원저 J Korean Neurol Assoc / Volume 24 / December, 2006 정상신경전도검사소견을보이는무증상성당뇨신경병증 서울의료원신경과, 강원대학교의과대학신경과학교실 a, 성균관대학교의과대학신경과학교실 b 배종석나성규고석민김성훈 a 김병준 b Subclinical Diabetic Neuropathy with Normal Conventional Nerve Conduction Study Jong Seok Bae, M.D., Sung Kyu Na, M.D., Seok Min Go, M.D., Sung Hun Kim, M.D. a, Byoung Joon Kim, M.D. b Department of Neurology Seoul Medical Center, Seoul; Department of Neurology, Kangwon National University College of Medicine a, Chunchon; Department of Neurology Sungkyunkwan University School of Medicine b, Seoul, Korea Background: For the early detection and prevention of diabetic neuropathy, it is important to identify subclinical diabetic neuropathies. A routine nerve conduction study often fails to detect the early stages of neuropathy. The purpose of this study is to evaluate the clinical usefulness of electrophysiological indexes including the residual latency(rl), terminal latency index (TLI) and modified F ratio (MFR) in detecting early diabetic neuropathy with no objective clinical or electrophysiological abnormalities. Methods: A nerve conduction study of the upper/lower limbs was investigated in 38 subclinical diabetic neuropathy patients with normal nerve conduction studies (group I), 35 clinical diabetic neuropathy patients with normal nerve conduction studies (group II) and 31 normal controls. RL, TLI and MFR were calculated and compared among the groups. Results: Compared with the control group, the MFR of the lower limbs and TLI of both the upper/lower limbs were significantly decreased in both group I and II (p<0.05). RL was increased in both groups, but the difference was not statistically significant. Comparing the indexes between group I and II, there was no significant difference. Conclusions: RL, TLI and MFR are useful indexes for reflecting distal conduction slowing especially in slowly progressing polyneuropathies such as diabetic neuropathy. The results also suggest that electrophysiological changes veiled in a routine nerve conduction study were present before the clinical manifestations. J Korean Neurol Assoc 24(6):557-563, 2006 Key Words: Diabetic neuropathy, Terminal latency index, Residual latency, Modified F ratio 서론 중증의당뇨신경병증은심각한장애를초래할수있으므로당뇨신경병증을조기에진단하고치료하는것이중요하다. 