Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/yacb20 Delayed cerebral thrombosis complicating bacterial meningitis Sofie Depoortere, Jonas Toeback, Sophie Lunskens, Erwig Van Buggenhout, Regilio Oedit & Dimitri Hemelsoet To cite this article: Sofie Depoortere, Jonas Toeback, Sophie Lunskens, Erwig Van Buggenhout, Regilio Oedit & Dimitri Hemelsoet (2021): Delayed cerebral thrombosis complicating bacterial meningitis, Acta Clinica Belgica, DOI: 10.1080/17843286.2021.1873583 To link to this article: https://doi.org/10.1080/17843286.2021.1873583 Published online: 17 Jan 2021. Submit your article to this journal Article views: 64 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=yacb20 ACTA CLINICA BELGICA https://doi.org/10.1080/17843286.2021.1873583 REVIEW Delayed cerebral thrombosis complicating bacterial meningitis Sofie Depoortere a*, Jonas Toebackb*, Sophie Lunskensc, Erwig Van Buggenhoutc, Regilio Oeditc and Dimitri Hemelsoetb a Department of Neurology, University Hospitals Leuven, Leuven, Belgium; bDepartment of Neurology, University Hospitals Ghent, Ghent, Belgium; cDepartment of Neurology, AZ Sint Blasius Dendermonde, Dendermonde, Belgium ABSTRACT KEYWORDS Background: Delayed cerebral thrombosis has been described as a potential cause of cere­ brovascular complications in patients with bacterial meningitis. We report a case of delayed cerebral thrombosis in a 63-year-old woman admitted for pneumococcal meningitis. Initially, there was a good clinical evolution under treatment with steroids and antibiotics. On day 8 after admission, she was found with a decreased level of consciousness. Her neurological condition gradually worsened. Repeated brain imaging showed extensive ischemic lesions. Despite treatment with high-dose corticosteroids, the patient died. Methods: A literature search was conducted. Data on patient characteristics, diagnosis, treat­ ment and outcome were collected. Results: To date, 28 cases with delayed cerebral thrombosis following bacterial meningitis have been reported. Streptococcus pneumoniae was the pathogen in 89% of cases. Clinical deterioration occurred in all patients, with a duration varying from 5 to 40 days between admission and deterioration. Most common symptom was altered consciousness (83%), fol­ lowed by hemiparesis (52%). Brain imaging typically shows new infarctions (96%). Fifty-six percent of patients were treated with corticosteroids after deterioration. Outcome was poor with mortality rate of 46%. Conclusion: Delayed cerebral thrombosis presents as a clinical deterioration, typically a sudden decline in consciousness, more than 5 days after meningitis onset. Brain imaging shows new widespread ischemic lesions. Diagnosis should be made carefully, based on clinical findings and brain imaging, after excluding endocarditis. The underlying etiology remains unknown. When delayed cerebral thrombosis is suspected, high-dose corticosteroids should be started empirically. The prognosis remains poor with high mortality rates. Bacterial meningitis; delayed cerebral thrombosis; cerebrovascular complication; corticosteroids Introduction Bacterial meningitis is a serious and life-threatening disease with an estimated incidence of 2.6–6 per 100 000 adults per year [1–3]. The development of cere­ brovascular events is an important complication asso­ ciated with poor outcome [4]. Arterial cerebrovascular complications are reported to occur in approximately 8% to 22% of patients with bacterial meningitis [5,6]. Streptococcus pneumoniae is the most common pathogen associated with cerebral infarction in bacter­ ial meningitis [3,6–8]. Historically, all vascular events occurring during bac­ terial meningitis were believed to be due to vasculitis, but different possible etiologies have been identified. Severe inflammation of the vessel walls, thus vascu­ litis, is a first important possible etiology [4]. However, in some patients histopathological examination could not reveal any inflammation at the sites of arterial narrowing, suggesting vasospasm as a second impor­ tant etiology of ischemic stroke [4]. Ischemic stroke can CONTACT Sofie Depoortere sofie.depoortere@uzleuven.be Belgium * Both the authors contribute equally also occur as a result of endocarditis and septic emboli that always have to be excluded [4]. A fourth possible cause of stroke with bacterial meningitis is delayed cerebral thrombosis (DCT) [4]. Schut