RETINAL DISORDERS

Emotional wellbeing of blind patients in a pilot trialwith subretinal implants

Tobias Peters & Stefan Klingberg & Eberhart Zrenner &

Barbara Wilhelm

Received: 11 July 2012 /Revised: 31 October 2012 /Accepted: 6 November 2012 /Published online: 29 November 2012# Springer-Verlag Berlin Heidelberg 2012

AbstractBackground Participation in first human applications of ret-inal neuroprosthesis may create psychological stress forblind retinitis pigmentosa patients. The aim of this studywas to assess the emotional wellbeing of patients undergoingimplantation of a subretinal implant.Methods Nine blind patients participating in a pilot trial withsubretinal implants were enlisted. The Brief Symptom Inven-tory (BSI), a short self-report scale of nine primary symptoms,was used to assess reaction to the psychological distress relatedto study participation. The number and the intensity of symp-toms were analysed, and global scores for overall psycholog-ical distress (tGSI), severity of reported symptoms (tPDSI), andlevel number of self-reported symptoms (tPST) were calculat-ed. The questionnaire was administered before implantation,2–3 times during the trial and before explantation.Results There were no significant alterations during the trialfor the average scores of the nine primary symptoms. Onepatient, however, showed values higher than the norm, forsix subscores before implantation and for eight subscoresbefore explantation. A significant improvement was foundin both the overall psychological distress level (tGSI) andthe severity of reported symptoms (tPDSI) at the final visit,compared to those at the study start. The number of self-reported symptoms (tPST) was not significantly altered.

Conclusion In the first ongoing pilot trial with an active,cable-bound subretinal implant, we found that trial participa-tion and the implant procedure and subsequent testing did nothave any adverse effects on the participants’ emotional well-being. Their distress generally improved during study partic-ipation, rather than showing signs of decreased wellbeing.

Keywords Emotional wellbeing . Retina . Implant

Introduction

An active microphotodiode array (aMPDA) has been devel-oped to restore vision in blind patients [1–7]. The cable-bound aMPDA is implanted subretinally, and enables nervecell stimulation by recoding an electrical signal according tothe strength of the brightness of the object to be seen and itssurroundings. The psychological effects of participation inthe implant project are difficult to predict, as the studyinvolves pioneer work where the outcome is unknown andwhich may induce severe stress for the patient.

In the planning stage of the very first pilot trial with thesubretinal implant, there was neither knowledge nor experi-ence of how blind patients would cope with the workload ofnovel visual perceptions, the potential stress of study pro-cedures, or the potential disappointment if no perceptionswould occur. Patient organizations involved in the prepara-tion phase of the trial raised the issue of a need for psycho-logical support and assessment in this unique trial.

With this background, the major objective of this studywas to obtain a measure for the psychological wellbeing ofpatients participating in the retinal implant project. Afterconsultation with experienced psychologists, the BriefSymptom Inventory (BSI) [8], an accepted and validatedtest, was chosen as the most suitable for monitoring the levelof distress of the patients during the trial. The BSI is a 53-item, self-report questionnaire which is aimed at supporting

T. Peters (*) :B. WilhelmSTZ eyetrial at the Centre for Ophthalmology,University Eye Hospital, Schleichstrasse 12–16,72076 Tuebingen, Germanye-mail: tobias.peters@stz-biomed.de

S. KlingbergDepartment of Psychiatry and Psychotherapy,University of Tübingen, Tübingen, Germany

E. ZrennerInstitute of Ophthalmic Research, University Eye Hospital,Tübingen, Germany

Graefes Arch Clin Exp Ophthalmol (2013) 251:1489–1493DOI 10.1007/s00417-012-2210-6

clinical decision-making by providing a score for nine psy-chological symptom parameters and three global indices ofdistress. Psychological counselling was also offered duringstudy participation.

