Barriers to Care for Poststroke Visual Deficits in Alberta, Canada.

Poststroke visual impairment (VI) negatively affects rehabilitation potential and quality of life for stroke survivors. In this cross-sectional observational study, stroke survivors and providers were surveyed to quantify perspectives regarding care for poststroke VI in Alberta, Canada (n = 46 survivors; n = 87 providers). Few patients (35%) felt prepared to cope with VI at the time of discharge from acute stroke and inpatient rehabilitation settings. Less than 25% of stroke survivors, and <16% of providers, felt referral processes were adequate. 95.2% of providers and 82% of stroke survivors advocated for a provincial clinical pathway to improve care quality for poststroke VI.

Transnasal transsphenoidal pituitary surgery in a large tertiary hospital, a retrospective study.

OBJECTIVES: Pituitary adenomas (PAs), although being small tumours, can have quite an impact on patients' lives causing hormonal and visual disturbances, for which surgery must be performed. As a large peripheral hospital with specialists in pituitary surgery, an assessment of the efficacy and safety of transnasal transsphenoidal pituitary surgery was made. METHODS: A retrospective analysis of neurosurgical reports as well as pre and postoperative imaging was made to evaluate the presenting symptoms, tumoural variables, peri-operative morbidity, and long-term outcome. RESULTS: This cohort included 105 patients who were operated for PAs over a 9-year period, with a slight male predominance. Adenomas had a mean maximum diameter of almost 25 mm, with one-third of tumours presenting with a Knosp-grade 3 or 4. As expected, most patients presented with either visual (32.4%) or hormonal (40.0%) disturbances. After surgery, 85.3% had complete resolution of visual deficits, and 97.1% had normalisation of hormonal hypersecretion. Postoperative hormonal insufficiency requiring substitution was observed in 43.1% and was significantly more frequent in males and in non-functioning pituitary adenomas (NFAs). Postoperative cerebrospinal fluid (CSF) leakage was observed in 2.9%, and merely one patient developed meningitis. Tumour recurrence was significantly more frequent in patients with partial resection as compared to complete resection (25.6 vs. 7.9%). CONCLUSIONS: This study demonstrates that transnasal transsphenoidal pituitary surgery can be performed safely and effectively in a large non-university hospital, improving visual and/or hormonal disturbances as well as providing long-term tumour control. Patients with larger adenomas are at an increased risk to develop postoperative hypopituitarism.

Raloxifene, a cannabinoid type-2 receptor inverse agonist, mitigates visual deficits and pathology and modulates microglia after ocular blast.

Visual deficits after ocular blast injury (OBI) are common, but pharmacological approaches to improve long-term outcomes have not been identified. Blast forces frequently damage the retina and optic nerves, and work on experimental animals has shown the pro-inflammatory actions of microglia can further exacerbate such injuries. Cannabinoid type-2 receptor (CB2) inverse agonists specifically target activated microglia, biasing them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state. We previously found that treating mice with CB2 inverse agonists after traumatic brain injury, produced by either focal cranial air blast or dorsal cranial impact, greatly attenuated the visual deficits and pathology that otherwise resulted. Here we examined the consequences of single and repeat OBI and the benefit provided by raloxifene, an FDA-approved estrogen receptor drug that possesses noteworthy CB2 inverse agonism. After single OBI, although the amplitudes of the A- and B-waves of the electroretinogram and pupil light response appeared to be normal, the mice showed hints of deficits in contrast sensitivity and visual acuity, a trend toward optic nerve axon loss, and significantly increased light aversion, which were reversed by 2 weeks of daily treatment with raloxifene. Mice subjected to repeat OBI (5 blasts spaced 1 min apart), exhibited more severe visual deficits, including decreases in contrast sensitivity, visual acuity, the amplitudes of the A- and B-waves of the electroretinogram, light aversion, and resting pupil diameter (i.e. hyperconstriction), accompanied by the loss of photoreceptor cells and optic nerve axons, nearly all of which were mitigated by raloxifene. Interestingly, optic nerve axon abundance was strongly correlated with contrast sensitivity and visual acuity across all groups of experimental mice in the repeat OBI study, suggesting optic nerve axon loss with repeat OBI and its attenuation with raloxifene are associated with the extent of these two deficits while photoreceptor abundance was highly correlated with A-wave amplitude and resting pupil size, suggesting a prominent role for photoreceptors in these two deficits. Quantitative PCR (qPCR) showed levels of M1-type microglial markers (e.g. iNOS, IL1ß, TNFα, and CD32) in retina, optic nerve, and thalamus were increased 3 days after repeat OBI. With raloxifene treatment, the overall expression of M1 markers was more similar to that in sham mice. Raloxifene treatment was also associated with the elevation of IL10 transcripts in all three tissues compared to repeat OBI alone, but the results for the three other M2 microglial markers we examined were more varied. Taken together, the qPCR results suggest that raloxifene benefit for visual function and pathology was associated with a lessening of the pro-inflammatory actions of microglia. The benefit we find for raloxifene following OBI provides a strong basis for phase-2 efficacy testing in human clinical trials for treating ocular injury.

