Compositional Deep Probabilistic Models of DNA-Encoded Libraries.

DNA-encoded library (DEL) has proven to be a powerful tool that utilizes combinatorially constructed small molecules to facilitate highly efficient screening experiments. These selection experiments, involving multiple stages of washing, elution, and identification of potent binders via unique DNA barcodes, often generate complex data. This complexity can potentially mask the underlying signals, necessitating the application of computational tools, such as machine learning, to uncover valuable insights. We introduce a compositional deep probabilistic model of DEL data, DEL-Compose, which decomposes molecular representations into their monosynthon, disynthon, and trisynthon building blocks and capitalizes on the inherent hierarchical structure of these molecules by modeling latent reactions between embedded synthons. Additionally, we investigate methods to improve the observation models for DEL count data, such as integrating covariate factors to more effectively account for data noise. Across two popular public benchmark data sets (CA-IX and HRP), our model demonstrates strong performance compared to count baselines, enriches the correct pharmacophores, and offers valuable insights via its intrinsic interpretable structure, thereby providing a robust tool for the analysis of DEL data.

Expanding the clinical spectrum of idiopathic intracranial hypertension.

PURPOSE OF REVIEW: Idiopathic intracranial hypertension (IIH) is a disorder of raised intracranial pressure (ICP). Although the majority of patients with IIH present classically with headache and papilledema, some patients may have unusual presentations or manifestations. Recent advancements in neuroimaging have facilitated the identification of other presentations associated with IIH. This review provides an overview of the expanding clinical spectrum of IIH. RECENT FINDINGS: Presentations of IIH that are considered unusual include highly asymmetric or unilateral papilledema, IIH without papilledema, and IIH associated with cranial nerve involvement. These presentations likely reflect differences in the way cerebrospinal fluid (CSF) pressure is transmitted intracranially. Radiological signs of intracranial hypertension are increasingly recognized in patients with IIH and provide further insights into the effects of raised ICP on intracranial structures. Osseous changes in the skull base leading to formation of meningoceles and encephaloceles have been identified in patients with IIH, spontaneous skull base CSF leak, and drug-resistant temporal lobe epilepsy, suggesting a possible association. SUMMARY: Clinicians should be familiar with the expanding clinical spectrum of IIH and the implications for the management of these presentations.

DEL-Dock: Molecular Docking-Enabled Modeling of DNA-Encoded Libraries.

DNA-encoded library (DEL) technology has enabled significant advances in hit identification by enabling efficient testing of combinatorially generated molecular libraries. DEL screens measure protein binding affinity though sequencing reads of molecules tagged with unique DNA barcodes that survive a series of selection experiments. Computational models have been deployed to learn the latent binding affinities that are correlated to the sequenced count data; however, this correlation is often obfuscated by various sources of noise introduced in its complicated data-generation process. In order to denoise DEL count data and screen for molecules with good binding affinity, computational models require the correct assumptions in their modeling structure to capture the correct signals underlying the data. Recent advances in DEL models have focused on probabilistic formulations of count data, but existing approaches have thus far been limited to only utilizing 2-D molecule-level representations. We introduce a new paradigm, DEL-Dock, that combines ligand-based descriptors with 3-D spatial information from docked protein-ligand complexes. 3-D spatial information allows our model to learn over the actual binding modality rather than using only structure-based information of the ligand. We show that our model is capable of effectively denoising DEL count data to predict molecule enrichment scores that are better correlated with experimental binding affinity measurements compared to prior works. Moreover, by learning over a collection of docked poses we demonstrate that our model, trained only on DEL data, implicitly learns to perform good docking pose selection without requiring external supervision from expensive-to-source protein crystal structures.

Presumptive Idiopathic Intracranial Hypertension Based on Neuroimaging Findings: A Referral Pattern Study.

