대한안과학회지 2017 년제 58 권제 1 호 J Korean Ophthalmol Soc 2017;58(1):74-78 ISSN 0378-6471 (Print) ISSN 2092-9374 (Online) https://doi.org/10.3341/jkos.2017.58.1.74 Original Article 정맥투여네오스티그민검사를이용한눈중증근무력증의진단 Intravenous Neostigmine Test for Diagnosis of Ocular Myasthenia Gravis 김동익 이병주 김성준 Dong Ik Kim, MD, Byung Joo Lee, MD, Seong-Joon Kim, MD, PhD 서울대학교의과대학안과학교실 Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea Purpose: In the present study, we evaluated the validity of intravenous neostigmine administration combined with alternate prism cover test (APCT) measurement as a confirmatory diagnostic method for confusing cases of myasthenia gravis with ocular involvement. Methods: Neostigmine was administered intravenously in 26 suspicious myasthenic diplopia patients under electrocardiographic monitoring. Distance deviation at primary position was evaluated with APCT at 5, 10, 15, 20, and 30 minutes after intravenous injection of neostigmine. Margin reflex distance was also evaluated at each time point. Results: Seven of 26 patients were diagnosed as myasthenic diplopia based on a positive neostigmine test. Among these patients, 6 had strabismus at the primary position and 5 patients had ptosis. In patients who showed positive results, all 6 patients showed improvement of strabismus. However, ptosis was not improved in 1 patient. The improvement of strabismus and ptosis reached a peak at 10 to 15 minutes after neostigmine administration. Conclusions: Intravenous neostigmine administration combined with APCT is a rapid, objective and safe method in hard-to-diagnose cases of myasthenia gravis with ocular involvement. When performing the neostigmine test for myasthenia gravis with ocular involvement, not only the lid position but also strabismus should be evaluated quantitatively to avoid a false negative results. J Korean Ophthalmol Soc 2017;58(1):74-78 Keywords: Neostigmine, Ocular myasthenia gravis, Ptosis, Strabismus 중증근무력증은신경근접합부의후접합부에있는아세틸콜린수용체에대한자가항체로인해발생하는자가면역질환이다. 눈중증근무력증은눈근육에만국한된중증근무력증으로전체중증근무력증의 15-20% 를차지한다. 네오스티그민은가역적인항콜린에스테라아제로 1935년에 Viets and Schwab에의해처음으로눈중증근무력증진단목적으로사용되었다. 1 당시에는네오스티그민 1.5 mg Received: 2016. 10. 13. Revised: 2016. 10. 24. Accepted: 2016. 12. 