McCune-Albright syndrome associated with pituitary adenoma: a clinicopathological study of ten cases and literature review.

BACKGROUND: McCune-Albright syndrome (MAS) is a rare genetic, non-inheritable disease and is characterized by fibrous dysplasia, hyperendocrinism, and café-au-lait macules. Pituitary adenomas could be concurrent with this syndrome but clinicopathological features and the surgical management of such disorders is unclear. METHODS: We retrospectively reviewed ten MAS-associated pituitary adenoma patients with follow-up in Beijing Tiantan Hospital and analyzed their clinicohistological data, surgical strategies, neuro-imaging, genetic mutations, and prognosis. Moreover, a critical review of the English language literature was also conducted. RESULTS: All of the ten MAS-associated adenoma patients underwent surgeries to remove the tumor (nine transsphenoidal approaches and one transcranial approach). None of these patients had a decompression of the optic canal. Notably, the growth hormone (GH), prolactin (PRL), and IGF-1 level had a significant reduction after the resection of the tumor while vision improvement was observed in most patients (6/7) with visual deficits. No tumor recurrence was observed during the follow-up from 16 to 150 months. The pathological examination showed a moderate Ki-67 LI (mean 1.19%, range from 0.1% to 3.3%) and the positive staining of Gsα and PKA C-beta. GNAS gene mutation (R201C) was detected in one patient. CONCLUSIONS: Hormone excess (including GH and PRL) could be significantly reduced and the visual deficits are greatly improved after the surgery without the decompression of the optic canal. In addition, MAS-associated pituitary adenomas have a moderate expression of Ki-67 and positive expression of Gsα and PKA C-beta, indicating a mildly proliferative nature of these tumors and the possible linking between MAS and adenomas.

Pilot Study: The Queen Square Screening Test for Visual Deficits in Dementia.

The Queen Square Screening Test for Visual Deficits (QS test) screens for changes in visual processing. Our pilot study aimed to review the applicability of the QS test in individuals with dementia compared with those with normal cognition. Participants with major and minor neurocognitive disorder scored 50/71 (n=12) and 61/71 (n=10) respectively on the QS test, compared to 65/71 for age-matched healthy controls (n=11). The QS test score correlated with cognitive impairment as measured using the Rowland Universal Dementia Assessment Scale (r = 0.74). The QS test is an affordable and easy bedside screening test for visual processing changes.

Amelioration of visual deficits and visual system pathology after mild TBI with the cannabinoid type-2 receptor inverse agonist SMM-189.

