Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy

Quattrini, Cristian; Tavakoli, Mitra; Jeziorska, Maria; Kallinikos, Panagiotis A.; Tesfaye, Solomon; Finnigan, Joanne; Marshall, Andrew; Boulton, Andrew J.M.; Efron, Nathan; Malik, Rayaz A.

doi:10.2337/db07-0285

Cited by 462 publications

(491 citation statements)

References 34 publications

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“…We show a greater loss of CNFs in CIDP patients with painful neuropathy, which is in keeping with previous studies showing that diabetic patients with painful neuropathy show a greater reduction in corneal nerve parameters compared to diabetic patients with painless neuropathy 56. Furthermore, in patients with painful neuropathy we detected a shift toward the infiltration of nondendritic cells, which suggests that these cells may play a pathophysiological role in painful neuropathy.…”

Section: Discussionsupporting

confidence: 92%

Corneal confocal microscopy in chronic inflammatory demyelinating polyneuropathy

Stettner

Hinrichs

Guthoff

et al. 2015

Ann Clin Transl Neurol

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105

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ObjectiveThere is an unmet need for better diagnostic tools to further delineate clinical subsets of heterogeneous chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) to facilitate treatment decisions. Corneal confocal microscopy (CCM) is a noninvasive and reproducible nerve imaging technique. This study evaluates the potential of CCM as a diagnostic surrogate in CIDP and MMN.MethodsIn a cross‐sectional prospective approach, 182 patients and healthy controls were studied using CCM to quantify corneal nerve damage and immune cell infiltration.ResultsPatients with CIDP and MMN had a reduction in corneal nerve fiber (CNF) measures and an increase in corneal immune cell infiltrates. In CIDP, CNF parameters decreased with increasing duration of disease. The number of dendritic cells in proximity to CNFs was increased in patients with early disease and correlated with the degree of motor affection. A further reduction in CNF parameters and an increase in nondendritic cells were observed in patients with painful neuropathy. In CIDP patients with antineuronal antibodies the number of nondendritic cells was increased.InterpretationOur findings suggest that CNF loss may reflect severity of neuropathy and quantification of distinct cells around the CNF plexus may help in stratifying CIDP subtypes, clinical course, and disease activity. However, further longitudinal studies are required before CCM can be considered as a valid surrogate endpoint for patients with CIDP and MMN.

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Section: Discussionsupporting

confidence: 92%

Corneal confocal microscopy in chronic inflammatory demyelinating polyneuropathy

Stettner

Hinrichs

Guthoff

et al. 2015

Ann Clin Transl Neurol

Self Cite

105

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“…Indeed, diabetic neuropathy is usually identified by clinical and neurophysiological examinations to detect indications of axonopathy, namely, reduced conduction velocity and amplitude in large fibres, and abnormal thresholds to sensory stimuli. The focus on axonopathy is highlighted by a growing interest in the detection of early degeneration of small sensory fibres by measuring intraepidermal nerve fibre density in skin biopsy samples or corneal nerve density by confocal microscopy 167 (FIG. 1).…”

Section: Towards a New Understandingmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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“…Morphological alterations in the epithelium, stroma and endothelium provide insights into a variety of corneal diseases [3,4] and assessment of the effects of wearing contact lenses [1], LASIK or PRK [5], fungal keratitis [6], corneal transplantation [7] or conditions such as keratoconus [8,9]. CCM has also been used in the assessment of peripheral neuropathies [10,11,12,13,14,15,16,17,18,19]. The development of automated imaging algorithms for the processing of CCM images [20,21,22,23] is a necessary accompaniment to such work.…”

Section: Introductionmentioning

confidence: 99%

“…Diabetes can result in nerve disorders and nerve damage that affect various parts of the human body, such as the digestive tract and the cardiovascular system [15,17]. Quantifying corneal nerve morphology has been shown to have promise as an imaging biomarker for early diagnosis of subclinical diabetic neuropathy [11,12,17,18] and to have value in predicting those who develop clinical neuropathy [16,24] and response to therapy [25]. Presently, most analysis methods of the corneal nerves are based on wearisome and very time consuming manual tracing programs [5,6,217,26].…”

Section: Introductionmentioning

confidence: 99%