Abstract Nerve Biopsy and Nerve Conduction Study Seung-Min Kim, M.D., Il-Nam Sunwoo, M.D. Department of Neurology, Yonsei University College of Medici

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1 Abstract Nerve Biopsy and Nerve Conduction Study Seung-Min Kim, MD, Il-Nam Sunwoo, MD Department of Neurology, Yonsei University College of Medicine Nerve conduction study and nerve biopsy are the most important diagnostic tools for the diagnosis of peripheral neuropathy Even the nerve conduction study is the electrophysiological aspect of structural changes of the peripheral nerve, there is some advantages and disadvantages in each study Comparing with the nerve conduction study which reveals the function of large myelinated fibers of peripheral nerve only, the nerve biopsy has clear advantages in observing the change of small nerve fibers as well as large myelinated nerves and also picking-up the pathology of supportive structures However the nerve biopsy is an invasive and complicated study which need several technical and clinical cautions and there is several limitations in clinical application In this review, these technical and clinical points of the nerve biopsy are described on which every EMGist has to know, and also the relationship of these two studies Key Words : Nerve biopsy, Nerve conduction study, Neuropathy pacinian corpuscle 5 (fasciculus gracilis) 139

1 5 barrier) 1,4 10 1 150,, (macrophage), (mast cell) (microvasculature) 6 ~ 14 06~12mm 2 1,4 ( ) (teased nerve fiber preparation), semithin section (micro-vascular networks) (tight junction) 1 1-3 (

2 1 5 barrier) 1, ,, (macrophage), (mast cell) (microvasculature) 6 ~ 14 06~12mm 2 1,4 ( ) (teased nerve fiber preparation), semithin section (micro-vascular networks) (tight junction) ( e p i n e u r i u m ) ( f a s c i c l e ) ( p e r- Fig 1 Diagram of peripheral nerve cross section i n e u r i u m ) ( e n d o - n e u r i u m ) (Fig 1) 1, 4 (areolar connective t i s s u e ) % (collagen bundle), (elastic fibers), (fibroblast), ( v a s a (node of Ranvier) nervorum) (fat tissue) (Fig 2) ( i n t e r n o d a l (dura mater) 1, 4 length) 02mm 18mm ( i n t e r n- 15 ode) (Schwann cell) ( t i g h t junction) g ratio(axon diameter/total fiber ( p e r i n e u r i a l diameter) g ratio 140

07 g ratio 3) 2 (Fig 4) 1,4 1 (artifacts) Fig 2 Electron microscopic finding of a normal sural nerve with myelinated and unmyelinated axons 10 ~ 60 7 500 ~ 10000/mm 2 1 22 3 ~ 4

3 07 g ratio 3) 2 (Fig 4) 1,4 1 (artifacts) Fig 2 Electron microscopic finding of a normal sural nerve with myelinated and unmyelinated axons 10 ~ ~ 10000/mm ~ 4 10 Fig 4 Frequency distribution of unmyelinated axon diameter (bimodal curve) in a sural nerve 3:1 ( F i g Fig 3 Histogram and morphometric data of a human proximal sural nerve 141

glutaraldehyde 1~2 (fascicular biopsy) 20 ~ 45 3cm (teased fiber preparation), semithin section 1, 2-5 1 ~ 2 ( m e t a c h r o m a t i c g r a n u l e s ) 1,2 h e m a- toxylin-eosin(he), trichrome,

4 glutaraldehyde 1~2 (fascicular biopsy) 20 ~ 45 3cm (teased fiber preparation), semithin section 1, ~ 2 ( m e t a c h r o m a t i c g r a n u l e s ) 1,2 h e m a- toxylin-eosin(he), trichrome, luxol fast blue(lfb), congo (artifact) red HE siliconepad trichrome LFB 3cm epoxy section (Fig 5) congo red, 2% paraformaldehyde buffer epoxy section 10 25% glutaraldehyde in 0025mol/L cacodylate buffer(ph 738) cacodylate buffer phosphate buffer 1 0 ( a u t o l y s i s ) 4 ( m i c r o t u b u l e ) (depolymerization) 1, 2 glutaraldehyde fixation 2 ~ 4 osmium tetroxide glycerol 1,2 glutaralydehyde Fig 5 Frozen section of the sural nerve from a CIDP patient 05cm semithin shows markedly decreased density of myelinated nerve 1cm fibers(modified Gomori trichrome 100) 142

