| Abstract|| |
Background: Nerve biopsy has been widely used to investigate patients with peripheral neuropathy and in many centers, it is still a part of the diagnostic armamentarium. In this study, the histopathological spectrum of the nerve biopsies received is being revisited to analyze the various clinical and pathologic features and also to assess their relevance. Materials and Methods: Retrospective analysis of the data retrieved was done for 74 cases of nerve biopsies. Results: On the basis of the data and histopathological features, broad diagnoses were obtained in 52 cases and further categorized into biopsies being supportive for patient management (including acute and chronic axonopathies and demyelinating neuropathies) and biopsies considered essential for patient management (including vasculitic neuropathies, leprous neuropathies, hereditary neuropathies, and chronic inflammatory demyelinating neuropathies). Nine nerve biopsies did not show any abnormal histopathological features, while 13 nerve biopsies were found to be inadequate for diagnosis, both these groups were categorized as noncontributory. Conclusion: With advanced nerve conduction studies available, nerve biopsy is losing its relevance. However, in our experience, nerve biopsy did complement the clinical findings and nerve conduction studies, with which a close correlation is required to make the histopathology of nerve biopsy more relevant in terms of guiding further specific workup and management.
Keywords: Nerve biopsy, peripheral neuropathy, sural nerve
|How to cite this article:|
Pant I, Jha K, Singh R, Kushwaha S, Chaturvedi S. Peripheral neuropathy and the role of nerve biopsy: A revisit. Indian J Pathol Microbiol 2018;61:339-44
|How to cite this URL:|
Pant I, Jha K, Singh R, Kushwaha S, Chaturvedi S. Peripheral neuropathy and the role of nerve biopsy: A revisit. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Jul 4];61:339-44. Available from: http://www.ijpmonline.org/text.asp?2018/61/3/339/236609
| Introduction|| |
Nerve biopsy has been widely used to investigate patients with peripheral neuropathy and is often the final step in the diagnostic workup of neuropathy of unknown origin. Although there are fewer indications for nerve biopsies today due to improved electrophysiological methods and new molecular tests, certain clinical diagnostic issues continue to require a nerve biopsy. Nevertheless, in many centers, it is still a part of the diagnostic armamentarium and continues to have a significant role in the diagnosis of peripheral neuropathies. In this study, the histopathological spectrum of the biopsies received in our department is being revisited with the aim to analyze the various clinical and pathologic features and also to assess their relevance.
| Materials and Methods|| |
A retrospective analysis of the histopathology records and clinical case files was done in 74 cases of nerve biopsies (entire thickness sural nerve biopsies, approximately 2–2.5 cm of length) received over a period of 10 years in our department. The cases were reviewed, and the following histopathological features were analyzed in detail (based on Hematoxylin and Eosin, Masson's trichrome, toluidine blue, Loyez stain, and immunohistochemistry in paraffin resin embedded sections): fascicular architecture, axonal degeneration, loss of small and large diameter fibers, axonal sprouts, demyelinating fibers, mixed axonal degeneration/demyelinating fibers, perivascular inflammatory infiltrate, fibrinoid necrosis of the vessel wall, inflammatory infiltrate in the endoneurium and perineurium, onion-bulb formation, and epithelioid cell granulomas.
Based on these histopathological findings, the histopathological changes were categorized as either nonspecific (axonal degeneration, segmental demyelination, and mixed axonal/demyelinating) or specific (vasculitic neuropathy, leprous neuropathy, and inflammatory neuropathy). Special stains including Masson's Trichrome (to assess fibrosis) and Ziehl Neelsen stain (to detect lepra bacilli) were done in cases showing granulomas in the nerve biopsy.
Accordingly, the nerve biopsies were broadly categorized into abnormal, normal, and inadequate, and after the clinicopathological correlation were further subclassified as noncontributory, supportive, or essential for patient management. Inadequate nerve biopsies and nerve biopsies showing normal histopathology were grouped under the noncontributory category.
A noncontributory biopsy did not add anything to the management of the patient.
