Rehabilitation of Visual Loss: Where We Are and Where We Need to Be

Background: Spontaneous recovery of visual loss resulting from injury to the brain is variable. A variety of traditional rehabilitative strategies, including the use of prisms or compensatory saccadic eye movements, have been used successfully to improve visual function and quality-of-life for patients with homonymous hemianopia. More recently, repetitive visual stimulation of the blind area has been reported to be of benefit in expanding the field of vision. Evidence Acquisition: We performed a literature review with main focus on clinical studies spanning from 1963 to 2016, including 52 peer-reviewed articles, relevant cross-referenced citations, editorials, and reviews. Results: Repetitive visual stimulation is reported to expand the visual field, although the interpretation of results is confounded by a variety of methodological factors and conflicting outcomes from different research groups. Many studies used subjective assessments of vision and did not include a sufficient number of subjects or controls. Conclusions: The available clinical evidence does not strongly support claims of visual restoration using repetitive visual stimulation beyond the time that spontaneous visual recovery might occur. This lack of firm supportive evidence does not preclude the potential of real benefit demonstrated in laboratories. Additional well-designed clinical studies with adequate controls and methods to record ocular fixation are needed.

State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD Rehabilitation of Visual Loss: Where We Are and Where We Need to Be Behzad Mansouri, MD, PhD, FRCPC, Marinya Roznik, BSc, Joseph F. Rizzo III, MD, Sashank Prasad, MD Background: Spontaneous recovery of visual loss resulting from injury to the brain is variable. A variety of traditional rehabilitative strategies, including the use of prisms or compensatory saccadic eye movements, have been used successfully to improve visual function and quality-of-life for patients with homonymous hemianopia. More recently, repetitive visual stimulation of the blind area has been reported to be of benefit in expanding the field of vision. Evidence Acquisition: We performed a literature review with main focus on clinical studies spanning from 1963 to 2016, including 52 peer-reviewed articles, relevant crossreferenced citations, editorials, and reviews. Results: Repetitive visual stimulation is reported to expand the visual field, although the interpretation of results is confounded by a variety of methodological factors and conflicting outcomes from different research groups. Many studies used subjective assessments of vision and did not include a sufficient number of subjects or controls. Conclusions: The available clinical evidence does not strongly support claims of visual restoration using repetitive visual stimulation beyond the time that spontaneous visual recovery might occur. This lack of firm supportive evidence does not preclude the potential of real benefit demonstrated in laboratories. Additional well-designed clinical studies with Neurology Section (BM, MR), Department of Internal Medicine, Department of Ophthalmology, and Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba, Canada; Neuro-Ophthalmology Service (JFR), Department of Ophthalmology, Harvard Medical School and the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Department of Neurology (SP), Brigham and Women's Hospital, Boston, Massachusetts; and Harvard Medical School (JFR, SP), Boston, Massachusetts. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Behzad Mansouri, MD, PhD, FRCPC, Neurology Section, Department of Internal Medicine, Department of Ophthalmology, and Biomedical Engineering Program, University of Manitoba, 2735 Pembina Hwy, R3T2H5, Winnipeg, Manitoba, Canada; E-mail: [e-mail]. Mansouri et al: J Neuro-Ophthalmol 2018; 38: 223-229 adequate controls and methods to record ocular fixation are needed. Journal of Neuro-Ophthalmology 2018;38:223-229 doi: 10.1097/WNO.0000000000000594 © 2017 by North American Neuro-Ophthalmology Society H omonymous hemianopia (HH), which may be partial or complete, is the most common visual deficit after stroke (1). Stroke patients with a visual field defect often require longer rehabilitation and may be chronically impaired in their daily activities (2-7). Although 50% of stroke patients with HH may show some degree of improvement, complete spontaneous resolution occurs in only 8%-12% of patients (8). Efforts to provide successful rehabilitation for visual deficits are, therefore, of critical importance. Some of the mechanisms that underlie recovery in the nervous system include the reactivation of partially damaged perilesional tissues (9), change in neuronal excitability (10), remodeling of the receptive field size (11), change in subcortical modeling of attention (12), change in neurochemical and channel properties (13), alteration in long-term potentiation (14), and activation of regions in preserved cortical zones that are physiologically linked to suboptimally firing neurons within the damaged occipital cortex (15). There is also reorganization of the visual pathway through the disinhibition of long-range horizontal connections within the primary visual