J Korean Diabetes 2018;19:153-159 Vol.19, No.3, 2018 ISSN 2233-7431 문성수동국대학교의과대학내과학교실내분비내과 Diagnosis and Management of Diabetic Peripheral Neuropathy Seong-Su Moon Division of Endocrinology, Department of Internal Medicine, Dongguk University College of Medicine, Gyeongju, Korea Abstract Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes and is diagnosed as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes. The prevalence of DPN was reported at 33.5% of type 2 diabetes patients by the Korean diabetes neuropathy study group. Early diagnosis is recommended to prevent diabetic foot ulcers, amputation, or disability. A questionnaire asking about symptoms and neurologic examination of feet is commonly used as a screening tool. However, complete diagnostic tests for DPN are not well established because of incomplete understanding of the pathogenetic mechanisms leading to the nerve injury, the various clinical manifestations, and the unclear natural history. Therefore, DPN has not been paid sufficient attention by clinicians. The roles of glycemic control and management of cardiovascular risk factors in the prevention and treatment of neuropathic complications are well known. Pathogenetically oriented or symptomatic agents are other options, though such treatments do not always produce a satisfactory outcome. Therefore, DPN remains a challenge for physicians to screen, diagnose, and treat. There have been recent advances in understanding the mechanisms underlying DPN and in the development of new diagnostic modalities and treatments. In this review, diagnosis and management of DPN will be discussed. Keywords: Diabetic complications, Diabetic polyneuropathy, Peripheral neuropathies Corresponding author: Seong-Su Moon Division of Endocrinology, Department of Internal Medicine, Dongguk University Gyeongju Hospital, 87 Dongdae-ro, Gyeongju 38067, Korea, E-mail: drmoonss@hanmail.net Received: Jul. 18, 2018; Accepted: Aug. 13, 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright c 2018 Korean Diabetes Association The Journal of Korean Diabetes 153
서론 당뇨병성말초신경병증은당뇨병환자에서가장흔한합병증으로알려져있다. 연구에따라다양한유병률을보이지만최근한국인을대상으로한다기관연구에서 33.5% 의유병률을보고하였다 [1]. 당뇨병성말초신경병증의위험인자로연령, 당뇨병유병기간, 혈당조절, 고혈압, 흡연, 이상지질혈증, 비만, 인슐린분비능저하, 심혈관계질환등이알려져있으며 [2-4], 대체로점진적인진행양상을보여임상에서간과하기쉬우나증상의악화로인해환자의삶의질을저하시킨다 [5,6]. 당뇨병성말초신경병증은결국족부의궤양과절단과같은심각한합병증까지초래할수있어서정확히진단하고초기부터적절히치료하는것이대단히중요하다 [7]. 그러나실제임상에서당뇨병성말초신경병증에대한관심이심혈관질환과같은다른당뇨병성합병증에비해상대적으로부족한것이사실이다. 이는표준화된진단법의부재, 혈당조절및심혈관위험인자관리와같은당뇨병의일반적인치료가신경병증치료에도근간을이루는점, 그리고대증치료에치중된치료의한계점등과연결된다. 최근병인적인치료에대한연구와임상적시도가있어왔으나아직은뚜렷한효과를보여주는경우는드물다. 이런실정에서당뇨병성말초신경병증의임상적중요성을감안하면진단검사법과치료에대한이해가당뇨병환자의관리에필수적이라고할수있다. 본고에서는최근당뇨병성신경병증소위원회에서제4판진료지침을개정하는데맞추어현재사용되고있는다양한진단및치료법을고찰하고정리하고자한다. 본론 1. 당뇨병성말초신경병증의진단당뇨병성말초신경병증의진단은병력청취로나타난임상양상과신경학적검사를통한신경계결손을바탕으로이루어진다. 당뇨병성신경병증환자의 30~40% 에서신경병 증증상을호소한다고보고되고있고, 가장흔한증상은사지의통증이며밤에악화되는특징을나타낸다. 그중통증성말초신경병증은국내연구에의하면전체당뇨병성말초신경병증의 43.1% 에서보고되었다 [8]. 전체적으로제2 형당뇨병에서제1형당뇨병환자보다유병률이높게보고된다 (17.9% vs. 5.8%) [4]. 전형적인감각이상은사지의원위부로갈수록심해지는 stocking-glove 형태로상지보다하지말단부의침범이더욱흔하며운동신경보다는주로감각신경의이상을호소한다. 혈당조절정도와당뇨병유병기간에비해심한증상을호소하거나급격히진행되는양상을보이는경우, 전형적인당뇨병성신경병증의양상과다른경우는당뇨병이외의다른원인에의한신경병증을배제하여야한다 [9]. 기본적으로당뇨병성말초신경병증은다른원인에의한신경병증이배제되고특별한원인을찾을수없을경우에진단될수있다 [9]. 그러나신경병증에의한통증은매우주관적이어서환자에따라서매우다양하게호소된다. 환자가호소하는증상은이상감각, 이질통, 통각과민, 저린감, 통증과같은양성증상과통각감퇴, 온도, 진동, 압력에대한감각저하, 반사저하, 무감각같은음성증상으로나눌수있다 [10]. 그러므로환자가전형적인증상을호소하면임상증상만으로진단할수있으나앞서언급한바와같이호소하는증상은환자마다다르게표현될수있고, 신경병증증상을호소하는경우도전체신경병증환자의절반수준에도못미치므로임상증상에만의존할경우진단을놓칠수있다. 한보고에의하면의사들이통증성당뇨병성말초신경병증환자의약 36.4% 만을인지하고있었다 [11]. 당뇨병성말초신경병증의진단을좀더체계적으로하기위해서토론토당뇨병성신경병증전문가집단에서는당뇨병성말초신경병증의정의를아래와같이 4가지분류로제안하였다 [12]. 가능 (possible) 진단은환자가당뇨병성말초신경병증의증상또는징후중한가지만보이는경우로정의하고, 유력 (probable) 진단은증상과징후를동시에보이는경우로정의하고, 확정 (confirmed) 진단은신경전도검사에서비정상적인소견이있고증상이나징후가있으면정의할수있으며, 만약신경전도검사가정상일경우에는검증 154
문성수 된소신경섬유기능검사가비정상일경우도진단할수있다. 불현성 (subclinical) 진단은신경전도검사나소신경기능검사에서신경결손이확진되었으나증상이나징후가없는경우로정의한다 [13]. 증상은앞서언급한양성증상과음성증상을포함하고징후는주로신경학적검사를통한소견을말한다. 신경학적진찰은감각기능검사와운동기능검사이며감각기능검사가더복잡하고당뇨병성말초신경병증을진단하는데더중요하다. 이것은당뇨병에의해감각신경이운동신경보다더손상이빠르고심각하며감각기능은촉각, 통각, 온도각, 진동, 관절감각을모두포함하기때문이다. 굵은유수신경섬유의이상은가벼운촉각, 진동감각과관절감각으로평가하고, 가는유수신경섬유나무수신경의이상은통증과온도감각을평가하여알수있다. 신경학적검사중 10 g 모노필라멘트검사는간단한검사로임상적으로가장많이사용되고있다 [14]. 발등과발바닥등 10군데에필라멘트가굽어질정도로압력을가하여환자가감각을느끼는지알아본다. 감각을느끼는곳이 9군데이상이면정상이고 3곳이상에서감각을느끼지못하면감각기능저하로판단한다. 통증은핀이나핀휠 (pinwheel) 을사용하고진동감각은 128 Hz의소리굽쇠를엄지발가락의등쪽원위수지간관절부위에대고진동감각을검사한다 [14]. 그외신경학적검사로차갑거나 (10 ) 뜨거운 (40 ) 물이있는시험관으로온도각검사와면봉을이용하여촉각을검사할수있다 [14]. 앞서기술한신경학적검사는검사자와피검자에의해결과가주관적일가능성이높다. 이러한한계점을보완하고자정량적감각신경검사가이용될수있다. 정량적감각신경검사는자극에대한역치를좀더정확하게측정하고자시도되며당뇨병환자에서진동감각, 온도감각, 통증의역치를측정함으로써불현성신경병증을진단하는데도움이되며대표적으로전류역치검사가있다 [13]. 하지만이검사방법도어느정도주관적인면이있을수있다. 신경전도검사는말초신경의기능을가장정확하고객관적으로평가할수있는검사로임상양상이비전형적이고진단이확실하지않아다른원인을배제하여야할경우시행할수있다 [13]. 신경전도검사를통하여신경의손상부위 와손상정도, 그리고탈수초와축삭변성과같은병리적인소견을알수있다. 그러나신경전도는주로굵은유수신경의기능에의해결정되므로가는유수신경이나무수신경의이상을정확하게평가할수는없으므로정량적감각검사를대신할수는없다. 최근에는각막다초점현미경검사가각광을받고있는데실제임상에적용되는경우보다는당뇨병성말초신경병증의여러임상연구에서활용되고있다 [15]. 각막신경섬유의길이, 밀도, 구불거림, 가지치기밀도등이신경전도검사및여러당뇨병성말초신경병증진단과상호연관성을보였다. 비침습적으로신속하게검사할수있고재현이가능한검사이므로향후임상적인활용이기대된다. 마지막으로, 말초신경병증검사의골드스탠다드 (gold standard) 는조직검사이다. 그러나이검사는침습적이며번거로우므로임상보다는연구에적용되고있는실정이다 [16]. 당뇨병성신경병증을선별하기위해고안된설문조사방법으로 Michigan Neuropathy Screening Instrument (MNSI) 가대표적이다 [13]. 신경병증의증상들중에서통증, 온도감각, 저린감에해당하는간단한 15개문항으로이루어져있으며설문조사와신경학적신체검사로구성되어있어서비교적외래에서신속하게시행할수있는검사이다. MNSI 설문조사는 15개항목이고총점은 13점으로 2 점이상이면신경병증을의심할수있고 7점이상이면신경병증이있음을시사한다. MNSI 신경학적신체검사는발의외형, 궤양유무를확인하고발목반사, 128 Hz 소리굽쇠를이용한진동각검사, 10 g 모노필라멘트검사로구성되어총 10점으로 2점을초과하면신경병증을시사한다. 비교적검사가쉽고, 일단숙달되면신속한검사가가능하므로임상적으로가장접근하기쉬운검사이다. 통증에대한설문조사로는 McGill Pain Questionnaire, Brief Pain Inventory, Neuropathic Pain Scale, Neurology Quality of Life (Neuro-QoL), Total Symptom Score 등이이용될수있으나실제진료에서활용하는경우는드물다. 대한당뇨병학회에서는 Fig. 1과같이진단적접근방법을요약하여제시하였다. 당뇨병성말초신경병증의진단과관련된수 www.diabetes.or.kr 155
Fig. 1. Diagnostic approach to diabetic peripheral neuropathy (DPN) proposed by the Korean Diabetes Association. Adapted from the book of the Korean Diabetes Association (Treatment guideline for diabetes 2015. 5th ed.) [7] with original copyright holder s permission. 정된진료지침은다음과같다. 라멘트검사를매년실시한다. [E] 2. 당뇨병성말초신경병증의진단을위한진료지침 3. 당뇨병성말초신경병증의치료 제1형당뇨병환자는진단후 5년부터, 제2형당뇨병환자는진단과동시에말초신경병증선별검사를시행해야한다. [B] 당뇨병성말초신경병증선별검사로 MNSI 설문조사, 10 g 모노필라멘트검사, 진동감각검사, 발목반사검사, 또는핀찌르기검사, 온도감각검사등을고려할수있다. [E] 진단을위해비슷한증상을일으키는다른원인들을배제하여야하고 [A] 필요시추가검사를진행할수있다. [B] 임상양상이비전형적이고진단이확실하지않아다른원인을배제하여야할경우전기생리적검사를시행하거나전문가에게의뢰할수있다. [E] 족부궤양및절단의위험을평가하기위해 10 g 모노필 당뇨병성말초신경병증의치료의주요목적은통증및증상을완화하여환자의삶의질을개선하고, 신경의퇴축을막아재생을돕고, 사지손상과같은심각한합병증을막는것이다 [14]. 치료는크게신경병증의원인에대한병인론적치료와환자의통증을치료하는대증치료로나눌수가있고, 병인론적치료에는혈당조절및위험요소를관리하는치료와신경병증의발병및병리기전에대한치료가있다 [17]. 당뇨병성말초신경병증의치료에서는무엇보다근본원인인혈당을조절하는것이중요하며, 여러연구들에서고혈당과당뇨병성말초신경병증의중증도는서로밀접한상관관계가있고적극적인혈당조절이치료에중요하다는것을보여주었다 [18]. 적극적인혈당조절에대한효과는주로제1형당뇨병환자에서보고되었다. 제1형당뇨병환자를대상으로한 Diabetes Control and Complications 156
