reported by physicians with negative CSF cultures could also beincluded if CSF results showed at least one individual predictor ofbacterial meningitis (defined as a glucose level of less than 34 mg/dL [1.9 mmol/L], a ratio of CSF glucose to blood glucose of lessthan 0.23, a protein level of more than 220 mg/dL, or a leukocytecount of more than 2,000/mL)13and the clinical presentation wascompatible with bacterial meningitis. Patients were consideredimmunocompromised if they used immunosuppressive drugs orhad a history of splenectomy, diabetes mellitus, alcoholism, cancer,or HIV infection. Patients with hospital-associated meningitis(defined as meningitis that occurred during hospitalization orwithin 1 week of discharge) including neurosurgery patients,and patients with a neurosurgical device, or neurotrauma within1 month of the onset of meningitis were excluded.Case-record forms were used to collect data on patient history,symptoms and signs on admission, clinical course, and outcome.Treatment information regarding antimicrobial treatment and(neuro)surgical interventions was collected. At discharge, all patientsunderwent neurologic examination performed by a neurologist, andthe outcome was graded according to the Glasgow Outcome Scale.The Glasgow Outcome Scale is a well-validated instrument withgood interobserver agreement.14A favorable outcome was definedas a score of 5, and an unfavorable outcome as a score of 1–4.Patients were classified as having subdural empyema if reportedby the treating physician and cranial imaging showed a crescent- orellipse-shaped fluid collection in the subdural space. We chose toclassify all subdural fluid collections as empyemas, as subdural effu-sion is a sterile fluid collection, mostly found in chronic disease.15The differentiation between subdural empyema and effusion isdifficult even with contrast-enhanced CT or MRI, and thereforeone can also read “subdural empyema or effusion” when we use“subdural empyema.” Cranial radiologic imaging was collected andindependently re-evaluated by 2 investigators (K.K.J., M.C.B.).Midline shift was measured, and the volume of the empyema wascalculated using the ABC/2 method.16To check for underreportingby physicians, we evaluated 150 consecutive patients who under-went cranial imaging in whom subdural empyema was not reported.None of these patients had subdural empyema.The Mann-Whitney U test was used to identify differencesbetween episodes with and without subdural empyema with respectto continuous variables, and dichotomous variables were comparedwith use of the x2test. Pearson correlation test was used to identifycorrelations between continuous variables. All tests were 2-tailedand a p value ,0.05 was considered significant. Statistical analyseswere performed with use of IBM SPSS Statistics, version 19.0.0.Standard protocol approvals, registrations, and patient consents.The study was approved by the ethics committee of the Academic Med-ical Center, Amsterdam.RESULTS From March 2006 to November 2011, weincluded 1,034 patients with bacterial meningitis. Atotal of 678 (66%) episodes were caused by S pneumo-niae, 107 (10%) by N meningitidis, and 165 (16%) byother bacteria. A total of 79 patients had negative CSFcultures but at least one individual CSF marker of bac-terial meningitis. Subdural empyema was diagnosed in28 of 1,034 episodes of bacterial meningitis (2.7%)and in 3.1% of 916 patients in whom cranial imagingwas performed. Subdural empyema was present onadmission in 10 patients (38%). In the remaining18 patients (64%) the empyema was detected dur-ing hospitalization with a median time to detectionof 5 days after admission (range 2–38 days).The mean age at diagnosis was 58 years (range,25–81; table 1). Predisposing conditions for bacterialTable 1 Clinical and laboratory features in 28adult bacterial meningitis patients withsubdural empyemasaClinical characteristics ValuesMean age, y (SD) 58 (14)Male 19/28 (68)Predisposing conditions 26/28 (93)Otitis or sinusitis 21/28 (75)Pneumonia 3/28 (11)Immunocompromised stateb8/28 (29)Symptoms and signs on admissionDuration of symptoms >24 h 18/28 (64)Headache 23/27 (85)Nausea 