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1 INVITED REVIEW online ML Comm J Neurocrit Care 2008;1 Suppl 1:S63-S68 ISSN 세균성뇌수막염과뇌농양 서울의료원신경과 박태환 김민기 Bacterial Meningitis and Brain Abscess Tai Hwan Park, MD and Min Ky Kim, MD Department of Neurology, Seoul Medical Center, Seoul, Korea Bacterial meningitis and brain abscess are infectious disease of central nervous system (CNS) that can cause significant neurological sequelae. Despite advances in neurocritical care, these CNS infectious diseases still have a high morbidity and mortality rate, especially in certain high-risk patients. Clinicians use epidemiologic, historical, and physical examination findings to identify patients at risk for these infections, and CNS imaging and lumbar puncture may be useful to further evaluate for these diagnoses. Bacterial meningitis is a medical emergency requiring prompt recognition and evaluation and urgent institution of appropriate antibacterial therapy. The diagnosis of brain abscess can not be challenging but also delayed frequently, as both imaging findings and clinical features of which overlap with more common neurological disorders. This article reviews recent reports and highlights considerations in clinical evaluation, specific antimicrobial therapy, imaging findings, and adjunctive corticosteroids therapy. J Neurocrit Care 2008;1 Suppl 1:S63-S68 KEY WORDS: Bacterial Meningitis Abscess. 세균성뇌수막염 서론세균성뇌수막염은원인균과발생연령에따라사망률이 30% 까지이르는신경계응급질환으로빠른인지및평가와함께신속하고적절한항생제투여가요구된다. 1 환절기에주로발생하는 H. influenzae type b를제외하고대부분겨울철에많이발생하며 2 국내의년간발생률은관련통계가없지만미국의경우 16세이상연령에서 10만명당 4~6예, 3 6세미만아동에서는 10만명당 87예정도로발생한다고알려져있다. 4 영아에서는 80~90% 가 H. influenzae에의한뇌수막염이지만 2세이상에서는그비율이 25% 미만으로급격히감소하여전체적으로는 S. pneumoniae와 N. meningitidis가원인균의 80% 가량을차지한다. 3 선진국에비해개발도상국의세균성뇌수막염발생 Address for correspondence: Tai Hwan Park, MD Department of Neurology, Seoul Medical Center, Samsungdong, Gangnam-gu, Seoul , Korea Tel: , Fax: strokezero@gmail.com 률은 3~4배더높을것으로추정되며 N. meningitidis가주요한원인균으로수막알균 (meningococcal) 뇌수막염은일정한주기로유행을하고있다. 5 국내의한대학병원자료에의하면 6 15세이상뇌수막염환자중세균성뇌수막염이차지하는비율은약 20% 였으며외국에비해결핵성뇌막염이 24% 정도로높은비율을보였다. 