The Utility of Corneal Nerve Fractal Dimension Analysis in Peripheral Neuropathies of Different Etiology

Petropoulos, Ioannis N.; Al-Mohammedi, Abdulrahman; Chen, Xin; Ferdousi, Maryam; Ponirakis, Georgios; Kemp, Harriet; Chopra, Reena; Hau, Scott; Schargus, Marc; Vollert, Jan; Sturm, Dietrich; Bharani, Tina; Kleinschnitz, Christopher; Stettner, Mark; Maier, Christoph; Rice, Andrew S.C.; Malik, Rayaz A.

doi:10.1167/tvst.9.9.43

Cited by 23 publications

(16 citation statements)

References 55 publications

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“…To the best of our knowledge, this is the first study to quantify function of large myelinated motor fibers in the iTAT-tg mouse model, although nerve conduction studies have been used for diagnosing peripheral neuropathy in HIV patients ( 43 – 46 ). Similarly, our novel finding of reduced corneal sensory nerve density is not a consequence of DOX exposure per se and is consistent with recent reports of reduced corneal nerve density in patients with HIV neuropathy ( 47 , 48 ). In a previous study we demonstrated that topical delivery of the HIV envelope protein gp120 to the eye of normal mice also leads to loss of corneal sensory nerves ( 32 ), so that two HIV-associated proteins linked with neuropathy independently impact corneal nerves.…”

Section: Discussionsupporting

confidence: 93%

“…Our study is limited to the use of a mouse model that expresses only one HIV-associated protein and the use of DOX to induce TAT expression. Although the iTAT-tg mouse model does not illustrate the complex interaction between HIV and HIV proteins that may impact development of HIV-DSP in humans, it does focus attention on one specific protein and its role in clinical features of HIV-DSP such as nerve conduction slowing and reduction of corneal sensory nerve density ( 2 , 47 , 48 ). Appropriate controls in our study also allowed us to segregate the impact of DOX on sensory nerve function.…”

Section: Discussionmentioning

confidence: 99%

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Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine

et al. 2021

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HIV-associated distal sensory polyneuropathy (HIV-DSP) affects about one third of people with HIV and is characterized by distal degeneration of axons. The pathogenesis of HIV-DSP is not known and there is currently no FDA-approved treatment. HIV trans-activator of transcription (TAT) is associated with mitochondrial dysfunction and neurotoxicity in the brain and may play a role in the pathogenesis of HIV-DSP. In the present study, we measured indices of peripheral neuropathy in the doxycycline (DOX)-inducible HIV-TAT (iTAT) transgenic mouse and investigated the therapeutic efficacy of a selective muscarinic subtype-1 receptor (M1R) antagonist, pirenzepine (PZ). PZ was selected as we have previously shown that it prevents and/or reverses indices of peripheral neuropathy in multiple disease models. DOX alone induced weight loss, tactile allodynia and paw thermal hypoalgesia in normal C57Bl/6J mice. Conduction velocity of large motor fibers, density of small sensory nerve fibers in the cornea and expression of mitochondria-associated proteins in sciatic nerve were unaffected by DOX in normal mice, whereas these parameters were disrupted when DOX was given to iTAT mice to induce TAT expression. Daily injection of PZ (10 mg/kg s.c.) prevented all of the disorders associated with TAT expression. These studies demonstrate that TAT expression disrupts mitochondria and induces indices of sensory and motor peripheral neuropathy and that M1R antagonism may be a viable treatment for HIV-DSP. However, some indices of neuropathy in the DOX-inducible TAT transgenic mouse model can be ascribed to DOX treatment rather than TAT expression and data obtained from animal models in which gene expression is modified by DOX should be accompanied by appropriate controls and treated with due caution.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine

et al. 2021

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“…CCM demonstrated no significant difference in corneal nerve fiber length, density or branch density between controls and patients with CIPN with and without small fibre neuropathy [ 216 ]. In a study comparing CCM in different peripheral neuropathies, patients with CIPN had evidence of corneal nerve fibre loss in a distinct pattern based on the corneal nerve fractal dimension, which differed from patients with diabetic neuropathy or chronic inflammatory demyelinating neuropathy [ 217 ]. A study of 70 patients with breast, colorectal, upper gastrointestinal and gynaecological cancer having received either paclitaxel ( n = 40) or oxaliplatin ( n = 30) within the past 3 to 24 months showed evidence of a significant reduction in the corneal nerve fibre and inferior whorl lengths [ 218 ].…”