10/26 (38)Neck stiffness 20/28 (71)Seizures 2/27 (7)Temperature ‡ 38°C 22/28 (79)Score on Glasgow Coma Scale (GCS) 10 (8–12)GCS score <14 indicating alteredmental status23/28 (82)GCS score <8 indicating coma 6/28 (21)Focal neurologic deficits 11/28 (39)Aphasia 4/14 (29)Ataxia 1/11 (9)Paresis 7/28 (25)Cranial nerve palsyc3/26 (12)CSF valuesdLeukocyte count, cells/mm32,133 (415–4,665)Protein, g/L 3.1 (1.6–5.7)CSF-blood glucose ratio 0.04 (0.00–0.29)Microbiologic findingsPositive CSF Gram staine22/24 (92)Positive blood culture 20/24 (83)CSF cultureStreptococcus pneumoniae 26/28 (93)Streptococcus pyogenes 1/28 (4)Negative 1/28 (4)aData are number/number evaluated (%) and continuous valuesare median (interquartile range) unless otherwise stated.bImmunocompromise was defined as the use of immuno-suppressive drugs or a history of splenectomy, diabetesmellitus, alcoholism, cancer, or HIV infection.cOculomotor nerve in 2 patients, abducens and facial nervein 1 patient each.dCSF leukocyte count was determined in 28 patients, CSF-blood glucose ratio in 27 patients, and CSF protein con-centration in 26 patients.eGram-positive cocci in 21 (88%) and Gram-negative rodsin 1 (4%).2134 Neurology 79 November 20, 2012ª 2012 American Academy of Neurology. 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meningitis were present in 26 of 28 patients (93%)and consisted of otitis, sinusitis, pneumonia, or animmunocompromised state. Of the patients with pre-disposing conditions, 21 had otitis or sinusitis (75%).On admission, 23 patients (82%) had an altered men-tal status (defined by a score on the Glasgow ComaScale below 14) and 6 patients (21%) were comatose(Glasgow Coma Scale score ,8). Focal neurologic def-icits were present on admission in 11 (39%) patients.The classic meningitis triad of neck stiffness, fever, andaltered mental status was present in 13 patients (46%).Of the 10 patients diagnosed with subdural empyemaon admission, 7 (70%) had a subacute presentationwith symptoms for more than 24 hours. Focal neuro-logic abnormalities were present in 6 of these 10 patients(60%). Twenty-five patients (89%) presented with neu-rologic symptoms (paresis, focal seizures, dysesthesia) onthe contralateral side of the empyema or effusion.Patients with subdural empyema were more likely tohave predisposing conditions on admission (93% vs54%; p , 0.001; table 2), especially otitis or sinusitis(75% vs 31%; p , 0.001), than patients withoutsubdural empyema. Furthermore, they were more likelyto present with a paresis on admission (25% vs 9%;p 5 0.007) than patients without subdural empyema.Lumbar puncture was performed on admission inall patients. At least one individual CSF finding pre-dictive of bacterial meningitis (a glucose level of lessthan 34 mg/dL [1.9 mmol/L], a ratio of CSF glucoseto blood glucose of less than 0.23, a protein level ofmore than 220 mg/dL, or a leukocyte count of morethan 2,000/mm3) was present in all patients withsubdural empyema. Eleven patients deteriorated clin-ically within 8 hours of initial lumbar puncture, buttranstentorial cerebral herniation with pupil dilationand abnormal posturing was not observed. The dete-rioration consisted of (increase in) hemiparesis in 6patients, respiratory failure in 4, and seizures in 4.Cranial imaging was repeated following deteriorationin 10 of 11 patients and did not show radiologic signsof transtentorial cerebral herniation. Gram staining ofCSF was done in 24 patients (86%) and showed pres-ence of bacteria in 22 patients (92%). CSF culturesshowed S pneumoniae in 26 patients, Streptococcuspyogenes in 1 patient, and 1 patient had a negativeCSF culture. The incidence of subdural empyemain patients with pneumococcal meningitis presentingwith otitis or sinusitis was 17 of 224 (8%). Patientswith subdural empyema were more likely to haveS pneumoniae as the causative microorganism com-pared to patients without empyema (93% vs 65%;p 5 0.002). Conversely, patients with pneumococcalmeningitis are more likely to have subdural empyemathan patients with meningitis due to another micro-organism (3.8% vs 0.6%, p , 0.001).The subdural empyema was located at the