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Seminars in Ophthalmology, 2016; 31(1–2): 59–70

! Taylor & Francis


ISSN: 0882-0538 print / 1744-5205 online
DOI: 10.3109/08820538.2015.1114853

REVIEW

Understanding Neuropathic Corneal Pain—Gaps and


Current Therapeutic Approaches
Sunali Goyal1 and Pedram Hamrah1,2,3,4

1
Cornea & Refractive Surgery Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard
Medical School, Boston, Massachusetts, USA, 2Ocular Surface Imaging Center, Massachusetts Eye and Ear Infirmary,
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA, 3Boston Image Reading Center
& Cornea Service, New England Eye Center, Boston, Massachusetts, USA, and 4Department of Ophthalmology, Tufts
Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA

ABSTRACT
The richly innervated corneal tissue is one of the most powerful pain generators in the body. Corneal neuropathic
pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache, and pain. Various
inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal
neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology
and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic
state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain,
describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience
with current therapeutic approaches for the treatment of corneal neuropathic pain.
Keywords: Autologous serum drops, corneal neural anatomy, corneal pain, dry eye, in vivo confocal
microscopy, neuropathic pain

INTRODUCTION repeatedly dismissed by their ophthalmologists.


Nevertheless, scientists have in recent years made
Corneal neuropathic disease, corneal neuropathy, significant advances and elucidated the pathophysi-
corneal neuralgia, or keratoneuralgia are the same ology and neurobiology of pain resulting from ini-
terms for a new and ill-defined disease entity in the tially protective physiological reflexes, to a more
field of ophthalmology.1 It has recently generated persistent chronic state. The goals of this clinical
significant interest among both clinicians and scien- review are to briefly summarize the pathophysiology
tists due to increasing awareness, and patients of neuropathic corneal pain, create confidence in
surfacing with unexplained ocular surface pain and identifying patients with neuropathic pain, and finally
symptoms.2,3 While the exact epidemiology of this summarize our experience with current therapeutic
disease remains to be elucidated, an increased approaches for clinicians to better serve and success-
number of patients present with vague perceptions fully treat these unfortunate patients.
of burning, stinging, eye-ache, photophobia (photo-
allodynia),2,4 or severe eye pain, without significant
findings on slit-lamp examination. Currently, the field NEURAL BASIS OF PHYSIOLOGICAL
of ophthalmology relies on slit-lamp examination to OCULAR SURFACE PAIN
assess signs of corneal and ocular surface diseases.
Unfortunately, with neuropathic pain, none to min- Innervation of the Ocular Surface
imal signs can be observed on slit-lamp examination
in patients who either have been given the rather The human cornea is the most richly innervated tissue
broad diagnosis of dry eye disease, or have been in the body.5 Corneal nerves provide an important

Accepted 2 April 2015; published online 1 March 2016


Correspondence: Pedram Hamrah, MD, FACS, Cornea Service, New England Eye Center, Tufts Medical Center, Tufts University School of
Medicine, 800 Washington St, Boston, MA 02111, USA. E-mail: phamrah@tuftsmedicalcenter.org; p_hamrah@yahoo.com
Color versions of one or more figures in the article can be found online at www.tandfonline.com/isio.

