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The transcorneal electrical stimulation
as a novel therapeutic strategy against retinal and optic neuropathy: a review
of experimental and clinical trials
Ye Tao1,
Tao Chen2, Bei Liu3, Li-Qiang Wang1, Guang-Hua
Peng1, Li-Min Qin1, Zhong-Jun Yan3, Yi-Fei
Huang1
1Department of
Ophthalmology, Ophthalmology & Visual Science Key Lab of PLA, General
Hospital of Chinese PLA, Beijing 100853, China
2Department of Clinical Aerospace Medicine, the Fourth
Military Medical University, Xi’an 710032, Shaanxi Province, China
3Department of Neurosurgery and Institute for Functional Brain
Disorders, Tangdu Hospital, the Fourth Military Medical University, Xi’an 710038,
Shaanxi Province, China
Co-first authors: Ye Tao and Tao Chen
Correspondence to: Yi-Fei Huang. Department of Ophthalmology, Ophthalmology
& Visual Science Key Lab of PLA, General Hospital of Chinese PLA, Beijing 100853,
China. huangyf301@163.com; Zhong-Jun Yan. Department of Neurosurgery and
Institute for Functional Brain Disorders, Tangdu Hospital, the Fourth Military
Medical University, Xi’an 710038, Shaanxi Province, China. yzj0207@126.com
Received: 2015-06-29
Accepted: 2016-02-25
Abstract
Transcorneal
electrical stimulation (TES) is a novel therapeutic approach to activate the retina
and related downstream structures. TES has multiple advantages over traditional
treatments, such as being minimally invasive and readily applicable in a
routine manner. Series of animal experiments have shown that TES protects the
retinal neuron from traumatic or genetic induced degeneration. These laboratory
evidences support its utilization in ophthalmological therapies against various
retinal and optical diseases including retinitis pigmentosa (RP), traumatic
optic neuropathy, anterior ischemic optic neuropathy (AION), and retinal artery
occlusions (RAOs). Several pioneering explorations sought to clarify the
functional mechanism underlying the neuroprotective effects of TES. It seems
that the neuroprotective effects should not be attributed to a solitary
pathway, on the contrary, multiple mechanisms might contribute collectively to
maintain cellular homeostasis and promote cell survival in the retina. More
precise evaluations via functional
and morphological techniques would determine the exact mechanism underlying the
remarkable neuroprotective effect of TES. Further studies to determine the
optimal parameters and the long-term stability of TES are crucial to justify
the clinical significance and to establish TES as a popularized therapeutic
modality against retinal and optic neuropathy.
KEYWORDS: transcorneal
electrical stimulation; therapeutic strategy; retinal disease; optic neuropathy
DOI:10.18240/ijo.2016.06.21
Citation: Tao Y, Chen T, Liu B, Wang LQ, Peng GH, Qin LM, Yan ZJ,
Huang YF. The transcorneal electrical stimulation as a novel therapeutic
strategy against retinal and optic neuropathy: a review of experimental and
clinical trials. Int J Ophthalmol 2016;9(6):914-919
INTRODUCTION
Electrical
stimulation is a promising therapeutic tool against various neurological
disorders such as the stroke, tinnitus and hyperalgesia. Several laboratory and
clinical studies on electrical stimulation have demonstrated significant
beneficial effects with optimum safety and tolerability profiles[1-5]. For the eye, transcorneal
electrical stimulation (TES) and transorbital electrical stimulation are both
noninvasive approaches to activate the retina and downstream structures and
thereby exert therapeutic effects on the subjects. Series of animal experiments
have shown that they can protect the retinal neurons such as retinal ganglion
cells (RGCs) and photoreceptors from traumatic or genetic induced degeneration,
and ameliorates the visual function loss[6-9]. These
therapeutic evidences support its utilization in ophthalmological therapies
against various retinal and optical diseases: TES has been adopted to induce
positive effects on patients with retinitis pigmentosa (RP), traumatic optic
neuropathy, anterior ischemic optic neuropathy (AION), and retinal artery
occlusions (RAOs) with negligible complications[10-13].
