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1 대한내과학회지 : 제 81 권제 2 호 2011 다발신경병증과근위축을동반한쇼그렌증후군 1 예 조선대학교의과대학내과학교실 김은정 이희정 정유진 홍수진 김윤성 김현숙 A Case of Sensorimotor Polyneuropathy in a Patient with Sjögren s Syndrome Eun-Jeong Kim, Hee-Jeong Lee, Yu-Jin Jeong, Su-Jin Hong, Yun-Sung Kim, and Hyun-Sook Kim Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, Korea Sjögren s syndrome is a chronic inflammatory disorder characterized by lymphocytic infiltration of the exocrine glands, especially the lacrimal and salivary glands. Although it is characterized primarily by a particular form of dry eyes (keratoconjunctivitis sicca) and a dry mouth (xerostomia), this condition may affect a wide variety of organ systems, including the skin, lungs, heart, and kidneys, and it may rarely have neurological manifestations. The peripheral neuropathy results from nerve damage due to vasculitis or nerve sheath demyelination, which adversely affects the ability of nerves to send messages. We report the case of a 71-year-old woman who presented with polyneuropathy of the lower limbs that was diagnosed as Sjögren s syndrome but progressed to muscle atrophy during her treatment. (Korean J Med 2011;81: ) Keywords: Sjögren s syndrome; Polyneuropathy; Muscle atrophy 서론쇼그렌증후군 (Sjögren's syndrome) 은눈물샘, 침샘과같은외분비샘에림프구가침윤되어눈마름증과입안마름증이나타나는만성자가면역질환이다. 대부분중년과노년의여성에서발생하고분비샘외증상으로관절염, 레이노현상, 림프절종대, 폐침범, 혈관염, 신장및간침범, 림프종, 비장종대, 그리고드물게신경침범이있다. 일차성쇼그렌 증후군에서말초신경계를침범하는경우는약 2% 로, 약 2-21% 에서말초신경계를침범하는전신성홍반성루푸스등다른자가면역질환에비해비교적그침범정도가낮다고볼수있다. 저자들은좌측하지의통증과근력약화를주소로내원하여다발성신경병증과동반한쇼그렌증후군을진단하였고, 이후근육위축의진행과정을보인 1예를경험하였기에문헌고찰과함께증례보고한다. Received: Revised: Accepted: Correspondence to Hyun-Sook Kim, M.D., Ph.D. Department of Internal Medicine, Division of Rheumatology, College of Medicine, Chosun University, 588 Seoseok-dong, Dong-gu, Gwangju , Korea Tel: , Fax: , healthyra@chosun.ac.kr * This study was supported by 2011 research funds from Chosun University

2 - The Korean Journal of Medicine: Vol. 81, No. 2, 증례환자 : 71세여자주소 : 좌측하지의근력약화와따끔거림현병력 : 수년전부터안구건조와구강건조있어왔으나이에대한심각한불편감이없어경과관찰하였으며, 내원 4 개월전부터주로좌측하지의근력약화와간헐적으로찌르는듯한따끔거리는통증이있어경과관찰하던중내원 1개월전전신무력감으로인근병원방문하여빈혈진단하에위내시경시행하였으나만성위염외에특이소견보이지않아경과관찰중, 내원 1주일전부터주로하지의따끔거리는통증의발생하면서내원 3일전부터상기증상이수면장애를일으킬만큼심해지고어지러움증과무기력함이동반되어자세한검사위해내원하였다. 과거력 : 5년전당뇨병진단받았으나, 식이요법만으로조절이잘되고있다. 내원 4년전 lumbar spinal stenosis로 laminectomy 시행하였다. 가족력 : 특이병력없었다. 신체검사소견 : 내원시활력징후는혈압 130/85 mmhg, 맥박 72회 / 분, 호흡수 20회 / 분, 체온 36.4 이었다. 