1,2 Received March 28, 2006 Accepted July 18, 2006 *Sung Hun Kim, M.D. Department of Neurology, Kangwon National University Hospital 17-1 Hyoja 3-dong, Chunchon-si, Gangwondo, 200-947, Korea Tel: +82-33-258-2413 Fax: +82-33-257-4636 E-mail: marinen@kangwon.ac.kr 당뇨신경병증의조기진단에있어서임상증상만을이용한진단은정확하지않고향후병의진행여부를판단하는데도한계가있으므로 3,4 보조적검사로서신경전도검사 (nerve conduction studies; NCS) 가당뇨신경병증의진단에가장흔히이용된다. 즉, 이상적인당뇨신경병증의진단은임상소견과이와연관된전기생리학적이상의확인을통해이루어진다. 5 하지만기존의당뇨신경병증의임상적, 전기생리학적진단기준은보고자마다다른경우가있어기존의당뇨신경병증의자연사에대한연구결과의해석은주의가필요하다. 6 초기당뇨신경병증에는소위 J Korean Neurol Assoc Volume 24 No. 6, 2006 557
배종석나성규고석민김성훈김병준 임상소견-전기생리학소견해리 (clinico-electrophysiological dissociation) 가존재할수있는데이는임상증상은전혀없는데전기생리학적이상소견이명확한경우혹은반대로임상증상은비교적심하지만전기생리학적으로는완전정상소견을보이는것을말한다. 전자는이전에무증상성당뇨신경병증 (subclinical neuropathy) 으로명명되었고 5 후자는조기당뇨신경병증또는 임상적으로정의된당뇨신경병증 (clinically defined DPN) 이라는다소모호한명칭으로불려진바가있다. 7 1형당뇨와달리 2형당뇨는당뇨신경병증이당뇨초기에시작하는것으로알려져있는데심지어 2형당뇨가진단되면당뇨신경병증은그순간이미존재하는것으로간주해야한다는주장도있다. 7 이러한점을고려한다면특히 2형당뇨환자의경우는앞서언급된임상소견-전기생리학소견해리를보이는환자들도당뇨신경병증의이환을확실히배제할수는없을것이다. 오히려이를고려함으로써당뇨신경병증의조기진단율을높이고진단의위음성율을낮출수있을것이다. 최근공식에의해계산된다양한이차적전기생리학적지표 (calculated index) 들이소개되었고다양한신경병증의전기생리학적이상소견을반영하는데기존의 NCS 척도보다더민감한도구로서의가능성이제시되었다. 8-10 특히당뇨신경병증은천천히진행하는진행성축삭성신경병증의전형이기때문에통상적 NCS 에서나타나는검사수치의작은변화가유의한변화인지판단하기가어렵고재현성과적정성의문제로인해 NCS 상의절대수치비교는한계가있다. 11 따라서통상적 NCS 만으로는감지하지못하는당뇨신경병증의미세한전기생리학적이상이나이상의진행이존재할가능성이크며당뇨신경병증의조기치료를위해서도이를감지해낼수있는도구의필요성이대두된다. Residual latency (RL), terminal latency index (TLI) 와 modified F-wave ratio (MFR) 같은계산된지표들은다발성신경병증의원위성전도지연을반영하는것으로알려져있고주로원위부가우세하게침범된탈수초성신경병증이나손목터널증후군등의질환에서연구된바있다. 8-10 반면, 축삭형신경병증에서의위의지표들의분석이나 2형당뇨와연관된길이의존성축삭성신경병증의진단에서위의지표들이민감한도구로이용될수있는지에대한연구는없었다. 저자들은통상적전기생리학적검사가감지하지못하는위음성의당뇨신경병증의존재가능성을생각해보았고이의확인을위한방법으로위에서언급한계산된지표들을이용하였다. 특히위음성율이높을가능성이있는초기의미세한당뇨신경병증을감지하는데이들지표가얼마나유용한지알아봄으로써당뇨신경병증의조기진단에통상적 NCS 의보완도구로이용가능한지판단하고자하였다. 대상과방법 1. 대상 본연구는 2002 년 4월에서 2004 년 4월까지삼성서울병원신경과로내원하여신경전도검사를시행한당뇨환자중에서정상으로판독되었던경우를대상으로병록지와검사결과지를후향적으로분석하였다. 포함된환자들은모두 2형당뇨환자로 American Diabetes Association Criteria 에합당하고 60세이하의연령만을대상으로하였다. 말초신경병증을일으킬수있는약물또는독물에의노출력, 유전성말초신경병증의가족력이나유전성말초신경병증에서나타나는근골격계의변형, 대사성말초신경병증에서나타나는전신성증상및검사실소견, 감각수준 (sensory level) 이나괄약근이상등의임상소견이있는경우와척추자기공명검사상증상과부합하는압박성신경근병증이의심되는환자는대상에서배제시켰다. 포함된환자들은주관적및객관적임상소견의유무에따라무증상성의 subclinical diabetic neuropathy with normal electrophysiological study (SDN-NEP) 군과양성및음성감각증상또는심부건반사저하소견이존재하는 clinical diabetic neuropathy with normal electrophysiological study (CDN- NEP) 군으로분류하였다. 상기명칭은실제신경병증의유무를객관적으로판단할수없는상황에서 2형당뇨는신경병증이조기에합병가능하다는기존가설들을토대로미세한신경병증이이미존재할것이라는저자들의주관적인가정을통해명명되었다. 대조군으로근막통증증후군또는섬유근육통과같은비신경기원의비특이증상으로 NCS 검사를시행하여정상결과를보인환자들의결과를이용하였다. 2. 통상적전기생리학검사환자는조용하고아늑한검사실에서 32~34 의사지표면온도를유지한가운데앙아위자세에서검사를받았다. 동일한검사자가표면기록과최대상자극 (supramaximal stimulation) 을통해표준신경전도검사를시행하였으며 Viking IV (Nicolet, Madison, U.S.A.) 기기를이용하였다. 저주파필터는 20 Hz 로, 고주파필터는 2 khz 로고정하였고자극은 0.1 msec 의기간으로일정하게하였다. 분석을위해서운동신경중상지에서척골신경과하지에서후경골신경의잠시 (distal motor latency; DML), 복합근육활동전위 (compound muscle action potential; CMAP), 운동신경전도속도 (motor conduction velocity; MCV), 558 J Korean Neurol Assoc Volume 24 No. 6, 2006
정상신경전도검사소견을보이는무증상성당뇨신경병증 및최소한 10회이상의 F 반응의시행을통해최소 F 반응잠복기치를측정하였다. 3. 계산된전기생리학적지표 TLI는계산된잠복기 (distal conduction distance/distal MCV) 와실제 NCS 에서측정되는 DML 의비를나타내는지표로손목하방원위부구획의 CV와손목과팔꿈치사이의 CV를비교한다. 계산방법은 Shahani 등 12 의다음방법을이용하였다. RL, TLI 와 MFR 를상지의척골신경과하지의후경골신경의통상적전기생리학검사치에서각각계산하였다. 척골신경과후경골신경은각각정중신경과비골신경에비해포착성신경병증발생에덜취약하며손과발의내인성근육을지배함으로인한 NCS 의기술적용이성과우수한재현성을갖기때문에선택되었다. 측정된통상적 NCS 결과중 DML, 원위CMAP, 손목과팔꿈치사이의원위MCV (distal MCV) 및팔꿈치와겨드랑사이의근위MCV (proximal MCV) 와최소 F파잠복기의절대치를이용하여계산하였다. TLI=Distal conduction distance (mm) / [distal MCV (m/s) DML (ms)] RL 은 NCS 에서측정된 DML 에서계산된잠복기를빼준값으로다음의공식을통해계산되었다. 13 RL=DML-[distal conduction distance / distal MCV] 원위 MCV 와근위 MCV 의비를나타내는 MFR 는근래에제 Table 1. Demographic features of control and patient groups Control (n=31) SDN-NEP (n=38) CDN-NEP (n=35) Age, y Male-female ratio Height, cm Duration of diabetes, mo Duration of neuropathic symptom, mo 47.9±9.1 11/20 164.3±7.8 - - 51.6±9.4 22/16 166.0±6.5 14.6±19.2-51.5±8.1 16/19 162.7±6.1 50.7±58.5 23.3±22.7 Data are means±sd. All variables do not show statistically significant difference among each group (P>0.05 in ANOVA, chi-square test), except for significant difference of diabetic duration between SDN-NEP and CDN-NEP groups (P=0.01 in student t-test). SDN-NEP; subclinical diabetic neuropathy with normal electrophysiologic study, CDN-NEP; clinical diabetic neuropathy with normal electrophysiologic study Table 2. Comparison of electrophysiologic data for ulnar and posterior tibial nerve in each group Ulnar nerve DML, ms PML, ms MNCV, m/s F-wave latency, ms RL, ms TLI Modified F ratio Posterior tibial nerve DML, ms PML, ms MNCV, m/s F-wave latency, ms RL, ms TLI Modified F ratio Control (n=31) SDN-NEP (n=38) CDN-NEP (n=35) P value a P value b 2.29±0.17 5.95±0.57 59.48±3.36 24.76±1.84 1.44±0.16 0.37±0.03 3.10±0.29 4.06±0.44 11.07±0.97 49.29±3.90 43.93±3.32 2.02±0.42 0.51±0.05 3.09±0.35 2.34±0.14 6.13±0.54 60.37±3.40 25.51±2.11 1.51±0.14 0.35±0.02 3.13±0.25 4.22±0.43 11.55±1.22 49.76±2.69 44.11±3.69 2.20±0.37 0.48±0.04 2.90±0.34 2.34±0.10 6.01±0.53 60.57±2.33 25.22±1.72 1.51±0.11 0.35±0.02 3.12±0.28 4.26±0.44 11.52±0.89 49.20±2.00 43.98±3.43 2.23±0.43 0.51±0.43 2.86±0.33 a P value comparing control versus SDN-NEP by student t-test. b P value comparing control versus CDN-NEP by student t-test. SDN-NEP; subclinical diabetic neuropathy with normal electrophysiologic study, CDN-NEP; clinical diabetic neuropathy with normal electrophysiologic study, DML; distal motor latency, PML; proximal motor latency (elbow-to-thenar muscle), MNCV; motor nerve conduction velocity, RL; residual latency, TLI; terminal latency index 0.15 0.19 0.28 0.13 0.07 0.047 0.65 0.14 0.08 0.58 0.84 0.06 0.03 0.03 0.17 0.65 0.13 0.29 0.05 0.02 0.81 0.07 0.06 0.91 0.95 0.05 0.049 0.007 J Korean Neurol Assoc Volume 24 No. 6, 2006 559
배종석나성규고석민김성훈김병준 시된다음과같은 Attarian 등 8 의공식을통해계산하였다. MFR=(F+DML-2xPML-1) / (2 DML) 여기서 PML (proximal motor latency) 는팔꿈치에서자극하였을때의소구지에서측정되는잠복기를의미한다. 4. 통계학적분석대조군과 SDN-NEP 및 CDN-NEP 의신경전도검사척도절대치및 TLI, RL, MFR 를비교하였다. 결과는평균 ± 표준편차로나타내었으며, 연속변수는 ANOVA test, unpaired student t test 를이용하여분석하였다. 상관관계는 Pearson s correlation test 를이용하였다통계프로그램으로는윈도우용 SPSS 10.0 을이용하였다. P 값이 0.05 이하인경우를통계학적으로유의한것으로해석하였다. 결과 38명의 SDN-NEP 환자와 35명의 CDN-NEP 환자가포함되었고 31명의정상대조군과함께비교분석되었다. 세군에서신장, 연령및성별의구성차이는없었으나당뇨유병기간은 SDN-NEP 군이 CDN-NEP 군보다유의하게짧았다. 특히처음당뇨를진단받고신경병증의선별검사로 1개월이내에 NCS 를시행한경우가 SDN-NEP 군에는 38명증 14명이포함된반면 CDN-NEP 군에는 31명중 4명이포함되었다 (Table 1). 각군사이의운동신경 NCS 척도즉, DML, PML, MCV, 와 F파잠복기를비교하였을때모든척도에서각군사이의유의한차이는없었다 (ANOVA test, P>0.05). 계산된지표즉, TLI, MFR, 와 RL 을비교하였을때, SDN-NEP 와 CDN-NEP 군사이에는어느지표에서도유의한차이를보이지않았다 (P>0.05). 대조군과 SDN-NEP 와 CDN-NEP 각각의비교에서는 TLI 가상하지모두에서두군모두대조군보다유의하게감소되었고 (Table 2, Fig.1) MFR 은하지에서만유의하게감소되었다 (Table 2, Fig. 2). RL은두군모두대조군보다증가되어보이는경향이었지만통계학적으로유의한차이는없었다 (Table 2, Fig. 3). 신장과 F파잠복기, 신장과 MFR 사이에는어느군에서도유의한상관관계를보이지않았다 (P>0.05). 고찰 당뇨신경병증의객관적진단을위하여통상적전기생리학검사가널리이용되고있다. 