Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312104 on 21 September 2018. Downloaded from http://bjo.bmj.com/ on 24 September 2018 by guest. Protected by copyright.
Review
1
Corneoplastic Unit and Eye
Bank, Queen Victoria Hospital,
East Grinstead, UK
2
Department of Plastic Surgery,
Queen Victoria Hospital, East
Grinstead, UK
Correspondence to
Raman Malhotra, Corneoplastic
Unit and Eye Bank, Queen
Victoria Hospital, East Grinstead
RH19 3DZ, UK; ​Raman.​
malhotra1@​nhs.​net
RM and MSE are joint first
authors.
Received 18 February 2018
Revised 22 May 2018
Accepted 12 August 2018
© Author(s) (or their
employer(s)) 2018. No
commercial re-use. See rights
and permissions. Published
by BMJ.
To cite: Malhotra R,
Elalfy MS, Kannan R, et al.
Br J Ophthalmol Epub ahead
of print: [please include Day
Month Year]. doi:10.1136/
bjophthalmol-2018-312104
Update on corneal neurotisation
Raman Malhotra,1 Mohamed Shafik Elalfy,1 Ruben Kannan,2 Charles Nduka,2
Samer Hamada1
Abstract
Corneal neurotisation describes surgical restoration
of nerve growth into the cornea to restore corneal
sensation and trophic function. It represents an exciting
and effective emerging treatment for neurotrophic
keratopathy. Techniques described to date involve
either direct nerve transfer or an interpositional nerve
graft coapted to a healthy donor nerve. We review
the experience to date with particular emphasis on a
detailed review of techniques, outcomes and current
thoughts.
Introduction
Corneal neural anatomy
The cornea is embryologically derived from the
interaction between the neural crest with the
endoderm with its innervating structures from
the neural crest and ectodermal placode-de-
rived trigeminal ganglion.1 Corneal sensation
is supplied by the ophthalmic division of the
trigeminal nerve. Intact corneal nerves are essen-
tial for the integrity of the ocular surface.2 Nerve
bundles of stromal nerves enter the cornea from
the limbus moving towards the central cornea.
The corneal stromal nerves, as they move in from
the periphery, are myelinated and form the limbal
plexus around the cornea, contributing to 71 tiny
nerve bundles.3 However, within 1 mm of passing
the corneoscleral limbus, they lose their thick
myelin sheaths with the preservation of a thin
Schwann cell sheath only. This allows for trans-
parency, the main function of the cornea.4 These
nerves travel in the anterior third of the stroma,
before penetrating Bowman’s membrane to form
terminal bulbs from which the sub-basal plexus
originates.2
The sub-basal nerve plexus lies immediately
beneath the corneal epithelium before giving
rise to the superficial branching network of
nerves towards the apex of the cornea which
turn perpendicularly and end in the corneal
epithelium.5 The sub-basal plexus is where the
sympathetic (superior cervical ganglion) and
parasympathetic (ciliary ganglion) nerves travel.
While it is estimated that only 50–450 trigeminal
nerve ganglions supply the entire cornea, due to
the extensive branching nature of its individual
axons, there exists up to 7000 nociceptors/mm2,
which are homogeneously distributed across the
cornea.6 The majority of these receptors (70%)
are polymodal, that is, for extreme temperatures,
chemical and inflammatory mediators, while 20%
are mechanoreceptors and the remaining 10% are
receptors for ‘cold’ sensation.7
Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104
Anatomy of the supraorbital and supratochlear
nerves
The frontal nerve is the largest branch of the
ophthalmic division of the trigeminal nerve. It
branches into the supraorbital and supratochlear
nerves. They exit from the supraorbital notch or
foramen, and continue beneath the corrugator and
frontalis muscles before piercing the muscle bellies.
The smaller supratrochlear nerve supplies the skin
of the lower forehead and the conjunctiva; the
supraorbital nerve is larger and its two terminal
branches reach the lambdoidal suture to supply the
integument of the scalp.8 Just distal to its notch,
the supraorbital nerve divides into a larger, lateral
coursing, deep (periosteal) division and a more
medial, thinner superficial division. The periosteal
division runs in the supraperiosteal plane, giving off
one or more branches. It penetrates the galea in the
region of the hair-bearing scalp providing sensation
to the frontoparietal scalp.9 The superficial divi-
sion forms multiple smaller branches, penetrating
the frontalis muscle to enter the subcutaneous
tissue approximately 2.5 cm above the superior
orbital rim and supplying the forehead and anterior
margin of the scalp in 90% of the population. In
the remaining 10% of individuals, it supplies more
cephalad scalp creating an area of overlapping
innervation with the deep division.9
In 2017, Domeshek et al presented a cadaveric
study on the anatomical characteristics of supraor-
bital and supratrochlear nerves.10 They observed
that proximal supraorbital and supratrochlear
nerves contain greater axon counts, providing
robust innervation sources for neurotisation,
despite use of a nerve graft, compared with the
distal nerve ends used in direct transfer. For each
of nine adult cadaver heads, bilateral supraorbital
and supratrochlear nerves were dissected from the
supraorbital rim to the anterior hairline. Histomor-
phometric analyses were performed on each spec-
imen’s left supraorbital and supratrochlear nerves
at the level of the supraorbital rim and at points 3
cm and 6 cm distally. They concluded that proximal
supraorbital nerve is the most robust innervation
source for corneal neurotisation, with twofold to
threefold greater fibre counts than at distal loca-
tions, and greater counts than ST nerves throughout
their lengths.
Corneal sensation
As first alluded to by Magendie, any disruption to
corneal innervation sets off a cascade of events,
leading up to neurotrophic keratitis.11 12 Corneal
nerves play a role in a complex process of wound
healing, cell proliferation, differentiation, DNA
1

