Corneal Confocal Microscopy: a Surrogate Endpoint for Neurodegeneration in Clinical Trials


Diagnostic Criteria for Mixed, Small and Large Fiber Idiopathic Peripheral Neuropathy in Clinical Trials: The IMMPACT / ACTION Recommendations

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Distal sensory polyneuropathy (DSP) results from damage to the peripheral nerves that presents as a variable cluster of symptoms and signs including pain, tingling, hyperalgesia, allodynia, sensory loss, and gait instability. DSP is caused by diabetes, toxins such as chemotherapeutic agents, immunological factors, and genetic mutations. However, in approximately 20 - 50% of peripheral neuropathy cases no cause is identified, leading to a diagnosis of idiopathic DSP (iDSP). No drugs are approved for iDSP and its subtypes, idiopathic small fiber neuropathy (iSFN) and idiopathic large fiber neuropathy (iLFN). One possible barrier to successful development of novel therapeutics is the lack of generally accepted diagnostic criteria for these conditions. To address this deficiency, the Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials (CONCEPPT) of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the FDA convened a meeting of experts experts (including neurologists, clinical trialists, and regulatory experts from academia, government, and the pharmaceutical industry to develop consensus diagnostic criteria for iDSP, iSFN and iLFN for use in research and clinical practice. After a series of background that included presentations of criteria used in disease-specific DSPs and previous research a collaborative approach was used to develop expert consensus for the new criteria. Diagnostic criteria included required symptoms, signs, neurophysiological and neuropathological assessments, and etiologies to be excluded. Requirements for iDSP diagnosis include: one of the following symptoms (1) constant or intermittent pain, (2) reported evoked pain, (3) a non-painful sensory symptom; one of the following signs: (1) abnormal sensory perception (e.g., pinprick, light touch, vibration or position sense), (2) allodynia (3) hyperalgesia; abnormalities in sensory nerve conduction studies (NCS) or distal intra-epidermal nerve fiber density (IENFD); and absence of specific causes of DSP. Diagnostic criteria for iSFN are similar, except absence of abnormalities in large fiber signs, abnormal IENFD and normal sensory NCS are required, whereas diagnostic criteria for iLFN required absence of small fiber symptoms and signs, abnormal NCS and normal IENFD.The consortium proposed that adoption of these standardized diagnostic criteria would advance research and clinical trials, spur development of novel therapies for iDSP and facilitate generalization of research results to the clinic