결막은창백하였으며, 경부림프절종대및갑상선비대소견은보이지않았다. 안구소견상건조안관찰되었으며, 이비인후과소견상구강건조관찰되었다. 위의증상은수년전부터있었으나별다른검사는시행하지않았다고한다. 전두동압통은없고이외의결절이나전신의부종소견은없었다. 흉부청진상양쪽호흡음과심음은정상이었다. 복부진찰에서특이소견없었다. 따끔거림을호소하였던하지는관절변형이나정맥염주, 함요부종등은관찰되지않았고 Medical Research Council (MRC) grading system을이용한신경학적검사상근력은정상이었으며, 통증, 촉각, 온도및심부건반사정상이었고, Babinski 징후는음성이었다. 검사실소견 : 입원당시시행한말초혈액검사에서백혈구 7,800/mm 3, 혈색소 6.6 g/dl ( 참고치 12-16), 적혈구침강속도 120 mm/hr ( 참고치 0-20), C-반응단백질 13 mg/l ( 참고치 0-0.5) 이었다. 혈액생화학검사에서 AST/ALT 13/9 IU/L, 총단백 6.08 g/dl, 알부민 2.9 g/dl, 혈액요소질소 21 mg/dl, 크레아티닌 1.05 mg/dl, 나트륨 142 meq/l, 칼륨 3.6 meq/l, 마그네슘 2.27 meq/l, 칼슘 8.2 mg/dl, 인 6.6 mg/dl, 혈당 98 mg/dl 이었다. 말초혈액도말표본상정적혈구성정색소성빈혈이관찰되며, 철 5.4 μg/dl, 총철결합능 120 μg/dl, 페 리틴 274 ng/ml, 시아노코발라민 2,000 pmol/l 이상, 엽산 24.0 ng/ml 이상, 적혈구생성인자 45.5 mu/ml 으로만성질환에의한빈혈양상이였다. 유산탈수소효소 574 U/L ( 참고치 ), 크레아틴인산효소 25 U/L, 요산 5.5 mg/dl보였다. 면역학적검사상항핵항체는양성 (1:160) 으로 speckled 형태였고, 류마티스인자는 620 IU/mL ( 참고치 0-15) 이었다. SS-A/Ro 항체 27.4 EU ( 참고치 0-20) 로양성이었으며, SS-A/La 항체 2.1EU ( 참고치 0-20), 항CCP 항체 4.3 U/mL ( 참고치 0-5) 이었다. 면역혈청검사에서 HBsAg 음성, anti-hbs 양성, anti-hcv 음성, VDRL음성, HIV 항체음성이었다. 또한 Schirmer 검사에서 5분동안우안 4 mm, 좌안 3 mm로눈물이적셔져분비감소소견을보였다. 방사선소견 : 타액선스캔영상에서귀밑샘과턱밑샘모두에서완전충만이잘되지않으며, 자극을준지 20분후에도배출이되지않는타액선배출장애를보여주고있으며, 이런소견은우측보다좌측에서정도가더심했다 (Fig. 1). 신경근전도검사소견 : 복합근활동전위 (compound muscle action potentials; CMAPs) 측정결과양측하지의비골신경은정상이었으나, 양측하지앞경골신경은감소되어있었다. 우측상지의정중신경과척골신경은정상이었으며, 좌측상지의정중신경과척골신경은감소되어있었다 (Fig. 2A). 치료경과중 1개월후복합근활동전위재검사결과이전검사에비해활동전위는더욱낮아졌으며, 근전도결과양하지의앞경골근과좌측하지의새끼외향근, 비복근에서근수축의저하소견을보였다 (Fig. 2B). Figure 1. On salivary gland scan, the full concentration of the salivary gland failed even 20 minutes after stimulation. The elimination disorder was observed as an excretion defect. As observed in the uptake difference, the right side had poorer overall function than the left side

3 - Eun-Jeong Kim, et al. Polyneuropathy in Sjögren's syndrome - 치료및경과 : 본환자는구강건조와건조안, 항핵항체와 SS-A/Ro 항체 27.4 EU 양성, Schirmer 검사양성, 그리고타액선스캔영상에서관찰된타액선배출장애로쇼그렌증후군을진단할수있었으며, 신경근전도를통해다발성신경병증이함께동반됨이확인되었다. 고령이고전신위약감이심하여침습적인검사를배제하고자침샘조직검사는시행하지않았으며또한최근연구결과타액선스캔영상이침샘조직 검사를대체할수있다는보고가있는점을감안하였다. 안구와구강의건조증상에대한보존적치료와함께심한다발성신경병증에대하여고용량스테로이드충격치료를시행하였다. 빈혈을교정하고도 ESR과 CRP 증가및임상양상에큰호전없어사이클로포스파마이드 (cyclophosphamide) 500 mg을 4주간격으로 3차례투여하였다. 