Background & Aims

Concussions, or mild traumatic brain injuries (mTBI) are one of the most prevalent neurologic conditions, and are highly comorbid with pain and light sensitivity (1). A large portion of mTBI patients experience ocular symptoms or visual disturbance, with light sensitivity presenting in many cases (2, 3). Altered corneal nerve morphology and density have been widely reported in studies using In Vivo Confocal Microscopy (IVCM) assessment in migraine and dry eye disease patients (4, 5), and these patients often experience photophobia (6). Photophobia in these conditions may share etiology with mTBI, including dysfunction along the trigeminothalamic pathway, especially in the terminal portions of the ophthalmic branch of the trigeminal nerve innervating the cornea (6). This study sought to use IVCM to assess potential changes in the corneal subbasal nerve plexus in patients with mTBI, and to define the relationship between corneal nerves and patient clinical symptoms.

Methods

In Vivo Confocal Microscopy was performed using a Heidelberg Retina Tomograph 3 and Rostock Cornea Module. Three quality, non-overlapping, images were selected from each eye. The selected nerve images were analyzed using ACCMetrics, an automated analysis software designed for use with IVCM images. The software outputs include corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), corneal nerve total branch density (CTBD), corneal nerve fiber area (CNFA), corneal nerve fiber width (CNFW), and corneal nerve fractal dimension (CNFrD).

Study participants completed 4 clinical surveys: the Ocular Pain Assessment Survey (OPAS), the Ocular Surface Disease Index (OSDI), the Post-Concussion Symptom Scale (PCSS), and a headache and concussion history survey.

Results

32 mTBI patients (18F:14M, 22±1.2 yrs) and 36 controls (20F:16M, 22±1.1 yrs) were recruited.

IVCM analysis revealed significant reductions in nerve metrics between mTBI patients and controls in CNFD (24.0±1.19 vs 27.9±0.81 n/mm2; p=0.006) CNFL (14.3±0.54 vs 16.0±0.41 mm/mm2; p=0.018), and CNFrD (1.47±0.0056 vs 1.49±0.0032; p=0.005). Surveys revealed significant differences between cohorts in eye pain (Scale 0-10: 2.31±0.39 vs 0; p<0.001), light sensitivity (% of time experienced: 46.1±6.3 vs 4.57±3.2; p<0.001), PCSS (36.5±3.4 vs 1.63±0.47; p<0.001), and OSDI (10.9±1.3 vs 1.63±0.47; p<0.001). mTBI patients were then divided into 3 groups based on time post-injury: acute <3 wks; recovery 3 wks-6 mo; chronic >6 mo. Patients in the recovery group had reduced CNFD (21.7±2.0 vs 27.4±0.81 nerves/mm2; p=0.005), CNFL (13.3±0.91 vs 16.0±0.41 mm/mm2; p=0.014), and CNFrD (1.46±0.010 vs 1.49±0.0032; p=0.010). The acute and chronic group IVCM data did not differ significantly from controls.

Conclusions

mTBI patients had altered corneal subbasal nerve morphology in density of main nerve trunks (CNFD), corneal nerve fiber length (CNFL), and nerve complexity, (Fractal Dimension), when compared to healthy controls. While other nerve metrics fell short of significance, CNFD and CNFL are considered the most robust measures(7). These findings highlight a correlation between corneal nerve measures and multiple post-concussive symptoms.

References

1.Polinder S, Cnossen MC, Real RG, Covic A, Gorbunova A, Voormolen DC, et al. A multidimensional approach to post-concussion symptoms in mild traumatic brain injury. Frontiers in neurology. 2018;9:1113.
2.Katz BJ, Digre KB. Diagnosis, pathophysiology, and treatment of photophobia. Survey of Ophthalmology. 2016;61(4):466-77.
3.Armstrong RA. Visual problems associated with traumatic brain injury. Clinical and Experimental Optometry. 2018;101(6):716-26.
4.Alhatem A, Cavalcanti B, Hamrah P, editors. In vivo confocal microscopy in dry eye disease and related conditions. Seminars in ophthalmology; 2012: Taylor & Francis.
5.Kinard KI, Smith AG, Singleton JR, Lessard MK, Katz BJ, Warner JE, et al. Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye. Headache: The Journal of Head and Face Pain. 2015;55(4):543-9.
6.Diel RJ, Mehra D, Kardon R, Buse DC, Moulton E, Galor A. Photophobia: shared pathophysiology underlying dry eye disease, migraine and traumatic brain injury leading to central neuroplasticity of the trigeminothalamic pathway. Br J Ophthalmol. 2021;105(6):751-60.
7.Zhang Y, Wu Y, Li W, Huang X. Semiautomated and Automated Quantitative Analysis of Corneal Sub-Basal Nerves in Patients With DED With Ocular Pain Using IVCM. Front Med (Lausanne). 2022;9:831307.

Presenting Author

Nicholas J. Pondelis

Poster Authors

Nicholas Pondelis

OTHR

Boston Children's Hospital

Lead Author

Alpen Ortug

PhD

Boston Children's Hospital

Lead Author

Cameron Talbert

BA

Boston Children's Hospital

Lead Author

Robert C. Cantu

MD

Emerson Hospital

Lead Author

Eric Moulton

Boston Children's Hospital, Harvard Medical School

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Ocular Pain