세균성뇌수막염은발병초기에원인균을동정하여적절한항생제를투여하고발생가능한합병증에대비함으로써신경계후유증을줄이고사망률을낮출수있다. 본고찰에서는세균성뇌수막염의임상적인지및진단적접근그리고치료측면에서최근까지의관련문헌을참고하여정리해보고자한다. 임상적인지및진단세균성뇌수막염은빠른임상적진단과함께뇌척수액검사를시행할지여부를결정해야한다. 외부로부터의수상이나신경외과적시술이동반되지않은경우대부분의환자는상기도감염의증세혹은소화기계의염증에의한증상이선행된다. 성인뇌수막염의약 2/3가사회집단감염 (community acquired) 으로부터발생한다. 7 사회집단감염 Copyright c 2008 The Korean Neurocritical Care Society S63

2 J Neurocrit Care 2008;1 Suppl 1:S63-S68 TABLE 1. Empirical antibiotics for community-acquired bacterial meningitis in adults S64 성인뇌수막염환자의약 2/3는두통, 발열, 경부경직, 의식변화등의주요증상들중 3가지를보인다. 7 하지만전형적인증상인경부경직의경우에도뇌수막염에대한진단적타당도는매우낮기때문에 8 뇌척수액검사를통한확진이필요하다. 하지만요추천자를통한뇌척수액검사가뇌수막염환자에서뇌이탈 (brain herniation) 을초래하여치명적인결과를가져올수있음을고려해야한다 년대이후의보고들을살펴보면성인세균성뇌수막염환자의뇌이탈발생률은 1.8~8% 정도였으며 7,9 소아의경우는 2~3배더높게보고되었다. 10 뇌이탈은세균성뇌수막염으로인한사망원인의 30% 가량을차지한다. 11 따라서요추천자전뇌이탈의위험성을알기위해서는뇌전산화단층촬영을시행하여뇌부종의증거가있는지확인하는것이안전하다. 중간선구조물의전위나시각위교차수조 (suprachiasmatic cistern) 나기저수조 (basal cistern) 의소실, 그리고제4 뇌실의폐색또는전위등이이에해당한다. 12 Hasbun 등 13 은뇌수막염이의심되는 301 명의성인환자의뇌전산화단층촬영상 24% 에서이상소견을관찰하였고, 5% 는종괴효과를보인다고하였는데이러한영상검사상의이상소견은국소신경학적이상증상이나의식저하가있는경우와밀접한관련이있었다. 임상적으로요추천자전 30분이내에발생한경련, 유두부종, 중등도이상의의식저하, 제뇌 (decerebrate) 또는제피 (decorticate) 자세등이있으면설령전산화단층촬영소견이정상이더라도요추천자를시행하지않고경험적항생제치료를시작하는것을권유하는보고들도있다 세균성뇌수막염환자의전형적인뇌척수액은혼탁하며높은압력을보이고호중구및단백의증가와당수치의감소를나타낸다. 20 평균 50세의성인세균성뇌수막염환자 696명을전향적으로조사한연구에서 21 88% 의환자가세포수 2,000/mm 3 이상이거나평균단백농도 220 mg/dl 이상또는혈장에대한당농도비 0.23 미만을보였다. 원인균을확인하기위해서뇌척수액그람염색과배양검사는필수적인검사이다. 그람염색은비록신속하지만매우비특이적이며민감도도비교적낮다. 22 뇌척수액과혈액배양검사는보통함께시행되는데혈액배양에서 N. meningitidis는 40~50%, S. pneumoniae 또는 H. influenza는 70~90% 정도에서동정된다. 23 하지만 3세대세파로스포린계항생제가먼저투여되었을경우뇌척수액배양검사는 N. meningitidis의경우 2 시간, S. pneumoniae의경우는 6시간이지나면무균화되어 24 항생제가투여된후시행된배양검사의민감도는낮아진다. 이러한검사상의약점을극복하기위해세균항원에대한면역학적검사들이시도되었는데 latex agglutination test (LAT) 와 polymerase chain reaction(pcr) 이대표적인방법이다. LAT는빠른원인균동정과선행하는항생제치료에영향을받지않는장점은있지만고비용등의문제로널리이용되지못하고있다. 25 최근 rrna-pcr 방법이 95% 이상의민감도와특이도를가진다는연구가있었지만대부분이 S. pneumoniae에의한뇌수막염이었다. 26 치료세균성뇌수막염에서항생제투여가지연되면나쁜예후가초래될수있다. 최근연구에의하면응급실도착후항생제투여시작까지 6시간이상걸릴경우사망률이 8 배가량올라가는것이관찰되었다. 27 또다른연구에서는응급실에서치료전상태의점진적악화가관찰되는경우나쁜치료결과의위험성을올린다고보고하였다. 28 따라서가능한뇌척수액검사와영상검사로인한치료시작지연을최소화할필요가있으며임상적인선행진단이이루어졌다면영상검사전또는요추천자직후바로항생제투여를시작하는것이좋다. 