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60 S. Goyal and P. Hamrah

sensory role by relaying touch, chemical, pain, and bodies of these sensory neurons are located in either
temperature signals to the brain. In addition, they the dorsal root ganglia or the trigeminal ganglia.
induce reflex tear production, induce blinking, and Sensory receptors are grouped into major categories of
release trophic factors, which help maintain the chemoreceptors (for olfaction), photoreceptors (for
important structural and functional integrity of the vision), mechanoreceptors, thermoreceptors, and
ocular surface.6–9 The blinking and tearing reflex arch polymodal receptors. Some others may be silent or
is dexterously regulated by the interplay among the sleeping. Of these, mechanoreceptors perceive pres-
ocular surface, intact corneal innervation, intercon- sure and distortion and thermoreceptors respond to
necting nerves, and the lacrimal gland.10 Any com- varying temperatures. Nociceptors are receptors,
promise in these may result in ocular surface damage which result in the perception of pain. Nociceptors
and disease. are mainly categorized by the various environmental
The cornea is also the most powerful pain gener- stimuli they respond to, which can be mechanical,
ator in the body. The estimated central corneal nerve thermal, or chemical in nature.24 Those nociceptors
density in humans approximates 7000 nerve terminals that can react to more than one of these modalities are
per square millimeter, and this progressively labeled as polymodal. Polymodal receptors are acti-
decreases peripherally.9,11 The presence of the densely vated by near noxious or noxious mechanical, thermal,
innervated nonkeratinized corneal epithelium then and a large variety of endogenous chemical stimuli.
allows for the detection of minute magnitude noci- Many chemical agents such as prostaglandins, brady-
ceptive insults of unparalleled sensitivity, in order to kinins, capsaicin, and acidic environment can excite
generate defense reflexes, crucial for protection of the polymodal nociceptors to evoke impulse discharges
ocular surface. Immuno-histochemical staining tech- in tissues, including the cornea.25 Further, tissue injury
niques using both light and electron microscopy have and inflammation can cause these polymodal recep-
yielded important information about detailed models tors to fire irregularly at lower thresholds.
of the normal human corneal innervation.9 However, These receptors are connected centrally to higher
studies using these techniques may be unreliable, as order pain pathways, and sensitization to these
nerves degenerate within hours of death.12 Other results in allodynia (pain due to innocuous stimuli),
methods including slit-lamp bio-microscopy, light and hyperalgesia (enhanced pain perception), and spon-
electron microscopy, and in more recent years in vivo taneous pain.25,26 The stimuli received by the receptors
confocal microscopy have helped us to better under- are detected and then converted to electrical energy
stand the anatomy and distribution of human corneal that when reaching a threshold value generates an
nerves in health and disease.12–17 action potential, which is carried along one or more
Corneal sensory nerves originate from the afferent neurons to the sensory cortex of the brain.
ophthalmic division of the trigeminal nerve.18 These
travel first in the nasociliary branch, and branch into
the two long ciliary nerves, before they ultimately rest Nociceptive Stimulus Transduction and
at equidistant intervals around the limbus. These then Somatosensory Representation
enter the cornea as radially directed mid-stromal
nerves.14,19–21 While some nerves then terminate as Nociceptors are free nerve endings that respond to
free nerve endings, others form anatomical relation- noxious stimuli. Nociceptors are found in the skin,
ships with stromal keratocytes,14 and various bone organ of motion (periosteum, joint capsule, ligaments,
marrow-derived cells, and finally many nerves pene- muscles), cornea, and dental pulp. The perception
trate the Bowman’s layer to rest under the basal of pain begins when nociceptors detect noxious
epithelial layer to form the subbasal nerve plexus. stimuli and via the activation of ion channels trans-
Nerves of the subbasal plexus then give rise to duce the stimulus into electrical energy, inducing
superficial intra-epithelial terminals.14 Intra-epithelial action potentials that find their way to the somatosen-
fibers terminate as bulbous free nerve endings that sory cortex and the paralimbic structures, where
contain nociceptors.22 Of note, 70–80% of these nerve different aspects of pain are deciphered.9,25 From
fibers are unmyelinated C fibers, while the rest are the thalamus, where perception of pain sensation
mainly A-d fibers.23 originates, pain then continues its path to the limbic
system and the cerebral cortex, where emotional and
additional facets of pain are perceived and interpreted.
The Sensory Nervous System There are two different types of nociceptor axons—
myelinated Ad fibers with an action potential travel
The sensory nervous system consists of sensory rate of about 20 meters/second, and the more slowly
receptors, neural pathways, and parts of the brain conducting unmyelinated C fiber axons that have a
involved in sensory perception. Sensory neurons speed of around 2 meters/second.26 As a result, pain
transmit sensory information from the peripheral has an early phase facilitated by the rapidly-conduct-
surroundings to the brain and spinal cord.22 The cell ing Ad fibers that can be tremendously sharp and a
Seminars in Ophthalmology
Corneal Neuropathy 61

