Benefit

What can TES therapy offer my patients?

In Germany, around 20,000 to 30,000 people are affected by retinitis pigmentosa (RP) and are therefore starting to go blind. As a rare retinal disorder it is less in the public’s focus and funds to research the disease and possible treatments are generally directed towards diseases with more common indications, such as age-related macular degeneration (AMD).
With transcorneal electrical stimulation (TES) therapy, Retina Implant now offers a scientifically proven outpatient therapy option for patients with early and middle-stage RP. In this way, people with residual vision can benefit in particular by positively influencing the course of their RP.
The RI OkuStim system uses weak electrical impulses to activate neuroprotective growth factors in the retina. These factors can generate a protective effect on the dying retinal cells, thus maintaining sight for longer.
After receiving instruction from medical personnel, patients can carry out the TES therapy themselves at home with the RI OkuStim system.
Offer your patients the opportunity to slow the progression of their disease now.

 

 

Analyses carried out by Massof et al. have shown an exponential reduction of the visual field with an average time constant of approximately 4,5 years.1 During this time, the remaining visual field of an RP-patient decreases in each case by 50%.1

 

Function

Studies2,10 have shown that the therapy with electrical stimulation activates a number of neuroprotective growth factors, which helps to preserve cells in the retina (Ni et al. 2009 andFu et. al. 2015).  It offers the chance to slow down the progression of the disease. People with residual vision can benefit in particular from retaining their sight for longer (for more details, see the section entitled “Use”).

Three components are required in order to be able to implement transcorneal electrical stimulation (TES) using the RI OkuStim system.

 

The RI OkuStim hand-held unit

The RI OkuStim hand-held unit is a mechanically stable, external component. It measures approx. 20 cm x 10 cm x 4 cm and is operated with four AA alkaline batteries. The TES user can switch the RI OkuStimhand-held unit on and off, as well as pause and start the stimulation session, via three buttons. The patient’s individual treatment parameters are saved on the USB memory card of the RI OkuStim device. These are programmed by a doctor prior to the start of treatment. The device not only displays information but also emits sounds so make it easier to use the system even with limited vision.

 

The RI Oku Elelectrodes

The RI OkuElelectrode delivers the individual dose of stimulation to the eye. During use, the RI OkuSpex frame is set up so that the electrode threads lie underneath the pupil on the surface of the eye. When the eye is closed, the patient can generally barely feel them. With a little practice, the electrodes can also be inserted into the RI OkuSpex frame independently, even with partial sight.
The silver-coated electrode threads measure just 100 µm and are hand-made. The RI OkuEl electrodes are sterile, single-use products.

 

The RI OkuSpex frame

The RI OkuSpex frame positions the RI Oku Ellectrodes directly on the eye. The design of the frame is such that it can be adjusted to any face shape.

 

 

Modes of action

Basic research into transcorneal electrical stimulation

The effects of transcorneal electrical stimulation (TES) in retinitis pigmentosa (RP) and other types of retinal degeneration have been investigated using various animal models. One widely used animal model for RP is Royal College of Surgeons (RCS) rats. The electrical stimulation in this model resulted in a deceleration of what is otherwise a fast-progressing degenerative process for the RCS rats, compared with sham stimulation (Morimoto et al., 2007). Rabbits carrying the rhodopsin P347L gene, as well as photodamaged rats, showed lower loss of photoreceptors and retained their outer nuclear layer for longer with retinal degeneration following electrical stimulation (Schatz et al., 2012; Ni et al., 2009; Morimoto et al., 2012). Furthermore, rats with optic nerve neuropathy also showed an induction of regenerative processes and reacquisition of sight following electrical stimulation (Miyake et al., 2007; Morimoto et al., 2005).