Materials and methods

Inclusion criteria, patients, and visit schedule

Participants were blind patients whose main diagnosis wasretinitis pigmentosa with no other serious eye or generaldiseases. They had been included in a pilot trial of subretinalimplants, in the Centre for Ophthalmology, Tübingen,Germany. In Table 1 we list details of the patients. Theywere between 26 and 56 years old (mean 45 years), and allwere males who had been blind for an average of 7.6 years(range 2–20 years). They had had no useful vision for up to20 years, and a visual acuity of >20/200 earlier in life.Bright light stimulation mediated some limited light percep-tion without any recognition of shapes. Twelve patientsparticipated in the pilot trial; one withdrew consent on theevening before the implantation due to concerns about theimplantation and sudden fear. Nine of the patients took partin this study: eight completed the study according to theprotocol, one patient disagreed about the explantation,which was planned at the end of the trial. The study wasapproved by the Ethics Committee of the Medical Faculty,University of Tübingen, and was performed in accordancewith the ethical standards laid down in the 1964 Declarationof Helsinki. All patients gave their informed consent prior totheir inclusion in the study.

The aMPDA was implanted into one eye. The trial dura-tion was initially planned for 4 weeks, and six patients had itexplanted at this time. Because of the positive observationsin these first patients, the protocol was amended; in onepatient, explantation followed 8 weeks after implantation,and in another patient, explantation was after 20 weeks. Oneof the patients refused to have the chip explanted.

The time-points of the examinations for each subject canbe seen in Fig. 1. Twenty-five visits were planned, irrespec-tive of the duration of implant. Explantation was performedafter the last examination. The data points show visits wherethe BSI was administered to assess emotional wellbeing.Overall, most subjects were measured 4 or 5 times. Thearrows show the time of aMPDA implantation andexplantation.

Psychological counselling was initially scheduled to takepart once a week on the patient’s request, and was per-formed by a consulting specialist from the neighbouringpsychiatric hospital, who also administered the BSI. Psy-chiatrists regularly perform psychological counselling inGermany. Counselling was performed, if possible, by thesame psychiatrist for the individual patient. All patientsunderwent one counselling session at screening, and eightof the nine patients were counselled a further 3 times. Onepatient felt that he did not require this service. For the sixpatients who had the device removed after 4 weeks, thecounselling was on a weekly basis. For the remainingpatients, the three sessions were spread out in the timebetween implantation and explantation.

Brief symptom inventory

We chose the BSI as an additional questionnaire to accom-pany the patients in the Retinal Implant Study, because wewished to obtain a measure of the psychological wellbeing(and hence a symptom inventory). This questionnaire pro-vides patient-reported data on 53 items, used to measurenine primary symptom dimensions: Somatization (SOM);Obsessive–Compulsive (O–C); Interpersonal Sensitivity(I-S); Depression (DEP); Anxiety (ANX); Hostility (HOS);Phobic Anxiety (PHOB); Paranoid Ideation (PAR) and Psy-choticism (PSY) [8]. The questionnaire provides three majorindices representing the overall psychological distress levelfor the time of testing (total Global Severity Index, tGSI),the severity of reported symptoms (total Positive SymptomDistress Index, tPSDI) and the number of self-reported

Table 1 Patient overviewSubject number Age Duration of

blindness (years)Time to explant(weeks)

Outcome

1 44 2.0 not explanted Visual sensations

2 48 6.0 4 Visual sensations

3 53 12.0 4 No sensations

4 51 10.0 4 No sensations

5 56 5.0 4 Light perception

6 26 3.5 4 Light perception

7 51 20.0 4 Visual sensations

8 35 5.0 8 Measurable visual acuity

9 41 5.0 20 Measurable visual acuity

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symptoms (total Positive Symptom Total, tPST). Patientsare requested to report only symptoms that have occurredduring the previous 7 days, including the day it was com-pleted. Answers are on a 5-point scale, from 0 0 “not at all”,to 4 0 “extremely”. The questionnaire takes about 10 min toperform. The BSI has been tested for reliability, validity, andutility in more than 400 studies, and provides normativedata. The individual values of the participants are thereforereported as standardized values, which we compare to thenormative adult non-patient sample of the BSI. Aworseningof the condition can be stated only if the value lies above thenormal limit of 63. These data are based on the results of

344 males and 341 females (mean age 46 ± 14.7 years), whowere a stratified random sample from a large Eastern countyof the USA [8].

