In-vivo corneal confocal microscopy in chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting up to 80% of treated patients with severe impact on their quality of life. While some patients experience improvement in signs and symptoms after dose reduction or cessation of treatment, many develop chronic neuropathy which can last for years leading to high economic and disease burden. Assessment of CIPN currently relies on crude severity grading by clinicians, subjective patient questionnaires and nerve conduction studies limited to large nerve fibre assessment. Unfortunately, there is still an absence of reliable and efficient methods which can provide sensitive endpoint measures particularly with small nerve fibre assessments. While ocular surface neural changes have been well established as potential diagnostic and prognostic markers in other aetiologies of peripheral neuropathy particularly diabetes, there have been limited studies in CIPN. Hence, the overall aim of this thesis was to investigate whether neural changes on the ocular surface occurred with neurotoxic chemotherapy along with CIPN development. This was explored across several studies primarily with in-vivo corneal confocal microscopy (CCM). The first series, comprised of five cross-sectional studies, assessed patients who have already completed neurotoxic chemotherapy treatment for cancer and may have persistent CIPN. Neurotoxic chemotherapeutic drugs including taxanes or platinum compounds were the focus as these were the most commonly associated with CIPN. Chapter 2 analysed the reproducibility of corneal nerve image selection and analysis outcomes from the central cornea and inferior whorl region, a distinct landmark of the sub-basal nerve plexus. Analysis of both regions produced reliable and reproducible findings, although the inferior whorl region had slightly higher variability compared to the central cornea. This study also demonstrated that complex inferior whorl patterns, more commonly found in patients with CIPN compared to healthy individuals, may reduce reproducibility of image selection and analysis. Chapter 3 assessed whether corneal nerve damage occurred in patients who have already completed treatment with neurotoxic chemotherapy prior to assessment. This study established that there was corneal nerve reduction particularly in patients treated with paclitaxel who still had peripheral neuropathy post-treatment cessation, and this reduction was associated with worse fine hand dexterity. Chapter 4 then investigated whether the loss of nerves described in the previous study contributed to ocular surface discomfort associated with dry eye disease, which is a widespread and overlooked condition severely impacting quality of life analogous to CIPN. In this study, paclitaxel-treated patients with CIPN who had more severe corneal nerve fibre reduction, also had higher risk of suffering from ocular surface discomfort and worse visual function compared to patients without neuropathy and healthy controls. The study highlighted the need for eye care clinicians and medical oncologists to be aware of such ocular surface symptoms even in those who have completed neurotoxic chemotherapy treatment. Chapter 5 investigated corneal dendritic cells which are antigen-presenting cells and potent initiators of inflammatory responses residing in the sub-basal corneal nerve plexus. This study was conducted as these immune cells can also be observed with CCM, and neuroinflammation and immune cell infiltration have been implicated in the pathophysiology of CIPN. The findings indicated that there was an elevated presence of immature dendritic cell density in oxaliplatin-treated patients well after treatment cessation, but not in paclitaxel-treated patients. Chapter 6 evaluated the concentration of substance P, a sensory neuropeptide primarily expressed by small nerve fibres in the cornea and essential for maintenance of ocular surface health, in the tears. While the previous study demonstrated elevated dendritic cell density in oxaliplatin-treated patients, this study showed reduced substance P concentration in paclitaxel-treated patients instead. These two studies further emphasise potential differences in pathophysiological mechanisms underlying CIPN associated with these two drugs. Chapter 7 involved a longitudinal study which observed ocular surface and peripheral neuropathic changes during the treatment period, and monitoring patients up to twelve months post-treatment cessation. The study found a progressive loss in corneal nerve parameters with increasing cumulative dose from baseline to end of treatment particularly with taxane treatment, while other ocular surface measures including corneal dendritic cells and tear film substance P levels did not have significant changes. The findings indicated a potential mixed pattern of small and large nerve fibre involvement with taxane treatment, while oxaliplatin affects predominantly large nerve fibres. Corneal nerve fibre length measured during the treatment period was also lower in patients who continued to have persistent CIPN after treatment cessation compared to patients who did not, indicating the potential for early detection of corneal nerve fibre loss as an indicator of CIPN progression. Future studies investigating corneal nerve changes at multiple timepoints in larger studies involving taxane-treated patients may provide greater insight into the diagnostic and predictive utility of CCM in CIPN. Improvements in CCM instrumentation and methodology may also contribute to better assessment of the state of the sub-basal corneal nerve plexus. The discussion section further explores these issues in relation to the clinical applicability or scalability of CCM and potential solutions to improve imaging capabilities in the future

The impact of dry eye disease on corneal nerve parameters::A systematic review and meta‐analysis

Purpose: Dry eye disease (DED) is a growing global health problem with a significant impact on the quality of life of patients. While neurosensory abnormalities have been recognised as a contributor to DED pathophysiology, the potential role of in vivo corneal confocal microscopy in detecting nerve loss or damage remains unclear. This systematic review with meta‐analysis (PROSPERO registered CRD42022381861) investigated whether DED has an impact on sub‐basal corneal nerve parameters. Methods: PubMed, Embase and Web of Science Core Collection databases were searched from inception to 9 December 2022. Studies using laser scanning confocal microscopy to compare corneal nerve parameters of DED with healthy eyes were included. Study selection process and data extraction were performed by two independent members of the review team. Results: Twenty‐two studies with 916 participants with DED and 491 healthy controls were included, with 21 of these studies included in subsequent meta‐analyses. There was a decrease in total corneal nerve length (−3.85 mm/mm2; 95% CI −5.16, −2.55), corneal main nerve trunk density (−4.81 number/mm2; 95% CI −7.94, −1.68) and corneal nerve branch density (−15.52 number/mm2; 95% CI −27.20, −3.84) in DED eyes compared with healthy eyes, with subgroup analysis demonstrating that these differences were more evident in studies using NeuronJ software, a semi‐automated procedure. While this review found evidence of loss of corneal nerve parameters in eyes with DED compared with healthy controls, particularly with the use of a semi‐automated image analysis method, it is evident that there is substantial heterogeneity between studies in terms of corneal nerve imaging methodology. Conclusions: Standardisation is required in terms of terminology and analysis, with more research needed to potentially improve the clinical applicability and practicality of corneal nerve imaging. Further investigation is also required to confirm the diagnostic accuracy of this imaging modality and its potential for monitoring DED treatment efficacy