Supportive biopsies supported the clinical diagnosis of a suspected etiology for which treatment was available. Biopsies considered as essential for patient management were the confirmatory biopsies which distinguished between two alternative diagnoses with therapeutic implications and revealed abnormalities that permitted definitive diagnoses of the cause of the neuropathy.
| Results|| |
In this study based on the histopathology, 74 nerve biopsies were broadly categorized into abnormal (52), normal (9), and inadequate (13) biopsies. After analyzing the histopathological diagnoses and the clinicopathological correlation, the abnormal biopsies were further categorized into biopsies being supportive (40) for patient management and biopsies considered essential (12) for patient management.
Biopsies being supportive for patient management included acute and chronic axonopathies (34) and demyelinating neuropathies (6), whereas biopsies considered essential for patient management included vasculitic neuropathy (5), leprous neuropathies (4), hereditary motor sensory neuropathy (HMSN) (2), and chronic inflammatory demyelinating neuropathy (CIDP) (1). Inadequate nerve biopsies (13) and biopsies showing normal histopathology (9) were considered as noncontributory in terms of patient management (22) [Table 1].
Biopsies comprising of acute and chronic axonopathies predominantly showed axonal degeneration, axonal atrophy, swollen axons, giant axons, axonal sprouts, myelin ovoids, and occasionally mixed axonal degeneration/demyelinating fibers [Figure 1]. Neurofilament protein showed marked axonal atrophy in majority of these cases.
|Figure 1: (a) Histopathology showing marked axonal degeneration (H and E, ×400); (b) marked axonal atrophy (neurofilament protein, ×400); (c) swollen axons (H and E, ×400, arrow); (d) giant axons (H and E, ×400, arrow); (e) axonal sprouts (Loyez, ×400, arrow); (f): myelin ovoids (Loyez, ×400, arrow)|
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Biopsies comprising of demyelinating neuropathies showed loss of myelinated fibers, thinly myelinated fibers, and occasional denuded axons [Figure 2]. Loss of myelin was confirmed by myelin basic protein in all the cases. Biopsies diagnosed as vasculitic neuropathies showed perivascular inflammatory infiltrate and fibrinoid necrosis of the vessel wall along with prominent axonal degeneration [Figure 3]. Biopsies diagnosed as CIDP showed the typical onion-bulb formation indicative of chronic demyelination and remyelination observed in hematoxylin and eosin [Figure 4]a and Loyez stain [Figure 4]b, endoneurial edema, inflammatory cell infiltrate, and variable fascicular involvement.
|Figure 2: (a) Histopathology showing thinly myelinated fibers (Loyez, ×400, arrow); (b and c) loss of myelinated fibers (Loyez, ×400); (d) occasional denuded axons (H and E, ×400, arrow)|
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|Figure 3: (a and b) Histopathology showing perivascular inflammatory infiltrate, fibrinoid necrosis of the vessel wall (H and E, ×200, ×400); (c) intravascular thrombus (H and E, ×400); (d) prominent axonal degeneration (Loyez, ×400)|
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|Figure 4: (a) Histopathology showing onion-bulb formation (H and E, ×400); (b) onion-bulb formation (Loyez, ×400)|
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Biopsies diagnosed as HMSNs showed a varied picture. Biopsies diagnosed as HMSNI showed numerous onion-bulb formation and loss of large diameter fibers [Figure 5], while biopsies diagnosed as HMSNIII showed numerous onion-bulb formation and loss of both large and small myelinated fibers [Figure 6]. Histopathologic diagnoses of CIDP, HMSNI, and HMSNIII were rendered after correlating the nerve biopsy findings with the electrophysiological studies and the clinical findings.
|Figure 5: (a) Histopathology showing onion-bulb formation (H and E, ×400); (b) loss of large myelinated fibers (Loyez, ×400)|
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|Figure 6: (a) Histopathology showing onion bulb formation (H and E, ×400); (b) onion-bulb formation (Loyez, ×400); (c) onion-bulb formation (MT, ×400); (d) loss of large and small myelinated fibers (Loyez, ×400)|
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Biopsies diagnosed as leprous neuropathies typically showed lymphocytic infiltration in the endoneurium and perineurium along with the caseating epithelioid cell granulomas [Figure 7]. Ziehl–Neelsen stain showed beaded acid-fast lepra bacilli in these cases [Table 2].
