증례 http://dx.doi.org/10.17340/jkna.2015.3.11 영남대학교의과대학신경과학교실 Acute-Onset Chronic Inflammatory Demyelinating Polyradiculoneuropathy Mimicking Miller-Fisher Syndrome Hyun-Seok Baek, MD, Chang Hun Bin, MD, Min Su Park, MD Department of Neurology, Yeungnam University College of Medicine, Daegu, Korea A 77-year-old man developed diplopia, gait ataxia, and paresthesia. A clinical examination also revealed ophthalmoplegia, facial palsy, ataxia of the limbs and trunk, and reduced deep tender reflexes. Laboratory and electrophysiological studies revealed albuminocytological dissociation and demyelination. He was diagnosed as Miller-Fisher syndrome and received intravenous immunoglobulin therapy. His clinical sympto deteriorated at 12 weeks after onset. We diagnosed acute-onset chronic inflammatory demyelinating polyradiculoneuropathy, and which the patient recovered from following corticosteroid therapy. J Korean Neurol Assoc 33(3):196-200, 2015 Key Words: Chronic inflammatory demyelinating polyradiculoneuropathy, Miller-Fisher syndrome, Guillain-Barré syndrome 만성염증탈수초다발신경뿌리병 (chronic inflammatory demyelinating polyradiculoneuropathy, CIDP) 은점차진행하거나완화와재발이반복되는경과를보이는말초신경계면역매개질환이다. 1 Miller-Fisher 증후군 (Miller-Fisher syndrome, MFS) 은특징적으로외안근마비, 보행실조및심부건반사의소실을보이는질환으로길랭 -바레증후군 (Guillain-Barré syndrome, GBS) 의여러아형중하나이다. CIDP 의뇌척수액및전기생리학적검사소견은 GBS와유사해초기 CIDP는 GBS와감별이어렵다. 2 하지만 CIDP는만성적인경과를보이며장기적인면역억제치료가필요하기때문에이둘을감별하는것은치료방향결정을위해중요하다. 3 MFS 로판단하여면역글로불린치료후점차회복되던환자 Received January 1, 2015 Revised March 26, 2015 Accepted March 26, 2015 Address for correspondence: Min Su Park, MD Department of Neurology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 705-703, Korea Tel: +82-53-627-3685 Fax: +82-53-627-1688 E-mail: minsupark@ynu.ac.kr 가첫발병 12주후에증상이다시악화되었으며, 급성발현 CIDP (Acute-onset CIDP, A-CIDP) 로다시진단되어스테로이드를사용하면서증상은호전되었다. 저자들은 MFS 형태로발현된 A-CIDP 1예를경험하였기에문헌고찰과함께보고한다. 증례 77세남자가 3일전부터발생한복시, 보행장애및하지의이상감각으로왔다. 증상은점차악화되어타인의도움없이걷기힘들었다. 증상발생 3주전상기도감염으로치료받았으며당뇨병, 심장질환, 중추신경계감염, 알레르기등에대한과거병력은없었고가계에서유전질환을가진사람도없었으며신경계독성을지닌물질이나약물을복용하지않았다. 신경학적진찰에서의식은명료하였고뇌신경검사에서양안의대칭적인전체외안근마비와양쪽얼굴마비가관찰되었다. 근력은대칭적으로상지는 medical research council (MRC) 4+ 등급, 하지근위부는 4+ 등급, 원위부는 5등급이었다. 이상감각을호소하는양쪽하지에서촉각, 온도및통각감각의저하를보였 196 대한신경과학회지제 33 권제 3 호, 2015
