대한안신경의학회지 : 제 1 권제 1 호 Clin Neuroophthalmol 1(1):39-46, June 2011 ISSN: REVIEW 근신경계질환에서의안구운동장애 허영은 분당서울대학교병원신경과 Eye Findings in Neuro-muscul

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1 대한안신경의학회지 : 제 1 권제 1 호 ISSN: REVIEW 근신경계질환에서의안구운동장애 허영은 분당서울대학교병원신경과 Eye Findings in Neuro-muscular Diseases Young-Eun Huh, MD Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea Ocular myasthenia is a subtype of myasthenia gravis causing diplopia, ptosis, and weakness of lid closure. Clinically, ocular myasthenia can mimic any form of pupil-sparing ocular motility disorder. Dynamic abnormalities of myasthenic eye movements may reflect the primary hallmarks of the disease, which are fatigability and variability in strength, or secondary adaptive effects by the central nervous system. Ice, sleep, and rest tests are safe and inexpensive test for ocular myasthenia with high specificity and sensitivity. Abnormal eye movements are increasingly recognized in patients with amyotrophic lateral sclerosis (ALS) and, when they occur, may provide insights into the pattern and pathogenesis of the disease process. Disorders of saccade (slow saccade, delayed memory-guided saccade, inaccurate and delayed antisaccade), smooth pursuit (decreased gain), ocular fixation (increased saccadic intrusion amplitude), and ophthalmoplegia are reported in patients with ALS. Keywords: Ocular myasthenia; Amyotrophic lateral sclerosis; Eye movement 근신경계질환에서도다양한형태의안증상을보일수있다. 본문에서는안구형중증근무력증 (ocular myasthenia gravis) 과근위축성측색경화증 (amyotrophic lateral sclerosis, ALS) 환자에서보이는안증상에대해간략하게기술하였다. 안구형중증근무력증 증에서차지하는비율은약 12-15% 정도이다. 2 안구형중증근무력증은침범하는근육에따라다양한형태의안증상을보이는데, 이는안근마비및피로 (fatigue) 에의한증상과이를보상하려는이차적중추신경계적응작용 (secondary adaptive mechanism) 이복합된형태를띤다. 본문에서는안구형중증근무력증에서나타나는특징적안증상을침범하는근육에따라기술하고이를진단하는방법을제시하였다. 안구형중증근무력증 (ocular myasthenia gravis) 은근위약이외안근 (extraocular muscle), 윗눈꺼풀올림근 (levator palpabrae superioris muscle), 눈둘레근 (orbicularis oculi muscle) 을포함한안구주변근육에국한되어나타나는중증근무력증의아형이다. 75% 의근무력증환자가초기증상으로안증상을호소하며이중 9% 이상은전신형으로발전한다 % 는초기에안증상만을보이는경우가있는데, 이중 3-4% 만이안구형으로남아결과적으로안구형이전체근무력 1. 안구형중증근무력증의안증상 1) 윗눈꺼풀올림근윗눈꺼풀올림근 (levator palpabrae superioris muscle) 위약으로인한안검하수 (ptosis) 는단독으로발생할수도있고다른안구주변근마비를동반할수도있다. 안검하수가있는환자에서피로현상및기복 (fluctuation) 을호소하는경우, 근무력증을강력히의심할수있다. 안검하수는일측성또는양측성으로발생하고, 대개는비대칭적이다. Correspondence to: Young Eun Huh, MD Department of Neurology, Seoul National University Bundang Hospital, 3 Gumi-dong, Bundang-gu, Seongnam , Korea Tel: ; Fax: ; nana188@hanmail.net Received: Jun. 8, 211 / Accepted: Jul. 11, 211 Copyright 211 The Korean Society of Neuro-Ophthalmology 39

Huh YE Eye Findings in Neuro-muscular Diseases 병력청취상아침에일어날때는증상이없다가시간이갈수록안검하 수가뚜렷해지는증상을호소하는것이특징적이다. 안검하수는지 속적상방주시시에악화 (lid fatigue test) 되므로, 환자에게수분간위 를쳐다보게하면안검하수가나타나거나악화됨을관찰할수있다.