Recently,
there is an upsurge of researches concentrate on the candidate mechanism of the
TES induced benefits[14-16]. It has
been proposed that multiple mechanisms would be responsible for the remarkable
effects. Moreover, the exact pathway of the TES induced neuroprotective effects
seem to vary among different pathology types. These investigations delineate
the precise mechanism underlying the pathophysiological process that would be
instrumental to repeat the experimentally attained effects, and enhance
clinical efficacy. In the present paper, the implementing measures of TES,
beneficial effects on various disease categories, together with related
mechanism and cellular principles, are systematically reviewed.
TRANSCORNEAL
ELECTRICAL STIMULATION APPLICATION
The
TES is readily available and relatively practicable: a bipolar contact lens
electrode or a microfiber DTL electrode is placed on the cornea of the
subjects after superficially anesthesia, and then the electric current pulses
that generated by an electronic pulse generator are delivered through a
stimulus isolation unit; another inactive electrode is placed on the skin
around the eye to act as the reference electrode.
The
existence of an optimal stimulated protocol that generally applies to all
subjective species is not realistic. The stimulation parameters such as the
pulse duration, current intensity, stimulation frequency, stimulation duration,
and repetition times should be adjusted reasonably, and varied according to
pathological types and subjective species[8,11]. For
example, the suggested current intensity of TES for photoreceptor protection in
rats (300 μA, 3ms/phase) is higher than that for RGCs survival (100 μA,
1ms/phase)[7,17]. In human, the threshold
intensity should be adjusted necessary to elicit phosphenes in both the
peripheral and central visual fields, and generally range between 300-900 μA[18]. A positron emission tomography
(PET) study found that TES resulted in retino-topographically matched primary
visual cortex activation and led to visual perception in both normal-sighted
controls and retinal degenerative patients. However, the threshold current
needed to evoke phosphene is significantly higher in the retinal degenerative
subjects compared to normal-sighted controls[19].
On the other hand, chronically high intensity stimulus is not proposed for the
potential damage to retinas or corneas. Therefore, advisable TES protocols for
individual patients should be designed to attain optimum therapeutic benefits
and to exclude possible side effects.
Transcorneal Electrical Stimulation
Induced Protection Against Photoreceptor Degeneration RP is a
hereditary disease characterized by the progressive photoreceptor degeneration
and no satisfactory therapy exists thus far[20-21]. TES
can alter the electrical activity or electrical charge balance of
photoreceptors and exert a neuroprotective effect on the degenerative retinas.
It has been demonstrated that TES promoted the survival of photoreceptors and
preserved the retinal function of the Royal College of Surgeons (RCS) rat, a
hereditary RP animal model[6]. The fundus
was examined at the end of the experiments, and neither retinal detachment nor
vitreous hemorrhage was observed in these TES treated eyes, indicating that the
TES was harmless to the vitreous or retinal tissues in the RP models and
providing positive safety profiles for the TES therapy. In another transgenic
RP model-the rhodopsin P347L transgenic rabbit, the TES was also proven to be
effective, implying that this protection on the degenerative retina was
independent of the initiated mutation cause[22].
Intriguingly, different photoreceptors showed different sensitivities to the
TES: the ERG examination found that TES preserved the cone components better
than rod components of the treated rabbits.
Although
the safety and efficacy of TES may be easily verified and more readily
acceptable in RP animal models, it remains challenging to prove these virtues
in RP patients. The natural course of disease progression in RP patients can be
highly variable as the tremendous heterogeneity implied in the initiating
mutation: sometimes with years of stagnation at any level followed by sudden
worsening, sometimes occurring rapidly within weeks[23-24].
This fact and the decades-long, heterogeneously genetically determined
degenerative processes make RP inherently difficult to prove therapeutic
efficacy of any treatment. So far, only a prospective, randomized,
sham-controlled preliminary clinical trial with a sample size of 24 RP patients
could be referred: the positive trends in the vision field (VF) area and
scotopic electroretinogram (ERG) were found in these TES treated patients
compared with the sham controls[10].
Furthermore, they found that the application of 30min TES weekly of for 6
consecutive times was tolerated well and the investigator suggested the TES
induced benefits in RP patients should be transferred to other ocular diseases
cautiously, especially to those in which growth factors play an important role,
such as diabetic retinopathy or age-related macular degeneration (AMD).
The
popularized mechanism suggested to explain the neuroprotective effects is that
TES could up-regulate the expression levels of endogenous neurotrophic factors,
and simultaneously enhance the neurons’ intrinsic sensitivity to these factors.