1,2 Semithin section, ( ), (regenerating cluster) ( m a c r o p h a g e infiltration)

sural nerve of a patient with the vasculitis shows very early axonal degeneration(osmium

section stained with osmium tetroxide and paraphenylenediamine 25) (Fig 7) (Fig 8, 9), (Fig

a patient with the vasculitis demonstrates early axonal degeneration(osmium tetroxide 4 00 )

tetroxide 400) Fig 10 Consecutive length along one teased nerve fiber from the sural nerve

5 1,2 Semithin section, ( ), (regenerating cluster) ( m a c r o p h a g e infiltration) (morphomerty) (Fig 6) 1,2 Fig 8 Consecutive length along one teased nerve fiber from the sural nerve of a patient with the vasculitis shows very early axonal degeneration(osmium tetroxide ) Fig 6 Cross-section of three fascicles of a normal nerve(plastic embedded section stained with osmium tetroxide and paraphenylenediamine 25) (Fig 7) (Fig 8, 9), (Fig 10), (Fig 11) Fig 9 Consecutive length along one teased nerve fiber from the sural nerve of a patient with the vasculitis demonstrates early axonal degeneration(osmium tetroxide 4 00 ) 1,2 Fig 7 Consecutive length of a teased nerve fiber without specific abnormality(osmium tetroxide 400) Fig 10 Consecutive length along one teased nerve fiber from the sural nerve of a patient with CIDP demonstrates segmental demyelination and remyelination(osmium t e t r o x i d e 2 50 ) 143

,,,,, Fig 11 Consecutive length of a teased nerve fiber from the sural nerve of a patient with CIDP demonstrates remyelination(osmium tetroxide 400)

semithin section (multifocal fiber loss pattern) (central fascicular fiber loss) ( p e r i v a s- cular cuffing) fibrinoid necrosis,,,

autonomic neuropathy thpe IV shows characteristic absence of unmyelinated nerve fibers Fig 13 Paraffin section of the sural nerve from a patient

6 ,,,,, Fig 11 Consecutive length of a teased nerve fiber from the sural nerve of a patient with CIDP demonstrates remyelination(osmium tetroxide 400) Krabbes disease, Fabry disease, Tangier s disease (inclusion body) neuroaxonal dystrophy(giant axon) ( n e u r o f i l a m e n t ) (Fig 12) 6 ( ) semithin section (multifocal fiber loss pattern) (central fascicular fiber loss) ( p e r i v a s- cular cuffing) fibrinoid necrosis,,, recannalization, (Fig 13) 7-10 hemosiderin laden macrophages Fig 12 Electron microscopic finding of the sural nerve with hereditary sensory autonomic neuropathy thpe IV shows characteristic absence of unmyelinated nerve fibers Fig 13 Paraffin section of the sural nerve from a patient with polyarteritis nodosa shows fibrinoid necrosis and prominent infiltration of in flammatory cells around a small epineurial vessel(h & E 250) (multiple mononeuropathy) 144

(conduction block) (Fig 14) Fig 14 Ulnar motor nerve conduction study in a patient with Churg-Strauss syndrome(eosinophilic vasculitis) shows definite conduction block but without changes of CMAP

inflammatory demyelinative polyneuropathy; AIDP), (chronic inflammatory demyelinative polyneuropathy; CIDP), (neuropathy associated with plasma cell dyscrasia), ( H I V neuropathy) Lyme s disease A I