2 Huh YE Eye Findings in Neuro-muscular Diseases 병력청취상아침에일어날때는증상이없다가시간이갈수록안검하 수가뚜렷해지는증상을호소하는것이특징적이다. 안검하수는지 속적상방주시시에악화 (lid fatigue test) 되므로, 환자에게수분간위 를쳐다보게하면안검하수가나타나거나악화됨을관찰할수있다. 일측성으로안검하수를보이는경우, 눈꺼풀을손가락으로들어올리 면정상처럼보였던눈에안검하수가뚜렷해지는현상 (enhanced ptosis) 을관찰할수있는데, 이는실제로양측안검하수가있으나 Hering 의법칙 ( 공액근에는동일한정도의신경지배가이루어짐 ) 에의해안 검하수정도가심하지않은쪽이정상처럼보이기때문이다. 3 근무력증환자는안검후퇴 (lid retraction) 역시보일수있다. 일측 성으로안검하수가있는경우반대편에안검후퇴를보일수있는데 (Fig. 1), 이역시 Hering 의법칙에의한것으로아래를바라보게하거 나안검하수가있는눈꺼풀을들어올리면안검후퇴는호전된다. 또 한, 근무력증환자의 4-1% 가갑상선질환을동반하므로갑상선안병 증의일종으로안검후퇴를보일수있다. 4 마지막으로지속적상방주 시후에일시적으로안검후퇴가발생할수있는데, 이는강직후촉진 (post-tetanic facilitation) 또는근긴장 (myotonia) 에의한현상이므로, 5 Lambert-Eaton 증후군의가능성도고려해야한다. 6 Fig. 1. Left upper eyelid retraction contralateral to a ptotic right upper eyelid because of Hering s law. 아래를 1-2 초간바라보게한뒤빠르게정면을보게하면눈꺼풀이일시적으로위로올라갔다가아래로처지는현상이나타날수있는데이를 Cogan s lid twitch 징후라한다. 7 이는아래를바라보는동안근무력이빠르게회복되었다가눈꺼풀을들어올리면서쉽게피로현상이생기기때문이다. 2) 눈둘레근눈둘레근 (orbicularis oculi muscle) 역시근무력증에서흔하게침범되며눈을힘껏감으라고한뒤검사자가눈을억지로띄우면서위약여부를판단한다. 눈을힘껏감을때속눈썹이눈꺼풀틈새에묻혀야정상이며, 눈을감을때눈꺼풀틈새가벌어져서는안된다. 눈을감고서시간이지나면눈둘레근의피로현상으로눈꺼풀틈새가서서히벌어지는 peek-a-boo 징후를보일수있다. 8 3) 외안근외안근 (extraocular muscle) 마비에의한복시는근무력증의두번째로흔한증상이며근무력증환자의 9% 가복시를호소한다. 대체로외안근마비는안검하수를동반한다. 다양한형태의사시를보이는데, 내직근 (medial rectus muscle), 하직근 (inferior rectus muscle), 상사근 (superior oblique muscle) 이흔히침범된다. 9 안구형근무력증은말초성외안근마비는물론중추성주시마비의형태로도나타날수있으므로, 동공침범이없는안근마비에서는항상안구형중증근무력증의가능성을염두하여야한다. 안구형근무력증의안구운동장애는 Table 1로요약하였다. 외안근이광범위하고심하게침범된경우에는만성진행성외안근마비 (chronic progressive external ophthalmoplegia) 와구별이어려울수있다. 1 두질환모두외안근완전마비, 안검하수, 눈둘레근위약을보일수있고, 단일근섬유근전도 (single fiber electromyography) 에서 jitter 증가를보일수있기때문이다. 만성 Table 1. Patterns of ocular motility impairment observed in myasthenia gravis Patterns of motility impairment Unilateral abduction deficit Unilateral infraduction deficit Adduction, infraduction, and supraduction deficit Ptosis and supraduction deficit Hypertropia on contralateral gaze Inferior oblique palsy Unilateral or bilateral adduction deficit with/without abducting nystagmus in opposite eye Bilateral upgaze palsy Horizontal gaze palsy Horizontal gaze palsy plus internuclear ophthalmoplegia Diffuse extraocular muscle weakness Mimicked syndrome Abducens nerve palsy Inferior divisional oculomotor nerve palsy Pupil-sparing oculomotor nerve palsy Superior division oculomotor nerve palsy Trochlear nerve palsy Brown syndrome Unilateral or bilateral internuclear ophthalmoplegia Supranuclear vertical gaze palsy (eg. progressive suparnuclear palsy) Parinaud s syndrome Nuclear or supranuclear horizontal gaze palsy One-and-a-half syndrome Chronic progressive external ophthalmoplegia 4

