Joachim Weis, Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
Jena-Michel Vallat, Department of Neurology, National Reference Center for Rare Peripheral Neuropathies, University Hospital (CHU Dupuytren), Limoges, France
Introduction
With a prevalence of 1:200, peripheral neuropathies (PNP) encompass one of the largest disease groups among the neurological disorders. The causes of PNP include metabolic, inflammatory, degenerative, toxic, hereditary, vascular, malnutritive, paraneoplastic and other processes. Even though clinical history and examination combined with electrophysiological and laboratory methods often uncover the cause of PNP, many cases remain unsolved. In such situations, nerve biopsy has been a method of choice for decades to classify PNPs and to find clues to uncover their aetiology. However, surgical removal of a piece of nerve causes a sensory deficit and – in some cases – chronic pain. Therefore, a nerve biopsy is usually performed only when other clinical, laboratory and electrophysiological methods have failed to clarify the cause of disease. It must be performed, processed and read by experienced physicians and technicians.
Indications of nerve biopsy
The major rationale to perform a (usually sural) nerve biopsy is to gain information about therapeutic options when inflammatory neuropathy is considered. E.g., immunosuppressive drugs can present a risk due to their side effects, and intravenous immunoglobulins are expensive. Nerve biopsies are also useful to detect pathological immunoglobulin deposits. In addition, they can provide guidance in the differential diagnosis of hereditary neuropathies with atypical presentation or ambiguous genetic testing results, identify pathological features in the context of an unidentified genetic condition, or detect an inflammatory component in hereditary neuropathies. Often, combined aetiologies are uncovered by nerve biopsy analysis, including microangiopathic/diabetic and inflammatory or hereditary and inflammatory.
Workup
Paraffin and resin semithin histology and immunohistochemistry (CD45RO, pan leukocyte; CD3, pan-T cells; CD8 cytotoxic T cells) are minimal requirements. Cryostat sections, teased fibre preparations, electron microscopy and molecular genetic analyses are potentially useful in a subset of cases.
Electron microscopy is important to detect changes of unmyelinated fibres including denervated Remak bundles, collagen pockets (non-myelinating Schwann cells ensheathing bundles of collagen fibres instead of axons), and abnormal processes of non-myelinating Schwann cells, as found in certain hereditary neuropathies.
3-4 mm punch skin biopsies biopsies are used to examine the various nerve fibre populations of the epidermis and dermis, especially the small, unmyelinated epidermal nerve fibres to diagnose small fiber neuropathy.
What to look for in a nerve biopsy
Microangiopathy is among the most frequent alterations observed in nerve biopsies. It is a hallmark of diabetic neuropathy and is also often present in elder non-diabetic patients suffering from chronic idiopathic axonal neuropathy (CIAP).
Acute polyradiculoneuritis (Guillain-Barré syndrome; GBS) is characterized by multifocal demyelination, lymphocytic infiltration and endoneurial oedema. It is usually diagnosed based on clinical and laboratory findings. Chronic neuritis (chronic inflammatory demyelinating neuropathy, CIDP; chronic inflammatory axonal neuropathy, CIAP) is more frequently diagnosed by nerve biopsy, especially in atypical cases.
Suspected vasculitis, often in the context of connective tissue disease, causing multiple mononeuropathy or progressive axonal neuropathy is the most frequent indication for nerve biopsy. The typical non-caseating granulomas of sarcoidosis are usually found in the epineurium. Chronic necrotizing vasculitis in the absence of granulomas can be present in other cases of neuropathy associated with sarcoidosis.
Borreliosis also leads to lymphocytic infiltration of epineurial blood vessel walls associated with perineurial thickening and fibrosis and axonal neuropathy. Leprosy is one of the most frequent neuromuscular diseases worldwide. Histological diagnosis is often achieved by skin biopsy, but may also require nerve biopsy. HIV infection can lead to a non-inflammatory, mostly sensory neuropathy which can also be caused by antiretroviral therapy. In addition, GBS/CIDP or chronic necrotizing PNS vasculitis can occur in HIV infection. Other viral infections, especially with hepatitis C, can be associated with necrotizing PNS vasculitis.
Alcoholic neuropathy is characterized by loss of predominantly small axons; in contrast, the neuropathy due to thiamine deficiency may affect mainly large fibres. In chronic alcoholic neuropathy clusters of regenerating nerve fibres may be frequent. Cytostatic drugs frequently lead to severe neuropathy. In fact, neuropathy is often dose-limiting. Taxol, vincristine and cisplatin induce predominantly axonal neuropathy. Other drugs including amiodarone and chloroquine cause predominantly demyelinating neuropathy with characteristic inclusions detectable by EM.
Paraneoplastic neuropathy in patients with solid tumours such as small-cell lung cancer is often associated with autoantibodies including anti-Hu or anti-CV2 and leads to rapid nerve fibre breakdown with numerous myelin ovoids.
Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematological abnormality may be referred to as ‘monoclonal gammopathy of undetermined significance’ (MGUS) or related to different types of hematological malignancies. The association of a peripheral neuropathy with a monoclonal gammopathy is also common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematological process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to discuss the objectives and main interests of nerve biopsy in this situation; we will present some anatomo-clinical cases to answer to the following questions: is the polyneuropathy really induced by the hemopathy and by which mechanism: CIDP: Chronic Inflammatory Demyelinating Polyneuropathy (multifocal macrophage-mediated demyelinating process), anti-MAG neuropathy, endoneurial immunoglobulin deposits, amyloidosis, lymphomatosis infiltrates, POEMS syndrome. This procedure may also reveal a combination of these pathologies in the same case. Of course the possible link between a neuropathy and a chemotherapy must be discussed at first. A coincidence has also to be excluded.
Both primary (AL) amyloidosis due to immunoglobulin light chain deposition and familial amyloidosis due to transthyretin mutations often affect the peripheral nerve. Congo red staining is a screening method, but Thioflavin S or T fluorescence is more sensitive. Transthyretin, amyloid A component, immunoglobulin and light chain immunohistochemistry is used to type the amyloid deposits.
Today, a definite diagnosis of many straightforward hereditary neuropathy cases is achieved by molecular genetic testing. However, nerve biopsy findings can help to define the disease gene in case of ambiguous next generation sequencing results. Moreover, morphological patterns suggestive of a hereditary neuropathy or of combined hereditary and inflammatory or toxic neuropathy are often found by chance in nerve biopsies from patients with seemingly sporadic neuropathy.
Finally, scientific nerve biopsy analysis has contributed greatly to our understanding of peripheral neuropathies. Combined with new molecular methods and in conjunction with the examination of animal models it will contribute informative findings in the future.
Literature
Weis J, Katona I, Nikolin S, Nobbio L, Prada V, Grandis M, Schenone A. Techniques for the standard histological and ultrastructural assessment of nerve biopsies. J Peripher Nerv Syst. 2021 Nov;26 Suppl 2:S3-S10. doi: 10.1111/jns.12468. PMID: 34768314.
Mathis S, Magy L, Le Masson G, Richard L, Soulages A, Solé G, Duval F, Ghorab K, Vallat JM, Duchesne M. Value of nerve biopsy in the management of peripheral neuropathies. Expert Rev Neurother. 2018 Jul;18(7):589-602. PMID: 29923431.
Weis J, Brandner S, Vallat JM. Diseases of the peripheral nerves. In: Greenfield´s Neuropathology, 10th ed. In press.