Review
synthesis as well as collagen expression.13 Molecular biological
studies have shown that there is significant interaction between
the corneal epithelium and trigeminal neurons via mediators, for
example, substance P and bone morphogenic protein-7 (BMP-
7),14 while murine models indicate that it is the electrical cues
due to ionic flux which guide corneal epithelial and neuron
regeneration, in case of corneal injury.15 This electrical field is
also sustained by the movement of the upper eyelids.16 Limbic
stem/progenitor cells have similarly been shown to rely on
optimal corneal neurotisation.17 Liu et al have recently reported
that loss of corneal innervation induces its epithelial cells to
undergo apoptosis, but conversely, the return of corneal epithe-
lial integrity with the aid of inflammatory cells also help regen-
erate corneal sensory nerves especially in the sub-basal plexus .18
Corneal anaesthesia
Corneal anaesthesia can arise from various aetiologies. Causes
may be congenital, either isolated or syndromic, or acquired,
due to infection, inflammation, trauma and neoplasm, or iatro-
genic. The cause of corneal anaesthesia can be confined only to
the ophthalmic nerve or associated with involvement of other
cranial nerves.19 20
Features of neurotrophic keratopathy
Neurotrophic keratopathy is caused by abnormal trigeminal
innervation to the cornea, leading to corneal decreased or absent
sensation. Disease may affect any part of the trigeminal nerve
from its nucleus to the long ciliary nerve. Corneal anaesthesia
could be caused by viral infections, chemical burns, physical
injuries, corneal surgery, intracranial tumours and aneurysms,
and systemic diseases such as diabetes, multiple sclerosis and
leprosy .21–24 The corneal epithelium is first affected showing
defects and poor healing. Neurotrophic keratopathy has three
stages25 26: stage 1, positive Bengal staining of the inferior palpe-
bral conjunctival surface, punctate keratopathy and a decrease
in tear breakup time; stage 2, epithelial breakdown with epithe-
lial deficits surrounded by loose hazy epithelium; and stage 3,
corneal ulceration that can progress to melting and perforation.27
Current management options
Prompt initiation of treatment is paramount in preventing
progression of the disease. Stage 1 disease is treated with preser-
vative-free artificial tear drops and ointments, punctal occlusion
and treatment for blink lagophthalmos.28 Epithelial defects in
stage 2 are treated to avoid progression to a corneal ulcer and to
promote healing. Antibiotic drops are needed to prevent bacte-
rial infections in addition to ocular surface lubrication. Options
include corneal and scleral contact lenses,29 a lateral tarsor-
rhaphy, botulinum A toxin into the levator muscle or amniotic
membrane transplantation to cover the non-healing epithelial
defect.30 Treatment of stage 3 disease is directed at stopping
the stromal melting to prevent perforation.31 Nishida et al32
successfully treated persistent epithelial defects in patients with
neurotrophic keratopathy using a substance P–derived peptide
(FGLM)-amide and insulin-like growth factor-1 (IGF-1). Other
modalities used to heal corneal damage and promote regenera-
tion include autologous serum drops, topical non-gelified plate-
let-rich plasma eye drops, umbilical cord serum, collagenase
inhibitors, cell attachment factors and tissue adhesives.33–39
There has been increasing evidence in recent years on vali-
dating the value of newer biological agents. These include nerve
growth factor (NGF), epidermal growth factor, vascular endo-
thelial growth factor, semaphorins, neurotrophins 3 and 4 (NT-3,
2 Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104
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NT-4) and growth-associated protein-43.29 40 41 Other biological
agents like IGF-1, substance P and matrix therapy agent (RGTA)
(Cacicol20, OTR 3, Paris, France) have also demonstrated prom-
ising results in promoting corneal epithelial healing.42 Ceneg-
ermin, a recombinant form of human nerve growth factor, was
recently approved in the European Union as an eye drop for
the treatment of moderate or severe neurotrophic keratitis in
adults.43 These different trophic factors showed positive results
in the healing of neurotrophic corneas, but only few proved
efficacious in restoring corneal sensitivity and nerve structure.44
Even with appropriate management, neurotrophic keratopathy
may still progress to stage 3 disease as the underlying cause has
not been treated.
Corneal neurotisation
Neurotisation involves the transfer of a healthy donor nerve
segment into a tissue to re-establish either motor45 or sensory46–50
innervation and its principles continue to gain popularity.45–50
Corneal neurotisation describes restoration of structural nerve
growth into the cornea to restore corneal sensation and trophic
function.48–50 Surgical corneal neurotisation may be either by
direct nerve transfer or by using an interpositional nerve graft
coapted to a healthy donor nerve.
The concept of corneal neurotisation was most likely intro-
duced by Samii in 1972 and described in his textbook in
1981.51 52 He described anastomosing the major occipital nerve
to the proximal ophthalmic nerve using a sural nerve graft
placed in the subgaleal plane. This was achieved by dissection of
the occipital nerve, followed by a frontal craniotomy approach
to expose and enter the orbital roof. The ophthalmic nerve
was exposed, transected and its distal stump anastomosed with
the sural nerve graft. Three patients were described in whom
trophic function of the cornea improved, but not full recovery
of sensation.
Direct neurotisation
Direct nerve transfer was first introduced by Dr Terzis and
colleagues in 2009.48 The authors reported their results
providing direct corneal neurotisation in cases of unilateral facial
nerve palsy (FNP) with corneal anaesthesia. They conducted the
procedure as part of a staged approach to FNP reanimation in
patients with combined FNP and ipsilateral trigeminal nerve
involvement. Their technique involved a nerve transfer of the
contralateral supratrochlear and supraorbital nerves to directly
neurotise the neurotrophic cornea. The contralateral intact
supraorbital and supratrochlear nerves were carefully dissected
and were long enough to reach and restore sensation to the
affected cornea.
Allevi et al53 reported a case in 2014 of a patient who had
previously undergone facial motor reanimation followed by
direct corneal neurotisation using the technique described by
Terzis et al.48 The authors transferred the contralateral supraor-
bital and supratrochlear nerves to four perilimbal cardinal points
around the affected cornea by the above technique.
In 2016, Jacinto et al54 reported the use of the ipsilateral
supraorbital nerve for direct neurotisation to treat neurotrophic
keratopathy due to direct damage to the long ciliary nerves.
Using a hemicoronal incision and flap, the authors transferred
three branches of the ipsilateral supraorbital nerve, 6 cm in
length (from the supraorbital notch), through to the sub-Tenon’s
space to place them 360 degrees perilimbally to reach 6 o’clock.
Ipsilateral nerve transfer is an ideal option for direct neuro-
tisation where neurotrophic keratopathy is due to long ciliary