After TES, the mRNA and protein levels of insulin-like growth factor-1 (IGF-1),
brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF),
and vascular endothelial growth factor (VEGF) increased significantly in the Müller
cells, which were crucial to activate the intrinsic survival system and
maintain the microenvironment homeostasis[6-7,13,15,25].
Moreover, the thinning of the vascular plexus and the obliteration of vessels
in the RP retinas would drastically restrict the retinal blood circulation and
relate to the nourishment deficiency. In view of this fact, the vasodilatory
function of TES may also contribute to the neuroprotective effects in the RP[21]. On the other hand, TES could
increase the expression levels of the B-cell lymphoma 2 (Bcl-2), while
down-regulate the expression levels of Bax and tumor necrosis factor (TNF)
super family in degenerative retinas[7,26]. These
bioactive factors act as key executors of the photoreceptor apoptotic program
and indicate that the TES could rectify the abnormities in the apoptotic
cascade, thereby preventing themselves from programmed death. Also, a
regulation effect of TES on the activator protein 1, an initiator of photoreceptor
degeneration, may also be involved[27-28].
Apoptosis is as recognized as the final common death pathway in all RP
phenotypes, although tremendous genetic heterogeneity exists in this disorder.
The existence of a common cell death mechanism (e.g. apoptosis) triggered off by different gene defects may provide
a mutation independent therapeutic target which could be generalized to RP
patients with different etiologic causes. Therefore, TES may act as a more
promising and general strategy for RP treatment in the future.
Chronic
inflammation is considered to be another etiologic factor of RP, although, it
is still unclear whether it is a central or minor contributor to the RP
pathogenesis[29-30]. More recent studies have
highlighted the activation of microglia in RP retina preceding photoreceptor
death: the highly toxic and inflammatory microglia phenotype, which is
designated as the “activated state”, can release a variety of highly
inflammatory cytokines, reactive oxygen species, nitrogen intermediates and
excitotoxins, which are hazardous to photoreceptors[31-33].
Additionally, activated microglia could influence the secondary neurotrophic
factor expression in Müller glial and indirectly modulate photoreceptor
survival[34]. Thus, restraining the proinflammatory
secretion of microglia and “resting” the superactivated microglia are crucial
to arrest the photoreceptor degeneration in RP retinas. Recently, an in vitro study found that the
application of trans-culture well electrical stimulation could ameliorate the
light-induced photoreceptor degeneration via
suppressing the proinflammatory effects of the microglia[14].
These exciting results suggest that the electrical stimulation is
anti-inflammatory, and if it is applied via
the trans-corneal pathway, the chronic inflammatory response of the RP patients
might be ameliorated. These possibilities remain to be verified by further
clinical investigations.
Moreover,
the TES was also shown to be beneficial in the best vitelliform macular
dystrophy (BVMD), an atrophy of the retinal pigment epithelium which then
affects the photoreceptors and leads to an impairment of central visual
function[35]. The case report showed that
the best-corrected visual acuity (BCVA) significantly improved for 2mo after
only two TES treatments. Consequently, both the clinical case reports and
laboratory evidences strongly indicate that TES is a safe, effective, and
readily available approach to protect against photoreceptor degeneration.
Further large case series studies with longer durations are be necessary to
establish TES as a popularized therapeutic modality for retinal and optical
nerve disorders.
Protective Effects of Transcorneal
Electrical Stimulation Against Ischemic Retinal Diseases RAOs usually
lead to permanent retinal damages and functional impairments, and in which the
central retinal artery occlusion (CRAO) act as especially terrible impediments
due to the blockage of retinal blood flow to the macula. Clinically studies
have found that TES improves visual functions in both the CRAO and the branch
retinal artery occlusion (BRAO) cases[13,18].
Examined with the Humphrey field analyzer, it was found that even these
longstanding cases had at least 3 dB augments in the mean deviation of the
visual fields after TES treatment. More importantly, multifocal
electroretinograms (mfERGs) examination showed that the amplitudes and implicit
time of all component waves were improved after the TES treatment, indicating
that TES had beneficial effects on both the inner and outer retinal neurons of
these RAO patients.