later segment carried out by the polymodal C fibers by a lesion or disease of the somatosensory system.’’37
that is more prolonged and slightly less intense. Long-term deregulation in the peripheral nociceptive
Continued input to a C fiber can cause excessive input can cause malfunctioning of the pain signaling
accumulation of action potentials in the spinal cord pathway, whereby central sensitization can become
dorsal horn, thereby resulting in increased sensitivity more autonomous. This is the basis of neuropathic
to pain.27 pain, which differs from chronic pain in having an
enduring underlying pathology. Damaged neurons
and central connections of A-d and C fibers are the
Peripheral and Central Sensitization underlying designators for neuropathic pain. Injured
neurons may develop micro-neuromata at proximal
Sensory neurons are important for the reception, ends, swelling (endobulbs) at their terminals, and
transduction and integration of various stimuli. They sprouts (neuroma) manifesting regenerative attempts,
have the unique characteristic to exhibit plasticity in all of which become sources of ectopic spontaneous
the form of sensitization, desensitization, or memory.28 pain.38–41 This input is then processed in the central
Peripheral sensitization signifies a form of functional nervous system (CNS), resulting in the classic triad of
plasticity of nociceptors, resulting in change of noci- hyperalgesia, allodynia, and spontaneous pain char-
ceptors from detectors of noxious stimuli to sensors of acterizing neuropathic pain.42
non-noxious stimuli. Peripheral axonal injury can
result in release of various inflammatory mediators,
such as cytokines,29 prostaglandins,30 and substance Neuropathic Pain of the Cornea
P,31 which can then lower the threshold potentials
of ion channels of those specific nerves endings. These Similar to the pain system elsewhere in the body,
changes can then spread to adjacent nociceptors, corneal nerve endings have various receptors, which
thereby intensifying peripheral pain signaling. have the capability of encoding different mechanical,
Collectively, these changes provoke alterations in thermal, and chemical stimuli.43 Different types of
axonal cell bodies, whereby silent receptors become noxious stimuli activate various populations of sen-
activated and new genes are upregulated,32,33 thus sory fibers to different extent and subsequently illicit
lowering the threshold to peripheral stimuli, resulting different unpleasant sensations. Neuropathic eye pain
in peripheral sensitization. can be perceived as itch, irritation, dryness, grittiness,
Increased peripheral sensitization in turn leads to burning, aching, and light sensitivity, which are
increased central sensitization over time, when the integrated at higher brain centers and are patient
central neurons become highly responsive to similar specific.44,45 Hyperalgesia and allodynia draw a par-
magnitude of pain, eventually resulting in heightened allel in the cornea. Hyperalgesia can be perceived as
awareness of overall pain.34 Increased peripheral hypersensitivity to moving air, to minimal noxious
activity releases glutamate from presynaptic afferent stimuli, and to normal light (photoallodynia). Corneal
nerves, triggering sodium channels in the second- allodynia can be manifested as a burning sensation
order neurons located in the dorsal spinal cord.35 These generated by normal non-noxious stimuli, such as
glutamate receptors can be of two types: the AMPA wetting drops or even by the patient’s own tears.3
(a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Injured corneal nerves (accidental or surgical) have
acid) receptors responding only to weak signals, and the ability to form neuromas, and in an attempt to
NMDA (N-methyl-D-aspartic acid) receptors that heal, may result in abnormal activity and become the
respond to strong stimuli. NMDA receptors, when source of these unpleasant sensations. Paradoxically,
activated, can promote a response that can be intense their response to natural stimuli is diminished.46 This
and long lasting. Stronger nociceptor signals can also can be measured by esthesiometry, which demon-
activate and cause genotype switching of Ab fibers, strates low sensitivity in these denervated areas.
which normally carry sensations of touch.36 The result
is hyperalgesia, when low-power stimuli from regular
activity initiate a painful sensation that lasts longer. Causes of Corneal Neuropathic Pain
Repeated injury or genetic defects can cause allodynia,
where an innocent stimulus such as light touch can Various inflammatory diseases, neurological diseases,
cause extreme pain, or photoallodynia, where innocu- or surgical interventions can be the underlying cause
ous light stimuli are perceived as extreme pain. of corneal neuropathic pain (Table 1). Some of them
include refractive surgery,47 dry eye disease,48,49
Sjögren’s syndrome,50,51 neuralgia associated with
NEUROPATHIC PAIN herpes virus,52 benzalkonium chloride (BAK) pre-
served eye drops, accutane, chemotherapy, and radio-
The International Association for the Study of Pain therapy, to mention a few.3 Suboptimally managed
recently redefined neuropathic pain as ‘‘pain caused severe eye pain is detrimental to both vision related
! 2016 Taylor & Francis
62 S. Goyal and P. Hamrah

TABLE 1. Causes of neuropathic corneal pain. these needs, our group has recently designed and
1. Dry eye disease validated a hybrid eye pain questionnaire, the
2. Infectious keratitis Ocular Pain Assessment Survey (OPAS), that helps
3. Herpetic keratitis evaluate corneal and ocular surface pain and its
4. Recurrent erosions impact on QoL.60 The OPAS seems to have high
5. Postsurgical (cataracts, refractive
surgery, corneal transplantation)
reliability and demonstrates significant decline in QoL
6. Chemical burns and associated symptoms with improvement in cor-
7. Toxic keratopathy neal pain.
8. Radiation keratopathy
9. Miscellaneous: ocular surface
neoplasia, trauma, post-blepharoplasty,
iatrogenic trigeminal neuralgia, chronic corneal pain with
blepharospasm, fibromyalgia, small fiber neuropathy ASSESSMENT OF OCULAR SURFACE
PAIN