균동정이전에투여하는항생제의선택은환자의나이와동반한임상적상황등을고려하여선택하고균동정및항생제감수성결과가나온후약제의조절이필요하다 (Table 1). Penicillin- 저항성폐렴알균의확산으로인해 vancomycin 과 3세대 cephalosporin 의병용투여가첫표준치료로권유된다. 29 수막알균뇌수막염환자와접촉한가족및의료인은나이에따라 rifampin이나 ceftriaxone 치료가권유되나발병후 2주가지난후에는약물투여로인한이득은거의없다. 30 소아환자에서청력소실합병증을감소시키는비교적확실한효과와달리성인환자에서스테로이드투여의효 Predisposing factor Common bacterial pathogen Antibiotics Age years N. meningitidis, S. pneumoniae Vancomycin plus cefotaxime or ceftriaxone >50 years S. pneumoniae, N. meningitides, Listeria monocytogens, aerobic G(-) bacilli Vancomycin plus cefotaxime or ceftriaxone plus ampicillin Immunosuppressed S. pneumoniae, L monocytogens, H influenzae Vancomycin plus cefotaxime or ceftriaxone plus ampicillin van de Beek, et al. N Engl J Med 2006;354:44-53

3 Bacterial Meningitis and Brain Abscess TH Park, et al. 과에대해서는논란의여지가있어왔다. 31,32 하지만동물연구에서거미막하공간의염증반응을감소시킨것이사람에서의치료효과를기대하는배경이되어왔다. 33 가장최근인 2007년도 Cochrane Review에서 18개의무작위대조군연구로부터 2,750 명의환자를분석하였다. 34 대부분 dexamethasone을첫 3~4일간 0.6~0.8 mg/kg/d 사용한연구들이었는데소아에서청력소실의의미있는감소뿐아니라성인에서도사망을의미있게감소시켰으며 (RR 0.57, 95% CI ), 신경학적장애도감소시키는 (RR 0.42, 95% CI ) 것으로나왔다. 특히폐렴알균뇌수막염의사망률감소와 H. influenzae로인한소아의청력소실감소에두드러진효과를보이는것으로조사되었다. 따라서세균성뇌수막염에서스테로이드치료는효과가있는것으로볼수있으나아직표준적인용량및치료시작시기와기간에대해서는확정된것은없다. 다만대부분의치료가성인에서 3~4일간치료를하였으며투여시점에있어서는가급적첫항생제투여전혹은동시투여가나중에투여된것보다유익하다는결론을내리고있다. 35,36 그외의일반적인치료들로는뇌이탈의위험이있는환자에서두개내압의모니터링및삼투압이뇨제의투여가필요하며의식저하나경련등국소신경학적이상이발생한경우영상검사를통해수두증및경막하축농, 뇌농양여부를확인해야한다. 환자의약 30% 에서저나트륨혈증이발생하는데의식저하의원인이될수있다. 반복적인뇌척수액검사는적절한항생제투여후 48시간이지나도임상적호전이없거나 penicillin-저항성폐렴알균뇌수막염그리고 vancomycin 과스테로이드를함께투여받은경우에필요하며통상적절한항생제투여후 24시간이경과하면그람염색이나배양검사는음성이된다. 1 세균성뇌수막염은예상보다빠르게진행하고악화될수있기때문에치료전에나쁜예후를예측하는것이치료방침결정에도움이될수있다. 696명의 16세이상세균성뇌수막염환자를대상으로한전향적연구에서내원시뇌척수액백혈구수치가 1,000/mm 3 미만, 의식저하, 폐렴알균감염, 고령, 빈맥 (>120/ 분 ), 그리고뇌신경마비등이일상생활로복귀가불가능한예후를시사하는예측인자들로조사되었다. 21,37 끝으로세균성뇌수막염의새로운진단및치료제의개발도중요하지만 H. influenza와페렴알균백신의임상적유용성에서밝혀졌듯이 38,39 뇌수막염의발생을막기위한예방적백신의개발및보급이지속적으로이루어져야할것이다. 뇌농양 서론뇌영상검사기술의발전과새로운항생제의개발, 그리고수술적처치의발달등으로인해뇌농양으로인한후유증및사망률은많이감소하고있다. 하지만적은빈도로인해흔히접할수없다는점과더불어늦어지는진단의문제는가능한빠른치료가필요한중추신경계감염성질환으로써뇌농양의임상양상에대해서임상의사들이익숙할필요가있다. 본고찰에서는뇌농양을유발하는흔한상황들및감별진단과치료의순서로정리해보고자한다. 임상적인지및진단뇌농양은감염원에따라구개내농양이나부비동농양등인접부위감염이거나심장판막질환이나폐질환으로부터의혈행전파이거나또는사고나수술에의해직접적인전파의경우로나눌수있다 (Table 2). 