 

Influencing factors for the neuroprotective effect of TES

According to Fu et al., the positive effects are due to the modulation, elevation and release of neuroprotective substances by the Müller cells (Fu et al., 2015). Numerous trials have proven the positive effects on growth factors and apoptosis regulators, such as: 

  • Insulin-like Growth Factor 1 (IGF-1; Sato et al., 2008a; Tagami et al., 2009)
  • Fibroblast Growth Factor-2 (FGF-2; Sato et al., 2008c; Ciavatta et al., 2009; Pardue et al., 2005)
  • Ciliary Neurotrophic Factor (CNTF; Ni et al., 2009)
  • Brain Derived Neurotrophic factor (BDNF; Ni et al., 2009; Sato et al., 2008b)
  • Anti-apoptotic Gene B-cell-lymphoma-2 (Bcl-2; Ni et al., 2009)
  • Bax Gene (Ni et al., 2009).

It has also been shown that TES can lead to changes in the transcriptome with a neuroprotective effect (Willmann et al., 2011). In 2011, Wang et al. observed the increased secretion of glutamine synthetase by the Müller cells, which resulted in the alleviation of the neuro-excitotoxicity caused by glutamate. The neural cell depolarisation caused by TES (Ca2+ influx) appears to contribute to an increase in intracellular adenosine monophosphate (cAMP), which thus promotes the survival of retinal cells (Morimoto et al., 2002). Furthermore, TES has been shown to contribute to improved chorioretinal circulation (Kurimoto et al., 2010).

 

Conclusions

Numerous studies show that TES activates neuroprotective systems and induces regeneration processes that slow or even prevent retinal degeneration. This also reduces the degradation of affected cells, which helps to maintain the function of existing cells for longer.

 


Literature
Ciavatta VT, Kim M, Wong P, Nickerson JM, Shuler RKJr, McLean GY, Pardue MT (2009) Retinal Expression of Fgf2 in RCS rats with subretinal microphotodiode array. Invest Ophthal. Vis Sci., 50:4523-30.
Fu L, LO AC, Lai JS, Shih KC (2015) The role of electrical stimulation in ophthalmic diseases. Graefe’s Archive for Clinical and Experimental Ophthalmology; 253: 171-176.
Fujikado, T. Ni YQ, Gan DK, Xu HD, Xu GZ, Da CD (2009) Neuroprotective effect of transcorneal electrical stimulation on light-induced photoreceptor degeneration. Exp neurol., 219: 439-452.
Kurimoto T, Oono S, Oku H, Tagami Y, Kashimoto R, Okamoto N, Ikeda T, Mimura O (2010) Transcorneal electrical stimulation increases chorioretinal blood flow in normal human subjects. Clin Ophthalmol., 4: 1441-1446.
Miyake K, Yoshida M, Inoue Y, Hata Y (2007) Neuroprotective effect of transcorneal electrical stimulation on the acute phase of optic nerve injury. IOVS, 48: 2346-2361.
Morimoto T, Fijukado T, Choi JS, Kanda H, Miyoshi T, Fukuda Y, Tano Y (2007) Transcorneal electricla stimulation promotes the surviva of photoreceptors and preserves retinal function in royal college of surgeons rats. Invest Ophthalmol Vis Sci., 48: 4725-4732.
Morimoto T, Miyoshi T, Fujikado T, Tano Y, Fukuda Y (2002) Electrical stimulation enhances the survival of axotomized retinal ganglion cells in vivo. Neuroreport 13(2):227–230.
Morimoto T, Miyoshi T, Matsuda S, Tano Y, Fujikado T, Fukuda Y (2005) Transcorneal electrical stimulation rescues axotomized retinal ganglion cells by activating endogenous retinal IGF-1 system. Invest Ophthalmol. Vis. Sci., 46: 2147-2155.
Morimoto T, Kanda H, Kondo M, Terasaki H, Nishida K (2012) Transcorneal electrical stimulation promotes survival of photoreceptors and improves retinal function in rhodopsin P347L transgenic rabbits. Invest Ophthalmol Vis Sci., 53: 4254-4261.
Ni et al. (2009) Neuroprotective effect of transcorneal electrical stimulation on light-induced photoreceptor degeneration, Experimental Neurology 219, 439–452
Pardue MT, Phillips MJ, Yin H, Sippy BD, Webb-Wood S, Chow AY et al (2005) Neuroprotective effects of subretinal implants in the RCS rat. Invest Ophthalmol Vis Sci 465: 674-682
Sato T, Fujikado T, Morimoto T, Matsushita K, Harada T,Tano Y (2008a) Effect of electrical stimulation on IGF-1 transcription by L-type calcium channels in cultured retinal Muller cells. Jpn J Ophthalmol., 52:217-223Sato t, Fujikado T, Lee TS, Tano Y (2008b) Direct effect of electrical stimulation on induction of brain-derived neurotrophic factor from cultured retinal Muller cells. Invest Ophthalmol Vis Sci.; 49:4641-4646.
Sato T, Lee TS, Takamatsu F, Fujikado T (2008c) Induction of fibroblast growth factor-2 by electricalstimulation in cultured Muller cells. Neuroreport; 19:1617-1621.
Schatz A, Arango-Gonzalez B, Fischer D, Enderle H, Bolz S, Röck T, Naycheva L, Grimm C, Messias A, Zrenner E, Bartz-Schmidt KU,  Willmann G, Gekeler F (2012) Transcorneal Electrical Stimulation Shows Neuroprotective Effects in Retinas of Light-Exposed Rats. Invest Ophthalmol Vis Sci, 53: 5552 -5561.
Tagami Y, Kurimoto T, Miyoshi T, Morimoto T, Sawai H, Mimura O (2009) Axonal regeneration induced by repetitive electrical stimulation of crushed optic nerve in adult rats. Ophthalmology, 53: 257-266.
Wang X, Mo X, Li D, Wang Y, Fang Y, Rong X, Miao H, Shou T (2011) Neuroprotective effect of transcorneal electrical stimulation on ischemic damage in the rat retina. Exp Eye Res 93(5):753–760.
Willmann G, Schäferhoff K, Fischer MD, Arango-Gonzalez B, Bolz S, Naycheva L, Röck T, Bonin M, Bartz-Schmidt KU, Zrenner E, Schatz A, Gekeler F (2011) Gene expression profiling of the retina after transcorneal electrical stimulation in wild-type Brown Norway rats. IOVS., 52: 7529-7537.

Use

Suitability for therapy

Transcorneal electrical stimulation (TES) therapy with the RI OkuStim system is suitable for patients over the age of 18 who are affected by the retinal degeneration disorder retinitis pigmentosa (including as a symptom of another illness such as Usher syndrome) and who are still at least able to perceive light. It may offer the chance to slow down the progression of the disease. Young people and people of working age in particular can benefit from maintaining their vision for longer (for more details, see the section entitled “Use”).

According to the AKF, the clinical issues working group of the Scientific Medical Board of PRO RETINA Deutschland e.V., there are no objections to treating retinal dystrophies such as rod-cone dystrophy or choroideremia with TES. However, this would constitute off-label use.

 

    Exclusion criteria

    • Diseases that could be triggered or worsened by negative growth processes of the retina following TES therapy, e.g. ocular neovascularisation, macular oedema, arterial or venous occlusion, diabetic retinopathy or age-related macular degeneration. Because the TES therapy promotes growth processes and chorioretinal circulation, these processes are contraindicated for the above-named diseases.
    • Severely acute or chronic diseases (medical, psychiatric, other abnormal findings) that could worsen as a result of the therapy. Any disease that may have a negative impact on the therapy, or vice versa (e.g. epilepsy), must be carefully evaluated before any treatment takes place.
    • Pregnancy or breastfeeding.
    • Other active implants, because reciprocal effects cannot be ruled out. One exception is a cochlea implant, provided it is deactivated and the external components are removed.

    How can your patient start the therapy?

    Your patients can access TES therapy with the RI OkuStim system at our certified RI Competence Centres. These are specialised in degenerative retinal disease and are usually university hospitals with a wealth of experience in diagnosing RP and caring for affected patients. These clinics usually have special retina or even RP consultations in order to be able to adequately address the needs of the patient.

    These centres are trained by product specialists from Retina Implant in the use of the RI OkuStim system, the suitability of patients for treatment, determining and setting individual patient therapy parameters, and in caring for patients with regular check-ups (see also “Therapy process”).