cortex (V1) (16), sprouting of new horizontal connections (17), changes in the functional interactions between intact regions of V1 and higher level visual cortical areas (18-21), and activation of the pathways that bypass V1, including for example, the direct pathway from lateral geniculate nucleus to middle temporal area (22). The fundamental goal of visual rehabilitation is to promote these mechanisms that underlie visual recovery. Here, we present the clinical approaches to visual rehabilitation in patients' with HH. We will not discuss 223 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review basic and laboratory research in detail but rather a practical review of clinically-tested visual rehabilitation methods. METHODS A literature review primarily focusing on clinical studies was performed using the PubMed database with keywords that included the following: visual rehabilitation, HH, visual restitution, visual restoration, blindsight, stroke, and visual plasticity. A total of 52 peer-reviewed articles, relevant crossreferenced citations, editorials, reviews, and retrospective/ original research from 1963 to 2016 were reviewed. Three approaches to the treatment of HH were identified and assessed: 1) the use of prisms, 2) compensatory methods using normal saccadic exploration, and 3) restorative techniques. A critical review of each therapeutic clinical method and relevant laboratory studies are discussed below. RESULTS Use of Prisms The goal of using prisms is to transpose portions of the nonseeing visual field onto seeing areas (See Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A292). Peli (23) developed a method of using high-powered Fresnel prisms that were placed unilaterally onto the upper and lower sections of spectacle lenses. The effectiveness of prisms has been suggested by several studies (23-27). The Peli group performed a randomized, double-masked, crossover clinical trial. Therapeutic prisms (57D) were compared with sham horizontal prisms (5D). The primary outcome was patient satisfaction, judged by the patient's decision to continue wearing the prisms. Patients with high-powered prisms were twice as likely to continue wearing the prisms compared with the sham group (28). The main criticism of this method is that for many patients, the transposition of portions of the visual field is confusing and ultimately not deemed beneficial. However, in patients without other significant cognitive or motor limitations, prisms can provide tangible benefits. Compensatory Method The compensatory method uses training to encourage the use of exploratory eye movements into the blind hemifield (See Supplemental Digital Content, Table E2, http:// links.lww.com/WNO/A293). A search task may include, for example, targets located within a background of distracting elements. One controlled study showed that after 4 weeks of training, detection rates, reaction time, selfassessment of performance in daily activities improved significantly (P , 0.05) (29). Subsequent studies, using more sophisticated computerbased methods and monitoring of eye movements (e.g., VISIOcoach or NeuroEyeCoach) (30-33), have shown im224 provements in a variety of parameters, including increased saccadic movements into the blind hemifield and an expansion in the visual search field (31). Another study showed significant improvement in the speed of reading and visual exploration, although the improvement was task specific and did not transfer between reading and visual exploration (34). These results suggest that training can provide specific improvements in function as opposed to general improvements that might relate to heightened mental awareness during this type of laboratory testing. A Cochrane review concluded that there was some evidence supporting the benefit of compensatory scanning training for patients with HH (35). Restorative Method The restorative approach of visual rehabilitation is based on the premise that the visual system is plastic and that visual recovery can be achieved through repetitive visual stimulation (See Supplemental Digital Content, Table E3, http://links.lww.com/WNO/A294). Primate studies have shown that systematic visual stimulation can produce expansion of the intact visual field beyond the expected spontaneous recovery (36). A critical amount of spared neural tissue is presumably necessary to support this type of return of function, but the exact factors that determine the ability to recover remain unknown. Zihl and von Cramon (37) were the first to use repetitive visual stimulation to restore vision in patients with HH. It was known by the late 1970s that the sensitivity for detecting visual images along the border between blind and seeing areas of the visual field fluctuated. These fluctuations in function were attributed to alterations in neural function within the penumbra of injury. Defects with abrupt borders were considered to have a lower potential for improvement than those with "sloping" borders (38,39). Although this appealing concept has not been directly substantiated, it may still hold relevance for assessing the potential for visual recovery, either spontaneously or after a period of training. Zihl and von Cramon (37) tested several methods of repetitive visual stimulation with the goal