome was similar to that of non-asplenic subjects. The morbidity and mortality of pneumococcal meningitis in adults are still devastating. We report higher incidences (diffuse brain swelling, hydrocephalus, cerebrovascular complications) or new incidences (myelitis, hearing loss, subarachnoid bleeding) of intracranial complications. Our detailed analysis of prognostic factors may help clinicians to identify patients at risk and may also be helpful in the design of clinical trials. Keywords: meningitis; subarachnoid haemorrhage; myelitis; hearing loss; prognosis
Abbreviations: CT = computed tomography; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; HIV = human immunodeficiency virus; ICH = intracerebral haemorrhage
|
Introduction |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
The leading cause of acute bacterial meningitis in adults is Streptococcus pneumoniae, with a mortality of 20–30% despite highly effective antibiotic therapy and modern intensive care facilities (Durand et al., 1993
; Schuchat et al., 1997). Many fatalities are due to cerebral complications (e.g. brain oedema, hydrocephalus, ischaemic infarction and septic sinus or venous thrombosis) or systemic complications (e.g. septic shock, disseminated intravascular coagulation and adult respiratory distress syndrome) (Pfister et al., 1993; Schuchat et al., 1997). Most studies of acute bacterial meningitis in adults have included cases due to different causative bacteria (Durand et al., 1993; Pfister et al., 1993; Sigurdardottir et al., 1997; Hussein and Shafran, 2000; McMillan et al., 2001). Few studies have included only adults with pneumococcal meningitis (Fiebush et al., 1952; Olsson et al., 1961; Bruyn et al., 1989; Kragsbjerg et al., 1994; Auburtin et al., 2002). In many studies [in particular those which were performed completely or in part before the introduction of computed tomography (CT)], mortality and sequelae (neurological deficits) were reported as outcome measures. Still, detailed information about the underlying meningitis-associated intracranial complications was seldom reported. Therefore, in the present study we included only adults with pneumococcal meningitis and chose a time period when CT was readily available in our hospital. Eighty-seven consecutive cases, who were all treated in our neurological intensive care unit (ICU) between 1984 and 2002, were analysed in order to characterize the spectrum and incidence of meningitis-associated intracranial and systemic complications and to identify factors prognostic of clinical outcome.
|
Patients and methods |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
We retrospectively identified all adults (patients
16 years old) who were treated for pneumococcal meningitis in the neurological ICU of the Klinikum Grosshadern (a 1400-bed tertiary medical centre) between January 1984 and April 2002 (87 episodes of pneumococcal meningitis in 87 subjects). In our department, as a rule, patients with acute bacterial meningitis are treated in the ICU at least during the first days of their illness, when most complications occur. The diagnosis of pneumococcal meningitis was based on the presence of clinical signs and symptoms of meningitis and identification of pneumococci in the CSF by culture, Gram stain, or antigen detection using latex particle agglutination and/or growth of pneumococci from blood cultures. All patients were treated with antibiotics. For empirical therapy of community-acquired meningitis, the combination of ceftriaxone and ampicillin is usually used in our department; after identification of the pathogen, the antibiotic therapy is chosen according to the antibiogram. Penicillin-resistant pneumococci were not detected during the study period. Patient data were obtained from the charts. The duration of disease until admission was counted from the first day of meningitis-related symptoms until admission to our hospital. All patients were initially examined neurologically and physically and had a cranial CT [the analysis of the initial CT findings of most patients from this cohort was part of a previous study (Kastenbauer et al., 2002)], consultation by an ear, nose and throat specialist, and a chest X-ray in order to detect underlying or associated infections, CSF fistulae and/or meningitis-associated complications. During their stay in the neurological ICU, the patients were examined neurologically and physically every day and, on suspicion of a complication, the indicated technical examinations (e.g. CT, MRI, cerebral angiography, Doppler sonography, audiometry) were performed. We systematically analysed the following meningitis-associated intracranial and systemic complications: seizures, arterial and venous cerebrovascular complications, diffuse brain swelling, hydrocephalus, acute spinal cord dysfunction, cerebritis, cranial nerve palsies, hearing loss, septic shock, disseminated intravascular coagulation, acute renal failure and adult respiratory distress syndrome (Pfister et al., 1992, 1993; Roos 1998; Kastenbauer et al., 2001). Hearing was classified as in a previous publication on meningitis-associated hearing loss in children (Dodge et al., 1984); in brief, hearing levels <30 dB were classified as normal, 30–55 dB as mild, 55–70 dB as moderate, 70–90 dB as severe and >90 dB as profound loss (deafness). The clinical status on the day of discharge from the intensive care unit was evaluated with the Glasgow Outcome Scale (GOS): 1, death; 2, persistent vegetative state; 3, severe disability; 4, moderate disability; 5, good recovery. Dichotomous variables were compared by the 
2 test. Continuous variables were compared by the Mann–Whitney U test. Correlation analyses were performed according to Spearman. All statistical tests applied were two-tailed. P < 0.05 was considered significant. Unless otherwise stated, data are given as mean ± standard deviation. Fifty-two patients (59.8%) were referred from other hospitals (regional hospitals in Upper Bavaria). However, there were no significant differences between referred patients and those who presented directly to the Klinikum Grosshadern (see below) except for a longer duration of disease until admission to our hospital in the referred patients (2.2 ± 1.7 versus 1.2 ± 1.0 days, P = 0.005). In particular, there were no differences between referred and non-referred patients with regard to age (49 ± 17 versus 53 ± 17 years, P = 0.216), clinical presentation [e.g. Glasgow Coma Score (GCS) 10.2 ± 3.4 versus 10.9 ± 3.7, P = 0.346], underlying or associated diseases (e.g. asplenia in 6 of 52 versus 5 of 35 patients, P = 0.750; chronic debilitating conditions in 15 of 52 versus 12 of 35 cases, P = 0.641; ear or sinus infection in 33 of 52 versus 17 of 35 subjects, P = 0.190), incidence and spectrum of meningitis-associated intracranial (40 of 52 versus 25 of 35 patients, P = 0.620) or systemic complications (19 of 52 versus 14 of 35 cases, P = 0.823) and outcome (GOS 3.7 ± 1.5 versus 3.5 ± 1.9, P = 0.864).
