Optometric Brain Injury Curriculum in Federal Residency Training Programs: A Consensus Report.

INTRODUCTION: Brain injury often impacts the visual system. Diagnosis and treatment of visual system problems related to brain injury is a field with less settled science and more variation in practice than most specialty fields. Most optometric brain injury residency programs are in federal clinics (VA and DoD). A consensus core curriculum has been created that will allow some consistency while facilitating program strengths. MATERIALS AND METHODS: Kern's curriculum development model and a focus group of subject matter experts were used to reach consensus in producing a core curriculum to provide a common framework for brain injury optometric residency programs. RESULTS: A common high-level curriculum was developed with educational goals through consensus. CONCLUSIONS: In a relatively new subspeciality without a firm foundation of settled science, a common curriculum will help provide a common framework to facilitate clinical and research progress in this field. The process sought out expertise and community building to help improve the adoption of this curriculum. This core curriculum will provide a framework for educating optometric residents in the diagnosis, management, and rehabilitation of patients with visual sequelae because of brain injury. It is intended to ensure that appropriate topics are covered while allowing for flexibility according to each program's strengths and resources.

Photophobia Associated with Traumatic Brain Injury: A Systematic Review and Meta-analysis.

SIGNIFICANCE: This study reports the prevalence and relative risk of photophobia in patients with traumatic brain injury (TBI). OBJECTIVES: This study aimed to conduct a systematic review and meta-analysis to determine the prevalence and relative risk of photophobia in patients with TBI. DATA SOURCES: Three databases were used for literature search: PubMed, EMBASE, and Cochrane Library. STUDY APPRAISAL AND SYNTHESIS METHODS: Publications reporting the prevalence of photophobia after TBI in patients of any age were included. A series of meta-regression analyses based on a generalized linear mixed model was performed to identify potential sources of heterogeneity in the prevalence estimates. RESULTS: Seventy-five eligible publications were identified. The prevalence of photophobia was 30.46% (95% confidence interval [CI], 20.05 to 40.88%) at 1 week after the injury. Prevalence decreased to 19.34% (95% CI, 10.40 to 28.27%) between 1 week and 1 month after TBI and to 13.51% (95% CI, 5.77 to 21.24%) between 1 and 3 months after the injury. The rapid decrease in the prevalence of photophobia in the first 3 months after a TBI injury was significant (P < .001). Three months post-TBI, the prevalence of photophobia leveled off to a near plateau with nonsignificant variability, increasing between 3 and 6 months (17.68%; 95% CI, 9.05 to 26.32%) and decreasing between 6 and 12 months since TBI (14.85%; 95% CI, 6.80 to 22.90%). Subgroup analysis of 14 publications that contained control data showed that the estimated risk ratio for photophobia was significantly higher in the TBI than in the control group during the entire 12 months after TBI. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This study demonstrates that photophobia is a frequent complaint after TBI, which largely resolves for many individuals within 3 months after the injury. For some patients, however, photophobia can last up to 12 months and possibly longer. Developing an objective quantitative methodology for measuring photophobia, validating a dedicated photophobia questionnaire, and having a specific photophobia International Classification of Diseases, Tenth Revision code would greatly improve data gathering and analysis.

Incidence and temporal presentation of visual dysfunction following diagnosis of traumatic brain injury, active component, U.S. Armed Forces, 2006-2017.

This analysis describes the incidence of visual dysfunctions following a diagnosis of traumatic brain injury (TBI) among active component service members. The visual dysfunctions were divided into 9 major categories. A comparison group of service members with no history of TBI was used to determine relative incidence rates. The most commonly diagnosed visual dysfunctions were subjective visual disturbances, convergence insufficiency (CI), visual field loss, and accommodative dysfunction (AD). Service members with mild or moderate/severe TBI had significantly higher incidences of AD and CI compared to service members with no TBI. Results of survival analysis showed that service members with mild or moderate/severe TBI had lower probabilities of remaining without the visual dysfunction outcome at almost every week of follow-up in the first year after TBI diagnosis compared to those with no TBI. The findings of this report suggest opportunities to improve both documentation and access to care for service members with these conditions.

Visual Deficits and Dysfunctions Associated with Traumatic Brain Injury: A Systematic Review and Meta-analysis.