et al. were the first to describe six patients admitted between 2003 and 2008 with a good or excellent initial recovery after pneumococcal meningitis and sudden deterioration 7 to 19 days after admission due to multiple cerebral infarctions [9]. Autopsy in one patient revealed focal thrombi in the posterior circulation without inflamma­ tory cells in any of the vessel wall layers after which the complication was described as ‘delayed cerebral thrombosis’ [9,10]. We add a case of DCT complicating pneumococcal meningitis and provide a review of literature. Case A 63-year-old woman was admitted to the emergency department for fever and altered level of consciousness. Department of Neurology, University Hospitals Ghent, Ghent, Belgium, Leuven, © Belgian Society of Internal Medicine and Royal Belgian Society of Laboratory Medicine (2021) 2 S. DEPOORTERE, J. TOEBACK ET AL. Figure 1. Evolution of brain imaging during hospitalization (a) Brain computed tomography (CT) on day 4 showing no significant lesions (b) Brain magnetic resonance imaging (MRI) on day 8, showing no lesions with restricted diffusion on diffusion-weighted imaging (DWI) (c) Brain CT on day 11, showing multiple hypodensities in both hemispheres (d) Brain MRI on day 15 confirming new bilateral fluid-attenuated inversion recovery (FLAIR) – hyperintense lesions, (e) all showing restricted diffusion on DWI. One day before presentation she had a fever and com­ plained of a cough. At physical examination, tempera­ ture was 39.0°C and Glasgow Coma Scale (GCS) 11/15 (E4M6V1). Neck stiffness could not be tested due to agitation. There was global aphasia without motor or sensible signs of lateralization. Blood tests showed an elevated white blood cell (WBC) count and increased C-reactive protein (CRP). The recent medical history of fever and altered level of consciousness raised suspicion for a viral or bacterial meningo-encephalitis. Empirical treatment with intravenous dexamethasone, ceftriax­ one, amoxicillin and aciclovir was initiated. Plain brain computed tomography (CT) did not reveal any specific lesion. Cerebrospinal fluid (CSF) was purulent and ana­ lysis revealed a neutrophilic pleocytosis of 715 white blood cells/µL, an elevated protein of 571 mg/dL and very low glucose (<2 mg/dL). Gram staining of the blood and CSF showed Gram-positive cocci that were cultured as Streptococcus pneumoniae, confirming the diagnosis of pneumococcal meningitis. Consecutively, amoxicillin and aciclovir were stopped. During admis­ sion at the intensive care department, clinical and bio­ chemical condition improved, with subtle remaining bradyfrenia and disorientation (GCS 14/15). Brain CT on day 4 showed no abnormalities (Figure 1a). The patient was transferred to the neurological ward and on day 8 following admission, she developed a sudden decrease of consciousness. EEG showed no epileptic activity. Brain magnetic resonance imaging (MRI) showed no restricted diffusion or other significant lesions (Figure 1b). Repeat lumbar puncture (LP) showed a normal opening pressure, but purulent CSF and persistent neutrophilic pleocytosis of 882 white blood cells/µL, elevated protein (259 mg/dl) and still very low glucose (<2 mg/dl). Blood and CSF cultures were now sterile. Although the antibiogram of the first culture confirmed sensitivity for ceftriaxone, antibiotic therapy was switched to a combination of vancomycin and amoxicillin. Steroids were restarted after being stopped on day 4. Neurological evaluation revealed slight improve­ ment of the level of consciousness, but a new subtle left hemiparesis. Brain CT on day 11 after admission showed bilateral frontal hypodensities (Figure 1c). Endocarditis was ruled out by transesophageal echo­ cardiography (TEE). A severe left hemiparesis was noted on day 12. New brain CT showed more extensive hypodensities. Brain MRI without contrast administra­ tion on day 15 confirmed extensive cortical T2- and fluid-attenuated inversion recovery (FLAIR)hyperintensities in both hemispheres, all showing dif­ fusion restriction on diffusion-weighted imaging (DWI) (Figure 1(d-e)). Digital subtraction angiography (DSA) confirmed vascular narrowing of mainly the right med­ ial cerebral artery. Despite increasing corticosteroids no clinical benefit was achieved. Control brain MRI showed further expansion of the cortical lesions seen on previous imaging. Supportive care was withdrawn on day 29 