nerve damage and ipsilateral supratrochlear and supraorbital
nerves are intact. This approach traditionally required a large
bi-coronal, or hemi-coronal54 incision and flap. Dissecting out
the supratrochlear and supraorbital nerves with a significant
length (approximately 12 cm to allow transfer to the contra-
lateral cornea and its lateral most limbus, or at least 6 cm for
the ipsilateral cornea) involves time-consuming careful dissec-
tion under high magnification. Reflection of the coronal flap
prevents the ophthalmologist from concurrently preparing the
ocular surface for insertion of nerve fascicles at the same time as
harvesting of the nerves, thus prolonging the procedure. It is also
not applicable for rarer, bilateral cases of FNP where bilateral
ophthalmic division of trigeminal nerve involvement exists.
In June 2016, the use of the ipsilateral infraorbital nerve to
directly neurotise an anaesthetic cornea in a patient with ipsilat-
eral trigeminal ophthalmic division damage only was presented
at the Congress of the Italian Society of Stem Cells and Ocular
Surface.55 At the same time as masseteric-to-facial nerve anasto-
mosis, the infraorbital nerve was dissected from its foramen to
lips and transected distally. The nerve was reflected superiorly
and tunnelled to the conjunctival fornix (personal communica-
tion with Professor Gennaro, 2017).
In 2018, Leyngold et al56 reported the use of the contralateral
supraorbital nerve, harvested through a combined transpalpe-
bral and endoscopic forehead approach, for direct neurotisation
to treat neurotrophic keratopathy following herpes zoster infec-
tion. Ting et al have recently reported two cases of direct corneal
neurotisation for severe unilateral neurotrophic keratopathy
secondary to cerebellopontine angle meningioma. They used the
original surgical technique described by Terzis et al in 2009.57
Interpositional nerve graft neurotisation
The technique and principles of this strategy were developed in
Toronto and reported by Elbaz et al49 and Bains et al50 to use
a reversed sural nerve graft, coapted to the supratrochlear or
supraorbital nerve and nerve fascicles sutured subconjunctivally
to the perilimbal region. A transverse sub-brow incision was used
to access the supratrochlear nerve, and end-to-side coaptation
of the sural nerve graft was achieved by creating an epineural
window. Fibrin glue and 10-0 nylon sutures were used for coap-
tation. In unilateral cases, the contralateral supratrochlear nerve
was used, requiring subcutaneous tunnelling of the reversed
nerve graft over the nasal bridge to the perilimbal area of the
cornea. The epineurium was removed distally and the individual
fascicles were separated. Approximately five fascicles were then
placed around the entire limbal circumference and secured to the
sclera with 10-0 nylon sutures. The authors have since changed
this aspect of their technique to insert each nerve fascicle into
separate corneoscleral tunnels (personal communication with
Drs Gregory H Borschel and Asim Ali, 2017).
Sepehripour et al58 reportedthis procedure in a 2-year-old
using a reversed sural nerve graft coapted end-to-end to a single
fascicle (divided distally) of the contralateral supratrochlear
nerve, exposed as it exited its notch. Six fascicles of the nerve
graft were tunnelled subconjunctivally and sutured to the peril-
imbal sclera.
More recently, Weis et al published their results in six adult
patients using this technique.59 They coapted the sural nerve graft
to the supraorbital nerve only when they expose a small supra-
trochlear nerve. They coapted the nerve graft to the ipsilateral
side if the skin sensation along the distribution of supraorbital
and supratrochlear nerves was intact, otherwise they coapted the
graft to the contralateral side. The bony supraorbital canal was
Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104
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Review
unroofed and the supraorbital nerve was coapted proximally in
the orbit if they found the supraorbital nerve to have divided
within the canal.59
In September 2017, at the meeting of the European Society of
Ophthalmic Plastic and Reconstructive Surgery, Stockholm,60 we
presented our technique and outcomes in nine cases of corneal
neurotisation. Our technique was similar to the current tech-
nique used by Drs Borschel, Zuker and Ali, using a reversed sural
nerve graft, coapted by end-to-end anastomosis to the supra-
trochlear or supraorbital nerve and nerve fascicles tunnelled into
individual corneoscleral tunnels.
Interpositional nerve graft neurotisation is known to occa-
sionally fail in providing appropriate innervation.61 62
Surgical techniques in detail
Direct neurotisation: nerve transfer technique by Terzis et al48
The contralateral supratrochlear and supraorbital nerves were
dissected through a bicoronal incision and flap proximal to the
supraorbital margin. The nerve branches were passed through
a tunnel over the nasal bridge to a small incision along the lid
crease of the upper lid of the affected eye. The conjunctival inci-
sion would presumably be supratarsal, with a tunnel dissected
directly to the overlying skin crease incision in order to avoid
damaging levator palpebrae superioris (figure 1).
The globe was directed downward and an incision was
created through the superior bulbar conjunctiva 7 mm behind
the superonasal position of the corneal limbus. Blunt dissection
was carried out to create a tunnel in the sub-Tenon’s space to
the points of planned insertion of the prepared nerves. Distal
nerve branches were then passed into the prepared perilimbal
space, and each distal nerve was fanned and sutured into place in
the conjunctival sac next to the corneal limbus using 10-0 nylon
sutures. The conjunctiva was repaired in a similar fashion with
buried sutures.
Due to the novel and pioneering nature of this procedure, the
authors avoided placement of the nerve endings closer to the
anaesthetic cornea in order to minimise additional manipulation
of the anaesthetic cornea that may prolong impaired wound
healing. No direct nerve-to-nerve coaptation was attempted.
Ipsilateral nerve transfer technique54
Ipsilateral supraorbital nerve
In 2016, Jacinto et al54 reported the use of the ipsilateral supraor-
bital nerve for direct neurotisation to treat neurotrophic keratop-
athy due to direct damage to the long ciliary nerves. The authors
placed a hemicoronal incision just behind the hairline. Dissection
was in the subgaleal plane and laterally over the deep temporal
fascia. The periosteum was incised 2 cm above the superior orbital
rim to continue thereon in a subperiosteal plane to the superior
orbital rim. The dissection of the deep branch of the supraorbital
nerve was then carried cephalad from the supraorbital notch to
isolate three branches of the nerve to a length of 6 cm from the
supraorbital notch. The nerves were tunnelled to emerge trans-
cutaneously through an upper eyelid skin-crease incision. Then,
through a medial blepharotomy, medial to the horn of the levator
aponeurosis, the nerves were tunnelled into the superior conjunc-
tival fornix. A conjunctival incision was made 7 mm above the
corneal scleral limbus at 12 o’clock. Using a blunt abdominal
needle, the sub-Tenon’s space was accessed and branches of the
nerves were placed 360 degrees around the limbus with no scleral
or conjunctival fixation, or use of fibrin glue. The conjunctiva was
then closed to completely cover the nerves. An amniotic membrane
graft was then sutured to the surface of the eye with interrupted
3
 Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312104 on 21 September 2018. Downloaded from http://bjo.bmj.com/ on 24 September 2018 by guest. Protected by copyright.
Review