Indirect Measures
and overall quality of life (QoL). It causes decrease in
work performance and can affect many aspects of Several clinical methods can be used to test the
physical, social, and psychological functioning.53,54 function of corneal nerves. Slit-lamp examination with
Corneal nerve damage may be associated with various vital dyes, such as fluorescein, rose bengal,
symptoms of pain, light sensitivity, irritation, and and lissamine green, reveal the general health of the
sometimes a vague sensation of pressure. Crucial ocular surface. While fluorescein can help in iden-
daily activities like reading, driving, and computer tifying corneal epithelial breakdown, lissamine green
work can all be affected in milder disease, giving the helps to stain the devitalized corneal and conjunctival
subject a sense of handicap.54 In more severe cases, surface. Other indirect tests used most often in clinical
this condition is debilitating, resulting in severe practice include Schirmer’s and phenol red tests to
photoallodynia and/or pain, requiring dark glasses evaluate tear production and state of lacrimal system
indoors, decreased autonomy, impaired physical and function. Tear film osmolarity and tear film breakup
social function, decreased enjoyment and quality of time are other useful adjuncts to assess or screen for
life, challenges to dignity, threat of increased physical dry eye disease. Various osmometers are available
suffering, sleep deprivation, anxiety, depression, and commercially, and in general, tear film osmolarity less
finally existential suffering that may lead to patients than 290 mOsmol/L is thought to be normal, with
actively seeking end of life. values above 316 mOsmol/L being highly suggestive
of dry eye disease.61 However, significant overlap
exists between normal subjects and patients with dry
MEASUREMENT AND eye disease, and increased variability in these patients
QUANTIFICATION OF OCULAR may affect measured outcomes.61 However, it is
SURFACE PAIN important to note that these tests may often be
within normal range and thus patient with neuro-
Various questionnaires can help to get an insight into pathic corneal pain may be difficult to diagnose by
the discomfort experienced by patients. These ques- these measures.
tionnaires are designed to help practitioners better
appreciate the bearing of the condition on everyday
life and also to objectively document their findings.55 Direct Measures
Most of these are, however, dry eye questionnaires—
the Ocular Surface Disease Index (OSDI),53 the Impact Direct measures use various esthesiometers, such as
of Dry Eye on Everyday Life (IDEEL),56 MacMonnies the Cochet–Bonnet contact esthesiometer, which can
Dry Eye Questionnaire,57 Subjective Evaluation of detect mechanical nociceptor responses, thereby
Symptom of Dryness, and the Standard Patient quantifying Ad fibers function. Further, the noncon-
Evaluation of Eye Dryness (SPEED) questionnaires.58 tact Belmonte ethesiometer is capable of detecting
These questionnaires ask for symptoms, frequency of polymodal functionality of both Ad and C fibers and
symptoms, severity of symptoms, use of medications, may be more informative.62
and so on. These surveys use a numerical scale and
thus make recording symptoms easy for patients and
clinicians. However, current questionnaires for eye Peripheral Versus Central Neuropathic
pain are subjective and not validated. The 2010 NEI Pain—The Proparacaine Challenge Test
Workshop on Ocular Pain & Sensitivity identified and
highlighted the need for validated quantitative tools Some basic tests may aid in distinguishing between
to assess, measure and quantify ocular pain.59 To meet peripheral and central pain, although many patients
Seminars in Ophthalmology
Corneal Neuropathy 63

may suffer from a combination of both. The APPROACH TO MANAGEMENT OF


proparacaine challenge with instillation of a topical NEUROPATHIC CORNEAL PAIN
anesthesia drop of 0.5% proparacaine hydrochloride
(Alcaine, Alcon) on the ocular surface will attenuate Nerve injury may result in the release of inflammatory
peripheral but not central pain. Measures such as cytokines from both the injured and healthy
the use of soft contact lenses and moisture goggles nerves.50,63 Intuitively, therapeutic strategies pro-
may also help to neutralize the evaporative compo- posed to decrease inflammation and induce nerve
nent of the tears and will decrease peripheral but regeneration form the rationale behind use of these
not central pain. Patients with no relief from any of agents for the treatment of neuropathic corneal pain.17
the preceding measures likely suffer, at least in part, Various studies and anecdotal evidence have emerged
from central neuropathic pain. Likewise, those who suggesting that biological factors, including nerve
have some relief with the proparacaine challenge growth factor (NGF), vascular endothelial growth
likely suffer from combined peripheral and central factor (VEGF), pigment epithelial growth factor
neuropathic pain. (PEDF), docosahexenoic acid (DHA), pituitary
adenylate cyclase-activating protein (PACAP), and
interleukin-17 (IL-17), as well as cells such as T
Laser In Vivo Confocal Microscopy lymphocytes, may result in nerve regeneration.17,75–78
Others, like cyclosporine and corticosteroids, have a
Patients with corneal neuropathy benefit from referral mixed action, and still others like BAK are purely
to a cornea specialist at a tertiary care center with neurotoxic.78–80 Steroids decrease many aspects of the
facilities with laser in vivo confocal microscopy inflammatory response by inhibiting transcription
(IVCM). IVCM is a noninvasive procedure that factors that activate pro-inflammatory cytokines.
allows imaging of the cornea at the cellular level.63 Cyclosporine acts as an anti-inflammatory agent by
IVCM allows the study of corneal cells, nerves, and decreasing lymphocytes and other pro-inflammatory
the immune cells and their various interactions in cytokines in the conjunctiva.79 NGF helps in regener-
ocular and systemic diseases.16,64 IVCM has been ation, remodulation, and restoration of the function of
utilized to study nerve changes in various conditions, the nerves.76 Similarly, autologous serum tear drops
including normal eyes, keratoconus, dry eye disease,65 supply the eye with several epithelial and nerve
contact lens wear, neurotrophic keratopathy,66 infec- growth factors, including vitamin A, epidermal
tious keratitis,67 and post refractive surgery, among growth factor, and fibronectin, and have shown to
others.16,63,64,68 Moreover, IVCM has enabled us to be helpful in nerve regeneration.4 However, a multi-
study the regenerative changes of the corneal nerves step approach is required in the treatment of corneal
and correlation with corneal sensation.6,64,69 Studies neuropathic pain (Table 2). Many of the therapies
have shown varying degrees of reduced nerve fiber discussed in the following for neuropathic corneal
density, increased subbasal nerve tortuosity, increase pain are derived from evidence-based literature for
in nerve fiber beading, branching, reflectivity, neur- noncorneal neuropathic pain. Their use for corneal
omas, and nerve sprouting.70–72 Beadlike formations neuropathic pain comes from long-standing personal
are thought to be metabolically active transmitter- experience of the authors and needs to be tested in
containing nerve fibers, which are likely an effort to larger randomized trials. The authors approach this
improve the abnormal epithelial trophism.73 by a three-step process of managing surface disease,
Alternatively, they are thought to represent nerve managing co-morbidities, and finally managing the
damage resulting in secretion of nerve growth fac- true component of pain, which itself encompasses
tors.74 A baseline IVCM in patients with neuropathic regenerative, anti-inflammatory, and environmental
pain can help assess and confirm nerve abnormalities modifiers.
like neuromas, increased nerve tortuosity, increased
beading, decreased density of nerve fibers, and
increase in dendritic cells, which can be subsequently Treatment of Ocular Surface Disease
followed by post-treatment IVCM to monitor for
changes and reversal of baseline findings.4 In a Treatment should begin with palliative care—no
recent study, our groups demonstrated that patients matter the underlying pathology of dry eye or neur-
with corneal neuropathy-induced photoallodynia algia, lubricating the surface with modest frequency
demonstrate profound alterations in the subbasal of nonpreserved artificial tears, emulsion-based tears
corneal nerves, including increased reflectivity, bead- or autologous serum tears may be beneficial. Often, a
ing, and neuromas. Further, we demonstrated that mixed component of aqueous-deficient and evapora-
autologous serum tears helped restore nerve tive types of dry eye disease is present. Lubricants
topography through nerve regeneration, and this may dilute inflammatory mediators, decrease tear
correlated with improvement in patient-reported film hyperosmolality, and also help in better spread of
photoallodynia.4 the lipid layer of tears. The addition of punctal plugs
! 2016 Taylor & Francis
64 S. Goyal and P. Hamrah