|
Results |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patient characteristics
The patients’ age was 50 ± 17 years (range 16–87 years) and the sex ratio (male : female) was 41 : 46. The duration of disease until admission was 1.8 ± 1.5 days. Eighty-four patients (96.6%) presented with fever (temperature >38°C) and 83 (95.4%) with neck stiffness. The GCS on admission was 10.5 ± 3.5 (range 3–15). Focal neurological deficits were present in 25 patients (28.7%): pyramidal signs (17 patients), dilated or poorly reactive pupils (4 patients), other cranial nerve palsies (4 patients), gaze palsy (5 patients) and aphasia (3 patients) (the total exceeds 25 due to the presence of multiple signs in several patients).
The initial lumbar CSF findings were not available for all patients, because in four patients a lumbar puncture could not be performed due to suspected increased intracranial pressure, and in others the CSF parameters were incomplete (mostly because the volume of CSF collected was too small). In the initial lumbar CSF, the leucocyte count was 3936 ± 5699 cells/µl (n = 81, range 3–33 334 µl), the protein concentration 458 ± 391 mg/dl (n = 75, range 33–1710 mg/dl) and the glucose concentration 22 ± 23 mg/dl (n = 71, range 0–92 mg/dl). The CSF leucocyte counts correlated positively with the glucose level (r = 0.337, n = 70, P = 0.004) but not with the protein concentration (r = –0.023, n = 74, P = 0.846). Furthermore, the protein concentration correlated negatively with the glucose level (r = –0.455, n = 69, P < 0.001).
CSF cultures were performed initially in 83 patients; they were positive in 63 cases (75.9%). Blood cultures were performed initially in 76 patients; they were positive in 49 cases (64.5%). Thirty-nine patients had positive CSF and blood cultures, 16 patients had positive CSF cultures and negative blood cultures, and in 8 patients with positive CSF cultures no blood cultures were performed. Seven of the patients with negative CSF cultures had positive blood cultures (all of these patients also had a positive Gram stain or antigen test in the CSF). Of the 4 patients in whom a lumbar puncture could not be performed initially, 3 had positive blood cultures and 1 with a negative blood culture had a positive Gram stain in ventricular CSF. Of the remaining 13 patients with negative cultures or lacking cultures, 8 tested positive for pneumococcal antigen in the CSF and in 5 subjects the diagnosis was based only on the detection of Gram-positive diplococci in the CSF.
Underlying conditions (predisposition for invasive pneumococcal infection) or associated infections were present in 80 patients (92.0%) (Table 1). Details about the asplenic patients are given in Table 2.
|
|
Of the 87 patients, 9 (10.3%) had recurrent bacterial meningitis (the episode under study was the second in 4, the third in 3, the fifth in 1 and the sixth in 1 patient). In 5 of them, a CSF fistula was diagnosed and treated surgically; 3 patients had chronic or relapsing sinusitis or otitis and 1 patient suffered from terminal renal insufficiency.
Spectrum of complications and clinical outcome
Sixty-five patients (74.7%) had meningitis-associated intracranial complications.
Twenty-four subjects (27.6%) developed seizures. In 9 patients, the seizures were clearly focal in origin (secondarily generalized tonic–clonic seizures occurred in 4 of them). In 6 of the 9 patients, a corresponding focal brain lesion could be detected neuroradiologically. Of the 15 patients in whom only primarily generalized tonic–clonic seizures were observed, no clear cerebral pathology was evident at the time of the first seizure in 11 patients; however, 4 of the patients had CT findings suggesting intracranial hypertension [brain oedema in 3 patients, hydrocephalus and multiple intracerebral haemorrhages (ICHs) in 1].
Arterial cerebrovascular complications were detected in 19 patients (21.8%) (Table 3) and venous complications in 9 (10.3%, Table 4). Eight patients (9.2%) suffered from intracranial bleedings: 4 had a subarachnoid haemorrhage (all had angiographic evidence of vasculitis, 2 also had ICHs) (Table 3), 1 had an ICH due to sinus thrombosis (Table 4), and in 3 patients the cause of their ICHs remained unclear (2 patient had multiple ICHs and a normal angiography; in a third patient with a frontal ICH no angiography was performed). In 2 additional patients, frontal ICHs were probably due to external ventricular drainages.
|
|
Diffuse brain swelling was observed in 25 patients (28.7%) and hydrocephalus in 14 (16.1%). Permanent CSF drainage of hydrocephalus was required in only 2 of the surviving 66 patients (3.3%). Hearing loss developed in 17 patients (19.5%). It was detected exclusively in survivors probably because audiometry was performed only on clinical suspicion of hearing loss after recovery from the critical stage of meningitis. Thus, 17 of 66 survivors (25.8%) suffered from meningitis-associated hearing loss. The hearing loss was symmetrical in 11 patients (mild in 6, moderate in 2, severe in 1 and profound in 2 cases) and asymmetrical in 6 (mild/normal in 2, moderate/normal in 1, moderate/severe in 2 and profound/mild in 1).