3 근신경계질환에서의안구운동장애 허영은 진행성외안근마비는병력상서서히진행하면서증상의기복이없고, 단속운동속도가근무력증에비해더느린것이감별점이다. Bell 현상 ( 눈을힘껏감을때눈동자가위로올라가는현상 ) 역시근무력증환자에서없거나감소될수있다. 이는상방주시장애정도와비례한다고알려져있다. 11 근무력증환자에서단속운동을반복적으로시킬경우, 초기에는정상이지만결국단속운동의속도와크기가감소하게된다. 12 단속운동중피로현상 (intrasaccadic fatigue) 이란큰단속운동도중에단속운동속도가감소하여서서히시표에도달하는현상 (Fig. 2) 으로이때단속운동의기간 (duration) 역시증가한다. 13 이는연축근섬유 (twit ch fiber) 의피로에의한것이다. 오히려작은단속운동의속도는비정상적으로증가하는현상을관찰할수있다. 단속운동속도또는단속운동크기에대한속도역시가변성 (variability) 을보일수있는데 (saccadic jitter) 이는근무력증환자에진단적가치가있다. 14 단속운동의궤적 (trajectory) 역시변동정도가증가하며, 지속적주시후에는단속운동크기가감소한다. 15 긴장성근섬유 (tonic fiber) 의피로현상으로편향된위치에서주시가유지되지못하는경우단속운동후 glissadic drift가반대방향으로발행하며이를 quiver 현상이라한다. 16 Quiver 현상은 작은단속운동시더잘나타난다. 동일한이유에서지속적편향주시 시주시유발안진 (gaze-evoked nystagmus) 이나타날수있다. 17 또한, 큰 단속운동은겨냥과소 (hypometria) 가나타나는반면, 작은단속운동 은겨냥과다 (hypermetria) 가나타나는데, 이는근위약에대한중추 성보상기전에의한것이다. 18 4) 동공및모양체 근무력증환자의동공과모양체 (pupil and ciliary body) 침범에대해 서는아직이론이있다. 대부분임상적으로동공침범은뚜렷하지않 으며, 이는안구형근무력증과다른유사질환과의감별에도중요한 1 sec 1 right 1 left Fig. 2. Slow and hypometric saccades in a patient with ocular myasthenia. The patient is making saccades to follow a target (dotted line) making 2-degree steps repetitively. Black lines show his eye position (y-axis) over time (x-axis). Occasional intrasaccadic fatigue (arrow) is shown. Table 2. Comparison of diagnostic tests for myasthenia gravis Test Sensitivity Specificity Advantage Disadvantage N ot as well-studied for ophthalmoparesis as for ptosis 9% (for ptosis) 1% (for ptosis) Office base Non invasive Inexpensive Safe Simple G reater improvement in ptosis than seen with rest test Sleep test 1% 1% Office base Ties up an exam room for a half hour Non invasive Inexpensive Safe Simple Rest test 5% 1% Much quicker than sleep test Less ptosis improvement than ice test E drophonium or neostigmine test A cetylcholine receptor antibody OM: 86-97% OM: 83% Office base Side effect GM: 82-1% Most useful with ptosis and ophthalmoparesis IV access Well-studied Monitoring of pulse and blood pressure OM: 25-75% -1% Most specific Less sensitive for OM than GM GM: 8-99% Expensive RNS OM: 15-5% OM: 89% Widely available Uncomfortable SFEMG GM: 71% OM: 62-1% (frontalis, orbicularis oculi, superior rectus-levator complex muscle) GM: 9% Low sensitivity MG: 89% Most sensitive Uncomfortable P ositive test means neuromuscular junction disorder, not specific for MG N eed experienced electrophysiologist with special equipment 41

Huh YE Eye Findings in Neuro-muscular Diseases 의미를갖는다. 그럼에도근무력증환자에서동공부등 (anisocoria) 이보고된바가있고이는콜린에스터라제저해제사용시호전되었다.

진단방법중증근무력증은일반적으로, 전기생리학적검사 ( 반복자극검사, 단일근섬유근전도 ), 아세틸콜린수용체항체검사, 아세틸콜린분해억제제에대한반응등으로진단할수있다. 그러나안구형근무력증의경우상기검사의민감도가전신형근무력증에비해낮아진단이용이하지않다. 중증근무력증의진단법과각각의민감도및특이도는 Table 2에요약하였다.

안검하수의경우 2 mm 이상호전을보이는경우근무력증을진단할수있는데 (Fig. 3), 보통 1분이내에이전상태로돌아간다. 각빙검사는외안근마비보다는안검하수에서더욱진단적가치가있는데, 이는안구운동제한정도및안구정렬정도의호전을정확히측정하기어렵기때문이다. 2) 수면검사환자를어둡고조용한방에 3분간수면을취하게한뒤증상의호전여부를알아보는검사이다.