TABLE 2. Management of neuropathic corneal pain. in the treatment of meibomian gland dysfunction and
A. Treatment of ocular surface disease subsequent increase of tear breakup time (TBUT).81
1. Increase tear production Patients with neuropathic pain may however show
– Use PFATs improvement of ocular surface signs, but exhibit
2. Increase tear retention partial, mild, or no improvement in symptoms after
– Punctal plugs, contact lenses, moisture goggles
3. Treatment of lids and ocular surface disease
prolonged treatment with the just-outlined
– Treat blepharitis with lid hygiene, warm compresses, treatments.
medical management
– Refractory cases: Meibomian gland probing, lipiflow,
intense pulse lighted therapy Anti-Inflammatory Agents
4. Managing comorbid conditions
– Treat allergies, conjunctival chalasis, lagophthalmos and
nocturnal exposure Patients with corneal neuropathic pain typically
B. Anti-inflammatory agents require chronic use of anti-inflammatory agents
1. Topical corticosteroids (Table 2) for relief of symptoms, to decrease the
2. Topical and oral azithromycin, oral doxycycline inflammatory milieu and break the cycle of chronic
3. Cyclosporine
4. Tacrolimus
inflammation, or to prevent recurrent episodes.
5. Anakinra Inflammation may not always be visible on slit-lamp
C. Regenerative therapy examination, and IVCM may aid in the assessment of
1. Autologous serum eye drops (20%) subclinical inflammation.64 Steroids are the mainstay
2. Nerve growth factor of treatment, especially for initial rapid relief. The
3. Platelet rich plasma
4. Umbilical cord serum eye drops
authors prefer loteprednol 0.5% at an initial qid dose
D. Protect ocular surface when required with bi-weekly taper to once or twice a week over a 6-
1. Bandage contact lenses to 12-week period. Further, cyclosporine A (CSA) is a
2. Scleral contact lenses (e.g. PROSE) well-known anti-inflammatory agent that modulates
E. Systemic pharmacotherapy for pain the T cells and works by reducing ocular surface
1.TCAs like nortriptyline, amitryptilline
2. Carbamazepine
inflammation and increasing tear production in dry
3. GABAergic drugs (gabapentin, pregabalin) eye disease.82 However, CSA has been shown in a
4. SNRI like duloxetine and venlafaxine preclinical study to potentially retard nerve fiber
5. Opioids like tramadol regeneration due to loss of proneural interleukin (IL)-
6. Class 1B sodium channel blocker mexiletine 6 signaling.79 Nevertheless, the use CSA in aqueous-
F. Complementary and alternative measures
1. Acupuncture
deficient patients may be of value by increasing tear
2. Transcranial magnetic stimulation volume.
3. Scrambler therapy Studies have shown that interleukin 1 (IL-1) by
4. Implantable neuromodulators promoting activating and migration of leukocytes is
4. Cardio-exercise closely involved in the regulation of ocular surface
5. Omega-3-rich diet
6. Gluten-free diet
inflammation.83 Anakinra (Kineret) is a human IL-1
receptor antagonist and has showed efficacy in
PFATs: preservative free artificial tears; PROSE: Prosthetic reducing corneal surface inflammation and epithelio-
Replacement of the Ocular Surface Ecosystem; TCAs: tricyclic pathy.83 The authors use Kineret 2.5% at TID dosing
antidepressants; SNRI: serotonin–norepinephrine reuptake
for 3–6 months in patients refractory to the treatment
inhibitors.
already described. Similarly, Tacrolimus, which is a
to maintain a more generous tear lake in the absence calcineurin inhibitor like cyclosporine, acts as an
of inflammation can be of benefit to some patients. immunosuppressive agent and has been found to be
Care must be taken, however, not to place plugs in a useful anti-inflammatory agent when used topically
eyes with active allergies and inflammation, as this at a concentration of 0.03% at bid dosing for 3–6
may increase the contact time of the allergens on the months.84 Topical azithromycin is a potentially effect-
surface or induce increased pain by trapping inflam- ive and well-tolerated therapy of lid margin disease
mation. Moisture chamber goggles increase moisture and meibomian gland dysfunction.85,86 It is anti-
and prevent evaporation at the ocular surface. Topical inflammatory, inhibits proinflammatory cytokines,
lipid supplements like castor oil or mineral oil and and is effective against gram-negative microorgan-
emulsion-based lubricants improve the stability of isms. It remains at therapeutic levels on the ocular
tear film. The authors recommend treating any con- surface days after stopping therapy.
comitant posterior blepharitis and meibomian gland Oral drug therapy may be useful in many cases.
dysfunction with hot compresses and lid massage or Doxycycline is an antimicrobial and inhibits matrix
medical therapy (Table 2). For cases refractory to metalloproteinases that degrade connective tissue.87 It
medical management, procedures such as intraductal has earned valuable use in treatment of ocular rosacea
meibomian gland probing, thermal pulsation devices and increasing tear film stability. Oral doxycycline at a
(Lipiflow), and intense pulse lighted therapy may aid dose of 100 mg once or twice a day for 2–3 months
Seminars in Ophthalmology
Corneal Neuropathy 65