이후 ESR, CRP는정상화되었고, 좌측하지의통증및근력약화도호전되었다 A MCS Tibial Left MCS Peroneal Left MCS Tibial Right MCS Peroneal Right 1: Ankle 1 mv / 5 ms 1: Ankle 2 mv / 5 ms 2: Popliteal 1 mv / 5 ms 2: Head of fibula 1 mv / 5 ms 3: Popliteal 1 mv / 5 ms SCS Sural Left SCS Sural Right 1: Ankle 2 mv / 5 ms 1: Ankle 5 mv / 5 ms 2: Popliteal 2 mv / 5 ms 2: Head of fibula 5 mv / 5 ms 3: Popliteal 2 mv / 5 ms 1: Sural 20 uv / 3 ms 1: Sural 10 uv / 3 ms B MCS Tibial Left MCS Peroneal Left MCS Tibial Right MCS Peroneal Right 1: Ankle 1 mv / 5 ms 1: Ankle 2 mv / 5 ms 2: Popliteal 1 mv / 5 ms 2: Head of fibula 1 mv / 5 ms 3: Popliteal 1 mv / 5 ms SCS Sural Left SCS Sural Right 1: Sural 20 uv / 3 ms 1: Sural 10 uv / 3 ms 1: Ankle 2 mv / 5 ms 1: Ankle 5 mv / 5 ms 2: Popliteal 2 mv / 5 ms 2: Head of fibula 5 mv / 5 ms 3: Popliteal 2 mv / 5 ms Figure 2. (A) The initial nerve conduction velocity (NCV) study showed increased insertional activity and decreased interference pattern of the left abductor digiti minimi, abductor digiti quinti, first dorsal interosseous, gastrocnemius, and anterior tibialis and right anterior tibialis muscles ( ). (B) A follow-up NCV study showed worsening of the left abductor digiti minimi, abductor digiti quinti, first dorsal interosseous, gastrocnemius, and anterior tibialis and right anterior tibialis muscle function ( )

- 대한내과학회지 : 제 81 권제 2 호통권제 612 호 2011 - Figure 3. At the time of diagnosis, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level were elevated.

4 - 대한내과학회지 : 제 81 권제 2 호통권제 612 호 Figure 3. At the time of diagnosis, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level were elevated. After steroid pulse therapy and immune suppression, the ESR and CRP were reduced compared with the initial values. Dx, diagnosis; CP, cyclophosphamide; Methyl PDS, methylprednisolone. 고 찰 Figure 4. Six months after treatment, atrophy of the first and fourth dorsal interosseous muscles of the left foot was observed (arrows). (Fig. 3). 그러나심한오심, 구토및기회감염으로인한발열로사이클로포스파마이드는 3차치료까지시행후중단되었다. 이후메칠프레드니솔론 (methylprednisolone) 8 mg으로유지치료중좌측하지의이상감각및통증이재발되었다. 메토트렉세이트 (metotrexate), 하이드록시클로로퀴닌 (hydroxychloroquine), 아자티오프린 (azathioprine) 등을투여하였으나무력감, 오심, 구토증상심하여저용량스테로이드외에는투여할수없었다. 치료시작약 1개월후근전도추적검사결과양측앞경골근과좌측비복근, 좌측족부의새끼외향근의근위축이진행됨이확인되었고 (Fig. 2B), 지속적인치료에도불구하고치료시작 6개월후에는외관상으로도뚜렷이확인되었다 (Fig. 4). 이후로는환자전신상태가양호하지못하여추가적인근전도검사는시행하지못하였으며, 보존적요법과통증조절하며외래추적관찰중이다. 쇼그렌증후군은 1892년 Mikulicz가처음으로양측누액선, 이하선, 악하선종창과함께조직검사상선포위축과림프구의광범위한침착을보이는질환을소개하였고, 1933년에 Henrik Sjogren이관절염과입의건조증상을동반한건성각막염을보인 19예를보고하면서 Sjogren s syndrome 이라고명명하였다 [1]. 1965년에 Bloch 등이동반된자가면역질환없이단독으로발생하는경우를일차성으로분류하였으며, 류마티스관절염, 전신성경화증, 전신홍반루푸스, 근염, 원발성담관성간경화등다른질환을동반하면서나타나는경우를이차성쇼그렌증후군으로분류하였다 [2]. 