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특수상황에서의간질환자치료 : 고찰및증례말초신경-근육질환의진단 대구가톨릭대학교의과대학신경과학교실이동국 Diagnosis of Peripheral Nerve-muscle Disorder Dong Kuck Lee, MD Department of Neurology, School of Medicine Catholic University of Daegu, Korea

1 특수상황에서의간질환자치료 : 고찰및증례말초신경-근육질환의진단 대구가톨릭대학교의과대학신경과학교실이동국 Diagnosis of Peripheral Nerve-muscle Disorder Dong Kuck Lee, MD Department of Neurology, School of Medicine Catholic University of Daegu, Korea 서론 말초신경계질환은척수로부터의해부학적구조에입각하여운동신경원질환 (motor neuron disease), 신경병증 (neuropathy), 신경근접합부질환 (neuromuscular junction disease), 및근병증 (myopathy) 등으로나누어살펴보는것이좋다. 이번강의에서는일단각부분에서잘생기는대표적인병에대해전체적인분류, 최근진단기준의변화, 분자생물학및유전학의발달로인해새로발견된유전자이상과특징적인임상양상, 및감별진단등에대해간략하게알아보도록하자. 본론 1. 운동신경원질환 1) 분류운동신경원질환은크게유전성과후천성으로나눌수있다. 유전성은보통염색체우성, 보통염색체열성, 및성염색체연관된것으로나누고후천성은급성, 만성, 및근위축측삭경화증과비슷한증상을보이는경우등으로분류한다. 2) 진단기준이병은언어가느려짐, 각종심부건반사항진, 강직, 구역 및턱반사항진, Hoffman 징후, 및 Babinski 징후양성과같은상위운동신경원징후와위축, 쇠약, 및근섬유다발수축 (fasciculation) 과같은하위운동신경원징후가뇌간을포함한뇌, 경수, 흉수, 및요수에나타나는양상을보고확실 (definite), 유력 (probable), 검사실소견이받쳐주는유력, 가능 (possible), 및의심 (suspect) 등으로진단한다 (Table 1, Fig. 1) ) 유전적운동신경원질환 1991 년 androgen 수용체유전자의이상에의해척수-연수근위축 (spinobulbar muscular atrphy) 이생긴다는보고이후최근 18q21 염색체의이상에의해 ALS6 가발병한다는경우까지수많은유전자이상이보고되었다 (Table 2). 4 4) 전두측두엽치매와의관계과거근위축측삭경화증과전두측두엽치매는별개의질환으로생각되었지만최근두질환사이에임상적및신경병리학적으로밀접한연관성이존재한다는증거가꾸준히제시되고있다 (Fig. 2). 5,6 5) 감별진단운동신경원질환은뇌, 두개골기저부, 경추척추증성척수병증, 신경근병증, 봉입체근염, 다초점성운동신경병증, 및 Kennedy 병등과의감별진단이필요하다 (Table 3). 1 Dong Kuck Lee, MD Department of Neurology, Catholic University of Daegu, School of Medicine, Daemyeong 4-dong, Nam-gu, Daegu , Korea Tel: Fax: dklee@cu.ac.kr 2. 신경병증 1) 분류말초신경에서병변이생긴위치에따라단일신경병증, 다발 J Korean Neurol Assoc Volume 29 Suppl. 2,