BACKGROUND: Radiologic findings of intracranial hypertension (RAD-IH) are common in idiopathic intracranial hypertension (IIH) patients. Paralleling the increasing rates of obesity, the burden of IIH is growing. Urgent neuro-ophthalmology consultations for possible IIH in patients with incidentally detected RAD-IH are increasing, with many patients receiving unnecessary lumbar punctures (LPs) and treatments. This retrospective observational study aimed to determine the prevalence of neuro-ophthalmology consultations for RAD-IH, rate of funduscopic examination by referring providers, prevalence of papilledema, outcomes after neuro-ophthalmic evaluation, and rates of misdiagnosis. METHODS: Records of 1,262 consecutive new patients seen in one neuro-ophthalmology clinic from January 2019 to January 2020 were reviewed. We identified patients who were: 1) referred with concern for IIH because of findings of RAD-IH; 2) referred for "papilledema"; 3) referred with a diagnosis of IIH; and 4) referred for spontaneous cranial cerebrospinal fluid (CSF) leaks. In addition to basic demographic profiles for all groups, detailed information was collected for patients referred solely for RAD-IH, including referral patterns, prior history of IIH, previous LPs, prior medical or surgical treatment(s), risk factors for increased intracranial pressure (ICP), presenting symptoms, radiologic features observed on neuroimaging, and final disposition. When available, the neuroimaging was reviewed by an expert neuroradiologist. RESULTS: Of 1,262 consecutive new patients, 66 (5%) were referred specifically for RAD-IH; most referrals came from neurologists (58%); 8/66 (12%) patients had papilledema; 16/66 (24%) patients had prior LP and 13/66 (20%) were already treated based on MRI findings; and 22/66 (33%) patients had ≤2 RAD-IH. Only 34/66 (52%) of patients referred for RAD-IH had prior funduscopic examinations. We confirmed papilledema in 26/82 (32%) patients referred for "papilledema." Only 29/83 (35%) patients referred with a diagnosis of IIH had active papilledema, and 3/16 (19%) patients with spontaneous CSF leaks had papilledema. In total, 247/1,262 (20%) new patients were referred to our clinic over 1 year with concern for IIH, among whom only 66 (27%) were confirmed to have active IIH with papilledema. CONCLUSIONS: One in 5 new patient referrals seen in our neuro-ophthalmology clinic were referred because of concern for increased ICP, but only 1/4 had active papilledema. Most patients referred for isolated RAD-IH do not have papilledema, many having undergone unnecessary LPs and treatments. The burden of these "rule-out IIH" consultations is overwhelming and will only continue to increase with the concurrent rise of obesity and IIH, straining the already limited neuro-ophthalmologic resources available in the US.

Developments in the Treatment of Leber Hereditary Optic Neuropathy.

PURPOSEOF REVIEW: To outline the current landscape of treatments for Leber hereditary optic neuropathy (LHON) along the therapeutic delivery pipeline, exploring the mechanisms of action and evidence for these therapeutic approaches. RECENT FINDINGS: Treatments for LHON can be broadly classified as either mutation-specific or mutation-independent. Mutation-specific therapies aim to correct the underlying mutation through the use of a gene-editing platform or replace the faulty mitochondrial DNA-encoded protein by delivering the wild-type gene using a suitable vector. Recent gene therapy clinical trials assessing the efficacy of allotopically expressed MT-ND4 for the treatment of LHON due to the m.11778G > A mutation in MT-ND4 have shown positive results when treated within 12 months of symptom onset. Mutation-independent therapies can have various downstream targets that aim to improve mitochondrial respiration, reduce mitochondrial stress, inhibit or delay retinal ganglion cell apoptosis, and/or promote retinal ganglion cell survival. Idebenone, a synthetic hydrosoluble analogue of co-enzyme Q10 (ubiquinone), is the only approved treatment for LHON. Mutation-independent approaches to gene therapy under pre-clinical investigation for other neurodegenerative disorders may have the potential to benefit patients with LHON. Although approved treatments are presently limited, innovations in gene therapy and editing are driving the expansion of the therapeutic delivery pipeline for LHON.

Capturing the experiences of patients with inherited optic neuropathies: a systematic review of patient-reported outcome measures (PROMs) and qualitative studies.