left con-vexity in 12 patients, right convexity in 14 patients,and bilateral in 2 patients (figures 1 and 2). Cranialimaging was available for re-evaluation in 25 of 28patients. The median volume of the subdural empy-ema was 16.7 mL (range 1.6–129 mL). The subduralempyema caused a mass effect in 21 of 25 patients(84%), resulting in midline shift in 19 patients (76%).Median midline shift measured 3.0 mm (range 1.0–10.7mm), and midline shift over 4 mm occurred more oftenin patients under 60 years (p 5 0.016). The degree ofmidline shift was strongly correlated to the volume of theempyema (coefficient 0.533, p 5 0.02). Cranial MRIwas performed in 7 patients and included diffusion-weighted imaging (DWI) and apparent diffusion coeffi-cient (ADC) imaging in 4. On all these 4 MRIs thesubdural fluid collection showed a DWI hyperintenseand ADC hypointense signal (figure 2). This pattern istypical for subdural empyema, in contrast to subduraleffusions, which are hypointense on DWI.17Other abnormalities on cranial imaging were sinus-itis or mastoiditis in 23 patients (82%), generalizedcerebral edema in 8 patients (28%), and cerebral abscessand infarction each in 2 patients (7%). Meningioma,sinus thrombosis, hydrocephalus, and intracerebralhemorrhage were each identified in 1 patient (3%). Inall 21 patients with mastoiditis the subdural empyemadeveloped on the same side.Initial antimicrobial treatment consisted of a combi-nation of amoxicillin/penicillin and third-generationcephalosporins for 9 patients (32%), monotherapyTable 2 Clinical and laboratory features in adults with and without subduralempyema among 1,034 episodes of bacterial meningitisaCharacteristicEpisodes withsubduralempyema (n 5 28)Episodes withoutsubduralempyema (n 5 1,006) p ValueAge, y, mean (SD) 58 (14) 57 (18) 0.836Predisposing conditions 26/28 (93) 548/1,006 (55) ,0.001Otitis or sinusitis 21/28 (75) 314/1,005 (31) ,0.001Symptoms and signs onadmissionHeadache 23/27 (85) 734/877 (84) 0.836Focal neurologic deficits 11/28 (39) 283/1,006 (28) 0.197Paresis 7/28 (25) 87/921 (9) 0.007Neurologic complicationsFocal neurologicabnormalities15/28 (54) 189/930 (20) ,0.001Seizures 14/28 (50) 100/1,003 (10) ,0.001Hearing impairment 11/28 (39) 193/840 (23) 0.045Causative organismStreptococcus pneumoniae 26/28 (93) 652/1,006 (65) 0.002OutcomeUnfavorable outcome 19/28 (68) 383/1,003 (38) ,0.001aData are number/number evaluated (%).Neurology 79 November 20, 2012 2135ª 2012 American Academy of Neurology. 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penicillin or amoxicillin in 10 patients (36%), mono-therapy with a third-generation cephalosporin in 7patients (25%), and monotherapy carbapenem and acombination of penicillin and carbapenem each in1 patient (4%). All patients received microbiologicallyadequate initial antimicrobial therapy. The medianduration of antimicrobial treatment in survivingpatients was 17 days (range 11–62). The durationof treatment was not associated with the size of theempyema, with the causative microorganism, or withwhether neurosurgical removal of the empyema wasperformed. None of the patients had a relapse ofsymptoms after discontinuation of antimicrobial ther-apy. Adjunctive steroids were administered in 25 pa-tients (89%). Dexamethasone, given 10 mg every 6hours for 4 days started before or with the first dose ofantibiotics, was given in 24 patients (86%).Nine patients underwent surgical treatment: cra-niectomy for evacuation of subdural empyema in 5patients, mastoidectomy in 4 patients, paracentesisin 3, and 1 patient required an external ventriculardrain for treatment of a hydrocephalus. All 5 patientswho underwent craniectomy survived, of whom 3had neurologic sequelae at discharge. The perfor-mance of craniectomy was associated with the degreeof midline shift (p 5 0.01), but not with the volumeof the empyema (p 5 0.41).Complications developed during clinical course in27 of 28 patients (96%; table 3). Neurologic compli-cations occurred in all 27 and systemic complicationsin 11. Focal neurologic abnormalities developed in 15patients (54%), seizures in 14 (50%), and hearingimpairment in 11 (39%). In 10 of 11 episodes (91%)that were complicated by hearing impairment, otitis wasFigure 1 CTs of empyema complicating bacterial meningitisAxial CT of patient with bacterial meningitis with bilateral subdural empyema (A), temporal subdural empyema (B), frontalsubdural empyema adjacent to intracerebral abscess causing brain shift (C), and parafalcine subdural empyema (D).2136 Neurology 79 November 20, 2012ª 2012 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