A B Figure 1. Abdominal X-ray at second day of admission. Small and large bowels were distended diffusely without evidence of obstruction (A). Previously shown distended bowel loops have been resolved after ten days (B). Facial NCS Nerve/sites Latency Amp. 2-4 mv Area 1-5 mv d Lat. L facial Ear-orb-oculi 3.05 0.6 2.7 3.05 Ear-orb-oris 2.60 0.5 0.9 2.60 R facial Ear-orb-oculi Ear-orb-oris Resp. No No Blink reflex Nerve/sites R1 mv R2 R2' Resp. L supraorbital Right NP No Lift 14.10 44.45 R supraorbital Right NP NP No Lift 47.10 A Blink reflex L supraorbital B Blink reflex R supraorbital Figure 2. The results of facial nerve conduction and blink reflex study. Facial nerve conduction study showed prolonged terminal latency and low CMAP amplitude with left facial nerve stimulation, no response with right one. Blink reflexes showed prolonged ipsilateral R1, R2 latencies and poor wave formation in contralateral R2 latency with left supraorbital nerve stimulation (A). There were no responses in ipsilateral R1, R2 latencies and prolonged contralateral R2 latency with right supraorbital nerve stimulation (B). NCS; nerve conduction study, CMAP; compound muscle action potential, NP; no potential, Amp; amplitude, d Lat; delta take off latency, Resp; response. J Korean Neurol Assoc Volume 33 No. 3, 2015 197
다. 심부건반사는양쪽상지에서감소되고하지에서는소실되어있었으며병적과다반사는보이지않았다. 경미한근력저하에비해보행장애가심하였으며이는사지와체간에서관찰된운동실조로인한것으로판단되었다. 입원이후에는혈압변동, 기립저혈압, 장마비로인한배변장애및배뇨장애와같은자율신경계이상이관찰되었다 (Fig. 1-A). 뇌척수액검사에서백혈구는관찰되지않았고단백질은 106.41 mg/dl로증가되어있었으며당은혈액에서 118 mg/dl, 뇌척수액에서 61 mg/dl로감소되지않았다. 갑상선기능검사를포함한혈액검사및소변검사는모두정상이었다. GM1, GM2, GD1a, GD1b, 그리고 GQ1b에대한자가 항체는음성이었다. 증상발생 7일째시행한전기생리학적검사에서양쪽얼굴신경마비가관찰되었고 (Fig. 2), 오른쪽비골신경의 F파가관찰되지않으며양쪽척골신경의전도차단이관찰되었다. 또한모든운동신경의종말잠복기가연장되었으며거의모든운동및감각신경의신경전도속도가감소되었다 (Table). 호흡기감염이후발생한외안근마비, 운동실조, 심부건반사소실, 양쪽얼굴마비와뇌척수액검사에서알부민세포해리를보이고신경전도검사에서탈수초신경병이관찰되어 MFS로판단하였고, 면역글로불린을하루 0.4 g/kg의용량으로 5일동안정맥 Table. Serial nerve conduction studies at 1 weeks and 21 weeks after first disease onset Motor NCS July 11, 2013 December 4, 2013 Amplitude ( mv ) NCV (m/s) Amplitude ( mv ) NCV (m/s) Median nerve (right/left) Normal value Terminal latency () 3.6 4.90/4.50 a 9.05/9.85 a Finger-wrist Amplitude 5 mv 7.3/8.4 0.7/2.6 a Wrist-elbow 49.96 7.2/7.0 44.2/41.0 a 0.5/2.2 a 22.3/20.8 a Elbow-axilla 55.96 7.2/6.7 43.2/39.6 a 0.5/2.0 a 25.5/27.7 a F-wave latency () 29.65 36.65/37.90 a 65.60/66.50 a Ulnar nerve (right/left) Terminal latency 2.51 3.70/3.75 a 7.05/6.60 a Finger-wrist Amplitude 5 mv 11.2/11.4 2.7/3.0 a Wrist-below elbow 50.61 5.9/9.0 45.1/42.0 a 1.5/1.6 a 15.7/15.8 a Below elbow-above elbow 42.81 5.7/8.4 33.7/43.1 a 1.5/1.6 a 19.4/16.6 a Above elbow-axilla 52.69 5.1/8.4 57.5/48.7 1.4/1.6 a 18.6/26.2 a F-wave latency 29.65 40.75/38.50 a 78.10/NP a Peroneal nerve (right/left) Terminal latency 4.78 5.10/7.60 a Ankle Amplitude 4 mv 2.0/2.1 a NP/NP a Knee 41.85 1.4/1.7 a 34.5 a NP/NP a F-wave latency 48.81 NP/62.05 a NP/NP a