29. Address reprint requests to Seong-Joon Kim, MD, PhD Department of Ophthalmology, Seoul National University Hospital, #101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: 82-2-2072-1979, Fax: 82-2-741-3187 E-mail: ophjun@gmail.com 과아트로핀 0.6 mg을근육투여하는검사법이사용되었으며, 이후 1948년에네오스티그민 0.5 mg을정맥투여하는검사법이 Tether에의하여소개되었다. 2 네오스티그민을정맥투여하게되면근육투여에비하여효과가더빠르게나타나효소억제효과는정맥주사 2-3분안에나타나는것으로알려져있다. 3 대부분의기관에서네오스티그민검사는신경과주관으로안과의사의참여없이시행되고있다. 검사양성판정은눈꺼풀처짐호전여부및주관적인복시호전여부로이루어지고있으며, 눈꺼풀처짐및사시정도에대한정량적평가는이루어지지않고있다. 이에본연구에서는눈중증근무력증이의심되는환자를대상으로정맥투여네오스티그민을시행하였고, 검사중안과의사가직접참여하여눈 c2017 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 74
- 김동익외 : 눈중증근무력증진단을위한네오스티그민검사 - Table 1. Clinical characteristics of patients who showed positive results in neostigmine test Patient Sex Age DM HTN Initial diagnosis Brain MRI RNST Ach R Ab TFT Case 1 F 31 (-) (+) MG, INO WNL (-) (+) WNL Case 2 M 45 (+) (-) MG, ALS (-) (+) (+) WNL Case 3 F 61 (-) (-) MG, TAO WNL (-) (+) WNL Case 4 M 57 (-) (-) MG, TAO, MF variant WNL (+) (-) WNL (Hyperthyroidism on medication) Case 5 M 37 (-) (-) Ocular MG (-) (-) (-) (-) Case 6 M 70 (-) (-) Left 6th nerve palsy, MG, WNL (-) (+) WNL multiple cranial neuropathy Case 7 F 69 (+) (-) Ocular MG WNL (-) (+) (-) DM = diabetes mellitus; HTN = hypertension; MRI = magnetic resonance imaging; RNST = repetitive nerve stimulation test; Ach R Ab = acetylcholine receptor antibody; TFT = thyroid function test; MG = myasthenia gravis; INO = internuclear ophthalmoplegia; ALS = amyotropic lateral sclerosis; TAO = thyroid associated orbitopathy; MF = miller-fisher syndrome; WNL = within normal limits. Table 2. Onset and peak time of strabismus improvement after neostigmine injection (data of patients who had positive results in neostigmine test) Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Mean Onset (minutes) 5 20 5 5 5 5 7.5 Peak (minutes) 10 20 10 5 5 20 11.7 꺼풀처짐및사시에대한검사를하여그결과를분석하였다. 대상과방법 2012년 3월부터 2015년 10월까지의기간동안서울대학교병원안과, 혹은신경과로복시및눈꺼풀처짐을주소로내원한환자들중병력청취및신체검진상눈중증근무력증이의심되는환자들을대상으로하였다. 이전사시의병력이있는환자나사시수술및눈꺼풀수술을받은병력이있는환자는제외하였다. 네오스티그민투여로발생할수있는부작용을고려하여심장이나폐질환이있는환자는제외하였고검사중지속적인심전도감시를시행하였다. 모든환자에게전처치로아트로핀 0.5 mg을정맥투여하였고 5분뒤네오스티그민 0.5 mg을정맥투여하였다. 3 네오스티그민투여전, 투여후 5분, 10분, 15분, 20분, 30분에검진을하여제일눈위치에서원거리사시각을교대프리즘가림검사로측정하였고, 눈꺼풀각막반사간거리 (margin reflex distance) 를측정하였다. 검진은안과전문의에의해서시행되었으며양성판정은사시에대해서는 10프리즘디옵터이상의수평사시각감소, 5프리즘디옵터이상의수직사시각감소가있을때로정의하였으며, 눈꺼풀처짐에대해서는눈꺼풀각막반사간거리의 2 mm 이상의증가가있을때로정의하였다. 