일차성쇼그렌증후군에서비교적선외증상이자주관찰되는데, 관절통과관절염이가장빈번하고, 신경계합병증은드물게발생하며, 중추신경계침범이더욱드문것으로알려져있다 [3-6]. 말초신경병증은신경병적임상증상, 운동- 감각결손, 주로감각신경의활동전위 (action potential) 의진폭감소로나타나는신경전도검사의비정상소견, 신경조직검사의병리적소견들중 2개이상의비정상소견을보일때진단할수있다 [7,8]. 증상으로는통증, 이상감각증과전반적인감각상실이특징이고, 주로손과발말단에서시작되는양상을보이며, 때때로자율신경병증이동반되기도한다. 본환자에서호소하였던전신무력감과근력약화증상은실제 Medical Research Council (MRC) grading system을이용한신경학적검사에서는근력약화는거의없었는데, 말초신경병증인다발성신경병증을동반한환자가호소하는근력약화가신경학적인검사와동일하지않는경우는종종있다. 병인적기전은잘알려져있지않지만, 혈관염에의한축삭신경병 (axonal neuroapthy) 과탈수초성신경병 (demyelinating neuropathy) 으로

5 - 김은정외 5 인. 다발신경병증을동반한쇼그렌증후군 1 예 - 나타나거나, 후근신경절 (dorsal root ganglia) 형태로나타난다는주장들이있으며, 감각증상이주로나타나는것은운동신경에비해감각신경의침범하는빈도가많기때문이다 [9]. 중추신경계의침범증상은경련, 인지장애, 무균뇌막염, 급성또는만성진행척수병증, 거미막밑출혈, 편측마비, 횡단척수염, 뇌염등의증상으로나타날수있다 [10]. 중추신경계침범은말초신경계침범에비해더심각한장애를초래할수있으므로빠른치료가요구되는데, 그중급성횡단척수염의사망률이가장높다고 Williams 등에의해보고되었다 [11]. 치료는주로고용량스테로이드와면역억제제의병합요법을추천하고, 질병초기에사이클로포스파마이드를투여할수록더효과적으로알려져있다 [12]. 그외에도아자티로프린, chlorambucil 등의다른면역억제제치료나혈장교환술등이시도되고있으나그효과는아직불분명하다. 스페인에서 1,010명의일차성쇼그렌증후군환자를대상으로전신증상의유병률을조사한 GEMESS 연구결과미미한증상까지포함한폭넓은범위의말초신경병증은 11% 의환자에서발생하였고, 일차성쇼그렌증후군의진단당시의유병률 19% 에비해 10년이상지속된환자에서유병률 58% 로확인되어질병이경과할수록말초신경병증이병발할수있음을짐작할수있었다. 또한 SS-A/Ro, La항체가양성일경우음성일때에비해그유병률이높게나타났다 [13]. 말초신경계의침범은각각의형태에대한구체적인유병률은알려져있지않으나대칭성감각운동신경병 (symmetric sensorimotor neuropathy) 이가장흔하며, 대칭성감각신경병 (symmetric sensory neuropathy), 삼차신경침범 (trigeminal sensory neuropathy), 다발성단신경병 (mononeuropathy mulitplex), 그리고순수감각신경원병 (pure sensory neuropathy) 등다양한형태로발생한다 [14-17]. 신경병증을동반한일차성쇼그렌증후군환자 9 명을대상으로조사결과 7명에서말초신경병증이확인되었고다발성단신경병, 감각운동신경병, sensitive neuropathy 등이진단된환자에게사이클로포스파마이드나스테로이드로치료한증례가발표되기도하였고 [18], Chol 등 [6] 은사지의감각과민증과운동쇠약증으로내원하여쇼그렌증후군에동반된말초의감각운동신경병증을진단하고, 스테로이드 (Prednisolone 0.5 mg/kg/day), 하이드록시클로로퀴닌 (300 mg/day) 및사이클로포스파마이드경구투여를추가함으로써약 3개월후사지의감각과민증및운동쇠약의호전을보인증 례를보고하였다. 또한운동실조와사지의건반사저하소견으로말초신경병증이동반된쇼그렌증후군에서 infliximab (3 mg/kg) 으로치료한증례도보고되었으나 [19], 본증례처럼근위축까지진행된경우는드물다. 이처럼일차성쇼그렌증후군에서는다양한면역억제제로치료를시도해볼수있으나, 특히노인에서는대사청소율과표적기관효과들의변화, 동반되는질환유무, 복용하고있는약물, 감염에취약한점등으로면역억제제를투여하는데어려움이따른다. 쇼그렌증후군에서특징적인다발성감각신경병증을초기증상으로하는신경계침범은많지않으며또한치료과정중근위축소견을보인보고는드물다. 이에저자들은 71 세여자환자에서감각운동성신경병증이병발된쇼그렌증후군을진단하고치료과정중근위축까지진행된환자를경험하였기에문헌고찰과함께증례보고하는바이다. 요 근력약화와따끔거림을주소로내원한환자에서일차성쇼그렌증후군에서병발한다발신경병증을진단하고고용량스테로이드치료및면역억제제치료하며경과관찰중근위축까지진행된 1예를경험하였기에문헌고찰과함께증례보고하는바이다. 