Corneal sub-basal whorl-like nerve plexus: a landmark for early and follow-up evaluation in transthyretin familial amyloid polyneuropathy
Y. Zhang
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
These authors contributed equally.Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (lead), Writing - original draft (lead)
Search for more papers by this authorZ. Liu
Department of Ophthalmology, Peking University Third Hospital, Beijing, China
These authors contributed equally.Contribution: Data curation (equal), Investigation (lead), Project administration (lead), Supervision (lead)
Search for more papers by this authorY. Zhang
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
Contribution: Conceptualization (equal), Investigation (equal), Supervision (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorH. Wang
Department of Ophthalmology, Peking University Third Hospital, Beijing, China
Contribution: Investigation (equal), Methodology (equal)
Search for more papers by this authorX. Liu
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
Contribution: Investigation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorS. Zhang
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
Contribution: Data curation (equal), Investigation (equal)
Search for more papers by this authorX. Liu
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
These authors contributed equally.Contribution: Conceptualization (lead), Formal analysis (lead), Investigation (supporting), Project administration (lead), Resources (lead), Supervision (lead), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
D. Fan
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
These authors contributed equally.Correspondence: D. Fan, Department of Neurology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China (tel.: (+86)13701023871; fax: 86-010-82266250; e-mail: [email protected]).
Contribution: Conceptualization (lead), Data curation (lead), Funding acquisition (lead), Investigation (lead), Methodology (lead), Project administration (lead), Resources (lead), Supervision (lead), Validation (lead), Writing - original draft (equal), Writing - review & editing (lead)
Search for more papers by this authorY. Zhang
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
These authors contributed equally.Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (lead), Writing - original draft (lead)
Search for more papers by this authorZ. Liu
Department of Ophthalmology, Peking University Third Hospital, Beijing, China
These authors contributed equally.Contribution: Data curation (equal), Investigation (lead), Project administration (lead), Supervision (lead)
Search for more papers by this authorY. Zhang
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
Contribution: Conceptualization (equal), Investigation (equal), Supervision (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorH. Wang
Department of Ophthalmology, Peking University Third Hospital, Beijing, China
Contribution: Investigation (equal), Methodology (equal)
Search for more papers by this authorX. Liu
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
Contribution: Investigation (equal), Writing - original draft (equal), Writing - review & editing (equal)
Search for more papers by this authorS. Zhang
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
Contribution: Data curation (equal), Investigation (equal)
Search for more papers by this authorX. Liu
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
These authors contributed equally.Contribution: Conceptualization (lead), Formal analysis (lead), Investigation (supporting), Project administration (lead), Resources (lead), Supervision (lead), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
D. Fan
Department of Neurology, Peking University Third Hospital, Beijing, China
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
These authors contributed equally.Correspondence: D. Fan, Department of Neurology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China (tel.: (+86)13701023871; fax: 86-010-82266250; e-mail: [email protected]).
Contribution: Conceptualization (lead), Data curation (lead), Funding acquisition (lead), Investigation (lead), Methodology (lead), Project administration (lead), Resources (lead), Supervision (lead), Validation (lead), Writing - original draft (equal), Writing - review & editing (lead)
Search for more papers by this authorAbstract
Background and purpose
Small-fiber nerves are the first to be involved in transthyretin familial amyloid polyneuropathy (TTR-FAP) patients. In vivo corneal confocal microscopy (CCM) is a noninvasive technique to detect small-fiber polyneuropathy (SFN) by quantifying corneal nerve morphology. The characteristic whorl-like pattern of the corneal nerve provides a static landmark for observation. We aimed to evaluate whether CCM images of the whorl-like plexus can sensitively evaluate and monitor disease progression in FAP patients.
Methods
Fifteen FAP patients and 15 controls underwent neurological evaluation and CCM observation. Corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) detected by conventional method and inferior whorl length (IWL), inferior whorl fiber density (IWFD), and inferior whorl branch density (IWBD) were compared in controls and patients. The Langerhans cell (LC) density in each image was calculated.
Results
All CCM parameters were significantly reduced with disease progression. Preclinical patients had significantly lower IWL (P = 0.008) than age-matched controls. IWL (P = 0.006), CNFL (P = 0.005), CNBD (P = 0.008), and CNFD (P = 0.014) were significantly lower in early-phase patients. LC density was significantly increased around the central whorl in early-phase patients and was relatively lower in progressive patients. Both IWL and CNFL correlated with the severity of neuropathy, and IWL was more significantly reduced. The area under the receiver operating characteristic (ROC) curve for FAP with CNFL and IWL was 88.0% (95% CI, 70.9%–96.9%) and 89.3% (95% CI, 72.6%–97.6%), respectively, exceeding other parameters.
Conclusions
IWL is a more sensitive surrogate to detect preclinical SFN in FAP and can best discriminate patients from controls. The clustering of immature LCs at the inferior whorl area might reflect the inflammatory response of small-fiber nerves at the early stage.
Disclosure of conflicts of interest
The authors report no competing interests.
Open Research
Data Availability Statement
Data that support the findings of this study are available upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ene14563-sup-0001-AppS1.docxWord document, 672.7 KB |
Tab S1. Clinical characteristics of patients. Tab S2. Electrophysiology results and grouped comparison. Fig S1. Group comparison of large nerve functions. The upper and lower limb conduction velocities and compound muscle action potential (CMAP) amplitudes were significantly reduced in the progressive group compared with the early group. However, no significant difference was detected between healthy control and early-phase patients. In the early-phase group, the small-fiber nerve assessments showed no difference compared with the healthy controls. Fig S2. Patients without any abnormal results in sympathetic skin responses (SSRs) or contact heat evoked potentials (CHEPs) had a significantly lower inferior whorl length (IWL) than age-matched healthy controls. Fig S3. Receiver operating characteristic analysis showing the area under the curve for corneal nerve fiber length (CNFL) and inferior whorl length (IWL) in distinguishing people with familial amyloid polyneuropathy (FAP) from healthy controls. Fig S4. Paired comparison of the coefficients of variation (CVs). The CV of the inferior whorl length (IWL) value was significantly smaller than that of the conventional method. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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