Small fiber neuropathy for assessment of disease severity in amyotrophic lateral sclerosis: corneal confocal microscopy findings

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with progressive motor system impairment, and recent evidence has identified the extra-motor involvement. Small fiber neuropathy reflecting by sensory and autonomic disturbances in ALS has been reported to accompany the motor damage. However, non-invasive assessment of this impairment and its application in disease evaluation of ALS is scarce. We aim to evaluate the use of corneal confocal microscopy (CCM) to non-invasively quantify the corneal small fiber neuropathy in ALS and explore its clinical value in assessing disease severity of ALS. Methods Sixty-six patients with ALS and 64 healthy controls were included in this cross-sectional study. Participants underwent detailed clinical assessments and corneal imaging with in vivo CCM. Using ImageJ, the following parameters were quantified: corneal nerve length (IWL) and dendritic cell density (IWDC) in the inferior whorl region and corneal nerve fiber length (CNFL), nerve fiber density (CNFD), nerve branch density (CNBD), and dendritic cell density (CDC) in the peripheral region. Disease severity was evaluated using recognized scales. Results Corneal nerve lengths (IWL and CNFL) were lower while dendritic cell densities (IWDC and CDC) were higher in patients with ALS than controls in peripheral and inferior whorl regions (p < 0.05). Additionally, corneal nerve complexity in the peripheral region was greater in patients than controls with higher CNBD (p = 0.040) and lower CNFD (p = 0.011). IWL was significantly associated with disease severity (p < 0.001) and progression (p = 0.002) in patients with ALS. Patients with bulbar involvement showed significantly lower IWL (p = 0.014) and higher IWDC (p = 0.043) than patients without bulbar involvement. Conclusions CCM quantified significant corneal neuropathy in ALS, and alterations in the inferior whorl region were closely associated with disease severity. CCM could serve as a noninvasive, objective imaging tool to detect corneal small fiber neuropathy for clinical evaluation in ALS.

Corneal Confocal Microscopy in the Diagnosis of Small Fiber Neuropathy: Faster, Easier, and More Efficient Than Skin Biopsy?

Chronic pain may affect 30–50% of the world’s population and an important cause is small fiber neuropathy (SFN). Recent research suggests that autoimmune diseases may be one of the most common causes of small nerve fiber damage. There is low awareness of SFN among patients and clinicians and it is difficult to diagnose as routine electrophysiological methods only detect large fiber abnormalities, and specialized small fiber tests, like skin biopsy and quantitative sensory testing, are not routinely available. Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible method for quantifying small nerve fiber degeneration and regeneration, and could be an important tool for diagnosing SFN. This review considers the advantages and disadvantages of CCM and highlights the evolution of this technique from a research tool to a diagnostic test for small fiber damage, which can be a valuable contribution to the study and management of autoimmune disease.

Small Fiber Neuropathy in Sarcoidosis

Sarcoidosis (SC) is a granulomatous disease of an unknown origin. The most common SC-related neurological complication is a small fiber neuropathy (SFN) that is often considered to be the result of chronic inflammation and remains significantly understudied. This study aimed to identify the clinical and histological correlates of small fiber neuropathy in sarcoidosis patients. The study was performed in 2018–2019 yy and included 50 patients with pulmonary sarcoidosis (n = 25) and healthy subjects (n = 25). For the clinical verification of the SFN, the “Small Fiber Neuropathy Screening List” (SFN-SL) was used. A punch biopsy of the skin was performed followed by enzyme immunoassay analysis with PGP 9.5 antibodies. Up to 60% of the sarcoidosis patients reported the presence of at least one complaint, and it was possible that these complaints were associated with SFN. The most frequent complaints included dysfunctions of the cardiovascular and musculoskeletal systems and the gastrointestinal tract. A negative, statistically significant correlation between the intraepidermal nerve fiber density (IEND) and SFN-SL score was revealed. In patients with pulmonary sarcoidosis, small fiber neuropathy might develop as a result of systemic immune-mediated inflammation. The most common symptoms of this complication were dysautonomia and mild sensory dysfunction.

Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson’s disease

The proximity ligation assay (PLA) is a specific and sensitive technique for the detection of αSyn oligomers (αSyn-PLA), early and toxic species implicated in the pathogenesis of PD. We aimed to evaluate by skin biopsy the diagnostic and prognostic capacity of αSyn-PLA and small nerve fiber reduction in PD in a longitudinal study. αSyn-PLA was performed in the ankle and cervical skin biopsies of PD (n = 30), atypical parkinsonisms (AP, n = 23) including multiple system atrophy (MSA, n = 12) and tauopathies (AP-Tau, n = 11), and healthy controls (HC, n = 22). Skin biopsy was also analyzed for phosphorylated αSyn (P-αSyn) and 5G4 (αSyn-5G4), a conformation-specific antibody to aggregated αSyn. Intraepidermal nerve fiber density (IENFD) was assessed as a measure of small fiber neuropathy. αSyn-PLA signal was more expressed in PD and MSA compared to controls and AP-Tau. αSyn-PLA showed the highest diagnostic accuracy (PD vs. HC sensitivity 80%, specificity 77%; PD vs. AP-Tau sensitivity 80%, specificity 82%), however, P-αSyn and 5G4, possible markers of later phases, performed better when considering the ankle site alone. A small fiber neuropathy was detected in PD and MSA. A progression of denervation not of pathological αSyn was detected at follow-up and a lower IENFD at baseline was associated with a greater cognitive and motor decline in PD. A skin biopsy-derived compound marker, resulting from a linear discrimination analysis model of αSyn-PLA, P-αSyn, αSyn-5G4, and IENFD, stratified patients with accuracy (77.8%), including the discrimination between PD and MSA (84.6%). In conclusion, the choice of pathological αSyn marker and anatomical site influences the diagnostic performance of skin biopsy and can help in understanding the temporal dynamics of αSyn spreading in the peripheral nervous system during the disease. Skin denervation, not pathological αSyn is a potential progression marker for PD.