PURPOSE: To identify and comprehensively evaluate studies capturing the experience of individuals affected by an inherited optic neuropathy (ION), focusing on patient-reported outcome measures (PROMs) and qualitative studies where the health status and quality of life (QoL) of these individuals have been explored. METHODS: Systematic review of five databases using a search strategy combining four concepts: (1) ION; (2) QoL and health status; (3) PROMs; and (4) qualitative research. Studies assessing the impact of ION on any QoL domain using a PROM or qualitative methodology were included and appraised, using criteria based on the COSMIN checklist (for PROM studies) and the CASP checklist (for qualitative studies). RESULTS: Of 1326 unique articles identified, six studies were included. Five PROMs were identified: Visual Function Index (VF-14); Hospital Anxiety and Depression Scale (HADS); a novel graphical online assessment tool (NGOAT) for reporting emotional response to vision loss; a new PROM informed by the DSM-V Criteria for Major Depressive Disorder; and an interpersonal and career 'impact rating' PROM. The psychometric performance of included PROMs were poorly described. Qualitative studies found that vision loss resulted in psychosocial losses including loss of social and communication skills and loss of independence and freedom. Factors that modified the response to vision loss were also identified. CONCLUSION: The current PROMs used by individuals with ION have poor content coverage, primarily measuring activity limitation and emotional well-being, and insufficient reporting of psychometric performance. There is a need to develop a PROM for individuals ION to report their experiences of living with their condition.

The Impact of Leber Hereditary Optic Neuropathy on the Quality of Life of Patients and Their Relatives: A Qualitative Study.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disease characterized by severe bilateral vision loss and chronic visual impairment. The objective of this study was to comprehensively explore the impact of LHON on the lives of patients and their relatives at the time of diagnosis and now. METHODS: Qualitative study design with 8 focus group interviews conducted in France, Germany, the United Kingdom, and the United States, involving 17 individuals with m.11778G>A mutation and their relatives. Separate focus groups for patients and their relatives were facilitated by a moderator in French, German, or English. Qualitative analysis of interviews using a pre-defined analytical framework. RESULTS: Participants reported feeling devastated by the diagnosis of LHON after a lengthy and worrisome diagnostic journey. Patients were frustrated by the loss of autonomy, which also affected their relatives. Participants described challenges across several domains: physical capabilities, emotional well-being, interpersonal relationships, work and studies, finances, and recreational activities. Access to disability allowances, vision aids, and funded or subsided idebenone varied by country, resulting in unequal financial impact. Patients are hopeful for therapy that would restore autonomy and improve their ability to enjoy a fulfilling life, while alleviating the demands placed on their relatives. CONCLUSIONS: The impact of LHON extends beyond vision-related activity limitations. Addressing the psychosocial impact of LHON and helping patients and their relatives adapt and cope with vision loss are vital. As part of this, an accurate and timely diagnosis is important to enable early intervention. Further investigation of specific unmet needs is required.

Prediction of Postoperative Risk of Raised Intracranial Pressure After Spontaneous Skull Base Cerebrospinal Fluid Leak Repair.

BACKGROUND: A relationship between idiopathic intracranial hypertension and spontaneous skull base cerebrospinal fluid (CSF) leaks has been proposed, by which CSF leak decreases intracranial pressure (ICP) and masks the symptoms and signs of elevated ICP. These patients are at risk of developing papilledema, symptoms of elevated ICP, or a recurrent CSF leak after CSF leak repair. The objective of this study was to assess whether radiographic signs of raised ICP on preoperative magnetic resonance or computed venography (MRI or CTV) are predictors of postoperative papilledema, recurrence of CSF leak, or need for CSF shunt surgery. METHODS: We performed a retrospective review of systematically collected demographics, fundus examination, and presurgical brain MRI and magnetic resonance venography/computed tomography venography (MRV/CTV) in patients seen at 1 institution between 2013 and 2019 with spontaneous skull base CSF leak repair. Patients were divided into 2 groups depending on whether they developed papilledema, recurrent CSF leak, or required CSF shunting (Group 1) or not (Group 2). RESULTS: Fifty-seven patients were included, among whom 19 were in Group 1. There was no difference in demographic characteristics or clinical features between patients in Group 1 and Group 2. Controlling for other imaging features, bilateral transverse venous sinus stenosis (TVSS) on preoperative imaging increased the odds of being in Group 1 by 4.2 times (95% confidence interval [CI], 1.04-21.2, P = 0.04), optic nerve tortuosity decreased the odds of being in Group 1 by 8.3 times (95% CI: 1.4-74.6, P = 0.02). CONCLUSION: Imaging of the intracranial venous system with MRV or CTV is warranted before repair of spontaneous CSF leak, as bilateral TVSS is an independent risk factor for postoperative papilledema, CSF leak recurrence, or need for a CSF shunting procedure.