after admission and comfort therapy was initiated. The patient died on day 31 after admission. Autopsy study was refused by his relatives. Methods A bibliographic Pubmed search was conducted using the key words ‘bacterial meningitis’, ‘delayed cerebral thrombosis’, ‘delayed cerebral injury’, ‘stroke’ and ‘cer­ ebral infarction’. We selected adult patients (≥18 years) with bacterial meningitis in whom DCT was reported. Patient characteristics were collected, including age, gender, clinical, neuro-imaging and CSF findings on admission, time to deterioration, clinical, neuroimaging, CSF and echocardiography findings at time of deterioration, treatment strategies and outcome. We noticed some cases were reported in multiple papers. We corrected for this overrepresentation. Results We identified 5 case series and 4 case reports, describ­ ing 27 cases with DCT complicating bacterial meningitis. 1/1 131 270 14 5/6 1787 (8,017,700) 526 (101–610) <1.8 (<1.8–61) 0/1 1/1 N.R. N.R. 6/6 0/6 6/6 6/6 1/1 0/1 0/1 N.R. N.R. 5/6 5/6 2/6 6/6 1/6 1/1 0/1 0/1 0/1 0/1 2/6 0/6 6/6 0/6 0/6 59 1/1 43 (30–73) 1/6 6 Kawaguchi et al. 1 1/1 1/1 1/1 0/1 0/1 1/1 N.R. 1700 <1.8 0/1 1/1 0/1 1/1 0/1 1/1 0/1 0/1 1/1 41 0/1 Rice et al. 1 1/1 1/1 1/1 0/1 0/1 1/1 1374 648 4 0/1 1/1 1/1 1/1 0/1 1/1 N.R. 0/1 0/1 52 0/1 Kato et al. 1 9/11 11/11 10/11 1/11 0/11 11/11 1843 510 N.R. 7/9 2/9 6/11 6/11 1/11 8/11 1/11 5/11 3/11 55 7/11 Lucas et al. 11 2/2 2/2 2/2 0/2 0/2 2/2 620 (410–830) 769 (567–970) 3 (0–6) 2/2 0/2 2/2 1/2 0/2 2/2 0/2 0/2 1/2 66 (53–79) 1/2 Wittebole et al. 2 4/4 4/4 4/4 0/4 0/4 4/4 N.R. N.R. N.R. N.R. N.R. 4/4 2/4 2/4 4/4 0/4 2/4 1/4 60 (39–73) 1/4 Engelen-Lee et al. 4 5/5 5/5 3/5 1/5 1/5 5/5 5160 (188–15,900) N.R. 8 (0–21) 5/5 0/5 N.R. N.R. N.R. N.R. N.R. N.R. N.R. 49 (26–69) 2/5 5 Gallegos et al. Data are number/number evaluated (%) or median (range). The total number of patients is not the sum of all patients in each separate study as some patients are reported more than once. Double reported patients are discarded. † Immunocompromised state is defined as a history of diabetes mellitus, alcoholism, asplenia or HIV infection or use of immunosuppressive drugs. N.R. = not reported; N.D. = not derivable Causative organism detected by blood/CSF culture Streptococcus pneumonia Listeria monocytogenes Staphyloccocus aureus Treatment Corticosteroids Antibiotics Number of patients Patient characteristics Age Female Predisposing factors Otitis/sinusitis Immunocompromised state† Symptoms on presentation (%) Fever, neck stiffness and altered consciousness Headache Focal neurologic signs Altered consciousness GCS ≤ 14 Altered consciousness, GCS ≤ 8 Initial brain imaging (CT/MR) Normal/no acute abnormalities Abnormal Lumbar puncture Performed White blood cell count (cells/mm3) Protein (mg/dL) Glucose (mg/dL) Schut et al. Table 1. Patient characteristics of patients developing delayed cerebral thrombosis complicating bacterial meningitis. 1/1 1/1 1/1 0/1 0/1 1/1 940 710 N.R. 1/1 0/1 1/1 1/1 0/1 1/1 N.R. 1/1 1/1 62 0/1 Mizrahi et al. 1 1/1 1/1 1/1 0/1 0/1 1/1 715 571 <2 1/1 0/1 0/1 0/1 1/1 1/1 0/1 0/1 0/1 63 1/1 This case report 1 Total 25/28 (89%) 28/28 (100%) 25/28 (89%) 2/28 (7%) 1/28 (4%) 27/28 (96%) N.D. N.D. N.D. 20/24 (83%) 4/24 (17%) 16/23 (70%) 13/23 (57%) 4/23 (17%) 19/22 (86%) 1/20 (5%) 8/23 (35%) 6/23 (26%) 65 13/28 (46%) 28 ACTA CLINICA BELGICA 3 1/1 0/1 0/1 1/1 0/1 0/1 1/1 0/1 0/1 0/1 5/5 0/5 4/6 5/6 6/6 4/6 1/6 1/6 0/6 0/6 1/1 normal normal normal 1/1 6/6 5/6 1080 (166–5933) 239 (130–774) 29 (<1.8–72) 0/1 1/1 0/1 0/1 0/1 6/6 2/6 4/6 2/6 0/6 Kawaguchi et al. 1 0/1 1/1 Schut et al. 5/6 1/6 6 0/1 0/1 0/1 1/1 0/1 1/1 0/1 0/1 1/1 0/1 1/1 16 138 54 1/1 1/1 0/1 1/1 1/1 0/1 1/1 0/1 Rice et al. 1 1/1 0/1 0/1 0/1 0/1 1/1 1/1 0/1 N.R. N.R. 1/1 30 68 44 1/1 1/1 0/1 0/1 0/1 0/1 0/1 1/1 Kato et al. 1 0/11 1/11 0/11 7/11 3/11 6/11 4/11 7/11 7/7 0/7 7/11 1090 170 45 11/11 8/11 9/11 3/11 1/11 3/11 N.R. N.R. Lucas et al. 11 0/2 0/2 0/2 0/2 2/2 0/2 0/2 0/2 N.R. N.R. N.R. N.R. N.R. N.R. 2/2 2/2 0/2 2/2 0/2 0/2 2/2 0/2 Wittebole et al. 2 0/4 0/4 0/4 0/4 4/4 N.R. N.R. 0/4 N.R. N.R. N.R. N.R. N.R. N.R. 4/4 4/4 0/4 1/4 1/4 0/4 4/4 0/4 Engelen-Lee et al. 4 1/5 0/5 1/5 1/5 2/5 N.R. N.R. 0/5 N.R. N.R. N.R. N.R. N.R. N.R. 4/5 N.R. N.R. N.R. N.R. N.R. 5/5 0/5 Gallegos et al. 5 Data are number/number evaluated (%) or median (range). The total number of patients is not the sum of all patients in each separate