Figure 1   Surgical corneal neurotisation techniques described and presented to date. Interpositional nerve graft techniques coapted to a healthy
donor nerve: A–F, Elbaz et al,49 Bains et al,50 Weis et al,59 Fung et al89; and direct nerve transfer (G, Terzis et al,48 Allevi et al,53 Ting et al,57 Leyngold et
al—supraorbital nerve only56; H, Jacinto et al54; I, Professor Gennaro (personal communication, 2017).

8-0 polyglactin suture. No detail was given as to whether this was
epithelial surface face-up or face-down.
Ipsilateral infraorbital nerve
In June 2016, the use of the ipsilateral infraorbital nerve to
directly neurotise an anaesthetic cornea in a patient with ipsilat-
eral trigeminal ophthalmic division damage only was presented
at the Congress of the Italian Society of Stem Cells and Ocular
Surface.55 The details of the procedure are described above. To
potentially avoid the cheek and lip paresthesia that resulted,
the senior author suggested only transecting and reflecting the
superior fibres and not the entire infraorbital nerve (personal
communication with Professor Gennaro, 2017)
Endoscopic-approach ipsilateral supraorbital nerve transfer
Leyngold et al56 reported a study on two fresh cadavers using
an endoscopic browlift approach to transfer the ipsilateral
supraorbital nerve to the corneal limbus. Their dissection was
within the subgaleal plane using a blunt endoscopic elevator to
the superior orbital rim. The supraorbital neurovascular bundle
was identified and preserved. Dissection of the deep division
4 Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104
of the supraorbital nerve was then continued cephalad from
the supraorbital notch. Two to three terminal branches of the
nerve were isolated and divided approximately 6 cm from the
supraorbital notch. The nerve was tunnelled into a pre-placed
upper eyelid incision. The nerves were then passed through
the medial blepharotomy incision into the superior conjunc-
tival fornix. A conjunctival incision was made at the 12 o’clock
position, 7 mm above the corneoscleral limbus, and a blunt
abdominal needle was used to access the space under Tenon’s
Capsule. The branches of the nerves were placed in the sub-Ten-
on’s space 360 degrees around the limbus. The conjunctiva was
then closed.
This proof-of-concept would be applicable to cases where loss
of corneal sensation was due to damage distally, for example,
long ciliary nerves and where ipsilateral supraorbital nerves
were intact. However, standard endoscopic forehead and brow
surgery is usually subperiosteal and not subgaleal in order to
minimise bleeding and, more importantly, nerve and muscle
trauma during dissection. Furthermore, without scalp entry
more cephalad the dissection of a longer nerve for contralateral
transfer is limited.

