- Email: [email protected]
Antithrombotic Therapy for Secondary Stroke Prevention in Bacterial Meningitis in Children
Antithrombotic Therapy for Secondary Stroke Prevention in Bacterial Meningitis in Children Cyrus Boelman, MD1, Manohar Shroff, MD2, Ivanna Yau, CNP1, Bruce Bjornson, MD3, Susan Richrdson, MD4, Gabrielle deVeber, MD1, Daune MacGregor, MD1, Mahendranathn Moharir, MD1, and Rand Askalan, PhD, MD1 Objective To assess the safety and efficacy of antithrombotic therapy (ATT) for secondary stroke prevention of childhood bacterial meningitis.
Study design A retrospective study of cases of stroke associated with bacterial meningitis in 2 pediatric hospitals during a period of 15 years. Patients were included in the study if between 28 days and 18 years of age and had at least 2 serial neuroimaging studies during the acute phase of their illness. The safety of ATT was assessed by the presence or absence of intracranial hemorrhage. Efficacy was assessed by the failure in preventing stroke recurrence. Neurologic outcome was determined by the last documented Pediatric Stroke Outcome Measure score. Results Twenty-two cases of childhood bacterial meningitis complicated by stroke were identified. Six cases were treated with heparin after either initial or recurrent infarction. None of the cases receiving heparin had further recurrence. Aspirin (acetylsalicylic acid [ASA]) was started after the initial or after recurrent infarction in 10 cases. Four (40%) had infarctions on ASA; 3 of these patients subsequently received heparin. In the 14 cases in which no ATT was begun, 8 (57%) had further recurrence of infarction. None of the patients, whether receiving heparin or ASA, had intracranial hemorrhage. Conclusion In this small sample, heparin and ASA appeared to be safe in childhood bacterial meningitis complicated by stroke and may be effective in improving outcome. Heparin may be more effective than aspirin in preventing recurrent infarction. (J Pediatr 2014;-:---).
B
acterial meningitis continues to take a toll on society despite population-wide immunization. Mortality has remained at approximately 15%.1 In childhood bacterial meningitis, morbidity is significant and includes long-term neurologic abnormalities in up to 40% of patients who have acute neurologic complications.2 Ischemic stroke is a major cause of morbidity and mortality in meningitis, occurring in 10%-25% of cases.3,4 Advances in supportive care and the early administration of antibiotics have improved outcomes. Dexamethasone has been well studied as an adjuvant therapy to decrease morbidity, such as hearing loss.5 The management of stroke in children with the use of antithrombotic therapy (ATT) has been established in international protocols for many systemic and neurologic disorders.6 However, no clear role has been established for ATT in prophylaxis against stroke in bacterial meningitis. The objectives of the current study were to retrospectively evaluate the safety and efficacy of acute ATTs (acetylsalicylic acid [ASA] and/or heparin) for secondary stroke prevention in children with acute bacterial meningitis.
Methods Children between 28 days and 18 years of age who had ischemic strokes between 1992 and 2010 in the context of acute bacterial meningitis were identified retrospectively from 2 sites of the Canadian Pediatric Ischemic Stroke Registry (The Hospital for Sick Children [HSC], Toronto, and B.C. Children’s Hospital [BCCH], Vancouver, Canada). In HSC, stroke case ascertainment was performed during the study period (1992-2010) by querying Canadian Pediatric Ischemic Stroke Registry via the use of International Classification of Diseases, 9th and 10th Revision search codes and trained chart reviewers validated the diagnosis of stroke. In BCCH, stroke cases were identified through weekly neuroradiology rounds. In both centers, meningitis case
ASA ATT BCCH CSF EVD HSC ICH LMWH PSOM TB
Acetylsalicylic acid Antithrombotic therapy B.C. Children’s Hospital Cerebrospinal fluid External ventricular drain The Hospital for Sick Children Intracranial hemorrhage Low-molecular-weight heparin Pediatric Stroke Outcome Measure Tuberculosis
From the 1Division of Neurology and 2Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada; 3Division of Neurology, British Columbia Children’s Hospital, Vancouver, Canada; and 4 Microbiology Division, Hospital for Sick Children, Toronto, Canada The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.06.013
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ascertainment was validated through chart reviews. Therefore, the series in this study attempts to be a true fully ascertained consecutive cohort of stroke and meningitis. Exclusion criteria included: (1) having fewer than 2 serial neuroimaging studies during the hospital admission of the acute presentation; and (2) the presence of cerebral sinus venous thrombosis before the detection of ischemic arterial stroke. The study was approved by the Research Ethics Board of HSC, Toronto. Bacterial meningitis was defined as having both clinical evidence of central nervous system infection on history and physical examination and laboratory evidence, including either pathogen isolation or cerebrospinal fluid (CSF) analysis consistent with probable bacterial meningitis (based on 2 of 3 measurements: protein level >0.40 g/L, low glucose <2.1 mmol/L, and/or leukocytosis). If CSF culture was negative but serum or other culture determined a pathogen, this pathogen was considered the causative pathogen. The incidences of causative bacteria (excluding tuberculosis [TB]) isolated from cultures of CSF collected as the result of meningitis in non-neonataes were queried from the HSC laboratory database over the years these data were available (2000-2010). Data extracted from chart reviews included initial symptoms of infection, presenting neurologic symptoms, subsequent clinical course, and management, including neuroimaging and timelines between all of these clinical events. Laboratory investigations were followed over time, in particular coagulation profiles and microbiology. Antithrombotic treatment (either standard unfractionated heparin or low-molecular-weight heparin [LMWH] and/or ASA) was documented in terms of the timing of its initiation, the ASA doses by weight, and when therapeutic heparin levels were achieved. Neuroimaging studies were centrally reviewed by a pediatric neuroradiologist (M.S.) who was blinded to the ATT received. Infarcts were defined on magnetic resonance imaging as persistent diffusion-weighted and/or T2 signal hyperintensity on serial imaging with subsequent infarct evolution over time. On computed tomography, infarcts were seen as decreased signal and/or loss of gray-white differentiation with subsequent evolution. Vascular imaging (magnetic resonance angiography, computed tomography angiography), when available, also was reviewed. Assessment of Safety and Efficacy of ATT There are no institutional protocols or guidelines regarding the initiation of ATT for stroke prevention secondary to bacterial meningitis. The decision to initiate ATT for the patients included in this study was based on personal clinical judgment and experience. Safety of ATT was determined by: (1) presence or absence of intracranial bleeding other than petechial hemorrhage expected at the sites of neurosurgical intervention (eg, external ventricular drain [EVD] or ventriculoperitoneal shunt tract); and (2) presence or absence of systemic bleeding. Stroke recurrence was defined by the detection of new ischemic lesion on follow-up neuroimaging with or without 2
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clinical neurologic deterioration. The presence of new radiologic findings consistent with an ischemic lesion was considered to be failure of ATT. ASA efficacy or failure was evaluated based on stroke recurrence after the initiation of ASA dose. Evaluation of neurologic outcome used the most recent complete and documented neurologic physical examination. A blinded reviewer retrospectively calculated an outcome score by the validated Pediatric Stroke Outcome Measure (PSOM), which assesses 5 areas of neurologic function: right sensorimotor, left sensorimotor, language production, language comprehension, and cognitive/behavioral performance.7 Data Analyses Although the study included the largest cohort of pediatric patients with ischemic stroke secondary to meningitis, the number of patients was too small to perform statistical analysis between groups. Therefore, the results were analyzed qualitatively.