Optic Nerve Angle in Idiopathic Intracranial Hypertension.

BACKGROUND: The tortuosity of the optic nerve can be quantified radiologically by measuring the angle of optic nerve deformation (the "optic nerve angle" [ONA]). In patients with idiopathic intracranial hypertension (IIH), lowering the intracranial pressure (ICP) to a normal range by lumbar puncture leads to straightening of the optic nerve and an increase in the measured sagittal ONA on MRI. It is uncertain whether there is any correlation between ONA and cerebrospinal fluid (CSF) opening pressure or visual function. METHODS: Retrospective study of patients with and without IIH who had MRI of the brain followed by lumbar puncture with CSF opening pressure within 24 hours of MRI. Before LP and within 24 hours of MRI of the brain, all patients with IIH had neuro-ophthalmologic assessment including visual acuity, Humphrey Visual Field (HVF), and fundus photography. Sagittal ONA was measured on multiplanar T2-SPACE images on a DICOM viewer. Papilledema on the fundus photographs was graded using the Frisén scale. RESULTS: Fifty-four patients with IIH and 30 unmatched controls were included. The IIH group was 6.3 years younger (95% CI 2.4-10.3, P = 0.002), had 8.7 kg/m2 higher body mass index (4.9-12.5, P < 0.001), and 26.3% more women (P = 0.011) compared with controls. In both eyes, the ONA was significantly smaller in patients with IIH by 12° compared with controls (7°-17°, P < 0.00001). In the IIH group, no correlation between ONA and the CSF opening pressure was present in either eye (right eye r = 0.19, P = 0.15; left eye r = 0.18, P = 0.19) The ONA did not correlate with logarithm of the minimum angle of resolution visual acuity (right eye r = 0.26, P = 0.063; left eye r = 0.15, P = 0.27), HVF mean deviation (right eye r = 0.0059, P = 0.97; left eye r = -0.069, P = 0.63), or Frisén grade (Spearman's rho right eye 0.058, P = 0.67; left eye 0.14, P = 0.30). CONCLUSIONS: The ONA is significantly smaller in patients with IIH compared to controls, but does not correlate with CSF opening pressure, severity of papilledema, or visual function. The ONA may be useful in identifying patients with raised ICP, but not necessarily those with a poor visual prognosis.

Improving Lung Function in Severe Heterogenous Emphysema with the Spiration Valve System (EMPROVE). A Multicenter, Open-Label Randomized Controlled Clinical Trial.

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema.Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management.Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control).Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax.Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Permanent peritoneal ports for the management of recurrent malignant ascites: a retrospective review of safety and efficacy.

Large volume paracentesis is effective in relieving the symptoms of malignant ascites, but frequent procedures are often required. Permanent peritoneal ports are an alternative to repeated procedures. We describe our experience with the use of peritoneal ports in patients at Middlemore Hospital (Auckland, New Zealand) who had a port inserted for the drainage of malignant ascites. Twenty-eight ports were inserted in 26 patients and accessed a total of 257 times with acceptably low rates of complications including cellulitis, peritonitis and wound dehiscence.

Inhibiting amyloid ß-protein assembly: Size-activity relationships among grape seed-derived polyphenols.