The
ability to attenuate the glutamate-mediated excitotoxicity in retinas could act
as one of the potential mechanisms that contribute to the TES induced
neuroprotective effects. Excessive exposure to glutamate is an essential
element to trigger a self-reinforcing destructive cascade involving calcium
influx and oxidative stress in the retinas[36-37]. A
novel investigation indicated that TES can protect RGCs against ischemic
insults in an ocular hypertension-induced retinal ischemia model, and the
markedly functional and morphological restorations are closely related to the
increasing levels of glutamine synthetase (GS) localized in the Müller cells[8]. Induction of GS expression protects
against neuronal degeneration while inhibiting GS activity causes neurons more
susceptible to injuries[38-39]. These
experimetal evidences verified that TES can affect the glutamate metabolic
process by enhancing the expression of GS, and thereby alleviated the ischemic
retina from glutamate-mediated excitotoxicity[8].
Another
underlying mechanism responsible for the TES induced protection against
ischemic retinal diseases would be the vasodilation effects. TES could increase
the retinal blood flow and improve the visual impairment induced by ischemic
insults[12]. A sham controlled study
based on the healthy human subjects suggested that a single application of TES
increased the retinal blood flow within 30min and persisted for at least for
40h while minimal effect was found on the systemic blood circulation and the
intraocular pressure (IOP). This vasodilation effect is sustainable and the
investigator hypothesized that TES might stimulate the synthesis of some
molecules to mediate the dilation of retinal vessels.
Neuroprotective Effects of Transcorneal
Electrical Stimulation Against the Optic Neuropathy Electric
stimulation is known to trigger off axonal regeneration, axon sprouting and
promote RGCs survival[40-41]. In vivo studies based on the optic nerve
crush (ONC) rat model displayed that TES significantly delayed the
post-traumatic RGCs death and the optic nerve benefited in long-term from TES
treatment[42]. TES could reduce
ONC-associated neuronal swelling and shrinkage especially in RGCs which
survived in long-term. TES would not only delay degeneration dynamics, but also
change the pathophysiology of early post-traumatic processes as indicated by
the less affected soma size of RGCs. Morimoto et al[9] reported
that TES could rescue the axotomized RGCs and promote the axonal regeneration of
injured RGCs in rat retinas. They defined in more detail the stimulation
parameters which lead to the most effective neuroprotection against optic nerve
cut. Miyake et al[43]
reported that a single TES given immediately after partial optic nerve injury can
induce a rapid functional recovery of visual evoked potentials (VEPs)
within hours and protect RGCs axons from the ensuing degeneration with slower
time course.
In
a clinical setting, such a delay of posttraumatic cascades and an induced
stability of the neuronal morphology would be advantageous to provide
additional time-window for early post-lesion therapeutic intervention. A recent
clinical study already verified that TES could improve the visual function of
the patients with traumatic optic lesions (TON) or nonarteritic ischemic optic
neuropathy (NION)[11]. An
improvement in visual acuity was defined as a change of > or =0.3 log
minimum angle of resolution (logMAR) units and it was found in
two patients with NAION and in four patients with TON. This
visual function recovery was relatively modest, and could be partially due to
the duration of TES application from the onset was late.
Neuroprotective Effects of Transcorneal
Electrical Stimulation on the Light Induced Retinal Injury Excessive
exposure to light induces irreversible visual dysfunction and photoreceptor
degeneration partly resembles that of RP and AMD patients. Moreover, the light
induced photoreceptor degeneration proceeds relatively faster and in a more
synchronized way than that of the hereditary mode. Therefore, this reproducible
model is now universally utilized in the explorations of photoreceptor
degeneration[44-45]. A sham-controlled study
showed that TES can protect photoreceptor against mild light-induced
degeneration in the Sprague Dawley rats[46]. Recently,
Ni et al[7]
reported the TES induced anti photo-toxicity effect might stem from the
modulation of an imbalance between the intrinsic survival system and the
apoptotic cascade signaling. Neutralizing this subtle imbalance could block
crucial steps in the programmed cell death to maintain cellular homeostasis,
which had been suggested as a key element for the TES induced neuroprotection.
Furthermore, TES resulted in the down-regulation of proinflammatory cytokines
which also constituted a nurturing environment suitable for the survival for
the light damaged photoreceptor cells[14]. In
greater detail, it was found that TES provided better preservation in the
central retina than the peripheral retina, and this regional difference may be
caused by the asymmetrical distribution of the relative low-density current as
it preferred to go through the vitreous via
a low-impedance path such as the optic nerve, which is located in the central
retina[7]. Another assumption is a better
intraretinal circulation and higher expression of neuroprotective factors in
the central retina after TES. It is especially noteworthy that BDNF might act
as the most important molecules than other Müller cells derived factors to
facilitate the survival of photoreceptor cells in light damaged retinal[7].