Results Incidence and Inclusion of Stroke and Meningitis Cases Between 1992 and 2010, 515 children older than 1 month of age (98 HSC, 417 BCCH) were identified in the Canadian Pediatric Ischemic Stroke Registry to have suffered an ischemic stroke. Twenty-four (4.6%) of these children had stroke and bacterial meningitis (18 HSC, 6 BCCH), of which 2 were excluded from this study because of inadequate neuroimaging. Between 2000 and 2010, HSC documented 128 cases of positive CSF-culture bacterial meningitis in nonneonates (excluding TB), of which 8 (6.3% overall; 24.0% due to Streptococcus pneumoniae and 18.2% due to Streptococcus agalactiae group B) had strokes and were included in the remaining 22 cases. There were 256 cases of nonneonatal strokes at HSC between 2000 and 2010, and 17 (6.6%) of these were associated with meningitis and included as part of the 22 cases in this study. Case Features The demographics and clinical features of the 22 cases with meningitis complicated by stroke and met the inclusion criteria of the study are shown in the Table. The median age was 13 months (range, 35 days to 17.5 years) with 14 males (64%). There were no cases with a family member with history of stroke younger than the age of 50 years or with a history of coagulopathy. The median time between onset of symptoms and admission to hospital was 3 days (range, 0-32 days). Initial signs and symptoms of infection described in the history or noted on presentation to medical attention included fever (18; 82%), common upper respiratory tract infectious symptoms (10; 45%), vomiting (11; 50%), otitis media (4; 18%), headache (4; 18%), lethargy (3; 14%), and respiratory distress Boelman et al
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Table. Patient demographics, cerebrovascular events, and antithrombotic treatment Location of infarcts
Final ATT
Case
Age, y/sex
Heparin prerecurrence Heparin postrecurrence
1 2 3 4
8.5/M 8/M 0.1/F 17.5/M
SCWM DWM, DGM BL; CGM, SCWM, DWM DWM, DGM
(0) (0) BL; CGM, SCWM (1) BL; DGM, BS (2)
None None ASA ASA
No BL, ICA, ACA, PCA, BA No No
5 6
1/M 15.5/M
CGM BL; DWM, DGM, CBLM, BS
(0) CGM, SCWM (2)
None ASA
No BL, ICA, MCA, ACA, BA, VA
7* 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
1/F 13/F 0.7/F 0.25/M 9/M 2.5/M 0.5/M 0.25/M 1/M 0.1/M 9.5/M 0.2/F 0.6/F 5.5/M 0.1/F 0.25/F
DWM SCWM BL, CGM, SCWM, DWM, DGM, BS CGM, SCWM, DWM CGM, SCWM CGM BL, CGM, SCWM, CBLM CGM, SCWM CGM, SCWM BL, CGM, SCWM BL, CGM, SCWM, DWM, DGM, CBLM BL, CGM, SCWM, DGM, CBLM BL, SCWM, DWM BL, CGM, SCWM, DGM, CBLM BL, CGM, SCWM, DWM, CBLM BL, CGM, SCWM, DWM, DGM, CBLM
(0) (0) Increased within same areas (1) Increased within same areas (1) CGM (1) BL, CGM, SCWM (2) Contra CBLM (1) (0) (0) (0) BL, CGM, SCWM, DWM, DGM, CBLM (1) (0) (0) CGM, SCWM, Contra DGM (1) (0) Global (2)
ASA None ASA ASA None None None None None None None None None None None None
No BL; ICA BL; MCA No No No Right MCA No No No Left ICA and MCA No No No No No
ASA prerecurrence ASA postrecurrence None
Initial
Recurrence (no. of recurrences)
ATT at time of recurrence
Arterial narrowing
ICH No No No Large right frontal epidural at EVD No Petechial right basal ganglia before ATT No No Scattered petechial No No No No No No No No No No Small at resection site No Petechial right frontal
Pathogen (in CSF unless indicated) Pneumoniae (blood) Pneumoniae S agalactiae M tuberculosis Pneumoniae (blood) TB M tuberculosis (gastric fluid) Fusobacterium sp (blood) Pneumoniae Pneumoniae (Not determined) Pneumoniae Pneumoniae Pneumoniae Pneumoniae (Not determined) Gram-negative Bacilli (blood) S agalactiae (blood) N meningitidis (skin biopsy) Pneumoniae S agalactiae S agalactiae (blood)
ACA, anterior cerebral; BA, basilar; BL, bilateral; BS, brainstem; CBLM, cerebellum; CGM, cortical gray matter; Contra, contralateral; DGM, deep gray matter; DWM, deep white matter; F, female; ICA, Internal carotid artery; M, male; MCA, middle cerebral; PCA, posterior cerebral; SCWM, subcortical white matter; VA, vertebral. *This patient received ASA before her DWM stroke and had no subsequent recurrences.
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Vol. -, No. ment. Arterial stenosis was found in 6 cases (27%) involving primarily the anterior circulation (Table). Occlusive cerebral sinus venous thrombosis was found after the initial ischemic arterial stroke was diagnosed in Cases 5, 10, and 17. One-half of the cases showed enlarged ventricles but only 5 (23%) required neurosurgical intervention (5 EVD/ventriculoperitoneal shunt, one of whom also had a suboccipital craniotomy with partial cerebellar resection).
(1; 4%). Patients were treated with antibiotics at meningitic doses on the day of admission except for case 2 and case 6, who were treated at day 2 and 4 after admission, respectively. Microbiology investigations revealed a bacterial pathogen in 20 (91%) cases (Table). Cases 11 and 16 had negative cultures. Case 11 had CSF with 137 white blood cells and 1 red blood cell, a low glucose, and increased level of protein (1.43 g/L). Case 16 had a traumatic lumbar puncture, with 205 white cells (92% neutrophils), 30 964 red cells, glucose 2.7 mmol/L, and protein 0.74 g/L. Hematologic laboratory values within 24 hours of the first documented or suspected acute ischemic event were available for 18 of 22 cases (82%). Investigations of underlying prothrombotic risk outside of the acute period were incomplete in all cases; however, prothrombotic screening results were normal in the 12 cases (55%) who had >3 prothrombotic measures.