of increasing contrast sensitivity and expanding the field of vision. They showed, albeit without sham controls, that treatment may improve light sensitivity within the original field defect. Another study by Zihl and von Cramon (40) used a similar method but incorporated the monitoring of saccadic eye movement. Eighty percent of patients had a visual field expansion of at least 1.5°. Furthermore, the saccadic eye movement measurement showed that the patient's accuracy in detecting stimuli along the border between seeing and blind areas was less than ±0.5° visual angle toward the blind area. The research described above provided motivation for commercial activity in the visual rehabilitative field. NovaVision (Boca Raton, FL) was the first company to commercialize a product called Vision Restoration Therapy Mansouri et al: J Neuro-Ophthalmol 2018; 38: 223-229 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review (VRT) that was a home-based training system developed with the goal of expanding the visual field by stimulating along the edge of the visual field deficit. VRT required 6 months of 1-hour daily training. Subjects responded to bright white stimuli (95 cd/m2) on a dark background (1 cd/m2) by pressing a key while maintaining fixation on a designated point (fixation was not monitored). Changes in the visual field were analyzed using high resolution perimetry (HRP) that provided high sensitivity. It consisted of a bright circular core stimulus surrounded by a dark border with the dimension and luminance carefully calculated to make it invisibly melt into the background. Up to 5 visual field assessments were obtained to define "absolute" defects and "relative" defects. These terms should not be taken literally, however, because neither the size nor the brightness of the stimulus was varied and there was no regard for the effects of false-positive errors. Using these methods, several studies reported an average expansion of 4.9°-5.8° of the visual field in patients with HH (41-54). However, most of this data were collected in retrospective evaluations of NovaVision customers and did not directly include a placebo control group, apart from reference to the previous study by Kasten et al (41). Role of Spatial Attention in Vision Restoration Spatial attention may play an important role in the rehabilitation of visual field deficits. For instance, spatial attention can be directed to different areas of the visual field without eye movement, decreasing the latency between presentation and detection of visual stimuli (55,56). Poggel et al (55) tested shifting visual attention by cueing to a specific area of the visual field by temporarily flashing a bright rectangular box before stimuli were presented; however, they did not find that manipulating visual attention altered the effect of VRT (43,44). Patient-Reported Outcomes With Vision Restoration Therapy VRT has been associated with subjective, patient-reported improvement in visual function and increased quality of life. Patient-reported outcomes, however, are subjective results that can be highly confounded by an expectation that a treatment is efficacious. Nine percent of patients in the study by Mueller et al (49) reported subjective improvement despite the minimal expansion of their visual field. In the study by Kasten et al (41), sixteen percent of the patients who received the sham treatment in the VRT study reported improvements in vision and quality of life. A retrospective study showed that 88% of patients reported improvements in domains such as visual confidence, reading ability, avoidance of collision with objects, and resuming of old hobbies (P , 0.05), although they still considered their visual field defect to be debilitating (49). When patients drew the perceived perimeters of their scotoma after VRT, Mansouri et al: J Neuro-Ophthalmol 2018; 38: 223-229 there was no change in comparison to baseline representations (P . 0.05) (55). In 2008, the Sabel group retrospectively studied 85 patients (who were customers of NovaVision) using validated self-assessment scales to assess the effect of VRT on the quality of visual function and general health (46). Both the National Eye Institute-Visual Function Questionnaire, which inquires about general health, general vision, ocular pain, near and far visual difficulties, dependency on others, driving, and social functioning, and SF-36 assessment, which assesses emotional and physical health in 8 subscales, revealed a statistically significant correlation between some categories of subjective functional improvement and increased detection performance in HRP. However, this study is very difficult to interpret given the lack of any control comparisons. Also, at least one-third of patients had a lesion age of less than 6 months, and the effects of spontaneous recovery could therefore confound the interpretation of the results. Effects of Vision Restoration Therapy Assessed by Functional Imaging Functional MRI technology has been attempted to gain insights into the underlying mechanisms of VRT's rehabilitative effects, but most studies have not incorporated adequate sham-controlled experiments. Moreover, eye fixation is inadequately controlled in most studies, making the results very challenging to interpret. It was