Tibial nerve (right/left) Terminal latency 5.11 7.00/7.60 a Ankle Amplitude 5 mv 5.5/5.5 NP/NP a Popliteal fossa 40.5 4.8 a /5.0 31.3/29.7 a NP/NP a F-wave latency 53.95 64.85/65.85 a NP/NP a Sensory NCS Amplitude (μv) NCV (m/s) Amplitude (μv) NCV (m/s) Median nerve (right/left) Amplitude 10 μv Finger-wrist 41.26 5.7/8.0 a 32.5/38.4 a 1.8/2.1 a 28.4/37.2 a Palm-wrist 34.05 2.7/5.8 a 37.4/39.3 a 1.5/3.1 a 39.1/36.6 a Wrist-elbow 49.39 11.4/4.4 a 46.0/46.5 a 2.0/3.0 a 34.5/43.4 a Elbow-axilla 53.95 10.5/9.6 a 23.1/33.3 a 6.2/4.1 a 24.7/29.5 a Ulnar nerve (right/left) Amplitude 10 μv Finger-wrist 39.26 4.2/6.2 a 28.6/31.1 a 1.6/1.6 a 29.0/29.0 a Wrist-elbow 47.46 4.2/6.5 a 38.4/39.3 a 2.7/2.2 a 39.3/33.5 a Above elbow-axilla 48.18 5.6 a /11.5 38.6/39.3 a 6.9/3.8 a 36.2/44.2 a Sural nerve (right/left) Amplitude 6 μv 3.3/3.1 a 35.9/36.8 NP/NP a 34.6 Superficial peroneal nerve (right/left) Amplitude 4 μv 40.5 3.5/2.0 a 35.9 a /40.6 NP/NP a a Abnormal findings. NCS; nerve conduction study, NCV; nerve conduction velocity, NP; no potential. 198 대한신경과학회지제 33 권제 3 호, 2015
주사하였다. 치료시작 8일째외안근마비와운동실조가호전되어붙잡고혼자서일어서는것이가능하였다. 2주째에는장마비가호전되었다 (Fig. 1-B). 3주째는보조기를사용하여혼자서조금씩걷는것이가능하였으나혈압변동과외안근마비의회복속도가빠르지않아두번째면역글로불린치료를처음과같은용량으로시행하였다. 두번째면역글로불린치료후 10일째외안근마비가많이호전되어복시는없어졌으며혼자서보조기를사용하여활동이가능한정도까지회복되어퇴원하였다. 퇴원후 6주동안은지속적으로보행및배뇨장애가호전을보였으나첫번째발병이후 12주정도부터하지의감각저하및저린증상이다시악화되기시작했고 16주후에는혼자서일어나지못했다. 신경학적진찰에서우안의가쪽주시제한과양쪽얼굴마비가다시관찰되었고사지와체간의운동실조도악화되었다. 근력은상지근위부는 MRC 5등급, 원위부는 4등급이었고하지근위부는 4등급, 원위부는 3등급이었다. 심부건반사는상지는감소, 하지는소실되어있었으며배뇨및배변기능의악화는관찰되지않았다. 뇌척수액검사에서백혈구는관찰되지않았으며, 단백질은 260.11 mg/dl로이전보다더증가되어있었다. 신경전도검사에서양쪽비골및경골신경의복합근육활동전위는관찰되지않았고종말잠복기연장및신경전도속도의감소가처음보다악화되었다. 복합근육및감각신경활동전위의진폭크기도이전보다감소되었으며이는이차축삭변성에의한것으로판단하였다 (Table). European Federation of Neurological Societies/Peripheral Nerve Society 지침에서제시한 CIDP의전기진단기준 4 에서확진에해당하는 50% 이상말단잠복기의연장이양측정중신경및척골신경에서, 30% 이상연장된 F파가양측정중신경과오른쪽척골신경에서, F파의소실이왼쪽척골신경, 양쪽비골신경, 경골신경에서, 전도차단이양쪽척골신경에서관찰되었다. 면역글로불린치료에도불구하고 12주만에증상이다시악화되었으며지속적으로뇌척수액의단백질수치가상승되어있어 A-CIDP로최종진단하였고메틸프레드니솔론 (methylprednisolone) 을하루 1 g의용량으로 5일간사용후경구프레드니솔론 (prednisolone) 60 mg으로변경하여유지하였다. 5일간의고용량스테로이드치료이후혼자서붙잡고서서버틸수있을정도로회복을보였고 3주후에는보조기를붙잡고걸을정도로호전되었다. 이후프레드니솔론 (prednisolone) 은점차감량하여 30 mg으로유지하였고아자티오프린 (azathioprine) 을추가하였다. 이후 1년간재발없이정상적인자가보행이가능하고감각증상도호전되었다. 고찰 본환자는 GQ1b에대한자가항체는발견되지않았지만 MFS 의 3대증상인외안근마비, 보행실조및심부건반사의소실이관찰되었고뇌척수액및신경전도검사에서관찰된소견을통해초기에 MFS로진단되었다. GBS 환자중치료후증상이일시적으로호전되었다가악화를보이면 GBS의치료와연관된변동 (GBS-Treatment related fluctuation, GBS-TRF) 으로판단할수있으며면역글로불린정맥주사나혈장교환술이후약 10% 에서 GBS-TRF가발생한다고보고된다. 5 본증례처럼 MFS로진단되고치료이후증상이다시악화되는경우 TRF를의심하게되지만 A-CIDP의재발을감별하는것이반드시필요하다. 