Benefit

In the mid-1990s, Professor Eberhart Zrenner had a bold idea: He wanted to restore a certain degree of useful vision to people who had lost their sight as a result of degenerative retinal diseases such as retinitis pigmentosa. The stimulation to create visual perception was not to take place epiretinally but via a camera chip that is so compact and flat that it can be positioned under the retina.
After more than 20 years of research and development, the current version of the RETINA IMPLANT Alpha AMS with its tiny 3 x 4 mm chip and 1,600 pixels can (technically) offer visual acuity of up to 0.07 (20/280) and a field of vision of up to approx. 13°.
The flat design (70 µm chip and 20 µm backing film) makes it possible for our experienced retinal surgeons to slide the chip between the RPE (retinal pigment epithelium) and the bipolar cells. Intraocular pressure holds the chip in place after the implantation so that no further fixation (e.g. in the form of a retinal tack) is necessary. This means that the retina remains intact and reimplantation in the same eye is possible.
The subretinal approach facilitates natural stimulus transmission within the eye. The incident light is converted into electrical signals by the 1,600 photodiodes in the chip and these signals are then transmitted via the attached electrodes into the still-functioning retinal layers capable of signal processing. This enables the patient to localise objects using their natural eye movement. This also retains the retinotopy (areas of the brain located downstream from the retina and optic nerve), which facilitates hand-eye coordination. In fact, many implant users were able to find and localise objects on a table the first time that the implant was switched on (around four weeks post-op) (Stingl et al., 2017. Frontiers of Neuroscience). Patients also reported better orientation in high-contrast light conditions, e.g. in twilight conditions. For more results, please refer to the section “Studies”.
In addition to maintaining the natural stimulus transmission, another major factor in the development of the RETINA IMPLANT Alpha AMS was its inconspicuousness. Because the subretinal implant does not require any external camera, it is practically unnoticeable to others.

 

 
  • Natural stimulus transmission in the eye
  • Facilitates hand-eye coordination
  • Helps localise objects using natural eye movement
  • No external camera system required
  • Discreet
 

Function

The intended use of the RETINA IMPLANT Alpha AMS is to help restore partial functional vision in adult patients with degeneration of the retina. To be eligible, the patients must, at most, be able to perceive light or not perceive light at all, and their inner retinal structures must be functional (see section titled “Use” for more details).
The RETINA IMPLANT Alpha AMS comprises an implantable component and an external hand-held unit for energy supply.

 

Implant

The RETINA IMPLANT Alpha AMS is a subretinal implant. It works by using the intact cell structures within the retina, particularly the signal processing cells upstream from transmission via the ganglion cells, in order to generate a visual impression that is produced as naturally as possible. This means that the patient’s natural eye movement can be used, which enables hand-eye coordination. With this technology, the best postoperative visual results so far have been acuity of 0.037, or 20/546 (Landolt-C) (source: Stingl et al, 2017).

 

RETINA IMPLANT Alpha AMS

Chip

The CMOS chip in the RETINA IMPLANT Alpha AMS comprises 1,600 pixels. Each pixel is made up of a light-sensitive photodiode, an amplifier and an electrode. During the implantation, the chip is positioned intraocularly between the outer plexiform layer and the retinal pigment epithelium, directly under the fovea. The photodiodes measure the light intensity. Via the measured parameter the stimulation intensity at the electrode of the pixel is determined. The retinal structures surrounding the electrodes, particularly the bipolar cells, are stimulated with an electric charge created between the electrodes in the retina and the counter electrode.

 

Ribbon and coil

The AMS chip is applied to a polyimide film that contains both the electrical connections and a fixation patch at the end. This patch is used during the operation to fix the implant to the sclera from the outside. The electrical connections are routed through a silicone cable to the ceramic casing positioned behind the ear in the cranial bone (link to “Operation” section). This casing contains an induction coil (receiver coil) for power supply, a permanent magnet for fixing the transponder in place, and some of the control electronics. The counter electrode that closes the electric circuit within the body also comes out of the ceramic casing.

 

External power supply

The part of the RETINA IMPLANT Alpha AMS implanted in the eye does not have any batteries or other power source. This is why it requires an external power supply. A hand-held unit that can be concealed in a bag or jacket during use contains the batteries and an electric switch that creates an alternating electromagnetic field in the transponder. This transmits the energy via induction through the skin to the receiver coil implanted in the cranial bone behind the ear. The implant is only active while the transmitter coil is connected magnetically to the receiver coil and the hand-held unit is switched on. It is easy to remove the transmitter coil if needed.

 

 

Hand-held unit

The hand-held unit is a mechanically stable, external component (non-implanted). It measures 15 cm x 9.2 cm x 2.8 cm and is operated with four AA alkaline batteries. The user can activate the implant via the hand-held device and adjust the brightness and contrast of the signal to the ambient conditions by using two controls. The knobs are positioned centrally on their surface with a tactile edge so that it is easy to find the central position (programmed by the Patient Care Manager as the optimum setting). The knobs also noticeably lock into this position. LEDs enable another person to read the set value. Various acoustic signals alert the user when the implant is in use, switched off, when the batteries are losing power or if the transponder is missing.

 

Transponder

The transponder consists of a transmitter coil and a hand-held unit connected by a cable. The power supply is inductively from the transmitter coil to the subcutaneous receiver coil. In order to operate the implant, the transponder is placed on the skin above the ceramic casing implanted behind the ear. The permanent magnet in the casing magnetically holds it in the correct position.
This design reflects the principle that has been successfully used in cochlea implants for many years now.

 

Use

Implant suitability

The RETINA IMPLANT Alpha AMS was developed to restore partial functional vision in adult patients who have lost sight due to inherited retinal degeneration. In order to benefit from the therapy, patients have to have perception of light only, or no perception of light. Certain clinical requirements also have to be met.

  • Degeneration of the photoreceptors in the outer retina (rods and cones)
  • Functional cells in the inner retina in order to be able to transmit the signals from the electrode matrix via the neuronal cell layers and pre-process the visual information
  • Intact optic nerve and visual cortex (good sight in youth, including ability to read print)

These points apply to people who are affected by significant retinal dystrophy, such as retinitis pigmentosa, cone dystrophy or choroideremia. Suitability must be determined in each individual case by evaluating the individual disease status. AMD is currently not considered an indication for the RETINA IMPLANT Alpha AMS.

    Exclusion criteria

    • Poor circulation in the retina: The loss of the tiny blood vessels is common with RP and starts with the narrowing of these blood vessels. However, adequate circulation of the inner retina is essential for proper function. In the initial tests, therefore, red-free ophthalmoscopy or angiography is used to establish whether sufficient vessels have been maintained in the central retina.
    • Retinal oedema or scar tissue in the target region for the implant: Swelling or scarring at the posterior pole hinders the contact of the electrodes with the retinal neurons. In order to rule out these pathological changes to the retina, an optical coherence tomography (OCT) is carried out during the screening phase.
    • Strong pigmentation at the posterior pole: One symptom of RP is the formation of pigment deposits in the retina. If these deposits are too thick, they may block the incident light so that the chip cannot be properly illuminated.
    • Missing retinal layers: In most cases of RP, the other retinal layers remain intact, which means that sufficient residual function can be assumed. To be on the safe side, the structure of the retina must be tested by OCT. This also determines the thickness of the retina. Because the neurons in the inner retina are essential for the successful connection with the microchip’s electrode matrix, a sufficient number of neurons have to be present. These neurons should show up as clearly structured layers on the OCT.
    • Any eye disease that has a relevant effect on visual function (e.g. glaucoma, optic neuropathy, trauma, diabetic retinopathy): These conditions would significantly impede or completely destroy neuron function in the retina and subsequent visual signal processing and transmission pathways. This would lead to inadequate signal transmission by the microchip to the brain and thus render it useless.
    • Systemic diseases that represent a high general risk with regard to surgery and general anaesthetic (e.g. cardiopulmonary disease, severe metabolic disorders).
    • Untreated/unadjusted systemic, neurological or psychological conditions that may represent a risk for the implantation and/or the subsequent training (Parkinson’s, epilepsy, depression): Any disease that may lead to uncontrolled movements during the operation or that may have a negative influence on the healing or training process must be carefully weighed up before the surgery.
    • Hyperactive thyroid or hypersensitivity to iodine (standard exclusion criteria for operations).
    • Pregnancy or breastfeeding (standard exclusion criteria for operations).