약 중심단어 : 쇼그렌증후군 ; 다발신경병증 ; 근위축 REFERENCES 1. Fox RI, Saito I. Criteria for diagnosis of Sjögren's syndrome. Rheum Dis Clin North Am 1994;20: Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sjögren's syndrome: a clinical, pathological and serological study of sixty-two cases, Medicine (Baltimore) 1992;71: ; discussion Lee CW, Lee WK, Lee JS, et al. Clinical analysis of Sjögren's syndrome. J Korean Rheum Assoc 1997;4: Skopouli FN, Dafni U, Ioannidis JP, Moutsopoulos HM. Clinical evoluation, and morbidity and mortality of primary Sjögren's syndrome. Semin Arthritis Rheum 2000;29: Talal N. Sjögren's syndrome: historical overview and clinical spectrum of disease. Rheum Dis Clin North Am 1992;18: Choi SW, Jung HC, Kim JC, Kang BS, Kim YM. A case of primary Sjögren's syndrome associated with acute transverse myelitis. J Korean Rheum Assoc 2006;13:

6 - The Korean Journal of Medicine: Vol. 81, No. 2, Grant IA, Hunder GG, Homburger HA, Dyck PJ. Peripheral neuropathy associated with sicca comple. Neurology 1997;48: Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 1981;10: Griffin JW, Cornblath DR, Alexander E, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren's syndrome. Ann Neurol 1990;27: Alexander EL, Provost TT, Stevens MB, Alexander GE. Neurologic complications of primary Sjögren's syndrome. Medicine (Baltimore) 1982;61: Williams CS, Butler E, Román GC. Treatment of myelopathy in Sjögren's syndrome with a combination of prednisone and cyclophosphamide. Arch Neurol 2001;58: De Seze J, Delalande S, Fauchais AL, et al. Myelopathies secondary to Sjögren's syndrome: treatment with monthly intravenous cyclophosphamide associated with corticosteroids. J Rheumatol 2006;33: Ramos-Casals M, Solans R, Rosas J, et al. Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine (Baltimore) 2008;87: Mellgren SI, Conn DL, Stevens JC, Dyck PJ. Peripheral neuropathy in primary Sjögren's syndrome. Neurology 1989;39: Kaltreider HB, Talal N. The neuropathy of Sjögren's syndrome: trigeminal nerve involvement. Ann Intern Med 1969;70: Kaplan JG, Rosenberg R, Reinitz E, Buchbinder S, Schaumburg HH. Invited review: peripheral neuropathy in Sjögren's syndrome. Muscle Nerve 1990;13: Gemignani F, Marbini A, Pavesi G, et al. Peripheral neuropathy associated with primary Sjögren's syndrome. J Neurol Neurosurg Psychiatry 1994;57: Rafai MA, Boulaajaj FZ, Moutawakil F, et al. Neurological manifestations revealing primitive Gougerot-Sjögren syndrome: 9 cases. Joint Bone Spine 2009;76: Caroyer JM, Manto MU, Steinfeld SD. Severe sensory neuronopathy responsive to infliximab in primary Sjögren's syndrome. Neurology 2002;59:

Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical