Doi:10.1016/j.nmd.2007.08.010

Neuromuscular Disorders 18 (2008) 90–96 Guideline on processing and evaluation of sural nerve biopsies, 15–17 December 2006, Naarden, The Netherlands C. Sommer a,*, S. Brandner b, P.J. Dyck c, L. Magy d, S.I. Mellgren e, M. Morbin f, A. Schenone g, E. Tan h, J. Weis i a Department of Neurology, University of Wu¨rzburg, Wu¨rzburg, Josef-Schneider-Str. 11, 97080 Wu¨rzburg, Germany b Department of Neuropathology, Institute of Neurology, London, United Kingdom c Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, United States d Department of Neurology, CHRU Dupuytren, Limoges, France e Department of Neurology, University of Tromso¨, Tromso¨, Norway f IRCCS Foundation - Neurological Institute ‘‘Carlo Besta’’, Milan, Italy g Department of Neurosciences, Ophthalmology and Genetics, Universita degli Studi, Genova, Italy h Department of Neurology, Hacettepe University, Ankara, Turkey i Department of Neuropathology, University of Aachen, Aachen, Germany Keywords: Nerve biopsy; Peripheral neuropathy; Light microscopy; Electron microscopy; Diagnostic performance The evaluation of a nerve biopsy is often the final step in the diagnostic workup of neuropathies of unknown Fourteen clinicians and researchers (8 neurologists and 6 origin. While it is usually not considered necessary in neuropathologists) from France, Germany, Italy, The neuropathies with causes which can be detected by other Netherlands, Norway, Spain, Turkey, United Kingdom, methods, like in diabetic neuropathies, or in Guillain- and United States of America assembled in Naarden, The Barre´ Syndrome (GBS), it is the only method for the Netherlands, from 15 to 17 December, 2006, to participate detection of some causes of neuropathies, like nonsystemic in a workshop on the indications for nerve biopsy, the vasculitic neuropathy, and it can be very helpful in methods available for nerve workup, and on their diagnostic guiding further systemic diagnostic evaluation, like in specificity and sensitivity. The results will lead to an amyloid neuropathies, and in some types of hereditary evidence based guideline on processing and evaluation of neuropathies, in which a straightforward genetic test is Peripheral neuropathies are a common and heterogeneous However, the value of nerve biopsy is still a matter of group of diseases. The differential diagnosis may be difficult debate. While some authors have clearly shown a benefit because of the multitude of potential causes. Diagnostic for patient management from sural nerve biopsies, others algorithms for the investigation of peripheral neuropathies have disagreed with this view. Obviously, the diagnostic have been proposed, and the rate of successful identification value depends on the standards set for the evaluation of of the underlying disease varies between investigators.
the biopsy, such that the questions of diagnostic valueand standards for evaluation are interrelated.
If a diagnostic nerve biopsy is performed, most often the Corresponding author. Tel.: +49 931 201 23763; fax: +49 931 201 sural nerve is chosen. Sural nerve biopsy is an invasive procedure which leaves the patients with a sensory deficit, 0960-8966/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.nmd.2007.08.010 C. Sommer et al. / Neuromuscular Disorders 18 (2008) 90–96 and, rarely, chronic pain. Therefore, the indication for a therapeutic consequences were those with inflammatory/dys- sural nerve biopsy should be considered carefully, and all immune neuropathies and with amyloid neuropathy. Toxic measures should be taken to obtain optimal results for neuropathies were identified as a group where nerve biopsy the benefit of the patients, if this procedure is performed.
did not contribute to finding the diagnosis, also metabolic Since sural nerve biopsy cannot be easily repeated in the neuropathies, with exceptions. In fact, focally swollen axons workup of peripheral neuropathies, failures due to lack may be seen in patients with hexacarbon neuropathy.
of adequate standards should be avoided.
In clinical practice, one often encounters the situation complications from sural nerve biopsy, two of which were that a sural nerve biopsy was performed in a patient, which presented. The conclusions were that sural nerve biopsy is in retrospect might not have been considered to be associated with prolonged sensory symptoms and sensory indicated because the cause of the neuropathy might have loss, that recovery occurs in all patients irrespective of been detected by less invasive tests. It also happens that diagnosis, and that residual sensory loss in diabetic and the indication was correct, but that the processing and nondiabetic patients are comparable. In particular, the evaluation are so poor that very little information can be outcome was not worse in patients with vasculitis or gained from the biopsy. This dilemma was the motivation diabetes. However, patients with diabetes and higher for performing research into the available evidence on pre-biopsy sural nerve potentials and better glycemic the diagnostic value of nerve biopsies and the specific techniques used in their processing and evaluation.