    How can your patient receive an implant?

    The RETINA IMPLANT Alpha AMS is only available at certified RI Implantation Centres. This means that the patient is cared for before, during and after the operation only by trained doctors and surgeons who are familiar with the implant and its functions.
    Find the current list of RI Implantation Centres to obtain a referral here.
    To test whether your patient is suited for the RETINA IMPLANT Alpha, the RI Implantation Centre will carry out a range of medical tests.

     

    • Examination of the ocular fundus: Here, the macula in particular is examined for pathological changes (scarring, oedema, pigmentation) that could have a negative impact on the implant. This examination is also used to analyse the blood vessels for nutrient transport and those in the optic nerve. The condition of the retina is documented photographically.
    • Examination of the retinal layers via optical coherence tomography (OCT): This examination investigates the thickness of the retina and its layers. It also checks whether there is evidence of fluid retention, macular holes (holes forming at the most sharply focused point of vision) and/or deposits (thickening) in the macula.
    • For patients unable to perceive light, tests will be done with an electroretinograph (ERG) as well as the RI OkuStim® system (if required) to check whether the visual pathway is intact.
    • Examination of the blood vessels in the retina: If necessary, fluorescence angiography can analyse the blood vessel status in more detail in order to guarantee the blood supply to the retina.

    Useful information

    With the implantation, a vitrectomy is performaded and the vitreous body is permanently replaced by silicon oil. In order to ensure a clear image on the chip, a cataract operation is carried out as a standard a few weeks prior to the implantation and an artificial lens is inserted.

    Patient pathway

    After the initial assessment by the RI Implantation Centre, the data for the suitable patient are forwarded to the RETINA IMPLANT Centre of Evaluation (RICE).
    RICE is an independent platform created to support our clinical partners in selecting patients. RICE comprises a group of experts (ophthalmologists and retina surgeons) who have acquired extensive experience and expertise in selecting candidates for our clinical trials, their treatment and follow-up care. The eye specialists are supported by a Patient Care Manager (PCM) from Retina Implant AG. Our PCMs also bring to RICE the technical expertise regarding the RETINA IMPLANT Alpha AMS and experience in working with partially sighted people so that all the critical aspects of the implantation (suitability for the operation and suitability for the subsequent vision training) can be assessed. This aims to reduce the risks for patients, offer a standard in terms of patient selection and create transparency for the health insurers.
    If all the experts agree that the patient is a suitable candidate, a cataract operation is agreed and the date for the implantation is set. Four to six weeks after the implantation, the implant is activated in the clinic for the first time under medical supervision (switch-on) and the patient will begin the vision training.

     

     

    Studies on RETINA IMPLANT Alpha AMS

    So far, the efficacy and safety of the RETINA IMPLANT Alpha AMS has been investigated in two independent studies. 16 patients were enrolled in these studies (6 in Oxford, UK, and 10 in Germany) and had regular follow-ups for a total of 12 months after the implantation. The studies included both medical check-up appointments and training units in a controlled clinic environment, as well as objective tests for recording vision results (Stingl et al., 2017; Edwards et al., 2018).

     

    Interim results

    80% of patients (diagnosis: nulla lux or light perception alone) were able to perceive and localise light with the RETINA IMPLANT Alpha AMS. The implant also had a significant influence on the ability to find and localise objects on a table (hand-eye coordination). Grating acuity tests showed a spectrum of 0.1 cpd to 3.3 cpd. Individual patients achieved a visual acuity of 0.037.
    A total of eight SAEs were observed, which were all successfully treated, including dehiscence of the conjunctiva and pain around the receiver coil.



    Literature:
    Stingl et al., Interim Results of a Multicenter Trial with the New Electronic Subretinal Implant Alpha AMS in 15 Patients Blind from Inherited Retinal Degenerations. Front Neurosci. 2017 Aug (11).