Section: Corneal Confocal Microscopymentioning

confidence: 99%

Chemotherapy-Induced Peripheral Neuropathy: Epidemiology, Pathomechanisms and Treatment

et al. 2021

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Purpose: This review provides an update on the current clinical, epidemiological and pathophysiological evidence alongside the diagnostic, prevention and treatment approach to chemotherapy-induced peripheral neuropathy (CIPN). Findings: The incidence of cancer and longterm survival after treatment is increasing. CIPN affects sensory, motor and autonomic nerves and is one of the most common adverse events caused by chemotherapeutic agents, which in severe cases leads to dose reduction or

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“…Patients with other neurodegenerative conditions like multiple sclerosis, Wilson's disease and Friedreich's ataxia have showed a decrease in CNBD compared to controls [37][38][39]. Thus, different etiologies may impact differently on corneal nerve fibers [40].…”

Section: Discussionmentioning

confidence: 99%

Corneal Nerve Fiber Loss Relates to Cognitive Impairment in Patients with Parkinson’s Disease

Che

Jiang

Ding

et al. 2020

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Background Cognitive impairment in Parkinson’s disease (PD) adversely influences quality of life. There is currently no available biomarker to predict cognitive decline in PD. PD involves both the central and peripheral nervous system and especially small fiber damage occurs in PD. Corneal confocal microscopy (CCM) has been used as a non-invasive tool for quantifying small nerve fibre damage in PD. The present study investigated whether corneal nerve measures were associated with cognitive function in PD. Methods Patients with PD were classified into those with normal cognitive function (PD-CN), mild cognitive impairment (PD-MCI), and dementia (PDD). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) were quantified with CCM and compared with a control group.Results Sixty-five PD patients (44.62% male; mean age 64.60±6.95 years; mean disease duration 4.63±2.53 years) and 30 controls (53.33% male; mean age 62.43±6.16 years) were studied. CNFD was decreased and CNBD was increased in PD patients compared to controls ( P <0.05). CNFD decreased progressively with decline in cognitive function in PD patients. CNBD and CNBD/CNFD ratio was higher in PD-CN compared to controls but decreased with worsening cognitive function in PD-MCI and PDD patients. CNFD correlated with the Montreal cognitive assessment (MoCA) score ( r =0.683, P <0.0001), unified Parkinson disease rating scale (UPDRS)-part III ( r =-0.481, P <0.0001) and total UPDRS scores ( r =-0.401, P <0.0001) in PD patients. CNFD, CNBD, CNFL were lower and CNBD/CNFD ratio was higher with increasing Hoehn and Yahr stage. There was no correlation between CNFD and Levodopa equivalent daily dose (LEDD) ( r =0.176, P =0.161). CNFD, CNBD and CNFL could discriminate between PD-MCI and PD-CN with an area under the curve (AUC) of 82.85%, 67.47%, and 78.74%, respectively. CNFD, CNBD and CNFL could discriminate between PDD and PD-CN with an AUC of 96.67%, 90.12% and 84.44%. A combination of all three CCM parameters further increased the AUC value. Conclusions PD patients show evidence of corneal nerve loss compared with controls and corneal nerve parameters are associated with the severity of cognitive and motor dysfunction in PD. CCM could serve as an objective in vivo ophthalmic imaging technique to assess neurodegeneration in PD.

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The Utility of Corneal Nerve Fractal Dimension Analysis in Peripheral Neuropathies of Different Etiology

Abstract: The utility of corneal nerve fractal dimension analysis in peripheral neuropathies of different etiology.

Cited by 23 publications

References 55 publications

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine

Chemotherapy-Induced Peripheral Neuropathy: Epidemiology, Pathomechanisms and Treatment

Corneal Nerve Fiber Loss Relates to Cognitive Impairment in Patients with Parkinson’s Disease

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