FIGURE 1. Representative in vivo confocal microscopic pictures: (A) Normal cornea of a patient showing subbasal plexus of nerves.
(B) Patient with corneal pain showing decrease in nerve density, increased tortuosity (yellow arrow) and beading (orange arrow). (C)
Same patient exhibiting improved symptoms, increase in nerve density, less tortuosity, and disappearance of beading with 8 weeks of
20% autologous serum tears and low dose loteprednol 0.5% treatment.

followed by daily dosing for another 3 months seems surface, preventing flares and thus likely allowing for
to be very helpful. In addition, topical antibiotics like undisturbed neuronal regeneration. However, it is
azithromycin 1% have immunomodulatory and anti- now recognized that some quantities of IL-17 and
inflammatory properties, and application to lids at VEGF-A are necessary for efficient nerve regener-
bedtime improves symptoms in many patients. ation.75 Although this suggests that a minor degree of
inflammation may trigger a milieu for corneal nerve
regeneration, excessive inflammation may lead to loss
of corneal innervation. In the aggregate and in our
Nerve Regenerative Therapy experience, limiting inflammation at the initiation of
therapy is crucial in successful therapy of patients
Autologous serum eye drops contain a variety of with neuropathic corneal pain.
proepithelial and proneural factors like epidermal Though not commercially available in the United
growth factor (EGF), NGF, insulin-like growth factor States, umbilical cord serum eye drops, platelet-
(IGF-1), and so on.4,88 Concentrations from 20 to 100% rich plasma, and NGF seem to show promising
have been shown to encourage epithelial healing, results in treating dry eye syndrome and neurotrophic
increase nerve density, and decrease nerve tortuosity.4 keratitis and result in nerve regeneration.91–94
In this first evidence-based study for treatment of Platelets contain many bioactive compounds like
corneal neuropathic pain, IVCM demonstrated sig- platelet-derived growth factor, active metabolites,
nificantly improved nerve parameters including total VEGF, and transforming growth factor (TGF)-b,
nerve length, number, and reflectivity, and also which have been shown to help in nerve regeneration
reduction of beading and neuromas in patients treated in experimental models.92 Clinical studies have
with 20% autologous serum tears.4 In our experience shown that autologous plasma use is capable of
we have noted that higher concentration of auto- nerve regeneration in patients of neurotrophic
logous serum tears at 50% and 100% may results in keratopathy.95
higher likelihood of initially increased symptoms.
However, inflammation may play a key role in
peripheral nerve degeneration.89 Recent studies with Protective Contact Lenses
the help of IVCM have shown a substantial correl-
ation between the increase in dendritic cell numbers When topical pharmacotherapy fails to provide
and decreased subbasal corneal nerves, signifying a adequate relief, the authors recommend a trial of
possible interaction between the immune and nervous extended wear soft bandage contact lenses to acceler-
system in the cornea.63 Clinical experience is compel- ate resurfacing of the corneal surface. A regular
ling for concurrent use of low-dose steroids with bandage contact lens may particularly be effective in
autologous serum eye drops for successful regener- cases of recurrent corneal abrasions. However, the
ation of corneal nerves.90 In our experience, the underlying dry ocular surface and increased risk of
combination of low-dose immunosuppressive therapy infections with prolonged wear make these less
with the use of autologous serum tears seems to be attractive options. Shielding the sensitized corneal
greatly beneficial (Figure 1), as steroids promote a receptors from the triggering environmental stimulus
decrease in the initial inflammatory load of the ocular forms the rationale behind the use of scleral lenses.
! 2016 Taylor & Francis
66 S. Goyal and P. Hamrah