하지만 GBS와초기 CIDP는신경계증상, 뇌척수액및전기생리학적검사소견이비슷하기때문에감별에어려움이따른다. CIDP 환자중약 16% 는 A-CIDP 형태로발생하며, GBS로진단된환자중에서도약 5% 는 CIDP의만성경과를보인다. 2 A-CIDP와 GBS를비교한최근연구들 6-8 에따르면 A-CIDP는 GBS에비해근력약화는걷지못하거나인공호흡기치료가필요할정도로심하지않았고감각증상은더뚜렷하게나타나는특징을보였다. 뇌신경침범은 GBS군에는 16명중 11명에서관찰된반면, CIDP군에서는 8명중 1명에서만관찰되었다. 7 자율신경계이상은 23% 에서관찰되었고주로위장관, 비뇨생식계증상이었으며심한자율신경계장애가발생하는경우는드물었다. 8 선행하는감염의유무, 강글리오시드 (ganglioside) 에대한자가항체의검출여부, 뇌척수액검사및전기생리학적검사에서유의한차이는없었다. 7 발병후임상경과에대한차이를보면증상의악화가최고조에이르는기간은 A-CIDP가 16.5일, GBS-TRF 는 8.5일로 A-CIDP에서더길었으며, 치료시작후첫번째증상의악화가일어날때까지의기간 (A-CIDP: 51일, GBS-TRF: 18일 ) 과두번째악화가일어날때까지의기간 (A-CIDP: 105일, GBS-TRF: 38일 ) 도 A-CIDP에서더길게관찰되었다. 7 또한이연구에포함된 GBS-TRF 환자중에서 8주이후에증상악화가나타난환자는한명도없었다. 한연구에서는 CIDP에서뇌척수액의단백질수치가지속적으로상승되어있는특징을보고하기도하였다. 9 이증례는기존연구에서드물게보이던뇌신경침범과자율신경계장애가관찰되었으며, GBS의아형인 MFS의특징으로발현된 A-CIDP라는점이특이하다고할수있다. 발병초기에는 CIDP로판단하기가어려웠으나재발이발생하기까지기간이길었다는점, 지속적으로뇌척수액의단백질수치가상승된점및악화된신경생리학검사를토대로 A-CIDP로진단할수있었다. 첫번째면역글로불린치료후증상의악화는없었으나추가 J Korean Neurol Assoc Volume 33 No. 3, 2015 199
적인증상호전을위해증상발생 3주후에두번째면역글로불린을사용했다. 12주부터환자의증상이악화된것이첫번째가아닌두번째면역글로불린치료와연관된 TRF를의심할수도있으나, 두번째면역글로불린치료와증상의악화사이에 8주이상의시간간격이있어 A-CIDP로판단할수있다. A-CIDP와 GBS를감별하는것은환자의향후치료방향을결정하고예후를추정하기위해중요하다. 발병초기 GBS에합당한증상을보이는경우라도증상악화를보일때는 GBS-TRF와 A-CIDP를감별해야하며, 특히 8주가지나서증상의악화를보일때는 CIDP의가능성을염두에두어야한다. 또한 A-CIDP 에서는드문증상이관찰될때에도감별진단으로 A-CIDP를염두에두는것이진료에많은도움이되겠다. REFERENCES 1. Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 1989;46: 878-884. 2. Sander HW, Latov N. Research criteria for defining patients with CIDP. Neurology 2003;60:S8-S15. 3. Ruts L, van Koningsveld R, van Doorn PA. Distinguishing acute-onset CIDP from Guillain Barré syndrome with treatment related fluctuations. Neurology 2005;65:138-140. 4. Van den Bergh PY, Hadden RD, Bouche P, Cornblath DR, Hahn A, Illa I, et al. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision. Eur J Neurol 2010;17:356-363. 5. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Lancet 1997;349:225-230. 6. Dionne A, Nicolle MW, Hahn AF. Clinical and electrophysiological parameters distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy. Muscle Nerve 2010;41:202-207. 7. Ruts L, Drenthen J, Jacobs BC, van Doorn PA; Dutch GBS Study Group. Distinguishing acute-onset CIDP from fluctuating Guillain-Barré syndrome: a prospective study. Neurology 2010;74:1680-1686. 8. Figueroa JJ, Dyck PJ, Laughlin RS, Mercado JA, Massie R, Sandroni P, et al. Autonomic dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 2012;78:702-708. 9. Grand Maison F, Feasby TE, Hahn AF, Koopman WJ. Recurrent Guillain-Barre syndrome: clinical and laboratory features. Brain 1992; 115:1093-1106. 200 대한신경과학회지제 33 권제 3 호, 2015