The corneal nerves and ocular surface homeostasis
The corneal nerves play a vital but often overlooked role in maintaining ocular surface homeostasis. With over 7,000 nerve endings per square millimeter, the cornea is the most densely innervated structure in the body.1,2
The nerves perform several key functions including supplying sensation to the corneal surface and metabolic support to corneal epithelial cells.1-12 The nerves also act as an integral component of the trigeminal reflex arc responsible for blinking and tear production.1-3,5,6,9-12
The corneal nerves arise from the ophthalmic branch of the trigeminal nerve and provide sensory innervation to the corneal tissue.1,3,4
This sensory feedback is relayed to the brainstem and brain, which then sends signals to various ocular and periocular structures, including the orbicularis oculi and levator palpebrae muscles as well as the lacrimal gland to stimulate blinking and tearing, respectively.4,5,13
Additionally, the corneal nerves share a vital reciprocal relationship with corneal epithelial cells. The cornea is by necessity avascular to allow for optical transparency, and thus relies on the corneal nerves as one of its sources of nourishment.1,8
Consequently, because of this lack of direct blood supply, the nerves provide the epithelium with trophic factors that promote epithelial cell proliferation, maturation, and metabolism, which are critical to proper cellular maintenance and function in addition to normal cellular turnover and wound healing.1,2,6,7-9
In turn, the epithelial cells provide the nerves with neurotrophins, such as nerve growth factor (NGF), that support nerve maturation, maintenance, and repair.1,7
Corneal nerve damage and neurotrophic keratitis (NK)
Given all the vital functions of the corneal nerves, it comes as no surprise that damage to the nerves can lead to significant disruption of ocular surface homeostasis. One of the most significant conditions resulting from the disruption of corneal nerve function is neurotrophic keratitis.
Neurotrophic keratitis (NK) is a degenerative disease of the cornea that results from corneal nerve damage, leading to a loss of corneal sensation and a subsequent breakdown of the corneal tissue.2,6,8,10,14,15
NK affects an estimated 65,000 to 70,000 people in the US, and though traditionally considered a rare disease, is now believed to be more common than previously thought.10,16
NK can result from damage to the corneal nerves directly or at any point along the trigeminal sensory pathway from which the corneal nerves arise.2,10 Therefore, NK can be caused by numerous infectious, systemic, surgical, and genetic etiologies.
Some specific causes include:
- Herpetic infection17-20
- Refractive surgery (e.g., laser-assisted in situ keratomileusis [LASIK])21-24
- Panretinal photocoagulation (PRP)25-27
- Retinal detachment repair28-30
- Cataract surgery9
- Contact lens wear—especially lens misuse31
- Medication-induced damage (i.e., medicamentosa), such as that observed in glaucoma patients, which is often due to chronic preservative exposure, typically benzalkonium chloride (BAK), from consistent, frequent dosing32,33
- Direct physical or chemical injury to the cornea2,9,10,34
Systemic diseases, such as diabetes and multiple sclerosis, can damage nerves, as can stroke and degenerative central nervous system (CNS) disorders like Alzheimer’s and Parkinson’s disease.35
Mechanical nerve damage can be caused by compressive lesions, including tumors (e.g., acoustic neuroma) and aneurysms,9,11,36-40 or be secondary to surgical trauma in cases of neoplasm removal or ablative procedures for trigeminal neuralgia.41
Additionally, there are numerous genetic and congenital conditions that can disrupt nerve function and cause NK, including:42-48
- Congenital corneal hypoesthesia
- Riley-Day syndrome
- Goldenhar-Gorlin syndrome
- Moebius syndrome
- Familial corneal hypoesthesia
- Congenital insensitivity to pain with anhidrosis
- Gómez-López-Hernández syndrome
Signs and symptoms of neurotrophic keratitis
With so many potential sources of nerve damage, it is crucial to properly recognize the clinical manifestations of NK. Unfortunately, many of these signs and symptoms, including dryness, photophobia, blurred vision, reduced blinking, and corneal surface disruption, are relatively nonspecific and therefore easily misattributed to more common ocular surface diseases like dry eye disease (DED).
This is especially true in the early stages of NK when the signs and symptoms are often subtle. To further compound this diagnostic dilemma, many patients with NK present with other ocular surface conditions as contributory or comorbid conditions, which can make delineating the diseases somewhat challenging.