Endoscopic-approach contralateral supraorbital nerve transfer
Leyngold et al56 subsequently reported the use of the contra-
lateral supraorbital nerve, harvested through a combined
transpalpebral and endoscopic forehead approach, for
direct neurotisation. A contralateral upper eyelid skin-crease
approach exposed the superior orbital rim and supraorbital
neurovascular bundle. Further dissection in the subgaleal
plane isolated approximately 1 cm of the periosteal branch of
the supraorbital nerve. Then, through a vertical incision made
5 mm posterior to the normal hairline, a subperiosteal plane
was dissected, stopping just cephalad to the previously isolated
segment of the supraorbital nerve. The periosteum was then
opened to visualise the previously dissected segment of the
supraorbital nerve and dissection of the remaining supraor-
bital nerve was then carried cephalad, under endoscopic guid-
ance, from both the eyelid and scalp incisions. Two branches
of the nerve were isolated and divided approximately 7 cm
superior to the supraorbital notch. They were then tunnelled
to an ipsilateral palpebral incision in the subgaleal plane and
transferred to superior medial conjunctival fornix through
a medial blepharotomy. A conjunctival incision was made 7
mm above the corneoscleral limbus at the 12 o’clock position
and the donor nerve branches were placed in the sub-Tenon’s
space. The epineurium of the donor nerve was then secured to
the conjunctiva with 8-0 vicryl interrupted sutures. No dissec-
tion of fascicles was documented.
Interpositional nerve graft neurotisation technique49 50 53
In 2014, Elbaz et al49 and Bains et al50 reported outcomes using a
reversed sural nerve graft, coapted to the supratrochlear or supra-
orbital nerve and nerve fascicles sutured subconjunctivally to the
perilimbal region. They harvested the sural nerve proximally to
distally using a nerve harvesting device placed around the nerve
and passed distally, freeing the nerve from surrounding tissues.63
The length harvested was approximately 10 to 15 cm long, and
they preserved the peroneal component of the nerve. The supra-
trochlear nerve was accessed through a transverse sub-brow inci-
sion and dissection superiorly for a short distance and deep to
the orbicularis oculi muscle to find the nerve as it exits the orbit
through the supratrochlear notch. They noted in some cases that
the nerve may exit from a bony foramen. An epineural window
was then created in the side for end-to-side coaptation of the sural
nerve graft. End-to-end coaptation was used in cases where the
nerve was small. For bilateral case, the authors initially divided
the nerve distally to perform the coaptation end-to-end. However,
since publication of these two initial reports, they have switched to
coaptation end-to-end for all cases (personal communication with
Dr Gregory H Borschel, 2017). Coaptation was performed using
10-0 nylon sutures and fibrin glue (Tisseel). In unilateral cases, the
contralateral supratrochlear nerve was used, requiring subcuta-
neous tunnelling of the reversed nerve graft over the nasal bridge
to the perilimbal area of the cornea. Distally, under the ophthalmic
operating microscope view, the epineurium was removed and
the individual fascicles were separated. Approximately five fasci-
cles were then placed around the entire limbal circumference and
secured to the sclera with 10-0 nylon sutures. The authors have
since changed this aspect of their technique to insert each nerve
fascicle into separate corneoscleral tunnels (personal commu-
nication with Drs Gregory H Borschel and Asim Ali, 2017).
The conjunctiva was closed and lateral temporary tarsorrhaphy
was performed. A temporary patch and topical lubricants were
prescribed in all cases.
Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104
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Review
Our technique
Isaac Newton said “If I have seen further, it is by standing on
the shoulders of giants”.64 Through the generosity of the above
authors in sharing their knowledge during meetings and through
personal communication, many centres internationally are now
beginning to perform these procedures. Our technique is similar
to that currently carried out and advised by Drs Borschel, Zuker
and Ali. Specific variations to mention:
1. When exposing the supratochlear or supraorbital nerves,
a skin-crease incision, extended medially, and pre-septal/
sub-orbicularis dissection to expose the superior orbital rim
help avoid a visible eyelid scar.
2. On the ipsilateral anaesthetic cornea side, the orbital sep-
tum is dissected to expose the postseptal space. By blunt dis-
section, a submuscular, pre-periosteal tunnel over the nasal
bridge is made to connect both upper eyelid skin-crease in-
cisions. A size 10 suction tube is passed through this tunnel.
The reversed sural nerve end is placed into the orifice of the
tube, and using suction from the anaesthetic cornea end, it is
atraumatically passed from the contralateral side for it then
to be transferred to the conjunctival fornix via a supratarsal
blepharotomy medial to levator palpebrae superioris.
3. In order to minimise handling and trauma to fascicles, we
handle the distal most tip of each fascicle when passing sub-
conjunctivally. This tip is then trimmed off to leave a fresh-
ly cut end. The four to five fascicles are each inserted into
pre-prepared corneoscleral lamella tunnels and secured with
fibrin glue (Tisseel). Placement in these tunnels is an attempt
to facilitate more direct nerve-to-nerve coaptation.
4. One or two fascicles are left in the perilimbal sub-Tenon’s
space either at 3 or 9 o’clock, within the area of the palpe-
bral aperture and secured with fibrin glue in an attempt to
restore sensation to the bulbar conjunctiva in the region of
the palpebral aperture.
5. Since our first nine cases, we have now begun wrapping
amniotic membrane around the coaptation of a reversed su-
ral nerve graft to the supraorbital or supratrochlear nerve.
The amniotic membrane is placed basement-membrane face
down around the nerve. Amniotic membrane has an abun-
dance of neurotrophic factors, particularly NGF, which may
also contribute to promoting nerve regeneration.65–67 Animal
studies suggest this may improve outcomes of nerve growth
after motor neurotisation.65 68–73 We continue to monitor
outcome measures since this amendment.
6. We do not use lateral tarsorraphies and simply pad the anaes-
thetic eye overnight.
7. Surgical time has gradually been reduced from up to 5 hours
to 3 hours, largely thanks to two surgeons concurrently
harvesting the sural nerve and exposing the supratrochlear
and supraorbital nerves and ipsilateral blepharoconjunctival
route.
Corneal reinnervation, sensation and in vivo confocal
microscopy of corneal nerves
Corneal re-innervation follows a timeline, with neurotisation of
the cornea observed at 8 weeks near the limbus postoperatively
in cases following penetrating keratoplasty, phototherapeutic
keratectomy and laser-assisted in situ keratomileusis. The nerve
growth could be detected at 3 to 7 months postoperatively in
superficial central cornea, and complete neurotisation including
the basal layers of the central cornea could be seen between 6
months and 2 years postoperatively. This timeline could vary due
to factors such as the patient’s age and health prior to surgery,
5