There are no generally accepted guidelines on nerve 3. Methods of nerve biopsy and specimen processing and biopsy processing and evaluation, and laboratories do not need to be certified to perform this procedure.
Although there are some national guidelines, these are On the subject of choice of nerve, Peter Dyck pointed out that the biopsied nerve is most likely to provide useful In preparation for the workshop, participants performed clinical information when the nerve to be biopsied is Medline researches on the subtopics discussed below and clinically affected and when an interstitial process is prepared evidence tables as a background for discussion in suspected. Usually a distal sensory nerve (i.e. the sural nerve) is biopsied. There are some rare indications for proximalbiopsies, but the following rules should be observed: an expert MRI consultant, peripheral nerve surgeon andpathologist should be available. There should be unequivocal Angelo Schenone presented the evidence available on the demonstration of a single MRI lesion (e.g. focal enlargement indications for sural nerve biopsy, prepared in collaboration or enhancement) whose diagnosis will aid diagnosis and with Catherine Lacroix. The aim was to define the following management. Benefits versus risks and side effects should be carefully assessed. The procedure should be carefullyexplained to the patient and agreement should be obtained.
1. Patients in whom sural nerve biopsy will be diagnostically Peter Dyck further pointed out that the procedures for nerve biopsies as well as for tissue processing and 2. Patients in whom sural nerve biopsy will have therapeutic evaluation have been detailed in various textbook articles, e.g. . However, to measure sensitivity, specificity, 3. Patients who will definitely not benefit from sural nerve reproducibility, accuracy, meaningfulness, and monotonicity (measuring a consistent trend of change with time) of a 4. Patients who are at risk for complications from sural method, a gold standard is needed. This gold standard is still lacking in the field of nerve biopsy evaluation. Therefore,a study was initiated by Caroline Klein, P. James B. Dyck, Out of an extensive Medline research, 20 papers were iden- Christopher J. Klein, JaNean Engelstad, Peter C. O’Brien, tified to be of relevance to the subject. Out of the studies by and Peter J. Dyck, with the title ‘‘Masked and Independent Gabriel with 50 and 355 patients, respectively, it could Evaluations of Various Histologic Preparations’’. The aim be concluded with grade IV evidence that sural nerve biopsy of this now ongoing study is to compare different methods is helpful in inflammatory and dysimmune neuropathies, of workup of sural nerve biopsies from 100 patients.
namely in vasculitis and chronic inflammatory demyelinating Comparisons will be performed between the diagnostic neuropathy (CIDP), also possibly in leprosy and in some yield of teased fibers (100 strands systematically sampled), forms of hereditary neuropathies. From the clinical perspec- of paraffin sections stained with H&E, trichrome, and other tive, sural nerve biopsy was more often helpful in patients with stains, of semithin epoxy sections, including morphometry, severe demyelinating, distal asymmetric, and multifocal types of immunohistochemistry on paraffin sections (CD45, of neuropathy than in axonal and symmetric types. Also, nerve biopsy was more often diagnostic in acute and microscopy. An adequate number of nerves of healthy subacute than in chronic forms. Patient groups with subjects will be prepared by similar methods.
C. Sommer et al. / Neuromuscular Disorders 18 (2008) 90–96 4. Diagnostic usefulness of paraffin histology and plastic sections for better visualization of myelin, in particular when resin sections are not available. Congo red staining for amy-loid and van Gieson Elastica staining for the evaluation of From an extensive literature search, Sebastian Brandner vessel walls were also considered useful. For the detection concluded that there are no data proving the superiority of of inflammation, he advocated immunohistochemistry on one staining method over another in nerve biopsies. In the paraffin sections using antibodies to UCLH1 (CD45RO, study of Deprez et al. the contribution of nerve biopsy pan T cell, memory cells, and monocytes), CD3 (pan T cell), varied according to the neuropathological techniques used.
CD8 (T-suppressor/cytotoxic), CD20 (B cells), and option- ally to CD4 (T-helper, inducer). CD68 immunohistochemis- resin-embedded material improved the sensitivity for try for macrophages was also considered standard, to interstitial pathology. A combined muscle and nerve biopsy identify florid axonal or myelin degeneration.
increased sensitivity in the detection of vasculitis. Teasingof nerve fibers added critical information to other classical 5. Diagnostic usefulness of frozen sections and immunohistochemistry: inflammatory cells Dr. Brandner presented the algorithm of sural nerve evaluation as practiced in his laboratory at the Institute Claudia Sommer performed a literature search trying to of Neurology, Queen Square. The value of paraffin histology and plastic embedded sections as presented byDr. Brandner is summarized in 1. What is the diagnostic value of immunohistochemistry Dr. Brandner suggested performing neurofilament immu- nohistochemistry, which labels axons of all sizes and gives a 2. Does immunohistochemistry for cellular infiltrates have quick and relatively accurate estimate of axonal loss. He also a higher diagnostic yield than H&E stains? recommended solochrome cyanine staining on longitudinal 3. What is the value of serial sections?4. What is the value of macrophage or lymphocyte subtype Value of paraffin histology and plastic embedded semithin sections 5. Can the biopsy predict a treatment response? (a) Value of paraffin histology with Haematoxylin & Eosin staining There were no prospective studies available to answer General appearance and quality of nerve biopsy Inflammation, in these questions. Information was collected from retrospective analyses asking the question of diagnostic utility, from Digestion chambers, but not degeneration of axons per seOthers, such as tumor cells, sarcoidosis, giant cells retrospective analyses asking a scientific question, andfrom individual clinical experience. In a retrospective study, Bosboom and colleagues investigated the Axon density and myelinationDegeneration of axons diagnostic value of sural nerve T cells in CIDP using biopsies from 23 patients with CIDP, 15 with otherneuropathies, and 10 autopsy controls. They concluded that T cells were found in sural nerves of all CIDP patients as well as in all disease and normal controls. Only 6 CIDP patients had increased numbers and densities of T cells Amyloid (unless there are big ‘plaques’) compared with patients with axonal neuropathy and controls.
Increased numbers and densities of sural nerve T cells in (b)Value of semithin plastic embedded sections patients with CIDP were associated with female sex, a more severe disease course, worse outcome, highly elevated CSF Fiber (axon) density of myelinated fibersNumber and distribution of large and small myelinated fibers protein level, and a larger sural nerve area. Eurelings et al.
investigated sural nerve biopsies from 25 patients with demyelinating neuropathy and monoclonal gammopathy.
Increased sural nerve T cells were significantly associated with more progressive disease course and more pronounced weakness, IgG isotype, and malignancy. In a small study with 15 patients, Jann et al. looked at the diagnostic value of sural nerve matrix metalloproteinase-9 (MMP-9) in dia- betic patients with CIDP. MMP-9 immunohistochemistry was useful to detect CIDP in diabetic patients. Another study investigated the diagnostic value of macrophage distribution in sural nerve sections . Whereas numbers of T cells and Amyloid (unless there are big ‘plaques’) macrophages were not helpful in the distinction between CIDP and hereditary demyelinating neuropathies, clustering C. Sommer et al. / Neuromuscular Disorders 18 (2008) 90–96 of macrophages around endoneurial vessels could be found 7. Diagnostic usefulness of electron microscopy more often in CIDP and served as an easily detectable addi-tional indication for an inflammatory neuropathy. A small Joachim Weis discussed the usefulness of electron number of further studies was identified, which asked a microscopy (EM) in nerve biopsy evaluation. The relevant scientific question regarding particular markers (e.g. B7 textbooks, including extensively cover the issue of costimulatory molecule, or specific chemokines), but these ultrastructural pathology of peripheral nerves. However, were not tested for their diagnostic performance. Dr. Som- there are no class I–III studies using a blinded evaluation mer concluded that high numbers of inflammatory cells indi- on the usefulness of electron microscopy in peripheral cate inflammatory neuropathy, but that small numbers of nerve biopsy evaluation thus far. Still, numerous case series inflammatory cells may be present in different kinds of neu- and studies of single cases (class IV evidence) suggest that ropathy. The distribution of the inflammatory cells and spe- electron microscopy might be helpful in the diagnosis of cial stains like for MMP-9 may aid in the diagnostic distinction. Immunohistochemistry is probably more sensi-tive in the detection of macrophages and T cells than • CIDP, by virtue of demonstrating macrophage-associated H&E stains, but prospective studies are needed to clarify • Neuropathy due to gammopathy, when associated with 6. Diagnostic usefulness of teased fiber studies ultrastructural abnormalities including focally folded Svein Ivar Mellgren reported on the technique for teased myelin in CMT1B caused by MPZ mutations and fiber studies and showed examples of teased fiber pathology.
in CMT4B2 caused by mutation of the SBF2 gene.
