원저 J Korean Neurol Assoc / Volume 23 / April, 2005 서울대학교의과대학신경과학교실 Abnormal Eye Movements in Brainstem Cavernous Malformations Dong Wook Kim, M.D., Kwang-Dong Choi, M.D., So Young Moon, M.D., Seong-Ho Park, M.D., Ji-Soo Kim, M.D. Department of Neurology, Seoul National University College of Medicine, Seongnam, Korea Background: Cavernous malformations consist of dilated vascular spaces separated by fibrous tissues that create a well-defined mass. They are increasingly recognized in the brainstem with the advent of magnetic resonance imaging (MRI). This study was aimed to understand neuro-ophthalmologic findings in the brainstem cavernous malformations. Methods: Fourteen patients with brainstem cavernous malformations, who presented mainly with neuroophthalmologic findings, were asked to participate in this study. The diagnosis was based on the characteristic MRI findings of well-circumscribed lesions with a mottled core of mixed-signal intensity. All patients received full neuro-ophthalmological evaluation, including oculography in some of them. Results: Seven patients mainly presented with ophthalmoplegia, 3 with abducens palsy, 1 with oculomotor palsy, 1 with gaze-evoked nystagmus, and another 2 with internuclear ophthalmoplegia. In the other 7 patients, the main neuro-ophthalmologic findings were ocular dyskinesia with variable degree of ophthalmoplegia. Six of them had oculopalatal tremor and the other patient showed macrosaccadic oscillation. Six of the 14 patients had a history of recurrent ophthalmoplegia from repeated bleedings of the cavernous malformations. Conclusions: Cavernous malformations in the brainstem can manifest with various ocular motor abnormalities. In patients with recurrent ophthalmoplegia or oculopalatal tremor, cavernous malformation in the brain stem should be considered in the differential diagnosis. J Korean Neurol Assoc 23(2):222-226, 2005 Key Words: Cavernous malformation, Brainstem, Ophthalmoplegia, Ocular dyskinesia 서론 해면기형 (cavernous malformation) 은모세혈관과유사한혈관들의복합체로, 이완된혈관들은섬유조직에의해구분되 Received August 2, 2004 Accepted November 4, 2004 *Ji Soo Kim, M.D., Ph.D. Department of Neurology, Seoul National University Bundang Hospital 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Korea Tel: +82-31-787-7463 Fax: +82-31-719-6828 E-mail: jisookim@snu.ac.kr * 이논문은 2004 년도한국학술진흥재단의지원에의하여연구되었음 (KRF-2004-03-E00202). 며경계가명확한덩어리를형성한다. 조직학적으로이들은근육이나탄력조직이없이팽창된내피세포로이루어진결체조직의복합체이며, 신경조직은포함하지않는다. 혈철소 (hemosiderin) 축적이나미세석회화, 섬유성혹은혈전성변화가흔히관찰된다. 1,2 해면기형은중추신경계의혈관기형의약 5~15% 를차지하고, 3-5 혈관조영검사에서이상이발견되지않는혈관기형은대부분해면기형으로생각된다. 6,7 전통적으로해면기형은태어날때부터존재하는선청성으로생각되어왔다. 1,8 그러나후천적 (de novo) 으로발생하는기형이가족형과산발형모두에서발견되었다. 9,10 가족형에서는다발성병변과함께신경외적인발현을보이는경향이있으며유적적원인이밝혀져있다. 9,11-13 222
