대한안신경의학회지 : 제 3 권제 2 호 Clin Neuroophthalmol 3(2):74-79, December 2013 ISSN: 2234-0971 REVIEW 항 GQ1b 항체증후군 김만영 허욱 최판규 김동욱 조선대학교의학전문대학원신경과학교실 Anti-GQ1b Antibody Syndrome Man Young Kim, MD, Wook Hur, MD, Pahn Kyu Choi, MD, Dong Uk Kim, MD Department of Neurology, College of Medicine, Chosun University, Chosun University Hospital, Gwangju, Korea Anti-GQ1b antibodies are commonly related to several neurological disorders including, Guillain Barré syndrome with ophthalmoplegia, Bickerstaff brainstem encephalitis, acute ophthalmoplegia without ataxia, constituting a continuous spectrum. Surrounding this typical disease entity, anti-gq1b positive patients displaying atypical central nervous system symptoms or variable central and peripheral involvement are reported. In this article, we review the concepts for classification, clinical considerations, pathogenesis, natural history and options for treatment of anti-gq1b antibody syndrome. Keywords: GQ1b ganglioside; Miller ; Encephalitis; Guillain-Barre syndrome 서론 1932년 Collier는실조 (ataxia), 무반사 (aref lexia), 안근마비 (ophthalmoplegia) 를증상으로하는급성다발성신경염의한형태를 Guillain-Barré syndrome (GBS) 의한변형으로처음기술하였고 1 이후 1956년 Fisher는이를독립된질환으로보고하였는데 2 이후피셔증후군 () 으로명명되었다. 현재까지 3대증상 (symptom triad) 중에한가지이상과다른신경학적증상들로조합된비슷한질환들이보고되었는데, 대표적으로 Bickerstaff 뇌간뇌염 (BBE, Bickerstaff brainstem encephalitis), acute ophthalmoplegia without ataxia (AO), ataxic GBS, GBS with ophthalmoplegia, polyneuritis cranialis 등이있다. 이들사이에는서로중복되는매우다양한임상양상이존재하며항 GQ1b 강글리오사이드항체 (anti- GQ1b ganglioside antibody) 가양성인경우가흔하다는점에서 3,4 이 를항 GQ1b 항체증후군 (anti-gq1b antibody syndrome) 또는 Fisher variant of GBS 또는 또는 Fisher-Bickerstaff syndrome 5 등의여러용어로혼용하고있다. 진단검사항목으로서항 GQ1b 항체가검출되는경우를항 GQ1b 항체증후군이라정의하는것이당연하겠지만, 진단기준이되는증상의다양한조합들이있을때 또는 Fisher-Bickerstaff 증후군으로부르기도한다. 하지만질환명조차통일되지않은이들사이에는뚜렷한경계가없으며, 구분할수있는특이적인방법도없다. 이에본종설에서항 GQ1b 항체증후군에속하는질환들에대하여문헌고찰과함께살펴보고자한다. 본론 GBS는 10만명당약 1-2명의발생률을보이는데 6, GBS 중 Fisher Correspondence to: Dong Uk Kim, MD Department of Neurology, College of Medicine, Chosun University, Chosun University Hospital, 309 Pilmun-daero, Dong-gu, Gwangju 501-717, Korea Tel: 82-62-220-3676; Fax: 82-62-232-7587; E-mail: donguk@chosun.ac.kr Received: Aug. 25, 2013 / Accepted: Sep. 18, 2013 74 Copyright 2013 The Korean Society of Neuro-Ophthalmology http://neuro-ophthalmology.co.kr
