대한임상신경생리학회지 14(1):12~19, 2012 ISSN 1229-6414 Review 경상대학교의학전문대학원신경과학교실, 건강과학연구원 박기종 Neurological Disorders Associated with Sweating Ki-Jong Park, M.D., Ph.D. Department of Neurology, School of Medicine, Gyeongsang Institute of Health Science, Gyeongsang National University, Jinju, Korea Received 11 June 2012; accepted 12 June 2012. Thermoregulatory sweat is principal mean for homeostasis of temperature. Sweat glands have eccrine gland, apocrine gland, and apoeccrine glands. Disorders of sweating are manifested by excess (hyperhidrosis) or deficit (hypohidrosis, anhidrosis) of sweat. Hyperhidrosis can be defined as excessive sweating beyond a level required to maintain normal body temperature. The sweating can be generalized or localized (axilla, palms, soles, palmar-plantar, perineal). Usually hypohidrosis or anhidrosis may be more serious than hyperhidrosis. Hyperhidrosis is usually benign, but interferes with one s daily activities. First step for diagnostic approach for sweating disorders might be dividing them into localized or generalized, and primary or secondary forms. Treatement for hyperhidrosis include topical agents, botulinum toxin A injections, systemic anticholinergics, and sympathectomy. Key Words: Thermogegulatory sweat, Hyperhidrosis, Hypohidrosis, Anhidorosis 포유류에서발한 (perspiration) 은다양한기전으로이루어지고있지만, 사람에서는크게네가지기전으로발한이이루어진다 (Table 1). 1 이들중에서도땀분비는온도조절을위한발한의가장주요한방법이다. 2 사람에게는약 4백만개의땀샘이있으며피지선 (sebaceous gland), 아포크린땀샘 (apocrine sweat gland), 에크린땀샘 (eccrine sweat gland), 아포에크린땀샘 (apoeccrine sweat gland) 이있다. 3 피지선은손 / 발을제외한몸전체에퍼져있으면서온 Address for correspondence; Ki-Jong Park, M.D., Ph.D. Department of Neurology, School of Medicine, Gyeongsang Institute of Health Science, Gyeongsang National University, 90 Chiramdong, Jinju 660-702, Korea Tel: +82-55-750-8735 Fax: +82-55-755-1709 E-mail: pkjong@gnu.ac.kr 도조절에는관여하지않는다. 아포크린땀샘은피지선과함께모낭표면에서분비를한다. 아포크린땀샘은비슷한수의에크린땀샘과함께겨드랑이장기를형성하는데, 아포크린땀샘은정신적자극에의해서분비를하고, 에크린땀샘은온도자극과스트레스에반응한다. 1 에크린땀샘은온도와전해질조절에주요역할을하며, 인체내부온도가시상하부의기준점 (set point) 을초과하면교감신경이활성화되고전신의땀분비, 혈관확장, 과호흡을통하여온도의항상성을유지한다. 4 땀분비가에크린땀샘보다 7배정도많이분비되는아포에크린땀샘은주로겨드랑이에위치하고있는것으로알려져있으며, 국소적다한증에주요역할을한다. 3 에크린땀샘은콜린성신경에의해지배를받고, 아포크린땀샘은아드레날린성신경에의해지배를받는다. 3 땀샘조절경로는 pre-optic 시상하부에서시작하여, 교 12 Copyright 2012 by The Korean Society for Clinical Neurophysiology
Table 1. Four systems of human perspiration 1 System Explanation Diffusion water Occurs all times from human skin and from the lungs Thermal sweating Depends on distinctive sweat from both apocrine and eccrine glands Palmar-sole sweating Depends on the eccrine glands located on the plams or plantar surfaces Emotional sweating Considered by some to be part of the palmar-sole eccrine system, which under appropriate stimuli 뇌덮개 (tegmentun of pons) 와숨뇌솔기 (medullary raphe), 척수의외중간세포기둥 (intermediolateral cell column) 을지나척수의앞뿔 (ventral horn) 에서나와서교감결절과연접 (synapse) 을형성한다. 5 땀샘은손과발에서가장많고, 등쪽에가장적게분포되어있다. 3 신경지배는안면과안검은 T1-T4 척추분절에의해지배받고, 상지는 T2-T8 척추분절, 몸통은 T4-T12 척추분절, 하지는 T10-L2 척추분절에의해지배받는다. 6 땀샘분비에영향을주는질환들은 anterior-cingulate-frontal ( 감정에의한 ) 중추기능장애, 뇌의온도조절중추장애, 숨뇌척수 (bulbospinal) 교감신경로장애, 척수의외중간세포기둥신경세포의손상, 결절혹은결절후신경에영향을주는말초신경질환, 땀샘의콜린성접합부에영향을주는질환들에의하여발생할수있다. 7 이들질환들은임상적으로땀저하증 (hypohidrosis) 혹은무한증 (anhidrosis), 땀과다증 ( 다한증, hyperhidrosis) 형태로나타난다. 땀저하증과무한증 (Hypohidrosis and anhidrosis) 무한증과땀저하증은적당한자극에도땀샘분비가일어나지않는질환으로서땀분비관의폐색, 선천적혹은후천적으로땀샘이없는경우, 피부염증으로인하여땀샘의기능손상, 온도조절신경로의손상으로인하여발생한다. 7 여기서는주로신경로의이상에의한땀분비감소를알아보기로한다. 1. 후천적특발성무한증을가진원발성자율신경질환 (Primary autonomic disorders with acquired idiopathic anhidrosis) 교감신경경로의발한운동계활동부전으로인하여전반적으로땀분비가소실되는특징을가지고있다. 임상적으로는열못견딤증 (heat intolerance) 에의한여러가지증상들을가지고있다. 특징적으로발이뜨겁게느껴지고, 숨이가쁘고, 어지럽고, 운동을할때나주위온도가올라갈때잘참지를못한다. 7 용어에대한논란은있지만, 임상적아형은분절형 (segmental), 특발성순수발한운동부전 (Idiopathid pure sudomotor failure), 만성특발성무한증 (Chronic idiopathic anhidrosis) 등이있다. 8-10 1) 분절형후천적특발성무한증 (Segmental acquired idiopathic anhidrosis) 이들환자들은교감신경의피부영역에해당하는신체부위에서비대칭적으로서서히진행하는땀분비의소실로나타난다. 11 동공크기와심부건반사가보존되어있어서 Ross 증후군과감별이가능하며, pilocarpine에대한반사적땀샘분비항진은결절전발한운동신경에병변이있음을시사한다. 12 2) 특발성순수발한운동부전 (Idiopathic pure sudomotor failure) 특발성순수발한운동부전은후천적무한증의가장흔한원인으로서다른자율신경계와체성신경계질환, 지속적인피부병변이없이전신적으로땀분비가없거나감소하는질환이다. 13 임상적으로는심한열못견딤증 ( 오심, 어지럼, 두통 ), 저림 (tingling), 따끔거림 (prickling), 화끈거리는통증이더운환경에노출되거나지속적인운동에의해서나타난다. 10 이들증상들은몸을차게했을때호전되었다. 50% 에서는혈청 IgE가증가되어있으며, 고용량 (methylprednisolone 500-1,000 mg) 의스테로이드사용에반응이좋다. 검사에서는체온조절성발한은모두소실되어있었지만, 감정에의한땀샘분비는보존되어있다. Pilocarpine 은땀을유도하지못하였으며, 피부의교감신경활동은보존되어있었다. 병변은땀샘의뮤스카린성콜린수용체에있을것으로생각한다. 3) 만성특발성무한증 (Chronic idiopathic anhidrosis) 만성특발성무한증은기립성저혈압과같은자율신경부전의증거나체성신경병증이없으면서열못견딤증과전반적인무한증이나타나는경우를말한다. 8 결절후병변과함께일부에서는결절전병변을가지고있으며, 일부에서는 IgE가상승되어관찰되기도한다. 7 Korean J Clin Neurophysiol / Volume 14 / June, 2012 13
박기종 4) Ross 증후군 Ross 증후군을가진환자들은열못견딤증, 무한증, 특정부위에보상적다한증을호소하며, 신경학적검사에서긴장성 (Adie) 동공과하지심부건반사의감소가관찰된다. 14 2. 신경학적질환들과연관된속발성무한증 (Secondary anhidrosis associated with neurologic disorders) 1) 중추신경계질환전반적인무한증은다발계위축 (multiple system atrophy) 에서흔하게관찰되고, 발한검사는다발계위축과파킨슨병을구별하는데도움이된다. 15 기립저혈압없이완전혹은반점형태의무한증은파킨슨병, 진행성핵상마비, pallidopontonigral degeneration에서잘동반된다. 이들질환에서안면발한의보존은보상성반응으로생각한다. 15-16 온도조절경로를침범하는중추성병변들은주로무한증이나땀샘분비감소로나타나는데, 다발성경화증, 뇌졸중, 시상절제술이후에동반될수있다. 17-19 2) 말초신경계질환원위부무한증이동반되지만종종무증상이기때문에말초신경병증을가진많은환자들에서발한운동검사에서만관찰되는수가있다. 20 (1) 유전성감각자율신경병증 (Hereditary sensory autonomic neuropathy, HSAN) 성인에서는 I형 HSAN이 10-30대에나타나고, II-V형은신생아나어릴때나타난다. 21 기립저혈압혹은교감신경항진증을동반한다한증이주로나타나는 III형 HSAN (Riley-Day 증후군 ) 과달리 I, II, IV, V형은원위부무한증혹은땀감소를동반하고, II형에서는긴장성동공과위장관계혹은방광기능장애를동반하기도한다. (2) 길랭-바레증후군길랭-바레증후군에서는환자의 10-20% 에서하지의땀분비가감소되어나타나는데, 운동과감각신경침범때문에무시되기도한다. 7 주로교감신경기능저하로인하여원위부무한증의형태로나타나며, 드물게체성감각침범없이자율신경병증만있는경우도있다. 22 (3) 당뇨병성말초신경병증당뇨병성신경병증을가진 51명의환자에서시행한온 도조절성발한검사에서 94% 가이상소견을보였다. 23 65% 에서는원위부무한증이관찰되었으며, 25% 에서는분절형태로관찰되었고, 25% 에서는특정피부영역에서만감소되어있었다. 다른심한자율신경병증의소견과함께 16% 에서완전무한증이관찰되었다. 무한증이관찰되는신체영역의크기는자율신경병증의정도와의미있는관계를보였다. (4) 아밀로이드신경병증발의저린감, 무딘감과함께하지원위부의무한증은 1형가족성아밀로이드신경병증을가진환자의특징적인소견이다. 24 비교적초기에장딴지신경 (sural nerve) 에서작은교감신경성 C-섬유를포함한수초성과무수초성신경섬유의소실이특징적이다. 신경조직검사에서발목위피부에있는에크라인샘의신경말단과무수초성축삭이뚜렷하게감소된소견이관찰되었다. (5) Lambert-Eaton 근무력증후군근위부위축, 심부근반사감소, 자율신경계증상 ( 입마름, 변비, 발기부전 ) 등이특징적인질환으로서 voltage-gated calcium 통로에대한자가항체로인하여발생한다. 25 흔하지는않지만땀샘분비형태의변화가동반된다. (6) 알코올성신경병증만성적인음주를하는환자에서말초신경병증과자율신경병증은비교적흔하게관찰할수있다. 26 이들에서는발에서땀감소와함께피부변화도같이동반된다. 그러나질병초기에는손바닥과발바닥의다한증이동반되기도한다. 27 (7) 파브리병 Anderson-Fabry병은 X-linked 열성리소좀축적병으로서 alpha-galactosidase A의활동결핍으로인해서발생한다. 신장, 심장, 눈등과같이다양한기관들을침범하면서, 신경학적으로는사지원위부의심한통증과함께무한증이나타날수있다. 28 (8) Erythromelalgia 원발성 erythromelalgia를가진환자들은소섬유신경병증을동반하고, 발한검사를포함한자율신경검사에서이상소견이관찰된다. 29 이환자들에서원위부무한증이흔하게관찰되고, 완전무한증도일부에서관찰된다. 14 Korean J Clin Neurophysiol / Volume 14 / June 2012
(9) 약물에의한땀감소혹은무한증다양한약물들이땀분비감소에영향을줄수있다 (Table 2). 30 다한증 (Hyperhidrosis) 다한증은개인의일상생활을방해하고많은부담을주면서사회생활에어려움을일으킨다. 일상생활을방해하 Table 2. Drugs that can cause hypohidrosis 30 Mode of action Drugs Anticholinergics Atropine, belladonna, dicycloverine, glycopyrrolate, hyoscyamine, propantheline Antidepressants (tricyclics) Amitriptyline, clomipramine, despiramine, doxepin, imipramine, nortriptyline, protriptyline Antiepileptics Topiramate, zonisamide, carbamazepine Anti-histamines Cyproheptadine, diphenhydramine, promethazine Antihypertensives Clonidine Antipsychotics and antiemetics Chlorpromazine, clozapine, olanzapine, thioridazine, quetiapine Antivertigo drugs Meclozine, scopolamine Bladder antispasmodics Darifenacin, oxybutynin, solifenacin, tolterodine Gastric antisecretory drugs Propantheline Muscle relaxants Cyclobenzaprine, tizanidine Neuromuscular paralytics Botulinum toxins Opioids Fentanyl, hydrocodone, methadone, morphine, oxycodone Table 3. Hyperhidrosis disease severity scale (HDSS) 31 How would you rate the severity of your hyperhidrosis? Level 1 My sweating is never noticeable and never interferes with my daily activities Level 2 My sweating is tolerable but sometimes interferes with my daily activities Level 3 My sweating is barely tolerable and frequently interferes with my daily activities Level 4 My sweating is intolerable and always interferes with my daily activities Table 4. Causes of hyperhidrosis 6 Type Generalized hyperhidrosis Focal hyperhidrosis Etiology - Hyperhidrosis with systemic illness (Pheochromocytoma, thyrotoxicosis, diabetes mellitus, hypoglycemia, diabetes insipidus, hypopituitarism, heart failure, dumping syndrome, anxiety, menopause, carcinoid syndrome, alcohol & drug withdrawal) - Nocturnal diaphoresis (Tuberculosis, lymphoma, endocarditis, diabetes, acromegaly, prinzmetal angina) - Episodic hyperhidrosis (Shapiro syndrome) - Medication-induced hyperhidrosis (Anticholineresterases, antidepressant (tricyclic and serotonin reuptake inhibitors), antigalucoma agents, bladder stimulants, opioid analgesics, sialogogues, acyclovir, naproxen) - Malignancy (Leukemia, renal cell carcinoma, castleman disease) - Essential palmar hyperhidrosis - Hyperhidrosis with spinal cord disease - Hyperhidrosis with intrathoracic neoplasms - Hyperhidrosis with cerebrovascular disease - Hyperhidrosis with peripheral neuropathy - Gustatory hyperhidrosis - Idiopathic unilateral circumscribed hyperhidrosis - Cold-induced hyperhidrosis - Hyperhidrosis with cutaneous lesions Korean J Clin Neurophysiol / Volume 14 / June, 2012 15
박기종 는정도에따라서심한정도를나눌수있다 (Table 3). 31 1. 전신다한증 (Generalized hyperhidrosis) 본태성전신다한증은땀분비에대한자극과특별한원인없이온도조절에필요한양을초과하여땀이분비되는것이특징이다. 6 낮은역치로인해서발생하는전신다한증은과도한체액소실과함께탈수와전해질소실을일으킬수도있다. 속발성다한증은다양한전신적질환들에서동반된다 (Table 4). Shapiro 증후군은반복적인저체온증과함께다한증이동반되어나타난다. 32 이증후군에서는뇌량과다른뇌의중심부구조물들의무발생이동반되며, 후천성면역결핍증환자에서도보고되었다. 저체온증을동반하지않는전신다한증이반복적인고혈압, 빈맥, 홍조와연관되는경우는시상하부의종양, 뇌경색등에의한손상에서관찰될수있다. 7 자율신경계질주 (autonomic storms) 혹은간뇌뇌전증 (diencephalic epileptic) 은교감신경을흥분시키는스트레스반응을조절하는시상하부의과도한흥분혹은억제가있다는것을시사한다. 다한증은파킨슨병에서도파민성약물의 off 상태에서흔하게보인다. 33 Hodgkin 질환은고열, 땀분비, 체중감소가특징적이다. 밤에관찰되는발한은 B-cell 임파종을가진환자에서잘관찰되고, 유일한증상인경우도있다. 34 다양한약물들에의해서도땀분비가증가할수있다 (Table 5). 2. 국소다한증 (Focal hyperhidrosis) 국소다한증은손바닥과발바닥에서가장흔하게관찰된다. 35 이경우를 palmar-plantar 다한증이라고한다. 겨드랑이다한증은대개 palmar-plantar 다한증과동반되어나타난다. 안면에만땀이많이나는두개안면다한증 (craniofacial hyperhidrosis) 은열, 감정, 매운음식 (gustatory hyperhidrosis) 에의해서악화될수있다. 겨드랑이의국소다한증에는아포에크린땀샘이주요역할을하는것으로알려져있는 Table 5. Drugs that can cause hyperhidrosis 30 Mode of action Anticholineresterases Antidepressants: selective serotonin reuptake inhibitors Antidepressants: tricyclics Antigalucoma agents Bladder stimulants Opioids Sialogogues Drugs Pyridostigmine Citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, trazodone, venlafaxine Amitriptyline, desipramine, doxepin, imipramine, nortriptyline, protriptyline Physostigmine, pilocarpine Bethanechol Fentanyl, hydrocodone, methadone, morphine, oxycodone Cevimeline, pilocarpine Table 6. Treatments for primary focal hyperhidrosis 38 Type Step 1 Step 2 Step 3 Step 4 Step 5 Axillary hyperhidrosis Palmar hyperhidrosis Plantar hyperhidrosis Craniofacial hyperhidrosis Topical aluminum chloride hexahydrate 15-20% in ethyl alcohol, salicyclic acid gel or thermophobic foam Topical aluminum chloride hexahydrate 15-20% in ethyl alcohol, salicyclic acid gel or thermophobic foam Topical aluminum chloride hexahydrate 15-20% in ethyl alcohol, salicyclic acid gel Topical aluminum chloride hexahydrate 15-20% in ethyl alcohol, Tropical glycopyrrolate (2%) Botolinum toxin A injections Iontophoresis, 15-20 ma, 20-30 min, tap water iontophoresis, Anticholinergics, Botulinum toxin A injections, Dry-type Iontophoresis, 15-20 ma, 20-30 min, tap water iontophoresis, Anticholinergics Systemic anticholinergics Systemic anticholinergics Botolinum toxin A injections Botolinum toxin A injections Botolinum toxin A injections Suction curettage or excision of the sweat glands Systemic anticholinergics Systemic anticholinergics Sympathetic denervation Repeat suction curettage or sympathetic denervation Sympathetic denervation 16 Korean J Clin Neurophysiol / Volume 14 / June 2012
데, 조직학과면역형광학적방법을이용한조직검사에서는겨드랑이에아포에크린땀샘이발견되지는않았다. 36 1) 원발성국소다한증 (Primary focal hyperhidrosis) 원발성국소다한증은에크라인땀샘질환에서가장흔한형태중의하나로뚜렷한원인없이국소적으로땀이많이나며정상인에서도발생할수있는다한증이다. 35 가족력이 25% 정도에서동반되기도하고, 수년동안동반되다가 30세이후에는자발적으로호전되기도한다. 원발성국소다한증은적어도 6개월이상뚜렷한원인없이국소적으로보이는땀분비의과다가있으면서적어도다음중 2개이상의특징을가지고있는경우에진단한다. 37 ㄱ. 양측성이며비교적대칭적이다. ㄴ. 환자의일상생활을방해한다. ㄷ. 1주일에적어도 1회이상발생한다. ㄹ. 25세이전에다한증이시작되어야한다. ㅁ. 가족력이있다. ㅂ. 잠을자는동안에는땀분비과다가없다. 원발성국소다한증의치료는땀이분비되는부위에따라서다양한치료를시도해볼수도있다 (Table 6). 38 2) 속발성국소다한증 (1) 뇌졸중대뇌섬 (insular) 과덮개피질 (opercular cortex) 을포함한대뇌반구를침범하는뇌졸중에서는반대측안면과상지에서땀의과다분비가관찰된다. 39 과다땀분비의정도는마비의정도와척수로징후에의미있는연관성을보였다. 편측의사상하부와뇌간경색에서호너증후군 (Horner syndrome) 이동반되지않은상태에서편측의다한증이동반될수도있다. 7 양측교뇌와소뇌경색에서는안면의다한증이발생할수있다. 이러한다한증은일시적이고급성기에만나타날수있다. 기전은반대쪽땀분비를조절하는억제경로가간섭을받으면서발생하는것으로추정한다. 39 (2) 말초신경손상땀분비과다가말초신경의소섬유신경병증에서동반될수있다. 땀분비과다는두경부같은근위부의보상현상으로발생할수있다. 6 때로는소섬유신경병증에서도손상된신경들의자발적인활성으로인하여원위부에서과도한땀분비가발생하는경우도있다. 40 (3) 척수질환 T6 이상의척수손상이있는환자에서자율신경계반사 기능장애 (autonomic dysreflexia) 는생명을위협하기도한다. 41 척수손상은발한운동에대한척수상부의조절능력을소실시키고, 방광이나장의팽창혹은피부자극같은일반적인자극에의해서도과도한자율신경계반응 ( 고혈압, 심한땀분비과다, 안면홍조, 심한두통, 코막힘, 발기, 서맥 ) 들이나타나면서치명적이될수도있다. (4) 척수종양에의한다한증교감신경결절혹은결절후교감신경섬유를침범하는종양들은동측의안면, 경부, 흉부에국소적인땀분비과다가있을수있다. 6 가장흔한원인으로는폐의선암종, 중피종 (mesothelioma), 골수종 (myeloma), 골종 (osteoma), 경부늑골 (cervical rib) 등이있다. 대개는동측의호너증후군, 상지위약, 감각소실이동반된다. 때로는반대측땀분비가줄어든것에비해정상적으로보존된땀분비를국소적땀분비과다로잘못해석하기도한다. (5) 미각다한증 (Gustatory hyperhidrosis) 매운음식을먹었을때땀이나는것은대부분의사람들에게정상적인반응이다. 이것은삼차신경혈관반사 (trigeminovascular reflex) 가주로안면과두피에고르게분포되어있기때문이다. 병적인경우에는음식의종류와상관없이대개비대칭적으로발생하는경우이다. 이하선부위의수술이나손상이후에나타나는경우를 Frey 증후군이라한다. 42 기전은침샘을지배하는부교감신경이귓바퀴앞땀샘과혈관을지배하는이개측두신경 (auriculotemporal nerve) 의결절후교감신경쪽으로잘못재생되면서나타나는것으로생각한다. 침분비와함께과도한땀분비는당뇨병, 군집성두통, 고실끈신경 (chorda tympani) 손상, 안면의대상포진에서동반되기도한다. 6 (6) Harlequin 증후군 Harlequin 증후군은편측안면의홍조와운동이나열에의해서땀이분비되는질환이다. 43 원인은외상, 뇌졸중, 면역성결절병증에의해서갑자기발생한다. 홍조와땀이많은부분이주목을받지만, 반대측의무한증과홍조소실은교감신경계의이상을시사한다. 때로는긴장성동공이동반될수있으며 Ross 증후군과중복되기도한다. REFERENCES 1. Folk GE, Jr., Semken HA, Jr. The evolution of sweat glands. Int J Biometeorol 1991;35:180-186. 2. Shibasaki M, Crandall CG. Mechanisms and controllers of eccrine Korean J Clin Neurophysiol / Volume 14 / June, 2012 17
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40. Low PA. Autonomic neuropathies. Current Opin Neurol 2002;15: 605-609. 41. Fast A. Reflex sweating in patients with spinal cord injury: a review. Arch Phys Med Rehabil 1977;58:435-437. 42. Drummond PD. Mechanism of gustatory flushing in Frey's syndrome. Clin Auton Res 2002;12:144-146. 43. Tascilar N, Tekin NS, Erdem Z, Alpay A, Emre U. Unnoticed dysautonomic syndrome of the face: Harlequin syndrome. Auton Neurosci 2007;137:1-9. Korean J Clin Neurophysiol / Volume 14 / June, 2012 19