Mild TBI is often accompanied by visual system dysfunction and injury, which is at least partly caused by microglial neuroinflammatory processes initiated by the injury. Using our focal cranial blast mouse model of closed-skull mild TBI, we evaluated the ability of the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189, which biases microglia from the harmful M1 state to the beneficial M2 state, to mitigate visual system dysfunction and injury after TBI. Male C57BL/6 or Thy1-EYFP reporter mice received a closed-head blast of either 0-psi (sham) or 50-psi to the left side of the cranium. Blast mice received vehicle or 6 mg/kg SMM-189 daily beginning 2 h after blast. Sham mice received vehicle. In some mice, retina and optic nerve/tract were assessed morphologically at 3-7 days after blast, while other mice were assessed functionally by Optomotry 30 days after blast and morphologically at ≥30 days after blast. Mice sacrificed at 3-7 days were treated daily until sacrificed, while those assessed ≥30 days after blast were treated daily for 2 weeks post blast. Axon damage was evident in the left optic nerve and its continuation as the right optic tract at 3 days post blast in vehicle-treated blast mice in the form of swollen axon bulbs, and was accompanied by a significant increase in the abundance of microglia. Testing at 30 days post blast revealed that the contrast sensitivity function was significantly reduced in both eyes in vehicle-treated blast mice compared to vehicle-treated sham blast mice, and axon counts at ≥30 days after blast revealed a ∼10% loss in left optic nerve in vehicle-treated blast mice. Left optic nerve axon loss was highly correlated with the left eye deficit in contrast sensitivity. Immunolabeling at 30 days post blast showed a significant increase in the abundance of microglia in the retinas of both eyes and in GFAP + Müller cell processes traversing the inner plexiform layer in the left eye of vehicle-treated blast mice. SMM-189 treatment reduced axon injury and microglial abundance at 3 days, and mitigated axon loss, contrast sensitivity deficits, microglial abundance, and Müller cell GFAP upregulation at ≥30 days after blast injury. Analysis of right optic tract microglia at 3 days post blast for M1 versus M2 markers revealed that SMM-189 biased microglia toward the M2 state, with this action of SMM-189 being linked to reduced axonal injury. Taken together, our results show that focal left side cranial blast resulted in impaired contrast sensitivity and retinal pathology bilaterally and optic nerve loss ipsilaterally. The novel cannabinoid drug SMM-189 significantly mitigated the functional deficit and the associated pathologies. Our findings suggest the value of combatting visual system injury after TBI by using CB2 inverse agonists such as SMM-189, which appear to target microglia and bias them away from the pro-inflammatory M1 state, toward the protective M2 state.

High level of pattern glare in major depressive disorder.

BACKGROUND: Visual deficits have been reported in abundance by recent studies on major depressive disorder. Pattern glare manifests as visual distortions, such as the symptoms of headache, glare, eyestrain, illusions of shapes, colors, and motion when viewing repetitive striped patterns, of which some can be observed in major depressive disorder. Inspired by what mentioned, the present study aims to explore whether there exists association between pattern glare and major depressive disorder and further attempts to explore possible clinical diagnostic value of pattern glare in major depressive disorder. METHODS: Twenty-four patients diagnosed with major depressive disorder (MDDs group) were compared with 30 age-, gender- and education level-matched healthy control subjects (HCs group) on their visual stress with black-and-white gratings of different spatial frequencies-0.3 (low-SF), 2.3 (mid-SF), and 9.4 (high-SF) cycles per degree (c/deg)-which was named pattern glare test. The MDDs group divided into first episode medication-free group (fMDD) and recurrent medicated group (rMDD), comparisons of pattern glare scores (PGS) were performed within the MDDs group. We used Pearson and Spearman analysis to explore the relationship between some clinical indexes and pattern glare scores. ROC (receiver operating characteristic) curve was used to evaluate whether pattern glare test was able to discriminate patients and healthy controls. RESULTS: The mid-SF pattern glare score significantly elevated in patients with major depressive disorder compared to control subjects. No differences of pattern glare scores were found between fMDD and rMDD. A significant negative correlation between mid-high difference and age in HCs group was found. There were no correlations between other variables and pattern glare scores. The mid-SF score has limited value in the diagnosis of major depressive disorder. CONCLUSIONS: We observed an increased level of pattern glare in patients with major depressive disorder, reflecting the existence of cortical hyper-excitability in major depressive disorder. The mid-SF score may have a value in understanding cortical excitability in major depressive disorder.

Acuity-independent effects of visual deprivation on human visual cortex.

Visual development depends on sensory input during an early developmental critical period. Deviation of the pointing direction of the two eyes (strabismus) or chronic optical blur (anisometropia) separately and together can disrupt the formation of normal binocular interactions and the development of spatial processing, leading to a loss of stereopsis and visual acuity known as amblyopia. To shed new light on how these two different forms of visual deprivation affect the development of visual cortex, we used event-related potentials (ERPs) to study the temporal evolution of visual responses in patients who had experienced either strabismus or anisometropia early in life. To make a specific statement about the locus of deprivation effects, we took advantage of a stimulation paradigm in which we could measure deprivation effects that arise either before or after a configuration-specific response to illusory contours (ICs). Extraction of ICs is known to first occur in extrastriate visual areas. Our ERP measurements indicate that deprivation via strabismus affects both the early part of the evoked response that occurs before ICs are formed as well as the later IC-selective response. Importantly, these effects are found in the normal-acuity nonamblyopic eyes of strabismic amblyopes and in both eyes of strabismic patients without amblyopia. The nonamblyopic eyes of anisometropic amblyopes, by contrast, are normal. Our results indicate that beyond the well-known effects of strabismus on the development of normal binocularity, it also affects the early stages of monocular feature processing in an acuity-independent fashion.

Neuropsychological findings associated with Panayiotopoulos syndrome in three children.

Panayiotopoulos syndrome is a common idiopathic benign epilepsy that has a peak age of onset in early childhood. The syndrome is multifocal and shows significant electroencephalogram (EEG) variability, with occipital predominance. Although a benign syndrome often refers to the absence of neurological and neuropsychological deficits, the syndrome has recently been associated with cognitive impairments. Also, despite frequent occipital EEG abnormalities, research regarding the visual functioning of patients is less reported and often contradictory. The purpose of this study was to gain additional knowledge regarding the neurocognitive functioning of patients with Panayiotopoulos syndrome and specifically to address any visual processing deficits associated with the syndrome. Following diagnosis of the syndrome based on typical clinical and electrophysiological criteria, three patients, aged 5, 8, and 10years were referred by epileptologists for neuropsychological evaluation. Neuropsychological findings suggest that the patients had notable impairments on visual memory tasks, especially in comparison with verbal memory. Further, they demonstrated increased difficulty on picture memory suggesting difficulty retaining information from a crowded visual field. Two of the three patients showed weakness in visual processing speed, which may account for weaker retention of complex visual stimuli. Abilities involving attention were normal for all patients, suggesting that inattention is not responsible for these visual deficits. Academically, the patients were weak in numerical operations and spelling, which both rely partially on visual memory and may affect achievement in these areas. Overall, the results suggest that patients with Panayiotopoulos syndrome may have visual processing and visual memory problems that could potentially affect their academic capabilities. Identifying such difficulties may be helpful in creating educational and remedial assistance programs for children with this syndrome, as well as developing appropriate presentation of information to these children in school.

Parent, Teacher, and Student Perspectives on How Corrective Lenses Improve Child Wellbeing and School Function.

OBJECTIVES: Up to 20 % of school-age children have a vision problem identifiable by screening, over 80 % of which can be corrected with glasses. While vision problems are associated with poor school performance, few studies describe whether and how corrective lenses affect academic achievement and health. Further, there are virtually no studies exploring how children with correctable visual deficits, their parents, and teachers perceive the connection between vision care and school function. METHODS: We conducted a qualitative evaluation of Vision to Learn (VTL), a school-based program providing free corrective lenses to low-income students in Los Angeles. Nine focus groups with students, parents, and teachers from three schools served by VTL explored the relationships between poor vision, receipt of corrective lenses, and school performance and health. RESULTS: Twenty parents, 25 teachers, and 21 students from three elementary schools participated. Participants described how uncorrected visual deficits reduced students' focus, perseverance, and class participation, affecting academic functioning and psychosocial stress; how receiving corrective lenses improved classroom attention, task persistence, and willingness to practice academic skills; and how serving students in school rather than in clinics increased both access to and use of corrective lenses. CONCLUSIONS: for Practice Corrective lenses may positively impact families, teachers, and students coping with visual deficits by improving school function and psychosocial wellbeing. Practices that increase ownership and use of glasses, such as serving students in school, may significantly improve both child health and academic performance.

Visual Defects in Patients With Pituitary Adenomas: The Myth of Bitemporal Hemianopsia.