항 GQ1b 항체증후군 김만영외 증후군의비율은서구에서는 1-7% 으로낮지만아시아에서는대만에서는 19%, 일본에서는 25% 정도로비교적높다고알려져있다. 7,8 BBE의빈도는정확히알려져있는것은없으나일본에서 1년 BBE 발생은 100건정도로전체뇌간뇌염의 43% 정도를차지하였다고하며, 75% 에서항 GQ1b항체가검출되었다고한다. 9 Snyder 등 10 은항 GQ1b 항체와관련된증후군을 Table 1과같이구분하였고, 최근 Yuki 등 11 은항 GQ1b 항체증후군의아형을 Table 2처럼분류하였고감별에필요한증상을나열하였다. 여기에서 Fisher-Bickerstaff syndrome의개념으로보면피셔증후군과 BBE로대별되는데, 각각의구별되는진단기준을제외하고비교하면 BBE는피셔증후군에비하여동공반사이상, 안면마비, 삼킴장애등뇌신경마비가더흔하고심부건반사가정상또는항진되어있거나병적반사가나타나는상위운동신경장애가보이는경우와 MRI나 EEG 이상이보이거나인공호흡기가필요한심각한경우가많았다 (Table 3). 이러한증상 의차이를종합하면 BBE는중추신경계의증상이더뚜렷하고피셔증후군은말초신경계의증상이더뚜렷하다고볼수있다 (Fig. 1). 1. 피셔증후군피셔증후군은외안근마비, 실조, 무반사의 3대증상모두를보이는경우로좁은의미로정의할수있으며과거에는 Miller Fisher syndrome으로불리우기도하였으나 Miller는 Charles Miller Fisher 의중간이름이므로줄여서피셔증후군 () 으로부르는것이더타당하겠다. 10 첫증상으로는복시 (65%) 와보행장애 (32%) 가가장흔하며, 동반증상으로는이상감각 (49%) 12, 안검하수 (< 58%) 13, 사지근력위약, 두통, 안면마비, 삼킴장애가있다. 피셔증후군의가장특징적인증상인외안근마비는 1/3에서는완전마비의형태로양쪽의외안근을침범하는데부분적으로일측성으로나타나는경우도있어주의가필요하다. 13 말초성외안근 Table 1. Clinical syndromes associated with the anti-gq1b antibody Acute ophthalmoparesis Clinical characteristics Ophthalmoplegia, ataxia, hyporeflexia or areflexia Ophthalmoplegia Rate of anti-gq1b positivity -95% Unknown (, required for diagnosis) Bickerstaff brain stem encephalitis Ophthalmoplegia, ataxia, impaired consciousness, hyperreflexia Guillain-Barre syndrome Weakness, sensory loss, cranial neuropathy, areflexia -68% -83% in patients with ophthalmoplegia Table 2. Subtypes and signs of anti-gq1b antibody syndrome Subtypes External ophthalmoplegia Oropharyngeal palsy Signs required for diagnosis Ataxia Impaired consciousness or hyperreflexia Areflexia or hyporeflexia Arm weakness Fisher-Bickerstaff syndrome Incomplete form Acute ophthalmoparesis (without ataxia) Acute ptosis Acute mydriasis Acute oropharyngeal palsy Acute ataxic neuropathy (without ophthalmoplegia) Ataxia Guillain-Barre syndrome Acute sensory ataxic neuropathy Bickerstaff brainstem encephalitis Pharyngeal-cervical-brachial weakness Overlap Fisher-Bickerstaff syndrome overlapped by pharyngeal-cervicalbrachial weakness Fisher-Bickerstaff syndrome overlapped by Guillain-Barre syndrome Leg weakness Clin Neuroophthalmol 3(2):74-79, December 2013 http://neuro-ophthalmology.co.kr 75
Kim M-Y, et al. Anti-GQ1b Antibody Syndrome Table 3. Clinical and laboratory findings in a cohort of patients with Bickerstaff brainstem encephalitis or Number of patients Median age (yr) Male Antecedent illness Upper respiratory illness Diarrhea Neurologic signs Consciousness disturbance Blepharoptosis External ophthalmoplegia Internal ophthalmoplegia Facial weakness Bulbar palsy Mild limb weakness Deep tendon reflex Absent of decreased Normal of brisk Extensor plantar reflex Ataxia Sensory disturbance Assisted ventilation Serum IgG anti-gq1b antibody Bickerstaff brainstem encephalitis 마비만으로는설명할수없는주기교대안진, 상방안진, 하방안진, 주시유발안진, 중추성체위안진, 핵간안근마비, saccadic dysmetria 등중추성안진이보이는경우도있어소뇌나뇌간을침범할수있 다는것을시사한다. 