The study of teased fibers allows evaluation of myelinated myelin outfoldings in CMT4B1, and a recently fibers and provides another window into the nerve biopsy described autosomal recessive CMT characterized by than cross and length oriented sections in light and electron exceedingly complex folding of myelin sheaths due microscopy. For most purposes 100 fibers are analyzed, to frabin/FGD4 , peculiar Schwann cell processes although it has not been formally shown which number is combined with basal lamina accumulation in CMT4C needed for reliable diagnostic evaluation. Pathological due to KIAA1985 gene mutation, as well as axonal neu- grades named A–H were classified by Dyck and colleagues rofilament accumulation in CMT2E due to NEFL gene and control values were established. Pathologic findings using this grading system were described in patients with • Hereditary diseases that affect both the PNS and Sjo¨gren’s syndrome and with diabetes compared to the CNS and potentially other organs such as the controls. Dr. Mellgren offered the following arguments in favor of teased fiber studies: teased fiber studies (1) usually show abnormalities supportive of a neuropathy; (2) can be inclusions exemplified by amiodarone neuropathy.
used for demonstration of fiber degeneration; (3) may showfibers in active axonal degeneration and their proportion; In addition, EM is the method of choice to visualize the (4) may show evidence of regeneration; (5) visualize axonal unmyelinated nerve fibers in nerve biopsies. By all means, atrophy and secondary segmental demyelination, axonal well-preserved and well-orientated tissue fixed in buffered swellings, and tomacula; (6) can show changes suggestive glutaraldehyde or a similar solution is required to obtain of primary or secondary demyelination. The following arguments were offered against the use of teased fiberpreparations: their usefulness is limited due to the age 8. Diagnostic usefulness of special markers: immunoglobulin dependent amount of’’pathology’’ especially in myelin in normal nerves; many centers consider nerve fiber teasingto be insufficiently informative to justify its cost in routine Michela Morbin presented the evidence for the value of evaluation of sural nerve biopsies. A few authors studied demonstrating immunoglobulin deposits in sural nerve the usefulness of teased fiber preparations formally.
sections. No prospective studies addressing this point Among 24 patients who fulfilled the clinical criteria were identified. In most cases studies were designed to for CIDP, 14 met the AAN teased fiber criterion for answer to other questions or to study pathogenetic mech- demyelination, whereas 7 of these did not fulfill the anisms and the search for immunoglobulin was a side electrodiagnostic criteria for demyelination. Three out of these 7 patients responded to treatment . In 21 patients Conditions in which immunoglobulin deposits in sural with CIDP, Bosboom and colleagues did not find teased nerve have been found encompassed: paraproteinemic- fiber analysis useful to distinguish CIDP from chronic idiopathic axonal neuropathy In the 102 cases of paraneoplastic neuropathy, AIDP/GBS, CIDP, hereditary Deprez et al. , in 4 cases fiber teasing provided neuropathy, rheumatic disease, toxic neuropathy, HIV, contributive information altering the patient management.
hepatitis B, post-streptococcal infection.
C. Sommer et al. / Neuromuscular Disorders 18 (2008) 90–96 Immunofluorescence or immunoperoxidase detection of Increased levels of RAGE were found in 16 cases of immunoglobulin deposits is reported in various pathological familial amyloidotic neuropathy compared to 4 controls processes. IgM perineurial deposits have been found even . RAGE immunoreactivity also distinguished vascu- in normal nerves, and there were some problems with methodologies (background). The presence of IgM in a healthy controls (n = 4) and diabetic neuropathy variety of neuropathological conditions suggests that such (n = 10) from controls (n = 8) . NFjB immunoreac- deposits may represent an unspecific process not only tivity was higher in 12 cases of GBS and CIDP com- related to immune-mediate pathogenetic mechanisms. It pared to 3 controls . NFjB immunoreactivity was has been suggested that IgM may be ‘‘entrapped’’ in the prominent in inflammatory neuropathies (n = 8) and FAP perineurium following an increase in permeability of the (n = 4), but not in hereditary neuropathies (n = 4) and con- blood-nerve barrier, or as a consequence of abnormal trols (n = 3) Dr. Tan gave a strength B recommenda- function of thickened perineurial sheath.