     

     

    Determining the therapy parameters in the RI Competence Centre

    Following the medical examination, an individual adjustment of the therapy parameters for the patient in question is necessary in order to apply the TES therapy. To do this, the RI Competence Centre has access to a special piece of software that determines the individual phosphene threshold of the patient using the RI OkuStim system. The phosphene threshold is the strength of the electric current at which a patient starts to perceive phosphenes in their field of vision. Trial results showed the positive effects of TES with stimulation above the patient’s individual phosphene threshold, ideally 200% of the threshold current.

    The stimulation parameters are saved on a special memory card, which can be read by all RI OkuStim systems. The card also saves the data from each application so that the relevant competence centre can obtain an overview of the stimulation sessions carried out. The stimulation parameters cannot be changed by the patient.

     

     

    Therapy process

    Once the therapy parameters have been established by the RI Competence Centre, the patient has several options available for the therapy itself. The stimulation sessions can either be carried out independently, by a certified low-vision optician or directly in a RI Competence Centre. The TES therapy is carry out weekly with a duration of 30 minutes.The following diagram depicts the complete therapy process with all of its steps.

    Therapy process for TES therapy with the RI OkuStim system:

     

    Clinical trials

    Numerous clinical trials carried out before the development of the RI OkuStim system indicated the potential of transcorneal electrical stimulation (TES) for the treatment of various eye diseases. Some of these diseases include arterial occlusion (Oono et al., 2011; Inomata et al., 2006), non-arteritic ischaemic optic neuropathy (NAION) and traumatic optic neuropathy (TON) (Fujikado et al., 2006) and age-related macular degeneration (AMD) (Shinoda et al., 2008). This basic research formed the basis for several clinical trials.

     

     Pilot study
    "EST I"
    Long-term study
    "EST II"
    Observational study
    "TESOLA"
    Trialdurations2009 ... 2010     2012 ... 20132012 ... 2015
    EndpointsSafety
    Efficacy
    Efficacy
    (Safety)
    Safety
    Patients per protocol245297
    Number of weeks stimulation65224
    Randomised / sham stimulationYesYesNo
    (Other eye was not
    stimulated)
    Trial sitesTübingenTübingen

    11
    (Oslo, Copenhagen, Oxford,
    London, Berlin, Rotterdam,
    Siegburg, Bonn, Regensburg,
    Tübingen, Florence)

    PublishedIOVS June 2011,
    Vol.52, No. 7
    IOVS January 2017,
    Vol. 58, No.1
    in preparation

     

    EST I – Pilot study on transcorneal electrical stimulation in RP

    EST I (Schatz et al., 2011) was the first clinical trial investigating the efficacy of TES in people with RP. 24 patients were treated over a period of six weeks, their field of vision tested and an ERG conducted. The trial participants were randomly assigned to one of three groups: sham stimulation, stimulation with 66% or with 150% of their individual phosphene threshold (phosphene = light perception), which was in this case was triggered via direct stimulation of the visual system by TES).

     

    Results

    The group stimulated with the highest current strength (150%) showed a significant increase in their field of vision and an improvement in their dark-adapted b-wave amplitude (ERG).

     

    EST II – Long-term study on transcorneal electrical stimulation in RP

    The aim of EST II (Schatz et al., 2017) was to investigate the safety and efficacy of TES over the longer term. In this trial, 52 patients were stimulated using the RI OkuStim system once a week over a period of a year. All patients applied the stimulation themselves at home.
    The patients were randomised into one of three groups: sham stimulation, 150% or 200% of their individual phosphene threshold. Field of vision, light-adapted and dark-adapted ERGs, visual acuity, eye pressure and other parameters were recorded regularly during the course of the study.

     

     

    Results

    EST II showed significant improvements in light-adapted b-wave amplitude (Fig. 1) in the 200% and 150% groups (ERG). The results of EST I with regard to dark-adapted ERG response could not be significantly replicated, however. This could be due to the fact that the mode of action of TES on the cones and rods changes depending on the stage of the disease. The more advanced the disease, the fewer rods are still intact in the RP patient.