본연구는헬싱키선언을준수하였고본원윤리위원회의승인을받아진행하였다 Figure 1. Degree of strabismus after neostigmine injection. Six patients showed positive results. The improvement of strabismus reached a peak at 11.7 minutes after neostigmine administration. PD = prism diopter. 결 과 총 26명의환자에서네오스티그민검사를시행하였고, 7 명에서양성결과를보였다 (Table 1). 뇌자기공명영상에서사시나눈꺼풀처짐을초래할만한병변이보고된환자는없었다. 갑상선호르몬및갑상선자극호르몬, 갑상선수용체자가항체검사에서도정상수치를보였다. 환자 1명 (Case 4) 은갑상선안병증으로고용량스테로이드정맥주사요법을시행한병력이있었으나갑상선호르몬및갑상선관련자가항체가정상범위로안정된양상이었으며, 복시증상에일중변동이있어갑상선안병증보다는눈중증근무력증이더의심되어검사를시행하였고양성결과를보였다. 75
- 대한안과학회지 2017 년제 58 권제 1 호 - 네오스티그민검사에서양성결과를보였던 7명의환자중반복신경자극검사양성은 2명, 아세틸콜린수용체결합항체양성은 5명이었다. 네오스티그민검사에서음성결과를보였던 16명의환자모두는반복신경자극검사와아세틸콜린수용체결합항체검사에서음성결과를보였다. 네오스티그민검사에서양성결과를보였던 7명모두에서사시, 혹은눈운동이상소견을보였고, 눈꺼풀처짐이동반된환자는 5명이었다. 제일눈위치에서사시가있었던 6명모두에서네오스티그민투여후사시각감소를보였다. 눈꺼풀처짐이있었던 5명중 4명에서는눈꺼풀처짐의호전도관찰되었다. 사시와눈꺼풀처짐이동반되었던 1명 (Case 6) 에서는사시각감소는있었으나눈꺼풀처짐은호전되지않았었다. 사시각감소를보였던 6명은네오스티그민을투여하고평균 7.5분뒤에사시각감소가나타났으며, 감소정도는평균 11.7분뒤에최대였다 (Table 2, Fig. 1). 눈꺼풀처짐의호전을보였던 4명은네오스티그민을투여하고평균 5분뒤에눈꺼풀각막반사간거리증가를보였고, 그증가정도는평균 11.3분뒤에최대였다 (Table 3, Fig. 2, 3). 눈꺼풀처짐이양안에있었던경우, 호전정도가컸던쪽을기준으로분석하였다. 네오스티그민검사양성을보였던환자중네오스티그민으로인한부작용이나타났었던환자는없었으며, 검사음성이었던환자중 1명에서입안의감각이상을호소하였다. 기관지경련, 혈압저하, 서맥, 부정맥, 심정지등의심각한 부작용을보였던환자는없었다. 검사에서음성결과를보였던 16명의환자들은갑상선안병증, 허혈성외향신경마비, 허혈성동안신경마비, 톨로사- 헌트증후군등으로진단되었고특발성사시혹은눈꺼풀처짐으로진단되었던환자도있었다. 고찰 눈중증근무력증은눈꺼풀처짐과사시, 눈운동장애가다양한형태로나타나며, 일중변동이특징적이다. 특히눈중증근무력증은전신중증근무력증에서사용되는여러진단검사에서전신중증근무력증에비해낮은양성률을보여진단이쉽지않다. 이에눈증중근무력증의진단에는혈액검사와전기생리검사등여러검사가동시에사용되고있으며, 아직표준검사법이라고할만한검사법은없다. 얼음검사는특별한장비없이도간단히시행할수있다는장점이있고, 민감도도 80-100% 로높은편이다. 4-6 그러나눈꺼풀처짐없이외안근이상만있는경우에는진단에큰도움이되지않는다. 반복신경자극검사는전신중증근무력증에서는유용하게쓰이지만눈중증근무력증의진단에는민감도가 33% 정도로낮아유용성이떨어진다. 7 또다른전기생리검사인단섬유근전도검사의민감도는반복신경자극검사보다높지만침습적이라는단점이있다. 8,9 아세틸콜린수용체결합항체검사또한전신중증근무력증에서는민감도가 80-90% 로높지만눈중증근무력증에서는민감 Table 3. Onset and peak time of ptosis improvement after neostigmine injection (data of patients who had positive results in neostigmine test) Case 2 Case 4 Case 5 Case 7 Mean Onset (minutes) 5 5 5 5 5 Peak (minutes) 5 10 15 15 11.3 Figure 2. Degree of ptosis after neostigmine injection in the right eye. Four patients showed positive results. The improvement of ptosis reached a peak at 11.3 minutes after neostigmine administration. MRD = margin reflex distance. Figure 3. Degree of ptosis after neostigmine injection in the left eye. Four patients showed positive results. The improvement of ptosis reached a peak at 11.3 minutes after neostigmine administration. MRD = margin reflex distance. 76