Rare CNS complications of meningitis were myelitis and cerebritis. Two patients (2.3%) developed acute spinal cord dysfunction and both had MRI findings consistent with myelitis. In 4 patients (4.6%) the diagnosis of cerebritis was made: 1 had a reversible cortical and subcortical lesion on the MRI without evidence of a vascular cause, and in 3 patients cerebritis was diagnosed neuropathologically post-mortem (intra vitam, 2 had diffuse periventricular hypodensities and marked brain swelling and 1 had focal hypodensities on the CT). It should be noted, though, that the incidence of cerebritis was probably higher because it is very difficult to diagnose intra vitam. Four patients (4.6%) developed cranial nerve palsies which could not be explained by central lesions: 1 developed complete bilateral internal and external ophthalmoplegia, 1 bilateral abducens nerve palsies, 1 peripheral facial palsy and 1 trochlear and ipsilateral peripheral facial palsy.
Meningitis-associated systemic complications occurred in 33 patients (37.9%): 27 (31%) developed septic shock, 20 (23.0%) disseminated intravascular coagulation, 10 (11.5%) renal failure requiring haemofiltration, and 6 (6.9%) adult respiratory distress syndrome
Fewer than half of the patients made a good recovery (GOS 5) before discharge from the ICU (42 patients, 48.3%). Twenty-one patients (24.1%) died. In 9 patients death was due to cerebral herniation. The other 12 patients succumbed to cardiac/circulatory or multiple organ failure, but 9 of them also had a catastrophic neurological status and neuroradiological evidence of severe and permanent cerebral complications of meningitis at the time of death.
In order to find out whether the patient cohort was homogeneous over the study period, we then compared the patients admitted between 1984 and 1992 (n = 44) with those admitted between 1993 and 2002 (n = 43). There was no difference in age (49 ± 17 versus 52 ± 17 years, P = 0.510), disease severity on presentation (GCS 10.1 ± 3.7 versus 10.8 ± 3.3, P = 0.397; presence of focal neurological deficits, 12 of 44, 27.3% versus 13 of 43, 30.2%, P = 0.816), incidence of intracranial complications (32 of 44, 72.7% versus 33 of 43, 76.7%, P = 0.806), incidence of systemic complications (13 of 43, 30.2% versus 20 of 43, 46.5%, P = 0.125) or outcome (mortality, 11 of 44, 25.0% versus 10 of 43, 25.3%, P = 1.000; GOS, 3.52 ± 1.71 versus 3.67 ± 1.64, P = 0.774).
Prognostic factors
Patients with an adverse outcome (GOS 4) differed from those with good a outcome (GOS = 5) (Table 5) in the following respects: on admission they had a lower GCS and more frequently had focal neurological deficits, they had lower CSF leucocyte counts (and tended to have higher CSF protein values), and more frequently had positive blood cultures, chronic debilitating conditions and pneumonia. For the continuous variables, the results were confirmed by correlation analyses: the GOS at discharge correlated with the GCS on admission (r = 0.487, n = 87, P < 0.001), CSF leucocyte counts (r = 0.482, n = 81, P < 0.001) and CSF protein values (r = –0.291, n = 75, P = 0.011). In addition, a correlation of GOS with age (r = –0.230, n = 87, P = 0.032) was observed. GOS was not significantly correlationed with CSF glucose level (r = 0.154, n = 71, P = 0.200) or duration of symptoms until admission (r = 0.025, n = 87, P = 0.821). Both meningitis-associated intracranial and systemic complications contributed to the adverse outcome (Table 6): seizures, cerebrovascular complications (arterial and venous), brain swelling and hydrocephalus, as well as septic shock, disseminated intravascular coagulation and acute renal failure, were each more frequent in patients with a GOS 4.
|
|
Because older age was not clearly associated with an adverse outcome (Table 5), although age
60 years is a known risk factor for mortality from acute bacterial meningitis (Durand et al., 1993), we then dichotomized the cohort with respect to age. Eleven of 30 patients aged 60 years (36.7%) but only 10 of the 57 younger subjects died (17.5%, P = 0.065). Systemic complications were the cause of death in 9 of the 11 older patients with a fatal course but in only 3 of the 10 younger patients (P = 0.030). Meningitis-associated systemic complications (12 of 30, 40%, versus 21 of 57, 36.8%, P = 0.819) and intracranial complications (22 of 30, 73.3%, versus 43 of 57, 75.4%, P = 1.000) were equally frequent in old and young patients. The surviving old and young patients had a comparable outcome (GOS, 4.4 ± 1.0 versus 4.4 ± 0.9, P = 0.804). Thus, old age seemed to be a risk factor for mortality from pneumococcal meningitis; the outcome of the survivors, however, did not depend on age. Because death in the elderly was mostly due to systemic complications, the incidence of which was not increased, the complications were probably more severe. We then analysed the cohort with regard to asplenia. In order to minimize confounding variables, we divided the control group (patients without previous splenectomy) into those with chronic debilitating diseases and those who had previously been healthy (patients without previous splenectomy and without any of the debilitating conditions listed in Table 1).
The demographics, duration of symptoms, presenting signs and microbiological findings (rate of positive CSF and blood cultures) of asplenic patients were not different from those of previously healthy subjects (not shown). The CSF leucocyte counts (2167 ± 2328 versus 5432 ± 7077 cells/µl, P = 0.130) and glucose levels (13 ± 15 versus 28 ± 26 mg/dl, P = 0.116) tended to be lower and the protein values higher (445 ± 146 versus 389 ± 341 mg/dl, P = 0.086) than those of the previously healthy subjects. There was a marked difference, however, with respect to underlying/associated infections, because ear or sinus infections were rare in asplenic compared with previously healthy patients (1 of 11, 9.1%, versus 34 of 49, 69.4%, P = 0.001). The prevalences of cranial CSF leakage and pneumonia, however, were similar (not shown).