2 이동국 신경병증, 신경얼기병증, 및다발성단일신경병증등으로나누고신경섬유크기에따라소섬유감각신경병증, 대섬유감각신경병증, 소섬유와대섬유혼합신경병증, 주로운동신경병증, 및자율신경병증등으로나눈다. 또한조직병리학적소견에따라탈수초성, 축삭성, 및신경세포성 (neuronal) 신경병증등으로나누고시간경과에따라급성, 아급성, 만성, 장기간이며유전성, 및재발성등으로분류한다. 2) 약물에의한신경병증알코올, 독소, 중금속, 기타임상에서쓰고있는다양한약물들이감각, 운동, 및감각운동혼합신경병증을일으킬수있다 (Table 4). 7 3) 유전성운동및감각신경병증이런병가운데가장대표적인질환인 Charcot Marie Tooth 병의최근까지밝혀진유전양상, 이상유전자, 및유전자자리 Weakness/atrophy/hyperreflexia/spasticity Progression over time EMG/NCV/neuroimaging/biopsy neuropathology LMN signs only 1 region UMN signs only 1 region LMN + UMN 1 region LMN + UMN 1 region or UMN 1 region LMN + UMN 2 regions LMN + UMN 3 regions Suspected ALS Possible ALS EMG acute denervation 2 limbs Probable ALS Definite ALS Idebtified DNA gene Probable ALS Laboratory supported Definite Familial ALS Laboratory supported Figure 1. EI Escorial revisited: revised criteria for the diagnosis of ALS. Clinical history consistent with FTLD Tau+ TDP43+ With or without motor neuron disease Tau- and TDP43-3R Tau+ FTLD with pick bodies 4R Tau+ CBD, PSP, or AGD 3R & 4R Tau+ NFTD MAPT mutation DLDH NIFID, BIBD nor CHMP2B mutation PGRN mutation VCP mutation Neither VCP nor PGRN mutation Figure 2. Diagnostic algorithm for FTLD based on neuropathology. AGD, argyrophilic grain disease; BIBD, basophilic inclusion body disease; CBD, corticobasal degeneration; CHMP28, charged multivesicular body protein 28 gene; DLDH, dementia lacking distinctive histopathology; FTLD, frontotemporal lobar degeneration; MAPT, microtubule-associated protein tau; NFTD, neurofibrillary tangle dementia; NIFID, neuronal intermediate filament inclusion disease: PGRN, progranulin; PSP, progressive supranuclear palsy; VCP, valosin-containing protein. 26 대한신경과학회지제 29 권부록 2, 2011

3 말초신경 - 근육질환의진단 Table 1. Revised El Escorial Research Diagnostic Criteria for ALS The diagnosis of ALS requires: 1 Evidence of LMN degeneration by clinical, electrophysiological or neuropathological examination; 2 Evidence of UMN degeneration by clinical examination, and 3 Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination, Together with the absence of: [1] Electrophysiological and pathological evidence of other disease that might explain the signs of LMN and/or UMN degeneration, and [2] Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs Definite ALS UMN signs and LMN signs in 3 regions Probable ALS UMN signs and LMN signs in 2 regions with at least some UMN signs rostral to LMN signs Probable ALS Laboratory supported UMN signs in 1 or more regions and LMN signs defined by EMG in at least 2 regions Possible ALS UMN signs and LMN signs in 1 region (together), or UMN signs in 2 or more regions UMN and LMN signs in 2 regions with no UMN signs rostral to LMN signs UMN signs: clonus, Babinski sign, absent abdominal skin reflexes, hypertonia, loss of dexterity. LMN signs: atrophy, weakness. If only fasciculation: search with EMG for active denervation. Regions reflect neuronal pools: bulbar, cervical, thoracic and lumbosacral. Table 2. Inherited Motor Neuron Diseases Name Site Gene Inheritance Comment ALS1 21q22.1 SOD1 AD Adult ALS2 2q33 Alsin AR Juvenile; may resemble PLS. Alsin a GTPase regulator protein? ALS3 Unknown ALS4 9q34 Senataxin (DNA/RNA helicase) AD Juvenile; allelic to CMT2 ALS5 15q - AR Juvenile ALS6 18q21 - AD Adult ALSㅡno number 20q AD Adult ALS-FTD 9q21-q22 - AD Adult FTD-PD-17 amyotrophy 17q21-q22 Tau AD Adult ALS-X - - XR Juvenile PMA 2p13 Dynactin AD Adult GM-2 gangliosidosis 15q23-23 Hexosaminidase AR - SMA 5q SMN AR Infantile (Werdnig-Hoffmann) Juvenile (Kugelberg-Welander) CMT2A 1p36 Mitochondrial kinesin KIF1Bβ AD Axonal CMT2A XBSMA Xq21-22 Androgen receptor XR Kennedy disease 3A syndrome 12q13 AR Allgrove syndrome: alacrima, achalasia, adrenal insufficiency, amyotrophy (locus) 는 Table 5 8 과같다. 병증과감별해야한다 (Table 7). 9 4) 다초점성운동신경병증 (Multifocal motor neuropathy) 수개월간서서히진행하며비대칭적인사지쇠약을보이고감각신경은정상이며운동신경전도검사상전도차단 (conduction block) 을보이는이병은면역글로불린주사로어느정도치료가가능하다 (Table 6). 9 이병은운동신경원질환, 만성염증성탈수초성다발신경병증, 및다초점성운동및감각탈수초성신경 5) 신경초음파검사최근근골격계질환의진단에널리이용되는초음파검사는정적및동적인해부학적구조를실시간으로볼수있고종횡으로도볼수있으며동시에인접구조물도관찰이가능하여발병원인을아는데도움이되는장점이있다. 10 J Korean Neurol Assoc Volume 29 Suppl. 2,

이동국 Table 3. Diagnostic errors and most common ALS mimic syndromes 3. 신경근접합부질환 1) 분류신경근접합부질환은크게유전성과후천성으로나눌수있고각각은연접 (synapse) 전, 중, 및후에생기는병으로나눌수있다.

4 이동국 Table 3. Diagnostic errors and most common ALS mimic syndromes 3. 신경근접합부질환 1) 분류신경근접합부질환은크게유전성과후천성으로나눌수있고각각은연접 (synapse) 전, 중, 및후에생기는병으로나눌수있다. 신경근접합부에생기는대표적인병인중증근무력증과 Lambert Eaton 근무력증후군과는서로감별진단이필요하다 (Table 8). 11 2) 근무력증을악화시키는약물임상에서흔히쓰이는약물인항생제, 근이완제, 베타차단제, 국소마취제, 보툴리눔독소, Quinine 유도체, Mg, 및 Penicillamine 28 대한신경과학회지제 29 권부록 2, 2011

5 말초신경 - 근육질환의진단 Table 4. Drugs inducing peripheral neuropathy 등이근무력증을악화시킬수있다 (Table 9). 12 3) Muscle-specific tyrosine kinase (MuSK) 항체양성근무력증중증근무력증환자중 acethlcholine 수용체에대한항체가없는사람가운데 40-60% 에서 MuSK 항체가양성이다. 이경우는여성에서더흔하며안면과인후침범이많고병의진행경과중더일찍위기 (crisis) 가생기고 acethlcholinesterase 억제제에대한반응이적으며 MuSK 항체음성에비해서는쇠약이뚜렷하고대부분면역억제제에반응이좋으며특히 Rituximab 에대한치료효과를기대해볼만하다. 13,14 4. 근병증 1) 분류근병증은크게유전성과후천성으로나눌수있다. Table 5. Hereditary motor and sensory neuropathies of CMT Table 9. Drug with Interactions in Myasthenia Gravis Drugs That May Exacerbate MG Antibiotics Aminoglycosides: streptomycin, tobramycin, kanamycin Quinolones: ciprofloxacin, levofloxacin, ofloxacin, gatifloxcin Macrolides: erythromycin, azithromycin, telithromycin Nondepolarizing muscle relaxants for surgery D-Tubocurarine (curare), pancuronium, vecuronium, atracurium Beta-blocking agents Propranalol, atenolol, metoprolol Local anesthetics and related agents Procaine, xylocaine in large amounts Procainamide (for arrhythmias) Botulinum toxin Botox exacerbates weakness Quinine derivatives Quinine, quinidine, chloroquine, mefloquine Magnesium Decreases ACh release Penicillamine May cause MG J Korean Neurol Assoc Volume 29 Suppl. 2,

6 이동국 Table 6. Diagnostic criteria of MMN Essential criteria for diagnosis of definite MMN 1. Slowly progressive or stepwise progressive asymmetric limb weakness related to at least two distinct peripheral nerves for more than 1 month (usually more than 6 months) 2. No objective sensory deficits except for minor vibration sense abnormalities in the lower limbs 3. Definite CB in two or more peripheral motor nerves outside the common entrapment sites 4. Normal neurography from at least three peripheral sensory nerves 5. Absence of upper motor neuron sings (spasticity, cloni, bulbar symptoms, pyramidal tract signs) Table 7. Important differential diagnoses of MMN MMN MND CIDP MADSAM neuropathy Symptom pattern Asymmetrical Asymmetrical Symmetrical Asymmetrical Sensory symptom No No Yes Yes + pain Tendon reflexes Decreased Increased Areflexia Decreased Disease course Slowly progressive Rapidly progressive Progressive/relapsing Progressive/relapsing CSF protein <1 g/l <1 g/l >1 g/l Rarely >1 g/l IgM anti-gm1 Ab ~30 50% ~10% Rare No Response to IVIg Yes No Yes Yes Response to steroids No (worsening) No Yes Yes Table 8. Differences between Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome 30 대한신경과학회지제 29 권부록 2, 2011

7 말초신경 - 근육질환의진단 Table 9. Drug with Interactions in Myasthenia Gravis Drugs That May Exacerbate MG Antibiotics Aminoglycosides: streptomycin, tobramycin, kanamycin Quinolones: ciprofloxacin, levofloxacin, ofloxacin, gatifloxcin Macrolides: erythromycin, azithromycin, telithromycin Nondepolarizing muscle relaxants for surgery D-Tubocurarine (curare), pancuronium, vecuronium, atracurium Beta-blocking agents Propranalol, atenolol, metoprolol Local anesthetics and related agents Procaine, xylocaine in large amounts Procainamide (for arrhythmias) Botulinum toxin Botox exacerbates weakness Quinine derivatives Quinine, quinidine, chloroquine, mefloquine Magnesium Decreases ACh release Penicillamine May cause MG Table 10. Genetic basis of muscular dystrophies Table 11. Drugs that cause true myalgia Cimetidine Cocaine Cyclosporine Danazol Emetine Epsilon aminocaproic acid Gold Heroin Labetalol Methadone D-Penicillamine Statins and other cholesterol-lowering agents L-Tryptophan Zidovudine 2) 근육디스트로피에대한유전적연구최근분자유전학이발달함에따라이병을일으키는것으로 Table 12. Drug-Induced Myopathies Lipid-lowering agents Fibric acid derivatives HMG-CoA reductase inhibitors Niacin (nicotinic acid) Glucocorticoids Nondepolarizing neuromuscular blocking agents Zidovudine Drugs of abuse Alcohol Amphetamines Cocaine Heroin Phencyclidine Meperidine Autoimmune toxic myopathy D-Penicillamine Amphophilic cationic drugs Amiodarone Chloroquine Hydroxychloroquine Antimicrotubular drugs Colchicine Table 13. Risk factors for statin adverse effects Advancing age Small body size Race/ethnicity History of statin intolerance Reduced hepatic function Reduced renal function Abnormal thyroid function Drugs affecting hepatic metabolism Other lipid-lowering therapy Alcoholism Congestive heart failure Intercurrent illness, surgery, or trauma Comorbidities and other conditions 추정되는이상유전자의위치및유전양상등이속속밝혀지고있다 (Table 10). 8,16 3) 근육통을일으키는약물임상에서흔히쓰이는약물들인 Cimetidine, Cocaine, Cyclosporine, 및 Statin 등이근육통을일으킬수있다 (Table 11). 17 4) 약물에의한근병증지질저하제, 글루코코르티코이드, Zidovudine, 알코올을포함한약물과용, 및 D-penicillamine 등다양한약물들이근병증을일으킨다 (Table 12). 15,18 5) Statin 에의한근병증지질저하제는크게 3 HMG-COA 환원효소억제제, Fibric acid 유도체, 및 Niacin 으로나눌수있으며그중에서도특히 J Korean Neurol Assoc Volume 29 Suppl. 2,

8 이동국 3 HMG-COA 환원효소억제제인 Statin 은근육통, 혈청 CK증가. 및횡문근융해등다양한근병증을일으킬수있으므로항상주의해야한다. Statin 에의해근병증이잘생길수있는위험인자는 Table 13과같다 결론 최근분자생물학, 유전학, 영상의학, 및임상신경생리학등의발전으로인해다양한진단기술이발달함에따라말초신경- 근육질환의분류, 병리기전, 진단, 및치료등에많은변화가생기고그결과새로운임상양상들이계속발견되고있다. 따라서말초신경-근육질환을진료하는의사는항상새로운변화에관심을가지고최신지식을습득하여진료에임해야할것으로생각한다. References 1. Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. BioMed Central 2009;4: Douglass CP, Kandler RH, Shaw PJ, McDermott CJ. An evaluation of neurophysiological criteria used in the diagnosis of motor neuron disease. J Neurol Neurosurg Psychiatry 2010;81: Kuwabara S, Sonoo M, Komori T, Shimizu T, Hirashima F, Inaba A, et al. Dissociated small hand muscle atrophy in amyotrophic lateral sclerosis. Muscle Nerve 2008;37: Lomen-Hoertb C. Treatment and management of adult motor neuron diseases. In: Bertorini TE. Neuromuscular Disorders Treatment and Management. 1st ed. New york: Saunders Elsevier, 2011; Rowland LP, Mitsumoto H, Przedborski S. Amyotrophic Lateral Sclerosis, Progressive Muscular Atrophy, and Primary Lateral Sclerosis. In: Rowland LP, Pedley TA. Merritt's Neurology. 12th ed. New York: Lippincott Williams & Wilkins, 2010; Sa-Yoon K. TAR DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. J Korean Neurol Assoc 2011;29: Chaudhry V. Peripheral Neuropathy. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. 17th ed. Vol. 2. New York: McGraw Hill Medical, 2008; Simon RP, Greenberg DA, Aminoff MJ. Clinical neurology. 7th ed. New York: McGraw Hill Medical, 2009; Meuth SG, Kleinschnitz C. Multifocal motor neuropathy: Update on clinical characteristics, Pathophysiological concepts and therapeutic. European Neurology 2010;63: Valle M, Zamorani MP. Nerve and blood vessels. In: Bianchi S, Martinoli C. Ultrasound of the Musculoskeketal System. 1st ed. Heidelberg: Springer-Verlag, 2007; Oh SJ. Treatment and management of disorders of the neuromuscular junction. In: Bertorini TE. Neuromuscular Disorders Treatment and Management. 1st ed. New york: Saunders Elsevier, 2011; Drachman DB. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Larry Jameson J, Loscalzo J. Harrison's Principles of Internal Medicine. 17th ed. Vol. 2. New York: McGraw Hill Medical, 2008; Lang B, Vincent A. Autoimmune disorders of the neuromuscular junction. Current Opinion in Pharmacology 2009;9: Guptill JT, Sanders DB. Update on muscle-specific tyrosine kinase antibody positive myasthenia gravis. Current Opinion in Neurology 2010;23: Brown RH, Amato AA, Mendell JR. Muscular Dystrophies and Other Muscle Diseases. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Larry Jameson J, Loscalzo J. Harrison's Principles of Internal Medicine. 17th ed. Vol. 2. New York: McGraw Hill Medical, 2008; Escolar DM, O'Carroll P, Lesbner R. Treatment and management of muscular dystrophies. In: Bertorini TE. Neuromuscular Disorders Treatment and Management. 1st ed. New york: Saunders Elsevier, 2011; Kompoliti K, Horn SS. Drug-Induced and Iatrogenic Neurological Disorders. In: Goetz CG. Textbook of clinical neurology. 3rd ed. New York: Saunders Elsevier. 2007; Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med 2010;48: Benatar M. Neuromuscular Disease. 1st ed. New York: Humana Press, 2006; Vandenberg BF, Robinson J. Management of the Patient with Statin Intolerance. Curr Atheroacler Rep 2010;12: Meador BM, Huey KA. Statin-Associated myopathy and its exacerbation with exercise. Muscle Nerve 2010;42: 대한신경과학회지제 29 권부록 2, 2011

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