- 김동익외 : 눈중증근무력증진단을위한네오스티그민검사 - 도가 40-55% 로낮은것으로보고되어있다. 10-13 텐실론검사는항콜린에스테라아제인에드로포니움 (edrophonium) 을투여한후반응을평가하는검사로민감도는 90% 정도로높지만국내에서는약제를구하기어려워임상에서사용할수없다. 13 국내에서는네오스티그민을사용한검사가시행되고있으며, 네오스티그민검사도그유용성이입증되어있다. 14,15 중증근무력증의치료약제로항콜린에스테라아제가사용된다는점에서항콜린에스테라아제투여검사는중증근무력증의진단및치료반응을예측하는데유용하게사용될수있다. 네오스티그민은아세틸콜린의니코틴성수용체를활성화시켜중증근무력증증상을완화시킬수있지만, 무스카린성수용체도같이활성화시키기에눈물, 침, 땀등의분비물증가, 복통, 구역, 구토, 근육연축등이생길수있다. 또한드물지만심각한부작용인기관지경련, 혈압저하, 서맥, 부정맥, 심정지등이발생할수있기에검사시에주의가필요하다. 이런부작용이발생하였을때에는무스카린성수용체의길항제인아트로핀을주사하여치료할수있는것으로알려져있다. 네오스티그민검사는유병기간이긴환자에서는위음성률이높게나타나므로검사결과의해석에주의가필요하다. 또한이튼-람버트증후군, 선천성종말판아세틸콜린수용체결핍증, 근위축성측삭경화증, 길랑- 바레증후군, 뇌줄기신경아교종과같은질환에서는위양성을보일수있으므로주의하여야한다. 14,16,17 본연구에서네오스티그민검사양성결과를보였던환자중 28.6% 가반복신경자극검사양성소견을나타냈고, 71.4% 가아세틸콜린수용체결합항체양성소견을나타냈다 (Table 1). 이를통해자가항체검사및전기생리검사만으로는진단할수없었던환자를네오스티그민검사를통해진단할수있음을확인할수있었다. 양성결과를보인 7명모두는결과에서언급하지는않았지만추적관찰과정에서경구피리도스티그민 (pyridostigmine bromide) 복용후임상증상의호전이있었다. 본연구결과에따르면양성반응을보였던모든환자는네오스티그민정맥주사 5-10분뒤검사에서사시각감소, 눈꺼풀각막반사간거리증가를보였고, 그효과는정맥주사 10-15분뒤에최고점에도달하였다 (Table 2, 3). 이를통해보았을때검사양성판정은네오스티그민투여 15분내에가능할것으로생각되며검사에오랜시간이소요되지않는다는점을확인할수있었다. 안과의사가직접사시각과눈꺼풀높이측정을함으로써검사결과를수치화, 객관화할수있었다는점에서검사민감도와특이도를높일수있을것으로생각된다. 하지만 전체환자수가적으며, 한번의네오스티그민검사만시행하였다는점은본연구의한계점으로위음성이나위양성결과를배제하긴힘들것으로생각된다. 검사를시행한전체 26명의환자중네오스티그민정맥주사후심각한부작용을보였던환자는없었다는점을보았을때아트로핀전처치와검사중심전도감시를시행한다면네오스티그민검사는임상에서비교적안전하게시행가능할것으로생각된다. 눈중증근무력증은아직표준검사법이라고할만한검사법은없다. 눈중증근무력증이의심되는복시환자에서정맥투여네오스티그민검사법은본연구에서제시되었듯이임상에서빠르고안전하게시행할수있는검사법이다. 또한눈꺼풀각막반사간거리의측정및교대프리즘가림검사를이용한사시각의측정을통하여눈꺼풀처짐과사시를객관적으로평가한다면네오스티그민검사의위음성결과를줄여줄것으로기대된다. REFERENCES 1) Viets HR, Schwab RS. Prostigmin in the diagnosis of myasthenia gravis. N Engl J Med 1935;213:1280-3. 2) Tether JE. Intravenous neostigmine in diagnosis of myasthenia gravis. Ann Intern Med 1948;29:1132-8. 3) Calvey TN, Wareing M, Williams NE, Chan K. Pharmacokinetics and pharmacological effects of neostigmine in man. Br J Clin Pharmacol 1979;7:149-55. 4) Sommer N, Melms A, Weller M, Dichgans J. Ocular myasthenia gravis. A critical review of clinical and pathophysiological aspects. Doc Ophthalmol 1993;84:309-33. 5) Osserman KE. Ocular myasthenia gravis. Invest Ophthalmol Vis Sci 1967;6:277-87. 6) Luchanok U, Kaminski HJ. Ocular myasthenia: diagnostic and treatment recommendations and the evidence base. Curr Opin Neurol 2008;21:8-15. 