study as some patients are reported more than once. Double reported patients are discarded. N.R. = not reported; N.D. = non derivable Numbers of patients Days between admission and deterioration Day 5–14 Day > 14 Symptoms Altered consciousness Hemiparesis Fever Headache Seizures Repeat brain imaging New infarctions on brain imaging (CT/MRI) Repeat lumbar puncture Performed WBC count (cells/mm3) Protein (mg/dL) Glucose (mg/dL) CSF gram stain and culture Negative Streptococcus pneumoniae Echocardiography reported negative Treatment after deterioration Corticosteroids Antibiotics Outcome Death Survival, severe disability Survival, moderate disability Survival, minor disability Recovery 0/1 0/1 0/1 0/1 1/1 0/1 1/1 0/1 0/1 1/1 1/1 N.R. N.R. N.R. 1/1 1/1 0/1 1/1 0/1 0/1 1/1 0/1 Mizrahi et al. 1 0/1 0/1 0/1 0/1 1/1 1/1 1/1 1/1 1/1 0/1 1/1 882 259 2 1/1 1/1 1/1 0/1 0/1 0/1 1/1 0/1 This case report 1 Total 3/28 (11%) 1/28 (4%) 1/28 (4%) 10/28 (36%) 13/28 (46%) 13/22 (59%) 11/22 (50%) 12/28 (43%) 13/14 (93%) 1/14 (7%) 15/20 (75%) N.D. N.D. N.D. 27/28 (96%) 19/23 (83%) 12/23 (52%) 9/23 (39%) 3/23 (13%) 3/23 (13%) 17/20 (85%) 3/20 (15%) 28 Table 2. Clinical, imaging, cerebrospinal fluid and echocardiography findings at time of deterioration, treatment strategies and outcome in patients with delayed cerebral thrombosis complicating bacterial meningitis. 4 S. DEPOORTERE, J. TOEBACK ET AL. ACTA CLINICA BELGICA Patient characteristics are summarized in Table 1. Median age was 65 years. Approximately half (54%) of the patients were male. About one-third (35%) were known to have an otitis or sinusitis and one-quarter (26%) had an immunocompromised state. Patients were judged to be immunocompromised when they were using immunosuppressive drugs or had diabetes mellitus, chronic alcohol use, asplenia or HIV infection [1,11]. Presentation with the classic triad of fever, neck stiffness and impaired consciousness (defined as a score on the GCS ≤ 14) occurred in 70%. Most common symptom on initial presentation was impaired consciousness (86%). Brain CT was performed in 24 out of 28 patients. Brain abnormalities were found in four patients and included hydrocephalus, ventriculitis, cerebral edema and com­ bined mastoiditis and pneumocephalus [11–13]. LP was performed to confirm the diagnosis of bacterial meningitis in all but one patient [9]. In the latter case, diagnosis was based upon clinical findings and positive blood cultures for Streptococcus pneumoniae [9]. Later in the disease course of this patient, particularly at the time of deteriora­ tion, LP was performed, revealing neutrophilic pleocytosis [9]. Streptococcus pneumoniae was the pathogen in 89% of cases. DCT occurred in two patients with Listeria mono­ cytogenes meningitis and in one patient with Staphylococcus aureus meningitis [11,14]. Delayed clinical deterioration occurred in all patients (Table 2). The range between admission and deterioration varied from 5 to 40 days with a vast majority (85%) deteriorating between 5 and 14 days. The most common symptom characterizing the clinical deterioration was impaired consciousness in 83% of patients, followed by hemiparesis in 52%. Recurrent fever, headache and sei­ zures were present in a minority of patients. Repeated brain imaging following the clinical dete­ rioration – mainly brain MRI – showed new infarctions in all but one patient. Repeated lumbar puncture was undertaken in 15 patients. WBC count was available in 14 patients. In 13 out of these 14 patients, analysis of the CSF revealed a persistent pleocytosis. CSF was unremarkable in one case [15]. CSF culture was negative in all but one patient [16]. Corticosteroids and antibiotics were continued and/or reinitiated in, respectively, 59% and 50% of cases. Despite these treatments, global outcome was poor when defined by the Glasgow Outcome Scale. Thirteen patients (46%) died, 10 (36%) survived with severe disability and three (11%) survived with moderate dis­ ability. Only two (7%) patients had a favorable out­ come: one patient had residual minor disability and only one patient fully recovered. Discussion DCT is a rare complication of bacterial meningitis [9]. Schut et al. were the first to introduce the term delayed 5 cerebral thrombosis in a report of six patients with a good initial recovery after pneumococcal meningitis and sudden deterioration more than one week after admission due to multiple cerebral