농양의위치, 수, 포낭형성경향, 피막의두께, 원인균등은감염원에따라다르다. 당연히예후도원인에따라다르며, 따라서원인균과발병유발원인을확인하는것이치료를결정하는데매우중요하다. 임상양상으로는발열, 국소뇌병변에의한증상, 그리고종괴효과로인한증상들이나타날수있으며발병초기에는한두가지증상만나타난다. 40,41 발열은병초기에 50% 정도에서관찰되며뇌막자극징후도 40% 정도에서만관찰된다. 42 농양의위치에따라국소신경학적증상이좌우되지만 toxoplasma와같이사람면역결핍바이러스감염환자에서특이적으로기저핵을침범해반무도병을주로일으키는경우도있다. 43 일반적으로자기공명영상검사 (MRI) 가컴퓨터단층촬영 (CT) 보다선호되지만진단의첫단계로서, 그리고치료에따른변화를관찰하는데있어 CT는중요하다. 뇌실질내농양은조직학적소견에따라 CT소견을뇌염초기 (early cerebritis), 뇌염후기 (late cereberitis), 피막 TABLE 2. Potential source of infection Otogenic Otitis media Suppurative sinusitis Mastoiditis Dental Cardiac Infective endocarditis Congenital heart disease Esophageal strictures Pulmonary Pulmonary arteriovenous fistula Lung abscess Bronchiectasis Cerebral infarcts and tumors Penetrating and nonpenetrating head injury Neurosurgical procedure Sepsis Immunosuppression S65

4 J Neurocrit Care 2008;1 Suppl 1:S63-S68 TABLE 3. Empirical antibiotics for bacterial brain abscess Predisposing condition Common pathogens Antibiotics Postsurgical or trauma Staphylococci, Enterobacter, Pseudomonas, Streptococci Naficillin or Vancomycin+3 rd cephalosporin +Metronidazole Dental abscess Streptococci, Bacteroides Penicillin+Metronidazole Congenital heart disease Streptococci 3 rd cephalosporin Pulmonary infection Nordardia, Bacteroides, Streptococci, Mixed flora Penicillin+Metronidazole+Bactrim Chronic otitis Bacteroides, Pseudomonas, Proteus, Klebsiella 3 rd cephalosporin+metronidazole Bacterial endocarditis or drug user Mixed flora, Streptococci, Staphylococci Naficillin or Vancomycin+3 rd cephalosporin +Metronidazole Sinusitis Streptococci, Hemophilus, Staphylococci 3 rd cephalosporin or naficillin+metronidazole 초기 (early capsule), 피막후기 (late capsule) 로나눌수있다. 44 뇌염초기에는동음영 (isodense) 또는저음영의병변으로서뇌회색질-백질경계가불분명해지며, 뇌염후기로가면서불규칙한경계와조영증강을갖는띠둘레가생기고주변조직의부종이두드러진다. 피막초기에는경계가명확하며조영증강되는띠둘레와주변부종이특징이고피막후기에는부종이감소하며둥근조영증강띠둘레가지속적으로남아있는상태이다. 44,45 MRI는뇌염초기단계에부종여부를정확히알수있게해준다. 뇌염후기에서피막초기에걸쳐농양의띠둘레는 T1 강조영상에서고음영, T2 강조영상에서는저음영으로보인다. 이는미세출혈과동반된철분의축적때문일것으로생각되었으나병리학적연구결과활발한포식활동을하는대식세포들에서분비된자유기들의불균등한분포가빚어낸 T1 상자성 (paramagnetic) 효과때문이라고여겨지고있다. 46 자기공명분광법 (MR spectroscopy) 은뇌농양을종양과구분하는데도움이된다. 