Epilepsy: Mitochondrial connections to the 'Sacred' disease.

Over 65 million people suffer from recurrent, unprovoked seizures. The lack of validated biomarkers specific for myriad forms of epilepsy makes diagnosis challenging. Diagnosis and monitoring of childhood epilepsy add to the need for non-invasive biomarkers, especially when evaluating antiseizure medications. Although underlying mechanisms of epileptogenesis are not fully understood, evidence for mitochondrial involvement is substantial. Seizures affect 35%-60% of patients diagnosed with mitochondrial diseases. Mitochondrial dysfunction is pathophysiological in various epilepsies, including those of non-mitochondrial origin. Decreased ATP production caused by malfunctioning brain cell mitochondria leads to altered neuronal bioenergetics, metabolism and neurological complications, including seizures. Iron-dependent lipid peroxidation initiates ferroptosis, a cell death pathway that aligns with altered mitochondrial bioenergetics, metabolism and morphology found in neurodegenerative diseases (NDDs). Studies in mouse genetic models with seizure phenotypes where the function of an essential selenoprotein (GPX4) is targeted suggest roles for ferroptosis in epilepsy. GPX4 is pivotal in NDDs, where selenium protects interneurons from ferroptosis. Selenium is an essential central nervous system micronutrient and trace element. Low serum concentrations of selenium and other trace elements and minerals, including iron, are noted in diagnosing childhood epilepsy. Selenium supplements alleviate intractable seizures in children with reduced GPX activity. Copper and cuproptosis, like iron and ferroptosis, link to mitochondria and NDDs. Connecting these mechanistic pathways to selenoproteins provides new insights into treating seizures, pointing to using medicines including prodrugs of lipoic acid to treat epilepsy and to potential alternative therapeutic approaches including transcranial magnetic stimulation (transcranial), photobiomodulation and vagus nerve stimulation.

Treatment and prevention of pathological mitochondrial dysfunction in retinal degeneration and in photoreceptor injury.

Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.

Pathogenic mitochondrial dysfunction and metabolic abnormalities.

Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs.

In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.

A New Approach to Treating Neurodegenerative Otologic Disorders.

Hearing loss, the most common neurological disorder and the fourth leading cause of years lived with disability, can have profound effects on quality of life. The impact of this "invisible disability," with significant consequences, economic and personal, is most substantial in low- and middle-income countries, where >80% of affected people live. Given the importance of hearing for communication, enjoyment, and safety, with up to 500 million affected globally at a cost of nearly $800 billion/year, research on new approaches toward prevention and treatment is attracting increased attention. The consequences of noise pollution are largely preventable, but irreversible hearing loss can result from aging, disease, or drug side effects. Once damage occurs, treatment relies on hearing aids and cochlear implants. Preventing, delaying, or reducing some degree of hearing loss may be possible by avoiding excessive noise and addressing major contributory factors such as cardiovascular risk. However, given the magnitude of the problem, these interventions alone are unlikely to be sufficient. Recent advances in understanding principal mechanisms that govern hearing function, together with new drug discovery paradigms designed to identify efficacious therapies, bode well for pharmaceutical intervention. This review surveys various causes of loss of auditory function and discusses potential neurological underpinnings, including mitochondrial dysfunction. Mitochondria mitigate cell protection, survival, and function and may succumb to cumulative degradation of energy production and performance; the end result is cell death. Energy-demanding neurons and vestibulocochlear hair cells are vulnerable to mitochondrial dysfunction, and hearing impairment and deafness are characteristic of neurodegenerative mitochondrial disease phenotypes. Beyond acting as cellular powerhouses, mitochondria regulate immune responses to infections, and studies of this phenomenon have aided in identifying nuclear factor kappa B and nuclear factor erythroid 2-related factor 2/antioxidant response element signaling as targets for discovery of otologic drugs, respectively, suppressing or upregulating these pathways. Treatment with free radical scavenging antioxidants is one therapeutic approach, with lipoic acid and corresponding carnitine esters exhibiting improved biodistribution and other features showing promise. These compounds are also histone deacetylase (HDAC) inhibitors, adding epigenetic modulation to the mechanistic milieu through which they act. These data suggest that new drugs targeting mitochondrial dysfunction and modulating epigenetic pathways via HDAC inhibition or other mechanisms hold great promise.