7) Costa J, Evangelista T, Conceição I, de Carvalho M. Repetitive nerve stimulation in myasthenia gravis--relative sensitivity of different muscles. Clin Neurophysiol 2004;115:2776-82. 8) Golnik KC, Pena R, Lee AG, Eggenberger ER. An ice test for the diagnosis of myasthenia gravis. Ophthalmology 1999;106:1282-6. 9) Ellis FD, Hoyt CS, Ellis FJ, et al. Extraocular muscle responses to orbital cooling (ice test) for ocular myasthenia gravis diagnosis. J AAPOS 2000;4:271-81. 10) Chatzistefanou KI, Kouris T, Iliakis E, et al. The ice pack test in the differential diagnosis of myasthenic diplopia. Ophthalmology 2009;116:2236-43. 11) Oey PL, Wieneke GH, Hoogenraad TU, van Huffelen AC. Ocular myasthenia gravis: the diagnostic yield of repetitive nerve stimulation and stimulated single fiber EMG of orbicularis oculi muscle and infrared reflection oculography. Muscle Nerve 1993;16: 142-9. 12) Padua L, Stalberg E, LoMonaco M, et al. SFEMG in ocular myasthenia gravis diagnosis. Clin Neurophysiol 2000;111:1203-7. 77
- 대한안과학회지 2017 년제 58 권제 1 호 - 13) Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985;48:1246-52. 14) Lindstrom JM, Seybold ME, Lennon VA, et al. Antibody to acetylcholine receptor in myasthenia gravis Prevalence, clinical correlates, and diagnostic value. J Neurology 1998;51:933. 15) Oda K, Ito Y. Myasthenia gravis: antibodies to acetylcholine receptor in ocular myasthenia gravis. J Neurol 1981;225:251-8. 16) Jacob S, Viegas S, Leite M, et al. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol 2012;69:994-1001. 17) Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol 2009;8:475-90. = 국문초록 = 정맥투여네오스티그민검사를이용한눈중증근무력증의진단 목적 : 두눈복시환자에서눈중증근무력증을감별하기위해시행된교대프리즘가림검사병행정맥투여네오스티그민검사의유용성을보고하고자한다. 대상과방법 : 눈중증근무력증으로인한복시가의심되는환자 26 명을대상으로심전도감시하에네오스티그민을정맥투여하였다. 네오스티그민정맥투여 5, 10, 15, 20, 30 분뒤제일눈위치에서원거리사시각을교대프리즘가림검사로측정하였고, 눈꺼풀각막반사간거리도함께측정하였다. 결과 : 26 명중 7 명에서네오스티그민검사양성결과를보여눈중증근무력증으로진단하였다. 6 명은제일눈위치에서사시가있었고 5 명은눈꺼풀처짐이있었다. 사시가있었던 6 명모두에서네오스티그민투여후사시각감소를보였다. 사시와눈꺼풀처짐이동반되었던 1 명에서는사시각감소는있었으나눈꺼풀처짐의호전은없었다. 양성결과를보였던환자들에서그효과는평균적으로 10-15 분사이에최고점에도달하였다. 결론 : 눈중증근무력증이의심되는복시환자에서정맥투여네오스티그민검사법은임상에서빠르고안전하게시행할수있는검사법이다. 눈꺼풀각막반사간거리의측정및교대프리즘가림검사를이용한사시각의측정을통하여눈꺼풀처짐과사시를객관적으로평가한다면네오스티그민검사의위음성결과를줄여줄것으로기대된다. < 대한안과학회지 2017;58(1):74-78> 78