|Figure 7: (a) Histopathology showing central area of necrosis (MT, ×400); (b) well-defined epithelioid cell granulomas (H and E, ×200) and epithelioid cells (H and E, ×400; inset); (c and d) dense endoneurial lymphocytic infiltrate with epithelioid cells (H and E, ×200)|
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|Table 2: Histopathological features for various categories of nerve biopsies (HE, MT and Loyez stain)|
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Normal and inadequate nerve biopsies collectively formed the noncontributory category. Although a standard protocol of biopsying an entire thickness sural nerve biopsy, approximately 2–2.5 cm of length was followed in all the cases, still the histopathological findings revealed only blood vessels in the cases categorized as inadequate biopsies. Retrospective analysis of the nine cases with normal histopathology revealed that these patients were clinically evaluated for symptomatology of peripheral neuropathy prior to being subjected to nerve biopsy. Electrophysiological studies were done in all the patients. Biopsy was considered only after a detailed clinical history and examination of the electrophysiological studies. Since the nerve histopathology was unremarkable, these patients were given supportive treatment with regular follow-up.
| Discussion|| |
Sural nerve biopsy has been a well-established diagnostic procedure for the investigation of peripheral neuropathies for over 45 years. The techniques and indications were introduced by Dyck and Lofgren at the Mayo Clinic in 1966. In the initial years, nerve biopsies emerged as a useful tool to learn about the histopathological basis of the peripheral neuropathies, but over the years, clinical indications for nerve biopsies became limited due to the development of more advanced and less invasive technologies such as high-quality electrophysiology and molecular genetic tests. However, nerve biopsy continues to have a role in suspected clinical conditions of vasculitic neuropathy, amyloid neuropathy, multifocal leprosy, and neuropathies of unknown origin.
Nevertheless, in many centers with limited resources, nerve biopsies are still a part of the diagnostic armamentarium and continue to have a significant role in the diagnosis. Under such circumstances, as highlighted in this article, histopathology of nerve biopsy, complemented with the clinical findings and nerve conduction studies, is always beneficial in guiding the further specific workup and management.
With this purview, this analysis was done in our department to evaluate the yield of nerve biopsies and to assess its relevance in terms of the clinical management. Nerve biopsies categorized as biopsies being supportive for patient management accounted for 54.1%. Our results were almost similar to the results of other authors as reported by Argov et al. in 1989, Midroni and Bilbao in 1995, Chia et al. in 1996, and Deprez et al. in 2000.,,, In our study, this category included acute and chronic axonopathies and demyelinating neuropathies. Overall, the biopsies categorized as acute and chronic axonopathies revealed diagnostic findings in a number of diseases such as axonal swellings in toxic neuropathies, marked axonal degeneration in metabolic neuropathies, and loss of myelinated and unmyelinated fibers in diabetic neuropathies. Biopsies diagnosed as demyelinating neuropathies showed the demyelinating and remyelinating nerve fibers, thus confirming the demyelinating nature of the peripheral neuropathy. These diagnoses were helpful in those cases where there was a discrepancy between clinical, electrophysiological, and cerebrospinal fluid findings. Overall, these nerve biopsies were considered as helpful by the authors as the histopathological findings supported the suspected clinical diagnosis and excluded the possibility of the differential diagnoses if any.
Nerve biopsies categorized as biopsies being essential for patient management accounted for 16.2%. This category included vasculitic neuropathy, leprous neuropathy, HMSN, and CIDP. Nerve biopsies diagnosed as vasculitic neuropathy accounted for 6.8%. Literature search highlighted that although sural nerve biopsy has been considered the standard method for diagnosing vasculitic neuropathy, the diagnostic yield is only around 20% as reported by Rappaport et al. and Hellmann et al., A study conducted by Collins et al. has further confirmed a higher diagnostic yield for vasculitic neuropathy when a biopsy of superficial peroneal nerve was combined with a peroneus brevis muscle biopsy. This is because of the higher frequency of involvement of the peroneal nerve in vasculitic neuropathy along with the frequent involvement of the muscle arteries. In a recent study conducted by Lawrence et al., analyzing vasculitic neuropathy in elderly, the authors concluded that vasculitis is an important, treatable cause of neuropathy, especially in elderly. Nerve biopsy should be used judiciously for early diagnosis and appropriate treatment.