tion to use RAGE and NFjB immunostaining for Dr. Morbin reported on the usefulness of immunoglobulin the distinction of inflammatory and noninflammatory stains in different etiological categories. Even if the detection of immunoglobulin deposits on nerve has no definitediagnostic value, its demonstration may be useful to 10. Performance of sural nerve histology in comparison with characterize amyloid neuropathies in patients with monoclonal gammopathies. Moreover, most patients suffering fromdemyelinating neuropathy associated with monoclonal Laurent Magy reported on an extensive search in gammopathy of unknown significance (MGUS) with Medline, the Cochrane databases, and in personal files anti-MAG activity, deposition of IgM and the corresponding to determine the diagnostic performance of sural nerve light chain were reported Detection of IgM deposits histology in comparison with peripheral blood and CSF.
might even precede the detection of IgM gammopathy in He found class IV evidence for the usefulness of antiglycolipid serum . The presence of immunoglobulin deposition antibodies in acute neuropathy syndromes. He also in sural nerve seems to be significantly associated reported on class IV evidence for the use of sural nerve with severe outcome Thus, the demonstration of biopsy in selected cases of anti-MAG neuropathy with an immunoglobulin deposits on sural nerve might endorse a IgM paraprotein. In contrast, for other paraproteinemic neuropathies, no recommendation could be made. InCANOMAD and POEMS syndrome, nerve histology may only be helpful in difficult cases. There was class VIevidence for the use of nerve biopsy in cryoglobulinemia.
Researching on the usefulness of immunohistochemis- In the diagnosis of paraneoplastic neuropathies, in try, Ersin Tan identified 8 articles for MMPs, 4 for recep- accordance with an EFNS task force Dr. Magy tor for advanced glycation end products (RAGE) and concluded that nerve biopsy was usually not necessary, nuclear factor jB (NFjB) combined, and one article for but might sometimes be helpful in distinguishing subacute NFjB alone. In a study with 7 vasculitic and 6 noninflam- matory neuropathies, immunostaining for MMP-1 distin- because of vasculitis. For borrelia-associated neuropathy, guished between the groups MMP-9 and MMP-7 there was class IV evidence that nerve biopsy may be immunohistochemistry was positive in 5 GBS cases, but helpful in unusual situations. Whether nerve biopsy was in none of 2 cases with hereditary neuropathy . Immu- useful in hepatitis-associated neuropathy remained unclear.
noreactivity for MMP-2 and MMP-9 were present in 14 Biopsy was considered of some value (class IV evidence) in specimens with inflammatory neuropathies, but not in 4 asymmetric neuropathy in HIV infected patients. The with noninflammatory neuropathies . A similar result question of whether nerve biopsy is of use in suspected was obtained in a follow-up study and for MMP-9 in a CIDP with high or low CSF protein is discussed study with 12 patients with vasculitic neuropathy com- controversially. In lymphoma, nerve biopsy may help pared to 8 hereditary neuropathies. MMP-3 and -9 were present in 12 patients with systemic lupus erythematodes,but not in controls. MMP-9 immunostaining was also useful to diagnose CIDP in diabetic patients . Immuno-reactivity for TNF-a converting enzyme (TACE) a mem- It was concluded that very little high quality evidence is ber of the A Disintegrin and Metalloproteinase (ADAM) available for the usefulness of specific methods in nerve family (ADAM 17) was seen in biopsies from 6 patients biopsy workup and evaluation. This is in contrast to a large with GBS, but not from 2 patients with hereditary neur- body of expert opinions and experience. An evidence based opathies Taking all studies together, Dr. Tan gave guideline on processing and evaluation of nerve biopsies a strength B recommendation to use MMP-staining for will be compiled from the research done by the workshop the distinction of inflammatory and noninflammatory participants. The following preliminary consensus was C. Sommer et al. / Neuromuscular Disorders 18 (2008) 90–96 Table 2Consensus on minimal requirements for processing of nerve biopsies • Nerve biopsies should be done for specific indications, for example to answer questions about diagnosis, H&E stain, Congo red or thioflavin S, optionally Trichrome, myelinstain, EvG, iron stain, and others Immunohistochemistry for macrophages and T cells • Nerve biopsy should not be done before adequate clinical, For optimal detection of inflammatory neuropathies, serial sections electrophysiological and laboratory characterization of • The leading indication is the suspicion of an interstitial path- ological process (e.g. vasculitis, inflammation, infection, amyloid deposition, lymphomatous infiltration, tumor).