ATT Early ATT (started after the first ischemic event and before recurrence) for secondary stroke prevention was initiated in 8 cases (36%) via the use of ASA in 6 cases (median dose 3.9 mg/kg/day, range 2.9-6.7 mg/kg/day) and unfractionated heparin infusions in 2 cases (Figure 1). A single case (case 7) with TB meningitis was started early on ASA (3.1 mg/kg/day) before the occurrence of stroke.
Neurologic Complications A neurologic deterioration suggestive of acute brain injury that was confirmed by neuroimaging occurred at a median of 4 days from initial infectious symptoms and 12 hours from initiation of antibiotic coverage. The changes in clinical status associated with neuroimaging documentation of stroke were: decreased level of consciousness (17; 77%), focal seizure (9; 40%), generalized seizure (6; 27%), focal neurologic deficit (5; 23%), and abnormal behavior (5; 23%). Locations of ischemic stroke were noted to be bilateral, deep and/or cortical, and involving multiple vascular territories (Table). All cases showed leptomeningeal enhance-
Recurrence New clinical events with confirmed imaging findings for further ischemic injury occurred at a median of 2 days (range, 1-15 days) from the initial stroke. Representative images of single and multiple recurrent arterial ischemic strokes are shown in Figure 2. Serial imaging of the 8 early treated cases showed no further ischemic injuries in 2 of 2 (100%) receiving early heparin therapy and 3 of 6 (50%) cases receiving early ASA after the initial stroke. Of the 3 early ASA failures, 2 had a single stroke recurrence and one had 2 recurrences. After the recurrences, 2 patients were started on heparin and had no
Figure 1. ATT treatment groups. Either heparin or aspirin was started prior to a stroke recurrence in 8 patients; ATT was started in 5 of 8 patients after they had stroke recurrence(s). No patients had a stroke recurrence once heparin was begun, but 4 of 10 patients treated with aspirin did have recurrences. 4
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Figure 2. Representative case of stroke recurrence. Case 6: A, DWI from initial MRI showed small right basal ganglia infarct. B, DWI from MRI at day 3 showed recurrent infarcts in left basal ganglia and thalamus. C, Fluid-attenuated inversion recovery image from MRI at day 14 showed new infarction involving the left caudate head. DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging.
further strokes (Figure 1). Unfractionated heparin that was started in the 4 cases was continued for a median of 6.5 days (range, 3-13 days) and converted to LMWH in 2 cases. Of the 14 of 22 cases (64%) who did not receive ATT after the initial stroke, 8 (57%) had another stroke. Late (after the second ischemic event) ATT was begun in 5 of 8 cases, ie, heparin in 1 case (case 5) and ASA in 4 cases (median dose 3.3 mg/kg/day, range 1.7-5 mg/kg/day). Seven of these 8 cases had no further recurrences. Case 6 had 2 further recurrences (despite the ASA dose being increased from 1.7 to 5 mg/kg/day). Subsequently, the patient was given heparin and had no subsequent episodes of stroke (Figure 1). Nine cases (38%) received glucocorticoid therapy during their acute management: for TB meningitis in 2 cases, for increased intracranial pressure in 2 cases, and for severe systemic illness in 5. Of these, 6 cases had stroke recurrences while on the glucocorticoids, and of the 2 cases who had no recurrences, one was already receiving LMWH and the other was begun on corticosteroids on the same day as a stroke recurrence. Outcome ATT did not cause cerebral hemorrhage in any of the treated patients whether received after the initial stroke or after recurrence (Table). The duration of follow-up in nondeceased cases was a median of 4 years (range, 16 months to 8.5 years). The PSOM score for each case is shown in Figure 3. Two of the 3 cases who were not given ATT after recurrence severely deteriorated (one with a further acute infarct recurrence), leading to brain death. In the 8 cases treated with LMWH, therapy was continued for a median of 3.5 months (range, 2 weeks to 8 months). Two of these cases (cases 7 and 9) were subsequently started on low-dose ASA as life-long therapy. In cases receiving ASA during the acute admission, the duration of ASA therapy was continued until at least discharge from hospital in all 10 cases
but, beyond this, medical records were not clear on when ASA was stopped in 7 of 10 cases who received ASA acutely; some records suggested life-long therapy.
Discussion This study reports the use of ATT for the management of childhood stroke in complicated bacterial meningitis. Our results show that children with bacterial meningitis, particularly those with TB meningitis, are at high risk of stroke recurrence (50%), and ATT appears to be safe in this small sample and may reduce stroke recurrence risk, therefore improving outcome in this population. The basic principles of Virchow’s prothrombotic triad of endothelial wall injury, hypercoagulability, and blood stasis/turbulence are met in bacterial meningitis. The vascular wall injury caused by secondary vasculitis is part of the inflammatory state that also manifests in cerebritis, inflammatory exudates, and meningeal enhancement. Turbulent flow through small- and medium-sized cerebral vessels as a result of vasculitis and/or external compression by basal exudates is believed to contribute to the etiology of cerebral infarctions.8 In our series and other cohorts, cerebral infarction occurs acutely but in some adult cohorts the cerebrovascular disease presented late, supporting the role of reactive vasculitic process such as seen in varicella zoster virus infections.9,10 Reactive vasospasm may contribute to the small- and medium-sized vessel stenosis that can be seen in vivo by conventional cerebral angiography but then is not proved to be vasculitic on the rare autopsy specimen.10,11 The functional consequence of this vessel narrowing associated with stroke is documented through decreased cerebral blood flow measured by transcranial Doppler ultrasound in bacterial meningitis.12 Bacterial pathogens vary in their virulence and predilection for causing stroke. During the period for which
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Figure 3. Neurologic outcome at last follow-up. PSOM score and final ATT received are shown for each case. Median follow-up time was 4 years (range, 16 months to 8.5 years). Striped bars are patients who had recurrence but did not receive any ATT.