     

    TESOLA – Clinical follow-up study

    TESOLA is a multicentric clinical follow-up study that was carried out in cooperation with eleven European sites (Jolly et al., in preparation). The aim was to investigate the safety of TES. Over a period of six months, 105 patients received TES on one eye at a strength of 150% of their individual threshold. The other eye was used as a control. The stimulation phase was followed by six months without stimulation, with follow-up checks in months 3 and 6.

     

    Results

    This study also demonstrated the safety of TES with the RI OkuStim system. The most common side effect was dry eyes (sicca) during the stimulation process (Fig. 3). However, this could be resolved by administering tear substitutes and never lasted longer than 24 hours.

     

    Conclusions

    Increased cell activity was shown in all studies. This leads us to the conclusion that TES has the potential to positively counteract the progression of RP. The therapy has been proven to be safe. Neither the trials nor the clinical follow-up study recorded any serious adverse events (SAEs) that were due to the therapy.

    TES therapy with RI OkuStim offers your patients the chance to slow the progression of retinitis pigmentosa.

     


    Literature
    Fujikado T, Morimoto T, Matsushita K, Shimojo H, Okawa Y, Tano Y  (2006) Effect of transcorneal electrical stimulation in patients with nonarteritic ischemic optic neuropathy or traumatic optic neuropathy. Jpn.J.Ophthalmol., 50: 266- 273.
    Gekeler F, Messias A, Ottinger M, Bartz-Schmid KU, Zrenner E  (2006)  Phosphenes electrically evoked with DTL electrodes: a study in patients with retinitis pigmentosa, glaucoma, and homonymous visual field loss and normal subjects. Invest Ophthal. Vis Sci  47, 4966–74.
    Inomata K, Shinoda K, Ohde H, Tsunoda K, Hanazono G, Kimura I, Yuzawa M, Tsubota K, Miyake Y  (2007) Transcorneal Electrical Stimulation of Retina to Treat Longstanding Retinal Artery Occlusion. Graefe's Archive for Clinical and Experimental Ophthalmology; 245: 1773-1780.
    Jolly JK, Wagner S, and TESOLA Study Group. Transcorneal electrical stimulation for the treatment of retinitis pigmentosa – a multicenter safety study of the OkuStim® System. Paper in preparation.
    Oono S, Kurimoto T, Kashimoto R, Tagami Y, Okamoto N, Mimura O (2011) Transcorneal electrical stimulation improves visual function in eyes with branch retinal artery occlusion. Clinical Ophthalmology., 5: 397–402.
    Schatz A, Röck T, Naycheva L, Willmann G, Wilhelm B, Peters T, Bartz-Schmidt KU, Zrenner E, Messias A, Gekeler F (2011) Transcorneal electrical stimulation for patients with retinitis pigmentosa: a prospective, randomized, sham-controlled exploratory study.  Invest Ophthal Vis Sci.; 52: 4485-96.
    Schatz A, Pach J, Gosheva M, Naycheva L, Willmann G, Wilhelm B, Peters T, Batrz-Schmid KU, Zrenner E, Messias A, Gekeler F (2017) Transcorneal Electrical Stimulation for Patients With Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Follow-up Study Over 1 Year. Invest Ophthal Vis Sci.; 58: 257-269.Shinoda K, Imamura Y, Matsuda S, Seki M, Uchida A, Grossman T, Tsubota K (2008) Transcutaneous electrical retinal stimulation therapy for age-related macular degeneration. Open Ophthalmol J. 2: 132-136.
    Sandberg MA, Weigel-DiFranco C, Rosner B, Berson E (1996). The relationship between visual field size and electroretinogram amplitude in retinitis pigmentosa. IOVS, 37: 1693-98.