13,14 내안근마비도피셔증후군의흔한증상으 로 42% 에서동공확대가, 5 에서동공부등이확인되었으며 42% 에서대광반사가느려지는현상이나타났다고하며, 8 빛근접반사 해리 (light-near dissociation) 가나타나는경우도있다. 15 많은경우에 서콜린성약물에대하여탈신경과민성 (denervation supersensitivity) 을보이므로 ciliary ganglion 이나 short ciliary nerve 의침범을시 사한다. 15 실조는첫증상으로도흔하여급성기의 3 에서는독립 적인보행이힘들게된다. 실조가나타나는기전은잘알려져있지 않지만, 자세검사에서고유감각 (proprioception) 의장애가원인으 로해석되며 16, 이는근육방추 (muscle spindle) 의구심섬유 (afferent fiber) 이상으로여겨진다. 하지만피셔증후군환자의혈청에서항소 뇌항체가발견되기도하고 17 FDG-PET 연구에서소뇌나뇌간의과 대사 (hypermetabolism) 가확인되면서급성염증반응이중추신경 계에도발생함을시사하여 18 피셔증후군의증상은말초신경계와 53 40 466 44 69% 6 6 29% 34% 55% 42% 34% 76% 25% 37% 35% 22% 17% 49% 25% 6 4 38% 42% 34% 68% 2% 52% 1% 83% MRI (number of patients) 47 353 Abnormal findings EEG (number of patients) Abnormal findings 11% 30 57% 1% 32 25% PNS involvement 중추신경계를모두침범하면서발생하는것으로추정된다. 항 GQ1b 항체는 1992 년처음발견되었으며 GQ1b 강글리오사이 드는사람의 3 번, 4 번, 6 번뇌신경의 paranodal region 에집중적으로 분포하고있는세포표면구성물이며 polysaccharide 를함유하고 있어특정박테리아의 lipopolysaccharide 와유사하여자가면역질 환을일으키는항체의목표가된다. 19 항 GQ1b 항체는신경근접합 부에영향을주면서보체 (complement) 의활성화를통하여축삭이 나슈반세포의변성을유발한다. 20-22 피셔증후군의임상적진단기 준에부합한경우항 GQ1b 항체의양성률은 95% 까지보고되어있 다. 23 207 명의피셔증후군환자중항 GQ1b 항체가발견되지않은 24 명 (12%) 을연구한보고에따르면임상양상만으로는항 GQ1b 항 체가양성환자들과구분하기힘들었으며, 4 명에서 GT1a, GM1b, GalNAc-GD1a 강글리오사이드에대한 IgG 항체가검출되었다고 한다. 24 다른보고에서는항 GA1 항체만검출된경우도있다. 25 MRI 는거의대부분정상이나 1% 정도에서는중뇌, 소뇌, 중간소뇌다리 에이상을보이며 12 부검에서염증성뇌간병변이확인된경우도있 어중추신경계의침범도발병기전임을시사한다. 26 CNS involvement Bickerstaff brainstem encephlalitis Fig. 1. Fisher-Bickerstaff syndrome. The GQ1b antigen is highly expressed in the oculomotor, trochlear and abducens nerves, muscle spindles in the limbs, and probably reticular formation in the brainstem. The binding of anti-gq1b antibodies to GQ1b antigens expressed on the relevant cranial nerves and muscle spindles induces. In some cases, the anti-gq1b antibodies may also enter the brainstem and bind to GQ1b, inducing Bickerstaff brainstem encephalitis. A continuous spectrum exists between these conditions presenting with variable central and peripheral nervous system (CNS and PNS) involvement. 대부분의피셔증후군환자는특별한치료없이 2-3 개월이내에 완전히회복한다. 50 명을대상으로한분석에따르면증상발생후 실조는 12 일, 안근마비는 15 일째회복이시작된다고하였으며, 완 전히회복될때까지실조는 1 개월, 안근마비는 3 개월이소요된다 고하며, 6 개월째에장애가남는경우는없었다고한다. 8 대규모의 무작위비교연구는아니었지만 92 명의피셔증후군환자를대상으 로한연구에서정맥면역글로불린투여는예후나경과에영향을 주지못했으며그이유로는피셔증후군이자발호전이잘일어나 며예후가좋기때문으로설명하였다. 27 또일부환자에게선택적으 로혈장분리교환술을시행할수는있겠으나임상적인이득이나 비용을고려할때추천되지않는다. 치료도중에인공호흡기를부 착하는경우는 1% 정도로경과가매우좋으며특징적으로일상성 76 http://neuro-ophthalmology.co.kr Clin Neuroophthalmol 3(2):74-79, December 2013