컴퓨터단층촬영 (CT) 의발달로, 해면기형의발견이급속도로증가하였다. 14 그러나 CT는천막하부위, 특히후사면부위 (retroclival region) 에서해상력이떨어져뇌간부위해면기형을진단하는데는한계가있다. 해면기형은자기공명영상 (MRI) 에서특징적인형태를보여, 15 MRI 도입후뇌간해면기형의진단은급속히증가하였다. 중추신경계에서부위별해면기형의발생빈도는각부위가차지하는부피에비례하여, 천막상부 (supratentorial) 에 80%, 천막하부 (infratentorial) 에 15%, 척수에 5% 의빈도로분포하는것으로알려져있다. 16,17 해면기형은경련을유발하거나출혈로인한신경학적결손을일으킨다. 임상양상은병변의위치에따라큰차이를보인다. 천막상부병변은대개경련혹은출혈에동반된국소신경학적결손을보이며, 천막하부의병변은뇌신경마비나운동마비를주로보인다. 1,18 천막상부병변에서는출혈의재발을막고난치성간질을치료하기위해수술적치료를한다. 19 그러나뇌간부위해면기형에서는병변에인접한중요한신경학적구조물로인하여많은의사들이수술적인치료를꺼리는경향이있다. 20 최근 MRI 의이용증가와수술기법의발달에의해, 뇌간부위해면기형의수술적치료에대한보고들이증가하고있다. 21-23 그러나대부분의보고들은수술적인관점에초점을맞추어기술되었고질환의임상양상에대한분석은상대적으로적으며, 신경안과학적인소견은체계적으로기술되지못했다. 저자들은주로신경안과학적인증상으로발현한 14명의뇌간부위해면기형의안구운동이상에대해보고한다. 대상과방법 본연구는안구운동이상을주소로대학병원안구운동장애클리닉을방문한 14명의뇌간부위해면기형환자를대상으로하였다. 해면기형은반복적인출혈로인한혈액산물들과석회질로인해 MRI 에서혼합영상강도를보이는, 비교적경계가명확한병변을통해진단하였다. 15-17 세명의환자에서뇌혈관조영술을하였고혈관기형은발견되지않았으나, 한명의환자에서정맥울혈이관찰되었다. 모든환자를대상으로표준화된신경안과적검사를하였으며, 이중 10명에서는전기안구도 (electroculography), 비디오안구운동검사 (videooculography) 및자기추적코일장치를이용하여이상안구운동에대한정량적인평가가이루어졌다. 초기평가이후추적관찰기간은 1~12 년이었다 ( 평균 : 5.2 년 ). 안구개진전을보인일부환자 ( 환자 12, 13) 들의안구운동이상은이전에보고된바있다. 24 결과 1. 안근마비 (ophthalmoplegia) 모든환자에서어느정도의안근마비가발견되었고, 7명에서는안근마비가주증상이었다 (Table 1). 이중 6명의환자에서는해면기형의반복적인출혈에의한것으로생각되는재발성안근마비의병력이있었다. 주증상이안근마비인 7명의환자중 3명은외전신경마비를, 1명은동안신경마비를보였다. 2명 Table 1. Clinical profiles of the patients Pts Sex/Age Neuro-ophthalmologic findings Imaging Ophthalmoplegia 1 2 3 4 5 6 7 F/32 M/60 F/57 F/61 M/30 M/60 M/49 Bilateral abducens palsy, Rt beating horizontal & torsional nystagmus, Rt esotropia Lt abducens palsy Lt abducens palsy, SD, GEN Rt oculomotor palsy Lt abducens palsy, Lt one-and-a-half, SD Bilateral INO, Gaze palsy GEN Ocular dyskinesia with ophthalmoplegia Lt Pontomedullary Lt pons Midbrain & medulla Ponto-mesencephalic 8 9 10 11 12 13 14 F/32 F/62 F/57 M/53 M/63 M/54 F/47 OPT, Lt abducens palsy, Rt gaze palsy OPT, Lt one-and-a-half, upgaze palsy, SD, GEN, Bobbing OPT, Rt one-and-a-half, Rt oculomotor palsy OPT, Rt gaze palsy, Rt abducens palsy OPT, Lt one-and-a-half, bilateral abducens palsy OPT, Rt gaze palsy, Rt abducens palsy MSO, Vertical gaze palsy Ponto-mesencephalic Pontomedullary Brachium conjunctivum F; female, GEN; gaze-evoked nystagmus, INO; internuclear ophthalmoplegia, Lt; left, M; male, MSO; macrosaccadic oscillation, OPT; oculopalatal tremor, Rt; right, SD; skew deviation 223