microbiology data were available, we calculated an incidence of stroke in CSF-culture–positive meningitis at one of the sites of this study (HSC) to be 6.3%. We found a high incidence of 24% occurrence of stroke in children with pneumococcal meningitis, which is comparable with a likely baseline greater stroke risk in adult cohorts with pneumococcal meningitis (36%).3 Of the strokes in children documented in the Canadian Pediatric Ischemis Stroke Registry during the study period, 6.6% were associated with a clinical diagnosis of bacterial meningitis. In our study population, there was a disproportionate number of S pneumonia and Mycobacterium tuberculosis–associated with stroke cases compared with available national surveillance figures for meningitis hospitalizations, although these latter figures are for all age groups.13 However, these 2 pathogens have been well established as causing cerebral infarctions, compared with other pathogens. Heparin has been postulated as a possible therapy for preventing stroke morbidity in meningitis, but the only study we found was in 1977 from Nigeria, in which 15 people were included.14 This study lacked neuroimaging, and the heparin-treated group had multiple pretreatment stroke recurrences compared with our study group. The authors found heparin to be ineffective most likely because of the 6
extensive brain injury that already had occurred before the initiation of ATT. In our study, ATT was not associated with stroke recurrence in two-thirds of treated cases. The recurrence risk without initiation of ATT was 50% (11 of 22). Heparin seemed to be more effective at preventing recurrence (0 of 6 recurrence rate) than ASA (4 of 10 recurrence rate). The antithrombotic benefit of heparin over ASA possibly is related to its inhibitory effect on fibrin clot formation, which is enhanced through the acquired hypercoagulable state associated with bacterial meningitis.15 Studies of CSF have shown greater procoagulants and attenuated fibrinolysis in cases of bacterial meningitis.16 Greater systemic coagulation activity also is seen in bacterial meningitis.17 Although extensive coagulopathy evaluation was not complete in most cases, none of our patients had evidence of a predisposing coagulation disorder. The efficacy of heparin in preventing stroke recurrence associated with meningitis also may be attributed to its anti-inflammatory effect. Heparin as an anti-inflammatory agent has been studied in vitro and in clinical trials, such as in asthma and inhalation burns.18-20 Heparin is believed to be an effective anti-inflammatory treatment for sepsis.21 Boelman et al
- 2014 However, the mechanism of the anti-inflammatory action of heparin is not well understood.22 The antithrombotic efficacy of ASA seemed to be less than that of heparin in our study. ASA acts through inhibition of platelet-derived thromboxane.23 Our ASA efficacy findings agree with 2 recent studies of ASA use in preventing stroke in cases with TB meningitis. Schoeman et al24 tested both low- and high-dose ASA (75 mg as a total dose/once daily and 100 mg/kg/day divided into 3 doses, respectively) given as primary stroke prevention in a placebo-controlled, double-blinded trial of 146 children. They found no difference among the 3 groups with respect to stroke occurrence or neurologic outcome. In a second study, investigators treated adults with ASA and found a reduction in stroke risk that did not reach significance, but did show a significant improvement in mortality.25 In our three cases with TB meningitis, we similarly found ASA to be ineffective in preventing stroke. In meningitis, glucocorticoid (usually dexamethasone) has been the focus of research on improving outcomes through controlling inflammation. Dexamethasone is the most established in treatment of H. influenza and TB and considered in S. pneumoniae meningitis.26-28 In a large prospective national cohort study of dexamethasone treatment in 700 adults with pneumococcal meningitis, investigators found a significant improvement in mortality and morbidity in the treated group.29 However, both dexamethasone and nondexamethasone treatment groups had similar occurrences of “focal neurologic deficits” (11%), likely representing strokes. In another trial, cases with TB meningitis treated with dexamethasone and ASA had a better outcome than those treated with dexamethasone alone, but the efficiency in stroke prevention was not different between the 2 groups.25 Two of the 3 cases in our study with TB meningitis cases were treated with corticosteroids but both continued to have recurrent strokes until heparin treatment was commenced. A study on the efficacy of combining dexamethasone and heparin for stroke prevention in this patient population is warranted. In a study of 87 adult cases of pneumococcal meningitis, 22% of patients were found to have infarctions, whereas only 9% had an intracranial hemorrhage (ICH).30 This finding is consistent with our study, with only 2 children, both not treated with ATT, having ICH. Of note, 2 children who died as a result of severe brain injury did not have an ICH. Indeed, the risk of ischemic infarction is much higher than hemorrhagic infarction. Heparin appeared to be safe in our patients with respect to ICH. There were no hemorrhagic complications in cases while receiving heparin, including 3 patients with previous neurosurgical intervention and 2 of these having previous ICH. One of these latter cases, while receiving ASA, had a frontal epidural hemorrhage directly related to the EVD placement site. We were not able to identify whether heparin was held during the single neurosurgical procedure in a case already receiving heparin though this would be routine practice. The PSOM quantifies disability such that a score of 2 or greater indicates significant neurologic disability. The me-
ORIGINAL ARTICLES dian score for all the groups together was 1, reflecting moderate overall disability. However, this median score does not include the 2 deaths in the untreated group. It is difficult to draw comparisons among the groups because of the small number of patients in each group. The trend suggests that earlier heparin treatment (prerecurrence) was associated with better outcomes, with patients receiving heparin having better outcomes than those on ASA. Both treatment groups (heparin or ASA) had better outcomes than the untreated patients with recurrence. There are limitations in this study. The first is that the work is retrospective and thus patients were selected by clinicians for the ATT treatments. However in contrast, we did not observe increased strokes in the heparin-treated group. Another potential decrease or increase in bias was possible as cases case from 2 different centers, representing a greater spectrum of meningitis management, or with one center (HSC) used ATT in non-TB cases and the other (BCCH) did not. Another limitation is that serial imaging was not standardized and thus the frequency of recurrent strokes may have been under estimated. Also this limitation made it difficult to account for infarction size that may contribute to the worse outcome in the untreated group. A multicenter, prospective study is needed to better understand the frequency, timing, and mechanisms of stroke in meningitis. Ideally, a clinical trial comparing heparin with other treatments in a randomized controlled study is needed to provide stronger levels of evidence for management of this very serious complication of a childhood infection. Given the global burden of bacterial meningitis, it is important to find improved methods of treatment. n The authors thank Ann-Marie Pontigon, Lauren Kielstra, Julia O’Mahony, Regina Cerys Starkey and Elisa Wilson of the Hospital for Sick Children Stroke Program for their technical assistance. Submitted for publication Dec 12, 2013; last revision received Apr 9, 2014; accepted Jun 5, 2014. Reprint requests: Rand Askalan, PhD, MD, Division of Neurology, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail: [email protected]
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Vol. -, No. 19. Bendstrup KE, Jensen JI. Inhaled heparin is effective in exacerbations of asthma. Respir Med 2000;94:174-5. 20. Miller AC, Rivero A, Ziad S, Smith DJ, Elamin EM. Influence of nebulized unfractionated heparin and N-acetylcysteine in acute lung injury after smoke inhalation injury. J Burn Care Res 2009;30:249-56. 21. Cornet AD, Smit EG, Beishuizen A, Groeneveld AB. The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007; 98:579-86. 22. Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res 2008;122:743-52. 23. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res 2003;110:255-8. 24. Schoeman JF, Janse van Rensburg A, Laubscher JA, Springer P. The role of aspirin in childhood tuberculous meningitis. J Child Neurol 2011;26: 956-62. 25. Misra UK, Kalita J, Nair PP. Role of aspirin in tuberculous meningitis: a randomized open label placebo controlled trial. J Neurol Sci 2010;293: 12-7. 26. Pneumococcal infections. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th Ed. Elk Grove Village (IL): American Academy of Pediatrics; 2012. p 345 and 571. 27. Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008;1:CD002244. 28. van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2007;1:CD004405. 29. Brouwer MC, Heckenberg SG, de Gans J, Spanjaard L, Reitsma JB, van de Beek D. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology 2010;75:1533-9. 30. Kastenbauer S, Pfister HW. Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Brain 2003;126:1015-25.