Epigenetic Treatment of Neurodegenerative Ophthalmic Disorders: An Eye Toward the Future.

Eye disease is one of the primary medical conditions that requires attention and therapeutic intervention in ageing populations worldwide. Further, the global burden of diabetes and obesity, along with heart disease, all lead to secondary manifestations of ophthalmic distress. Therefore, there is increased interest in developing innovative new approaches that target various mechanisms and sequelae driving conditions that result in adverse vision. The research challenge is even greater given that the terrain of eye diseases is difficult to landscape into a single therapeutic theme. This report addresses the burden of eye disease due to mitochondrial dysfunction, including antioxidant, autophagic, epigenetic, mitophagic, and other cellular processes that modulate the biomedical end result. In this light, we single out lipoic acid as a potent known natural activator of these pathways, along with alternative and potentially more effective conjugates, which together harness the necessary potency, specificity, and biodistribution parameters required for improved therapeutic outcomes.

Epigenetic Treatment of Persistent Viral Infections.

Preclinical Research Approximately 2,500 years ago, Hippocrates used the word herpes as a medical term to describe lesions that appeared to creep or crawl on the skin, advocating heat as a possible treatment. During the last 50 years, pharmaceutical research has made great strides, and therapeutic options have expanded to include small molecule antiviral agents, protease inhibitors, preventive vaccines for a handful of the papillomaviruses, and even cures for hepatitis C virus infections. However, effective treatments for persistent and recurrent viral infections, particularly the highly prevalent herpesviruses, continue to represent a significant unmet medical need, affecting the majority of the world's population. Exploring the population diversity of the human microbiome and the effects its compositional variances have on the immune system, health, and disease are the subjects of intense investigational research and study. Among the collection of viruses, bacteria, fungi, and single-cell eukaryotes that comprise the human microbiome, the virome has been grossly understudied relative to the influence it exerts on human pathophysiology, much as mitochondria have until recently failed to receive the attention they deserve, given their critical biomedical importance. Fortunately, cellular epigenetic machinery offers a wealth of druggable targets for therapeutic intervention in numerous disease indications, including those outlined above. With advances in synthetic biology, engineering our body's commensal microorganisms to seek out and destroy pathogenic species is clearly on the horizon. This is especially the case given recent breakthroughs in genetic manipulation with tools such as the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated) gene-editing platforms. Tying these concepts together with our previous work on the microbiome and neurodegenerative and neuropsychiatric diseases, we suggest that, because mammalian cells respond to a viral infection by triggering a cascade of antiviral innate immune responses governed substantially by the cell's mitochondria, small molecule carnitinoids represent a new class of therapeutics with potential widespread utility against many infectious insults. Drug Dev Res 78 : 24-36, 2017. © 2016 Wiley Periodicals, Inc.

Orbital fractures: a review.

THIS REVIEW OF ORBITAL FRACTURES HAS THREE GOALS: 1) to understand the clinically relevant orbital anatomy with regard to periorbital trauma and orbital fractures, 2) to explain how to assess and examine a patient after periorbital trauma, and 3) to understand the medical and surgical management of orbital fractures. The article aims to summarize the evaluation and management of commonly encountered orbital fractures from the ophthalmologic perspective and to provide an overview for all practicing ophthalmologists and ophthalmologists in training.

Anatomic properties of the upper eyelid in Asian Americans.