    Reimbursement

    Financing TES therapy with the RI OkuStim system

    The following information outlines the possibilities for financing TES therapy in Germany. Generally speaking, patients receiving therapy with the RI OkuStim system have to pay for the treatment themselves.
    If the patient is suitable for TES therapy, he or she will receive a prescription for the RI OkuStim system from the TES Competence Centre, which can be submitted to a certified low-vision optician. The optician takes care of the delivery, technical service and supports the competence centre in the one-to-one care of patients, particularly when it comes to fitting frames and with regard to technical aspects.
    Because RI OkuStim therapy has not yet been added to the German statutory health insurance catalogue of services, patients have to bear the cost of the therapy themselves. The medical services can be invoiced by the doctors on the basis of the scale of fees for physicians (GOÄ). Patients have the option of applying for reimbursement by either statutory or private health insurers.

     

    Information about the cost coverage process in Germany

    If patients apply to health insurance providers for reimbursement, the health insurers can decide via a case-by-case check whether the cost of the prescription and therapy will be covered and the patient can receive the requested treatment. Prior to submitting the application, it is generally recommended for the patient to speak personally with the claim handler at the health insurer in question, or the area manager.

     

    Requirements for applying for reimbursement by German statutory health insurers (GKV)

    • The treatment must be carried out by an authorised SHI doctor (RI Competence Centres are generally authorised SHI doctors).
    • The application must be submitted prior to the start of treatment and the purchase of the RI OkuStim system. The premature acquisition of the medical aid or starting the therapy before time are not conducive to obtaining support.

    Necessary documents for applying for reimbursement

    • An informal letter from the patient to the health insurer (“Application for reimbursement of cost”) Informal release from confidentiality for the treating physician
    • Prescription for the RI OkuStim system and RI OkuEl electrodes
    • Doctor’s letter with diagnosis, in-depth explanation of the disease progression and expected development, as well as the medical argument in favour of the therapy. This letter will be written by the RI Competence Centre.
    • Cost estimate of the medical treatment costs. This letter will be written by the RI Competence Centre.
    • Cost estimate of the material costs. This letter will be written by the certified low-vision optician.

    The doctors at the RI Competence Centres support the patient after they receive their diagnosis and therapy recommendation in terms of making the application with doctor’s letters regarding their individual disease progression, the mode of action of the therapy, as well as regarding the therapy benefit as outlined by the clinical trials.

     

    Trial process: Prospects for financing

    As a manufacturer, we play an active role in championing the future inclusion of TES therapy with the RI OkuStim system in the German statutory health insurance catalogue of services, thus offering all patients a therapy option. For this reason, the German Federal Joint Committee (G-BA) has been conducting a trial according to Section 137e of the German Social Security Code (SGB V) since 2014. We are happy to provide you with in-depth information about this in the doctors’ leaflet on the trial.

     

    Steps in the cost coverage process in Germany

    Working together with the doctor at the RI Competence Centre, the patient compiles the application for cost coverage with the necessary documents.

    With the assumption of approval under the Act to Protect Patient Rights, which came into force in February 2013, health insurers are forced to process applications more quickly. For this reason, patients should actively enquire about the approval of the application if:

    • Either the health insurer has not responded within three weeks of the health insurer receiving the application
    • Or information has been provided that the medical commission has been involved to assess the case, but no decision has been made five weeks after submitting the application.

    Unfortunately, applications are often turned down at the deadline.

    If no response has been received within the deadlines above, or the application is denied, we recommend finding out whether it may be useful to seek advice on social welfare law.

    This information has been kindly provided by rbm gemeinnützigen GmbH, a charity promoting the rights of people with disabilities. For more information, please click on the following link: www.rbm-rechtsberatung.de.

    Useful tips and pointers for RP patients submitting applications

    • A conversation with the health insurer’s claim handler (e.g. at the local level) in good time is both helpful and highly recommended. Health insurers have a duty to inform people seeking advice.
    • For patients whose applications are rejected, we recommended requesting a written statement of the reasons for the rejection from the health insurer. In case of an appeal procedure, this makes it easier for the lawyers to make their case in cooperation with the treating physician.
    • Although cost coverage via case-by-case consideration by the health insurers can take some time and effort, we still encourage patients to attempt this step.