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Study design A retrospective study of cases of stroke associated with bacterial meningitis in 2 pediatric hospitals during a period of 15 years. Patients were included in the study if between 28 days and 18 years of age and had at least 2 serial neuroimaging studies during the acute phase of their illness. The safety of ATT was assessed by the presence or absence of intracranial hemorrhage. Efficacy was assessed by the failure in preventing stroke recurrence. Neurologic outcome was determined by the last documented Pediatric Stroke Outcome Measure score. Results Twenty-two cases of childhood bacterial meningitis complicated by stroke were identified. Six cases were treated with heparin after either initial or recurrent infarction. None of the cases receiving heparin had further recurrence. Aspirin (acetylsalicylic acid [ASA]) was started after the initial or after recurrent infarction in 10 cases. Four (40%) had infarctions on ASA; 3 of these patients subsequently received heparin. In the 14 cases in which no ATT was begun, 8 (57%) had further recurrence of infarction. None of the patients, whether receiving heparin or ASA, had intracranial hemorrhage. Conclusion In this small sample, heparin and ASA appeared to be safe in childhood bacterial meningitis complicated by stroke and may be effective in improving outcome. Heparin may be more effective than aspirin in preventing recurrent infarction. (J Pediatr 2014;-:---).
B
acterial meningitis continues to take a toll on society despite population-wide immunization. Mortality has remained at approximately 15%.1 In childhood bacterial meningitis, morbidity is significant and includes long-term neurologic abnormalities in up to 40% of patients who have acute neurologic complications.2 Ischemic stroke is a major cause of morbidity and mortality in meningitis, occurring in 10%-25% of cases.3,4 Advances in supportive care and the early administration of antibiotics have improved outcomes. Dexamethasone has been well studied as an adjuvant therapy to decrease morbidity, such as hearing loss.5 The management of stroke in children with the use of antithrombotic therapy (ATT) has been established in international protocols for many systemic and neurologic disorders.6 However, no clear role has been established for ATT in prophylaxis against stroke in bacterial meningitis. The objectives of the current study were to retrospectively evaluate the safety and efficacy of acute ATTs (acetylsalicylic acid [ASA] and/or heparin) for secondary stroke prevention in children with acute bacterial meningitis.
Methods Children between 28 days and 18 years of age who had ischemic strokes between 1992 and 2010 in the context of acute bacterial meningitis were identified retrospectively from 2 sites of the Canadian Pediatric Ischemic Stroke Registry (The Hospital for Sick Children [HSC], Toronto, and B.C. Children’s Hospital [BCCH], Vancouver, Canada). In HSC, stroke case ascertainment was performed during the study period (1992-2010) by querying Canadian Pediatric Ischemic Stroke Registry via the use of International Classification of Diseases, 9th and 10th Revision search codes and trained chart reviewers validated the diagnosis of stroke. In BCCH, stroke cases were identified through weekly neuroradiology rounds. In both centers, meningitis case
ASA ATT BCCH CSF EVD HSC ICH LMWH PSOM TB
Acetylsalicylic acid Antithrombotic therapy B.C. Children’s Hospital Cerebrospinal fluid External ventricular drain The Hospital for Sick Children Intracranial hemorrhage Low-molecular-weight heparin Pediatric Stroke Outcome Measure Tuberculosis
From the 1Division of Neurology and 2Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada; 3Division of Neurology, British Columbia Children’s Hospital, Vancouver, Canada; and 4 Microbiology Division, Hospital for Sick Children, Toronto, Canada The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.06.013
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ascertainment was validated through chart reviews. Therefore, the series in this study attempts to be a true fully ascertained consecutive cohort of stroke and meningitis. Exclusion criteria included: (1) having fewer than 2 serial neuroimaging studies during the hospital admission of the acute presentation; and (2) the presence of cerebral sinus venous thrombosis before the detection of ischemic arterial stroke. The study was approved by the Research Ethics Board of HSC, Toronto. Bacterial meningitis was defined as having both clinical evidence of central nervous system infection on history and physical examination and laboratory evidence, including either pathogen isolation or cerebrospinal fluid (CSF) analysis consistent with probable bacterial meningitis (based on 2 of 3 measurements: protein level >0.40 g/L, low glucose <2.1 mmol/L, and/or leukocytosis). If CSF culture was negative but serum or other culture determined a pathogen, this pathogen was considered the causative pathogen. The incidences of causative bacteria (excluding tuberculosis [TB]) isolated from cultures of CSF collected as the result of meningitis in non-neonataes were queried from the HSC laboratory database over the years these data were available (2000-2010). Data extracted from chart reviews included initial symptoms of infection, presenting neurologic symptoms, subsequent clinical course, and management, including neuroimaging and timelines between all of these clinical events. Laboratory investigations were followed over time, in particular coagulation profiles and microbiology. Antithrombotic treatment (either standard unfractionated heparin or low-molecular-weight heparin [LMWH] and/or ASA) was documented in terms of the timing of its initiation, the ASA doses by weight, and when therapeutic heparin levels were achieved. Neuroimaging studies were centrally reviewed by a pediatric neuroradiologist (M.S.) who was blinded to the ATT received. Infarcts were defined on magnetic resonance imaging as persistent diffusion-weighted and/or T2 signal hyperintensity on serial imaging with subsequent infarct evolution over time. On computed tomography, infarcts were seen as decreased signal and/or loss of gray-white differentiation with subsequent evolution. Vascular imaging (magnetic resonance angiography, computed tomography angiography), when available, also was reviewed. Assessment of Safety and Efficacy of ATT There are no institutional protocols or guidelines regarding the initiation of ATT for stroke prevention secondary to bacterial meningitis. The decision to initiate ATT for the patients included in this study was based on personal clinical judgment and experience. Safety of ATT was determined by: (1) presence or absence of intracranial bleeding other than petechial hemorrhage expected at the sites of neurosurgical intervention (eg, external ventricular drain [EVD] or ventriculoperitoneal shunt tract); and (2) presence or absence of systemic bleeding. Stroke recurrence was defined by the detection of new ischemic lesion on follow-up neuroimaging with or without 2
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clinical neurologic deterioration. The presence of new radiologic findings consistent with an ischemic lesion was considered to be failure of ATT. ASA efficacy or failure was evaluated based on stroke recurrence after the initiation of ASA dose. Evaluation of neurologic outcome used the most recent complete and documented neurologic physical examination. A blinded reviewer retrospectively calculated an outcome score by the validated Pediatric Stroke Outcome Measure (PSOM), which assesses 5 areas of neurologic function: right sensorimotor, left sensorimotor, language production, language comprehension, and cognitive/behavioral performance.7 Data Analyses Although the study included the largest cohort of pediatric patients with ischemic stroke secondary to meningitis, the number of patients was too small to perform statistical analysis between groups. Therefore, the results were analyzed qualitatively.
