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1 Brain & NeuroRehabilitation Vol. 3, No. 1, March, 2010 뇌졸중후실어증환자의근거중심치료 경희대학교의과대학재활의학교실 유승돈 Evidence Based Therapies for Aphasia following Stroke Seung Don Yoo, M.D., Ph.D. Department of Physical Medicine and Rehabilitation, Kyung Hee University Postgraduate College of Medicine Aphasia is defined as the loss of ability to communicate orally, through signs, or in writing, or the inability to understand such communications; the loss of language usage ability. Aphasia is present in 21 38% of acute stroke patients and is associated with high morbidity, mortality and expenditure. The evidence based challenges was described that occurred when carrying out systematic reviews of language therapy for aphasia following stroke. Language therapy in treating aphasia is efficacious when provided intensely for the first 3 months. There is strong evidence that computer-based aphasia therapy results in improved language skills. Constraint induced language therapy can result in improved language function and everyday communication in chronic aphasics. Treatment with rtms may be associated with improved naming performance in patients with non-fluent, chronic aphasia. But, further investigation is required. Several placebo-controlled trials suggest that piracetam is effective in recovery from aphasia when started soon after the stroke. Drugs acting on catecholamine systems (d-amphetamine) have shown varying degrees of efficacy when combined with language therapy. Data from single-case studies, case series and an open-label study suggest that donepezil may have beneficial effects on chronic poststroke aphasia. Preliminary evidence suggests that donepezil is well tolerated and its efficacy is maintained in the long term. Significant language and communication gains have been demonstrated following the use of memantine in conjunction with constraint-induced language therapy. (Brain & NeuroRehabilitation 2010; 3: 27-33) Key Words: aphasia, evidence based therapy, stroke 서론 실어증은뇌손상에의해발생되는언어의이해와생성의후천적인장애라고할수있으며 Agency for Health Care Policy and Research (AHCPR) 의뇌졸중후재활진료지침에서는말이나상징체계, 쓰기로의사소통하는능력의소실또는그러한의사소통을이해하는능력의소실, 즉언어사용능력의소실상태를실어증이라고정의하였다. 실어증은뇌졸중후가장심한인지장애의한형태로최근의최초발병한뇌경색이후실어증환자는 10만명당 33 3명에서발생한다고보고하였다. 1 급성기뇌졸중환자에서는 21 38% 2 의실어증환자가발생하며그가운 교신저자 : 유승돈, 서울시강동구상일동 , 경희대학교의과대학재활의학교실 Tel: , Fax: kidlife@paran.com 데전실어증 (global aphasia) 이 2 32% 로가장흔하다. 3- 하지만 Godefroy 등에의하면 Boston 분류체계로정의하기어려워분류되지않는실어증이약 2% 나된다고한다. 4 실어증환자의재활은언어평가를통하여환자를분류하고언어치료나약물치료, 비약물뇌자극치료를통하여이루어진다. 언어치료는크게재구성 (reorganization) 과보상 (compensation) 의두가지이론적배경을가지고실시되지만실어증환자로진단된개개의환자에게어떤치료를어떤이론적배경을통하여치료할것인가에대한명확한근거가부족하다. 6 기존의언어치료에대한효과에대한한계는약물치료, 뇌자극치료를포함한다른치료법에대한관심을가져오고있으며집중언어치료를포함한근거중심의언어치료가중요하다고할수있다. 본종설에서는실어증환자의언어재활치료, 약물치료, 및뇌자극치료에대하여현재까지진행된자료를분석하여뇌졸중후실어증환자의근거중심치료의효과에대해서주로기술하고자한다. 27