7 (conduction block) (Fig 14) Fig 14 Ulnar motor nerve conduction study in a patient with Churg-Strauss syndrome(eosinophilic vasculitis) shows definite conduction block but without changes of CMAP duration Fig 15 Semithin section of the sural nerve form a patient with CIDP shows relatively thin myelin sheath comparing to the axon diameter(toluidine blue 400) (dispersion) (Fig 16) (acute inflammatory demyelinative polyneuropathy; AIDP), (chronic inflammatory demyelinative polyneuropathy; CIDP), (neuropathy associated with plasma cell dyscrasia), ( H I V neuropathy) Lyme s disease A I D P C I D P (Fig 10, 11) semithin s e c t i o n (Fig 15) Fig 16 Ulnar motor nerve conduction study of a patient with T- AIDP shows markedly slow NCV with conduction 11 block and dispersed CMAPs CIDP onion bulb formation (subperineurial edema) 1 (hereditary motor sensory neuropathy; HMSN) type I, type III, Refsum's disease 145

onion bulb formation HMSN onion bulb formation type I type III semithin (Fig 17, 18) 1,4 onion bulb formation

19, 20) (focal hypertrophic neuropathy) 13 (neurofibroma) onion bulb like structure, microfasciculation Fig 17

formations(toluidine blue 400) Fig 19 Teased myelinated nerve fibers of the sural nerve from a patient with HNPP

Dejerine-Sottas disease shows numerous onion bulb formations and demyelinated fibers(methylene blue 4 0 0 ) Fig 20

8 onion bulb formation HMSN onion bulb formation type I type III semithin (Fig 17, 18) 1,4 onion bulb formation Schwann cell process 12 Hereditary neuropathy with liability to pressure palsies ( H N P P ) t o m a c u l a, (Fig 19, 20) (focal hypertrophic neuropathy) 13 (neurofibroma) onion bulb like structure, microfasciculation Fig 17 Semithin section of the sural nerve from a patient with HMSN type 1A shows numerous onion bulb formations(toluidine blue 400) Fig 19 Teased myelinated nerve fibers of the sural nerve from a patient with HNPP shows typical tomacular changes(toluidine blue 400) Fig 18 Semithin section of the sural nerve from a patient with Dejerine-Sottas disease shows numerous onion bulb formations and demyelinated fibers(methylene blue ) Fig 20 Semithin section of the sural nerve from a patient with HNPP shows a large nerve fiber with loose myelin sheath(osmium tetroxide ) 146

PMP22 (deletion) (mutation) HNPP (entrapment neuropathy) (Fig 21) 14 Fig 22 Congophilic amorphous infiltrations are seen in endoneurium of the sural nerve from a patient with primary

non-caseating granuloma epithelioid cell, lymphocyte, Langerhan's HMSN type II onion bulb giant cell granulomatous periangitis (Fig 23) 1,4,17,18 1,4,15 1 6 HE methyl violet congo red ( m e t a c h r

9 PMP22 (deletion) (mutation) HNPP (entrapment neuropathy) (Fig 21) 14 Fig 22 Congophilic amorphous infiltrations are seen in endoneurium of the sural nerve from a patient with primary amyloidosis(congo red 250) Fig 21 Median sensory and mixed nerve conduction study of a patient with HNPP shows prolonged duration of CNAPs with slow NCV over transcarpal tunnel (sarcoid granuloma) non-caseating granuloma epithelioid cell, lymphocyte, Langerhan's HMSN type II onion bulb giant cell granulomatous periangitis (Fig 23) 1,4,17,18 1,4, HE methyl violet congo red ( m e t a c h r o m a s i a ) congo red polarized microscope apple green bi-refringence (Fig 22) amyloid P protein Fig 23 Noncaseating granulomas with giant cells are noted in and chain epineurium in a patient with sarcoid neuropathy(h &, transthyretin E 250) 147

1, 4, 19, 20 (acid fast bacilli; AFB) Mycobacterium leprae (large myelinated fibers) (granuloma) (caseation) AFB cocco-bacilli formy cell (Fig 24) 1,4 REFERENCES Fig 24 Panfascicular infiltration of

10 1, 4, 19, 20 (acid fast bacilli; AFB) Mycobacterium leprae (large myelinated fibers) (granuloma) (caseation) AFB cocco-bacilli formy cell (Fig 24) 1,4 REFERENCES Fig 24 Panfascicular infiltration of inflammatory cells and hypertrophied endoneurium are noted in paraffin section of a patient with lepromatous leprosy(h & E ) metachromatic leukodystrophy sulfatase galactosyl-3-sulfate Cresyl violet (metachromatic granule) 1,4 01 Dyck PJ, Thomas PK, Griffin JW, Low PA, Podulso JF: Peripheral neuropathy 3rd ed Philadelphia: Saunders, eds Peripheral neuropathy 3rd ed Philadelphia: Saunders, 1993: Cohen RD, Conn DL, Ilsturp DM: Clinical features prognosis, and response to treatment in polyarteritis Mayo Clin Proc 1980: 55: : Diagnostic value of nerve biopsy 1994: 12(sup): : 33: Richardson EP, Girolami U: Pathology of the peripheral nerves Philadelphia: Saunders, Asubury AK, Connolly ES: Sural nerve biopsy: Technical note J Neurosurg 1973: 38: ,,,,,, : : 15: Chalk CH, Dyck PJ, Conn DL: Vasculitic neuropathy In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Podulso JF, 148

11 09 Dyck PJ, Conn DJ, Okasaki H: Necrotizing angiopathic neuropathy Three-dimensional morphology of fiber degeneration related to sites of occluded vessels Mayo Clin Proc 1972: 47: Fauci AS, Katz P, Haynes BF, Wolff SM: Cyclophosphamide therapy of severe systemic necrotizing vasculitis N Eng J Med 1979: 301: Dyck PJ, Lais AC, Ohta M, Baston JA, Okasaki H, Grover RV: Chronic inflammatory polyradiculoneuropathy Mayo Clin Proc 1975: 50: Dyck PJ: Experimental hypertrophic neuropathy Pathogenesis of onion-bulb formations produced by repeated tourniquet application Arch Neurol 1969: 21: Mitsumoto H, Wilbourn AJ, Goren H: Perineurioma as the cause of localized hypertrophic neuropathy Muscle Nerve 1980: 3: ,,,, : 17p112- p12 hereditary neuropathy with liability to pressure palsies 1999: 1: Cohens AS: The diagnosis of amyloidosis In: Laboratory diagnostic methods in the rheumatic disease 2nd ed Boston: Little & Brown, 1975: ,,,, : : 13: Nemi R, Galassi G, Cohen M, et al: Symmetric sarcoid polyneuropathy: analysis of a sural nerve biopsy Neurology 1981: 31: Oh SJ: Sarcoid polyneuropathy: a histologic proven case Ann Neurol 1980: 7: Dyck PJ, Logfren EP: Nerve biopsy Choice of nerve, method, symptoms and usefulness Med Clin North Am 1968: 52: Oh SJ: Diagnostic usefulness and limitations of the sural nerve biopsy Yonsei Med J 1990: 31:

388 The Korean Journal of Hepatology : Vol. 6. No COMMENT 1. (dysplastic nodule) (adenomatous hyperplasia, AH), (macroregenerative nodule, MR

388 The Korean Journal of Hepatology : Vol. 6. No COMMENT 1. (dysplastic nodule) (adenomatous hyperplasia, AH), (macroregenerative nodule, MR 6 3 2000 ; 387-392 (3) Dysplastic Nodule Young Nyun Park, M.D., Chanil Park, M.D. Department of Pathology, Yonsei University College of Medicine BRIEF HISTORY 56. AST/ALT 72/73 IU/L, total bilirubin 0.7