Results Incidence and Inclusion of Stroke and Meningitis Cases Between 1992 and 2010, 515 children older than 1 month of age (98 HSC, 417 BCCH) were identified in the Canadian Pediatric Ischemic Stroke Registry to have suffered an ischemic stroke. Twenty-four (4.6%) of these children had stroke and bacterial meningitis (18 HSC, 6 BCCH), of which 2 were excluded from this study because of inadequate neuroimaging. Between 2000 and 2010, HSC documented 128 cases of positive CSF-culture bacterial meningitis in nonneonates (excluding TB), of which 8 (6.3% overall; 24.0% due to Streptococcus pneumoniae and 18.2% due to Streptococcus agalactiae group B) had strokes and were included in the remaining 22 cases. There were 256 cases of nonneonatal strokes at HSC between 2000 and 2010, and 17 (6.6%) of these were associated with meningitis and included as part of the 22 cases in this study. Case Features The demographics and clinical features of the 22 cases with meningitis complicated by stroke and met the inclusion criteria of the study are shown in the Table. The median age was 13 months (range, 35 days to 17.5 years) with 14 males (64%). There were no cases with a family member with history of stroke younger than the age of 50 years or with a history of coagulopathy. The median time between onset of symptoms and admission to hospital was 3 days (range, 0-32 days). Initial signs and symptoms of infection described in the history or noted on presentation to medical attention included fever (18; 82%), common upper respiratory tract infectious symptoms (10; 45%), vomiting (11; 50%), otitis media (4; 18%), headache (4; 18%), lethargy (3; 14%), and respiratory distress Boelman et al
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Table. Patient demographics, cerebrovascular events, and antithrombotic treatment Location of infarcts
Final ATT
Case
Age, y/sex
Heparin prerecurrence Heparin postrecurrence
1 2 3 4
8.5/M 8/M 0.1/F 17.5/M
SCWM DWM, DGM BL; CGM, SCWM, DWM DWM, DGM
(0) (0) BL; CGM, SCWM (1) BL; DGM, BS (2)
None None ASA ASA
No BL, ICA, ACA, PCA, BA No No
5 6
1/M 15.5/M
CGM BL; DWM, DGM, CBLM, BS
(0) CGM, SCWM (2)
None ASA
No BL, ICA, MCA, ACA, BA, VA
7* 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
1/F 13/F 0.7/F 0.25/M 9/M 2.5/M 0.5/M 0.25/M 1/M 0.1/M 9.5/M 0.2/F 0.6/F 5.5/M 0.1/F 0.25/F
DWM SCWM BL, CGM, SCWM, DWM, DGM, BS CGM, SCWM, DWM CGM, SCWM CGM BL, CGM, SCWM, CBLM CGM, SCWM CGM, SCWM BL, CGM, SCWM BL, CGM, SCWM, DWM, DGM, CBLM BL, CGM, SCWM, DGM, CBLM BL, SCWM, DWM BL, CGM, SCWM, DGM, CBLM BL, CGM, SCWM, DWM, CBLM BL, CGM, SCWM, DWM, DGM, CBLM
(0) (0) Increased within same areas (1) Increased within same areas (1) CGM (1) BL, CGM, SCWM (2) Contra CBLM (1) (0) (0) (0) BL, CGM, SCWM, DWM, DGM, CBLM (1) (0) (0) CGM, SCWM, Contra DGM (1) (0) Global (2)
ASA None ASA ASA None None None None None None None None None None None None
No BL; ICA BL; MCA No No No Right MCA No No No Left ICA and MCA No No No No No
ASA prerecurrence ASA postrecurrence None
Initial
Recurrence (no. of recurrences)
ATT at time of recurrence
Arterial narrowing
ICH No No No Large right frontal epidural at EVD No Petechial right basal ganglia before ATT No No Scattered petechial No No No No No No No No No No Small at resection site No Petechial right frontal
Pathogen (in CSF unless indicated) Pneumoniae (blood) Pneumoniae S agalactiae M tuberculosis Pneumoniae (blood) TB M tuberculosis (gastric fluid) Fusobacterium sp (blood) Pneumoniae Pneumoniae (Not determined) Pneumoniae Pneumoniae Pneumoniae Pneumoniae (Not determined) Gram-negative Bacilli (blood) S agalactiae (blood) N meningitidis (skin biopsy) Pneumoniae S agalactiae S agalactiae (blood)
ACA, anterior cerebral; BA, basilar; BL, bilateral; BS, brainstem; CBLM, cerebellum; CGM, cortical gray matter; Contra, contralateral; DGM, deep gray matter; DWM, deep white matter; F, female; ICA, Internal carotid artery; M, male; MCA, middle cerebral; PCA, posterior cerebral; SCWM, subcortical white matter; VA, vertebral. *This patient received ASA before her DWM stroke and had no subsequent recurrences.
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Vol. -, No. ment. Arterial stenosis was found in 6 cases (27%) involving primarily the anterior circulation (Table). Occlusive cerebral sinus venous thrombosis was found after the initial ischemic arterial stroke was diagnosed in Cases 5, 10, and 17. One-half of the cases showed enlarged ventricles but only 5 (23%) required neurosurgical intervention (5 EVD/ventriculoperitoneal shunt, one of whom also had a suboccipital craniotomy with partial cerebellar resection).