하지만통상적전기생리학검사는초기미세한변화만을보이는신경병증을반영하는데는한계가있기때문에 11,14 이외의단섬유근전도나자율신경계검사와같은다른검사법의병행이시도되기도한다. 15-17 이러한특수검사들은대개의검사실에서통상적으로시행하기에현실적으로많은시간적경제적인어려움이존재한다. 본연구의주된목적은통상적전기생리학검사가가려내지 Figure 1. Distribution of TLI for ulnar (A) and posterior tibial nerves (B) in different groups. The TLI of both ulnar and posterior tibial nerves were significantly lower in the SDN-NEP and in the CDN-NEP (P<0.001) than in the control group. TLI; terminal latency index, SDN-NEP; subclinical diabetic neuropathy with normal electrophysiologic study, CDN-NEP; clinical diabetic neuropathy with normal electrophysiologic study. 560 J Korean Neurol Assoc Volume 24 No. 6, 2006
정상신경전도검사소견을보이는무증상성당뇨신경병증 Figure 2. Distribution of MFR for ulnar (A) and posterior tibial nerves (B) in different groups. The MFR of ulnar nerve is significantly decreased in the SDN-NEP and in the CDN-NEP (P<0.001) than in the control group. MFR; modified F ratio, SDN-NEP; subclinical diabetic neuropathy with normal electrophysiologic study, CDN-NEP; clinical diabetic neuropathy with normal electrophysiologic study. Figure 3. Distribution of RL for ulnar (A) and posterior tibial nerves (B) in different groups. Mean value of RL is slightly increased in the SDN-NEP and in the CDN-NEP than in the control group but, there was no significant difference between them. RL; residual latency, SDN-NEP; subclinical diabetic neuropathy with normal electrophysiologic study, CDN-NEP; clinical diabetic neuropathy with normal electrophysiologic study 못하는초기당뇨신경병증의존재유무를특수검사에의하지않고통상적전기생리학검사척도에서계산된지표를통해밝혀낼수있는가하는점이었다. 일반적으로당뇨신경병증은원위부에서시작되어상행하는길이의존성축삭신경병증으로알려져있으므로 18-20 저자들은초기의변화는주로원위부에국한될가능성을가정하게되었고따라서 TLI, MFR, 와 RL과같은원위부의전도지연을반영하는지표들 8-10 을이용하였다. 부가적인목적으로 임상소견- 전기생리학적소견해리 (clinico-electrophysiological dissociations) 가빈번히나타나는초기의당뇨 신경병증 5,7 의증상유무가위의지표들에의해전기생리학적으로구분될수있는지알아보고자하였다. 이러한목적으로분석된결과들은다음과같이요약될수있는데, 첫째, 후기반응 (late response) 을포함한통상적 NCS 척도가완전히정상범위이고정상대조군과비교하여도유의한차이가없는초기당뇨환자에서도원위부전도지연을나타내는지표상에는유의한차이가존재한다는점이다. 물론유의성은없지만평균수치면에서는당뇨환자의 NCS 척도가대조군보다는신경병증의양상으로나타난경향은있지만 (Table 2) 이들을이용한간단한계산 J Korean Neurol Assoc Volume 24 No. 6, 2006 561
