Degeneration and Regeneration of Subbasal Corneal Nerves after Infectious Keratitis: A Longitudinal In Vivo Confocal Microscopy Study

Ophthalmology. 2015 Nov;122(11):2200-9. doi: 10.1016/j.ophtha.2015.06.047. Epub 2015 Aug 6.


Purpose: To investigate the longitudinal alterations of subbasal corneal nerves in patients with infectious keratitis (IK) during the acute phase, cessation of treatment, and the recovery phase by in vivo confocal microscopy (IVCM).

Design: Prospective, longitudinal, case-control, single-center study.

Participants: Fifty-six eyes of 56 patients with the diagnosis of bacterial (n=28), fungal (n=15), or Acanthamoeba (n=13) keratitis were included in the study. Thirty eyes of 30 normal volunteers constituted the control group.

Methods: Corneal sensation and serial IVCM of the central cornea were performed prospectively using the Heidelberg Retina Tomograph 3/Rostock Cornea Module (Heidelberg Engineering, Heidelberg, Germany). The IVCM images were assessed at 3 time points: at the acute phase (first visit to the cornea service), at cessation of antimicrobial treatment, and up to 6 months after the resolution of infection.

Main outcome measures: Total nerve number and length, main nerve trunks, branching, and corneal sensation were assessed during the follow-up period.

Results: Corneal nerves were reduced significantly during the acute phase in eyes with IK compared with controls across all subgroups, with total nerve length of 5.47±0.69 mm/mm2 versus 20.59±1.06 mm/mm2 (P<0.0001). At the cessation of treatment, corneal nerves in patients with IK had regenerated, including total nerve length (8.49±0.94 mm/mm2; P=0.02) and nerve branch length (4.80±0.37 mm/mm2; P=0.005). During the recovery phase, after resolution of infection, corneal nerves regenerated further, including total nerve length (12.13±1.97 mm/mm2; P=0.005), main nerve trunk length (5.80±1.00 mm/mm2; P=0.01), and nerve branch length (6.33±0.76 mm/mm2; P=0.003) as compared with the acute phase, but were still significantly lower when compared with controls (P<0.05 for all parameters). Corneal degeneration and regeneration correlated with corneal sensation (r=0.47; P=0.0009).

Conclusions: Patients with IK who sustain profound loss of corneal nerves during the acute phase of infection demonstrate increased corneal nerve density during the first 6 months after the resolution of infection. However, despite significant nerve regeneration, corneal nerve density does not recover fully and remains low compared to controls. By providing an objective methodology to monitor corneal re-innervation, IVCM adds potentially important findings that may have implications for clinical management and surgical planning.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Bacterial Agents / therapeutic use
  • Antiprotozoal Agents / therapeutic use
  • Case-Control Studies
  • Cornea / innervation*
  • Corneal Ulcer / drug therapy
  • Corneal Ulcer / microbiology
  • Corneal Ulcer / parasitology
  • Corneal Ulcer / pathology*
  • Eye Infections / drug therapy
  • Eye Infections / microbiology
  • Eye Infections / parasitology
  • Eye Infections / pathology*
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Nerve Degeneration / pathology*
  • Nerve Regeneration / physiology*
  • Prospective Studies
  • Single-Blind Method
  • Trigeminal Nerve Diseases / pathology*
  • Trigeminal Nerve* / pathology
  • Trigeminal Nerve* / physiology


  • Anti-Bacterial Agents
  • Antiprotozoal Agents