infarctions without evidence of vasculitis on autopsy in two patients [9]. Since then, this complication has been reported by other authors in a few case reports and case series [10–17]. According to our findings, an altered conscious­ ness is the most frequent symptom of clinical deteriora­ tion, followed by hemiparesis and recurrent fever. Incidence was studied in two retrospective analyses, first in the Netherlands and later in the United States, with an incidence of, respectively, 1.1% and 4.1% [11,14]. This could be an underestimation as not all patients who deteriorated received further investigations [11]. To date, no clinical characteristics predicting devel­ opment of DCT in bacterial meningitis have been iden­ tified, as no significant difference between those with or without DCT was found in regard to sex, age, abnor­ mal neurologic examination and coagulopathy [14]. Clinical presentation in patients who subsequently develop DCT do not differ from those with bacterial meningitis who do not. When comparing our data with the large prospective cohort study of Weisfelt et al., we found an altered mental status (defined as a score on the GCS ≤ 14) as the most common symptom of bac­ terial meningitis in both groups (82% vs 85%) [1]. The prevalence of the classic triad of neck stiffness, fever and altered mental status on admission was 70% in our cohort and 59% reported by Weisfelt et al. [1]. Remarkably, a score of ≤8 on the GCS on presentation, indicating coma, was found in a minority of patients with DCT thrombosis compared to those without DCT (5% vs 19%) [1]. Investigations generally include (repeated) brain ima­ ging, showing new cerebral infarctions. Remarkably, in our case, brain MRI was done immediately after clinical dete­ rioration was observed and could not show any restricted diffusion or new FLAIR-hyperintensities. However, 3 days later, brain CT revealed new frontal hypodensities bilater­ ally, compatible with ischemia, later confirmed on repeat MRI. In literature, imaging at time of deterioration con­ sisted of a brain CT, negative for recent ischemia in most cases. New ischemic lesions were detected by brain MRI with a delay of a variable amount of days. Only Wittebole et al. reported a time course of brain imaging similar to our case [17]. In this case, brain MRI was performed on day 11 after admission, after noticing clinical deterioration the same day [17]. The authors report only a faint hyperin­ tense signal on DWI, compatible with few ischemic micro­ lesions within the right lenticulate nucleus and left central grey nuclei [17]. As in our case, brain MRI was repeated several days later, revealing extensive acute ischemic damage on FLAIR- and diffusion-weighted images [17]. A clear explanation for the lag between clinical deteriora­ tion and appearance of imaging abnormalities is lacking in both cases. 6 S. DEPOORTERE, J. TOEBACK ET AL. In our case, once brain imaging revealed multiple zones of ischemia, TEE was performed, showing no evidence of endocarditis. We emphasize that a cardioembolic cause should always be ruled out by echocardiography since bacterial meningitis and endocarditis may coexist. It is remarkable that TEE was not reported in some previously published cases [9–17]. Some cases of endocarditis with cerebral embo­ lism may have been mistaken for the entity of DCT. Repeated CSF analysis was performed in half of all patients, revealing a persistent pleocytosis in the vast majority of patients, which is not in line with the expected quick decrease of CSF cell count between 3 and 14 days after start of treatment in uncomplicated bacterial meningitis [18]. Glucose levels were not com­ monly reported, but in our case, remained very low, although glucose levels are expected to show a quick increase within 2 days of treatment [18]. CSF analysis came back normal in one patient [15]. Noteworthy, the latter case also differs from the other reports of DCT because of the late development of clin­ ical deterioration 40 days after meningitis onset [15]. It is debatable whether in this time window, the develop­ ment of a new hemiparesis should be considered as a late complication of bacterial meningitis or as a new unrelated pathology. All CSF cultures were negative, except in one case, in which the patient developed resistance to ceftriax­ one during treatment for pneumococcal meningitis due to a mutation in the pathogen [16]. The etiopathogenesis of DCT remains unknown. The term ‘delayed cerebral thrombosis’ was introduced by Schut et al. after autopsy in two patients showed arter­ ial thrombosis without evidence for vasculitis [9]. According to our research, one of those patients was reported almost a decade later in an autopsy study by Engelen-Lee et al. Opposed to Schut et al., they describe presence of dilatation of the basilary artery with thickening of the endothelial layer and disruption of the elastic layer without inflammation [10]. This autopsy study included three additional patients with DCT [10]. The authors found arterial inflammation in these three other patients, resembling arterial inflam­ mation in acute necrotizing vasculitis with fibrinoid necrosis seen in type III hypersensitivity vasculitis [10]. Furthermore, they report in another patient a similar dilatation of the basilary artery with thicken­ ing of the endothelial layer and disruption of the elas­ tic layer. The presence of vessel wall disruption in the context of predisposing infections such as Streptococcus pneumoniae infections, suggests the presence of an intracranial microbial infectious aneur­ ysm [19]. The direct invasion of blood vessels with destruction of vessel walls leading to intracranial microbial infectious aneurysms has been reported as a manifestation of infectious vasculitis [20]. However, when compared with eight cases of bacterial meningitis without DCT, immunoglobulin deposition patterns between the control meningitis and DCT cases proved not to be different, suggesting that accu­ mulation of immune complexes is not the key driver of DCT [10,14]. An association with the routine use of adjunctive corticosteroids in the treatment of bacterial meningitis was suggested by Schut et al. [9]. Remarkably, the authors could not find cases in literature with a similar clinical presentation, neither did they identify cases with DCT in a nationwide cohort of 696 cases with community-acquired bacterial meningitis between 1998 and 2002 [9]. As this cohort study was performed in the period before routine use of adjunc­ tive dexamethasone therapy and all cases reported by Schut et al. were initially treated with adjunctive dex­ amethasone therapy, the role of corticosteroids was questioned [9]. However, only one retrospective study recently revealed a significant lower use of adjunctive corticosteroids in baseline characteristics of patients with uncomplicated meningitis [14]. Corticosteroids are known to enhance interleukin-1 – mediated calcium dependent vasoconstriction and to reduce levels of vasodilator nitric oxide; which both might contribute to cerebral vasospasms [21]. As DCT also occurs in patients who were not treated with corticosteroids and the beneficial effect of corticoster­ oids could also be demonstrated in a cohort including patients with DCT, current European guidelines still recommend to start dexamethasone together with antibiotic treatment in all cases of suspected bacterial meningitis [11,22]. Some authors suggest that the use of dexamethasone delays vasculitis-associated cere­ bral infarctions. Following this hypothesis, some authors suggest a gradual steroid withdrawal rather than the abruptly terminated 4-day course currently recommended as DCT may be a rebound effect of the primary inflammatory response after withdrawal of steroids [11,13]. Another hypothesis involves the complement sys­ tem, which plays a key role in the innate immune system [23]. Patients with deficiencies in the comple­ ment system are known to have a higher risk of bac­ terial infections, among which invasive pneumococcal or meningococcal disease, but interestingly have higher rates of favorable outcome [23–25]. Specifically in bacterial meningitis, Woehrl et al. showed that C5 fragment levels in CSF of patients with pneumococcal meningitis correlated with disease severity and poor outcome [26]. They identified a genetic variation in the C5 encod­ ing region, which was associated with unfavorable outcome of pneumococcal meningitis [26]. Subsequently, Lucas et al. suggested that the mechan­ ism of DCT may be partly complement-mediated through C5a as analysis of the CSF revealed higher concentrations of C5a and sC5b-9 in patients who ACTA CLINICA BELGICA developed DCT later during the clinical course [11]. Interaction of the complement system with coagula­ tion and fibrinolysis has been