2 Brain& NeuroRehabilitation:2010; 3: 27~33 본론 1) 뇌졸중후언어치료 (1) 언어치료개괄 Robey 7 는 논문의메타분석결과급성기에언어치료를시작하는경우언어기능회복이치료받지않은환자보다두배의효과가있다고하였고치료가지연되어만성기에시작하는경우치료효과는적으나언어치료시행하지않는군보다는치료효과가있다. 치료의강도가셀수록치료효과는좋았으며언어치료를받을수있는환자의경우최소한주 2시간의치료는받아야한다고제안하였다. Greener 등 8 의 Cochrane Systematic Review에서뇌졸중후실어증환자에대한 12개의연구논문을고찰하였다. 하지만 1980년대와 90년대의논문들로매우오래되었고평가방법이나질적인측면에서이의가많아언어치료의무작위대조군연구측면에서확실히효과가있는지의여부는불분명하다고결론내렸다. (2) 개인언어치료 Evidence based review 9 에서 Physiotherapy Evidence Database (PEDro) 를이용하여 10개의무작위대조군연구를분석하였으며이가운데 8개가훈련받은언어치료사에의해실시된언어치료여부를고찰하였으며 4개의논문에서효과가있었으며 4개의논문에서는효과가없다고하였다 (Table 1). Bhogal 등 10 은치료의강도에관한연구에서평균주당 11.2주동안주당 8.8시간언어치료하는경우에는치료효과가있었지만 22.9주동안주당 2시간치료하는경우에는언어치료의효과가없었다. 따라서뇌졸중후실어증환자의언어치료에서짧은기간이라도치료강도를높여치료하는것이언어기능의예후를좋게할수있다. Bakheit 등 11 은 97명의뇌졸중환자에서무작위로주당 회 (1시간언어치료 ) 의높은강도군과주당 2회 (1시간언어치료 ) 하는대조군을선정하여 24주간추적관찰한결과두군간유의한차이가없었다. 뇌졸중후실어증환자에서언어치료의효과는아직확실치않으며효과는짧은기간이라도치료의강도와관련되어있고메타분석에서급성기에의미있는언어기능의회복이일어난다. 만성기에도어느정도의언어기능의회복은일어나며언어장애가심한경우좀더강한강도로치료하는것이언어기능회복의효과적이다. 즉실어증에대한언어치료는첫 3개월에강한강도로시행할경우언어기능회복에통계적으로효과적이라할수있다. (3) 집단언어치료 Wertz 등 12 과 Elman 등 13 의집단언어치료에대한무작위대조군연구에서사회관계와언어평가결과는개선되지만의사소통능력에서는제한적으로호전이관찰된다고하였다. 집단언어치료는개인치료와비교하여글쓰기의호전이적었다. (4) 지역사회기반언어치료 Aftonomos 등 14 은실어증의언어치료의효과에관한결론은주로연구하는곳에서나왔으나실어증이발견되고치료되어야할곳은바로지역사회이다. 따라서언어치료의성공여부는제한이따르는실제생활터전에서기능적회복이일어나는가에달려있다고도볼수있다. 그러나지역사회기반언어치료에대한자료가거의없으며한개의무작위대조군연구가있을뿐이다. Worrall 과 Yiu 1 연구에서레크리에이션활동에참여한환자와언어치료를받은군간의차이가없었다고하였다. 지역사회언어치료프로그램은실제세계의제한점과한계를고려하여언어기능을호전시킬수있도록제공되어야한다. Table 1. Efficacy of Aphasia Therapy Following Stroke Study PEDro score N Intensity of therapy Result Lincoln et al Wertz et al Hartman 1987 David et al Shewan et al Marshall et al Prins et al Meikle et al Brindley et al Hinckley & Carr 200 Bakheit et al No score , 1-hour sessions per week for 34 weeks 8 to 10 hours a week for 12 weeks 2 times a week for 6 months 30 hours over 1 to 20 weeks 3, 1-hour session a week for 1 year 8 to 10 hours a week for 12 weeks 2 sessions a week for months Minimum 3 and maximum sessions/week for 4 minutes hours over days a week for 12 weeks 2 hours/week vs. 4 hours/week 4 hrs/week vs. 2 hrs/week (over 12 weeks) 28

3 유승돈 : 뇌졸중후실어증환자의근거중심치료 () 컴퓨터기반언어치료 1980년대에처음으로컴퓨터기반언어치료에대한연구가시행된이래최근까지연구가진행되고있다. 컴퓨터기반언어치료는치료사의시간과자원이한정되어있으므로치료의강도를증가시켜집중치료의수단으로하기위해개발되었다. 16,17 그러나그효과에대해서는충분한연구가이루어지지않았으나 9개의연구결과에서치료효과가있다고보고하였다. 이중 3개의연구에서언어장애의평가결과에대한호전뿐아니라기능적인의사소통능력도호전되었다고보고하였다. 14,18,19 2개의무작위대조군연구중 Katz & Wertz 17 은 1년이상된 명의뇌경색실어증환자에서 1) 컴퓨터읽기치료 2) 컴퓨터인지재활 ( 비언어 ), 3) 대조군으로나누어주 3회, 26주동안실시한결과컴퓨터읽기군에서 Western Aphasia Battery 점수가다른두군과유의한차이가있었으며일반화효과도증명하였다. 다른하나의무작위대조군연구로 Doesborgh 등 20 은 18명의뇌졸중후실어증환자를대상으로 8명에게 Multicue 치료를주당 2 3회, 2개월간치료한결과이름명명검사결과는의미있게호전되었으나매일의언어의사소통으로의일반화는두군간차이가없었다. 2009년의최근연구로 Fridriksson 등 21 은 10명의만성비유창성실어증환자에서개인교습용컴퓨터기반치료를실시하였다. 