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Preliminary Results of Transorbital Alternating Current Stimulation in Chronic Low Vision: Correlation of Clinical and Neurophysiological Results

Published:October 13, 2022DOI:https://doi.org/10.1016/j.neurom.2022.09.002
      Repetitive transorbital alternating current stimulation (rtACS) is a new option for the treatment of patients with low vision, and several studies report the benefit of rtACS in both pre- and postchiasmatic pathologies.
      • Perin C.
      • Viganò B.
      • Piscitelli D.
      • Matteo B.M.
      • Meroni R.
      • Cerri C.G.
      Non-invasive current stimulation in vision recovery: a review of the literature.
      However, it is also common clinical experience that the effect of this treatment is rather variable between patients, even with the same pathology.
      • Sabel B.A.
      • Thut G.
      • Haueisen J.
      • et al.
      Vision modulation, plasticity and restoration using non-invasive brain stimulation – an IFCN-sponsored review.
      This variability probably reflects two intertwined factors, the mechanism of action of rtACS and the characteristic of patients under treatment. According to the state of the art, it seems clear that rtACS could enhance the functionality of neurons along the visual pathway by increasing the coordination of firing and their excitability.
      • Sabel B.A.
      • Thut G.
      • Haueisen J.
      • et al.
      Vision modulation, plasticity and restoration using non-invasive brain stimulation – an IFCN-sponsored review.
      • Granata G.
      • Iodice F.
      • Romanello R.
      • et al.
      Neurophysiological effect of transorbital electrical stimulation: early results in advanced optic atrophy.
      • Bola M.
      • Gall C.
      • Moewes C.
      • Fedorov A.
      • Hinrichs H.
      • Sabel B.A.
      Brain functional connectivity network breakdown and restoration in blindness.
      A neuroprotective role was also hypothesized.
      • Sehic A.
      • Guo S.
      • Cho K.S.
      • Corraya R.M.
      • Chen D.F.
      • Utheim T.P.
      Electrical stimulation as a means for improving vision.
      These mechanisms can be considered pathology independent and can act as long as the so-called “silent” or “awaken” neurons exist. According to the predominant view, these neurons, neither dead nor healthy, can be activated with rtACS, and people with a high number of these neurons, depending on the kind of pathology and severity of the clinical picture, have a better chance of improvement of symptoms from a clinical point of view.
      • Sabel B.A.
      • Thut G.
      • Haueisen J.
      • et al.
      Vision modulation, plasticity and restoration using non-invasive brain stimulation – an IFCN-sponsored review.
      A better understanding of the reason for this variability has become of the utmost importance, both to find methods able to identify the presence of awaken neurons and to clarify the mechanism of action of rtACS, identifying possible biomarkers able to predict its effect. We recently observed a significant increase of visual evoked potentials (VEP) amplitude after rtACS in a small group of patients with severe low vision, indicating the increase of primary visual cortex excitability as one of the possible mechanisms of action of rtACS.
      • Granata G.
      • Iodice F.
      • Romanello R.
      • et al.
      Neurophysiological effect of transorbital electrical stimulation: early results in advanced optic atrophy.
      In this study, we report the results of a larger group of patients with low vision, aiming to confirm the previous results and correlate neurophysiological data with the subjective clinical outcome of the treatment. The local ethical committee approved the study. Written informed consent was obtained from all subjects. The work described was carried out in accordance with the Declaration of Helsinki. The methods used were the same as in the previous study.
      • Granata G.
      • Iodice F.
      • Romanello R.
      • et al.
      Neurophysiological effect of transorbital electrical stimulation: early results in advanced optic atrophy.
      Briefly, each subject underwent a baseline comprehensive neurophysiological examination, including flicker VEP, flash electroretinogram (ERG), and the photopic negative response (PhNR) in a light-adapted condition. After rtACS, each patient underwent the same neurophysiological tests at baseline and was asked to answer the patient global impression of change questionnaire (PGIC). The PIGC is a patient-oriented questionnaire designed specifically to assess the subjective perception of changes after a treatment, with a score from 1 to 7: 1) no change (or condition has gotten worse); 2) almost the same, hardly any change at all; 3) a little better, but no noticeable change; 4) somewhat better, but the change has not made any real difference; 5) moderately better, and a slight but noticeable change; 6) better, and a definite improvement that has made a real and worthwhile difference; and 7) a great deal better, and a considerable improvement that has made all the difference. rtACS was performed with two bipolar channels, placing the cathode and the anode, respectively, over and below the eyeballs. The frequency of stimulation was 10 Hz, and the intensity of stimulation was set at 1 mA (+0.5 and −0.5 mA). The treatment duration was 20 minutes per day for ten consecutive days, excluding the weekend. The statistical analyses were performed with the SPSS (version 21; IBM, Armonk, NY) and R software (R Foundation for Statistical Computing, Vienna, Austria). Outcome measures were 1) peak to peak amplitude of flicker VEP; 2) amplitude of a, b waves