은핵간안근마비 (internuclear ophthalmoplegia; INO) 의소견을보였으며, 다른 1명에서는주시유발안진 (gaze-evoked nystagmus) 이관찰되었다. 2. 안구이상운동증 (ocular dyskinesia) 7명의환자가안구이상운동증을주소로방문하였다. 이들중 6명은안구개진전 (oculopalatal tremor; OPT) 을, 다른한명은거대속진 (macrosaccadic oscillation; MSO) 을보였다. 안구개진전를보인환자에서시계추 (pendular) 안진은대개수직성 (vertical) 으로나타났으나, 수직및회선성분이혼합된형태의안진도한환자 ( 환자 8) 에서관찰되었다. 시계추안진은특징적으로외전신경마비나하나반증후군 (one-and-a-half syndrome) 같은안근마비와동반되어나타났다. MSO 는결합완 (brachium conjuntivum) 에병변이있었던한환자에서관찰되었고, 수직안구운동이상이동반되었다. 3. 병변위치 Figure 1. Brain MRI of patient 8. This shows a 1.2 cm focus of mixed signals with a peripheral hemosiderin ring in the posterior aspect of the pons. 동시에발생하는구개진전이동반되었다. 환자는실조증상을보였고일자보행 (tandem gait) 을할수없었다. 다른신경학적검사는정상이었다. 뇌 MRI 상교뇌후방부에 1.2 cm의혼합성신호를보이며혈철소링을동반한병변이관찰되었으며해면기형에합당한소견이었다 (Fig. 1). 환자는안구내 botulinum toxin 주입과 gabapentin, clonazepam, baclofen, amatadine 등으로치료를받았으나뚜렷한호전은없었다. 대부분의환자에서해면기형은교뇌의후방부위나교뇌 -연수혹은교뇌- 중뇌접합부위에서관찰되었다. 두명의환자만이다른부위에병변을갖고있었다. 한환자에서는 Weber 증후군에동반된동안신경마비가중뇌병변에서관찰되었고, MSO 를보인다른환자에서는결합완에병변이있었다. 반복적안구운동마비와안구개진전의소견을보였던대표적인환자 1명에대해기술한다. 환자 8 32세여자가진동시 (oscillopsia) 와주시마비로의뢰되었다. 과거력상 16 세이후로 좌안마비 를포함한다양한안구운동장애를호소한병력이있었다. 당시뇌혈관조영검사에서이상소견은없었고, 뇌 MRI 상불균질성의석회화혹은출혈영상이제4 뇌실바닥에서관찰되었다. 환자는 23세에마지막출혈이있었고, 좌안의내사시와완전외직근마비에대해외안근전위수술을받았다. 이후해면기형에대한절제수술을받았고, 수술이후지속적인안진과복시가발생하였다. 이러한증상들로인해일상생활이심하게제한되었다. 독서가불가능하였으며어지럼과자세불안이지속되었다. 검사에서원거리시력은양안모두 20/60 이였고, 근거리시력은우안이 20/25, 좌안이 20/20 였다. 색각, 동공및안저소견은정상이었다. 좌측내사시가관찰되었고우안의안구운동은정상이었으나좌안의외전은정상의 10% 미만이었으며, 내전은 80% 정도가능했다. 우측으로의단속운동 (saccade) 이느렸으며, 우안에서는수직성, 좌안에서는회선성 (torsional) 안진이관찰되었고, 안진과 고찰 뇌간부위해면기형은반복적인출혈로흔히심한신경학적증상을일으킨다. 그러나대부분에서첫번째출혈은치명적이지는않고다양한국소신경학적이상증상으로나타난다. 이러한제한적인출혈은뇌간부위에서혈관형성이빈약하여이루어진낮은혈류상태와연관될것으로생각된다. 따라서많은환자가최초의출혈로부터는회복하나, 반복적인출혈을경험하면서서서히악화되는경과를밟는다. 이전의뇌간부위해면기형에대한보고에서는, 약절반의환자가교뇌부위에병변을갖고있었고, 중뇌와교뇌- 중뇌접합부위의병변이흔하였다. 21-23 흥미로운점은대다수의환자에서신경학적결손이안구나안면운동에국한되었으며, 몸통의운동이나감각을지배하는부위의병변은드물었다. 해면기형의정확한위치가분석된보고에따르면, 22 많은병변이안구나안면운동에장애를줄수있는교뇌후방부, 교뇌-중뇌접합부, 혹은교뇌-연수접합부에서발견되었다. 뇌간부위해면기형은국소신경학적결손이외에, 삼차신경통, 25 지속적딸국질 26 을포함한다양한양상으로발현할수있다. 해면기형은또한몇가지운동장애를유발하는데, 27,28 이경우에도대부분의환자에서뇌간이침범되었다. 그러나기존의보고에서안구운동의이상에대한기술은극히드물었다. 29 본연구에서는대부분의환자들이반복적안근마비또는안구이상 224
운동증을보여, 환자를크게안근마비군과안구이상운동증군으로분류할수있었다. 4. 안근마비뇌신경마비는해면기형의가장흔한증상이며, 뇌신경핵, 18,21-23 또는뇌신경다발을직접침범하여발생한다. 30-33 본연구에서는모든환자가안근마비증상을보였고, 안근마비는핵상주시마비부터신경다발 (fascicular) 을침범한안구운동마비까지다양하였다. 특징적인소견은환자중여섯명이반복적인안근마비를경험하였다는것이다. 물론반복적인마비의병력이있는환자가신경안과클리닉에의뢰되어올확률이높기때문일수있지만, 뇌간해면기형의반복적인출혈경향때문일가능성이높다. 비록최초의출혈이대부분제한적으로끝나기는하지만, 천막상부의병변에비해뇌간해면기형의출혈확률이높고, 일단출혈이되었을경우반복적출혈의가능성이더욱높아지는것으로알려져있다. 22,34-36 5. 안구이상운동증안구이상운동증역시흔히관찰되는소견이었다. 본연구에서는여섯명의환자가안구개진전을보였고다른한명환자에서는 MSO 가관찰되었다. 구개진전 (palatal tremor) 은연구개의지속적이고규칙적인수축이며, 때로동일아가미궁 (branchial arch) 에서유래한인접구조물들의수축을동반하기도한다. 구개진전이시계추안진과동반될때안구개진전이라한다. 37 안구개진전은치아핵-적핵-올리브핵연결로 (dentate-rubroolivary pathway), 즉 Guillain-Mollaret 삼각로의병변과이에속발된아래올리브핵의비대성변성에의한지연성합병증이다. 안구개진전은뇌간혹은소뇌의국소병변이나진행성실조구개진전증후군에서관찰된다. 