shown that after 1 month of VRT in 6 patients, blood oxygenation level dependent (BOLD) fMRI activity was increased at the border between seeing and blind areas, possibly suggesting that VRT training may increase visual responsiveness in these areas (56). A follow-up study in 2010 focused on retinotopic BOLD response before and after 2 weeks of Goldmann perimetric static stimuli training with visual fixation assessed with the Eyelink II tracker (57). Although the visual field was reported to expand by a mean of 3.94° visual angle in 7 of 8 patients, fMRI results showed a general dispersion of BOLD response that was difficult to interpret. A magnetoencephalography study, without a control comparison, suggested that 40 hours of intensive training of flickering letter detection induced reorganization of V1, V2, V3, V3a, and V5 cortical areas in one patient (58). This finding was reinforced by fMRI, which indicated that these changes correlated with a shift of receptive field activation to the unaffected hemisphere; heightened responses were recorded in V5, V3a, and the superior temporal polysensory area (59). Together, these studies suggest that some aspects of visual plasticity may contribute to visual recovery after visual training, but evidence is lacking to support the notion of large-scale retinotopic reorganization in keeping with a substantial increase of visual field. Critique of Vision Restoration Therapy As alluded to throughout the preceding sections, there have been several important criticisms of VRT, including 225 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review questionable accuracy and reliability of visual field testing strategies and inadequate control for visual fixation. A Cochrane review in 2011 that used stringent inclusion criteria only reviewed one study (41) and concluded that there is insufficient evidence to reach a conclusion about the benefits of visual restoration (35). Questionable Accuracy and Reliability of the Visual Field Testing Strategies Several older studies in support of VRT mainly relied on a method termed Tubingen Automated Perimetry (TAP), but the reliability of this method has been questioned. TAP presents 191 near-threshold stimuli in locations that cover the central 30° of vision. Although some investigators have defined successful expansion of the visual field simply as an increased detection rate as small as 0.43° visual angle (41), others used more stringent measures to define "success," for example, a minimum shift of 2° centrally and 5° peripherally between seeing and nonseeing areas. When applying the latter parameters, the visual field improvements after VRT were hardly significant (60-64). Inadequate Control of Visual Fixation A major concern of essentially all previous studies that used visual field testing as the primary outcome is the degree to which there was adequate control of visual fixation. Balliet et al (62) suggested that the positive VRT results could be explained by the effects of poor ocular fixation during the visual field testing because small, saccadic eye movements will enable patients to see stimuli by inadvertent scanning into the "blind" region. Horton (63) later seized on this concern in his editorial comments, in which he pointed out that the methods to monitor fixation in most VRT studies have been primitive. In response, the group headed by Sabel (42) published a series of studies to defend the credibility of VRT. First, they used a more rigid eye fixation strategy called the "2D Eyetracker," which measured horizontal and vertical eye positions at a rate of 200 frames/sec and could measure excursions from 240° to +40° with a resolution of 0.05° of visual angle. This method demonstrated that eye position was relatively steady, remaining within ±1° of fixation 80% of the time and within ±2° 95% of the time. Using this approach, these authors reported that despite the reduced fixation stability in these patients, there were no preferential saccades into the blind hemifield. In addition, the researchers showed that the pattern of eye movements did not change after a 3-month course of VRT. They concluded that increased saccades disrupting fixation did not fully account for observed improvements in visual field defects in these patients. In an attempt to further control for the effects of ocular fixation, a scanning laser ophthalmoscope (SLO) was used in some studies attempting to assess vision restoration therapies. With SLO, stimuli are projected directly onto the 226 retina to account for real-time changes in eye position. In one study, patients who completed VRT reported subjective improvements, although SLO-aided visual field testing did not show a statistically significant reduction in the area of absolute visual field loss (64). It is possible, however, that SLO methods can overestimate the extent of a field deficit. For example, some techniques used a binary response task to a single intensity of visual stimulus; thus, it could not have provided a relative measure of the area of visual deficit. In addition, a "filling-in" effect makes it harder to perceive "inverted" black stimuli on a bright red background of flickering red lines (65). Similarly, when inverse stimuli parameters were used with HRP (i.e., switching the gray background