Test Id : SPBX

A battery of enzyme histochemical stains or immunostains are performed; other tests can be performed, as indicated, at an additional charge.

Wet tissue for consultation: When adequately prepared tissue is provided, routine testing will include PGP 9.5 (protein gene product 9.5) immunostain, morphometric analysis, Congo red stain, and hematoxylin and eosin stain. PGP 9.5 reactions cannot be done on previously embedded tissue, eg, paraffin blocks, epoxy blocks.

Slides and blocks sent for consultation must include PGP 9.5-reacted sections:

Special stains and studies performed on the case should be sent with the case for review. In order to determine an accurate diagnosis, some of these stains or studies may be deemed to warrant repeat testing, at an additional charge, at the discretion of the reviewing Mayo Clinic neuromuscular pathologist. In addition, testing requested by the referring physician (immunostains, molecular studies, etc) may not be performed if deemed unnecessary by the reviewing Mayo Clinic neuromuscular pathologist. For all consultations, ancillary testing necessary to determine a diagnosis is ordered at the discretion of the Mayo Clinic neuromuscular pathologist. An interpretation, which includes an evaluation of the specimen and determination of a diagnosis, will be provided within a formal pathology report.

For more information see Pathology Consultation Ordering Algorithm.

Transport specimen per instructions on the Epidermal Nerve Fiber Density Preparation Instructions (T703).

All requisition and supporting information must be submitted in English.

Each of the following items is required:

1. All requisitions must be labeled with:

-Patient name, date of birth, and medical record number

-Name and phone number of the referring pathologist or ordering provider

-Anatomic site and collection date

2. Epidermal Nerve Fiber Density Patient Information (T702)

3. Additional clinical information:

-Neurology clinical notes

-Electromyography results if performed

Preferred:

Specimen Type: Skin punch biopsy

Supplies: Skin Punch Biopsy Kit (to order call either 507-284-8065 or 800-533-1710) containing fixatives, buffer, and cryoprotectant

Source: Distal leg, mid-thigh, dorsal foot, or lower abdomen

Container/Tube: A Skin Punch Biopsy Kit is required (no substitutions accepted) for collection.

Collection Instructions:

1. The standard biopsy for evaluating distal small fiber sensory neuropathy includes two 3-mm skin punch biopsies from the same side of the body.

2. Prepare specimen per instructions on the Epidermal Nerve Fiber Density Preparation Instructions (T703).

Acceptable:

Specimen Type: PGP 9.5-reacted slides

Additional Information:

1. At least one slide reacted with PGP 9.5, using a PGP 9.5 protocol for visualizing epidermal nerve fibers, is required.

2. At least one hematoxylin and eosin-stained slide and one Congo red-stained slide are optional.

Specimen Type: PGP 9.5-reacted slides and tissue block

Note: Visualization of epidermal nerve fibers cannot be done on paraffin blocks.

Additional Information:

1. At least one slide reacted with PGP 9.5, using a PGP 9.5 protocol for visualizing epidermal nerve fibers, is required.

2. Tissue block may only be used to create hematoxylin and eosin-stained slides and Congo red-stained slides.

• Epidermal Nerve Fiber Density Patient Information
• Epidermal Nerve Fiber Density Preparation Instructions
• Pathology Consultation Ordering Algorithm

Epidermal Nerve Fiber Density Patient Information (T702) is required.

Investigating polyneuropathies

A battery of enzyme histochemical stains or immunostains are performed; other tests can be performed, as indicated, at an additional charge.

Wet tissue for consultation: When adequately prepared tissue is provided, routine testing will include PGP 9.5 (protein gene product 9.5) immunostain, morphometric analysis, Congo red stain, and hematoxylin and eosin stain. PGP 9.5 reactions cannot be done on previously embedded tissue, eg, paraffin blocks, epoxy blocks.

Slides and blocks sent for consultation must include PGP 9.5-reacted sections:

Special stains and studies performed on the case should be sent with the case for review. In order to determine an accurate diagnosis, some of these stains or studies may be deemed to warrant repeat testing, at an additional charge, at the discretion of the reviewing Mayo Clinic neuromuscular pathologist. In addition, testing requested by the referring physician (immunostains, molecular studies, etc) may not be performed if deemed unnecessary by the reviewing Mayo Clinic neuromuscular pathologist. For all consultations, ancillary testing necessary to determine a diagnosis is ordered at the discretion of the Mayo Clinic neuromuscular pathologist. An interpretation, which includes an evaluation of the specimen and determination of a diagnosis, will be provided within a formal pathology report.

