Brain & N eurorehabilitation Vol. 1, No. 2, September, 2008 뇌손상후중증의식장애 ( 식물인간상태와최소의식상태 ) 환자의치료 원광대학교의과대학재활의학교실및의과학연구소, 1 원광대학교일반대학원보건학과신용일ㆍ조진호 1 Emerging Therapies in Vegetative and Minimally Conscious State after Brain Injury Yong-Il Shin, M.D., Ph.D. and Jin-Ho Cho, M.S. 1 Department of Rehabilitation Medicine, Wonkwang University College of Medicine and Institute of Wonkwang Medical Science, 1 Department of Public Health, Wonkwang University Graduate School The practice of coma arousal and brain stimulation in vegetative state or minimally conscious state is becoming the focus of heated debate. There is no definite theory on which patients may benefit, at what time in their recovery, or how the arousal' or stimulation' procedures should be applied. In this review, old and new therapeutic methods for recovery of vegetative state or minimally conscious state will discussed. And we consider some of the information processing mechanisms that are important mediators of arousal and awareness in current practices. (Brain & NeuroRehabilitation 2008; 1: 143-147) Key Words: brain injury, deep brain stimulation, minimally conscious state, rehabilitation, vegetative state 서론 식물인간상태 (vegetative state) 는자신스스로또는외부환경에대한행동적인반응을보이지는않지만자신스스로또는자극에따른각성상태를보이며, 코마와달리수면주기를가지고있는것으로정의된다. 1 최소의식상태 (minimally conscious state) 는식물인간상태의기준에는합당하지않으나심각한의식저하가있으며, 반복적이지는않지만외부의자극에대하여부분적인행동반응을보이는경우를가리킨다. 2 식물인간상태또는최소의식상태는중증의외상성뇌손상환자의 14% 에서나타나는것으로보고되었으며, 3 이들중 52% 의환자에서뇌손상후 1년내에의식회복을관찰할수있고나머지는죽거나식물인간상태또는최소의식상태를수년간지속하는것으로보고되고있다. 4 이러한환자들이적절한치료를받고있는가에대한의료윤리적측면과치료에따른비용부담으로인한의료경제적측면에서매우중요하다. 교신저자 : 신용일, 전라북도익산시신용동 344-2 570-711, 원광대학교의과대학재활의학교실 Tel: 063-859-1621, Fax: 063-843-1385 E-mail: cbrmshin@wku.ac.kr 이에본종설에서는뇌손상후식물인간상태또는최소의식상태환자의의식상태의개선을위해최근에시도되고있는치료방법을재활치료적접근법, 약물치료적접근법, 전기자극치료법등으로분류하여소개하고자한다. 본론 1) 재활치료적접근법 (1) 단모드감각자극법 (unimodal sensory stimulation): 재활치료과정에서널리시행되고있는단모드감각자극치료는과학적인근거가없음이밝혀졌음에도불구하고, 몇몇의연구자들에의해식물인간상태에서수개월후감각자극치료에의해의식의회복이있다고보고되었다. 5-7 감각자극의종류로는청각자극, 시각자극, 후각자극, 미각자극, 촉각자극, 통증자극등이이용되고있으며, 자극치료는일반적으로하루에 1 2 회, 각 1시간씩적용된다. 그러나단모드감각자극치료에대한연구가모두무작위대조군이중맹검연구가아니거나자연적인회복을배제할수없는점, 과학적인회복기전의설명이부족한점등의여러가지제한에의해과학적인근거가없는것으로판단되고있다. (2) 다모드감각자극법 (multimodal sensory stimulation): 단모드자극법이부분적으로효과가있다는연구 143