of HRP to red and using black "inverse" stimulus targets), detection rates fell from 89% to 80% and false-positive responses increased (66). It is not surprising, therefore, for SLO perimetry and HRP to produce differing results. It was found in one study, for example, that at baseline the border between the seeing and blind areas was closer to the vertical midline when tested with SLO compared with when it was tested with HRP using standard fixation controls. After VRT, the absolute borders receded from the midline when defined by HRP, but remain unchanged when tested by SLO. The authors interpreted this result as an expansion of the visual field that had not been captured by the SLO method (67). Recent Promising Attempts in Visual Restoration In the past 2 decades, several studies have incorporated stringent eye fixation and psychophysical methods for visual rehabilitation (See Supplemental Digital Content, Table E3, http://links.lww.com/WNO/A294) (41,42,68,69). Although these preliminary studies have shown promising visual improvement in HH, they examined a limited number of patients (mostly ,10 patients) and none of these methods have been tested in a clinical environment with randomized sham-controlled clinical trial. For example, Sahraie et al (70) tested 12 patients (the largest number of patients with HH in this group of studies), used grating stimuli, and showed a modest improvement in visual field defect (less than 3.5°). Adjuvant Therapies in Visual Rehabilitation Newer techniques that have been studied in stroke rehabilitation include transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). In TMS, pulses of alternating magnetic field over the scalp create an electrical current in the cortex that can be delivered in a manner to either excite or inhibit underlying neurons. TDCS uses a weak current pathway between scalp electrodes, changing the excitability of underlying neurons in a targeted area. TMS and tDCS can be used to target specific neural areas that are mapped by anatomical and Mansouri et al: J Neuro-Ophthalmol 2018; 38: 223-229 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review functional MRI and are being systemically studied for stroke rehabilitation (71). TDCS has been evaluated as an adjuvant treatment to VRT for visual rehabilitation in a randomized, double-blind study that demonstrated on average 1° further increase in expansion of the central vision and w10% increase in stimulus detection accuracy (72). Furthermore, a single case study that combined VRT training with bilateral occipital excitatory tDCS stimulation revealed a 4° border shift between the seeing and blind areas (73). More studies with rigorous controls are necessary to evaluate the potential effects of these therapies. CONCLUSION Ideally, visual rehabilitation would be an integral component of the delivery of medical care for patients who have significant visual deficits after a stroke or other destructive pathologies. Prisms, compensatory techniques, and restorative methods have been studied, and in general the first 2 methods have been reported to show an improved quality of life. However, significant questions have been raised about the legitimacy of some claims of clinical success in visual restoration. The lingering technical questions and the lack of unambiguous benefit do not allow one to conclude with confidence that the proposed vision rehabilitation strategies and techniques have improved visual function in areas that had been blind beyond the period when spontaneous recovery of vision might have occurred. There remains a significant need for new restoration treatment paradigms, additional randomized, shamcontrolled clinical trials, with adequate visual fixation monitoring of patients with HH and methods that capture physiological responses to treatments, such as functional magnetic imaging. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: B. Mansouri, M. Roznik, J. F. Rizzo III, and S. Prasad; b. Acquisition of data: B. Mansouri, M. Roznik, J. F. Rizzo III, and S. Prasad; c. Analysis and interpretation of data: B. Mansouri, M. Roznik, J. F. Rizzo III, and S. Prasad. Category 2: a. Drafting the manuscript: B. Mansouri, M. Roznik, J. F. Rizzo III, and S. Prasad; b. Revising it for intellectual content: B. Mansouri, M. Roznik, J. F. Rizzo III, and S. Prasad. Category 3: a. Final approval of the completed manuscript: B. Mansouri, M. Roznik, J. F. Rizzo III, and S. Prasad. REFERENCES 1. Rowe F, Brand D, Jackson CA, Price A, Walker L, Harrison S, Eccleston C, Scott C, Akerman N, Dodridge C, Howard C, Shipman T, Sperring U, MacDiarmid S, Freeman C. Visual impairment following stroke: do stroke patients require vision assessment? Age Ageing. 2009;38:188-193. 2. Ijaola FO, Kausar SA. Visual impairment following stroke: do stroke patients require vision assessment? Age Ageing. 2009;38:629-630; author reply 630-621. Mansouri et al: J Neuro-Ophthalmol 2018; 38: 223-229 3. Feigenson JS, McCarthy ML. Stroke rehabilitation. II. Guidelines for establishing a stroke rehabilitation unit. N Y State J Med. 1977;77:1430-1434. 4. Feigenson JS, McCarthy ML, Meese PD, Feigenson DW. Stroke rehabilitation I. Factors predicting outcome and length of stay- an overview. 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