Inherited Optic Neuropathies: Real-World Experience in the Paediatric Neuro-Ophthalmology Clinic.

Inherited optic neuropathies affect around 1 in 10,000 people in England; in these conditions, vision is lost as retinal ganglion cells lose function or die (usually due to pathological variants in genes concerned with mitochondrial function). Emerging gene therapies for these conditions have emphasised the importance of early and expedient molecular diagnoses, particularly in the paediatric population. Here, we report our real-world clinical experience of such a population, exploring which children presented with the condition, how they were investigated and the time taken for a molecular diagnosis to be reached. A retrospective case-note review of paediatric inherited optic neuropathy patients (0-16 years) in the tertiary neuro-ophthalmology service at Moorfields Eye Hospital between 2016 and 2020 identified 19 patients. Their mean age was 9.3 ± 4.6 (mean ± SD) years at presentation; 68% were male, and 32% were female; and 26% had comorbidities, with diversity of ethnicity. Most patients had undergone genetic testing (95% (n = 18)), of whom 43% (n = 8) received a molecular diagnosis. On average, this took 54.8 ± 19.5 weeks from presentation. A cerebral MRI was performed in 70% (n = 14) and blood testing in 75% (n = 15) of patients as part of their workup. Continual improvement in the investigative pathways for inherited optic neuropathies will be paramount as novel therapeutics become available.

Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium.

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

Mitochondria and the eye-manifestations of mitochondrial diseases and their management.

Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.

Optogenetics for visual restoration: From proof of principle to translational challenges.

Degenerative retinal disorders are a diverse family of diseases commonly leading to irreversible photoreceptor death, while leaving the inner retina relatively intact. Over recent years, innovative gene replacement therapies aiming to halt the progression of certain inherited retinal disorders have made their way into clinics. By rendering surviving retinal neurons light sensitive optogenetic gene therapy now offers a feasible treatment option that can restore lost vision, even in late disease stages and widely independent of the underlying cause of degeneration. Since proof-of-concept almost fifteen years ago, this field has rapidly evolved and a detailed first report on a treated patient has recently been published. In this article, we provide a review of optogenetic approaches for vision restoration. We discuss the currently available optogenetic tools and their relative advantages and disadvantages. Possible cellular targets will be discussed and we will address the question how retinal remodelling may affect the choice of the target and to what extent it may limit the outcomes of optogenetic vision restoration. Finally, we will analyse the evidence for and against optogenetic tool mediated toxicity and will discuss the challenges associated with clinical translation of this promising therapeutic concept.

A systematic comparison of optogenetic approaches to visual restoration.

During inherited retinal degenerations (IRDs), vision is lost due to photoreceptor cell death; however, a range of optogenetic tools have been shown to restore light responses in animal models. Restored response characteristics vary between tools and the neuronal cell population to which they are delivered: the interplay between these is complex, but targeting upstream neurons (such as retinal bipolar cells) may provide functional benefit by retaining intraretinal signal processing. In this study, our aim was to compare two optogenetic tools: mammalian melanopsin (hOPN4) and microbial red-shifted channelrhodopsin (ReaChR) expressed within two subpopulations of surviving cells in a degenerate retina. Intravitreal adeno-associated viral vectors and mouse models utilising the Cre/lox system restricted expression to populations dominated by bipolar cells or retinal ganglion cells and was compared with non-targeted delivery using the chicken beta actin (CBA) promoter. In summary, we found bipolar-targeted optogenetic tools produced faster kinetics and flatter intensity-response relationships compared with non-targeted or retinal-ganglion-cell-targeted hOPN4. Hence, optogenetic tools of both mammalian and microbial origins show advantages when targeted to bipolar cells. This demonstrates the advantage of bipolar-cell-targeted optogenetics for vision restoration in IRDs. We therefore developed a bipolar-cell-specific gene delivery system employing a compressed promoter with the potential for clinical translation.

ON-bipolar cell gene expression during retinal degeneration: Implications for optogenetic visual restoration.