Brain& NeuroRehabilitation:2008; 1: 143~147 에더해져서일부연구자에의해하루에단모드자극법과다모드자극법을각각 10분씩적용한경우식물인간상태환자의의식개선에효과가있다는보고를 8 토대로하루동안제한적시간이아닌집중적인다모드자극치료가효과가있을것이라는가설아래많은연구가시행되었다. Doman 등은하루 12 14시간동안매시간 15 20분의집중다감각자극치료 (intense multisensorial stimulation) 를 6주간시행하여코마또는식물인간상태환자의의식상태개선에효과가있다고하였다. 9 또한뇌손상후 48시간이상코마상태에있었던중증뇌손상환자 14명에대하여뇌손상후 48시간에시작한조기 (early) 다모드감각자극치료를수상후 2년까지추적한연구에서수상전의직업으로복귀한경우가 2명에서있었으며, 다른환자에서도여러가지의식상태평가지표에서호전이있음을보고하였다. 10 이들의연구에서여러가지감각자극치료중특히, 촉각자극과청각자극이두부와눈동자운동자극에가장효과적임이밝혀졌다. 그러나 2004년 Cochrane systemic review에의하면장기간의혼수상태또는식물인간상태에있는환자에게수행된몇몇의무작위대조군연구와비무작위대조군임상연구 (nonrandomized controlled clinical trials) 방법을통한다모드감각자극치료의효과를분석한결과의식개선에확실한증거가없다고하였다. 11 그러면서다모드감각자극치료의효과를증명하기위하여대규모다기관무작위대조군임상연구가필요하다고하였다. (3) 자세변화자극법 (postural stimulation): 일부의보고에서경사대에기립위를유지시키는것이식물인간상태또는최소의식상태의환자의각성과인식의개선에긍정적인효과가있다고하였다. 12,13 실제로경사대를이용한기립위유지는고유수용체감각자극, 혈액양감소증 (hypovolemia) 감소, 휴식상태의근육의길이변화유도, 척추에하중 (load) 가하기효과, 피부에가해지는압력의재분배, 심폐기능의잇점등으로인한전신적상태의개선을통해각성과인식의호전을가져온다고한다. (4) 저체온유지법 (hypothermia): 뇌손상후급성기에저체온치료방법에대한연구에서중증의뇌손상환자에대한급성기저체온치료를시행한그룹이정상체온으로유지한그룹에비해식물인간상태나사망과같은나쁜예후를보이는비율이의미있게낮다고하였다. 14 그러나이러한긍정적인효과는뇌압상승을억제하는것과관련이있으며, 초급성기즉, 수상후 3 6시간이내에저체온치료를받은경우에효과가있다고하였고, 이외의다른연구에서는효과가없다고한다. 2) 약물치료적접근법 (1) 도파민약물치료법 : 식물인간상태또는최소의식상태의환자의의식상태개선을위한약물치료요법중가장대표적인것은도파민약물치료법이다. 이중에서도레보도파 (levodopa) 치료법이가장대표적인데, Matsuda 등의연구에서 3 6 사이의그래스고우코마점수 (Glasgow coma scale) 를보인뇌손상후 3 22개월의식물인간상태환자에서두부컴퓨터단층촬영또는뇌자기공명영상에서흑색질 (substantia nigra) 또는시상밑핵 (subthalamic nucleus) 을침범한소견이있는경우레보도파투여후뇌파에서알파파의의미있는증가를동반한의식상태의개선이관찰되었다. 15 연구자들은레보도파의치료선택의기준을첫째, 식물인간상태또는최소의식상태의환자로진단된경우, 둘째, 편측에집중된강직 (ridigity) 이나경직 (spasticity), 무동증 (akinesia) 과같은파킨슨양상의증상이동반된경우, 셋째, 급성기뇌자기공명영상에서대뇌다리 (cerebral peduncle) 의흑색질또는배뒤쪽지역 (ventral tegmental area) 을침범하거나뒤가쪽중뇌 (dorsolateral midbrain) 와같은도파민경로에병변이있는경우로하였다. 15 약물치료방법은약물의부작용을최소화하기위하여낮은단위의레보도파로시작하여레보도파 450 mg 하루 1회용법, 레보도파 / 카비도파 (levodopa/carbidopa) 100/10 mg 하루 2회용법, 레보도파 / 밴서라지드 (levodopa/ benserazide) 100/25 mg 하루 2회용법을하나를적용하는것을추천하고, 소아의경우하루에레보도파 2 mg/kg 을복용시키는것을추천한다. 수개월간의복용에도효과가없거나부작용이큰경우에는중단한다. 브로모크립틴 (bromocriptine) 도도파민약물치료의하나로뇌손상후식물인간상태환자에서브로모크립틴치료후 12개월간의추적관찰에서치료하기않은집단에비해치료받은집단에서의미있게낮은장애점수척도 (disability rating scale) 의점수를나타냈다 (Fig. 1). 16,17 하루에 2회 1.25 mg으로시작하여하루 2회 2.5 mg을투약이권장되는용법이다. 아만타딘 (amantadine) 도브로모크립튼과같이도파민효과를나타내며, 뇌손상환자에서인지기능과행동장애의개선에부분적인효과가있음이보고되었다. 18 (2) 기타뇌자극약물치료가 ) 메틸페니데이트 (methylphenidate): 식물인간상태또는최소의식상태의환자의의식상태개선을위한메틸페니데이트에대한연구는많지않다. 많은연구가 Whyte 등에의해연구되었는데, 과거의일부분의연구에서는메틸페니데이트가의식상태의개선에효과적이다고 144
신용일ㆍ조진호 : 뇌손상후중증의식장애 ( 식물인간상태와최소의식상태 ) 환자의치료 Fig. 1. Mean disability rating scale (DRS) scores at 1, 3, 6, and 12 months post-injury for 5 traumatic brain injury-vegetative state (TBI-VS) patients with bromocriptine compared with TBI-VS patients. 16 하였다. 19 그러나 2007년의보고에서는일부분의환자에서는의식상태의개선에의미있는효과가있었으나메타분석을통한전체적인연구에서는의미있는효과가증명되지않았다고하였으며, 메틸페니데이트 (1일 7.5 20 mg, 평균용량 10 mg) 의효과가나타나는외상성뇌손상환자군에대한부가적인연구가필요하다고하였다. 