diagnosed on admission. Five patients died (18%) and19 had an unfavorable outcome (68%; table 3). A high-er rate of unfavorable outcome was observed in patientswith subdural empyema compared to patients withmeningitis without subdural fluid collection (68% vs38%; p , 0.001). Thirteen of 23 survivors had neu-rologic sequelae on discharge (57%).DISCUSSION Our study shows that subdural empy-ema complicates 2.7% of adult cases of community-acquired bacterial meningitis but is associated with ahigh rate of unfavorable outcome (68%). Subdural fluidcollection has been reported previously to occur in 1%–3.4%.3,4,18Important clues for the diagnosis of empyemawere otitis or sinusitis, focal neurologic deficits, or epi-leptic seizures. For patients with meningitis who developneurologic complications during admission, cranialimaging to detect subdural empyema is indicated.3,19MRI with DWI remains the preferred imaging modalityfor detecting subdural empyema. DWI and diffusion onthe ADC map have proven to be valuable in evaluationof intracranial pyogenic processes (abscess and empy-ema). Furthermore, DWI can distinguish subduralempyema from reactive subdural effusion.17The incidence of subdural empyema in patients withpneumococcal meningitis presenting with otitis washigh (8%). In all patients with otitis or sinusitis the bac-teria spread from the mastoid or sinus to the adjacentsubdural space causing the subdural empyema. Becauseof the increased risk of empyema in patients with otitisor sinusitis, consultation of an ear, nose, and throatspecialist is warranted early during clinical course inall patients with bacterial meningitis.Only a minority of patients underwent neurosurgicalevacuation of the empyema. In our series, midline shiftwas associated with the decision to evacuate the empy-ema and increased shift was associated with youngerage rather than thickness or volume of the empyema.Figure 2 MRIs of empyema complicating bacterial meningitisAxial (A) and sagittal (B) T1-weighted gadolinium-enhanced MRI of patients with parafalcine subdural empyema (arrows/as-terisks), and diffusion-weighted (C) and apparent diffusion coefficient (D)–weighted MRI of a subdural empyema over the leftconvexity (arrows).Neurology 79 November 20, 2012 2137ª 2012 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
This may well be explained by age-related cerebral atro-phy. In our study, all 5 patients with subdural empyemawho underwent craniectomy survived, albeit with neu-rologic sequelae at discharge in 3 of them. Nevertheless,neurosurgical intervention should be regarded as first-choice therapy in patients with empyema causingmidline shift and focal neurologic abnormalities ora decreased level of consciousness.A substantial number of patients deteriorated inthe first 8 hours after lumbar puncture, developingseizures, respiratory failure, and hemiparesis contra-lateral to the empyema. These symptoms may be ex-plained by local expansion of the empyema but couldalso be the result of brain shift following the lumbarpuncture, although no transtentorial cerebral hernia-tion was observed on cranial imaging. Patients withsubdural empyema should be carefully monitored fol-lowing lumbar puncture, as the empyema couldexpand and cause brain shift.In our study, the median duration of antimicrobialtreatment in surviving patients was only 17 days, andwas not associated with the size of the empyema, mid-line shift, or whether the empyema was neurosurgi-cally evacuated. The optimal duration of antimicrobialtreatment for patients with subdural empyema or effu-sion has not been established in trials or comparativestudies, but general recommendations are to treat pa-tients with empyema