The Role of Skin Innervation for Assessment of Neurological Involvement in Disorders: A Review

Skin biopsy is an affordable, minimally invasive technique that provides direct access to peripheral neural structures for in vivo evaluation of cutaneous nerve pathology, with relevance to both peripheral and central nervous system disorders. Skin biopsy allows the assessment of somatic and autonomic fibers as well as their innervated structures, representing the gold standard for the diagnosis of Small-Fiber Neuropathy. Nonetheless, the assessment of autonomic fibers remains challenging, as the patterns of sympathetic and parasympathetic skin innervation have not yet been fully elucidated, and the intricate organization of effector structures (e.g., arrector pilorum muscles, sweat glands, blood vessels) poses methodological difficulties. Beyond small-fiber evaluation, skin biopsy allows the detection of disease-specific deposits of abnormally accumulating proteins in a broad spectrum of clinical entities. It has proven highly accurate in detecting synucleinopathies in vivo, with near-complete specificity in the discrimination of affected patients from healthy controls and from alternative neurodegenerative disorders. Furthermore, the pattern of α-synuclein deposition serves to differentiate Lewy body from non-Lewy body synucleinopathies, thereby distinguishing disorders with similar clinical manifestations but distinct physiopathology and prognostic implications. In this narrative review, we outline the current indications for skin biopsy in the evaluation of diverse neurological disorders and address the main methodological aspects of the technique.