OBJECTIVE: The objective of this study was to test the hypothesis that bitemporal hemianopsia (BHA) is the most common visual field (VF) defect in patients with pituitary macroadenoma and to assess the degree of optic pathway compression necessary to produce visual defects. MATERIALS AND METHODS: We reviewed the MRI findings and medical records of 119 patients with pituitary macroadenoma who had undergone formal assessment of VFs. We then evaluated the degree of optic pathway displacement caused by the pituitary macroadenoma, as observed on MR images. The classifications of optic pathway displacement included no contact, abutment but no displacement, mild displacement (< 3 mm), and moderate displacement (≥ 3 mm). Qualitative analysis classified VFs as normal or as having defects that were monocular, bitemporal, mixed (bitemporal with additional defects), homonymous, or nonspecific. RESULTS: A total of 89 of 115 patients had an abnormal VF. Only one patient had true BHA. The most common defects were bitemporal or mixed defects (in 49 of 115 patients [42.6%]), likely because more than just the chiasm is often compressed by the pituitary macroadenoma. Classification of optic pathway displacement by the pituitary macroadenoma was as follows: 23 patients had no contact, eight had abutment but no displacement, 27 had mild displacement, and 57 had moderate displacement. In 78 of the 92 patients (84.8%) with pituitary macroadenoma that had contact with the optic pathway, contact was with the optic chiasm and the prechiasmal optic nerve. Of the 49 patients with bitemporal or mixed defects, 42 had moderate displacement of the optic pathway caused by their tumors. CONCLUSION: BHA is exceedingly uncommon in patients with pituitary macroadenoma. However, although bitemporal and mixed defects are the most common abnormal VF findings, they were found in only 42.6% of patients. Such defects rarely occur if the tumor displaces the optic pathway less than 3 mm from baseline.

Optic pathway glioma in children: does visual deficit correlate with radiology in focal exophytic lesions?

PURPOSE: Unlike pilocytic astrocytomas in other parts of the brain, optic pathway gliomas (OPG) are usually diffuse lesions involving the anterior optic pathways and hypothalamus. Their infiltrative nature often precludes complete surgical resection. We sought to determine whether careful magnetic resonance (MR) analysis, correlated with visual deficits, could be sufficient to identify those focal lesions that may be amenable to more aggressive surgical resection at presentation. METHODS: We retrospectively reviewed the medical records of patients from two sites: children under 20 years of age treated for OPG between 1985 and 2009 at St Jude's Children's Research Hospital and children under 16 years of age treated at Great Ormond Street Hospital, London, UK, between 1984 and 2011. Patients with isolated optic nerve tumors were excluded. Visual acuity and visual field data at presentation were reviewed and correlated with MR characteristics, including extent of optic pathway involvement, symmetry, and lateral extension. RESULTS: Two hundred and one children were treated for OPG between 1984 and 2011 in the two institutions; 74 had neurofibromatosis 1 (NF1). At presentation, visual loss was symmetrical in 132 patients and asymmetrical in 69. Potential correlation between pattern of visual loss and tumor characteristics on routine MRI was found in only 13 patients with asymmetrical vision. There was no difference between patients with and without NF1. CONCLUSION: The decision for aggressive surgical resection for optic pathway gliomas should be based on clinical criteria, particularly in children with good vision in one eye and poor vision in the other, as current MRI results do not reliably predict visual field deficits.

Immersive Virtual Reality for Treatment of Unilateral Spatial Neglect via Eye-Tracking Biofeedback: RCT Protocol and Usability Testing.

About one-third of stroke survivors present unilateral spatial neglect (USN) that negatively impacts the rehabilitation outcome. We reported the study protocol and usability results of an eye-tracking (ET) biofeedback immersive virtual reality (iVR) protocol. Healthy controls and stroke patients with and without USN underwent a single session of the three iVR tasks. The system usability scale (SUS), adverse events (AEs), and ET data were collected and analyzed via parametric analysis. Twelve healthy controls (six young adults and six older adults) and seven patients with a diagnosis of single ischemic stroke (four without USN and three with confirmed diagnosis of USN) completed the usability investigation. SUS results showed good acceptability of the system for healthy controls and stroke patients without USN. ET results showed a lower performance for patients with USN concerning healthy controls and stroke patients without USN, in particular in the exploration of the left visual field. The results showed that the proposed iVR-ET biofeedback protocol is a safe and well-tolerated technique in patients with USN. The real-time feedback can induce a performance response supporting its investigation such as a treatment approach.