뇌농양은보통 choline, creatine, N-acetyl-aspartate 모두감소하지만뇌종양에서는 choline 이증가한다. 47 치료경험적항생제치료가수술보다우선시되는조건은농양의크기가 3 cm 미만이거나뇌간등수술적접근이어려운심부뇌농양, 피막이없는뇌염초기단계, 작은다발성뇌농양일경우등이다. 48,49 그외의경우에는수술적치료, 즉배액이나정위흡인, 절제등을먼저고려해야한다. 수술적처치는종괴효과를감소시키고동반한증상을없앨수있을뿐아니라세포학적검사와배양을통해감수성이있는항생제를선택할수있게해준다. 항생제치료의원칙은먼저신경계외의원인병소가확인된경우에는동정된원인균에맞는항생제를선택하며만일균동정이불가능한경우에는동반한임상적상황을고려해야한다 (Table 3). 경험적항생제치료중에는신경학적검사와반복적인영상검사를통해치료효과를확인해야하며반응이없을 때는조직학적검사를고려해야한다. 보조요법으로써스테로이드가증가한두개내압력의조절및부종의치료를위해사용되고있으나 50 피막형성을늦추고염증반응의감소로인한항생제투과성저하등이동물실험에서관찰되어 51 치료적효과에대해아직도논란이되고있으며, 이러한이유로스테로이드사용시더고용량의항생제투여가권유되고있다. 52 항생제치료기간은일반적인화농성농양의경우 6주가일반적이지만 53 정해진치료지침은없으며원인균에따라서는더장기간의치료가필요하다. 진균성농양의경우일반적으로수술적처치와약물치료를병행하며, 면역결핍환자에서는적절한항진균제치료에도불구하고높은사망률을보인다. 사망률과관련된여러요인중에혈행성원인이있는데이는흔히이러한원인의농양에서진단이늦어질뿐아니라원인질환인호흡기및심장질환의높은사망률과도관련성이있다. 54,55 지난수십년간뇌농양의진단및치료기술의발달은분명사망률감소에많은기여를해왔지만앞으로도보다효과적인수술적치료와내과적치료의병합등을평가하는전향적연구가더필요한상태이다. REFERENCES 1. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF. Communityacquired bacterial meningitis in adults. N Engl J Med 2006;354: Schlech WF 3 rd, Ward JI, Band JD, Hightower A, Fraser DW, Broome CV. Bacterial meningitis in the united states, 1978 through The national bacterial meningitis surveillance study. JAMA 1985; 253: Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, Reingold AL, et al. Bacterial meningitis in the united states in Active surveillance team. N Engl J Med 1997;337: Skoch MG, Walling AD. Meningitis: describing the community health problem. Am J Public Health 1985;75: Bijlmer HA. World-wide epidemiology of haemophilus influenzae meningitis; industrialized versus non-industrialized countries. Vaccine 1991;9 Suppl:S5-9; discussion S Park SA, Chun HW, IS C. Clinical characteristics of bacterial meningitis. J Korean Neurol Assoc 1997;15: Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, S66

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<30322EBABBB9AE2E687770> 대한내과학회지 : 제 73 권부록 2 호 2007 임상강좌 급성세균성수막염 성균관대학교의과대학내과학교실 정두련 서론뇌는두개골 ; 연질막 (pia), 거미막 (subarachnoid), 경질막 (dura) 으로구성되는뇌를덮고있는수막 ; 혈액뇌장벽에의해감염으로부터보호받고있다. 하지만, 중추신경계에감염이발생하면심각한결과를초래할수있는데이는감염발생부위가두개골안의해부학적으로폐쇄된공간일뿐아니라면역학적으로도인체의다른부위와분리된곳이어서중요한숙주방어기전이결여되어있거나매우다르게작용하기때문이다