(1; 4%). Patients were treated with antibiotics at meningitic doses on the day of admission except for case 2 and case 6, who were treated at day 2 and 4 after admission, respectively. Microbiology investigations revealed a bacterial pathogen in 20 (91%) cases (Table). Cases 11 and 16 had negative cultures. Case 11 had CSF with 137 white blood cells and 1 red blood cell, a low glucose, and increased level of protein (1.43 g/L). Case 16 had a traumatic lumbar puncture, with 205 white cells (92% neutrophils), 30 964 red cells, glucose 2.7 mmol/L, and protein 0.74 g/L. Hematologic laboratory values within 24 hours of the first documented or suspected acute ischemic event were available for 18 of 22 cases (82%). Investigations of underlying prothrombotic risk outside of the acute period were incomplete in all cases; however, prothrombotic screening results were normal in the 12 cases (55%) who had >3 prothrombotic measures.
ATT Early ATT (started after the first ischemic event and before recurrence) for secondary stroke prevention was initiated in 8 cases (36%) via the use of ASA in 6 cases (median dose 3.9 mg/kg/day, range 2.9-6.7 mg/kg/day) and unfractionated heparin infusions in 2 cases (Figure 1). A single case (case 7) with TB meningitis was started early on ASA (3.1 mg/kg/day) before the occurrence of stroke.
Neurologic Complications A neurologic deterioration suggestive of acute brain injury that was confirmed by neuroimaging occurred at a median of 4 days from initial infectious symptoms and 12 hours from initiation of antibiotic coverage. The changes in clinical status associated with neuroimaging documentation of stroke were: decreased level of consciousness (17; 77%), focal seizure (9; 40%), generalized seizure (6; 27%), focal neurologic deficit (5; 23%), and abnormal behavior (5; 23%). Locations of ischemic stroke were noted to be bilateral, deep and/or cortical, and involving multiple vascular territories (Table). All cases showed leptomeningeal enhance-
Recurrence New clinical events with confirmed imaging findings for further ischemic injury occurred at a median of 2 days (range, 1-15 days) from the initial stroke. Representative images of single and multiple recurrent arterial ischemic strokes are shown in Figure 2. Serial imaging of the 8 early treated cases showed no further ischemic injuries in 2 of 2 (100%) receiving early heparin therapy and 3 of 6 (50%) cases receiving early ASA after the initial stroke. Of the 3 early ASA failures, 2 had a single stroke recurrence and one had 2 recurrences. After the recurrences, 2 patients were started on heparin and had no
Figure 1. ATT treatment groups. Either heparin or aspirin was started prior to a stroke recurrence in 8 patients; ATT was started in 5 of 8 patients after they had stroke recurrence(s). No patients had a stroke recurrence once heparin was begun, but 4 of 10 patients treated with aspirin did have recurrences. 4
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Figure 2. Representative case of stroke recurrence. Case 6: A, DWI from initial MRI showed small right basal ganglia infarct. B, DWI from MRI at day 3 showed recurrent infarcts in left basal ganglia and thalamus. C, Fluid-attenuated inversion recovery image from MRI at day 14 showed new infarction involving the left caudate head. DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging.
further strokes (Figure 1). Unfractionated heparin that was started in the 4 cases was continued for a median of 6.5 days (range, 3-13 days) and converted to LMWH in 2 cases. Of the 14 of 22 cases (64%) who did not receive ATT after the initial stroke, 8 (57%) had another stroke. Late (after the second ischemic event) ATT was begun in 5 of 8 cases, ie, heparin in 1 case (case 5) and ASA in 4 cases (median dose 3.3 mg/kg/day, range 1.7-5 mg/kg/day). Seven of these 8 cases had no further recurrences. Case 6 had 2 further recurrences (despite the ASA dose being increased from 1.7 to 5 mg/kg/day). Subsequently, the patient was given heparin and had no subsequent episodes of stroke (Figure 1). Nine cases (38%) received glucocorticoid therapy during their acute management: for TB meningitis in 2 cases, for increased intracranial pressure in 2 cases, and for severe systemic illness in 5. Of these, 6 cases had stroke recurrences while on the glucocorticoids, and of the 2 cases who had no recurrences, one was already receiving LMWH and the other was begun on corticosteroids on the same day as a stroke recurrence. Outcome ATT did not cause cerebral hemorrhage in any of the treated patients whether received after the initial stroke or after recurrence (Table). The duration of follow-up in nondeceased cases was a median of 4 years (range, 16 months to 8.5 years). The PSOM score for each case is shown in Figure 3. Two of the 3 cases who were not given ATT after recurrence severely deteriorated (one with a further acute infarct recurrence), leading to brain death. In the 8 cases treated with LMWH, therapy was continued for a median of 3.5 months (range, 2 weeks to 8 months). Two of these cases (cases 7 and 9) were subsequently started on low-dose ASA as life-long therapy. In cases receiving ASA during the acute admission, the duration of ASA therapy was continued until at least discharge from hospital in all 10 cases
but, beyond this, medical records were not clear on when ASA was stopped in 7 of 10 cases who received ASA acutely; some records suggested life-long therapy.
Discussion This study reports the use of ATT for the management of childhood stroke in complicated bacterial meningitis. Our results show that children with bacterial meningitis, particularly those with TB meningitis, are at high risk of stroke recurrence (50%), and ATT appears to be safe in this small sample and may reduce stroke recurrence risk, therefore improving outcome in this population. The basic principles of Virchow’s prothrombotic triad of endothelial wall injury, hypercoagulability, and blood stasis/turbulence are met in bacterial meningitis. The vascular wall injury caused by secondary vasculitis is part of the inflammatory state that also manifests in cerebritis, inflammatory exudates, and meningeal enhancement. Turbulent flow through small- and medium-sized cerebral vessels as a result of vasculitis and/or external compression by basal exudates is believed to contribute to the etiology of cerebral infarctions.8 In our series and other cohorts, cerebral infarction occurs acutely but in some adult cohorts the cerebrovascular disease presented late, supporting the role of reactive vasculitic process such as seen in varicella zoster virus infections.9,10 Reactive vasospasm may contribute to the small- and medium-sized vessel stenosis that can be seen in vivo by conventional cerebral angiography but then is not proved to be vasculitic on the rare autopsy specimen.10,11 The functional consequence of this vessel narrowing associated with stroke is documented through decreased cerebral blood flow measured by transcranial Doppler ultrasound in bacterial meningitis.12 Bacterial pathogens vary in their virulence and predilection for causing stroke. During the period for which
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Figure 3. Neurologic outcome at last follow-up. PSOM score and final ATT received are shown for each case. Median follow-up time was 4 years (range, 16 months to 8.5 years). Striped bars are patients who had recurrence but did not receive any ATT.