Fortunately, the hallmark sign of NK is reduced or absent corneal sensation, which sets the condition apart from otherwise similarly-presenting ocular surface diseases and facilitates diagnosis.2,6,8-11,35,49 The signs and clinical manifestations of NK are directly related to the results of disrupted nerve function. Patients with NK will experience reduced blinking and tear production secondary to disrupted corneal sensation, as there is a loss or reduction of sensory input to the trigeminal reflex arc.6,9-12
They will also display reduced routine epithelial cell turnover and impaired corneal wound healing owing to disrupted trophic support from the nerves.2,6,8-11,35 If left untreated, these disruptions will ultimately lead to a loss of ocular surface and corneal integrity resulting in a spontaneous breakdown of the corneal surface.2,6,8,15
The Mackie classification system for NK
The progression and severity of NK has classically been divided into three stages using the Mackie classification system.2,6,9-11,15,50,51
Stage 1
Early NK is often subtle and marked by epithelial changes and corneal irregularity, including a dull or cloudy appearance and punctate keratitis, signaling the initial breakdown of the corneal surface.
If the condition becomes chronic, neovascularization and stromal scarring can occur. Additionally, the tear film may display decreased stability and increased viscosity. Patients at this stage may also complain of general irritation and dryness as well as blurred vision.
Stage 2
Moderate NK is characterized by nonhealing corneal lesions referred to as persistent epithelial defects (PEDs). These PEDs typically have a round or oval shape with smooth, rolled edges consisting of opaque, edematous epithelium.
At this stage, Descemet’s folds can occur due to corneal edema, and in rare cases, a sterile anterior chamber reaction with hypopyon may develop.
Stage 3
In severe or advanced NK, the breakdown of the corneal surface progresses to ulceration with stromal involvement. Patients at this stage are at risk for corneal melting and perforation. These ulcers will also have smooth, rolled edges characteristic of NK.
It is important to note there is often a disconnect between the severity of corneal disruption and the patient’s reported symptoms. Because patients with NK have reduced or absent corneal sensation, they may not feel the breakdown of the corneal surface, even in cases of significant PEDs or ulcers.
This phenomenon has given rise to the “stain without pain” descriptor commonly used in reference to NK, which refers to the staining of corneal surface disruptions with vital dyes but with little or no associated discomfort. In the same vein, all stages of NK from mild to severe will have one thing in common—reduced or absent corneal sensitivity.2,6,8,9-11,15,35,49
Detection and diagnosis – corneal sensitivity testing
Therefore, corneal sensitivity testing is crucial to diagnosing NK, since a reduction or absence of corneal sensation is pathognomonic for the disease.2,6,8,9,11,35,49 Although assessing corneal sensation is necessary to make the diagnosis of NK, there are several ways sensitivity can be evaluated.
The importance of corneal innervation in maintaining ocular surface health has long been recognized, as the first device for assessing corneal sensation, referred to as an aesthesiometer or esthesiometer, was created by von Frey around 1894, using horse hairs of various lengths to measure corneal sensitivity.52
This design was refined by Franceschetti in 1932 but was later replaced by a new device developed by Boberg-Ans that utilized a nylon filament rather than horse hair to measure sensation, ultimately giving rise to the modern Cochet-Bonnet aesthesiometer used today.52,53
Figure 1 is an image of a Cochet-Bonnet aesthesiometer.
Figure 1: Spadea et al.
Devices for measuring corneal sensitivity
The Cochet-Bonnet aesthesiometer can be used to quantitatively assess corneal sensitivity by placing a filament against the corneal surface. The filament is then retracted, thereby stiffening it, until the pressure is sensed by the patient. The filament length at which the sensation is first felt will then be displayed on the instrument, providing a numeric value of the patient’s sensitivity.2,8,54
There are also devices that employ noninvasive techniques to assess corneal sensitivity, such as the Belmonte noncontact gas esthesiometer, which uses a gas jet with varied flow, temperature, and CO2 concentrations to assess mechanical, thermal, and chemical sensation of the mechanoreceptors, thermoreceptors, and polymodal receptors present at the corneal nerve endings.55-59
Another device available specifically for assessing corneal sensitivity is the Brill Engines corneal esthesiometer, which is a portable, handheld noncontact aesthesiometer that uses pulses of air at varying intensities to measure sensation.60
Other methods of evaluating corneal sensitivity include the use of a CO2 laser aesthesiometer, warmed saline, hyperosmolar eye drops, and capsaicin to assess the corneal nerves’ response to heat and chemical stimulation.59,61-64
Although these dedicated aesthesiometers are excellent tools that allow for precise measurements of corneal sensitivity, they are often not readily available in most clinics. Additionally, although chemical testing with substances such as capsaicin can provide useful data, it can be irritating for the patient and may be impractical in day-to-day practice.