for 3–4 weeks if an empyemahas been evacuated, and even longer if the patient isconservatively treated.20This indicates that subduralempyemas do not trigger Dutch physicians to prolongantimicrobial treatment, but also that relatively shortcourses of antibiotics do not result in microbiologic treat-ment failures in these patients.Our study has several important limitations. First,cranial imaging was not performed in all patients inthe cohort and cases of subdural fluid collectionmight have been missed. This could have led to anunderestimation of the incidence of subdural empy-ema or effusion. Furthermore, subdural empyemasthat remain subclinical may go undetected, whichmay lead to an overestimation of the severity of thedisorder in our study. Asymptomatic subdural collec-tions may resolve without neurosurgical intervention.Second, culture-negative patients are underrepresentedin our study. Negative CSF cultures occur in 11%–30% of patients with bacterial meningitis.1,2,4Thesepatients were only included if the treating physiciancontacted the investigators, which occurred in 11% ofthe episodes.21Third, the diagnosis subdural effusionor subdural empyema was classified by the treatingphysician, and therefore it is unclear if the differenti-ation between subdural empyema and subdural effusionalways occurred in a similar fashion. To differentiatebetween subdural empyema and subdural effusioncontrast-enhanced cranial imaging is necessary. Somepatients did not undergo contrast-enhanced cranialimaging, and therefore the differentiation betweenempyema and effusion may not have been accurate inall cases.Although rare, subdural empyema must be consid-ered in patients with community-acquired bacterialmeningitis and otitis or sinusitis, focal neurologic def-icits, or epileptic seizures. S pneumoniae is the pre-dominant causative organism and patients are at highrisk of developing seizures and unfavorable outcome(68%). Therefore, early diagnosis of empyema is nec-essary and neurosurgical intervention should be regardedas first-choice therapy in patients with empyema causingmidline shift and focal neurologic abnormalities or adecreased level of consciousness.AUTHOR CONTRIBUTIONSKin K. Jim, Matthijs Brouwer, and Diederik van de Beek performed the dataanalyses and wrote the manuscript. Arie van der Ende wrote the manuscript.Diederik van de Beek was the principal investigator of the study andprovided funding.Table 3 Complications and outcome in 28 adultbacterial meningitis patients withsubdural empyemaaClinical characteristics ValuesNeurologic complications 27/28 (97)Impairment of consciousness 19/28 (68)Focal neurologic deficits 15/28 (54)Hearing impairment 11/28 (39)Seizures 14/28 (50)Cerebrovascular complicationsb4/28 (14)Cerebral abscess 2/28 (7)Hydrocephalus 1/28 (4)Systemic complications 13/28 (46)Pneumonia 4/28 (14)Respiratory failure 7/28 (25)Otherc4/28 (15)Glasgow Outcome Scale1) Death 5 (17)2) Vegetative state 03) Severe disability 1 (3)4) Moderate disability 13 (46)5) Complete recovery 9 (32)Neurologic sequelaed13/28 (46)aData are number/number evaluated (%).bCerebral infarction in 2, sinus thrombosis in 1, and intra-cranial hemorrhage in 1.cOsteomyelitis, hyponatremia, rhabdomyolysis, and deepvenous thrombosis of the arm each occurred in 1 patient.dHemiparesis in 9 patients, sensory change in 7 patients,cognitive impairment in 6, cranial nerve palsy in 6, ataxiaand aphasia both occurred in 1 patient.2138 Neurology 79 November 20, 2012ª 2012 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