PURPOSE: Retinal bipolar cells survive even in the later stages of inherited retinal degenerations (IRDs) and so are attractive targets for optogenetic approaches to vision restoration. However, it is not known to what extent the remodelling that these cells undergo during degeneration affects their function. Specifically, it is unclear if they are free from metabolic stress, receptive to adeno-associated viral vectors, suitable for opsin-based optogenetic tools and able to propagate signals by releasing neurotransmitter. METHODS: Fluorescence activated cell sorting (FACS) was performed to isolate labelled bipolar cells from dissociated retinae of litter-mates with or without the IRD mutation Pde6brd1/rd1 selectively expressing an enhanced yellow fluorescent protein (EYFP) as a marker in ON-bipolar cells. Subsequent mRNA extraction allowed Illumina® microarray comparison of gene expression in bipolar cells from degenerate to those of wild type retinae. Changes in four candidate genes were further investigated at the protein level using retinal immunohistochemistry over the course of degeneration. RESULTS: A total of sixty differentially expressed transcripts reached statistical significance: these did not include any genes directly associated with native primary bipolar cell signalling, nor changes consistent with metabolic stress. Four significantly altered genes (Srm2, Slf2, Anxa7 & Cntn1), implicated in synaptic remodelling, neurotransmitter release and viral vector entry had immunohistochemical staining colocalising with ON-bipolar cell markers and varying over the course of degeneration. CONCLUSION: Our findings suggest relatively few gene expression changes in the context of degeneration: that despite remodelling, bipolar cells are likely to remain viable targets for optogenetic vision restoration. In addition, several genes where changes were seen could provide a basis for investigations to enhance the efficacy of optogenetic therapies.

From Transcriptomics to Treatment in Inherited Optic Neuropathies.

Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process-implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies.

Pembrolizumab for the treatment of progressive multifocal leukoencephalopathy following anti-CD19 CAR-T therapy: a case report.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection with few treatment options and poor survival when reversal of the underlying immune dysfunction is not achievable. JC polyomavirus reactivation resulting in PML can rarely complicate chimeric antigen receptor T-cell (CAR-T) therapy. We describe successful treatment of PML with Programmed death-1 (PD-1) blockade using pembrolizumab, 4 months following axicabtagene ciloleucel. Radiological features of immune reconstitution inflammatory syndrome without clinical deterioration were seen. Evidence of anti-viral immune reconstitution by in vitro detection of JC-specific T-cells and sustained neurological recovery in this patient suggest PD-1 blockade may be an effective treatment approach for PML post-CAR-T.

"Genetic and clinical findings in an ethnically diverse retinitis pigmentosa cohort associated with pathogenic variants in EYS".

BACKGROUND AND OBJECTIVES: The EYS gene is an important cause of autosomal recessive retinitis pigmentosa (arRP). The objective of this study is to report on novel pathogenic variants in EYS and the range of associated phenotypes. SUBJECTS AND METHODS: This retrospective case series at a tertiary referral centre for inherited retinal diseases describes patients with an IRD and at least two variants in the EYS gene. Phenotyping included multimodal retinal imaging; genotyping molecular genetic analysis using targeted next generation sequencing. Sanger sequencing verification and analysis of novel variants using in silico approaches to determine their predicted pathogenicity. RESULTS: Eight male and four female patients were included. Age at onset ranged from 11 to 62 years with variable symptom presentation; ten patients showed classical features of retinitis pigmentosa, albeit with great variation in disease severity and extent. Two patients had atypical phenotypes: one with localised inferior sector pigmentation and a mild RP phenotype with changes predominantly at the posterior pole. Eighteen variants in EYS were identified, located across the gene: six were novel. Eight variants were missense, two altered splicing, one was a whole exon duplication and the remainder were predicted to result in premature truncation of the protein. CONCLUSION: The marked variability in severity and age of onset in most patients in this ethnically diverse cohort adds to growing evidence that that mild phenotypes are associated with EYS variants. Similarly, the two atypical cases add to the growing diversity of EYS disease as do the six novel pathogenic variants described.

The functional characteristics of optogenetic gene therapy for vision restoration.

Optogenetic strategies to restore vision in patients blind from end-stage retinal degenerations aim to render remaining retinal neurons light-sensitive. We present an innovative combination of multi-electrode array recordings together with a complex pattern-generating light source as a toolset to determine the extent to which neural retinal responses to complex light stimuli can be restored following viral delivery of red-shifted channelrhodopsin in the retinally degenerated mouse. Our data indicate that retinal output level spatiotemporal response characteristics achieved by optogenetic gene therapy closely parallel those observed for normal mice but equally reveal important limitations, some of which could be mitigated using bipolar-cell targeted gene-delivery approaches. As clinical trials are commencing, these data provide important new information on the capacity and limitations of channelrhodopsin-based gene therapies. The toolset we established enables comparing optogenetic constructs and stem-cell-based techniques, thereby providing an efficient and sensitive starting point to identify future approaches for vision restoration.