항 GQ1b 항체증후군 김만영외 (monophasic) 회복경과를보이나드물게재발된보고도있다. 2. Acute ophthalmoplegia without ataxia Acute ophthalmoplegia without ataxia (AO) 는피셔증후군의불 완전한형태 (incomplete form) 로도보는견해도있지만외안근장 애말고는피셔증후군과공유되는증상이없으므로항 GQ1b 증후 군의아형이지만피셔증후군과는다른질환으로보는것이타당 하며제시된진단기준은 Table 4 에나타내었다. 3 Lee 등 28 의보고에 의하면 11 명의항 GQ1b 항체양성인 AO 환자와 20 명의항 GQ1b 항 체양성이지만 AO 가아닌환자의안근마비양상을비교하였을때 두군의외안근마비의형태는매우유사하였으며외전장애가 73% 로가장흔하였다. 다른연구에서는 21 명의 AO 환자를분석하였을 때 76% 에서양측성이면서, 수평 / 수직안구운동장애가같이보이 는경우가 48%, 수평안구운동장애만나타나는경우는 52% 였다고 하며, 33% 에서는양측성외전마비형태로나타났다고보고하였 다. 19 또다른보고에따르면가장특징적인안근마비형태로는초기 에양측외전장애로나타나는경우가가장흔하고, 내안근마비를 동반하면서 3 번뇌신경마비를보이는경우가흔하지만동공수축 이상을보이는경우의비율은피셔증후군의경우보다는낮다. 다 Table 4. Criteria of acute ophthalmoplegia without ataxia Features required for diagnosis Internal* or external ophthalmoplegia of acute or subacute onset No other neurologic symptoms than those associated with the ophthalmoplegia Presence of anti-gq1b IgG antibody No other identifiable causes of ophthalmoplegia Supportive features for diagnosis A history of infectious symptoms within 4 weeks before the onset of neurologic symptoms CSF albuminocytological dissociation *The internal ophthalmoplegia included sluggish or dilated nonreactive pupils with or without anisocoria. 른신경학적증상없이 6번뇌신경마비만발생하였던경우중에그원인으로는당뇨나혈관질환, 외상, 종양이배제된환자의 25% 에서항 GQ1b 항체가발견되었다는보고가있어 AO가알려진것보다더흔한질환임을암시하고있다. 29 3. Bickerstaff brainstem encephalitis BBE의최근제시된진단기준은 Table 5와같다. 9 BBE와피셔증후군은별개의질환으로보기에는임상적또는검사실소견이비슷한점을공유한다. Table 3을보면의식장애는 BBE의진단기준이고무반사는피셔증후군의진단기준임을감안하고보면 MRI나 EEG 의이상을보이는비율외에는다른소견들은거의비슷함을알수있다. BBE환자들은다양한정도의의식장애를나타내는데, 이는망상활성계 (reticular activating system) 의침범에의하여일어난다고믿어진다. 큰분자량을가지는물질은 BBB ( 혈액뇌장벽 ) 를통과할수없지만맨아래구역 (area postrema) 은 BBB가존재하지않는구역으로통로가될수있다는가설이있으며 30, BBE환자의혈청이 BBB 를파괴할수있음을증명한실험실결과도있어항 GQ1b 항체가중추신경계를직접침범할수있다는가설을뒷받침해준다. 31 정맥면역글로불린이나혈장분리교환술은비용이나부작용의위험성을생각하고매우신중해야한다. 스테로이드의사용에의해임상적호전을보였다고하는보고가있긴하나 32 항 GQ1b 증후군에서스테로이드의사용은경과를좋게하거나장기예후에영향을미치지못하는것으로여겨진다. 33 자연경과는매우좋아서특별한치료없이도거의대부분 6개월이내에완전한회복하는데, 일부에서는감각이상이나복시, 심하지않은실조는남아있을수있다. 경련이나폐렴같은합병증으로사망하는경우를제외하고는질환자체로사망하는경우는없다. Table 5. Diagnostic criteria for Bickerstaff brainstem encephalitis Definite Bickerstaff brainstem encephalitis is defined when (1), (2) and (4) are satisfied. Probable Bickerstaff brainstem encephalitis is defined when (1) and (4), or when (2), (3) and (4) are satisfied. (1) Acute progressive external ophthalmoplegia,* ataxia and impaired conscious level by 4 weeks, followed by spontaneous recovery within 12 weeks after onset. (2) Positive for serum IgG anti-gq1b antibodies. (3) Incomplete agreement on (1) because of one or more of the following reasons. - It is impossible to evaluate ataxia because of