About Neurotrophic Keratitis

Neurotrophic keratitis is a degenerative corneal disease caused by impairment of trigeminal innervation1

Watch the video to hear from Dr. Francis Mah about how he performs corneal sensitivity testing.

Corneal denervation is central to neurotrophic keratitis; it impacts corneal homeostasis and can lead to epithelial breakdown, including ulceration, melting, and perforation. Critical to corneal homeostasis is the interplay between corneal nerves and corneal epithelial cells mediated through the production of trophic factors, such as neuromediators and nerve growth factor.1,3

Patient presentation and signs

People with neurotrophic keratitis may be asymptomatic due to decreased corneal sensation and present with the following signs1,4:

Conditions that may cause neurotrophic keratitis1,4

A number of conditions and procedures can lead to impairment of corneal innervation and should prompt suspicion of NK. Common conditions and procedures that can lead to impairment of corneal innervation may include:

Ocular conditions
  • Infections, e.g., post herpes
  • Surgery, e.g., post laser correction
    surgery
  • Contact lens use
Systemic conditions
  • Diabetes
  • Multiple Sclerosis
Central nervous system conditions
  • Post neurosurgical procedures
  • Stroke
Genetic conditions
  • Riley-Day syndrome

NK could be present in patients with one or more of these conditions and/or procedures in their medical history.5

When NK is suspected, confirm with corneal sensitivity testing3

Qualitative (e.g., cotton swab) or quantitative (e.g., Cochet-Bonnet) testing should be considered as part of a broader diagnostic workup including medical history, microbiological exam, fluorescein staining, and evaluation for systemic conditions.1

Chronic comorbidities such as dry eye disease can confound NK diagnosis, strongly suggesting the need for confirmation via corneal sensitivity testing.1,4

Early treatment is imperative to prevent further epithelial damage and potential vision loss1,2,5

NK is a progressive condition with 3 stages of increasing severity (based on the Mackie classification):4,5

About NK Stages Desktop About NK Stages Mobile

NK can present at any stage, and treatment is warranted immediately upon NK diagnosis to prevent disease progression.

Connect with us to access resources and learn more about neurotrophic keratitis

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    Important Safety Information

    Contact lenses should be removed before applying OXERVATE because the presence of a contact lens (either therapeutic or corrective) could theoretically limit the distribution of cenegermin-bkbj onto the area of the corneal lesion. Lenses may be reinserted 15 minutes after administration.

    OXERVATE may cause mild to moderate eye discomfort such as eye pain during treatment. The patient should be advised to contact their doctor if a more serious eye reaction occurs.

    The most common adverse reaction in clinical trials that occurred more frequently with OXERVATE was eye pain (16% of patients). Adverse reactions included corneal deposits, foreign body sensation in the eye, ocular hyperemia (enlarged blood vessels in the white of the eye), swelling (inflammation) of the eye, and increase of tears (1-10% of patients).

    INDICATION
    OXERVATE (cenegermin-bkbj) ophthalmic solution 0.002% is indicated for the treatment of neurotrophic keratitis.

    DOSAGE FORMS AND STRENGTHS
    Ophthalmic solution for topical use in the eye: cenegermin-bkbj 0.002% (20 mcg/mL) is a clear, colorless solution in a multiple-dose vial.

    CONTRAINDICATIONS
    None.

    WARNINGS AND PRECAUTIONS
    Use With Contact Lenses
    Contact lenses should be removed before applying OXERVATE because the presence of a contact lens (either therapeutic or corrective) could theoretically limit the distribution of cenegermin-bkbj onto the area of the corneal lesion. Lenses may be reinserted 15 minutes after administration.

    Eye Discomfort
    OXERVATE may cause mild to moderate eye discomfort such as eye pain during treatment. The patient should be advised to contact their doctor if a more serious eye reaction occurs.