SIGNIFICANCE: This study reports prevalence data combined independently for accommodative dysfunction, convergence insufficiency, visual field loss, and visual acuity loss in patients with traumatic brain injury in the absence of eye injury. OBJECTIVE: The objective of this study was to conduct a systematic review and meta-analysis to determine the prevalence rates of accommodative dysfunction, convergence insufficiency, visual field loss, and visual acuity loss in TBI patients without concomitant eye injury. DATA SOURCES: The data sources used in this study were PubMed, EMBASE, EBSCO, and Cochrane Library. STUDY APPRAISAL AND SYNTHESIS METHODS: Publications reporting the prevalence of diagnosed accommodative dysfunction, convergence insufficiency, visual field loss, or visual acuity loss to the level of legal blindness in TBI patients of any age were included. Univariate metaregression analyses and subgroup analyses were performed to account for statistical heterogeneity. RESULTS: Twenty-two eligible publications were identified across the four visual conditions. Random-effects models yielded combined prevalence estimates: accommodative dysfunction (42.8; 95% confidence interval [CI], 31.3 to 54.7), convergence insufficiency (36.3%; 95% CI, 28.2 to 44.9%), visual field loss (18.2%; 95% CI, 10.6 to 27.1%), and visual acuity loss (0.0%; 95% CI, 0.0 to 1.1%). Metaregression and subgroup analyses revealed that visual field loss was significantly more prevalent in moderate to severe (39.8%; 95% CI, 29.8 to 50.3%) compared with mild TBI (6.6%; 95% CI, 0 to 19.5%). CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This study demonstrates that accommodative dysfunction, convergence insufficiency, and visual field loss are common sequelae of TBI. Prospective longitudinal research with rigorous and uniform methodology is needed to better understand short- and long-term effects of TBI on the vision system.

The Joint Pathology Center/Vision Center of Excellence Approach to Analyzing Intra-Ocular "Foreign Bodies".

BACKGROUND: The Military Health System recognizes the importance of analyzing "foreign bodies" removed from US service members through several policy documents. This activity focuses on detecting potentially toxic metals. Intra-ocular "foreign bodies" (IOFBs) represent a small, clinically important subset. The development of ocular metallosis with iron and copper fragments is a specific local reaction to IOFBs. The results of the compositional analysis of removed IOFBs can influence clinical management decisions aimed at optimizing the preservation of sight. METHOD: The Joint Pathology Center (JPC) and Vision Center of Excellence (VCE) have established a pathway for the analysis of IOFBs removed from Department of Defense and Veterans Health Administration patients. The analysis of IOFBs uses analytical methods to provide information about the fragments' surface elemental and molecular composition. RESULTS: Metallic specimens analyzed included iron and copper-containing fragments. Non-metallic IOFBs analyzed include glass, plastic (polyurethane), and nitro-cellulose fragments. CONCLUSION: The JPC/VCE approach to analyzing IOFBs promotes uniform handling and shipping of specimens to minimize contamination. The analytical approach allows for the characterization of IOFBs with a wide variety of compositions. The results support clinical management decisions aimed at optimal treatment for the preservation of patients' visual acuity.

Monocarboxylate transport in human corneal epithelium and cell lines.

Monocarboxylate transporters (MCTs) are transmembrane proteins capable of transferring lactate and other endogenous and exogenous monocarboxylates across the cell membrane. The aim of the present study was to assess the expression and transporter role of human MCT1, MCT3 and MCT4 in the corneal epithelium, corneal epithelial cell lines (primary HCEpiC and immortalized HCE cells) and isolated rabbit corneas. MCT1 and MCT4 were expressed in the human corneal epithelium and the cell lines at mRNA and protein levels. Cellular uptake studies showed saturable and pH-dependent l-lactic acid transport, which was inhibited by various monocarboxylates like diclofenac and flurbiprofen. The permeability of benzoic acid across the rabbit cornea was higher in absorptive direction and this directionality was diminished in the presence of monocarboxylate drug valproic acid. Monocarboxylate transport was functional in the human corneal epithelial cells and rabbit cornea and it may play a role in the ocular drug absorption.

Monocarboxylate transporters: past, present, and future.