The most effective lens in maintaining the precorneal TCAs. The Neuropathic Pain Special Interest Group of
nociceptive barrier is the liquid corneal bandage the International Association for the Study of Pain
created by the fluid filled scleral lenses like PROSE (IASP) recommends secondary amine TCAs like
(Prosthetic Replacement of the Ocular Surface nortriptyline and desipramine as first-line treatment
Ecosystem, Boston Foundation for Sight).96,97 It is choice for neuropathic pain. It recommends use of
felt that timely treatment of corneal epitheliopathy in tertiary amines like amitriptyline and imipramine
the disease process may help to reverse chronic pain. only if a secondary amine is not accessible.103 The
However, once the chronic pain is established, the TCAs are initially given at a dose of 10 to 25 mg
corneal bandage by itself is usually not adequate. nightly. Depending on the response and tolerance, this
Moreover, given that patients may suffer from con- can be titrated by 10 to 25 mg every 3 to 7 days up to a
current hyperalgesia, placement of contact lenses on maximum of 150 mg nightly. Patients need to be
the ocular surface may be a strong noxious stimulus in educated and warned about the anticholinergic side
this cohort. effects, which are frequent and may be dose limiting.
Some of these include dry mouth and eyes, excess
Systemic Pharmacotherapy for Pain sedation, urinary retention, constipation, orthostatic
hypotension, and blurry vision. Again, these can be
Despite these measures, the pain-generating minimized by starting at a lower dose and slow
nerves can still fire spontaneously and thus may titration.103 Serotonin-norepinephrine inhibitors like
need to be targeted directly. Corneal pain can result duloxetine (Cymbalta) and venlafaxine (Effexor) have
from peripheral and/or central sensitization. also been studied for the treatment of neuropathic
Pharmacotherapy used for pain management may pain.101,103 While we recommend that one agent at a
provide significant relief, in particular in patients with time be tried in patient with corneal neuropathic pain,
a central component of neuropathic pain.98–104 Data combination therapy is often required in refractory
on the use of systemic pharmacotherapy for corneal cases.
neuropathic pain are, however, scarce. Various Carbamazepine is a class of antiepileptic drug
options are available that include anticonvulsants that has been used for trigeminal neuralgia. Relief of
(e.g., carbamazepine), tricyclic antidepressants (e.g. corneal pain may be achieved at low doses, but the
Nortriptyline), serotonin uptake inhibitors, opioids, usual effective dose ranges from 800 to 1600 mg,
and so on. No randomized studies have been per- divided in two to four doses per day. Once response
formed to date to study their usage in corneal has been achieved it can be tapered to a minimal
neuropathic pain, but their use can be extrapolated effective dose. Another class of drugs validated for the
from treatment of neuropathic pain elsewhere.99 treatment of neuropathic pain by randomized con-
Gamma-aminobutyric acid (GABA) is the key inhibi- trolled trials is opioids, such as Tramadol. This binds
tory neurotransmitter of the central nervous to the m-opioid receptor and inhibits the reuptake of
system.100 Drugs like gabapentin (Neurontin) and serotonin and norepinephrine and has been found to
pregabalin (Lyrica) that were first developed and used be effective in moderate to severe pain. Again,
as anticonvulsants are now endorsed as first-line side effects such as nausea, vomiting, constipation,
agents for the treatment of neuropathic pain arising sedation, and dependence limit the use of opioids as
from diabetic neuropathy, postherpetic neuralgia, and second-line medications, when the first-line medica-
central neuropathic pain.101 These drugs bind to the tions fail to achieve a satisfactory response. In
a-2-delta subunit of voltage-dependent calcium chan- cases where immediate and short-term relief for
nels, causing decrease in the inflow of calcium into the acute neuropathic pain is desired, they may be
neurons and thus stabilizing them throughout the justified as first-line use.101,103 When the drugs just
central nervous system.102 Gabapentin therapy can be described are ineffective or not well tolerated,
initiated on day 1 as a single 600-mg dose, on day 2 as Mexiletine can serve as an alternative second-line
1200 mg/day, and on day 3 as 1800 mg/day. Patients therapy.104 Mexiletine (225 to 675 mg/day) is an
are instructed to subsequently titrate the dose up as orally active local anesthetic agent, is structurally
needed for pain relief to a maximum dose of 3600 mg/ related to lidocaine, and has been used to alleviate
day (900 mg, four times per day). The most common neuropathic pain of various origins.104 Side effects
dose-limiting side effects include sedation, somno- like nausea, sleep disturbance, headache, shakiness,
lence, and dizziness and can often be judicially fared dizziness, and tiredness may, however, limit its
by a slow titration of the dose. prolonged use.
Tricyclic antidepressants (TCAs) are a class of
drugs that exert effect by inhibiting presynaptic Complementary and Alternative Medical
reuptake of serotonin and norepinephrine and by Approaches
blocking cholinergic, adrenergic, histaminergic, and
sodium channels. Drugs like amitriptyline, nortripty- The numerous mechanisms involved in generating
line, desipramine, and imipramine are classified as pain explain why single treatments may not be
Seminars in Ophthalmology
Corneal Neuropathy 67