BACKGROUND: With increasing demand for "double eyelid" surgery within the United States, it becomes prudent for U.S. surgeons to become familiar with Asian eyelid anatomy. OBJECTIVE: To identify and describe anatomic characteristics of the Asian upper eyelid. METHODS: A cross-sectional descriptive series of 9 Korean-American and 10 Chinese-American subjects. Standardized photographs of the eyes were analyzed. Three types of eyelid anatomy were described: single eyelid, low eyelid crease, and double eyelid. RESULTS: The incidence rate for the three types of eyelid anatomies varied between Chinese and Korean Americans. The mean palpebral fissure height, width, and inclination were not statistically different between the two populations. A few subjects had asymmetric eyelid configurations. Chinese American and Korean American double eyelids tended to flare up laterally when the eye was open. The mean double eyelid crease height at the medial limbus was 3.7 +/- 1.1 mm, and the mean height at the lateral limbus 4.6 +/- 1.0 mm. This difference was statistically significant (p<.04). CONCLUSION: Eyelid anatomies vary in different Asian Americans. Surgeons need to be mindful of different eyelid configurations and measurement patterns to achieve the most natural-looking Asian double eyelids.

Definition of the tear trough and the tear trough rating scale.

BACKGROUND: Nasojugal groove and tear trough are interchangeably used terms by many authors in the literature despite the fact that they describe distinct and different anatomic entities. In the same vein, there are multiple descriptions of treatments and techniques for the cosmetic improvement of these anatomic areas without specifically addressing the anatomic difference between them. OBJECTIVE: This study aims to define the anatomic characteristics of the tear trough and describe a novel classification scale for the evaluation of the tear trough deformity. METHODS: The tear trough rating scale (TTRS) was applied to a representative sample of our patient population. Five of the authors evaluated each patient using the TTRS, and the numeric results were tabulated and compared. Results The TTRS provided an effective, reproducible method for evaluating tear trough deformities, and there was very little interobserver variability. CONCLUSION: The tear trough should be defined as the depression of the medial lower eyelid just lateral to the anterior lacrimal crest and limited in its inferior aspect by the inferior orbital rim. The TTRS is a reliable tool for the classification of the tear trough and evaluation of therapeutic and cosmetic interventions.

Noninvasive techniques in periorbital rejuvenation.

The combination of noninvasive treatments in the periorbital area can be used to achieve dramatic and long-lasting results. New technologies and current therapies may supplement or even delay traditional surgical procedures.

Filling agents.

Injectable fillers have become an important component of minimally invasive facial rejuvenation modalities. Their ease of use, effectiveness, low morbidity, and fast results with minimal downtime are factors that have made them popular among patients. Soft tissue augmentation has evolved to a unique combination of medicine and art. A wide selection of available agents and new products, each one with unique properties, may be used alone or in combination. The physician acquires the tools to rebalance facial characteristics not only by filling wrinkles but also by having the ability to shape the face and restore bony contours and lines. Careful selection of candidates, realistic expectations, and an understanding of the limitations of fillers are crucial for a successful result.

Nonanimal stabilized hyaluronic acid for lip augmentation and facial rhytid ablation.

OBJECTIVE: To evaluate the effectiveness of nonanimal stabilized hyaluronic acid as an injectable filling agent. DESIGN: Nonrandomized, retrospective, interventional case series. RESULTS: A total of 1446 consecutive patients (1029 women and 417 men) underwent intradermal injection of commercially available nonanimal stabilized hyaluronic acid (2242 treatments) for the enhancement of lip volume and contour and the reduction of visible facial rhytids. Almost 61% of all patients remained satisfied with their results after 9 months. The effect was longest in the glabellar and nasolabial fold areas. Minimal transient sequelae were noted. CONCLUSIONS: Nonanimal stabilized hyaluronic acid is an effective and safe facial soft tissue expander. Its duration varies with each facial area treated.

Contact transscleral neodymium:yttrium-aluminum-garnet laser cyclophotocoagulation Long-term outcome.