severe limb weakness or consciousness disturbance. - Unconfirmed recovery of the symptoms. - Remarkable laterality of external ophthalmoplegia. - Long tract sign (hemisensory disturbance, pyramidal sign or spasticity) instead of impaired level of consciousness. (4) Other conditions are excluded in laboratory and image tests: The excluded conditions are Wernicke encephalopathy, cerebrovascular disorder, multiple sclerosis, neuromye litis optica, neuro-behçet syndrome, neuro-sweet disease, pituitary apoplexy, viral brainstem encephalitis, myasthenia gravis, brainstem tumor, vasculitis, botulism, Hashi moto encephalopathy. *Lateral symmetry is the rule but mild laterality is also permitted. Features other than the incomplete item(s) must meet (1). Clin Neuroophthalmol 3(2):74-79, December 2013 http://neuro-ophthalmology.co.kr 77
Kim M-Y, et al. Anti-GQ1b Antibody Syndrome 결론 Fisher와 Bickerstaff에의하여기술된이후약 50년의시간이지난최근까지항 GQ1b 증후군에대하여많은연구와업적이있어왔다. 자가면역성발병기전이나임상적또는검사실소견을종합하여볼때이피셔증후군과 BBE는전혀다른질환이아니라중추신경계나말초신경계중어느부분에더병변이위치하는가에따라증상이다를뿐 유사한질환임을알수있다. 항 GQ1b 증후군의가장대표적인증상인급성안근마비를호소하는경우여러다른질환에의할수있음을염두에두고배제하여야하며, 이를감별하는데필요한개념적인차이를 Table 6에나타내었다. 향후포괄적인개념으로서의 항 GQ1b 증후군 에대한더많은이해는물론공통된분류법이나손쉬운진단방법의개발이필요하다. Table 6. Differential diagnosis of a patient with acute ophthalmopegia Disorder Extra-ocular motility abnormality Lid abnormality Guillain-Barré syndrome Bickerstaff brainstem encephalitis Acute ophthalmoplegia without ataxia Ocular myasthenia gravis Brainstem stroke Pituitary apoplexy Botulism * Appearance of gaze palsy Appearance of internuclear ophthalmoplegia Lid jerk Lid nystagmus Lid retraction Lagophthalmos Lagophthalmos Pupil abnormality * * Appearance of gaze palsy Appearance of gaze palsy Appearance of internuclear ophthalmoplegia Appearance skew deviation Nystagmus Gaze palsy Nystagmus Completes bilateral external ophthalmoplegia Nystagmus Wernicke encephalopathy Upbeat nystagmus Anticonvulsant intoxication Partial or complete bilateral external ophthalmoplegia Gaze evoked and vertical nystagmus Impaired smooth pursuit *Key phenotype of disease. (fatigable) Cogan lid twitch None Relative afferent papillary defect /tonic pupil Other abnormality Ataxia* Areflexia* Facial weakness Flaccid paralysis* Bulbar weakness* Sensory loss* Back pain Ataxia* Pyramidal weakness* Altered level of consciousness* Sensory loss Bulbar weakness Proximal limb weakness Pyramidal weakness Bulbar weakness Sensory loss Ataxia Headache Vision loss Altered level of consciousness Flaccid paralysis Bulbar weakness Sphincter disturbance (rarely) None Ataxia Confusion Vision loss (rarely) (rarely) None Ataxia Altered level of consciousness Prevalence of anti-gq1b antibody > 9 Up to 83% in patients with ophthalmoplegia Up to 68% (required for diagnosis) 78 http://neuro-ophthalmology.co.kr Clin Neuroophthalmol 3(2):74-79, December 2013