Expression and Localization of Kcne2 in the Vertebrate Retina.

Purpose: To characterize the retinal expression and localization of Kcne2, an ancillary (ß) ion-channel subunit with an important role in fine-tuning cellular excitability. Methods: We analyzed available single-cell transcriptome data from tens of thousands of murine retinal cells for cell-type-specific expression of Kcne2 using state-of-the-art bioinformatics techniques. This evidence at the transcriptome level was complemented with a comprehensive immunohistochemical characterization of mouse retina (C57BL/6, ages 8-12 weeks) employing co-labeling techniques and cell-type-specific antibody markers. We furthermore examined how conserved the Kcne2 localization pattern in the retina was across species by performing immunostaining on zebrafish, cowbird, sheep, mice, and macaque. Results: Kcne2 is distinctly expressed in cone photoreceptors and rod bipolar cells. At a subcellular level, the bulk of Kcne2 immunoreactivity can be observed in the outer plexiform layer. Here, it localizes into cone pedicles and likely the postsynaptic membrane of the rod bipolar cells. Thus, the vast majority of Kcne2 immunoreactivity is observed in a thin band in the outer plexiform layer. In addition to this, faint Kcne2 immunoreactivity can also be observed in cone inner segments and the somata of a small subset of cone ON bipolar cells. Strikingly, the localization of Kcne2 in the outer plexiform layer was preserved among all of the species studied, spanning at least 300 million years of evolution of the vertebrate kingdom. Conclusions: The data we present here suggest an important and specific role for Kcne2 in the highly specialized photoreceptor-bipolar cell synapse.

Artificial vision: principles and prospects.

PURPOSE OF REVIEW: The aim of this article is to give an overview of the strategies and technologies currently under development to return vision to blind patients and will answer the question: What options exist for artificial vision in patients blind from retinal disease; how close are these to clinical practice? RECENT FINDINGS: Retinal approaches will be the focus of this review as they are most advanced in terms not only of development, but entry into the imagination of the general public; they are technologies patients ask about, but may be less familiar to practicing neurologists.The prerequisites for retinal survivor cell stimulation are discussed, followed by consideration of the state of the art of four promising methods making use of this principle: electronic prostheses, stem cells, gene therapy and the developing field of ophthalmic optogenetics. SUMMARY: Human applications of artificial vision by survivor cell stimulation are certainly with us in the research clinic and very close to commercialization and general use. This, together with their place in the public consciousness, makes the overview provided by this review particularly helpful to practicing neurologists.

Idiopathic Acquired Temporal Wedge Visual Field Defects.

Our aim is to report 13 unusual cases of acquired, temporal sectoral scotomas. Such stationary "wedge" field defects have been reported previously in cases of presumed congenital nasal hypoplasia of the optic disc and as a complication of vitreoretinal surgery. To our knowledge, the literature provides no reports of similar defects occurring spontaneously. This is a descriptive clinical case series of 13 patients presenting with sub-acute monocular temporal visual field loss. All were clinically assessed and investigated with Goldmann perimetry, automated Humphrey visual fields, retinal optical coherence tomography, orbital ultrasound, and standard and multi-focal electroretinography. Cases were followed with serial perimetry for a mean of 3.9 years (range: 6 months to 10 years). Goldmann and Humphrey perimetry both demonstrated "wedge"-shaped defects extending temporally from an apex contiguous with, or lateral to, the blind spot. There was no evidence of optic disc drusen, glaucoma, disc hypoplasia, or focal retinitis. Sectoral optic disc swelling was not present in any patient at presentation. In all cases, the visual field defect remained stable. One patient developed a similar defect in the fellow eye after an interval of 5 years. Here we describe 13 cases of acquired, stationary temporal wedge scotomas, novel in the literature. Although the aetiology is uncertain, we propose damage to the nasal rim of the optic disc as a likely mechanism.

Acute intermittent porphyria leading to posterior reversible encephalopathy syndrome (PRES): a rare cause of abdominal pain and seizures.