The Role of Visual Factors in Dyslexia.

What are the causes of dyslexia? Decades of research reflect a determined search for a single cause where a common assumption is that dyslexia is a consequence of problems with converting phonological information into lexical codes. But reading is a highly complex activity requiring many well-functioning mechanisms, and several different visual problems have been documented in dyslexic readers. We critically review evidence from various sources for the role of visual factors in dyslexia, from magnocellular dysfunction through accounts based on abnormal eye movements and attentional processing, to recent proposals that problems with high-level vision contribute to dyslexia. We believe that the role of visual problems in dyslexia has been underestimated in the literature, to the detriment of the understanding and treatment of the disorder. We propose that rather than focusing on a single core cause, the role of visual factors in dyslexia fits well with risk and resilience models that assume that several variables interact throughout prenatal and postnatal development to either promote or hinder efficient reading.

Self-Perception and the Relation to Actual Driving Abilities for Individuals With Visual Field Loss.

Background: In Sweden, individuals with visual field loss (VFL) have their driving license withdrawn. The literature clearly indicates that individuals with VFL are unsafe drivers on a group level. However, many drivers with VFL can be safe on an individual level. The literature also suggests that self-perception, beliefs, and insights of one's own capabilities are related to driving performance. This study had three aims: (1) To investigate self-perceived driving capability ratings for individuals with VFL; (2) to compare these ratings between groups with different medical conditions associated with VFL (stroke, glaucoma, and diabetes); and (3) to relate the self-perception ratings to actual driving performance in an advanced driving simulator. Methods: Participants comprised 723 individuals whose driver's license had been withdrawn because of VFL and 92 normally sighted elderly individuals. All participants completed a background survey, rated difficulties with different traffic situations, rated their strengths and weaknesses as drivers, and rated aspects that were important for causing traffic accidents. Of the VFL group participants, 264 also completed a simulator-based driving test that they knew could lead to renewal of their driving license. VFL participants and normally sighted was at the same age when they completed the simulator driving test. Results: Overall, individuals with VFL rated their capabilities as high on all instruments and scales used, even higher than the elderly normally sighted control group. The only VFL etiology group that rated lower than other groups was the diabetes group. Safety orientation and internal control orientation values were best at discriminating between VFL participants in terms of self-perception of driving performance. Participants categorized as "high" in terms of safety skills and internal control were more modest in their ratings. Finally, participants who passed the simulated driving test did not differ from those who failed, in any of the self-perception measures. Conclusion: Self-perception ratings among individuals with VFL were higher than those of normally sighted elderly individuals. Self-assessed skills did not predict driving performance. Groups with different VFL etiologies rated similarly. Self-ratings of driving abilities cannot be used to assess actual driving performance. Actual driving tests (on road or in the simulator) are necessary to discriminate between safe and unsafe drivers with VFL.

Motor Skills and Visual Deficits in Developmental Coordination Disorder: A Narrative Review.

BACKGROUND: Developmental coordination disorder (DCD) is a developmental disorder in which numerous comorbidities seem to coexist, such as motor and visual impairment and some executive functions; Methods: A narrative review on motor and visual deficits in children with DCD was carried out; Results and Discussion: Fine and gross motor skills are affected in children with DCD. In addition, they seem to be related to visual deficits, such as difficulty in visual perception, sensory processing and visual memory. Limitations have also been found in accommodation. Interventions in children with DCD should be aimed at improving both aspects, since vision affects motor skills and vice versa; Conclusions: In children with DCD, who present a marked deficit in global shape processing, it causes an association between deficiencies in visual perception and motor skills.

Retinal Degeneration: A Window to Understand the Origin and Progression of Parkinson's Disease?