established in several publications [27–30]. C5a was found to induce expres­ sion of plasminogen-activator inhibitor 1 in basophil granulocytes with a simultaneous loss of tissue-type plasminogen activator; also, generation of C5a seemed to contribute to up-regulation of tissue factor, which triggers coagulation [27–29]. In conclusion, the clinical deterioration of these patients with a characteristic presentation is a parainfectious process. An exaggerated pro-inflammatory response triggering coagulation in patients genetically prone to be inflammatory seems the most likely hypothesis. Corticosteroids, infection and vasculitis remain candidates to be contributing factors. According to our findings, vasculitic features are a consistent finding in pathology reports for all but one patient to date. To temper the inflammatory response, immediate high-dose steroids should be started if DCT is sus­ pected. This is based on the case series of Schut et al., in which 2 out of 6 patients survived. Both received prolonged treatment with intravenous highdose steroids [9]. Although no relapse of bacterial meningitis was proven, Schut et al. also recommend prolonged antibiotic therapy until CSF cultures remain negative [9]. Outcome is generally poor in patients with bacterial meningitis and DCT, despite treatment with corticos­ teroids. In this literature review, we found one case with complete recovery [14]. Unfortunately, a detailed description of the clinical characteristics and objective findings in this patient is lacking. Moreover, brain MRI was atypical, showing a left frontal cortical vein throm­ bosis, but no recent infarctions, making the diagnosis of DCT debatable. The diagnostic criteria used by Gallegos et al. to retrospectively determine DCT in their cohort of 120 patients with community-acquired bacterial meningitis are not mentioned [14]. Since C5a seems associated with poor outcome of bacterial meningitis and more specifically with DCT, targeting C5a production seems the most promising therapeutic intervention to add to the current treat­ ment regimen for bacterial meningitis [23]. Targeting C5a production can be achieved in three ways. First, by preventing conversion from C5 to C5a and C5b, as does eculizumab, a monoclonal C5 antibody, regis­ tered for paroxysmal nocturnal hemoglobinuria, atypi­ cal hemolytic uremic syndrome and generalized myasthenia gravis [31–33]. However, the major pro­ blem with targeting C5 conversion is the inhibition of membrane attack complex (MAC) formation, resulting in limited bacterial killing, especially in meningococcal meningitis [23]. Therefore, targeting C5a by anti-C5a or C5a-receptor antagonists seems the most promising 7 therapeutic strategies to reduce mortality and morbid­ ity in bacterial meningitis. They are expected to be safe, as complement-mediated meningococcal killing via MAC is preserved, but it remains challenging to develop targeted therapies that cross the blood-brain barrier [23]. Further clinical research and preclinical studies on this topic are needed [6]. DCT remains an entity which is not fully understood. Prospective observational studies with consecutive imaging and laboratory analysis, comparison of differ­ ent treatment strategies and autopsy studies in fatal cases are needed. Authors’ contribution ● Sofie Depoortere and Jonas Toeback: conceptualization, writing of the paper, editing of the paper, final approval of the paper ● Sophie Lunskens, Erwig Van Buggenhout, Regilio Oedit: reviewing and editing of the paper, final approval of the paper ● Dimitri Hemelsoet: conceptualization, reviewing and edit­ ing of the paper, final approval of the paper. Disclosure statement No conflicts of interest ORCID Sofie Depoortere http://orcid.org/0000-0001-5509-0048 References [1] Weisfelt M, van de Beek D, Spanjaard L, et al. Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series. Lancet Neurol. 2006;5(2):123–129. [2] Engelen-Lee JY, Brouwer MC, Aronica E, et al. Pneumococcal meningitis: clinical-pathological correla­ tions (MeninGene-Path). Acta Neuropathol Commun. 2016;4(1):26. [3] van de Beek D, Brouwer M, Hasbun R, et al. Communityacquired bacterial meningitis. Nat Rev Dis Primers. 2016;2:16074. [4] Klein M, Koedel U, Pfefferkorn T, et al. Arterial cerebro­ vascular complications in 94 adults with acute bacter­ ial meningitis. Crit Care. 2011;15(6):R281. [5] Kastenbauer S, Pfister HW. Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Brain. 2003;126(Pt 5):1015–1025. [6] Katchanov J, Heuschmann PU, Endres M, et al. Cerebral infarction in bacterial meningitis: predictive factors and outcome. J Neurol. 2010;257(5):716–720. [7] Pfister HW, Borasio GD, Dirnagl U, et al. Cerebrovascular complications of bacterial meningitis in adults. Neurology. 1992;42(8):1497–1504. [8] Pfister HW, Feiden W, Einhäupl KM. Spectrum of com­ plications during bacterial meningitis in adults. Results 8 S. DEPOORTERE, J. TOEBACK ET AL. of a prospective clinical study. Arch Neurol. 1993;50 (6):575–581. [9] Schut ES, Brouwer MC, de Gans J, et al. Delayed cerebral thrombosis after initial good recovery from pneumococ­ cal meningitis. Neurology. 2009;73(23):1988–1995. [10] Engelen-Lee JY, Brouwer MC, Aronica E, et al.. Delayed cerebral thrombosis complicating pneumococcal menin­ gitis: an autopsy study. Ann Intensive Care. 2018;8(1):20. [11] Lucas MJ, Brouwer MC, van de Beek D. Delayed cere­ bral thrombosis in bacterial meningitis: a prospective cohort study. Intensive Care Med. 2013;39(5):866–871. [12] Kato Y, Takeda H, Dembo T, et al. Delayed recurrent ischemic stroke after initial good recovery from pneu­ mococcal meningitis. Intern Med. 2012;51(6):647–650. [13] Rice CM, Ramamoorthi M, Renowden SA, et al. Cerebral ischaemia in the context of improving, steroid-treated pneumococcal meningitis. Qjm. 2012;105(5):473–475. [14] Gallegos C, Tobolowsky F, Nigo M, et al. Delayed cere­ bral injury in adults with bacterial meningitis: a novel complication of adjunctive steroids? Crit Care Med. 2018;46(8):e811–e4. [15] Kawaguchi T, Ogawa Y, Inoue T, et al. Cerebral arteritis with extremely late onset secondary to bacterial meningitis - case report. Neurol Med Chir (Tokyo). 2011;51(4):302–305. [16] Mizrahi A, Marvaud JC, Pilmis B, et al. Emergence of ceftriaxone resistance during a case of pneumococcal meningitis with fatal evolution. Antimicrob Agents Chemother. 2020;64(3):3. [17] Wittebole X, Duprez T, Hantson P. Delayed cerebral ischaemic injury following apparent recovery from Streptococcus pneumoniae meningitis. Acta Clin Belg. 2016;71(5):343–346. [18] Costerus JM, Brouwer MC, van der Ende A, et al. Repeat lumbar puncture in adults with bacterial meningitis. Clin Microbiol Infect. 2016;22(5):428–433. [19] Kannoth S, Thomas SV. Intracranial microbial aneurysm (infectious aneurysm): current options for diagnosis and management. Neurocrit Care. 2009;11(1):120–129. [20] Pagnoux C, Cohen P, Guillevin L. Vasculitides second­ ary to infections. Clin Exp Rheumatol. 2006;24(2 Suppl 41):S71–81. [21] Eisenhut M. The potential role of steroid-induced cer­ ebral vasospasm in the pathogenesis of delayed cere­ bral injury in bacterial meningitis. Crit Care Med. 2018;46(8):1383–1384. [22] van Ettekoven CN, van de Beek D, Brouwer MC. Update on community-acquired bacterial meningitis: gui­ dance and challenges. Clin Microbiol Infect. 2017;23 (9):601–606. [23] Koelman DLH, Brouwer MC, van de Beek D. Targeting the complement system in bacterial meningitis. Brain. 2019;142(11):3325–3337. [24] Ross SC, Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and conse­ quences of neisserial and other infections in an immune deficiency. Medicine (Baltimore). 1984;63 (5):243–273. [25] Brouwer MC, de Gans J, Heckenberg SG, et al. Host genetic susceptibility to pneumococcal and meningo­ coccal disease: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9(1):31–44. [26] Woehrl B, Klein M, Grandgirard D, et al. Bacterial meningitis: current therapy and possible future treat­ ment options. Expert Rev Anti Infect Ther. 2011;9 (11):1053–1065. [27] Ritis K, Doumas M, Mastellos D, et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol. 2006;177(7):4794–4802. . [28] Kourtzelis I, Markiewski MM, Doumas M, et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood. 2010;116 (4):631–639. . [29] Kambas K, Markiewski MM, Pneumatikos IA, et al. C5a and TNF-alpha up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome. J Immunol. 2008;180(11):7368–7375. . [30] Wojta J, Kaun C, Zorn G, et al. C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood. 2002;100 (2):517–523. . [31] Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89(3):701–711. . [32] Dhillon S. Eculizumab: A Review in Generalized Myasthenia Gravis. Drugs. 2018;78(3):367–376. [33] Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355 (12):1233–1243. .