4 Huh YE Eye Findings in Neuro-muscular Diseases 의미를갖는다. 그럼에도근무력증환자에서동공부등 (anisocoria) 이보고된바가있고이는콜린에스터라제저해제사용시호전되었다. 19 동공빛반사 (pupillary light reflex) 의속도가느려지거나, 2 지속적빛자극시동공수축 (pupil constriction) 의피로현상 21 이보고되었다. 또한지속적눈모음 (convergence) 으로축동 (accommodation) 피로현상이유발된예가있으며, 이는 edrophonium 투약후호전되었다 진단방법중증근무력증은일반적으로, 전기생리학적검사 ( 반복자극검사, 단일근섬유근전도 ), 아세틸콜린수용체항체검사, 아세틸콜린분해억제제에대한반응등으로진단할수있다. 그러나안구형근무력증의경우상기검사의민감도가전신형근무력증에비해낮아진단이용이하지않다. 중증근무력증의진단법과각각의민감도및특이도는 Table 2에요약하였다. 여기에서는각빙검사 (ice cube test), 수면검사 (sleep test), 휴식검사 (rest test) 에대해간단하게기술하였다. 한다. 눈을감은상태에서얼음조각을 2-5분간 ( 안검하수에는 2분, 외안근마비에는 5분간 ) 환자의눈꺼풀위에댄뒤안검하수와외안근마비의호전정도를관찰한다. 얼음조각적용전후로사진을찍어객관적으로기록하는것이중요하다. 안검하수의경우 2 mm 이상호전을보이는경우근무력증을진단할수있는데 (Fig. 3), 보통 1분이내에이전상태로돌아간다. 각빙검사는외안근마비보다는안검하수에서더욱진단적가치가있는데, 이는안구운동제한정도및안구정렬정도의호전을정확히측정하기어렵기때문이다. 2) 수면검사환자를어둡고조용한방에 3분간수면을취하게한뒤증상의호전여부를알아보는검사이다. 역시검사전후로안검하수와외안근마비등을사진으로찍어객관적으로기록해야한다. 수면검사 (sleep test) 는안구형근무력증환자에서 edrophonium test보다민감도가더높은것으로보고된바있다. 26 1) 각빙검사각빙검사 (ice cube test) 는안구주변근육을얼음조각으로국소냉각하여, 안구형근무력증을진단하는데빠르고, 안전하고, 저렴하면서도민감도와특이도가매우높은검사이다 온도가떨어지면아세틸콜린에스터라제의활동성이감소하여신경근접합부에아세틸콜린의양이증가하고, 이로인해근무력증이호전되는것을원리로 3) 휴식검사간이수면검사로 2-5분간눈을감고난뒤증상의호전여부를알아보는검사이다. 일부에서는각빙검사역시냉각에의해서가아니라눈을감은상태로검사를하므로휴식에의해증상이호전되는것이라는주장이있다. 실제같은방법으로뜨거운팩을얼음조각대신적용하였을때도유사한정도의증상호전을보였기때문이다. 27 휴식 A B C Fig. 3. Ice test. (A) Preceding the test, bilateral asymmetric upper eyelid ptosis is present, much worse on the left. (B) An ice pack is applied to the closed left eye for 2 minutes. (C) After the application of ice, the left upper eyelid ptosis is significantly improved. 42

5 근신경계질환에서의안구운동장애 허영은 검사 (rest test) 와각빙검사를비교한연구에서, 정상군에서는두군모두음성을보인반면, 근무력환자군에서는휴식검사시평균 2 mm, 각빙검사시 4.5 mm 정도로안검하수가호전되었다. 28 근위축성측색경화증고전적으로근위축성측색경화증 (amyotrophic lateral sclerosis, ALS) 환자는인공호흡기로생명이연장된환자를제외하고안구운동이보존된다고알려져있었다. 29 그러나최근 2년간보고된바에의하면 ALS에서도다른신경계퇴행성질환과마찬가지로다양한정도의안구운동장애가있음이밝혀졌다. 본문에서는 ALS 환자에서보이는단속운동 (saccade), 원활추종운동 (smooth pursuit), 시선고정 (ocular fixation) 장애와안근마비 (ophthalmoplegia) 에대해살펴보고이들안 구운동장애가 ALS와 ALS 유사질환장애를감별하고정확한진단을하는데유용한지에대해알아보기로한다. 1. ALS에서단속운동장애단속운동 (saccade) 이란선명한시력을유지하기위해시선을빨리이동하여관심대상이되는물체를망막의중심오목 (fovea) 에맺히게하는안구운동이다. 몇가지패러다임으로단속운동을검사할수있는데, 본문에서는반사적단속운동 (reflexive: visually-guided saccade) 과자발적단속운동 (volitional: memory-guided saccade and antisaccade) 장애에대해기술하였다. 1) ALS에서반사적단속운동장애이전까지 ALS 환자에서반사적 (reflexive: visually-guided) 단속운 Rightward saccade Leftward saccade Upward saccade Downward saccade Eye position (deg) Right eye Left eye Eye position (deg) Right eye Left eye Eye velocity (deg/s) Peak velocity (deg/s) Duration (ms) , , Time (ms) Rightward saccade Right eye Left eye Leftward saccades Amplitude (deg) Eye velocity (deg/s) Peak velocity (deg/s) Duration (ms) Amplitude (deg) Fig. 4. Saccadic abnormalities in a 7-year-old man with bulbar onset amyotrophic lateral sclerosis. Eye movement recordings using the magnetic search coil technique revealed slowing and reduced amplitude of vertical saccades. Horizontal saccades were also mildly slowed, with saccades of the adducting eye being slower than those of the abducting eye, giving the appearance of bilateral internuclear ophthalmoplegia. Shaded zones indicate the 95% prediction intervals for a group of normal control subjects, with the white line indicating the mean , , Time (ms) Upward saccades Downward saccades Right eye Left eye 43