effective. Some patients, despite use of all the above least 2–3 times a week. Nutritional intervention
measures in various combinations, still do not achieve strategies like increasing the ratio of omega-3 to
adequate pain relief. The authors have found that use omega-6 fatty acids has been shown to regulate
of adjunctive therapies, such as acupuncture and inflammation in the body, and this knowledge can
vigorous exercise, may provide temporary relief be exploited to optimize health in pain patients
and/or decrease the need for pharmacotherapy in also.113 Foods like flaxseed oil, fish oil, walnuts, and
many patients as well as decreased pain memory. soybeans are rich in omega-3 fatty acids. We recom-
There is increasing evidence that acupuncture stimu- mend that our patients be on 1000 mg bid to tid daily
lates endogenous opioid mechanisms, may stimulate dosing of either fish oil or flaxseed oil. Presence of
gene expression of neuropeptides, and if safely done allergies and conditions like conjunctival chalasis,
may be a traditional pain management treatment lagophthalmos, and nocturnal exposure should be
contributing to modern medicine.105 Many of our carefully assessed and addressed appropriately, med-
patients report getting extra relief ranging between a ically or surgically. Gluten sensitivity may be etio-
few hours to a few days that could not have been logically linked to a substantial number of idiopathic
achieved by following the algorithm for modern axonal neuropathies.114 Gluten seems to cause and
medicine. support neuronal inflammation, and in our experi-
Patients who have been refractory to all above ence, change to a gluten-free diet has resulted in
treatment could be referred for a trial of transcranial variable decrease in neuropathic corneal pain. We
magnetic stimulation (TMS) or Scrambler therapy. recommend our patients to be tested for gluten
TMS is a noninvasive method to cause depolarization sensitivity and if tested positive to abstain from
or hyperpolarization in the neurons of the brain. It is gluten products.
being agreed upon that where evidence-based medi-
cine is failing to treat neuropathic pain, high-fre-
quency repetitive TMS (rTMS) of those brain regions CONCLUSIONS
which parallel the body parts in pain may be
effective.106 A meta-analysis gaging the analgesic Neuropathic corneal pain in itself results from a
effect of rTMS on various neuropathic pain states complex interplay of various central and peripheral
proposes rTMS to be more effective in suppressing mechanisms. Currently, our knowledge and appreci-
central than peripheral neuropathic pain.107 Another ation of the pathophysiology of corneal pain are in
useful therapy used to control chronic neuropathic early stages. Most of the already-mentioned pain
pain is Scrambler therapy. Scrambler therapy works treatments in ophthalmology have been borrowed
on the principle of interfering with pain signal from other areas of medicine. The complexities of
transmission, by mixing nonpain information with these pathways have yet to be unfolded. No single
the pain signal into the nerve fibers and thus therapeutic approach or drug is satisfactory currently,
confusing the nervous system’s ability to sense although the use of autologous serum tears provides
pain.108 An increasing number of studies are reporting the highest likelihood for success in our experience.
that Scrambler therapy may give relief from chronic Awareness over the past few years that corneal pain is
neuropathic pain due to various underlying etiologies real has been a step in the right direction. However,
more successfully than the previous outlined much work has to be done to assess therapeutic
drugs.109 Neuromodulation is an intervention with approaches for this patients suffering from a debilitat-
involves stimulation or administration of medications ing disease. Working together with other disciplines
directly to the body’s nervous system for therapeutic of both conventional (e.g. neurology and rheumatol-
purposes. It involves implantable as well as non- ogy) and alternative medicine may be the best current
implantable devices that deliver electrical, chemical, approach to be followed.
or other agents to reversibly modify brain and nerve
cell activity. Neuromodulation therapies allow DECLARATION OF INTEREST
focused delivery of modifying agents—for example,
electrical, optical, or chemical signals—to targeted The authors report no conflicts of interest. The authors
areas of the nervous system in order to improve alone are responsible for the content and writing of
neural function.110 this article.
Recent evidence from both animal and human
studies suggests that cardio-exercise, by inhibiting FUNDING
pain pathways, may alter the perception of pain
experience centrally. Exercise may help to increase the This study was supported by NIH R01-EY022695
brain neurotrophic factors and thus contribute to (PH), Research to Prevent Blindness Career
neuroplasticity and neurorestoration.111,112 We there- Development Award (PH), and Falk Medical
fore recommend that our patients be involved in some Research Trust (PH). The funding organizations had
kind of cardio-exercise for about 30–45 minutes at no role in the design or conduct of this research.
! 2016 Taylor & Francis
68 S. Goyal and P. Hamrah

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