     

     

    Studies with predecessor models

    Pilot study with RETINA IMPLANT Alpha IMS (1st generation)

    The first generation of the sub-retinal implant did not yet have an induction coil for energy transmission and therefore only stayed in the patient’s body for a few weeks. Between 2005 and 2009, eleven patients received the wired RETINA IMPLANT Alpha IMS. This study provided proof of principle, i.e. it was possible to achieve useful visual impressions with the aid of sub-retinal stimulation, up to being able to read large print.

    Literature:
    Wilke et al., Spatial resolution and perception of patterns mediated by a subretinal 16-electrode array in patients blinded by hereditary retinal dystrophies. Invest Ophthalmol Vis Sci. 2011 Jul 29;52(8):5995-6003.
    Kusnyerik et al., Positioning of electronic subretinal implants in blind retinitis pigmentosa patients through multimodal assessment of retinal structures. Invest Ophthalmol Vis Sci. 2012 Jun 20;53(7):3748-55.
    Stingl et al., Functional outcome in subretinal electronic implants depends on foveal eccentricity. Invest Ophthalmol Vis Sci. 2013 Nov 19; 54(12):7658-65.

     

     

    studies with RETINA IMPLANT Alpha IMS (2nd generation)

    As part of three studies, 29 subjects received a RETINA IMPLANT Alpha IMS. These studies were carried out in Germany, the UK and Hungary, as well as in Singapore and Hong Kong. The results were analysed one year after implantation with regard to visual results, experiences and safety.

    Results
    Of 29 patients, 86% were able to perceive light with the implant. The implant had a significant influence on the ability to find and localise objects on a table (hand-eye coordination). Grating acuity tests showed a spectrum of 0.1 cpd to 3.3 cpd. Individual patients were able to read large print.
    The patients described their perception as blurred, slightly flickering images made up of shapes and various shades of grey. Just over half of the patients stated that the implant helps them to recognise the outlines and details of objects, e.g. building outlines, the horizon, lights and street lights, windows and pictures on walls, etc.


    Literature:
    Stingl et al.; Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS. Proc Biol Sci. 2013 Feb 20;280(1757):20130077. (This publication describes the efficacy results from 9 patients participating in the Main study, module 1.)
    Kitiratschky et al.; Safety evaluation of "retina implant alpha IMS" - a prospective clinical trial. Graefes Arch Clin Exp Ophthalmol. 2015 Mar;253(3):381-7. (This publication describes the safety results from 9 patients participating in the Main study, module 1.)
    Stingl et al.; Subretinal Visual Implant Alpha IMS - Clinical trial interim report. Vision Res. 2015 Jun;111(Pt B):149-60. (This publication describes the efficacy results from the 25 patients included in the Main study (both modules), the 2 patients included in the Hong Kong study and the 2 patients participating in the Singapore study.)

     

    Conclusions

    Positive visual results were shown in all studies. It was shown that the subretinal implant could restore partial functional vision in adult patients who had lost sight due to degeneration of the retina. This was then able to restore a certain amount of independence in day-to-day life for those patients. The side effects were mainly mild and resolved within a short period of time or could be treated surgically without any subsequent problems.

     

    Reimbursement of costs

    Germany

    The first NUB application (for new examination and treatment methods) for the subretinal implant was submitted in 2005 to the Institut für Entgeltsystem im Krankenhaus (Institute for Payment Systems in Hospitals, InEK).
    The NUB process promotes the introduction of innovation in the German healthcare system because the methods falling under the NUB process cannot be invoiced via the flat-rate payment system. NUB applications have to be submitted by clinics to the InEK every year by 31 October.
    Since its initial application in 2005, the subretinal implant has always received status level 1. This status enables the clinic to negotiate rates with the regional cost centres. While any clinic can submit an NUB application for the RETINA IMPLANT Alpha AMS in theory, as a result of the complexity of the implantation of a subretinal implant and in order to minimise all medical risks, Retina Implant cooperates with a select group of RI Implantation Centres and their specially trained retinal surgeons. These RI Implantation Centres are university clinics and leading teaching hospitals.
    Since 2014, our RI Implantation Centres have successfully negotiated with the health insurers on charges. This means that the subretinal RETINA IMPLANT Alpha AMS is available to patients with congenital retinitis pigmentosa, among other conditions (link to “Use”). Depending on the agreement, however, an individual insurance reimbursement request may have to be submitted to the patient’s health insurer prior to the implantation.