20 나 ) 암페타민 (dextro-amphetamine): 식물인간상태또는최소의식상태의환자의의식상태개선을위한암페타민의연구에서글래스고우결과척도 (Glasgow outcome scale) 의호전이있다는보고가있으나 21 근거중심의학측면에서증명된효과는밝혀지지않았다. 다 ) 이외에삼환계항우울제, 세로토닌계항우울제등이식물인간상태또는최소의식상태의환자의의식상태개선에부분적인효과를지닌다는보고가있다. 22,23 3) 전기자극치료법식물인간상태또는최소의식상태의환자의의식상태개선을위해최근에새로이시도되고있는대표적인치료로말초성또는중추성전기자극치료가있다. 이는직접또는간접적으로뇌자극을시도함으로써식물인간상태의의식상태개선또는각성을유도하는치료이다. (1) 말초성전기자극치료법 (peripheral nerve stimulation): 말초성전기자극치료의대표적인방법은우측정중신경신경자극법으로 10명의식물인간상태환자에게수행된무작위대조군이중맹검연구에서정중신경자극군은대조군에비해코마로부터일찍회복되고기능적평가지수의큰회복을관찰할수있었다. 24 이는대뇌피질의감각표시 (sensory representation) 영역중손에해당하는부위가다른신체부위에비해가장크고, 각성상 Fig. 2. Right median nerve stimulation (RMNS) go to the ascending reticular activating system (ARAS) via anterior cingulate cortex and cholinergic system. 태를유지하는역할을하는뇌간의 ascending reticular activating system (ARAS) 이정중신경의구심성경로인척수그물로 (spinoreticular tract) 와시냅스를이루고있다는이론을바탕으로시도되었다 (Fig. 2). 25,26 한편으로식물인간상태또는최소의식상태의환자에대한제2번경추부위의뒤쪽기둥 (dorsal column) 자극법은뇌내도파민과노르에피네프린을증가시키고, 뇌내혈류량을증가시키는것으로나타났다. 27 이러한여러가지기전에의해말초신경전기자극치료는식물인간상태또는최소의식상태의환자에서의식상태의개선에효과적임이밝혀져비침습적치료법으로제시되고있다. (2) 심부뇌전기자극치료법 (deep brain stimulation): 대표적인중추성전기자극치료법은심부뇌자극술 (deep brain stimulation) 이다. 이에대한연구는주로일본의 Katayama 등에의해시도되었는데, 그들의 10 년연구결과를볼때, 6개월이상된 21명의식물인간상태의환자에게 mesencephalic reticular formation과 thalamic centre median-parafascicular complex 에심부뇌자극술을 3 6개월간시도하여 8명에서구두지시에따라하기가가능한정도의호전을관찰할수있었다고보고하였다. 28 특히이렇게호전된경우다른호전이나타나지않은 13명에비해생명유지기간이의미있게길었다고하였다 (Fig. 3). 식물인간상태의뇌손상에서는뇌간의기능손상에비해대뇌피질의기능손상이더욱크고, 의식상태의유지에뇌간과대뇌피질간의관계가중요하여위 145
Brain& NeuroRehabilitation:2008; 1: 143~147 Fig. 3. Long-term follow-up results for the persistent vegetative state after deep brain stimulation (DBS) therapy giving a comparison of the survival period between recovered and non-recovered cases. 28 *p<0.05. 와같은부위에자극을가했을때기능적호전을기대할수있다는기전을바탕으로한다. 한편이들은 5명의최소의식상태의환자에게도심부뇌자극술을시행하였는데, 이경우모든환자에서긍정적인효과를보였다. 결론 뇌손상후식물인간상태또는최소의식상태의환자에대한여러가지고식적인치료와새로운치료가시도되고있으나아직까지근거중심의학측면에서뚜렷한치료법이규명되지않았다. 그러나감각자극치료법을포함한다양한재활의학적치료법과약물치료, 전기자극치료등이부분적이나마의식상태의개선에효과적임이보고되었다. 한편으로모든치료에서긍정적인효과를보인경우에도침상을벋어나지못하는상태의신체적기능상태에만족해야만하는새로운문제점을지닌다. 식물인간상태또는최소의식상태의환자에대한치료를위해서는국한된치료법에의존하지않는다양하고포괄적인치료적접근이필요하며, 치료효과의규명을위한체계적인학문적연구가진행되어야하겠다. 참고문헌 1) Jennett B, Plum F. Persistent vegetative state after brain damage. A syndrome in search of a name. Lancet. 1972; 1:734-737 2) Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, Kelly JP, Rosenberg JH, Whyte J, Zafonte RD, Zasler ND. The minimally conscious state: definition and diagnostic criteria. Neurology. 2002;58:349-353 3) Levin HS, Saydjari C, Eisenberg HM, Foulkes M, Marshall LF, Ruff RM, Jane JA, Marmarou A. Vegetative state after closed head injury: a traumatic coma data bank report. Arch Neurol. 