Epidemiological evidence that red wine consumption negatively correlates with risk of Alzheimer's disease has led to experimental studies demonstrating that grape seed extracts inhibit the aggregation and oligomerization of Aß in vitro and ameliorate neuropathology and behavioral deficits in a mouse model of Alzheimer's disease. The active agent in the extracts is a mixed population of polyphenolic compounds. To evaluate the relative potency of each of these compounds, HPLC was used to fractionate the mixture into monomers, dimers, and oligomers. Each fraction was analyzed for its effect on Aß conformational dynamics (circular dichroism), oligomerization (zero-length photochemical cross-linking), aggregation kinetics (Thioflavin T fluorescence), and morphology (electron microscopy). The relative activities of each fraction were determined on the basis of molar concentration (mol/L) or mass concentration (g/L). When molar concentration, the number concentration of each polyphenolic compound, was considered, the oligomer fraction was the most potent inhibitor of Aß oligomerization and aggregation. However, when mass concentration, the number concentration of phenolic groups, was considered, monomers were the most potent inhibitors. To understand these ostensibly contradictory results, a model of polyphenol:Aß complexation was developed. This model, which was found to be consistent with published X-ray crystallographic studies, offers an explanation for the effects of functional group polyvalency on inhibitor activity. Our data emphasize the importance of an in-depth understanding of the mechanism(s) underlying 'concentration dependence' in inhibitor systems involving polyfunctional agents.

Visual outcome measures in clinical trials of remyelinating drugs.

One of the most promising approaches to delay, prevent or reverse disability progression in multiple sclerosis (MS) is to enhance endogenous remyelination and limit axonal degeneration. In clinical trials of remyelinating drugs, there is a need for reliable, sensitive and clinically relevant outcome measures. The visual pathway, which is frequently affected by MS, provides a unique model system to evaluate remyelination of acute and chronic MS lesions in vivo and non-invasively. In this review, we discuss the different measures that have been used and scrutinise visual outcome measure selection in current and future remyelination trials.

Thioamide quenching of fluorescent probes through photoinduced electron transfer: mechanistic studies and applications.

Previously we have shown that thioamides can be incorporated into proteins as minimally perturbing fluorescence-quenching probes to study protein dynamics, folding, and aggregation. Here, we show that the spontaneity of photoinduced electron transfer between a thioamide and an excited fluorophore is governed by the redox potentials of each moiety according to a Rehm-Weller-type model. We have used this model to predict thioamide quenching of various common fluorophores, and we rigorously tested more than a dozen examples. In each case, we found excellent agreement between our theoretical predictions and experimental observations. In this way, we have been able to expand the scope of fluorophores quenched by thioamides to include dyes suitable for microscopy and single-molecule studies, including fluorescein, Alexa Fluor 488, BODIPY FL, and rhodamine 6G. We describe the photochemistry of these systems and explore applications that demonstrate the utility of thioamide quenching of fluorescein to studying protein folding and proteolysis.

The diagnosis and management of pleural effusions in the ICU.

Pleural effusions are common in critically ill patients. Most effusions in intensive care unit (ICU) patients are of limited clinical significance; however, some are important and require aggressive management. Transudative effusions in the ICU are commonly caused by volume overload, decreased plasma oncotic pressure, and regions of altered pleural pressure attributable to atelectasis and mechanical ventilation. Exudates are sequelae of pulmonary or pleural infection, pulmonary embolism, postsurgical complications, and malignancy. Increases in pleural fluid volume are accommodated principally by chest wall expansion and, to a lesser degree, by lung collapse. Studies in mechanically ventilated patients suggest that pleural fluid drainage can result in improved oxygenation for up to 48 hours, but data on clinical outcomes are limited. Mechanically ventilated patients with pleural effusions should be semirecumbant and treated with higher levels of positive-end expiratory pressure. Rarely, large effusions can cause cardiac tamponade or tension physiology, requiring urgent drainage. Bedside ultrasound is both sensitive and specific for diagnosing pleural effusions in mechanically ventilated patients. Sonographic findings of septation and homogenous echogenicity may suggest an exudative effusion, but definitive diagnosis requires pleural fluid sampling. Thoracentesis should be carried out under ultrasound guidance. Antibiotic regimens for parapneumonic effusions should be based on current pneumonia guidelines, and anaerobic coverage should be included in the case of empyema. Decompression of the pleural space may be necessary to improve respiratory mechanics, as well as to treat complicated effusions. While small-bore catheters inserted under ultrasound guidance may be used for nonseptated effusions, surgical consultation should be sought in cases where this approach fails, or where the effusion appears complex and septated at the outset. Further research is needed to determine the effects of pleural fluid drainage on clinical outcomes in mechanically ventilated patients, to evaluate weaning strategies that include pleural fluid drainage, and to better identify patients in whom pleural effusions are more likely to be infected.