치료는그림명명치료로청각및시각자극군과청각자극군으로나누어하루에한세션으로주 세션를실시하였으며적어도 1세션을실시한결과청각및시각자극군에서치료전과비교하여그림명명검사에서호전이관찰되었으며청각자극군에서는호전이관찰되지않았다. (6) 실어증에대한 Constraint induced language therapy (CILT) 가 ) 이론적배경 : learned non-use: Constraint induced language therapy (CILT) 는상대적으로최근의실어증치 Table 2. Constraint Induced Therapy for Aphasia Study Methods Treatment schedule Outcome Maher et al., 2006 (CILT) Meinzer et al., 2004 (CILT) Meinzer et al., 200 (CILT) Pulvermuller et al., 2001 (CILT and Intensity), RCT 11 patients were assigned to receive either CILT or PACE (promoting aphasic communicative effectiveness) therapy. PACE participants were encouraged to communicate using any or all modalities available to them (gesturing, writing etc.) whereas CILT participants were restricting to verbal production only. 28 patients with chronic aphasia (>12 months post onset following stroke) participated in intensive speech and language therapy. Training techniques included intense use of language together with restraint of non-verbal methods of communication. 27 patients with chronic aphasia were assigned to receive either constraint induced therapy (CIAT, n=12) or constraint induced therapy "plus" (CIATplus, n=1). 17 patients with language impairment due to a single stroke affecting the left middle cerebral artery with no severe perceptual or cognitive deficits were randomized to either treatment or control groups. All participants 3-hr sessions 4 sessions/wk 2 wks; 24 hr All participants 3 hr/day for 10 days; 2 wks; 30 hr All participants 3 hr/day for 10 days; 2 wks; 30 hr CIAT group 3 hr/day for 10 days; 2 wks Conventional treatment session length 3 wks There was a higher incidence of severe apraxia of speech impairment in the PACE group. Both groups demonstrated significant change on the WAB AQ over the course of therapy (p=0.004). subjective analysis revealed qualitative differences in favor of the CILT group. Following training, performance increased on the Aachen Aphasia Test (AAT) (p<0.0001) and TokenTest (p<0.0001). 2/28 patients improved on at least one AAT subtest. Participants in both training groups demonstrated significant improvements on the AAT and all subtests (p< & p<0.001 respectively) Communication effectiveness, assessed by patient relatives, was significantly improved for both groups. Relatives of patients in the CIATplus group reported further improvements at the 6- month follow-up. Patients in the CI group demonstrated significant improvement on 3 of the 4 components of Aachen Aphasia Test scores while patients in the control group did not demonstrated significant improvement. Patients in the CI group had significantly higher Communicative Activity Log scores of communication of everyday life compared to patients in the control group. 29

Brain& NeuroRehabilitation:2010; 3: 27~33 료로실시되는것으로 2가지의주요원칙이있다.

나 ) Systemic review (Table 2): 하나의 17명을대상으로한무작위대조군연구에서 CILT는언어장애와기능수준에서의미있는호전이있었다. 23 최근의무작위대조군연구는아니지만 3개의연구에서도 CILT 후언어기능의호전이있으며대화소통의기능도좋아지고 6개월이상효과가지속되기도하였다. 24 하지만더많은수의연구가필요하다.

Meinzer 등 26 은만성뇌졸중후실어증환자에서하루에 3시간 10일간 CILT를실시한후환자의뇌병변주변의영역에서 MEG delta dipole density (DDD) 의감소를관찰하였으며이는뇌의가소성이증가한것임을시사한다 (Fig. 1).