Neuropatia de fibras finas na doença de Wilson: revisão de literatura / Small fiber neuropathy in Wilson's disease: literature review

Introdução: A neuropatia periférica é um distúrbio neurológico bastante comum e vem aumentando sua prevalência devido ao processo de envelhecimento da população e aumento de comorbidades como diabetes e obesidade. A neuropatia periférica de fibras finas (NFF) é considerada uma síndrome que apresenta manifestações sensitivas isoladas, ou a combinação de manifestações sensitivas e autonômicas. A doença de Wilson (DW) é um transtorno autossômico recessivo causado por deficiência na metabolização do cobre decorrente de mutações no gene ATP7B. Entre as alterações neurológicas apresentadas pelos pacientes com DW está a neuropatia periférica. Objetivo: Revisar a literatura acerca da neuropatia de fibras finas na Doença de Wilson aumentando a compreensão dessa disfunção sobre suas causas e tipos de abordagens apresentadas na literatura. Métodos: Foi realizada uma revisão bibliográfica a partir do levantamento de dados presente nas bases de dados Scielo e PUBMED no período de janeiro a junho de 2021, utilizando os descritores: “Small Fiber Neuropathy”, “Wilson’s Disease”, “Peripheral Neuropathy". Resultados: Foram selecionados 29 artigos, cujos originais foram utilizados para composição deste estudo. Para melhor compreensão, os resultados encontrados no levantamento bibliográfico foram divididos em tópicos. Dos 29 artigos recrutados 15 foram excluídos, pois apresentavam outras doenças de base que pudessem justificar a presença de neuropatia além da doença de Wilson. Dos 14 artigos incluídos na pesquisa: 3 descreveram a presença de neuropatia de fibras finas na DW, 4 artigos destacaram a presença de leve polineuropatia sensitivo motora axonal na DW, 7 artigos mostraram evidência de neuropatia autonômica, sendo 2 com disfunção predominantemente simpática e 1 parassimpática. Conclusão: Neuropatia de fibras finas permanece como um diagnóstico desafiador na literatura, podendo estar presente em formas leves, mesmo em doenças com envolvimento predominante do SNC. Na DW também há relatos desse acometimento neurológico periférico, com predomínio de envolvimento de fibras finas autonômicas de repercussões ainda não completamente compreendidas. A compreensão dessa disfunção ainda não está totalmente esclarecida e ainda há muitas coisas a serem compreendidas sobre a doença de Wilson, portanto faz-se necessário mais estudo sobre essa temática uma vez que ainda é escasso na literatura estudos que abordem esse assunto mesmo havendo aumento do número de casos diagnosticados com doença de Wilson e que apresentam queixas sensitivas associadas. Palavras chave: Neuropatia de fibras finas, Doença de Wilson, Doenças do sistema nervoso periférico, Neuropatias periféricas Abstract Introduction: Peripheral neuropathy is a very common neurological disorder and its prevalence is increasing due to the aging process of the population and the increase in comorbidities such as diabetes and obesity. Fine fiber peripheral neuropathy (NFF) is considered a syndrome that presents isolated sensory manifestations, or a combination of sensory and autonomic manifestations. Wilson's disease (WD) is an autosomal recessive disorder caused by impaired copper metabolism due to mutations in the ATP7B gene. Among the neurological alterations presented by patients with WD is peripheral neuropathy. Objective: To review the literature about thin fiber neuropathy in Wilson's Disease, increasing the understanding of this dysfunction about its causes and types of approaches presented in the literature. Methods: A literature review was carried out based on the data survey present in the Scielo and PUBMED databases from January to June 2021, using the descriptors: "Small Fiber Neuropathy", "Wilson's Disease", "Peripheral Neuropathy". Results: 29 articles were selected, whose For a better understanding, the results found in the literature review were divided into topics.From 29 recruited articles, 15 were excluded, as they had other underlying diseases that could justify the presence of neuropathy in addition to Wilson's disease. Of the 14 articles included in the research: 3 described the presence of fine fiber neuropathy in WD, 4 articles highlighted the presence of mild axonal sensory motor polyneuropathy in WD, 7 articles showed evidence of autonomic neuropathy, 2 with predominantly sympathetic dysfunction and 1 parasympathetic. Conclusion: Fine fiber neuropathy remains a challenging diagnosis in the field. and may be present in mild forms, even in diseases with predominant involvement of the CNS. In WD there are also reports of this peripheral neurological involvement, with a predominance of involvement of thin autonomic fibers with repercussions that are not yet completely understood. The understanding of this dysfunction is still not fully clarified and there are still many things to be understood about Wilson's disease, so further study on this topic is necessary since studies addressing this issue are still scarce in the literature, even with an increase in number of cases diagnosed with Wilson's disease and presenting associated sensory complaints. Keywords: Small fiber neuropathy, Wilson disease, Peripheral nervous system diseases, Peripheral neuropathies