We review here the 14 members of the Monocarboxylate transporter family (MCTs), their relationship based on sequence homology. The range of substrates transported by different members of this family extends from the standard monocarboxylate metabolites, lactic and pyruvic acids, to aromatic amino acids and thyroid hormones. The family is denoted Solute Carrier Family 16, or SLC16, among 43 SLC families constituting more than 300 members, which are annotated regularly at the website http://www.bioparadigms.org/slc/intro.htm. MCTs classically transport metabolites across plasma membranes with direction controlled by proton and metabolite concentrations independently of energy input, but they may also function in subcellular membranes. Their regulation may be complex, and they are implicated in leukocyte-mediated immunity, hypoxia induced cellular responses, and partitioning of the energy supply in several tissues. We focus here on histologic evidence (involving human tissue where available) and the first four 'classical' members; but we do annotate all 14, and note several candidate or proven genetic diseases that have arisen from MCT mutations. The review progresses through the following sections: (1) MCT1-4: genetics, kinetics, and modulation; (2) Chaperonins and targeting cofactors; (3) Tissue distribution of MCTs; (4) Intercellular lactate/pyruvate shuttles; (5) Transcriptional and translational regulation of MCTs; (6) Properties of other MCTs; and (7) Subcellular localization of MCTs and some future considerations. Along the way we posit questions or suggestions for future research.

Distribution of the monocarboxylate transporter MCT2 in human cerebral cortex: an immunohistochemical study.

The monocarboxylate transporter MCT2 belongs to a large family of membrane proteins involved in the transport of lactate, pyruvate and ketone bodies. Although its expression in rodent brain has been well documented, the presence of MCT2 in the human brain has been questioned on the basis of low mRNA abundance. In this study, the distribution of the monocarboxylate transporter MCT2 has been investigated in the cortex of normal adult human brain using an immunohistochemical approach. Widespread neuropil staining in all cortical layers was observed by light microscopy. Such a distribution was very similar in three different cortical areas investigated. At the cellular level, the expression of MCT2 could be observed in a large number of neurons, in fibers both in grey and white matter, as well as in some astrocytes, mostly localized in layer I and in the white matter. Double staining experiments combined with confocal microscopy confirmed the neuronal expression but also suggested a preferential postsynaptic localization of synaptic MCT2 expression. A few astrocytes in the grey matter appeared to exhibit MCT2 labelling but at low levels. Electron microscopy revealed strong MCT2 expression at asymmetric synapses in the postsynaptic density and also within the spine head but not in the presynaptic terminal. These data not only demonstrate neuronal MCT2 expression in human, but since a portion of it exhibits a distinct synaptic localization, it further supports a putative role for MCT2 in adjustment of energy supply to levels of activity.

Expression of the monocarboxylate transporter MCT1 in the adult human brain cortex.

Distribution of the monocarboxylate transporter MCT1 has been investigated in the cortex of normal adult human brain. Similarly to the glucose transporter GLUT1 55 kDa isoform, MCT1 was found to be strongly expressed on blood vessels in all cortical layers. In addition, laminar analysis revealed intense MCT1 expression in the neuropil of layer IV in primary auditory (AI) and visual (VI) areas, while this expression was more homogeneous in the non-primary auditory area STA. The cellular distribution shows that MCT1 is strongly expressed by glial cells often associated with blood vessels that were identified as astrocytes. The observed distribution of MCT1 supports the concept that, under certain circumstances, monocarboxylates could be provided as energy substrates to the adult human brain. Moreover, the distinct laminar pattern of MCT1 expression between primary and non-primary cortical areas may reflect different types of neuronal activity requiring adequate supply of specific energy substrates.

Expression of monocarboxylate transporter 4 in human platelets, leukocytes, and tissues assessed by antibodies raised against terminal versus pre-terminal peptides.