    ADVERSE REACTIONS
    Clinical Studies Experience
    Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be compared directly to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

    In 2 clinical trials of patients with neurotrophic keratitis, a total of 101 patients received cenegermin-bkbj eye drops at 20 mcg/mL at a frequency of 6 times daily in the affected eye(s) for a duration of 8 weeks. The mean age of the population was 61 to 65 years of age (18 to 95).

    The most common adverse reaction in clinical trials that occurred more frequently with OXERVATE was eye pain (16% of patients). Other adverse reactions included corneal deposits, foreign body sensation in the eye, ocular hyperemia (enlarged blood vessels in the white of the eye), swelling (inflammation) of the eye, and increase in tears (1%-10% of patients).

    USE IN SPECIFIC POPULATIONS
    Pregnancy
    Risk Summary
    There are no data from the use of OXERVATE in pregnant women to inform any drug-associated risks.

    Administration of cenegermin-bkbj to pregnant rats or rabbits during the period of organogenesis did not produce adverse fetal effects at clinically relevant doses. In a pre- and postnatal development study, administration of cenegermin-bkbj to pregnant rats throughout gestation and lactation did not produce adverse effects in offspring at clinically relevant doses.

    Data
    Animal Data
    In embryofetal development studies, daily subcutaneous administration of cenegermin-bkbj to pregnant rats and rabbits throughout the period of organogenesis produced a slight increase in postimplantation loss at doses greater than or equal to 42 mcg/kg/day (267 times the maximum recommended human ophthalmic dose [MRHOD]). A no-observed-adverse-effect level (NOAEL) was not established for postimplantation loss in either species. In rats, hydrocephaly and ureter anomalies were observed once each in fetuses at 267 mcg/kg/day (1709 times the MRHOD). In rabbits, cardiovascular malformations, including ventricular and atrial septal defects, enlarged heart, and aortic arch dilation, were observed once each in fetuses at 83 mcg/kg/day (534 times the MRHOD). No fetal malformations were observed in rats and rabbits at doses of 133 mcg/kg/day and 42 mcg/kg/day, respectively.

    In a pre- and postnatal development study, daily subcutaneous administration of cenegermin-bkbj to pregnant rats during the period of organogenesis and lactation did not affect parturition and was not associated with adverse toxicity in offspring at doses up to 267 mcg/kg/day.

    In parental rats and rabbits, an immunogenic response to cenegermin-bkbj was observed. Given that cenegermin-bkbj is a heterologous protein in animals, this response may not be relevant to humans.

    Lactation
    Risk Summary
    There are no data on the presence of OXERVATE in human milk, the effects on breastfed infants, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OXERVATE and with any potential adverse effects on the breastfed infant.

    Pediatric Use
    The safety and effectiveness of OXERVATE have been established in the pediatric population. Use of OXERVATE in pediatric patients 2 years of age and older is supported by evidence from adequate and well-controlled trials of OXERVATE in adults with additional safety data in children.

    Geriatric Use
    Of the total number of subjects in clinical studies of OXERVATE, 43.5% were 65 years old and older. No overall differences in safety or effectiveness were observed between elderly and younger adult patients.

    The FDA-approved product labeling can be found here. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Dompé at 1-833-366-7387 or Usmedinfo@dompe.com.

    References

    1. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalm. 2014 Mar;8:571-579.
    2. Bonini S, Lambiase A, Rama P, Sinigaglia F, Allegretti M, Chao W, Mantelli F, for the REPARO Study Group. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology. 2018 Sep;125(9):1332-1343.
    3. Mastropasqua L, Massaro-Giordano G, Nubile M, Sachetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J. Cell Physiol. 2017 Apr;232;(4):717-724.
    4. Dua HS, Said DG, Messmer EM, et al. Neurotrophic keratopathy. Prog Retin Eye Res. 2018;66:107-131.
    5. Versura P, Giannaccare G, Pellegrini M, et al. Neurotrophic keratitis: current challenges and future prospects. Eye Brain. 2018 Jun 28;10:37-45.

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