Fortunately, qualitative assessment of corneal sensitivity can be effectively performed with several common items found in nearly any eyecare clinic including a cotton-wisp teased crisply at the end of a cotton-tipped applicator, the edge of a tissue, or the tip of a piece of dental floss.2,8,65
The S.I.G.N. method for assessing corneal sensitivity
When using any of these tools, corneal sensitivity can be tested using the S.I.G.N. method.35,66 This begins with (S)etting a baseline of normal sensitivity by testing the patient’s healthy eye first in order to observe a normal response.
It is also recommended to practice prior corneal sensitivity testing on healthy patients to “calibrate” the eyecare provider’s (ECP’s) technique and establish what would be considered a “normal” response to sensitivity testing in general, as an ECP may encounter patients with bilateral NK in which case there is no “normal” eye to act as a standard for comparison.
Next, (I)nvestigate the eye that is suspected to have nerve damage by (G)ently touching the testing implement to either the central cornea to start or at an area of visible damage. Then (N)ote the patient’s reaction to the tool touching their cornea.
In patients with normal corneal sensation, they typically reflexively blink, flinch, or even recoil when the testing tool is touched to their corneal surface. If the patient has abnormal sensation, they may report barely feeling the touch of the instrument, or they may not feel anything at all. Sensitivity is then typically assessed qualitatively and recorded as being normal, reduced, or absent.
How to perform comprehensive corneal sensitivity testing
When performing corneal sensitivity testing it is considered best practice to assess sensation in the four primary quadrants of the cornea, and also centrally. By testing all five of these regions, ECPs will have performed a complete assessment of corneal innervation.
This is critical because corneal nerve damage can be localized to one region of the cornea, which may be missed if only the central region is tested.35 For instance, a patient may have reduced corneal sensation that is localized to the superior quadrant whereas the other four regions have normal sensitivity.
If an ECP were to only test the central region in this scenario, they could mistakenly report the patient as having normal sensitivity since they performed an incomplete assessment of corneal sensation and the diagnosis of NK would consequently be missed.
Detecting neurotrophic keratitis early with corneal sensitivity testing
Complete testing takes on increased importance when detecting early disease. Patients in the nascent stages will often still report some level of discomfort or irritation, which can mislead many ECPs into prematurely dismissing NK as a potential cause of the patient’s condition due to the presence of discomfort, which seemingly contradicts the aforementioned “stain without pain” description. However, this description is not axiomatic nor is it required criteria to diagnose NK.2,8,10,35
Take, for example, a patient with diffuse punctate keratitis. In this scenario, the patient could have decreased and/or absent sensation in three of the five regions of their cornea but still experience pain in the two functional ones, thus defying the “stain without pain” description even though they have NK by definition.
Therefore, the definitive diagnosis of NK is made by the finding of reduced or absent corneal sensitivity, even if the patient is experiencing irritation or the diminished sensation is isolated to one area. For this reason, a complete assessment of corneal sensation in all four quadrants and centrally is considered best practice in corneal sensitivity testing.
Additionally, it is recommended to consider testing corneal sensitivity in all ocular surface disease patients, especially if they have a history of a condition that may predispose them to corneal nerve damage, such as herpetic infection, diabetes, or refractive surgery.
Likewise, if an alteration in corneal sensation is found upon corneal sensitivity testing, a thorough patient history is necessary to determine the underlying cause of the nerve damage.2,6,8,9-11,35,49
Takeaways
Corneal innervation is vital to proper ocular surface homeostasis. Therefore, damage to the corneal nerves can profoundly disrupt ocular surface function, as is the case in NK in which a loss of corneal sensation can ultimately lead to a breakdown of the corneal surface in the form of vision-threatening ulcers, scarring, or even eye-threatening corneal perforation.
In its earliest stages, the signs and symptoms of NK are often subtle and nonspecific, and can be misattributed to other more common conditions such as DED. Fortunately, NK can be easily and quickly diagnosed by testing corneal sensitivity with commonly available items such as a cotton wisp.
If a patient is found to have reduced or absent sensation, there are many potential treatment options available, ranging from lubricating drops to prescription medications and surgical interventions.
However, successful management and prevention of NK progression requires recognizing and diagnosing the condition at the earliest stage possible, which all starts with corneal sensitivity testing.