6 Huh YE Eye Findings in Neuro-muscular Diseases 동은정상이라고알려져있었다. 그러나 bulbar onset ALS환자에서 spinal onset 환자에비해반사적단속운동의최대속도 (peak velocity) 가느려져있음이관찰되었으며 (Fig. 4), 3 특히급속히진행하는 ALS 환자 1명중 2명에서느린단속운동이관찰되었다. 31 동일연령대조군비교에서도 9명중 4명의 ALS 환자에서단속운동이느려져있었다. 32 단속운동의 pulse가뇌간에서생성됨을고려할때 ALS 환자에서보이는느린단속운동은뇌간자체에병태생리로발생한다고추정할수있다. 2) ALS에서자발적 (volitional: memory-guided and antisaccade) 단속운동장애 Memory-guided saccade는시표를시야의주변부에수초간보여준뒤사라지게한다음주변부에나타났던시표의위치를기억하여바라보게하는검사이다. ALS 환자는 short-term memory-guided saccade ( 시표를수초전에보여준뒤검사 ) 의반응시간 (latency) 이연장되어있는반면, 정확도 (accuracy) 는정상이다. 33 Antisaccade 는제시된시표의정반대방향을바라보게하여검사하는데, 예를들면중심에서 1도좌측에시표를보여줄때실제우측 1도위치로단속운동을수행하는것이다. ALS 환자는 antisaccade 의정확도가감소하고반응시간이연장되는데, 3, 33 특히 type I error ( 부정확한 antisaccade 후이를스스로교정하지못함 ) 가증가하는것으로알려져있다. 3 또한 type I error율은 Stroop test 및 bulbar subscore 를포함하는 Amyotrophic Lateral Sclerosis Functional Rating Scale과도비례하는것으로나타났다. Antisaccade는전두안영역 (frontal eye field, FEF) 과배측외측전전두엽 (dorsolateral prefrontal cortex, DLPC) 에서담당하는데 FEF는주로 antisaccade 의반응시간을, DLPC는주로 error율을조절한다. 34 즉, ALS 환자에서 antisaccade 의장애는이두영역의장애로인한것으로생각할수있다. 또한 DLPC는 short-term memory-guided saccade의생성과도관련된다고알려져있어, 34 ALS 환자에서나타나는자발적단속운동의장애는전두엽기능이상에의한것이라할수있다. 신경심리검사상임상적으로치매가없는 ALS 환자의 5% 가전두엽기능이상을보였으며, 35 임상병리연구에서 ALS와전두측두엽치매가하나의질환스펙트럼상에있음을시사하는소견이발견되었다는점 36 도 ALS 환자에서의자발적단속운동장애가전두엽기능장애로부터기인하는것임을시사하는소견이다. 2. ALS에서원활추종운동장애원활추종운동 (smooth pursuit) 은생리학적으로초기가속기 (pursuit initiation) 와유지기 (pursuit maintenance) 로구분할수있다. 대부분의연구는 ALS 환자에서원활추종운동유지기의속도이득 (velocity gain) 이감소됨을보고하였다. 31, 37, 38 반면 Shaunak 등 33 은예측가능한 triangular waveform stimulus를이용하여검사하였을때, 원활추종운동의속도이득이정상이라주장하였다. 또다른연구에서는파킨슨양상을동반한 ALS 환자에서만속도이득이감소하며, 산발성 -2 Position (degrees) Saccadic intrusion Fixation period , 4, 6, 8, 1, Position (degrees) Time (ms) Saccadic intrusion Fixation period VFI (s letters) E-5-1 1, 12, 14, 16, 18, 2, Time (ms) A GMSIA ON (degrees) B Fig. 5. (A) Saccadic intrusions, measured by their amplitude (degrees) and fixation periods (milliseconds) are depicted by arrows. The top record is from a MND patient revealing larger amplitude saccadic intrusions compared to the record below from a control subject. (B) Scatter plot highlighting the correlation between GMSIA ON and VFI (s letters). Regression coefficient, R=.33. GMSIA ON Geometric mean saccadic intrusion amplitude with the target stimulus on (degrees); VFI Verbal Fluency Index (seconds). 44