and PhNR of ERG; and 3) score of PGIC and its correlation with neurophysiological measures. We included in the evaluation 32 patients with low vision (seven women, 25 men; a mean age of 57.21 years) treated with rtACS between March 2017 and November 2019 (Table 1). Ten patients had glaucoma, six a posttraumatic opticopathy, six an occipital stroke, three an ischemic opticopathy, three an opticopathy secondary to neoplasia, one an opticopathy secondary to hyperglycemic coma, one an opticopathy associated with drusen, one a compressive opticopathy due to spina bifida complications, and one a postinfectious opticopathy (postsyphilis). According to the PGIC, 23 of 32 patients reported, after rtACS treatment, a clinical improvement with a PGIC mean score of 3.2 (Fig. 1), corresponding to “a little better.” Mean VEP pretreatment amplitude was 2.2 μV (SD 1.98), and mean VEP posttreatment amplitude was 2.7 μV (SD 2.42). The Wilcoxon signed-rank test, used to compare VEP amplitude before and after the treatment, highlighted a statistically significant difference (p = 0.003). Mean ERG amplitude was 4.2 μV (SD 2.45) at baseline and 4.65 μV (SD 2.72) after the treatment in the better eye (ie, in the eye with the higher increase in percentage). The t-test did not show any statistically significant change of ERG amplitude before and after the treatment (p = 0.32). Mean PhNR pretreatment amplitude was 4.84 μV (SD 2.17), and mean PhNR posttreatment amplitude was 4.87 μV (SD 2.61) in the better eye (ie, in the eye with the higher increase in percentage). The t test did not show any statistically significant difference (p = 0.92). The regression analysis (Fig. 1a–c), performed by correlating the delta of the VEP amplitude before and after rtACS with the PGIC score, showed a statistically significant correlation (p = 0.01067) (Spearman correlation coefficient = 0.46687). In contrast, the same analysis, when performed by correlating the delta of the ERG and PhNR amplitudes before and after rtACS with the PGIC score, did not show a statistically significant correlation (p > 0.05) (Spearman correlation coefficient = 0.2). The separate analysis of pre- and postchiasmatic lesions did not reach statistical significance.
      Table 1The Table Summarize the Main Clinical Characteristics of Patients Included in the Study, Age, Sex, Pathology, Kind of Visual Deficit and Score of PGIC
      Patients Age Sex Pathology Visual deficit PGIC
      1 67 F Ischemic optic neuropathy Light perception 1
      2 41 F Opticopathy associated with drusen Bilateral severe reduction of visual field 2
      3 52 M Glaucoma Bilateral severe reduction of visual field and visual acuity 5
      4 77 M Ischemic optic neuropathy Bilateral severe reduction of visual field and visual acuity 3
      5 35 M Left eye posttraumatic opticopathy Light perception 3
      6 67 M Stroke Severe reduction of visual field 3
      7 49 M Opticopathy due to hyperglycemic coma Light perception 4
      8 77 F Glaucoma Bilateral severe reduction of visual field 3
      9 44 M Opticopathy due to cerebral neoplasia Bilateral reduction of visual field and visual acuity 6
      10 43 M Bilateral posttraumatic opticopathy Bilateral reduction of visual field and visual acuity 1
      11 39 F Opticopathy due to neoplasia Light perception 1
      12 84 M Glaucoma Bilateral severe reduction of visual field 2
      13 71 M Glaucoma Bilateral severe reduction of visual field 1
      14 68 M Stroke Severe reduction of visual field 6
      15 53 M Right eye posttraumatic opticopathy Bilateral severe reduction of visual field 1
      16 78 M Stroke Severe reduction of visual field and visual acuity 4
      17 55 M Stroke Severe reduction of visual field and visual acuity 5
      18 55 M Postsyphilis opticopathy Severe bilateral reduction of visual field and visual acuity 4
      19 21 M Bilateral posttraumatic opticopathy Severe bilateral reduction of visual field and visual acuity 3
      20 61 M Glaucoma Severe bilateral reduction of visual field and visual acuity 6
      21 81 M Glaucoma Severe bilateral reduction of visual field and visual acuity 5
      22 24 M Bilateral posttraumatic opticopathy Severe bilateral reduction of visual field and visual acuity 1
      23 35 M Stroke Severe reduction of visual field and visual acuity 5
      24 73 M Glaucoma Bilateral severe reduction of visual field 3
      25 77 F Glaucoma Severe bilateral reduction of visual field and visual acuity 4
      26 83 M Ischemic optic neuropathy Severe bilateral reduction of visual field 5
      27 58 M Glaucoma Severe reduction of visual field and visual acuity 1
      28 38 M Bilateral posttraumatic opticopathy Blind one eye, severe reduction of visual field and visual acuity other eye 5
      29 34 F Stroke Severe reduction of visual field and visual acuity 7
      30 43 M Opticopathy due to cerebral neoplasia Severe bilateral reduction of visual field and visual acuity 3
      31 72 M Glaucoma Light perception 1
      32 76 F Opticopathy due to spina bifida complications Light perception 2
      F, female; M, male.
      Figure thumbnail gr1
      Figure 1a. Correlation between the PGIC questionnaire (x axis, independent variable) and delta of VEP amplitude (expressed as percentage on the y axis, dependent variable), before and after rtACS. b. Correlation between PGIC questionnaire (x axis, independent variable) and delta of ERG waves (expressed as percentage on the y axis, dependent variable), before and after rtACS. c. Correlation between PGIC questionnaire (x axis, independent variable) and PhNR amplitudes (expressed as percentage on the y axis, dependent variable), before and after rtACS.

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