An
in vitro study on the light-induced
photoreceptor degeneration suggested that electrical stimulation had a
prominent inhibitive effect on the microglia secretion of interleukin (IL)-1β and
TNF-α[14]. Furthermore, electrical
stimulation significantly restrained the light-damage induced microglia
activation and promoted the trophic Müller cell reaction, as verified by the
decreased the numbers of ameboid shape microglia cells and the increased
numbers of reactive Müller cells. These findings indicate the potential
anti-inflammatory mechanism is involved in the neuroprotective effects of
electrical stimulation, and it would be rational to create a nourishing
microenvironment that characterized by the diminished microglia activation and
the fortified Müller cells reactive gliosis[47-48].
The Primary
Principle of the Transcorneal Electrical Stimulation Induced Cellular
Activation Several
physiological investigations sought to clarify the primary principle by which
the electrical stimulation activates retina neurons and exerts beneficial
effects on retinal neurons. The most plausible theory is that electrical
stimulation could change the functional status of retinal neurons by adjusting
the activity voltage-gated ion channels. The retinal neuron membrane is rich of
the voltage-gated ion channels, which are reactive to extracellular electric
changes and leading a central role in the visual signal transmission[49-52]. For example, it has been
verified that the electrical stimulation enhances the Ca2+ influx
through the L-type voltage-gated channels and triggers off neurotrophin
exocytosis[25]. Moreover, the Ca2+
influx can activate an anti apoptotic cellular pathway[53].
Therefore, it seems feasible that TES induces calcium influx in the retinal
cells by activating the voltage-gated Ca2+ channels, and thereby
initiate the Ca2+ mediated neuroprotection. Additional
pharmacological experiments using various channel blockers are needed to
explore whether the functional mechanism of the TES conform to this rule.
Recently,
an electrophysiological study was established on the base of optic imagining
technique. It was found that the TES induced reflectance changes in the retinal
neurons represented the secondary hemodynamic responses to neural activity[54-55]. Therefore, it can be deduced
that TES does not activate the retinal neurons or vessel independently. On the
contrary, it might extensively act on the “neurovascular coupling”, which
stands for the fundamental relationship between the neural activity, blood
flow, and cellar metabolism.
DISCUSSION
There
is an upsurge of interests concentrate on the mechanism of the TES induced
protective effects against the retinal and optic pathology[13-14,26,48].
Generally, five theories are prevailing: 1) vasodilatory mechanism; 2)
neurotrophic mechanism; 3) anti-apoptotic mechanism; 4) anti-glutamate
mechanism; 5) anti-inflammatory mechanism. However, the exact pathway
responsible for the TES induced neuroprotection has not been determined definitively.
On one hand, the exact mechanism underlying the TES induced neuroprotection
seems to be varied according to the specific pathology type. On the other hand,
multiple mechanisms might collectively contribute to maintain cellular
homeostasis and promote cell survival. For example, at least three potential
protective mechanisms should be responsible for the anti phototoxicity effects
of TES: TES simultaneously regulates the expression of both
apoptosis-associated genes and retinal neurotrophic factors to neutralize the
intrinsic survival microenvironment of light damaged retinas. Meanwhile, the
TES-induced anti inflammatory effects are also involved in the whole
amelioration process. These experimental and clinical studies might have
considerable impacts on the potential use of TES to protect the retina and
optic nerve from trauma or diseases.
ACKNOWLEDGEMENTS
Foundation: Supported by the National Key Basic
Research Program of China (973 Program, No. 2013CB967001).
Conflicts of Interest: Tao Y, None; Chen T, None; Liu B, None; Wang LQ, None; Peng GH, None;
Qin LM, None; Yan ZJ, None; Huang YF, None.
REFERENCES
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Y, Mihashi T, Kitaguchi Y, Nishida K, Fujikado T.
Characteristics of retinal reflectance changes induced by transcorneal electrical stimulation in cat eyes.
PLoS One 2014;9(3):e92186. [CrossRef] [PubMed] [PMC free article]
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