7 근신경계질환에서의안구운동장애 허영은 ALS 환자에서는정상이라보고한바있다. 39 그러나대부분의 ALS 환자에서원활추종운동의속도이득은감소하며이는따라잡기단속운동 (catch-up saccade) 으로대체되는경향을보인다. 4 원활추종운동은대뇌에서시작하여교뇌및소뇌를거치는해부학적경로를통해이루어지며, 속도이득은정상노인을비롯하여파킨슨증후군, 알츠하이머치매, 전두측두엽치매, 소뇌기능이상질환, 대사성뇌병증및약물중독등다양한상황에서감소할수있다. 34 따라서원활추종운동의속도이득감소가진단특이적이라하기는어렵다. 그러나전두안영역을미세전기자극하였을때원활추종운동의속도이득이조절되는현상을근거로, 41 ALS 환자에서속도이득감소는전두안영역기능이상으로설명할수있다. 3. ALS에서시선고정장애 1) 단속운동간섭 ALS 환자에서는사각파된떨림 (square wave jerk) 의빈도가동일연령대조군에비해증가됨이알려져있다. 33 특히 ALS 환자의시선고정 (ocular fixation) 장애를정량화한연구에서, 단속운동간섭 (saccadic intrusion) 의크기 (amplitude) 가증가할뿐아니라, 증가정도는전두엽기능장애를반영하는유창성검사와 Stroop 검사점수와비례함을보고하였다 (Fig. 5). 42 단속운동간섭은단속안구운동경로의이상으로발생한다. 실제, 문측상구 (rostral pole of superior colliculus), 중뇌그물체 (mesencephalic reticular formation), 소뇌꼭지핵 (fastigial nucleus) 과기저핵 (basal ganglia) 병변시단속운동간섭이발생하는것으로알려져있다. 34 문측상구로투사하는전두안영역역시지속적시선고정시불필요한단속운동을억제하는기능을하므로이부위의병변으로도단속운동간섭이유발될수있다. 34 ALS 환자에서단속운동간섭의크기와전두엽기능이상정도가비례하는점을고려하였을때, ALS 환자에서단속운동간섭은전두-상구경로의침범으로발생한다하겠다. 2) 안진안진 (nystagmus) 은 ALS 환자에서매우드문소견이다. 한증례보고에서주시유발안진 (gaze-evoked nystagmus) 을보인 ALS 환자가핵상안구마비 (supranuclear ophthalmoplegia) 와수평안진으로진행된예를보고하였고, 안구마비없이주시유발안진만있었던예를기술한바있다. 43 그러나이들중한명은부검결과소장의악성종양이발견되어, 안진이부종양증후군 (paraneoplastic syndrome) 과관련하여발생하였을가능성을배제하기어렵다. 또다른연구에서는하부운동신경원증후군 (lower motor neuron syndrome) 양상을보인세명의환자가하방안진 (downbeat nystagmus) 을보인사례를보고하였다. 44 그 러나이들중한명은소뇌위축이있고자세불균형이주증상이었으 므로, 전기생리학적으로는 ALS 에합당하다하더라도다른질환군일 가능성이높다. 즉, ALS 가의심되는환자에서안진을보일경우에는 이를가장할수있는다른질환을의심하는것이더욱타당할것이다. 4. 안근마비 안근마비 (ophthalmoplegia) 는인공호흡기를이용하여생명이장기 간연장되었던일부를제외하면 ALS 환자에서드문소견이다. 29 Harvey 등 45 은외안근마비가질환초기에나타나사망전까지완전한외안 근마비로진행된증례를보고한바있다. 이환자의부검결과에서안 구운동핵에광범위한신경세포소실과교세포증식 (gliosis) 이관찰되 었다. ALS 에서안구운동핵은척수운동핵에비해상대적으로보존된 다고알려져있다. 46 이를설명하는가설로흥분성글루타메이트신경 전달물질, 칼슘결합단백질, 영양요소 (trophic factor), 안드로젠수용 체의분포정도의차이가제시되었으나, 아직기전은확실하지않다. 5. ALS 유사질환에서의안구운동장애 1) 진행성핵상마비 ALS 환자에서도진행성핵상마비 (progressive supranuclear palsy) 에 서보이는느린단속운동과핵상안구마비를보일수있을뿐아니 라, 47-5 진행성핵상마비에서흔히동반되는단속운동간섭, antisaccade error 증가, 원활추종운동이득감소를보이므로이와의감별이 필요하다. 2) 케네디병 케네디병 (Kennedy s disease) 은성염색체연관열성유전질환으로 구와척수의하부운동원을침범하여후발성근위축을유발한다. 케 네디병은진행속도가상대적으로느리고, 추체로를침범하지않는다 는점에서 ALS 와감별이가능하다. 최근케네디병에서는수직 / 수평 방향의반사적신속운동이감소되는반면, 다른안구운동은보존되 어있음이알려져 51 ALS 와의감별이필요하다. REFRENCES 1. Bever CT Jr, Aquino AV, Penn AS, Lovelace RE, Rowland LP. Prognosis of ocular myasthenia. Ann Neurol 1983;14: Oosterhuis HJ. The natural course of myasthenia gravis: a long term follow up study. J Neurol Neurosurg Psychiatry 1989;52: Gorelick PB, Rosenberg M, Pagano RJ. Enhanced ptosis in myasthenia gravis. Arch Neurol 1981;38: Silver S, Osserman KE. Hyperthryoidism and myasthenia gravis. J Mt Sinai Hosp 1957;24: Puklin JE, Sacks JG, Boshes B. Transient eyelid retraction in myasthenia 45

8 Huh YE Eye Findings in Neuro-muscular Diseases gravis. J Neurol Neurosurg Psychiatry 1976;39: Breen LA, Gutmann L, Brick JF, Riggs JR. Paradoxical lid elevation with sustained upgaze: a sign of Lambert-Eaton syndrome. Muscle Nerve 1991; 14: Cogan DG. Myasthenia Gravis: a review of the disease and a description of lid twitch as a characteristic sign. Arch Ophthalmol 1965;74: Osher RH, Griggs RC. Orbicularis fatigue: the peek sign of myasthenia gravis. Arch Ophthalmol 1979;97: Weinberg DA, Lesser RL, Vollmer TL. Ocular myasthenia: a protean