Results

The psychological counselling, including BSI testing, wasvoluntary for the patients. One patient refused to take theopportunity, with the explanation that he felt well, had noproblems and had no need to see the psychiatrist; ninepatients answered the BSI.

In Table 2, we show the results of the BSI for the nineprimary subscales. For every patient, a standardized scorefor each subscale has been computed, which is based on thenormative data for adults provided in the test manual. Thestandardized scores have been transformed into t-values,which have by definition a mean of 50 and a standarddeviation of 10.

There are no significant differences in the means of thesescores, and none of the means lie outside the normal range.In four of the subscales (Somatization, Phobic Anxiety,Paranoid Ideation and Hostility) there is a small increasein score, (shown in bold in Table 2) and in five symptoms(Obsessive–Compulsive, Interpersonal Sensitivity, Depres-sion, Anxiety and Psychoticism) there is a decrease (shownin italics in Table 2), but alterations are small and around themean (50). To examine the significance of these findings, welooked at the number of patients who show a significantchange (1SD plus measurement errors) over 63. This is shownin parentheses in Table 1. The patient who refused counsellingshowed scores over or equal to 63 for all but three symptoms(SOM, ANX and PHOB) before implant, and for all parame-ters except PHOB at the end of the study. Chip explantationwas not performed on this patient. Two other patients hadincreased scores for SOM before implantation.

To obtain an overall view of the psychological state of thesubjects, we calculated the total Global Severity Index (tGSI)as shown in Fig. 1 upper panel. Only one subject’s response toBSI led to tGSI value above the normal limit at the beginningof the study (paired t-test: mean difference 0 7.22, p 0 0.04).

In the central panel of Fig. 1, the total Positive SymptomDistress (tPSDI) is plotted. In this case, three subjects showlarge scores at the beginning of the study, indicating anemotional burden. The scores at the last visit before explan-tation were significantly lower than those at the screeningvisit, i.e., there was less distress at the end of trial partici-pation (paired t-test: mean difference 0 16.89; p 0 0.02).

In the lower panel of Fig. 1, the total Positive SymptomTotal (tPST) scores are plotted. The scores at the last visitare not significantly different to those at screening. Onesubject shows scores that are consistently above 63, indicat-ing more subscales affected than in normals.

Fig. 1 Results of each patient for each BSI test. The x axis indicatesthe visit number of the ophthalmological examination. Data pointsshow the time points of BSI administration. The results of each subjectare shown with a different symbol. Horizontal lines indicate the normalrange. Upper panel tGSI scores; centre panel tPSDI scores; lowerpanel tPST scores. A paired t-test shows significant decrease in tGSIand tPSD values at the end of the trial

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The patient who refused counselling does not showresults outside the normal limit. However, the patient whorefused to have chip explanted shows results for all tGSIscores, for pre-implant tPSDI scores, and for all tPST scoreswhich are worse than the normal limit.

In Table 1, we also list the outcome of the implant for thesubjects. A total of seven patients had visual sensationsmediated by the aMPDA (e.g., phosphenes), four of whomhad light perception. Two of these four patients had ameasurable visual acuity. The patients with a successfuloutcome showed average scores for these three indices.

Discussion

The technical and physiological challenges of retina implanttrials are enormous, but one must not forget the psychologicalaspects of such interventions. Psychological stress related totrial participation may raise ethical concerns, and may alsoinfluence functional test results. Supported by patient organ-izations and psychologists, we tried to cope with psycholog-ical aspects of the stress which study participation might bringfor the pioneer participants. To our knowledge, this is the firsttime that the emotional wellbeing in patients taking part inretina implant trials has been investigated, although there areseveral projects worldwide (see, for example, [9]).

The emotional wellbeing of patients is not a topic that isoften covered by common patient-reported outcome meas-ures in ophthalmology. Rather widespread questionnaires,such as the National Eye Institute Visual Functioning Ques-tionnaire — 25 (NEI VFQ25), which is often used to assessvisual function and wellbeing, does not measure stress relatedto the participation in a trial like the one presented here.