Nerve biopsies categorized as leprous neuropathy accounted for 5.4% in this study. Leprosy is still a common cause of peripheral neuropathy in the developing countries. In all the four patients with the clinical diagnosis of leprosy, biopsy revealed pathological findings that supported the clinical diagnoses and led to specific disease-modifying treatment. It is worth highlighting that clinical diagnosis of leprosy is easily suspected in patients presenting with peripheral neuropathy in endemic areas; however, nerve biopsy becomes mandatory in patients presenting with peripheral neuropathy in nonendemic areas with a clinical suspicion of leprosy, especially in patients with no skin lesions.,
Clinical suspicion of HMSNs led to nerve biopsies in two patients. Both biopsies on histopathology were categorized as HMSN, thus providing contributory as well as confirmatory information in our setup where facilities for molecular genetics are yet to be initiated. Based on the histopathological criteria suggested by Oh in HMSNI, loss of large diameter fibers was appreciated with onion-bulb formation, while in HMSN III, loss of both large and small diameter fibers was appreciated with onion-bulb formation. In addition, diagnosis of HMSNI and HMSNIII was rendered after correlating the detailed clinical history with the histopathological findings.
The single nerve biopsy categorized as CIDP revealed unequivocal inflammatory features confirming CIDP in a patient with provisional clinical diagnosis of CIDP, thus corroborating the clinical and electrophysiological findings. The authors followed the criteria of the American Academy of Neurology, where biopsy evidence of demyelination in sural nerve was considered mandatory, whereas subperineurial/endoneurial edema, inflammatory cell infiltrate, onion-bulb formation, and variation in fascicular involvement were considered as supportive diagnostic criteria.
Although with hereditary neuropathies and CIDP, it is now seldom necessary to perform nerve biopsies as it has been replaced by minimally invasive advanced techniques such as molecular genetics. Unfortunately, availability of these diagnostic tools is still limited in the majority of the laboratory settings in our country. Under such circumstances, interpretation of nerve biopsy histopathology in the perspective of clinical details can serve reasonable definitive diagnoses. Studies conducted by Haq et al. and Kulkarni et al., assessing the usefulness of supportive criteria for the diagnosis of CIDP stated that, even in the absence of advanced techniques, detection of supportive features of CIDP aids in the diagnosis, prognostication, and management in the developing countries., Regarding hereditary neuropathies, diagnostic value of sural nerve biopsy is still relevant in selected cases of unknown origin, in certain sporadic cases where an inherited neuropathy is strongly suspected, but acquired neuropathies such as CIDP need to be excluded.
Thus, in this study, it was recognized that specific diagnoses based on nerve histopathology were made in only 16.2% of cases. In 54.1% of cases, the diagnoses of axonal or demyelinating neuropathy were made without further elucidation of any specific cause. In the latter cases, clinicopathologic correlation led to the final diagnoses in almost all the cases highlighting the importance of exhaustive and detailed clinicopathologic correlation in the workup of peripheral neuropathies. Only a relatively small number of causes of neuropathy can be diagnosed on the basis of histology alone. More often, contributory biopsies will result from the combination of nonspecific suggestive histological features with relevant clinical information. The diagnostic yield of nerve biopsy is a function of careful patient selection, which includes stage of disease, prior treatment, nerve selected, and close collaboration between the clinician and the neuropathologist.
| Conclusion|| |
Only a relatively small number of causes of neuropathies can be diagnosed on the basis of histopathology alone. However, in our experience, nerve biopsy findings complemented with the clinical findings and nerve conduction studies, with which a close correlation is required to make the histopathology of nerve biopsy more relevant in terms of guiding further specific workup and management.
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Department of Pathology, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, New Delhi - 110 095
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2]