We compared antibodies (Abs) raised in rabbits against two non-overlapping peptides, terminal (T) and pre-terminal (PT) of the human monocarboxylate transporter (MCT4) lactate transporter in a variety of human tissues. Upon stringent SDS extraction, the PT Ab recognized a major 32 kDa band in many tissues, but not in leukocytes, while the T Ab recognized a 45 kDa band in leukocytes but only in a few other tissues. In two cell lines, human adult retinal pigment epithelial and Madin-Darby canine kidney, however, both Abs identified the same 45 kDa band only, whether extracted by stringent SDS or by a mild Triton X-100 procedure. Applying Triton X-100 and milder SDS methods to human tissues led us to conclude that: (1) MCT4 is more labile to proteolysis than MCT1 or 2; (2) the proteolysis involves an enzyme system which is absent from the cell lines, is of variable content in human tissues, and is accelerated by SDS and/or heat; (3) a major product is the 32 kDa band, which is missing the C-terminal peptide, since it is seen by the Ab to MCT4-PT, but not the Ab to MCT4-T; (4) this truncated 32 kDa form is prone to aggregate, producing oligomers also detected only by the MCT4-PT; (5) the 32 kDa form may have a physiological function, since (except in the cell lines and monocytes) it is the major form seen with the PT Ab even with our mildest extractions, and since MCT4-PT stained two compartments that were not stained by the T Ab in our immunohistochemistry survey: the capsule of the muscle spindle, and the cytoplasm of the lymphocyte; (6) platelets contained MCT4, stained by both Abs, and verified by the 45kDa band on Western blotting, in addition to the presence of MCT2 that we had demonstrated previously [N. Merezhinskaya, S.A. Ogunwuyi, F.G. Mullick, W.N. Fishbein, Presence and localization of three lactic acid transporters (MCT1, -2, and -4) in separated human granulocytes, lymphocytes, and monocytes, J. Histochem. Cytochem. 52 (2004) 1483-1493.

Presence and localization of three lactic acid transporters (MCT1, -2, and -4) in separated human granulocytes, lymphocytes, and monocytes.

We fractionated leukocytes from three donors into >90% pure samples of granulocytes, lymphocytes, and monocytes and tested them for transcriptional and translational expression of three physiologically-proven lactate transporters, monocarboxylate transporter 1(MCT1), MCT2, and MCT4, using RT-PCR and affinity-purified rabbit antibody (Ab) to the C-terminal segment of each human MCT. Transcripts of all three MCTs were identified in each leukocyte fraction by RT-PCR and proven by sequencing of fragments extracted after isolation on agarose gels. Transporter protein of the appropriate size was demonstrated for each of the monocarboxylate transporters MCTs in lymphocytes and monocytes by Western blot, while lower-molecular-weight bands were found in granulocytes and are presumed to be degraded forms, because they were blocked by antibody-antigen (Ab-Ag) preincubation. IHC demonstrated all three MCTs in methanol-fixed droplets of all three leukocyte fractions; stain was abolished on omission of the primary Ab. Plasmalemmal staining occurred with all MCTs in all leukocyte fractions. Because the K(m) for lactate increases approximately fivefold at each step, with MCT2<1<4, leukocytes must use the full range of lactate binding to survive in acidic and hypoxic environments. Except for MCT4 in lymphocytes, all the MCTs also stained leukocyte cytoplasm, often with distinct granularity. Nuclear membrane staining was also seen with MCT1 and MCT2, while platelet plasmalemma stained only with MCT2.

Relative distribution of three major lactate transporters in frozen human tissues and their localization in unfixed skeletal muscle.

We have prepared affinity-purified rabbit polyclonal antibodies to the near-C-terminal peptides of human monocarboxylate transporters (MCTs) 1, 2, and 4 coupled to keyhole limpet hemocyanin. Each antiserum reacted only with its specific peptide antigen and gave a distinct molecular weight band (blocked by preincubation with antigen) after chemiluminescence reaction on Western blots from sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of tissue membrane proteins. Densitometry showed distinctive expression patterns for each MCT in a panel of 15 frozen human tissues, with the distribution of MCT1 >>MCT2>MCT4. Fluorescence microscopy of unfixed skeletal muscle using fluorescein-conjugated secondary antibody was correlated with reverse adenosine triphosphatase (ATPase) stained sequential sections to identify fiber-type localization. MCT1 expression was high in the sarcolemma of type 1 fibers, modest to low in type 2a fibers, and almost absent in type 2b fibers. In contrast, MCT4 expression was low to absent in the membrane of most type 1 fibers, but high in most 2a and in all 2b fibers, favoring the view that their high lactate levels during work may be channeled in part to neighboring type 1 (and perhaps 2a) fibers for oxidation, thereby delaying fatigue. MCT2 expression was limited to the sarcolemma of a type 1 fiber subset, which varied from <5 to 40%, depending on the specific muscle under study. Quantitative chemiluminescent densitometry of 10 muscle biopsies for their MCT2 and MCT4 content, each normalized to MCT1, confirmed the unique variation of MCT2 expression with biopsy site. The application of these antibodies should add to the understanding of motor unit physiology, and may contribute to the muscle-biopsy assessment of low-level denervation.