Review
but the regained corneal sensation in patients of all ages is suffi-
cient to maintain a healthy epithelium and to initiate the blinking
reflex.74–76 The new nerves generally have abnormal branching
and accessory thin nerve fibres.
Terzis et al48 compared their results with this predictable healing
timeline in relatively healthy eyes, and stated that their patients’
re-innervation time was lengthened. They rejected the hypoth-
esis that the healing could be by spontaneous re-innervation from
surrounding tissues rather than an ingrowth of nerve fibres from
the transposed donor nerves, as to them this seemed unlikely to
have occurred after such long periods of denervation prior to
neurotisation. They suggested that where long donor axons may
have been unknowingly injured during the surgical procedure,
regrowth following Wallerian degeneration might have taken
longer. They suggested the use of nerve blocks in future studies to
clarify the nerve supply for any corneal re-innervation.48
Theoretically, we expect that the process of corneal re-inner-
vation after corneal neurotisation to take longer than in cases
after corneal grafting or corneal laser refractive surgery where
corneal stromal nerve endings at the host side of the graft–host
junction are located in close proximity to the edge of the corneal
graft. This is not the case in corneal neurotisation where a nerve
graft or transfer is used to guide viable nerve fibres, by place-
ment in the proximity of a denervated/desensitised cornea.
Szaflik77 reported the presence of stromal nerves in 94% of 16
eye bank donor corneas preserved at 4°C for up to 3 weeks using
white-light confocal microscopy. Another study which looked
at organ-cultured eye bank eyes showed that corneal stromal
nerves/nerve sheaths are preserved and could persist post-trans-
plantation for up to 3 months. These could help direct the new
growing nerves into the corneal stroma.78 Corneal stromal
nerves were detected as early as 2–6 months after surgery using
in vivo confocal microscopy, while sub-basal nerves could not be
detected before 1–2 years after surgery.79–81
Electron microscopic studies in both animal and human
corneas showed that unmyelinated corneal stromal nerves possess
Schwann cell (SC) elements and cytoplasm.7 82 The loss of viable
SC in a nerve graft results in reduced neurotrophic support with
associated reduction in regeneration.83 84 Corneal stromal nerves
lose their SC sheath on penetrating Bowman’s membrane and
continue as sub-basal nerves. The column of SC forms a pathway
for regenerating axons of peripheral nerves.85 86 Transplanted SC
assist in nerve regeneration as detached SC from degenerating
nerves can upregulate the NGF expression.87 Hence, Dhillon et
al concluded that the SC tube in corneal grafts could help direct
the regenerating host stromal nerves after corneal grafting.78
Again, this fact could prove helpful as a prognostic factor in
counselling corneal neurotisation patients if preoperative in vivo
confocal microscopy (IVCM) could detect elements of corneal
stromal nerves/sheath structures.
Ting et al57 recently showed IVCM postoperative results in two
patients following corneal neurotisation. Both patients showed
improved corneal sensation, but only one patient had IVCM
detectable sub-basal and stromal corneal nerves postoperatively.
The patient who did not show corneal nerves on IVCM had
recurrence of corneal anaesthesia by 2 years postoperatively. This
patient had evisceration performed 5 years after corneal neuroti-
sation for uncontrolled persistent ocular pain with vision of only
perception of light and poor cosmesis. Histopathological examina-
tion of the excised corneoscleral disc showed normal-sized, central
corneal stromal nerves which were not structurally connected to
the transplanted perilimbal nerve bundles. They concluded that
the regeneration and maintenance of corneal nerves after corneal
neurotisation surgery is likely due to the paracrine neurotrophic
6 Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104
Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312104 on 21 September 2018. Downloaded from http://bjo.bmj.com/ on 24 September 2018 by guest. Protected by copyright.
support rather than direct sprouting, from the perilimbal trans-
planted nerve fascicles.57 This provides novel explanation to
the restoration of corneal nerves after corneal neurotisation but
requires larger controlled sample size.
Comparing reported outcome measures and data sets
Outcome measures to assess corneal nerve function
The main outcome measure in all published studies reporting cases
of corneal neurotisation was improvement in corneal sensation.
Terzis et al, Elbaz et al, Bains et al and Allevi at al48–50 53 all used
Cochet-Bonnet aesthesiometer to assess corneal sensation. Terzis et
al also used Von Frey hair aesthesiometry on one of the follow-up
visits to assess corneal sensation. Only Jacinto et al54 and Leyngold
et al56 used a wisp of cotton for this assessment. Sepehripour et al58
used surrogate measures to monitor outcome as corneal sensation
was not possible to be assessed in a 2-year-old and furthermore is
impractical in children under the age of 7. They reported complete
regression of corneal vascularisation at 10 months, reduced corneal
fluorescein staining and improved corneal clarity using Retcam
photography during examination under anaesthesia. Ocular lubri-
cants were gradually discontinued and tarsorrhaphy reversed. In
comparison with other studies, this certainly represents the most
dramatic rate of recovery, particularly considering only a single
nerve fascicle was coapted.
Assessing the structure of corneal nerves using in vivo
confocal microscopy and histopathology
IVCM is currently the gold standard and only method used
for real-time examination of the human cornea and conjunc-
tiva at the cellular level to evaluate both their physiological
and pathological states in the living eye.2 78 88 Fung et al89
published recently their results of two cases where they showed
the growth of corneal nerves after corneal neurotisation. To the
best of our knowledge, this is the first report in the literature
of using IVCM in assessing corneal nerves after corneal neuro-
tisation. This was followed by the more recent publication of
two cases by Ting et al using IVCM in assessing corneal nerves
postoperatively. This report was the first to describe the corneal
nerves histopathologically after corneal neurotisation in an evis-
cerated eye.57
Comparison of study results
Elbaz et al reported that one of their cases postoperatively
felt ipsilateral corneal tactile stimulation as if the examiner was
stroking the skin territory of the contralateral supratrochlear
nerve above the contralateral brow (table 1). This was 3 months
after surgery. Six months postoperatively, the same patient
reported that ipsilateral corneal stimulation was perceived as
originating from the ipsilateral cornea. Another case reported
the same pattern of response, but this time returned to normal
after 3 months only.49
We have performed 11 corneal neurotisation eyes at the time of
submission of this manuscript. The age range of our patients was
24–62 years. We operated on three male and eight female patients.
Two of the operated eyes were right and nine were left eyes, with
follow-up period exceeding 2 years for two patients. All eyes
showed improved trophic functions and ocular surface. Six corneas
had improved sensation at 3 months’ follow-up. No patients had
intraoperative or postoperative complications. Our follow-up
protocol includes IVCM for all patients (detailed results will be
included in another manuscript—currently under preparation).
 Table 1 
Outcome measure Terzis et al48 Elbaz et al49 Bains et al50 Jacinto et al54 Allevi et al53 Fung et al89 Lyengold et al56 Ting et al57 Weis et al59
Age range (years) 20–50 9–17 Four children (age range), 61 45 4,10 83 25, 39 35–77
one adult (age)
No of eyes 6 4 6 1 1 2 1 2 6
Gender 4 F, 2 M 1 F, 2 M NR F F 1 M, 1 F 1F 2M 5 M, 1 F
Duration of aetiology Mean 7 years (1–24) NR NR NR <1 year 6 and 12 years NR 3.7 and 14 years 23 months
Previous corneal grafts One tectonic PK 7.5 years Two cases failed PK- None None None None None None
prior to neurotisation. Two opacified
subsequent failed PKs
one failed tectonic PK 6
years prior to neurotisation
surgery
Aetiology FNP and TGN due to BSF, PFTS, CH, bilateral CCA Bilateral CCA, T, CNST LCN damage following FNP and TGN due to AN CCA and MGM Herpes zoster infection Cerebellopontine angle Trauma, herpes zoster
MGM, AN, T intraocular surgeries surgery MGM removal ophthalmicus, AN
Ocular complications Mackie stages 1, 2 Corneal perforation and/ Corneal ulceration and Absent corneal Corneal scarring, poor One case had recalcitrant PED and dense corneal Central corneal Corneal ulcer, corneal scarring
preoperatively and 3 or significant scarring opacification. Two cases had sensation and blink vision, inability to PED and subsequent stromal scarring involvement, corneal
from previous infectious opaque corneal transplants in all four quadrants, close eye corneal perforation, neovessels, keratinisation
keratitis. No detectable anterior stromal other had irregular
corneal sensation opacification, inferior epithelium, multiple PEDs,
neovascularisation, subepithelial and deep
epithelial defect stromal scarring and
neovascularisation
Assessment of outcome Cochet-Bonnet Cochet-Bonnet Cochet-Bonnet Wisp of cotton Cochet-Bonnet Cochet-Bonnet Wisp of cotton Cochet-Bonnet Forehead sensation, tissue paper
measures aesthesiometer, aesthesiometer aesthesiometer, Semmes- aesthesiometer aesthesiometer, IVCM aesthesiometer, IVCM, for CS, Schirmer test
Von Frey hair was Weinstein monofilaments Schirmer test
used on a single visit

Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104

Reported outcomes CS, synesthesia, CS CS, FS CS, VA Lagophthalmos, CS in CS, VA, morphology CS, corneal epithelial VA, nerves identified on Corneal epithelium integrity, VA,
VA, QoL four quadrants of epithelium, stroma, healing IVCM light touch CS
endothelium, nerve plexus
in sub-basal layer
Procedure Contralateral SOn Unilateral and bilateral Unilateral and bilateral Ipsilateral SOn transfer Contralateral SOn and Absence of Pedicled contralateral Same as Terzis et al48 Contralateral or ipsilateral
and STn transfer neurotisation, SURn graft. neurotisation, SURn graft. STn transfer contralateral SOn and SOn was harvested coaptation to SOn, end-to-end
E-Sc, contralateral STn E-Sc, contralateral STn STn was discovered endoscopically through fashion with SURn in four
intraoperatively in one small eyelid crease patients. Ipsilateral coaptation
case, and therefore SURn and scalp incisions and to STn nerve end-to-side in one
graft was coapted to the transferred to affected eye patient. Due to an anatomical
ipsilateral infraorbital variation resulting in a small SOn,
nerve instead. In the other a contralateral coaptation to SOn
case, SURn graft was and STn was performed in an
coapted to contralateral end-to-end fashion using SURn in
STn one patient
Symptoms reported during Transient discomfort Patients initially reported Continued ocular None None None Regain of motor and None
recovery and itching at mechanical stimulation comfort and improved sensory functions of
contralateral of the cornea felt as if vision forehead, awareness of
forehead cutaneous skin territory of sensation in eye
supratrochlear nerve being
stimulated. Later patients
shifted their perception
to recognise mechanical
stimulation of cornea as true
corneal sensation
Average time to sensation 2.8±2.17 years 6 months 6 months 8 months 6 months 6 and 8.5 months 3 months 9 and 13 months 6 months
restoration

Continued
Review

7
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 Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312104 on 21 September 2018. Downloaded from http://bjo.bmj.com/ on 24 September 2018 by guest. Protected by copyright.
Review
Denervation of the contralateral forehead and scalp

AN, acoustic neuroma; BSF, basal skull fracture; CCA, congenital corneal anaesthesia; CH, cerebellar Hhypoplasia; CNST, central nervous system tumour; CS, corneal sensation; E-Sc, end-to-side coaptation; F, female; FNP, facial nerve palsy; FS, forehead sensation; LCN, long ciliary nerve; M, male; MGM,
Direct contralateral nerve transfer48 risks denervating contralateral

meningioma; NR, not reported; PEDs, persistent epithelial defects; PFTS, posterior fossa tumour surgery; PK, penetrating keratoplasty; QoL, Quality of Life questionnaire (related to blink reflex, adaptation, overall wellness and satisfaction, home acceptance, workplace acceptance, self-consciousness
forehead sensation; however, Terzis et al48 reported itching and
pain in the area of the contralateral forehead but numbness of the
contralateral forehead resolved over a median of 3 months. Bains

Weis et al59
et al accessed only the supratrochlear nerve, through a small upper
lid incision, and preserved the supraorbital nerve to preserve fore-

None
head skin sensation. They reported ‘no detectable loss of forehead
sensation as measured by Semmes-Weinstein monofilaments’.

with light perception VA.