Acute intermittent porphyria (AIP) is an inherited deficiency in the haem biosynthesis pathway. AIP is rare, affecting around 1 in 75 000 people. Acute attacks are characterised by abdominal pain associated with autonomic, neurological and psychiatric symptoms. AIP is rarely associated with posterior reversible encephalopathy syndrome (PRES). PRES is a clinicoradiological condition caused by the failure of the posterior circulation to autoregulate, resulting in cerebral oedema, headaches, nausea and seizures. This association is important because drugs used in the management of seizures may worsen an attack of AIP. This article describes a case of AIP and PRES in a young woman.

Recurrent presumed herpes simplex keratitis and episcleritis in keratosis follicularis (Darier's disease).

Keratosis follicularis (Darier's disease) is an autosomal dominant dermatological disorder characterised by abnormal epidermal differentiation and loss of normal cell-to-cell adhesion. Cardinal features include diffuse hyperkeratotic warty papules with scaly plaques in seborrhoeic regions with associated mucous membrane changes. Darier's disease is rare (prevalence 2.7 in 100,000), with few ocular sequelae reported: commonly dry eye with or without Sjögren's syndrome. This is the first report, to the best of our knowledge, to describe a case of recurrent herpes simplex virus (HSV) keratitis and episcleritis in a 47-year-old man suffering from Darier's disease. The patient's condition predisposed him towards developing ocular complications due to several factors: impaired desmosome function leading to poor cell-to-cell adhesion in the corneal epithelium, dry eye and HSV invasion of inflamed periocular skin presumably combining to allow viral colonisation of a poorly protected cornea.

Using non-steroidal anti-inflammatory drugs in the treatment of depression.

BACKGROUND: clinicians have long noticed a correlation between physiological markers of inflammation and depression. The best-known example is the activation of the hypothalamus-pituitary-adrenal axis and cortisol secretion; however more recent studies have demonstrated increased salivary prostaglandins and plasma acute phase proteins in depressed patients. To date four randomised controlled trials have used celecoxib or rofecoxib as adjuncts to serotonin selective reuptake inhibitors in the treatment of depression. These suggested a statistically significant decrease in depressive symptoms in the patients taking NSAIDs and SSRIs, compared to patients taking SSRIs alone. Interpretation of these results is limited by the small sample size and short duration of these preliminary studies. The research only considers depressed patients receiving treatment in secondary care; no study has examined the effectiveness of NSAIDs as an adjunct in primary care, even though most cases of depression in the UK are managed in the community by general practitioners. PROPOSAL: we propose a multi-centre double-blinded randomised controlled trial with two objectives: to determine whether citalopram plus celecoxib dual therapy achieves a greater reduction in depressive symptoms (quantified using the Hamilton Depression Rating Scale (HDRS)) within four weeks, compared to citalopram monotherapy; and to determine whether citalopram plus celecoxib dual therapy is more likely to achieve remission (HDRS score ?7) of moderate to severe depression within six months, compared with citalopram monotherapy. The endpoints will be the reduction in HDRS score after 4 weeks of treatment, and the HDRS score after 26 weeks of treatment. The study will enrol 452 participants from general practices who have a moderate or severe, current or recurrent major depressive episode when medication with an SSRI is considered. The study population will be stratified according to age, sex, HDRS score, age of onset of first episode, number of previous depressive episodes and duration of current episode. The population will then be randomised into two groups. Subjects will be interviewed to determine HDRS score, measure blood pressure, count pills and discuss side-effects. This will occur weekly for the first four weeks, and every four weeks thereafter.

Adult neurogenesis and depression: an introduction.

The following essay provides a summary of a seminar given on the sixth of November, 2010 at the combined annual congress, held at Brussels of the Centro Studi Psichatrici Vrije Universiteit Brussel, Université Catholique de Louvain & the Bedfordshire Centre for Mental Health Research. The talk aimed to present a brief taster, assuming no prior knowledge, of adult neurogenesis, the formation of new nerve cells, in relation to the aetiology and treatment of depression. The talk begins with an introduction to the principles of adult neurogenesis: from initial investigations by Ramon y Cajal in the 19th century, resulting in a "static brain hypothesis", to their subsequent challenge almost one hundred years later. The potential functional implications emerging, especially in relation to depression, are explored. The fascinating effects of corticosteroids and antidepressants are used as examples to explore the possible roles of neurogenesis that have led some to propose a neurogenic theory of depression. Arguments against this theory are then presented. Finally, a consideration of future opinion: could neurogenesis be less important in the aetiology of depression, but involved in its treatment - a property of antidepressant action rather than a central final aetiological pathway. In this young branch of neuroscience controversy abounds: our understanding of the process itself, its relations and most importantly its implications are all in their infancy. This has allowed for some of the most interesting debate of recent years as to the neurological basis and treatment of affective disorders.