     

     

    France

    Starting 2018, the subretinal implant RETINA IMPLANT Alpha AMS is reimbursed within the "Forfait Innovation" program. Prerequisite for reimbursement is the conduct of an accompanying study which provides answers concerning the benefit of the implant in the daily lives of patients. This study is being conducted in two centers in France, the St. Jean Clinic in Montpellier and the University Hospital Poitiers. As part of the Forfait Innovation program, 20 patients will be implanted and 20 further patients can follow until the final decision on the technology reimbursement.

    Abroad

    Several clinics and surgeons are currently undergoing our validation process in other European countries, too, including the UK and the Netherlands, or have already successfully completed it. In close collaboration with our local clinical partners, we are working towards securing reimbursement so that people outside of Germany who are affected by RP can also benefit from the innovative RETINA IMPLANT Alpha AMS. Please click here for the current status of our clinical partners.

     

    The surgery

    The operation is done in two stages: An extraocular stage involves placing the receiver coil behind the ear, and an intraocular stage involves implanting the light-sensitive chip beneath the fovea centralis.
    The whole operation is conducted under general anaesthetic.

     

    Extraocular stage

    In the first stage of the implantation, the ceramic casing that contains the receiver coil (for power supply and transmitting implant settings) is positioned behind the ear. To do this, the surgeon (in most cases ENT surgeons) creates a small recess in the cranial bone, similar to positioning a cochlea implant. A channel also has to be created around the orbital rim to accommodate the wire connecting the coil and the chip. Using a trocar, a tunnel is prepared between the bone and the periosteum that runs from the edge of the eyebrow to behind the ear underneath the temporal muscle. The implant is then positioned below the muscle using the trocar.
    The extraocular stage of the implantation is only carried out by surgeons with the relevant qualifications, acquired by regularly conducting cochlea implant surgeries.

     

     

    Intraocular stage

    The chip is positioned under the retina by a specially trained retinal surgeon. To start with, a flap is prepared in the sclera in the superior frontal quadrant of the globe, under which a tiny opening is created in the choroid later in the operation. Once the vitrectomy is complete, the retina is elevated by intraocular fluid injection. Via the opening in the choroid, a guide film is inserted between the choroid and retina and pushed forward as far as the macula. The implant with chip can now be correctly positioned along the guide film. Once this is done, the implant is sewn in place by epibulbar suture as soon as the flap previously opened has been closed. Finally, the wire is inserted in a loop in the orbit and the remaining openings are sutured.
    Patients should avoid exertion in the first few days after the implantation. Generally speaking, the wounds are healed within four weeks and the implant can then be put into operation.

     

     

    Postoperative care and patient training

    Generally speaking, the postoperative care rests on two pillars – medical care and functional care, which comprises technical support and training.

     

     

    Medical postoperative care and training

    Both the medical postoperative care and training take place in an outpatient setting. The medical postoperative care is carried out by doctors who have experience with the RETINA IMPLANT Alpha AMS. The medical care of the implant user is the responsibility of the centre carrying out the surgery and comprises recording the tolerability and safety of the implant by direct observation of the RETINA IMPLANT Alpha AMS in the eye, as well as standard imaging procedures. The medical postoperative care is carried out by an experienced team of doctors, orthoptists (experienced in the care of people with severely restricted vision and blindness) and nursing staff.

     

    Functional postoperative care

    The functional postoperative care in terms of instruction and vision training is carried out by qualified RI Patient Care Managers and/or mobility trainer, who are experienced in dealing with RETINA IMPLANT patients and in performance tests and mobility training. The training primarily takes place in the first few months after the implantation because previous experience has shown us that this is when the biggest learning processes take place. The training is generally carried out in the home environment of the implant user. In this way, the user is able to learn how to use the implant in everyday situations around the home, at the table and to find their way around buildings. The user also practises their orientation outdoors, both near to home and further away. The aim is to help patients familiarise themselves with their new ability to see within their environment and to return to them a degree of independence.
    The functional postoperative care in terms of technical support is also carried out by qualified Patient Care Managers. Working together with the patient, they establish individual stimulation parameters and check the technical functioning of the implant if required.