Eye was eviscerated due
to persistent ocular pain
recurrence of complete

years postoperatively.
corneal anaesthesia 2

and poor cosmesis

One patient had

Direct transfer versus interpositional nerve graft

Ting et al57

Once a nerve has been divided, the distal portion of the nerve
undergoes Wallerian degeneration while an axonal growth cone
develops and grows through the SC scaffolds, which form after
Wallerian degeneration. However, this process is hampered by
perineural scarring which occurs at the site of nerve coaptation.
Lyengold et al56

It stands to reason that the greater the number of coaptations,

the greater the degree of perineural scarring and the lesser the
final axonal count at the target organ. This has been illustrated
None

by a case–cohort study of 46 facial palsy patients (n=46) which

showed that direct nerve transfers had better outcomes as
compared with nerve-graft-assisted nerve transfers.89
As regards donor-site morbidity, direct nerve transfers negate
Fung et al89

the need to sacrifice a secondary nerve graft, however require

extended dissection of the primary nerve, a process that requires
None

more dissection and surgical time. The latter becomes more of

an issue if endoscopic-assisted nerve dissection is employed.56
Allevi et al53

Interpositional nerve graft coaptation

Clinicians appear to have moved to end-to-end coaptation of
None

the nerve graft to host nerve. There does not appear to be any
additional donor-site morbidity in comparison with end-to-side
and symmetry); SOn, supraorbital nerve; STn, supratrochlear nerve; SURn, sural nerve; T, trauma; TGN, trigeminal neuropathy; VA, visual acuity.

and outcomes in terms of rate of sensory recovery and end-point

re-innervation appears similar.49 50 58 90
Jacinto et al54

However, it must be said that all of the current literature citing

the use of nerve grafts, either ‘end-to-side’ or ‘end-to-end’, relate
None

to outcomes in the paediatric population where cortical plasticity

is at its peak and sensory readaptation is optimal.91 Terzis and
colleagues report that in the absence of significant sensory distur-
bances in the adult cohort, detailed analysis of the six patients in
that study indicates the best sensory outcome in the youngest of
Bains et al50

them; a 20-year-old.48 Weis et al reported improved corneal sensa-

tion in all six eyes operated on within 6 months postoperatively.59
None

There is currently no comparative data available to evaluate func-

tional recoveries in corneal re-innervation. However, evidence
from reviews on sensory recovery following peripheral nerve repair
supports the generally held view that the younger the patient, the
Elbaz et al49

greater the likelihood of recovery.92 A comparative series of nerve

grafts for corneal neurotisation procedures in the adult population
None

is necessary to gain some perspective.

subconjunctival
asymptomatic
Terzis et al48

Sensation and trophic functions

(evacuated),
haematoma
Subgaleal

neuroma

It has been recently shown that trophic function of the

ophthalmic branch of trigeminal nerve is independent to sensory
function and can be dissociated by disease or injury. Complete
Table 1 Continued

damage at the level of the nerve ganglion or distal to it along

Outcome measure

the course of the ophthalmic branch of the trigeminal nerve

results in corneal hypoesthesia and neurotrophic keratopathy,
complications
Postoperative

while partial damage at the level of the ganglion or proximal to

it results in hypoesthesia only, with preservation of trophic func-
tion considered essential to a healthy ocular surface.78
8 Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104

Sensory re-learning
Based on evidence from peripheral nerve injuries, the recovery
of sensory modalities and function of regenerated peripheral
nerve fibres and reinnervated mechanoreceptors is not uniform.
Recovery of touch sensation may be influenced by the number
and function of regenerated fibres, while tactile gnosis requires
the input and plasticity of the central nervous system.93 Further-
more, early re-learning can improve outcomes after median
and ulnar nerve repair.94 Rosén et al94 95 were able to enhance
functional outcomes using mirror visual feedback to stimulate
the sensory and motor cortex and reported a statistically signif-
icant improvement in one outcome (discriminatory touch) at 6
months. This evidence of discriminative change occurring due to
specific exercises directed at modulating cortical mapping raises
the possibility of potential sensory enhancement or re-learning
in improving either trophic or sensory function after corneal
neurotisation. Further studies to explore whether ocular surface
stimulation, for example, with either cold or warm ocular lubri-
cants, gentle corneal stimulation or NGFs, has a significant
impact on outcomes are needed.
As the sensory innervation of the bulbar conjunctiva is derived
mainly by long ciliary nerves from the ophthalmic branch of
the trigeminal nerve, monitoring of the sensation on the ocular
surface in the bulbar conjunctiva in cases of neurotrophic kera-
titis treated by corneal neurotisation should be included in the
outcome measures in future studies.
Amniotic membrane and NGF
The efficacy of cryopreserved amniotic membrane in the treat-
ment of severe dry eye disease and ocular surface involvement
has been traditionally attributed to its known anti-inflamma-
tory effect.96 However, amniotic membrane has an abundance
of neurotrophic factors, particularly NGF, which may also
contribute to promoting corneal nerve regeneration. This may
also be partly responsible for its lasting effect in severe dry eye
treatment.66 67 96Animal studies suggest evidence of improved
nerve growth and outcomes of motor neurotisation by sealing
amniotic membrane around nerve coaptations.65 68–73 Further
studies are needed to explore the role of available NGFs as an
adjunct to corneal neurotisation surgery.
International dataset
The wide range of techniques and reported outcome method-
ologies highlights the possible need for an international data-
base with a standardised dataset of outcome measures in order
to help clinicians involved in corneal neurotisation to improve
technique and outcomes by shared data and communication.
Cost of procedure
Corneal neurotisation requires a multidisciplinary surgical
approach with the involvement of up to three surgeons in an
operation lasting approximately 4 hours. In the UK, due to the
lack of an OPCS code, specifically for corneal neurotisation,
the baseline tariff used is that of a nerve graft procedure. In
the National Health Service setting, this is £1500, which for
the amount of resources required is not financially sustainable
for a corneal neurotisation service. This calls for a cost–benefit
approach to patients with corneal anaesthesia, in line with the
current healthcare mantra of ‘Getting it right the first time’.
In the UK, expect corneal neurotisation to gain ‘specialised
commissioning’ status to rectify this.
Malhotra R, et al. Br J Ophthalmol 2018;0:1–10. doi:10.1136/bjophthalmol-2018-312104
Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312104 on 21 September 2018. Downloaded from http://bjo.bmj.com/ on 24 September 2018 by guest. Protected by copyright.
Review
Contributors  RM planned for the review. RM and MSE designed the work and
provided first draft of figure. RM, MSE, RK, CN and SH edited the manuscript and
reviewed the literature. All authors provided final proof-reads.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-for-profit sectors.
Competing interests  None declared.
Patient consent  Not required.
Provenance and peer review  Not commissioned; externally peer reviewed.
Data sharing statement  This is a review article.
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