4 Brain& NeuroRehabilitation:2010; 3: 27~33 료로실시되는것으로 2가지의주요원칙이있다. 22 비언어적인몸짓, 그림, 쓰기등을자제하고말의적극적인사용 (forced use of verbal language) 을하도록하는것과하루에 3 4시간, 2주동안치료하는등의집중치료하는것 (massed practice) 을주요원칙으로하며뇌회복의가소성의원리에근거를두고있다. 따라서 CILT의치료효과판정을할때뇌가소성에영향을미치는치료강도가중요한인자가된다. 나 ) Systemic review (Table 2): 하나의 17명을대상으로한무작위대조군연구에서 CILT는언어장애와기능수준에서의미있는호전이있었다. 23 최근의무작위대조군연구는아니지만 3개의연구에서도 CILT 후언어기능의호전이있으며대화소통의기능도좋아지고 6개월이상효과가지속되기도하였다. 24 하지만더많은수의연구가필요하다. 다 ) 최근연구 : Szaflarski 등 2 은뇌경색이후발생한만성뇌졸중환자에서 CILT가언어회복을자극하였다고보고하였다. 중등도에서심한실어증환자에서하루에 3 4시간, 일연속실시한결과언어이해력과언어소통능력이 31% 에서 9% 로호전되었고 story retell task에서도 7% 에서 7% 로호전이관찰되었다. Meinzer 등 26 은만성뇌졸중후실어증환자에서하루에 3시간 10일간 CILT를실시한후환자의뇌병변주변의영역에서 MEG delta dipole density (DDD) 의감소를관찰하였으며이는뇌의가소성이증가한것임을시사한다 (Fig. 1). 2) 약물치료 Cochrane review와 systematic review에서약물치료는실어증환자의언어기능을회복시킬수있으나언어치료 와같이시행하였을때효과가있는경우가많으며언어치료보다더효과적인지는알수없으며약물상호간에도어느것이더효과적인지알수없다. (1) GABA계에작용하는약물 : Piracetam Piracetam은인지, 언어및기억력과관련하여중요한역할을하며신경보호작용과항혈전작용이있는 GABA계에작용하는뇌보조제 (nootropic) 이다. 글루타민계와콜린계에작용하여학습과기억력에관여하며뇌경색의허혈성경계영역 (ischemic penumbra) 에대사를정상화시키는신경보호작용을한다. 27 이러한뇌보호작용이실어증의회복과관련된인지장애의회복을도와주며여러개의무작위대조군연구논문이이를뒷받침해주고있다. Piracetam에대한 4개의무작위대조군연구에서하루 4.8 g, 6 12주간치료한결과실어증회복에의미있는호전이있었다. 최근의전향적인, 무작위, 이중맹검, placebo control 연구에서언어치료와 piracetam을함께투여하였을때실어증회복이되었다. 27 (2) Catecholamine계에작용하는약물 : d-amphetamine Dexamphetamine은노르아드레날린, 도파민, 세로토닌의시냅스전분비를촉진하며재흡수를억제하여뇌경색으로부터멀리있는뇌영역의신경전달을촉진시킨다. 또한장기적활성화 (long term potentiation) 과언어의가소성을자극함으로써기억력의저장기능을촉진하며뇌졸중후운동기능과언어기능의회복에도기여한다. 전향적인이중맹검, placebo control 연구에서 21명의실어증환자에게 10 mg의 dextroamphetamine을 10 세션으로투여하고 1시간의언어치료를시행한결과약물치료군에서의미있게언어기능이개선되었으며 6개월까지약효가지속되었다. 28 Fig. 1. Decrease of MEG delta dipole density (DDD) in perilesional areas in a representative patient before (left panel) and after (right panel) intensive language training. The center panel shows the lesion (MRI). 30