38 본연구에서많은환자가안구개진전소견을보인것은뇌간해면기형이잘침범하는부위가 Guillain-Mollaret 삼각로와대체로일치한다는해부학적관점에서설명될수있다. 이전보고에서안구개진전의빈도가드물게관찰된것은안구개진전이지연성으로발생하거나, 일부환자에서신경안과적검사가충분히이루어지지못했기때문일가능성도있다. MSO 는약 200 ms 의간격을두고발생하는단속안구운동의이상을지칭하며, 일련의단속안구운동이제일안위를중심으로좌우로지나치면서점차커졌다줄어드는양상의방추 (spindle) 를형성한다. 37 MSO 의정확한발병기전은모르나, 소뇌심부핵을침범하는등쪽소뇌부위의급성병변이나뇌간부 위정지세포 (pause cell) 병변에서보고된바있다. 39,40 MSO 는또한척수소뇌변성 (spinocerebellar degeneration) 환자에서일시적으로관찰된다. 37 결론적으로, 뇌간부위해면기형은다양한양상의안구운동장애로발현할수있다. 특히많은환자에서반복적인안구운동마비나안구개진전소견을보였다. 이러한특징은교뇌에서중뇌에이르는피개부위를주로침범하며반복적인출혈을일으키는뇌간부위해면기형의특성과일치하는소견이다. 따라서핵상주시마비에서핵하 (infranuclear) 안구운동마비에이르기까지다양한양상의안구운동장애를반복적으로보이거나안구개진전의소견을보이는환자에서는해면기형의가능성을염두에두고검사를하여야한다. REFERENCES 1. Isamat F, Conesa G. Cavernous angiomas of the brain stem. Neurosurg Clin N Am 1993;4:507-518. 2. Zabramski JM, Henn JS, Coons S. Pathology of cerebral vascular malformations. Neurosurg Clin N Am 1999;10:395-410. 3. Sarwar M, McCormick WF. Intracerebral venous angioma. case report and review. Arch Neurol 1978;35:323-325. 4. Lobato RD, Perez C, Rivas JJ, Cordobes F. Clinical, radiological, and pathological spectrum of angiographically occult intracranial vascular malformations Analysis of 21 cases and review of the literature. J Neurosurg 1988;68:518-531. 5. Di Rocco C, Iannelli A, Tamburrini G. Cavernous angiomas of the brain stem in children. Pediatr Neurosurg 1999;27:92-99. 6. Tomlinson FH, Houser OW, Scheithauer BW, Sundt TM Jr, Okazaki H, Parisi JE. Angiographically occult vascular malformations: a correlative study of features on magnetic resonance imagings and histological examination. Neurosurgery 1994;34:792-800. 7. Dillon WP. Cryptic vascular malformations: controversies in terminology, diagnosis, pathophysiology, and treatment. AJNR Am J Neuroradiol 1997;18:1839-1846. 8. Kondziolka D, Lunsford LD, Kestle JR. The natural history of cerebral cavernous malformations. J Neurosurg 1995;83:820-824. 9. Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, et al. The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 1994; 80:422-432. 10. Detwilder PW, Porter RW, Zabramski JM, Spetzler RF. De novo formation of a central nervous system cavernous malformation: implications for predicting risk of hemorrhage. Case report and review of the literature. J Neurosurg 1997;87:629-632. 11. Labauge P, Enjolras O, Bonerandi JJ, Laberge S, Dandurand M, Joujoux JM, et al. An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families. Ann Neurol 1999;45:250-254. 12. Laberge-le Couteulx S, Jung HH, Labauge P, Houtteville JP, Lescoat C, Cecillon M et al. Truncating mutations in CCM1, 225
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