Psychometric Validity of the Visual Function Index in Leber Hereditary Optic Neuropathy.

Purpose: The purpose of this study was to determine the psychometric validity of the Visual Function Index (VF-14) for use by patients with Leber hereditary optic neuropathy (LHON). Methods: Rasch analysis was conducted in two stages using data for 196 individuals (74.5% male) carrying one of the three primary LHON mutations and affected by vision loss. In stage 1, scale unidimensionality, scale-to-sample targeting, response category threshold ordering, item fit statistics, local dependency, and reliability were assessed. In stage 2, iterative post-hoc revisions of the VF-14 structure (VF-14R) were applied and psychometrically re-evaluated. Results: Issues identified with the VF-14 included disordered response thresholds (12/14 items), local dependency (10/91 pairwise dependencies), and evidence of multidimensionality. However, the distribution of person estimates and item thresholds were fairly well matched, only one item showed misfit to the Rasch model, and there was good reliability (Person Separation Index 0.84). Rasch-informed VF-14 revisions included removing both driving items and the misfitting sports item, rescoring response options across all items by merging two response categories, and accounting for the dependency between two reading items. The VF-14R demonstrated improved psychometric validity. Conclusions: Clinicians and researchers using the VF-14 with LHON patients should be aware of its limitations. Compared to the original version, the proposed Rasch-based structure of the VF-14R appears to offer improved psychometric performance and interpretation of vision-related activity limitation. Translational Relevance: The original version of the VF-14 exhibits several limitations that undermines its psychometric validity as a patient-reported outcome measure for patients with LHON.

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.

Childhood-Onset Leber Hereditary Optic Neuropathy-Clinical and Prognostic Insights.

PURPOSE: To investigate the clinical and molecular genetic features of childhood-onset Leber hereditary optic neuropathy (LHON) to gain a better understanding of the factors influencing the visual outcome in this atypical form of the disease. DESIGN: Retrospective cohort study. METHODS: We retrospectively included 2 cohorts of patients with LHON with onset of visual loss before the age of 12 years from Italy and the United Kingdom. Ophthalmologic evaluation, including best-corrected visual acuity, orthoptic evaluation, slit-lamp biomicroscopy, visual field testing, and optical coherence tomography, was considered. Patients were classified based on both the age of onset and the pattern of visual loss. RESULTS: A total of 68 patients were stratified based on the age of onset of visual loss: group 1 (<3 years): 14 patients (20.6%); group 2 (≥3 to <9 years): 27 patients (39.7%); and group 3 (≥9 to ≤12 years): 27 patients (39.7%). Patients in group 2 achieved a better visual outcome than those in group 3. Patients in groups 1 and 2 had better mean deviation on visual field testing than those in group 3. The mean ganglion cell layer thickness on optical coherence tomography in group 2 was higher than those in groups 1 and 3. Patients were also categorized based on the pattern of visual loss as follows: Subacute Bilateral: 54 patients (66.7%); Insidious Bilateral: 14 patients (17.3%); Unilateral: 9 patients (11.1%); and Subclinical Bilateral: 4 patients (4.9%). CONCLUSIONS: Children who lose vision from LHON before the age of 9 years have a better visual prognosis than those who become affected in later years, likely representing a "form frustre" of the disease.