What do large scale studies of medication in schizophrenia add to our management strategies?

INTRODUCTION: A number of large naturalistic trials have reported in recent years comparing second generation antipsychotic drugs with their predecessors. The conclusions they draw have rightly sparked much debate, but are these studies truly comparable? If not, which of them are most methodologically robust and are these the studies most suitable as a foundation for clinical care guidelines with a strong evidence base. We aimed to conduct a review of the current literature to establish the appropriateness of several recent major clinical studies being used as the basis for clinical guidelines. METHOD: A literature search using the PUBMED database was carried out. Five major studies comparing antipsychotic efficacy were selected as possible candidates and subjected to further analysis. The studies were: * CUTLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia study); * CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness study); * SOHO (Schizophrenia outpatients Health Outcomes study); * CAFE (Comparison of Atypicals in First Episode study); * EUFEST (European First Episode Schizophrenia Trial). DISCUSSION: The trials: * CAFE - the trial, although well randomised and blinded, uses discontinuation as a primary endpoint - this is hard to draw conclusions from: patients may discontinue due to side effects, due to lack of efficacy or with against medical advice for a multitude of reasons. As a secondary endpoint, the study does make use of a PANSS scoring system to measure efficacy, adding some weight to the conclusion that olanzapine, quetiaine and risperidone in early psychosis patients have equivalent efficacies. * CATIE - This trial was a comparative study, and so lacked a control arm and used discontinuation of medication an inverse measure of efficacy - an easily quantifiable event, but making for difficult interpretation. However most criticism has been directed at the unusually low (quitiapine, ziprasidone) and high (olanzapine and perphenazine) doses of drug used, which were reflected in their differing rates of efficacy. * CUtLASS This trial allows for less generalisation of its findings to the general population as it makes use a specific sub-population (those switching from one medication to another after a period of treatment). Also some patients were prescribed oral medications and some depot injections - making comparisons difficult due to possible differences in compliance. * EUFEST This trial makes use of discontinuation as an endpoint with the weaknesses we have described. Treatment of first episodes of psychosis is shown to be feasible, but it could not suggest if haloperidol or second generation drugs may be more efficacious. * SOHO - This trial hindered by the observational design of the study and small numbers reaching the primary end point (4%) caution should be exercised in the conclusion that olanzapine is superior to risperidone, quetiapine or typical antipsychotics. CONCLUSION: There is much information useful for clinical practice to be gathered from the results of these major studies, however, interpretation is hampered by both variations and weakness in study design. On balance it does appear that different antipsychotics possess differing efficacy, but also of relevance to the development of sound clinical guidelines is their differing side effects profile.

Suicide risk and choice of antidepressant.

INTRODUCTION: There is presently concern that patients treated for depression with venlafaxine have a higher suicide rate than those treated with other antidepressants, based on results from observational studies. The aim of this study was to determine whether higher suicide risk, defined as previous suicide attempt or suicidal ideation, influenced the choice of antidepressant prescribed in an outpatient mental health unit, the Bedford East Community Mental Health Team. SUBJECTS AND METHOD: A database held by a the Community Mental Health Team was used to identify patients with Depression who have been treated with Venlafaxine, Citalopram, and patients diagnosed with bipolar II affective disorder. The data was analysed in terms of presence of suicide risk, gender, and whether bipolar II patients on venlafaxine were treated with mood stabilisers. RESULTS: The results showed that a risk of suicide did not prevent the prescription of venlafaxine, that less venlafaxine was prescribed to male patients than females, and that bipolar II patients were indeed treated with mood stabilisers. DISCUSSION: It appears that in this Community Mental Health Team, the possibility of suicide risk with venlafaxine therapy is considered and appropriately managed. CONCLUSION: Early diagnosis and appropriate treatment of bipolar disorder is likely to be the most effective step that we can take to reduce the risk of suicide in patients with bipolar disorder .Appropriate care regarding the judicious use of Venlafaxine as a first line treatment in Unipolar Depression is secondary to this.