PURPOSE: Contact transscleral neodymium:yttrium-aluminum-garnet (Nd:YAG) laser cyclophotocoagulation (CYC) is a treatment option for advanced glaucoma refractory to alternative treatments. This study determined the long-term efficacy and risks of contact transscleral Nd:YAG laser CYC. DESIGN: A prospective study was performed with patients with advanced, uncontrolled glaucoma who received CYC from 1988 through 1989. PARTICIPANTS: Records for 68 eyes of 64 patients were obtained and reviewed for the 10-year follow-up. METHODS: A transscleral continuous-wave Nd:YAG laser was used for photocoagulation of the ciliary body. MAIN OUTCOME MEASURES: Intraocular pressure (IOP), visual acuity, and second intervention. Failure was defined as the need for second intervention, IOP of more than 25 mmHg, or IOP of less than 3 mmHg. RESULTS: The mean follow-up period was 5.85+/-4.0 years (range, 0.1-10 years). The mean preoperative IOP of 36.3+/-10.1 mmHg decreased to 22.6+/-11.3 mmHg at 1 year of follow-up (P<0.001). The mean postoperative IOP at 5 years was 21.8+/-13.3 mmHg (P<0.001) and was 18.9+/-12.2 mmHg at 10 years of follow-up (P<0.001). A second intervention after CYC was required in 30 eyes (44.1%). Six eyes (8.8%) with initial visual acuity of counting fingers or worse progressed to no light perception, and 5 of 8 eyes (62.5%) with visual acuity better than 20/200 lost 2 or more Snellen lines. Hypotony developed in 3 eyes (4.4%). Overall, the failure rate by 10 years of follow-up was 51.5% (35/68 eyes). CONCLUSIONS: Cyclophotocoagulation resulted in a significant reduction of IOP after surgery at 1, 5, and 10 years of follow-up; however, 51.5% of eyes failed by the end of 10 years, with most failures occurring within the first year (40%). Although CYC provides a useful method to lower IOP significantly, this study suggests that its success in controlling IOP is tempered by its failure rate and risk of complications, including visual loss, phthisis, and loss of light perception.

Sunglasses- and photochromic lens-wearing patterns in spectacle and/or contact lens-wearing individuals.

PURPOSE: To determine differences in wearing patterns of sunglasses and/or photochromic lenses in spectacle and contact lens wearers, to assess patient awareness of the indications for the use of tinted lenses, and to identify wearers' lens tint preferences. METHODS: A total of 100 individuals wearing some combination of contact lenses and spectacles participated in a survey questionnaire composed of 14 questions. Participants were asked if they used sunglasses/photochromic lenses, why they used them, their preferred lens tints, and temporal and seasonal patterns of use. They were also queried on their awareness of the potential adverse effects of ultraviolet radiation (UVR) exposure on the health of the eye and appropriate protective measures. Participants were categorized based on their use of spectacles and/or contact lenses. Demographic characteristics of sex and age were taken into account for the analysis. The data were imported and analyzed using commercial statistical analysis software. RESULTS: A total of 52% of the participants wore spectacles exclusively, while 48% wore some combination of spectacles and contact lenses. In the spectacle group, 36% and 20% wore sunglasses and photochromic lenses, respectively. In the contact lens group, 20% and 10% wore sunglasses and photochromic lenses, respectively. Overall gray was the preferred lens tint, especially in the younger age groups. Summer was the primary season for use of tinted lenses. Approximately one-third of the sample were not aware of the UVR protective properties of their eyewear. A total of 77% believed that UVR could be harmful to the eyes, but only a small percentage of the participants wore sunglasses or photochromic lenses specifically for UVR protection. CONCLUSION: There was no statistically significant difference (P = 0.07) for preference between sunglasses versus photochromic lenses and in seasonal patterns for tinted lens use among spectacles and contact lens wearers. Spectacle wearers (as well as contact lens wearers) used sunglasses more than photochromic lenses (P = 0.004). Most of the participants wore sunglasses in the summer and to protect their eyes from bright light. Overall gray was the preferred lens tint. Potentially adverse effects of UVR exposure to the eye and the importance of proper UVR eye protection were not generally appreciated by the subjects queried.