disorder. Surv Ophthalmol 1994;39: Brust JC, List TA, Catalano LW, Lovelace R. Ocular myasthenia gravis mimicking progressive external ophthalmoplegia. Rare case of myasthenia associated with peripheral neuropathy and spastic paraparesis. Neurology 1974;24: Miller NR, Griffin J, Cornblath D, Guerin C. Intact Bell s phenomenon in a patient with myasthenia gravis and upward gaze paresis. Arch Ophthalmol 1989;17: Baloh RW, Keesey JC. Saccade fatigue and response to edrophonium for the diagnosis of myasthenia gravis. Ann N Y Acad Sci 1976;274: Schmidt D, Dell Osso LF, Abel LA, Daroff RB. Myasthenia gravis: saccadic eye movement waveforms. Exp Neurol 198;68: Barton JJ, Sharpe JA. Saccadic jitter is a quantitative ocular sign in myasthenia gravis. Invest Ophthalmol Vis Sci 1995;36: Sollberger CE, Meienberg O, Ludin HP. The contribution of oculography to early diagnosis of myasthenia gravis. A study of saccadic eye movements using the infrared reflection method in 22 cases. Eur Arch Psychiatry Neurol Sci 1986;236: Cogan DG, Yee RD, Gittinger J. Rapid eye movements in myasthenia gravis. I. Clinical observations. Arch Ophthalmol 1976;94: Spooner JW, Baloh RW. Eye movement fatigue in myasthenia gravis. Neurology 1979;29: Yee RD, Cogan DG, Zee DS, Baloh RW, Honrubia V. Rapid eye movements in myasthenia gravis. II. Electro-oculographic analysis. Arch Ophthalmol 1976;94: Herishanu Y, Lavy S. Internal ophthalmoplegia in myasthenia gravis. Ophthalmologica 1971;163: Yamazaki A, Ishikawa S. Abnormal pupillary responses in myasthenia gravis. A pupillographic study. Br J Ophthalmol 1976;6: Dutton GN, Garson JA, Richardson RB. Pupillary fatigue in myasthenia gravis. Trans Ophthalmol Soc U K 1982;12(Pt 4): Manson N, Stern G. Defects of near vision in myasthenia gravis. Lancet 1965;1: Sethi KD, Rivner MH, Swift TR. Ice pack test for myasthenia gravis. Neurology 1987;37: Ertas M, Arac N, Kumral K, Tuncbay T. Ice test as a simple diagnostic aid for myasthenia gravis. Acta Neurol Scand 1994;89: Golnik KC, Pena R, Lee AG, Eggenberger ER. An ice test for the diagnosis of myasthenia gravis. Ophthalmology 1999;16: Odel JG, Winterkorn JM, Behrens MM. The sleep test for myasthenia gravis. A safe alternative to tensilon. J Clin Neuroophthalmol 1991;11: Movaghar M, Slavin ML. Effect of local heat versus ice on blepharoptosis resulting from ocular myasthenia. Ophthalmology 2;17: Kubis KC, Danesh-Meyer HV, Savino PJ, Sergott RC. The ice test versus the rest test in myasthenia gravis. Ophthalmology 2;17: Mizutani T, Aki M, Shiozawa R, Unakami M, Nozawa T, Yajima K, et al. Development of ophthalmoplegia in amyotrophic lateral sclerosis during long-term use of respirators. J Neu rol Sci 199;99: Donaghy C, Pinnock R, Abrahams S, Cardwell C, Hardiman O, Patterson V, et al. Slow saccades in bulbar-onset motor neurone disease. J Neurol 21;257: Leveille A, Kiernan J, Goodwin JA, Antel J. Eye movements in amyotrophic lateral sclerosis. Arch Neurol 1982;39: Ohki M, Kanayama R, Nakamura T, Okuyama T, Kimura Y, Koike Y. Ocular abnormalities in amyotrophic lateral sclerosis. Acta Otolaryngol Suppl 1994;511: Shaunak S, Orrell RW, O Sullivan E, Hawken MB, Lane RJM, Henderson L, et al. Oculomotor function in amyotrophic lateral sclerosis: eviden ce for frontal impairment. Ann Neurol 1995;38: Leigh RJ, Zee DS. The neurology of eye movements. 4 ed. New York: Oxford University Press; Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 25;65: Geser F, Lee VM, Trojanowski JQ. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology Apr 21;3: Abel LA, Williams IM, Gibson KL, Levi L. Effects of stimulus velocity and acceleration on smooth pursuit in motor neuron disease. J Neurol 1995;242: Marti-Fabregas J, Roig C. Oculomotor abnormalities in motor neuron disease. J Neurol 1993;24: Gizzi M, DiRocco A, Sivak M, Cohen B. Ocular motor function in motor neuron disease. Neurology 1992;42: Jacobs L, Bozian D, Heffner RR, Jr, Barron SA. An eye movement disorder in amyotrophic lateral sclerosis. Neurology 1981;31: Tanaka M, Lisberger SG. Regulation of the gain of visually guided smoothpursuit eye movements by frontal cortex. Nature 21;49: Donaghy C, Pinnock R, Abrahams S, Cardwell C, Hardiman O, Patterson V, et al. Ocular fixation instabilities in motor neurone disease. A marker of frontal lobe dysfunction? J Neurol 29;256: Kushner MJ, Parrish M, Burke A, Behrens M, Hays AP, Frame B, et al. Nystagmus in motor neuron disease: clinicopathological study of two cases. Ann Neurol 1984;16: Thakore NJ, Pioro EP, Rucker JC, Leigh RJ. Motor neuronopathy with dropped hands and downbeat nystagmus: a distinctive disorder? A case report. BMC Neurol 26;6: Harvey DG, Torack RM, Rosenbaum HE. Amyotrophic lateral sclerosis with ophthalmoplegia. A clinicopathologic study. Arch Neurol 1979;36: Kaminski HJ, Richmonds CR, Kusner LL, Mitsumoto H. Differential susceptibility of the ocular motor system to disease. Ann N Y Acad Sci 22; 956: Averbuch-Heller L, Helmchen C, Horn AK, Leigh RJ, Buttner-Ennerver JA. Slow vertical saccades in motor neuron disease: correlation of structure and function. Ann Neurol 1998;44: Okuda B, Yamamoto T, Yamasaki M, Maya K, Imai T. Motor neuron disease with slow eye movements and vertical gaze palsy. Acta Neurol Scand 1992;85: Ushio M, Iwasaki S, Sugasawa K, Murofushi T. Atypical motor neuron disease with supranuclear vertical gaze palsy and slow saccades. Auris Nasus Larynx 29;36: Kobayashi M, Ikeda K, Kinoshita M, Iwasaki Y. Amyotrophic lateral sclerosis with supranuclear ophthalmoplegia and rigidity. Neurol Res 1999;21: Thurtell MJ, Pioro EP, Leigh RJ. Abnormal eye movements in Kennedy disease. Neurology 29;72:

975_983 특집-한규철, 정원호

975_983 특집-한규철, 정원호 Focused Issue of This Month Gyu Cheol an, MD Department of Otolaryngology ead & Neck Surgery, Gachon University of College Medicine E - mail : han@gilhospital.com Won-o Jung, MD Department of Otolaryngology