1991;48:580-585 4) The Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state (second of two parts). N Engl J Med. 1994;330:1572 1579 5) Wood RL. Critical analysis of the concept of sensory stimulation for patients in vegetative states. Brain Inj. 1991; 5:401-409 6) Andrews K. International working party on the management of the vegetative state: summary report. BMJ. 1996; 10:797-806 7) Magee WL. Music therapy with patients in low awareness states: approaches to assessment and treatment in multidisciplinary care. Neuropsychol Rehabil. 2005;15:522-536 8) Wilson SL, Powell GE, Elliot K, Thwaites H. Sensory stimulation in prolonged coma: four single case studies. Brain Injury. 1991;5:393-400 9) Doman G, Wilkinson R, Dimancescu MD, Pelligra R. The effect of intense multisensory stimulation on coma arousal and recovery. Neuropsychol Rehabil. 1993;3:203 212 10) Grüner ML, Terhaag D. Multimodal early onset stimulation (MEOS) in rehabilitation after brain injury. Brain Inj. 2000; 14:585-594 11) Lombardi F, Taricco M, De Tanti A, Telaro E, Liberati A. Sensory stimulation of brain-injured individuals in coma or vegetative state: results of a Cochrane systematic review. Clin Rehabil. 2002;16:464-472 12) Elliott L, Coleman M, Shiel A, Wilson BA, Badwan D, Menon D, Pickard J. Effect of posture on levels of arousal and awareness in vegetative and minimally conscious state patients: a preliminary investigation. J Neurol Neurosurg Psychiatry. 2005;76:298-299 13) Morgan CL, Cullen GP, Stokes M, Swan AV. Effects of knee joint angle and tilt table incline on force distribution at the feet and supporting straps. Clin Rehabil. 2003;17:871-878 14) Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR Jr, Muizelaar JP, Wagner FC Jr, Marion DW, Luerssen TG, Chesnut RM, Schwartz M. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344:556-563 15) Matsuda W, Komatsu Y, Yanaka K, Matsumura A. Levodopa treatment for patients in persistent vegetative or minimally conscious states. Neuropsychol Rehabil. 2005;15:414-427 16) Passler MA, Riggs RV. Positive outcomes in traumatic brain injury-vegetative state: patients treated with bromocriptine. Arch Phys Med Rehabil. 2001;82:311-315 17) Giacino JT, Kalmar K. The vegetative and minimally conscious states: a comparison of clinical features and functional outcome. J Head Trauma Rehabil. 1997;12:36-51 18) Schneider WN, Drew-Cates J, Wong TM, Dombovy ML. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo- 146
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