5 유승돈 : 뇌졸중후실어증환자의근거중심치료 (3) Acetcholine계에작용하는약물 : Donepezil Donepezil은 selective acetylcholinesterase inhibitor 로서경도와중등도의치매환자에서인지기능을안정화시키는데사용하는약물이다. Berthier 등 29 은 11명의만성실어증환자에서 20주간 open label, pilot study 실시하였는데환자에게 donepezil은 4주간하루 mg을투여하고 4 주간약을끊은뒤다시 12주간하루 10 mg의약물을투여한결과 4주, 16주에웨스턴실어증검사의실어증점수가의미있게증가하였다. 20주에는 16주와비교하여감소하였다. Berthier 등 30 의 2006년후속연구에서 26명의환자를대상으로무작위, placebo control 연구를실시하였다. 환자들은 mg 4주, 10 mg 12주투여후 4주간약을끊는기간을두었으며 16주후평가하였다. 웨스턴실어증점수는약물치료군에서 16주에의미있는증가가있었으며약물투여후 4주간끊은뒤에는언어소통검사결과가감소하였다. (4) NMDA 수용체길항작용 : Memantine Memantine 은 NMDA 수용체길항작용을하는약물로알쯔하이머치매환자와혈관성치매환자에서사용해왔다. 2009년 Berthier 등 31 은 28명의뇌졸중후만성실어증환자에서무작위, 이중맹검, placebo control 방법으로 memantine 10 mg을하루에 2회 16주간약물만투여하였고 memantine 과언어치료 (CILT) 를 16주에서 18주에실시하였으며 18주부터 20주까지는다시약물만투여하였고 20주에 4주간약물을끊고추적관찰하였다. 약물만투여한 16주까지는 placebo군과비교하여언어기능이의미있게증가하였고약물과언어치료를동시에시행한기간에가장언어기능이호전되었으나약물을끊은경우약물과관련된언어기능의호전의감소가관찰되었다. 하지만 placebo군과비교하여의미있게증가되어있었다. 3) 비약물뇌자극치료 (rtms, tdc) (1) 반복경두개자기자극치료 (rtms) 뇌졸중후비유창성실어증환자에서기능적뇌자기공명영상연구결과우측 Broca 해당부위의활성화가관찰되었고언어회복에우측전두엽의활성이중요하다고알려져왔다. 32 다만 maladaptation의결과로활성화가관찰될수도있다. 최근의비유창성실어증에대한 rtms 연구는우측브로카해당부위의흥분성을억제하는저빈도 rtms를적용하여명명기능 (naming function) 을호전시키는것이대부분이다. 대개의논문은비유창성만성실어증환자를대상으로한예비연구이며향후무작위대조군연구등이필요하다. Martin 등 33,34 은뇌졸중후만성비유창성실어증환자에서 1 Hz 10분, 600회, 운동역치의 90% 로그림명명검사에서활성화가가장뚜렷한부위에 rtms 를적용하였고이어 CILT (2주간, 20분, 주당 일 ) 를실시하여그림명명의호전을관찰하였다. Naeser 등 3 은뇌졸중발병후 년에서 11년된 4명의비유창성실어증환자에서자기공명영상결과우측의브로카해당부위의활성화영역을 Maladaptive 로가정하여저빈도 1 Hz, 20분, 주 일 2주간 (10회) rtms 를실시하였다. 환자는보스톤명명검사를뇌자극전, 뇌자극후 2주, 2개월, 8개월에실시한결과뇌자극후 2개월에그림명명검사의호전이있었으며뇌자극후 8개월에도 3명의환자에서치료효과가지속되었다. (2) Direct current 반복경두개자기자극치료처럼경두개직류자극치료는뇌의흥분성의변화를야기시키며전류의극성에따라흥분성을증가 (anodal tdcs) 시키거나감소 (cathodal tdcs) 시킨다. 36 건강한 19명의성인을대상으로좌측실비안영역후방부 (Wernicke 영역 ) 에 20분간, anodal, cathodal, sham tdcs (20 min, 1 ma) 를시행한결과 anodal tdcs 에서단어습득능력이더빨랐으며이는이치료법이언어재활에사용될수있으리라는것을시사한다. Monti 37 는 8명의만성비유창성실어증환자에서좌측브로카영역에 anodal 또는 cathodal tdcs 그리고 sham 자극을시행하였고후두뇌피질에도같은프로토콜로자극을시행하였다. 그결과 anodal tdcs 와 sham tdcs 는어떠한변화도없었으며 cathodal tdcs에서그림명명검사의정확성에서의미있는호전이관찰되었다. 향후추가연구가필요하다. 결론 뇌졸중후실어증은의사소통, 인지기능, 삶의질및사회복귀를저해하는요인이다. 지난수년간신경생리, 뇌영상기법의발달및신경인지의발달로실어증의치료에대한근거중심의연구가가능하게되었다. 조기에강도높게언어치료를실시하고지역사회와컴퓨터기반치료를포함하여약물치료를적절하게사용하였을때근거중심의가장합당한효과적인언어재활치료라할수있다. 뇌자극치료와같은다각적인치료의시도는더많은연구가필요하다. 실어증에대한약물치료의효과판정에있어서환자의실어증정도에대한평가뿐아니라기능적의사소통, 일상생활동작에도긍정적인효과를가져오는지에대한연구 31

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R