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, manifests with motor and non-motor symptoms associated with two main pathological hallmarks, including the deterioration of dopaminergic cells and aggregation of alpha-synuclein. Yet, PD is a neurodegenerative process whose origin is uncertain and progression difficult to monitor and predict. Currently, a possibility is that PD may be secondary to long lasting peripheral affectations. In this regard, it has been shown that retinal degeneration is present in PD patients. Although it is unknown if retinal degeneration precedes PD motor symptoms, the possibility exists since degeneration of peripheral organs (e.g., olfaction, gut) have already been proven to antedate PD motor symptoms. In this paper, we explore this possibility by introducing the anatomical and functional relationship of retina and brain and providing an overview of the physiopathological changes of retinal structure and visual function in PD. On the basis of the current status of visual deficits in individuals with PD, we discuss the modalities and pathological mechanism of visual function or morphological changes in the retina and focus on the correlation between visual impairment and some representative structural features with clinical significance. To consider retinal degeneration as a contributor to PD origin and progress is important because PD evolution may be monitored and predicted by retinal studies through state-of-the-art techniques of the retina. It is significant to integrally understand the role of retinal morphological and functional changes in the neurodegenerative process for the diagnosis and therapeutic strategies of PD.

Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration leading to various pathological complications such as motor and sensory (visual) deficits, cognitive impairment, and depression. N-3 polyunsaturated fatty acid (n-3 PUFA) containing lipids are known to be anti-inflammatory, whereas the sphingolipid, ceramide (Cer), is an inducer of neuroinflammation and degeneration. Using Fat1+-transgenic mice that contain elevated levels of systemic n-3 PUFA, we tested whether they are resistant to mild TBI-mediated sensory-motor and emotional deficits by subjecting Fat1-transgenic mice and their WT littermates to focal cranial air blast (50 psi) or sham blast (0 psi, control). We observed that visual function in WT mice was reduced significantly following TBI but not in Fat1+-blast animals. We also found Fat1+-blast mice were resistant to the decline in motor functions, depression, and fear-producing effects of blast, as well as the reduction in the area of oculomotor nucleus and increase in activated microglia in the optic tract in brain sections seen following blast in WT mice. Lipid and gene expression analyses confirmed an elevated level of the n-3 PUFA eicosapentaenoic acid (EPA) in the plasma and brain, blocking of TBI-mediated increase of Cer in the brain, and decrease in TBI-mediated induction of Cer biosynthetic and inflammatory gene expression in the brain of the Fat1+ mice. Our results demonstrate that suppression of ceramide biosynthesis and inflammatory factors in Fat1+-transgenic mice is associated with significant protection against the visual, motor, and emotional deficits caused by mild TBI. This study suggests that n-3 PUFA (especially, EPA) has a promising therapeutic role in preventing neurodegeneration after TBI.

Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury.

Mild traumatic brain injury (TBI) involves widespread axonal injury and activation of microglia, which initiates secondary processes that worsen the TBI outcome. The upregulation of cannabinoid type-2 receptors (CB2) when microglia become activated allows CB2-binding drugs to selectively target microglia. CB2 inverse agonists modulate activated microglia by shifting them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state and thus can stem secondary injury cascades. We previously found that treatment with the CB2 inverse agonist SMM-189 after mild TBI in mice produced by focal cranial blast rescues visual deficits and the optic nerve axon loss that would otherwise result. We have further shown that raloxifene, which is Food and Drug Administration (FDA)-approved as an estrogen receptor modulator to treat osteoporosis, but also possesses CB2 inverse agonism, yields similar benefit in this TBI model through its modulation of microglia. As many different traumatic events produce TBI in humans, it is widely acknowledged that diverse animal models must be used in evaluating possible therapies. Here we examine the consequences of TBI created by blunt impact to the mouse head for visual function and associated pathologies and assess raloxifene benefit. We found that mice subjected to impact TBI exhibited decreases in contrast sensitivity and the B-wave of the electroretinogram, increases in light aversion and resting pupil diameter, and optic nerve axon loss, which were rescued by daily injection of raloxifene at 5 or 10 mg/ml for 2 weeks. Raloxifene treatment was associated with reduced M1 activation and/or enhanced M2 activation in retina, optic nerve, and optic tract after impact TBI. Our results suggest that the higher raloxifene dose, in particular, may be therapeutic for the optic nerve by enhancing the phagocytosis of axonal debris that would otherwise promote inflammation, thereby salvaging less damaged axons. Our current work, together with our prior studies, shows that microglial activation drives secondary injury processes after both impact and cranial blast TBI and raloxifene mitigates microglial activation and visual system injury in both cases. The results thus provide a strong basis for phase 2 human clinical trials evaluating raloxifene as a TBI therapy.