At the end of this study, before the retinal implants wereextracted, the average results from nine patients showed anincrease in score, for four of the nine symptoms measured inthe BSI (see Table 1), indicating a small but not significantworsening of emotional wellbeing: The subjects showedan increase in their perception of bodily dysfunction

(Somatization), fear in public and open places (PhobicAnxiety), projection of hostility, suspiciousness, fear of lossof autonomy (Paranoid Ideation) and Hostility in thoughts,feelings and actions. All patients appeared to cope well withthe situation; they were pleased to have participated in thestudy, and would happily take part again.

We do not believe that bias or giving answers in a directionsupposed to be socially expected have influenced the rating bythe patients. Being aware of such effects, the BSI was neverperformed by someone belonging to the trial team at the eyehospital. It was regarded as important that regular counsellingand BSI testing should be carried out by someone independentfrom the ophthalmological trial team, in case the patient hadproblems that he did not want to discuss with the studyphysician. Often the patient developed a mutual trust withthe responsible psychiatrist, and kept in touch with him/herfor longer than the duration of the trial.

Last but not least, we regard the intensive medical andsocial care related to trial participation over many weekscontributed to the observed results. Some of the patients hadrelatively poor social contacts in their normal life, whichmay have been improved by intensive daily contacts withphysicians and the trial team. All patients expressed theirsatisfaction with the medical and social care provided duringthe trial, for example that they were accompanied to and fromthe hospital by a team member, or during their spare time inthe hospital if they were without accompanying persons.

Limitations

Beyond the small sample size — which is typical for pilottrials with novel medical products for rare diseases anddemanding intensive trial procedures — there are furtherlimitations of this paper. The baseline or screening valuesmay have been influenced by the closeness of the implan-tation date. The patients may have been excited or afraid ofthe long surgery, etc., so the baseline scores may have beenartificially increased, facilitating a decrease during thecourse of the trial. On the other hand, only a few of the

Table 2 Mean BSI results forthe primary symptoms. Thenumber of patients who showvalues above the normal range(>63) is shown in parentheses

bold type indicates an increasein score, italic type indicates adecrease in score

Symptom dimensions Pre-implant Pre-explant

Somatization (SOM) 47.67 ± 7.97 (0) 54.44 ± 11.05 (3)

Obsessive–Compulsive (O–C) 46.22 ± 11.05 (1) 42.78 ± 11.73 (1)

Interpersonal Sensitivity (I-S) 51.22 ± 9.58 (1) 45.44 ± 9.15 (1)

Depression (DEP) 49.44 ± 10.91 (1) 48.11 ± 10.21 (1)

Anxiety (ANX) 52.89 ± 5.97 (0) 46.67 ± 9.74 (0)

Hostility (HOS) 47.89 ± 10.64 (1) 48.11 ± 10.63 (1)

Phobic Anxiety (PHOB) 48.89 ± 6.37 (0) 55.33 ± 10.35 (1)

Paranoid Ideation (PAR) 46.89 ± 11.15 (1) 52.56 ± 10.31 (1)

Psychoticism (PSY) 48.11 ± 11.88 (1) 47.67 ± 11.47 (1)

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baseline values were outside the normal range. It is alsopossible that persons who volunteer to participate in suchtrials as this have certain personality traits, which mayinfluence how they respond.

Conclusions

Our study gives important information about the emotionalwellbeing of patients involved in participation in retinalimplant tests. None of the subjects reported undue stress,and at the start of the trial, average results were withinnormal population limits and none showed any deteriorationduring the course of the study.

Acknowledgments We thank the following people for their supportin this trial: H. Oelman, C. Kuttenkeuler, R. Wilke and T. Zabel. Theauthors also thank Anne Kurtenbach for her help in preparing thismanuscript. The study was supported by the German Federal Ministryof Education and Research (BMBF: 01KP0401) and the Retinal Im-plant GmBH, Reutlingen, Germany

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