배종석나성규고석민김성훈김병준 에의해얻어진지표들이확연한유의성을보였다는것은이들지표가당뇨신경병증혹은나아가길이의존성축삭신경병증의초기선택적원위부이상을민감하게반영할수있음을시사한다고할수있다. 둘째, 임상소견으로구분된 SDN-NEP 군과 CDN-NEP 군사이에모든지표와척도들이유의한차이를보이고있지않았다. 이는위의지표들이원위부전도지연을민감하게반영하기는하지만초기의무증상성유증상성신경병증의미세한전기생리학적분류가가능할정도의민감성은보이지않을가능성과반대로무증상성유증상성신경병증은임상소견만으로구분되어지는실제병태생리학적으로동일한단계의신경병증일가능성이있다. 종합하면통상적전기생리학검사가정상인당뇨신경병증이존재하며신경병증의증상이있는경우는물론이고이러한증상이전혀없는경우에도당뇨신경병증존재를배제할수없음을본연구는시사한다. 이는또한당뇨신경병증의진단민감도를더높여야한다는최근의주장 7 에설득력을주는결과가되겠다. TLI, MFR 와 RL 등의지표들은통상적인전기생리학검사에서반영하지못하는원위부-근위부의상대적인이상정도를반영하는지표이다. 8,10,21-24 이중 TLI 와 RL은실제 NCS 술기중에측정된 DL과계산된 DL사이의비와차의개념을나타내는지표들이고 MFR 은더넓은구간의비로서팔꿈치와척수사이의특정전도시간을근위부전도의기준으로삼고원위부전도시간과비교하는지표이다. 8,12,13 최근에는이러한지표들을두가지이상종합하여원위부에집중된전도지연의여부를판단하는데이용하고있다. 8,10,21 이전의연구로는 TLI 와 RL 이손목터널증후군과같은원위부에국한된단신경병증에서민감한진단도구로서시행된바가있었고 22,23,25,26 최근에는만성염증성탈수초성다발신경병증 (chronic inflammatory demyelinating polyneuropathy; CIDP) 과항 MAG (myelin associated glycoprotein) 항체와연관된만성탈수초성다발성신경병증 (chronic demyelinating polyneuropathy; CDP) 의감별진단에유용하게이용되고있다. 8,10,21,24,26 TLI, MFR 와 RL 각각에서어느것이민감도나특이도면에서우수한지또는신경병증의단계에따라어떠한지표가더유용한지에대한논의는현재까지없었다. 본연구의결과에서는특히 TLI 가상하지모두에서유의성을띠는민감한원위성전도지연의지표로나타났고 MFR 는하지에서만유의성을보인반면, RL은경향은보이나유의성은없었던지표로나타났다. 하지만이전의탈수초성신경병증을주된대상으로시행된연구들에서는, 원위부탈수초의정도에따라 RL 뿐만아니라 DML 이유의한차이를나타내며이들이 TLI 보다더민감하게유의한차이를보임을보고 8,10,21 하여본연구와다른결과를보였다. 저 자들은이의원인으로본연구에포함된환자군의특수성을고려하였는데, 즉, 본연구의당뇨신경병증환자들중특히 SDN- NEP 군경우는선별검사에서처음당뇨가발견된후 1개월내에아무런신경병증의증상이없이 NCS 를시행하였던경우가 38명중 14명이나차지하고있었기때문에이환자들은당뇨신경병증의극도의초기또는거의정상상태일가능성이높고따라서이점이위의보고들과다르게 DML 과 RL이대조군과유의한차이를보이지않은원인으로작용했을가능성이있다. 반면 TLI, MFR 이오히려유의한차이를보이는점에대한이유로저자들은근위부에대한원위부의상대적전도이상을나타내는신경병증의진행이이들지표들을크게 3단계의변화양상을보이게했을가능성을생각하였다. 즉, 극도의초기병변은주로 CV의원위부에우세한선택적전도지연으로나타나고따라서 TLI 의감소만이우세하게나타나는첫단계가존재할가능성이있다. 이후 CV 지연정도가더욱증가하면서 MFR 이감소할정도로근위성전도지연에비해원위성전도지연이명확해지는다음단계로진행한다. 마지막으로 DML 이증가하고따라서 RL 이함께증가하는반면원위부뿐만아니라근위부까지전도지연이현저해져원위부근위부전도지연의상대적차이및비가상쇄되는단계에서는 TLI 와 MFR 의유의성은사라지는단계가된다. 이가설에의하면 Radziwill 등 10 의환자들은진행된셋째단계를, 본연구의환자들은첫단계와둘째단계의과도기를반영하는전기생리학적단계라고볼수있다. 물론이가설은통상적 NCS 의운동신경전도에국한된전기생리학적가설이며본연구는 NCS 이외에자율신경기능검사혹은병리적검사를종합하여판단한것이아니기때문에전반적인당뇨신경병증의자연사에적용하는것은무리가있다. 또한저자들의가설은이전의또다른가설에서유추된것으로이론적인면에치우쳤다는비판을불러일으킬소지가있음을인정한다. 하지만현재까지 RL, TLI 와 MLF 의상호관계나신경병의진행에따를이들지표의변화패턴에대한연구가전혀이루어지지않았다는점에서볼때이를논리적으로설명해보려는하나의시도로고려될수있을것이다. 마지막으로비록각군간의평균치에서통계학적으로유의한차이를확인하였지만개개의환자에있어서는수치의중첩부위가크기때문에이지표들만을갖고조기신경병증의유무를개개의환자에서확인하기는불가능하였다. 하지만통상적전기생리학적검사가정상이라도일단 2형당뇨가있는경우에는 SDN-NEP 이나 CDN-NEP 와같은초기의당뇨신경병증이존재할가능성을확인하였다는점은본연구의의의로생각된다. 향후, 극도의초기당뇨신경병증에서부터치료적고려와이의효과에대한검증이요구될가능성이높은데이를위해서본 562 J Korean Neurol Assoc Volume 24 No. 6, 2006
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