항 GQ1b 항체증후군 김만영외 REFERENCES 1. Collier J. Peripheral neuritis. Edinb Med J 1932;39:601-618. 2. Fisher M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med 1956;255:57-65. 3. Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: clinical and immunological range. J Neurol Neurosurg Psychiatry 2001;70:50-55. 4. Chiba A, Kusunoki S, Shimizu T, Kanazawa I. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller. Ann Neurol 1992;31:677-679. 5. Yuki N. and Bickerstaff brainstem encephalitis (Fisher- Bickerstaff syndrome). J Neuroimmunol 2009;215:1-9. 6. Sejvar JJ, Baughman AL, Wise M, Morgan OW. Population incidence of Guillain-Barré syndrome: a systematic review and meta-analysis. Neuroepidemiology 2011;36:123-133. 7. Yuan CL, Wang YJ, Tsai CP. Miller : a hospital based retrospective study. Eur Neurol 2000;44:79-85. 8. Mori M, Kuwabara S, Fukutake T, Yuki N, Hattori T. Clinical features and prognosis of Miller. Neurology 2001;56:1104-1106. 9. Koga M, Kusunoki S, Kaida K, Uehara R, Nakamura Y, Kohriyama T, et al. Nationwide survey of patients in Japan with Bickerstaff brainstem encephalitis: epidemiological and clinical characteristics. J Neurol Neurosurg Psychiatry 2012;83:1210-1215. 10. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (). J Neuroophthalmol 2009;29:312-324. 11. Shahrizaila N, Yuki N. Bickerstaff brainstem encephalitis and : anti-gq1b antibody syndrome. J Neurol Neurosurg Psychiatry 2013;84:576-583. 12. Ito M, Kuwabara S, Odaka M, Misawa S, Koga M, Hirata K, et al. Bickerstaff s brainstem encephalitis and form a continuous spectrum: clinical analysis of 581 cases. J Neurol 2008;255:674-682. 13. Jeong SH, Nam J, Kwon MJ, Kim JK, Kim JS. Nystagmus and ataxia associated with antiganglioside antibodies. J Neuroophthalmol 2011;31:326-330. 14. Najim al-din AS, Anderson M, Eeg-Olofsson O, Trontelj JV. Neuro-ophthalmic manifestations of the syndrome of ophthalmoplegia, ataxia and areflexia. Observations on 20 patients. Acta Neurol Scand 1994;89:87-94. 15. Nitta T, Kase M, Shinmei Y, Yoshida K, Ohno S. with light-near dissociation in Fisher s syndrome. Jpn J Ophthalmol 2007;51:224-227. 16. Ropper AH, Shahani B. Proposed mechanism of ataxia in Fisher s syndrome. Arch Neurol 1983;40:537-538. 17. Inoue A, Koh C, Iwahashi T. Detection of serum anticerebellar antibodies in patients with Miller. Eur Neurol 1999;42:230-234. 