Patients with chronic debilitating diseases were older than the previously healthy patients (58 ± 14 versus 48 ± 17 years, P = 0.025); the sex ratios and the duration of symptoms were not different (not shown). The clinical presentation was also similar, except that patients with chronic debilitating diseases more often had focal neurological deficits than previously healthy subjects (13 of 27, 48.1%, versus 8 of 49, 16.3%, P = 0.006). Their CSF leucocyte counts were lower (2154 ± 2633 versus 5432 ± 7077 cells/µl, P = 0.007), the protein values were higher (569 ± 495 versus 389 ± 341 mg/dl, P = 0.047) and the glucose levels tended to be lower (17 ± 19 versus 28 ± 26 mg/dl, P = 0.065) than those of the previously healthy individuals. The microbiological findings were similar in the two patient groups (not shown). Of the underlying and associated conditions, CSF leakages and ear and sinus infections were similarly frequent, but pneumonia was more prevalent in patients with chronic debilitating diseases (10 of 27, 37.0%, versus 7 of 49, 14.3%, P = 0.042).
In a last step, we compared the incidence of complications and the outcome of asplenic patients and of those with chronic debilitating diseases with those of the previously healthy subjects (Table 7). The percentage of asplenic patients who developed meningitis-associated intracranial complications was higher than that of the previously healthy individuals. Meningitis-associated systemic complications (P = 0.107), in particular, septic shock (4 of 11, 36.4%, versus 7 of 49, 14.3%, P = 0.104) and disseminated intravascular coagulation (4 of 11, 36.4%, versus 5 of 49, 10.2%, P = 0.50), tended be more frequent in asplenic patients than in previously healthy subjects. The outcome of asplenic patients, however, was not different from that of previously healthy patients. Subjects with chronic debilitating diseases more frequently developed meningitis-associated intracranial and systemic complications and had a clearly worse outcome than previously healthy individuals.
|
|
Discussion |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Many previous studies on pneumococcal meningitis have included all age groups (Weiss et al., 1967
; Tugwell et al., 1976; Bohr et al., 1984; Hoen et al., 1993; Kirkpatrick et al., 1994; Stanek and Mufson, 1999), although complications and fatalities are less frequent in children than in adults (Kornelisse et al., 1995; Arditi et al., 1998). On the other hand, studies on adults have usually included cases of acute meningitis due to various bacterial pathogens (Pfister et al., 1993; Durand et al., 1993; Sigurdardottir et al., 1997; Hussein and Shafran, 2000; McMillan et al., 2001). In these studies, mortality has sometimes been analysed separately for the different causative bacteria, but not the incidence and spectrum of complications. Very few of the recent studies have focused on adults with pneumococcal meningitis (Bruyn et al., 1989; Kragsbjerg et al., 1994; Auburtin et al., 2002) and two of these reports have analysed a relatively low number of patients [36 and 31, respectively (Bruyn et al., 1989; Kragsbjerg et al., 1994)]. Many investigations have reported mortality and/or the presence of sequelae (neurological deficits) as outcome measures; however, the underlying intracranial complications of meningitis have seldom been analysed. The interpretation of previous studies was therefore hampered by heterogeneous cohorts (adults and children and/or different causative bacteria), small sample size, or lack of detailed information on neurological complications. Therefore, we analysed a large cohort consisting only of adults with pneumococcal meningitis. An additional strength of our study was that the sensitivity for the detection of meningitis-associated complications was very high, because the patients were monitored closely in our neurological ICU and neuroradiological diagnostics (in particular CT and angiography) were readily available throughout the whole study period (1984–2002).
Patient characteristics
The composition of our patient cohort appears to be fairly representative with regard to predisposing or associated conditions, as it was relatively similar to the population from another recent paper on pneumococcal meninigitis in adults (Auburtin et al., 2002); e.g. in that report 7.5% of the patients were asplenic, 21% suffered from chronic alcoholism, 8.8% had cancer or were on immunosuppressive therapy, 6.3% had diabetes mellitus, 50% had an ear or sinus infection, and 18.8% had recurrent episodes of bacterial meningitis. Furthermore, our analysis revealed that the patient characteristics (e.g. age) and disease severity on presentation (e.g. GOS, incidence of focal neurological deficits) did not change during the study period.
Spectrum of complications and outcome
The mortality of 24.1% is in good agreement with previous work that included or studied exclusively adults with pneumococcal meningitis [mean 26.2%, range 16–33% in seven recent studies (Bruyn et al., 1989; Durand et al., 1993; Kragsbjerg et al., 1994; Sigurdardottir et al., 1997; Hussein and Shafran, 2000; McMillan et al., 2001; Auburtin et al., 2002)]. Also, the incidence of seizures (27.6%) was very similar to that in previous studies on pneumococcal meningitis in adults [22.0% (Sigurdardottir et al., 1997), 25.6% (Bruyn et al., 1989) and 25.8% (Kragsbjerg et al., 1994)].
The high incidence of cerebrovascular complications (19 arterial, 21.8%, and 9 venous, 10.3%), however, is a new finding. Comparable figures were only available from a previous study from our department, which showed cerebrovascular complications in 15.1% of adults with acute meningitis due to various bacteria (Pfister et al., 1992, 1993). Also, the incidence of intracranial bleedings (8 spontaneous haemorrhages, 9.2%, and 2 probably iatrogenic cases due to external ventricular drainages) was surprisingly high, although the arterial blood pressure and blood coagulation parameters were monitored closely and kept within tolerable limits in all patients. Previous studies of intracranial bleeding in adults with acute meningitis due to various bacteria reported much lower incidences, of 1–2% (Pfister et al., 1993; Gironell et al., 1995). Four of our patients (4.6%) suffered subarachnoid haemorrhages and all of them had angiographic evidence of vasculitis but not of another source of bleeding, such as an aneurysm. Thus, vasculitic destruction of the arterial wall may have been the cause of subarachnoid bleeding in these patients.