microbiology data were available, we calculated an incidence of stroke in CSF-culture–positive meningitis at one of the sites of this study (HSC) to be 6.3%. We found a high incidence of 24% occurrence of stroke in children with pneumococcal meningitis, which is comparable with a likely baseline greater stroke risk in adult cohorts with pneumococcal meningitis (36%).3 Of the strokes in children documented in the Canadian Pediatric Ischemis Stroke Registry during the study period, 6.6% were associated with a clinical diagnosis of bacterial meningitis. In our study population, there was a disproportionate number of S pneumonia and Mycobacterium tuberculosis–associated with stroke cases compared with available national surveillance figures for meningitis hospitalizations, although these latter figures are for all age groups.13 However, these 2 pathogens have been well established as causing cerebral infarctions, compared with other pathogens. Heparin has been postulated as a possible therapy for preventing stroke morbidity in meningitis, but the only study we found was in 1977 from Nigeria, in which 15 people were included.14 This study lacked neuroimaging, and the heparin-treated group had multiple pretreatment stroke recurrences compared with our study group. The authors found heparin to be ineffective most likely because of the 6
extensive brain injury that already had occurred before the initiation of ATT. In our study, ATT was not associated with stroke recurrence in two-thirds of treated cases. The recurrence risk without initiation of ATT was 50% (11 of 22). Heparin seemed to be more effective at preventing recurrence (0 of 6 recurrence rate) than ASA (4 of 10 recurrence rate). The antithrombotic benefit of heparin over ASA possibly is related to its inhibitory effect on fibrin clot formation, which is enhanced through the acquired hypercoagulable state associated with bacterial meningitis.15 Studies of CSF have shown greater procoagulants and attenuated fibrinolysis in cases of bacterial meningitis.16 Greater systemic coagulation activity also is seen in bacterial meningitis.17 Although extensive coagulopathy evaluation was not complete in most cases, none of our patients had evidence of a predisposing coagulation disorder. The efficacy of heparin in preventing stroke recurrence associated with meningitis also may be attributed to its anti-inflammatory effect. Heparin as an anti-inflammatory agent has been studied in vitro and in clinical trials, such as in asthma and inhalation burns.18-20 Heparin is believed to be an effective anti-inflammatory treatment for sepsis.21 Boelman et al
- 2014 However, the mechanism of the anti-inflammatory action of heparin is not well understood.22 The antithrombotic efficacy of ASA seemed to be less than that of heparin in our study. ASA acts through inhibition of platelet-derived thromboxane.23 Our ASA efficacy findings agree with 2 recent studies of ASA use in preventing stroke in cases with TB meningitis. Schoeman et al24 tested both low- and high-dose ASA (75 mg as a total dose/once daily and 100 mg/kg/day divided into 3 doses, respectively) given as primary stroke prevention in a placebo-controlled, double-blinded trial of 146 children. They found no difference among the 3 groups with respect to stroke occurrence or neurologic outcome. In a second study, investigators treated adults with ASA and found a reduction in stroke risk that did not reach significance, but did show a significant improvement in mortality.25 In our three cases with TB meningitis, we similarly found ASA to be ineffective in preventing stroke. In meningitis, glucocorticoid (usually dexamethasone) has been the focus of research on improving outcomes through controlling inflammation. Dexamethasone is the most established in treatment of H. influenza and TB and considered in S. pneumoniae meningitis.26-28 In a large prospective national cohort study of dexamethasone treatment in 700 adults with pneumococcal meningitis, investigators found a significant improvement in mortality and morbidity in the treated group.29 However, both dexamethasone and nondexamethasone treatment groups had similar occurrences of “focal neurologic deficits” (11%), likely representing strokes. In another trial, cases with TB meningitis treated with dexamethasone and ASA had a better outcome than those treated with dexamethasone alone, but the efficiency in stroke prevention was not different between the 2 groups.25 Two of the 3 cases in our study with TB meningitis cases were treated with corticosteroids but both continued to have recurrent strokes until heparin treatment was commenced. A study on the efficacy of combining dexamethasone and heparin for stroke prevention in this patient population is warranted. In a study of 87 adult cases of pneumococcal meningitis, 22% of patients were found to have infarctions, whereas only 9% had an intracranial hemorrhage (ICH).30 This finding is consistent with our study, with only 2 children, both not treated with ATT, having ICH. Of note, 2 children who died as a result of severe brain injury did not have an ICH. Indeed, the risk of ischemic infarction is much higher than hemorrhagic infarction. Heparin appeared to be safe in our patients with respect to ICH. There were no hemorrhagic complications in cases while receiving heparin, including 3 patients with previous neurosurgical intervention and 2 of these having previous ICH. One of these latter cases, while receiving ASA, had a frontal epidural hemorrhage directly related to the EVD placement site. We were not able to identify whether heparin was held during the single neurosurgical procedure in a case already receiving heparin though this would be routine practice. The PSOM quantifies disability such that a score of 2 or greater indicates significant neurologic disability. The me-
ORIGINAL ARTICLES dian score for all the groups together was 1, reflecting moderate overall disability. However, this median score does not include the 2 deaths in the untreated group. It is difficult to draw comparisons among the groups because of the small number of patients in each group. The trend suggests that earlier heparin treatment (prerecurrence) was associated with better outcomes, with patients receiving heparin having better outcomes than those on ASA. Both treatment groups (heparin or ASA) had better outcomes than the untreated patients with recurrence. There are limitations in this study. The first is that the work is retrospective and thus patients were selected by clinicians for the ATT treatments. However in contrast, we did not observe increased strokes in the heparin-treated group. Another potential decrease or increase in bias was possible as cases case from 2 different centers, representing a greater spectrum of meningitis management, or with one center (HSC) used ATT in non-TB cases and the other (BCCH) did not. Another limitation is that serial imaging was not standardized and thus the frequency of recurrent strokes may have been under estimated. Also this limitation made it difficult to account for infarction size that may contribute to the worse outcome in the untreated group. A multicenter, prospective study is needed to better understand the frequency, timing, and mechanisms of stroke in meningitis. Ideally, a clinical trial comparing heparin with other treatments in a randomized controlled study is needed to provide stronger levels of evidence for management of this very serious complication of a childhood infection. Given the global burden of bacterial meningitis, it is important to find improved methods of treatment. n The authors thank Ann-Marie Pontigon, Lauren Kielstra, Julia O’Mahony, Regina Cerys Starkey and Elisa Wilson of the Hospital for Sick Children Stroke Program for their technical assistance. Submitted for publication Dec 12, 2013; last revision received Apr 9, 2014; accepted Jun 5, 2014. Reprint requests: Rand Askalan, PhD, MD, Division of Neurology, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail: [email protected]
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