18. Kim YK, Kim JS, Jeong SH, Park KS, Kim SE, Park SH. Cerebral glucose metabolism in. J Neurol Neurosurg Psychiatry 2009;80:512-517. 19. Yuki N, Odaka M, Hirata K. Acute ophthalmoparesis (without ataxia) associated with anti-gq1b IgG antibody: clinical features. Ophthalmology 2001;108:196-200. 20. Silverstein MP, Zimnowodzki S, Rucker JC. Neuromuscular Junction Dysfunction in Miller Fisher Syndrome. Semin Ophthalmol 2008;23:211-213. 21. Halstead SK, Morrison I, O Hanlon GM, Humphreys PD, Goodfellow JA, Plomp JJ, et al. Anti-disialosyl antibodies mediate selective neuronal or Schwann cell injury at mouse neuromuscular junctions. Glia 2005;52:177-189. 22. Willison HJ, Plomp JJ. Anti-ganglioside antibodies and the presynaptic motor nerve terminal. Ann N Y Acad Sci 2008;1132:114-123. 23. Lo YL. Clinical and immunological spectrum of the Miller. Muscle Nerve 2007;36:615-627. 24. Koga M, Gilbert M, Takahashi M, Li J, Hirata K, Kanda T, et al. GQ1b-seronegative : clinical features and new serological markers. J Neurol 2012;259:1366-1374. 25. Oyazato Y, Shiihara T, Kusunoki S, Adachi M, Ohnishi N, Taniguchi H, et al. A case of anti-ga1 antibody-positive with elevated tau protein in cerebrospinal fluid. Brain Dev 2012;34:329-332. 26. Berlit P, Rakicky J. The Miller : review of the literature. J Clin Neuroophthalmol 1992;12:57-63. 27. Mori M, Kuwabara S, Fukutake T, Hattori T. Intravenous immunoglobulin therapy for Miller. Neurology 2007;68:1144-1146. 28. Lee SH, Lim GH, Kim JS, Oh SY, Kim JK, Cha JK, et al. Acute ophthalmoplegia (without ataxia) associated with anti-gq1b antibody. Neurology 2008;71:426-429. 29. Tatsumoto M, Odaka M, Hirata K, Yuki N. Isolated abducens nerve palsy as a regional variant of Guillain-Barre syndrome. J Neurol Sci 2006;243:35-38. 30. Faraci FM, Choi J, Baumbach GL, Mayhan WG, Heistad DD. Microcirculation of the area postrema. Permeability and vascular responses. Circ Res. 1989;65:417-425. 31. Saito K, Shimizu F, Koga M, Sano Y, Tasaki A, Abe M, et al. Blood-brain barrier destruction determines Fisher/Bickerstaff clinical phenotypes: an in vitro study. J Neurol Neurosurg Psychiatry 2013;84:756-765. 32. Roos RP, Soliven B, Goldenberg F, Badruddin A, Baron JM. An elderly patient with Bickerstaff brainstem encephalitis and transient episodes of brainstem dysfunction. Arch Neurol 2008;65:821-824. 33. Hughes RAC, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev 2010;(2):CD001446. Clin Neuroophthalmol 3(2):74-79, December 2013 http://neuro-ophthalmology.co.kr 79