Although there is no formal proof (Class I–IV evidence) that IHC for • The patient should be properly instructed, and nerve biopsy cellular infiltrates is more efficient than H&E stain, experience shows should only be done with appropriate informed consent.
that inflammatory cells are more easily detected and thus should beperformed Requirements for the person evaluating a nerve biopsy: • Biopsies should be read by professionals with adequate Examples: detect decompacted myelin, focally folded myelin, detectaxonal dystrophy, and other axonal changes, autonomic training and experience in reading and interpretation neuropathies, evaluation of unmyelinated axons, mitochondrial • Adequate clinical information should be provided and addi- tional clinical information should be accessible on request.
• An interactive working relationship with the relevant • The results should be discussed with clinicians taking care of the patient and regular nerve biopsy conferencesare recommended.
This workshop was made possible by the financial support of the European Neuromuscular Centre (ENMC) Recommendation of specific procedures and stains: and its main sponsors and associated members: Although consensus can be reached that certain procedures and stains should be mandatory (e.g. paraffin – Association Franc¸aise contre les Myopathies (France) sections, semithin sections, immunohistochemistry for – Deutsche Gesellschaft fu¨r Muskelkranke (Germany) inflammatory cells), there is no formal evidence about the superiority of one method over another (e.g. whether demyelination can be better detected in teased fibers or in longitudinal semithin sections). A prospective study on these – Prinses Beatrix Fonds (The Netherlands) issues (Caroline Klein et al.) is underway. Details on the procedures recommended will be published in the final guideline. A preliminary recommendation is given in .
¨ sterreichische Muskelforschung (Austria) – Vereniging Spierziekten Nederland (The Netherlands) S. Brandner (United Kingdom)P.J. Dyck (USA) Additional support was provided by the Peripheral C. Lacroix (France)M. Lammens (The Netherlands) [1] Gabriel CM, Howard R, Kinsella N, Lucas S, McColl I, Saldanha G, et al. Prospective study of the usefulness of sural nerve biopsy. J Neurol Neurosurg Psychiatry 2000;69:442–6.
[2] Deprez M, de Groote CC, Gollogly L, Reznik M, Martin JJ. Clinical and neuropathological parameters affecting the diagnostic yield of nerve biopsy. Neuromuscul Disord 2000;10:92–8.
[3] Dyck PJ, Dyck PJB, Engelstad JN. Pathological alterations of nerves.
In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. Philadel- phia: Elsevier Saunders; 2005. p. 733–29.
[4] Bosboom WM, Van den Berg LH, De Boer L, Van Son MJ, Veldman H, Franssen H, et al. The diagnostic value of sural nerve T cells in C. Sommer et al. / Neuromuscular Disorders 18 (2008) 90–96 chronic inflammatory demyelinating polyneuropathy. Neurology initially lacking a detectable IgM gammopathy. Acta Neuropathol [5] Eurelings M, van den Berg LH, Wokke JH, Franssen H, Vrancken [20] Eurelings M, Moons KG, Notermans NC, Sasker LD, De Jager AE, AF, Notermans NC. Increase of sural nerve T cells in progressive Wintzen AR, et al. Neuropathy and IgM M-proteins: prognostic axonal polyneuropathy and monoclonal gammopathy. Neurology value of antibodies to MAG, SGPG, and sulfatide. Neurology [6] Jann S, Bramerio MA, Beretta S, Koch S, Defanti CA, Toyka KV, [21] Satoi H, Oka N, Kawasaki T, Miyamoto K, Akiguchi I, Kimura J.
et al. Diagnostic value of sural nerve matrix metalloproteinase-9 in Mechanisms of tissue injury in vasculitic neuropathies. Neurology diabetic patients with CIDP. Neurology 2003;61:1607–10.
[7] Sommer C, Koch S, Lammens M, Gabreels-Festen A, Stoll G, Toyka [22] Kieseier BC, Clements JM, Pischel HB, Wells GM, Miller K, Gearing KV. Macrophage clustering as a diagnostic marker in sural nerve AJ, et al. Matrix metalloproteinases MMP-9 and MMP-7 are biopsies of patients with CIDP. Neurology 2005;65:1924–9.
expressed in experimental autoimmune neuritis and the Guillain- [8] Dyck PJ, Johnson WJ, Lambert EH, O’Brien PC. Segmental Barre syndrome. Ann Neurol 1998;43:427–34.
demyelination secondary to axonal degeneration in uremic neurop- [23] Leppert D, Hughes P, Huber S, Erne B, Grygar C, Said G, et al.
athy. Mayo Clin Proc 1971;46:400–31.