문성수 Trial (DCCT) 연구에서적극적인혈당조절은이환율을 50% 정도까지감소시켰다 [19]. 반면에제2형당뇨병환자에서는제1형당뇨병에비해서적극적인혈당조절의신경병증에대한효과가뚜렷하지않아서제2형당뇨병에서는신경병증발병에보다복잡한병인이작용할것으로보인다 [20]. 혈당조절외에도흡연, 심혈관질환의과거력, 고혈압, 이상지질혈증등과같은심혈관위험인자도당뇨병성말초신경병증에중요하게관여하고있다고알려져있어이와같은위험요소에대한관리도중요하다 [2]. 병인론적치료제를살펴보면, 알도스환원효소억제제는폴리올대사물질의생성을저하시켜당뇨병성신경병증의병인론적치료로주목을받았다 [21]. 그러나지난 30여년간치료제로서연구가이루어졌으나기대와는달리대부분의약제가높은부작용의발현과미흡한효과등으로아직당뇨병성신경병증의치료제로허가된약물은 epalrestat를제외하고는거의없는실정이다. 알파리포산은산화스트레스에의한신경내막혈관의손상을저하시키는약제로여러임상연구에서매일 600 mg의알파리포산을 3주간정맥투여하였을때중요한부작용없이위약군에비해신경병증의주요증상들을호전시켰다. 그러나경구투여약물에있어서는그효과의증명이더필요한상황이다. 그외감마리놀렌산, 비타민 E, 혈관확장제, 신경성장인자에대해일부효과가있었다는보고가있으나약제의유효성을증명하는연구가더욱필요한상황이다. 마지막으로, 신경병증통증치료에임상적으로가장많이사용되고있는것이대증치료이다 [22]. 신경병증통증은환자에게수면장애, 우울증, 불안등삶의질의저하를초래하므로적극적인치료가필요하다. 다양한관련학회에서신경병증통증에대한치료를제시하고있는데현재미국임상내분비학회, 유럽신경과학회, 영국 NICE (The National Institute for Health and Care Excellence), 미국당뇨병학회에서공통적으로 1차치료제로제시하는약제는 duloxetine과 pregabalin이다 [21,22]. 그외삼환계항우울제, 항경련제, 선택적세로토닌재흡수억제제등의경구약제가사용될수있고초기용량부터서서히증량하며증상호전이없으면기전이서로다른약물로변경, 병합요법, 또는아편유사제를추가해볼수있다 [7,23]. 4. 당뇨병성말초신경병증의치료를위한진료지침 제1형당뇨병환자에서철저한혈당조절은당뇨병성신경병증발생을예방및지연시킨다. [A] 제2형당뇨병환자에서철저한혈당조절은당뇨병성신경병증진행을예방할수있다. [B] 대사증후군, 당뇨전단계및제2형당뇨병환자에서생활습관개선은당뇨병성신경병증발생을예방하기위해권고되어야한다. [B] 당뇨병성신경병증의치료목적은신경의퇴축을막고재생을증진하여삶의질을높이고의료비의부담을감소시키는것이다. [E] 당뇨병성신경병증의치료는당뇨병성신경병증의근본적인원인인혈당조절, 당뇨병성신경병증의병인론에기초한치료, 당뇨병성신경병증의통증과증상에대한치료가있다. [E] 당뇨병성말초신경병증대증치료는통증을경감시키며 [A], 삶의질을향상시킬수있다. [E] 병인론에근거한당뇨병성신경병증치료제에는항산화제, 혈관확장제, benfotiamine, 알도스환원효소억제제등이있으며 [C], 장기적으로는신경병증의임상경과에도움을줄수도있다. [E] 당뇨병성신경병증통증의치료는항경련제, 삼환계항우울제, 선택적세로토닌 / 노르아드레날린재흡수억제제를초기용량부터서서히증량하며약제의효과가충분히발현될때까지관찰한다. [A] 증상호전이없으면기전이서로다른약물로변경, 병합요법, 또는아편유사제를추가해볼수있다. [E] 결론 당뇨병성말초신경병증은가장흔한당뇨병합병증이지만현실적으로적절히진단되고관리되지않고있다. 임상 www.diabetes.or.kr 157
적으로당뇨병성말초신경병증에대한관심을가진다면병력청취와신경학적검사를통해진단할수있다. 간단한문진과신체검사에익숙해져서제한된진료실환경에서조기에환자를진단하고치료하는것이합병증으로진행하는것을예방하고증상의개선을통해환자의삶의질을개선할수있다. 혈당조절을비롯하여심혈관위험인자를관리하고병인치료와대증치료를적절히시행하고, 충분한효과가없으면다양한기전의약물의병합치료를고려하여야한다. REFERENCES 1. Won JC, Kwon HS, Kim CH, Lee JH, Park TS, Ko KS, Cha BY. Prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with Type 2 diabetes in Korea. Diabet Med 2012;29:e290-6. 2. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH; EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341-50. 3. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A; KORA Study Group. Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg surveys S2 and S3. Pain Med 2009;10:393-400. 4. Van Acker K, Bouhassira D, De Bacquer D, Weiss S, Matthys K, Raemen H, Mathieu C, Colin IM. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab 2009;35:206-13. 5. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009;32:1-32. 6. Won JC, Kim SS, Ko KS, Cha BY. Current status of diabetic peripheral neuropathy in Korea: report of a hospital-based study of type 2 diabetic patients in Korea by the diabetic neuropathy study group of the Korean Diabetes Association. Diabetes Metab J 2014;38:25-31. 7. Korean Diabetes Association. Treatment guideline for diabetes 2015. 5th ed. Seoul: Korean Diabetes Association; 2015. ps109-12. 8. Kim SS, Won JC, Kwon HS, Kim CH, Lee JH, Park TS, Ko KS, Cha BY. Prevalence and clinical implications of painful diabetic peripheral neuropathy in type 2 diabetes: results from a nationwide hospital-based study of diabetic neuropathy in Korea. Diabetes Res Clin Pract 2014;103:522-9. 9. American Diabetes Association. 10. Microvascular complications and foot care: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41(Suppl 1):S105-18. 10. Jensen TS, Backonja MM, Hernández Jiménez S, Tesfaye S, Valensi P, Ziegler D. New perspectives on the management of diabetic peripheral neuropathic pain. Diab Vasc Dis Res 2006;3:108-19. 11. Tsuji M, Yasuda T, Kaneto H, Matsuoka TA, Hirose T, Kawamori R, Iseki M, Shimomura I, Shibata M. Painful diabetic neuropathy in Japanese diabetic patients is common but underrecognized. Pain Res Treat 2013;2013:318352. 12. Dyck PJ, Albers JW, Andersen H, Arezzo JC, Biessels GJ, Bril V, Feldman EL, Litchy WJ, O'Brien PC, Russell JW; Toronto Expert Panel on Diabetic Neuropathy. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev 2011;27:620-8. 13. Won JC, Park TS. Recent advances in diagnostic strategies for diabetic peripheral neuropathy. Endocrinol Metab (Seoul) 2016;31:230-8. 14. Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic 158
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