The frequencies of brain swelling (28.7%) and hydrocephalus (16.1%) in our study population also clearly exceeded the figures published for adults with acute meningitis due to various bacteria, which were 14.0 and 11.6%, respectively, in a study from our department (Pfister et al., 1993) and 5.7 and 14.9% in another report (Durand et al., 1993). The high prevalence of hearing loss in survivors of meningitis in our study (25.8%) is in good agreement with the 31% reported for children after pneumococcal meningitis (Dodge et al., 1984).
Another new finding of this study is that it gives the first estimate of the incidence of acute spinal cord dysfunction (due to myelitis) during pneumococcal meningitis (2.3%), because it has been described previously only in case reports and not in any larger series on acute bacterial meningitis (Moffett and Berkowitz, 1997; Kastenbauer et al., 2001).
Thus, this report confirms previous studies of pneumococcal meningitis in adults with respect to mortality and the incidence of seizures. Furthermore, we show that loss of hearing was similarly frequent as in children with pneumococcal meningitis. Finally, our study provides much higher or first incidences for complications which can only be diagnosed reliably intra vitam by CT, angiography or MRI, namely cerebrovascular complications, brain swelling, hydrocephalus and myelitis.
Prognostic factors
A low GCS on admission, bacteraemia, pneumonia and the development of intracranial and systemic complications were associated with an adverse outcome, confirming previous studies. As in our investigation, the level of consciousness has been identified repeatedly as a strong predictor of outcome in reports on acute meningitis in adults due to pneumococci (Auburtin et al., 2002) or various bacteria (Durand et al., 1993; Hussein and Shafran, 2000; McMillan et al., 2001). Also, the severity of pneumonia-associated pneumococcal meningitis has been demonstrated in studies including all age groups (Carpenter and Petersdorf, 1962; Bohr et al., 1985; Hoen et al., 1993) and also in a smaller study on adults (Bruyn et al., 1989). Bacteraemia was known to be associated with a higher mortality, too (Hoen et al., 1993). Finally, the significance of meningitis-associated intracranial and systemic complications confirms an earlier study from our department on acute meningitis in adults due to various bacteria (Pfister et al., 1993).
Lower CSF leucocyte counts were clearly associated with an adverse outcome; this is a new finding in pneumococcal meningitis in adults. Similar findings were reported recently in acute meningitis due to various bacteria in adults (McMillan et al., 2001). However, previous studies of pneumococcal meningitis in children, adults or all age groups did not [except one investigation (Tugwell et al., 1976)] show a significant association (though some reported a tendency) of low CSF leucocyte count with mortality (Carpenter and Petersdorf, 1962; Bohr et al., 1984; Bruyn et al., 1989; Kornelisse et al., 1995; Auburtin et al., 2002). Our discrepant result cannot be explained by the outcome measure used, because the CSF leucocyte counts were also different when the patients were dichotomized with respect to mortality instead of GOS (surviving patients versus fatal cases, 4792 ± 6228 versus 1324 ± 2176 cells/µl, P < 0.001). Furthermore, the CSF leucocyte counts were lower in patients with meningitis-associated intracranial complications than in those without (2611 ± 3425 versus 7489 ± 8554 cells/µl, P < 0.001). Our findings agree well with animal studies of pneumococcal meningitis, which have shown an association of low initial CSF leucocyte counts with high bacterial titres, development of intracranial complications and unfavourable outcome (Giampaolo et al., 1981; Tauber et al., 1992). Clinically, this may be best illustrated by the extreme cases of ‘apurulent meningitis’, which carry a dismal prognosis and are characterized by excessive bacterial growth and lack of leucocyte response in the CSF (Felgenhauer and Kober, 1985). This is the first clinical study which demonstrates that a strong initial leucocyte response in the CSF is associated with a lower incidence of intracranial complications and a good prognosis for pneumococcal meningitis. Thus, the CSF leucocytes might be mediators, or at least indicators, of a beneficial host response.
In contrast to our study, focal neurological deficits were not predictive of adverse outcome in previous reports on acute meningitis in adults due to various bacteria (Durand et al., 1993; McMillan et al., 2001) and in one of the smaller investigations of pneumococcal meningitis (Bruyn et al., 1989). Moreover, in many studies focal neurological signs were not analysed as prognostic factors (Sigurdardottir et al., 1997; Hussein and Shafran, 2000; Auburtin et al., 2002). Our discrepant result cannot be explained by the different outcome measure (GOS instead of mortality), because focal signs were associated with mortality, too (12 of 21 fatal cases, 57.1%, versus 13 of 66 survivors, 19.7%, P = 0.002).
Some factors that were clearly predictive of an adverse outcome in other studies were not so in our investigation, in particular old age. Old age was associated with greater mortality in several studies on adults with meningitis due to various bacteria (Durand et al., 1993; McMillan et al., 2001) or pneumococci (Bruyn et al., 1989); only one study of pneumococcal meningitis in adults reported no difference in age between survivors and fatal cases (Auburtin et al., 2002). In our investigation, the mean age was not different between patients with good and adverse outcome (GOS 4). Only after dichotomization with respect to age 60 years did we find a strong trend towards greater mortality in the older patients (36.7 versus 17.5%, P = 0.065). However, the GOS of the surviving older patients did not differ from that of the younger survivors. The older patients died from systemic rather than intracranial complications (the opposite was true for the younger patients). The incidence of systemic and intracranial complications, however, did not differ between young and old patients. Thus, the systemic complications were probably more severe. Using the GOS as the outcome measure, we thus demonstrate for the first time that, despite increased mortality, the outcome of the surviving older patients did not differ from the younger ones.
Comorbidity has been shown to be associated with an adverse outcome for adults with acute bacterial meningitis (McMillan et al., 2001). However, the definition of comorbidity is difficult. Some studies have combined e.g. pneumonia, head trauma and ear or sinus infections with malignant diseases or immune disorders as underlying or predisposing diseases, and did not find an association with adverse outcome (Hoen et al., 1993; Stanek and Mufson, 1999). However, pneumonia is not necessarily an underlying condition but can also be a complication of advanced pneumococcal meningitis due to haematogenous spread of the bacteria from the CNS (Koedel et al., 2002). Head trauma or CSF fistulae, on the other hand, are of course underlying or predisposing conditions (facilitating entry of bacteria into the CNS), but were not associated with an adverse outcome in our study and another study (Auburtin et al., 2002), and were even predictive of good outcome in another paper (Bruyn et al., 1989). Also, ear or sinus infections were not associated with an adverse outcome in our study and in another (Bohr et al., 1984; Bruyn et al., 1989). Malignant disease not in remission, immunosuppressive medication, human immunodeficiency virus (HIV) infection and asplenia were often combined in the group of patients with immune disorders in previous studies (McMillan et al., 2001; Auburtin et al., 2002). Chronic debilitating conditions were strongly associated with an impaired host response (low CSF leucocyte counts), the development of intracranial and systemic complications and an adverse outcome in our study. On the other hand, the prognosis of acute bacterial meningitis has been shown to be even better for HIV-1-positive than for HIV-1-negative patients (Almirante et al., 1998). Asplenia is considered by some to be an adverse prognostic factor for bacterial meningitis, although it has not been studied systematically in any of the larger series on acute bacterial meningitis in adults. One reason for this belief may be that case reports with a fatal outcome may be over-represented in the literature. This is probably also the reason why Holdsworth et al. (1991), in their review of postsplenectomy infections (which included many single case reports), reported an excessive mortality rate of up to 75% for asplenic adults with pneumococcal meningitis. Therefore, we decided to analyse the role of asplenia in the clinical course of pneumococcal meningitis. The clinical presentation of asplenic patients was not different from that of previously healthy subjects. The long latency between splenectomy and meningitis (4–36 years) in our patients agrees well with previous findings in the literature, that the majority of severe late postsplenectomy infections did not occur within the first 2 years and 42% of infections occurred >5 years after splenectomy (Cullingford et al., 1991). Ear or sinus infections were an exception in our asplenic patients (9.1% of cases), whereas they were present in the majority of previously healthy subjects (69.4%). This finding suggests a different main route of infection in these two patient groups, namely contiguous spread of infection from an ear or sinus infection in previously healthy subjects and haematogenous spread to the meninges in the asplenic patients. The similar rate of positive blood cultures in asplenic and non-asplenic patients does not argue against this assumption, because bacteraemia is no proof of a haematogenous pathogenesis of meningitis as it can also be observed within a few hours after intracisternal injection of bacteria in experimental animals (Quagliarello et al., 1986). A predominantly haematogenous pathogenesis of pneumococcal meningitis in asplenic subjects is also in agreement with animal experimental studies, which have shown that one of the main functions of the spleen is the clearance of encapsulated bacteria, such as pneumococci, from the blood (Shinefield et al., 1966). Furthermore, three of the asplenic patients reported procedures that might have been a cause of transient bacteraemia (1 patient underwent surgery for an ingrown toenail 1 day before and 2 patients received intramuscular injections a few days before onset of meningitis). The clinical course of meningitis in asplenic patients was characterized by an increased incidence of meningitis-associated intracranial complications and also a tendency towards more frequent systemic complications, namely septic shock and disseminated intravascular coagulation. However, in contrast to the occasionally expressed belief that asplenia is predictive of a dismal prognosis, the asplenic patients’ outcome was not at all different from that of previously healthy adults.
The present study has two major limitations: the data were collected retrospectively and outcome was determined only at discharge from the neurological ICU. Therefore, the patients did not receive a standardized treatment according to a study protocol and long-term morbidity and mortality could not be assessed. However, our analysis of underlying and associated conditions, meningitis-associated complications, outcome and prognostic factors in a relatively large sample of 87 adults with pneumococcal meningitis will hopefully help clinicians to identify patients at high risk and may also be useful in the design of clinical trials.
|
Acknowledgements |
|---|
We thank all our colleagues who were involved in the care of the patients in the ICU of our department. We also thank our colleagues from the Department of Neuroradiology, Dr M. Wick (Department of Clinical Chemistry) and Dr B. Grabein (Max von Pettenkofer Institute for Medical Microbiology) for their clinical cooperation.
|
References |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Almirante B, Saballs M, Ribera E, Pigrau C, Gavalda J, Gasser I et al. Favorable prognosis of purulent meningitis in patients infected with human immunodeficiency virus. Clin Infect Dis 1998; 27: 176–80.[Web of Science][Medline]
Arditi M, Mason EO Jr, Bradley JS, Tan TQ, Barson WJ, Schutze GE, et al. Three-year multicenter surveillance of pneumococcal meningitis in children: clinical characteristics, and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics 1998; 102: 1087–97.
Auburtin M, Porcher R, Bruneel F, Scanvic A, Trouillet JL, Bedos JP, et al. Pneumococcal meningitis in the intensive care unit: prognostic factors of clinical outcome in a series of 80 cases. Am J Respir Crit Care Med 2002; 165: 713–7.
Bohr V, Paulson OB, Rasmussen N. Pneumococcal meningitis. Late neurologic sequelae and features of prognostic impact. Arch Neurol 1984; 41: 1045–9.
Bohr V, Rasmussen N, Hansen B, Gade A, Kjersem H, Johnsen N, et al. Pneumococcal meningitis: an evaluation of prognostic factors in 164 cases based on mortality and on a study of lasting sequelae. J Infect 1985; 10: 143–57.[CrossRef][Web of Science][Medline]
Bruyn GA, Kremer HP, de Marie S, Padberg GW, Hermans J, van-Furth R. Clinical evaluation of pneumococcal meningitis in adults over a twelve-year period. Eur J Clin Microbiol Infect Dis 1989; 8: 695–700.[CrossRef][Web of Science][Medline]
Carpenter RR, Petersdorf RG. The clinical spectrum of bacterial meningitis. Am J Med 1962; 33: 262–75.[CrossRef][Medline]
Cullingford GL, Watkins DN, Watts AD, Mallon DF. Severe late postsplenectomy infection. Br J Surg 1991; 78: 716–21.[Web of Science][Medline]
Dodge PR, Davis H, Feigin RD, Holmes SJ, Kaplan SL, Jubelirer DP, et al. Prospective evaluation of hearing impairment as a sequela of acute bacterial meningitis. New Engl J Med 1984; 311: 869–74.[Abstract]
Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS Jr, et al. Acute bacterial meningitis in adults. A review of 493 episodes. New Engl J Med 1993; 328: 21–8.
Felgenhauer K, Kober D. Apurulent bacterial meningitis (compartmental leucopenia in purulent meningitis). J Neurol 1985; 232: 157–61.[CrossRef][Web of Science][Medline]
Fiebush JS, Murphy EJ, Lubart A. Pneumococcal meningitis in adults. Ann Intern Med 1952; 37: 65–74.
Giampaolo C, Scheld M, Boyd J, Savory J, Sande M, Wills M. Leukocyte and bacterial interrelationships in experimental meningitis. Ann Neurol 1981; 9: 328–33.[CrossRef][Web of Science][Medline]
Gironell A, Domingo P, Mancebo J, Coll P, Marti-Vilalta JL. Hemorrhagic stroke as a complication of bacterial meningitis in adults: report of three cases and review. Clin Infect Dis 1995; 21: 1488–91.[Web of Science][Medline]
Hoen B, Viel JF, Gerard A, Dureux JB, Canton P. Mortality in pneumococcal meningitis: a multivariate analysis of prognostic factors. Eur J Med 1993; 2: 28–32.[Medline]
Holdsworth RJ, Irving AD, Cuschieri A. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Surg 1991; 78: 1031–8.[Web of Science][Medline]
Hussein AS, Shafran SD. Acute bacterial meningitis in adults. A 12-year review. Medicine (Baltimore) 2000; 79: 360–8.[Medline]
Kastenbauer S, Winkler F, Fesl G, Schiel X, Ostermann H, Yousry TA, et al. Acute severe spinal cord dysfunction in bacterial meningitis in adults: MRI findings suggest extensive myelitis. Arch Neurol 2001; 58: 806–10.
Kastenbauer S, Winkler F, Pfister HW. Cranial CT before lumbar puncture in suspected meningitis. New Engl J Med 2002; 346: 1248–51.
Kirkpatrick B, Reeves DS, MacGowan AP. A review of the clinical presentation, laboratory features, antimicrobial therapy and outcome of 77 episodes of pneumococcal meningitis occurring in children and adults. J Infect 1994; 29: 171–82.[CrossRef][Web of Science][Medline]
Koedel U, Winkler F, Angele B, Fontana A, Flavell RA, Pfister HW. Role of Caspase-1 in experimental pneumococcal meningitis: evidence from pharmacologic caspase inhibition and caspase-1-deficient mice. Ann Neurol 2002; 51: 319–29.[CrossRef][Web of Science][Medline]
Kornelisse RF, Westerbeek CM, Spoor AB, van der Heijde B, Spanjaard L, Neijens HJ, et al. Pneumococcal meningitis in children: prognostic indicators and outcome. Clin Infect Dis 1995; 21: 1390–7.[Web of Science][Medline]
Kragsbjerg P, Kallman J, Olcen P. Pneumococcal meningitis in adults. Scand J Infect Dis 1994; 26: 659–66.[Web of Science][Medline]
McMillan DA, Lin CY, Aronin SI, Quagliarello VJ. Community-acquired bacterial meningitis in adults: categorization of causes and timing of death. Clin Infect Dis 2001; 33: 969–75.[CrossRef][Web of Science][Medline]
Moffett KS, Berkowitz FE. Quadriplegia complicating Escherichia coli meningitis in a newborn infant: case report and review of 22 cases of spinal cord dysfunction in patients with acute bacterial meningitis. Clin Infect Dis 1997; 25: 211–4.[Web of Science][Medline]
Olsson RA, Kirby JC, Romansky MJ. Pneumococcal meningitis in the adult. clinical, therapeutic, and prognostic aspects in forty-three patients. Ann Intern Med 1961; 55: 545–9.
Pfister HW, Borasio GD, Dirnagl U, Bauer M, Einhaupl KM. Cerebrovascular complications of bacterial meningitis in adults. Neurology 1992; 42: 1497–504.
Pfister HW, Feiden W, Einhaupl KM. Spectrum of complications during bacterial meningitis in adults. Results of a prospective clinical study. Arch Neurol 1993; 50: 575–81.
Quagliarello VJ, Long WJ, Scheld WM. Morphologic alterations of the blood–brain barrier with experimental meningitis in the rat. Temporal sequence and role of encapsulation. J Clin Invest 1986; 77: 1084–95.[Web of Science][Medline]
Roos KL. Bacterial meningitis. In: Roos KL, editor. Central nervous system infectious diseases and therapy. New York: Marcel Decker; 1998. p. 99–126.
Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, Reingold AL, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. New Engl J Med 1997; 337: 970–6.
Shinefield HR, Steinberg CR, Kaye D. Effect of splenectomy on the susceptibility of mice inoculated with Diplococcus pneumoniae. J Exp Med 1966; 123: 777–94.[Abstract]
Sigurdardottir B, Bjornsson OM, Jonsdottir KE, Erlendsdottir H, Gudmundsson S. Acute bacterial meningitis in adults. A 20-year overview. Arch Intern Med 1997; 157: 425–30.
Stanek RJ, Mufson MA. A 20-year epidemiological study of pneumococcal meningitis. Clin Infect Dis 1999; 28: 1265–72.[CrossRef][Web of Science][Medline]
Tauber MG, Kennedy SL, Tureen JH, Lowenstein DH. Experimental pneumococcal meningitis causes central nervous system pathology without inducing the 72-kd heat shock protein. Am J Pathol 1992; 141: 53–60.[Abstract]
Tugwell P, Greenwood BM, Warrell DA. Pneumococcal meningitis: a clinical and laboratory study. Q J Med 1976; 45: 583–601.[Web of Science][Medline]
Weiss W, Figueroa W, Shapiro WH, Flippin HF. Prognostic factors in pneumococcal meningitis. Arch Intern Med 1967; 120: 517–24.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  O. Hoffman and J. R. Weber Review: Pathophysiology and treatment of bacterial meningitis Therapeutic Advances in Neurological Disorders, November 1, 2009; 2(6): 401 - 412. [Abstract] [PDF]
|
|
|
|
 |
|
 R. Paul, B. Obermaier, J. Van Ziffle, B. Angele, H.-W. Pfister, C. A. Lowell, and U. Koedel Myeloid Src kinases regulate phagocytosis and oxidative burst in pneumococcal meningitis by activating NADPH oxidase J. Leukoc. Biol., October 1, 2008; 84(4): 1141 - 1150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Roach, M. R. Golomb, R. Adams, J. Biller, S. Daniels, G. deVeber, D. Ferriero, B. V. Jones, F. J. Kirkham, R. M. Scott, et al. Management of Stroke in Infants and Children: A Scientific Statement From a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young Stroke, September 1, 2008; 39(9): 2644 - 2691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Zoons, M. Weisfelt, J. de Gans, L. Spanjaard, J. H.T.M. Koelman, J. B. Reitsma, and D. van de Beek Seizures in adults with bacterial meningitis Neurology, May 27, 2008; 70(22_Part_2): 2109 - 2115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Conlon, B. O'Brien, G. P. Herbison, and B. Marsh Long-term functional outcome and performance status after intensive care unit re-admission: a prospective survey Br. J. Anaesth., February 1, 2008; 100(2): 219 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Keane Bilateral Ocular Paralysis: Analysis of 31 Inpatients Arch Neurol, February 1, 2007; 64(2): 178 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. T. Brandt, N. Frimodt-Moller, J. D. Lundgren, M. Pedersen, I. C. Skovsted, I. J. Rowland, and C. Ostergaard Evaluation of anti-pneumococcal capsular antibodies as adjunctive therapy in experimental pneumococcal meningitis J. Antimicrob. Chemother., December 1, 2006; 58(6): 1291 - 1294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Malipiero, U. Koedel, H.-W. Pfister, P. Leveen, K. Burki, W. Reith, and A. Fontana TGF{beta} receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis Brain, September 1, 2006; 129(9): 2404 - 2415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Meli, R. S. Coimbra, D. G. Erhart, G. Loquet, C. L. Bellac, M. G. Tauber, U. Neumann, and S. L. Leib Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis Infect. Immun., July 1, 2006; 74(7): 3890 - 3896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. van de Beek, J. de Gans, A. R. Tunkel, and E. F.M. Wijdicks Community-Acquired Bacterial Meningitis in Adults N. Engl. J. Med., January 5, 2006; 354(1): 44 - 53. [Full Text] [PDF]
|
|
|
|
|
|
G. Sebire, B. Tabarki, D. E. Saunders, I. Leroy, R. Liesner, C. Saint-Martin, B. Husson, A. N. Williams, A. Wade, and F. J. Kirkham Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome Brain, March 1, 2005; 128(3): 477 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Samuels Update in Neurology Ann Intern Med, January 4, 2005; 142(1): 28 - 36. [Full Text] [PDF]
|
|
|
|
|
|
D. van de Beek, J. de Gans, L. Spanjaard, M. Weisfelt, J. B. Reitsma, and M. Vermeulen Clinical Features and Prognostic Factors in Adults with Bacterial Meningitis N. Engl. J. Med., October 28, 2004; 351(18): 1849 - 1859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Koedel, T. Rupprecht, B. Angele, J. Heesemann, H. Wagner, H.-W. Pfister, and C. J. Kirschning MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS Brain, June 1, 2004; 127(6): 1437 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L Ginsberg DIFFICULT AND RECURRENT MENINGITIS J. Neurol. Neurosurg. Psychiatry, March 1, 2004; 75(90001): i16 - 21. [Full Text] [PDF]
|
|
|
|
 |
|
 Complications of Pneumococcal Meningitis in Adults Journal Watch Neurology, July 11, 2003; 2003(711): 8 - 8. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||