Matrix metalloproteinase upregulation in chronic inflammatory [9] Haq RU, Fries TJ, Pendlebury WW, Kenny MJ, Badger GJ, Tandan demyelinating polyneuropathy and nonsystemic vasculitic neuropa- R. Chronic inflammatory demyelinating polyradiculoneuropathy: a study of proposed electrodiagnostic and histologic criteria. Arch [24] Kurz M, Pischel H, Hartung HP, Kieseier BC. Tumor necrosis factor-alpha-converting enzyme is expressed in the inflamed periph- [10] Bosboom WM, van den Berg LH, Franssen H, Giesbergen PC, Flach eral nervous system. J Peripher Nerv Syst 2005;10:311–8.
HZ, van Putten AM, et al. Diagnostic value of sural nerve [25] Sousa MM, Du Yan S, Fernandes R, Guimaraes A, Stern D, demyelination in chronic inflammatory demyelinating polyneuropa- advanced glycation end products-dependent triggering of neuronal [11] Dyck PJ, Thomas PK. Peripheral neuropathy. 4th ed. Philadel- [12] King R. Atlas of peripheral nerve pathology. London: Arnold; 1999.
[26] Haslbeck KM, Bierhaus A, Erwin S, Kirchner A, Nawroth P, [13] Schro¨der JM. Pathologie peripherer Nerven. Berlin: Springer-Ver- Schlotzer U, et al. Receptor for advanced glycation endproduct (RAGE)-mediated nuclear factor-kappaB activation in vasculitic [14] Midroni G, Bilbao JM. Biopsy diagnosis of peripheral neuropa- neuropathy. Muscle Nerve 2004;29:853–60.
thy. Boston: Butterworth-Heinemann; 1995.
[27] Bierhaus A, Haslbeck KM, Humpert PM, Liliensiek B, Dehmer T, [15] Vital C, Vallat JM. Ultrastructural study of the human diseased Morcos M, et al. Loss of pain perception in diabetes is dependent on peripheral nerve. New York: Elsevier; 1987.
a receptor of the immunoglobulin superfamily. J Clin Invest [16] Stendel C, Roos A, Deconinck T, Pereira J, Castagner F, Niemann A, et al. Peripheral nerve demyelination caused by a mutant rho [28] Andorfer B, Kieseier BC, Mathey E, Armati P, Pollard J, Oka N, GTPase guanine nucleotide exchange factor, Frabin/FGD4. Am J et al. Expression and distribution of transcription factor NF-kappaB and inhibitor IkappaB in the inflamed peripheral nervous system. J [17] Yeung KB, Thomas PK, King RH, Waddy H, Will RG, Hughes RA, et al. The clinical spectrum of peripheral neuropathies associated [29] Mazzeo A, Aguennouz M, Messina C, Vita G. Immunolocalization with benign monoclonal IgM, IgG and IgA paraproteinaemia.
and activation of transcription factor nuclear factor kappa B in Comparative clinical, immunological and nerve biopsy findings. J dysimmune neuropathies and familial amyloidotic polyneuropathy.
[18] Ritz MF, Erne B, Ferracin F, Vital A, Vital C, Steck AJ. Anti-MAG [30] Vedeler CA, Antoine JC, Giometto B, Graus F, Grisold W, Hart IK, IgM penetration into myelinated fibers correlates with the extent of et al. Management of paraneoplastic neurological syndromes: report myelin widening. Muscle Nerve 1999;22:1030–7.
of an EFNS task force. Eur J Neurol 2006;13:682–90.
[19] Gabriel JM, Erne B, Bernasconi L, Tosi C, Probst A, Landmann L, [31] Vallat JM, De MH, Bordessoule D, Jauberteau MO, Tabaraud F, et al. Confocal microscopic localization of anti-myelin-associated Gelot A, Vallat AV. Non-Hodgkin malignant lymphomas and glycoprotein autoantibodies in a patient with peripheral neuropathy peripheral neuropathies – 13 cases. Brain 1995;118:1233–45.

Source: http://www.neuromuskulaeres-referenzzentrum.dgnn.rwth-aachen.de/Downloads/guidelines_suralnervebiopsy.pdf