STUDY FUNDINGD.v.d.B. is supported by grants from the Netherlands Organization forHealth Research and Development (ZonMw; NWO-Vidi grant 2010),the Academic Medical Center (AMC Fellowship 2008), and the Euro-pean Research Council (ERC Starting Grant 2011).DISCLOSUREThe authors report no disclosures relevant to the manuscript. Go toNeurology.org for full disclosures.Received April 23, 2012. Accepted in final form July 31, 2012.REFERENCES1. Brouwer MC, Tunkel AR, van de Beek D. Epidemiology,diagnosis, and antimicrobial treatment of acute bacterialmeningitis. Clin Microbiol Rev 2010;23:467–492.2. van de Beek D, de Gans J, Spanjaard L, Weisfelt M,Reitsma JB, Vermeulen M. Clinical features and prognos-tic factors in adults with bacterial meningitis. N Engl JMed 2004;351:1849–1859.3. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF.Community-acquired bacterial meningitis in adults. NEngl J Med 2006;354:44–53.4. Durand ML, Calderwood SB, Weber DJ, et al. Acutebacterial meningitis in adults: a review of 493 episodes.N Engl J Med 1993;328:21–28.5. Kastenbauer S, Pfister HW. Pneumococcal meningitis inadults: spectrum of complications and prognostic factors ina series of 87 cases. Brain 2003;126:1015–1025.6. Swartz MN, Dodge PR. Bacterial meningitis: a review ofselected aspects: 1: general clinical features, special prob-lems and unusual meningeal reaction mimicking bacterialmeningitis. N Engl J Med 1965;272:842–848.7. Kasanmoentalib ES, Brouwer MC, van der Ende A, van deBeek D. Hydrocephalus in adults with community-acquiredbacterial meningitis. Neurology 2010;75:918–923.8. Jim KK, Brouwer MC, van der Ende A, van de Beek D.Cerebral abscesses in patients with bacterial meningitis.J Infect 2012;64:236–238.9. Weisfelt M, de Gans J, van der Poll T, van de Beek D.Pneumococcal meningitis in adults: new approaches tomanagement and prevention. Lancet Neurol 2006;5:332–342.10. Pfister HW, Feiden W, Einhaupl KM. Spectrum of com-plications during bacterial meningitis in adults. Results of aprospective clinical study. Arch Neurol 1993;50:575–581.11. Statistics Netherlands. Available at: http://www.cbs.nl. Ac-cessed June 13, 2011.12. van der Ende A, Spanjaard L. Bacterial meningitis in theNetherlands: annual report 2009. Available at: http://www.amc.nl/upload/teksten/medical%20microbiology/nrlbm%20jv/jv2009site.pdf. Accessed June 13, 2011.13. Spanos A, Harrell FE Jr, Durack DT. Differential diagno-sis of acute meningitis: an analysis of the predictive valueof initial observations. JAMA 1989;262:2700–2707.14. Jennett B, Teasdale G. Management of Head Injuries, 2nded. Philadelphia: F.A. Davis; 1981.15. Hughes DC, Raghavan A, Mordekar SR, Griffiths PD,Connolly DJ. Role of imaging in the diagnosis of acutebacterial meningitis and its complications. Postgrad Med J2010;86:478–485.16. Gebel JM, Sila CA, Sloan MA, et al. Comparison of theABC/2 estimation technique to computer-assisted volu-metric analysis of intraparenchymal and subdural hemato-mas complicating the GUSTO-1 trial. Stroke 1998;29:1799–1801.17. Wong AM, Zimmerman RA, Simon EM, Pollock AN,Bilaniuk LT. Diffusion-weighted MR imaging of subduralempyemas in children. AJNR Am J Neuroradiol 2004;25:1016–1021.18. Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, deGans J. Clinical features, complications, and outcome inadults with pneumococcal meningitis: a prospective caseseries. Lancet Neurol 2006;5:123–129.19. Dill SR, Cobbs CG, McDonald CK. Subdural empyema:analysis of 32 cases and review. Clin Infect Dis 1995;20:372–386.20. Tunkel AR. Subdural empyema, epidural abscess and sup-purative intracranial thrombophlebitis. In: Mandell GL,Bennett JE, Dolin R, eds. Principles and Practice of Infec-tious Diseases, 7th ed. Philadelphia: Churchill LivingstoneElsevier; 2010:1279–1287.21. Brouwer MC, Heckenberg SG, de Gans J, Spanjaard L,Reitsma JB, van de Beek D. Nationwide implementationof adjunctive dexamethasone therapy for pneumococcalmeningitis. Neurology 2010;75:1533–1539.Share Your Artistic Expressions in Neurology ‘Visions’AAN members are urged to submit medically or scientifically related artistic images, such as photo-graphs, photomicrographs, and paintings, to the “Visions” section of Neurology®. These images arecreative in nature, rather than the medically instructive images published in the NeuroImages sec-tion. The image or series of up to six images may be black and white or color and must fit into onepublished journal page. Accompanying description should be 100 words or less; the title should be amaximum of 96 characters including spaces and punctuation.Learn more at www.aan.com/view/Visions, or upload a Visions submission at submit.neurology.org.Neurology 79 November 20, 2012 2139ª 2012 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.