Corneal dendritic cells and the subbasal nerve plexus following neurotoxic treatment with oxaliplatin or paclitaxel

Immune cell infiltration has been implicated in neurotoxic chemotherapy for cancer treatment. However, our understanding of immune processes is still incomplete and current methods of observing immune cells are time consuming or invasive. Corneal dendritic cells are potent antigen-presenting cells and can be imaged with in-vivo corneal confocal microscopy. Corneal dendritic cell densities and nerve parameters in patients treated with neurotoxic chemotherapy were investigated. Patients treated for cancer with oxaliplatin (n = 39) or paclitaxel (n = 48), 3 to 24 months prior to assessment were recruited along with 40 healthy controls. Immature (ImDC), mature (MDC) and total dendritic cell densities (TotalDC), and corneal nerve parameters were analyzed from in-vivo corneal confocal microscopy images. ImDC was increased in the oxaliplatin group (Median, Md = 22.7 cells/mm 2) compared to healthy controls (Md = 10.1 cells/mm 2, p = 0.001), but not in the paclitaxel group (Md = 10.6 cells/mm 2). ImDC was also associated with higher oxaliplatin cumulative dose (r = 0.33, p = 0.04) and treatment cycles (r = 0.40, p = 0.01). There was no significant difference in MDC between the three groups (p > 0.05). Corneal nerve parameters were reduced in both oxaliplatin and paclitaxel groups compared to healthy controls (p < 0.05). There is evidence of elevation of corneal ImDC in oxaliplatin-treated patients. Further investigation is required to explore this potential link through longitudinal studies and animal or laboratory-based immunohistochemical research

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M&gt;70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0&lt;e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Topical ivermectin 1.0% cream in the treatment of ocular demodicosis

Purpose Ocular demodicosis can cause debilitating ocular surface disease. As ivermectin is effective at reducing Demodex proliferation in rosacea, this study investigated the efficacy of topical ivermectin 1.0% cream in treating ocular demodicosis. Methods This retrospective single-centre clinical practice chart analysis involved the off-label treatment of patients who had ocular demodicosis with topical ivermectin 1.0 % cream (Soolantra, Galderma Ltd, UK) applied nightly to the lid margins of both eyes for 3 months. Ocular surface health was assessed at baseline when the treatment was prescribed and followed up at 3 and 12 months after baseline. Slit lamp biomicroscopy was used to take digital images of the upper eyelid lashes. Manual image analysis with ImageJ was conducted by a masked assessor to quantify signs of ocular demodicosis including the number of lashes with collarettes, with visible Demodex tails and with follicle pouting. Results Data from a total of 75 patients with ocular demodicosis were analysed for this study (mean age 66.6 ± 13.9 years, 44 female). The numbers of lashes with collarettes (Median [Interquartile range]: 8 [4–13] at baseline to 0 [0–2] at the final visit, p < 0.001) and lashes with follicle pouting (3 [1–5] at baseline to 0 [0–1.8] at the final visit, p < 0.001) decreased with treatment. Any sign of lashes with visible tails was eliminated by the final visit (p < 0.007). Fluorescein staining severity score also improved, particularly from baseline (1 [0–2]) to the second visit (0 [0–1], p < 0.001). Conclusions The findings of this study show evidence for the efficacy of a 3-month course of topical ivermectin 1.0% cream in treating ocular demodicosis as indicated by reduction in collarettes, follicle pouting and visible Demodex tails. More research is warranted to improve the diagnosis, management and monitoring of this condition which is often overlooked or misdiagnosed

Current and Emerging Pharmacotherapeutic Interventions for the Treatment of Peripheral Nerve Disorders

Peripheral nerve disorders are caused by a range of different aetiologies. The range of causes include metabolic conditions such as diabetes, obesity and chronic kidney disease. Diabetic neuropathy may be associated with severe weakness and the loss of sensation, leading to gangrene and amputation in advanced cases. Recent studies have indicated a high prevalence of neuropathy in patients with chronic kidney disease, also known as uraemic neuropathy. Immune-mediated neuropathies including Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy may cause significant physical disability. As survival rates continue to improve in cancer, the prevalence of treatment complications, such as chemotherapy-induced peripheral neuropathy, has also increased in treated patients and survivors. Notably, peripheral neuropathy associated with these conditions may be chronic and long-lasting, drastically affecting the quality of life of affected individuals, and leading to a large socioeconomic burden. This review article explores some of the major emerging clinical and experimental therapeutic agents that have been investigated for the treatment of peripheral neuropathy due to metabolic, toxic and immune aetiologies

In-vivo corneal confocal microscopy::Imaging analysis, biological insights and future directions

In-vivo corneal confocal microscopy is a powerful imaging technique which provides clinicians and researcher with the capabilities to observe microstructures at the ocular surfaces in significant detail. In this Mini Review, the optics and image analysis methods with the use of corneal confocal microscopy are discussed. While novel insights of neuroanatomy and biology of the eyes, particularly the ocular surface, have been provided by corneal confocal microscopy, some debatable elements observed using this technique remain and these are explored in this Mini Review. Potential improvements in imaging methodology and instrumentation are also suggested