For more information see Pathology Consultation Ordering Algorithm.

Small fiber peripheral neuropathy is a common neurological complaint and a frequent source of morbidity in many patient populations. Direct investigation of small fiber involvement has been limited as most classical techniques (eg, electromyography, nerve conduction studies, and nerve biopsy) focus on large diameter nerve fibers and may be normal in patients with small fiber neuropathies.

The advent of epidermal skin biopsies and PGP 9.5 (protein gene product 9.5) immunohistochemistry allows the direct visualization and morphologic assessment of small sensory fibers innervating the skin.(1) Assessment of intraepidermal nerve fiber density has been used to reliably demonstrate pathologic abnormalities in small fiber neuropathy of various etiologies including diabetes, HIV, systemic lupus erythematosus, and neurosarcoidosis. Further, the technique has been validated, shown to have acceptable sensitivity and specificity, and is minimally invasive. The publication of normative data for commonly tested sites such as the distal and proximal legs and arms permits direct comparison of patients to age- and sex-matched controls facilitating localization and diagnosis.(2-4)

Based on class 1 evidence and American Medical Association CPT code review process acceptance, intraepidermal nerve fiber density (IENFD) measurements are now an accepted investigational method in the workup of polyneuropathy, including the characterization and diagnosis of varieties of length-dependent small fiber polyneuropathies. IEFND measurements have been incorporated in recent practice guidelines published by the American Academy of Neurology and the European Federation of Neurological Science.(5,6)

An interpretive report will be provided.

The number of intraepidermally originating nerve fibers that cross the basement membrane between the dermis and epidermis are counted in several sections.(2,5) The total linear length of the epidermis is measured using standard morphometric techniques and a density of epidermal nerve fibers (number of fibers/mm) is reported. This value is compared to previously published normative data.

Poor fixation, orientation, and improper handling of the tissue may hinder the neuromuscular pathologist's interpretation of the biopsy. For more information see Epidermal Nerve Fiber Density Preparation Instructions.

Investigators at Mayo Clinic (Bolton, Winkelmann, Dyck) did previous work on cutaneous receptors preceding the recent work on intraepidermal nerve fiber densities. With recent findings, PJ Dyck and colleagues have developed the technique to national standards.(7)

1. Lauria G, Lombardi R, Camozzi F, Devigili G. Skin biopsy for the diagnosis of peripheral neuropathy. Histopathology. 2009;54(3):273-285

2. McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol. 1998;55(12):1513-1520

3. Goransson LG, Mellgren SI, Lindal S, Omdal R. The effect of age and gender on epidermal nerve fiber density. Neurology. 2004;62(5):774-777

4. Umapathi T, Tan WL, Tan NCK, Chan YH. Determinants of epidermal nerve fiber density in normal individuals. Muscle Nerve. 2006;33(6):742-746

5. Lauria G, Cornblath DR, Johansson O, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol. 2005;12(10):747-758

6. England JD, Gronseth GS, Franklin G, et al. Practice parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72(2):177-184

7. Engelstad JK, Taylor SW, Witt LV, et al. Epidermal nerve fibers: confidence intervals and continuous measures with nerve conduction. Neurology. 2012;79(22):2187-2193

8. England JD, Gronseth GS, Franklin G, et al. Evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Muscle Nerve. 2009;39(1):106-115

9. Landowski LM, Dyck PJB, Engelstad J, Taylor BV. Axonopathy in peripheral neuropathies: Mechanisms and therapeutic approaches for regeneration. J Chem Neuroanat. 2016;76(Pt A):19-27. doi:10.1016/j.jchemneu.2016.04.006

Immunohistochemical preparations are prepared using standard immunohistochemical techniques for PGP 9.5.(5) Using light microscopy, epidermal nerve fiber density is counted from PGP 9.5-reactive sections. Hematoxylin- and-eosin and Congo red stains are also reviewed.(Unpublished Mayo method)

Monday through Friday

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This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

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