Optic Nerve Research Articles

Transcriptomics of Various Diseases Reveals the Core Role of Immune System Pathways in Retinal Damage Repair and Nerve Regeneration.

Retinal ganglion cells (RGCs) are the only neuronal bridges connecting retinal inputs to the brain's visual processing centers, enabling visual perception. The axon of RGCs forms the optic nerve, which transmits visual information to the visual cortex. Damage to RGCs and their axons results in irreversible visual impairment. Acute retinal damage is commonly induced by conditions such as optic nerve compression, glaucoma, and optic neuritis, for which effective clinical treatments are currently unavailable. Therefore, understanding the response of RGCs and their axons to injury is crucial for the development of potential treatments. This study utilizes multiple models including optic nerve crush (ONC), acute intraocular pressure (IOP) elevation, and local lipopolysaccharide (LPS) injection into the optic nerve to mimic eye diseases. Three days post-surgery, mice underwent retinal isolation followed by bulk-RNA sequencing to analyze differential gene expression among models. Using thresholds of |Log2 fold change (FC)|> 2 and p-value < 0.05, the significant gene expression changes observed in each model were as follows: ONC (upregulated, 456; downregulated, 84), IOP (upregulated, 1946; downregulated, 655), and LPS (upregulated, 219; downregulated, 94). Gene ontology (GO) analysis of the upregulated genes unexpectedly revealed that immune system pathways were the primary shared targets across all three models. In contrast, the downregulated genes exhibited model-specific enrichment: synaptic components and functions in IOP, neurogenesis and neuronal development in ONC, and inflammation and antioxidant in LPS. These findings were further confirmed by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. This suggests that managing immune activation is essential for treating acute retinal injury, and therapeutic strategies should address model-specific targets as well. Notably, 39 genes intersected across the models, and the protein-protein interaction (PPI) network identified Ccl5 as a key hub gene, underscoring its critical role in the pathophysiology of all three diseases.

How can MRI descriptors be optimally combined to predict idiopathic intracranial hypertension?

To establish how MRI descriptors on standard MRI sequences can be optimally combined to predict idiopathic intracranial hypertension (IIH). A retrospective single institution cross-sectional study evaluated consecutive IIH patients undergoing MRI between 2002-2015 and a control group. Six established and eight exploratory MRI descriptors were evaluated. Two observers independently analysed MRI descriptors on T1w sagittal and T2w axial sequences whilst blinded to clinical data with consensus obtained. Inter-rater reliability was calculated, and the presence of MRI descriptors was compared between IIH patients and controls (Bonferroni correction, p < 0.004). Forward stepwise logistic regression determined which combination of MRI descriptors best predicted IIH. 54 IIH patients (mean age 31.2, standard deviation 10.2, 3 men) and 54 control subjects (mean age 31.7, standard deviation 7.1, 3 men) were evaluated. There was excellent inter-rater reliability for 13/14 MRI descriptors. There were 4/6 established and 6/8 exploratory MRI descriptors associated with IIH (p < 0.004). The optimal combination of descriptors to predict IIH were vertical tortuosity of the optic nerve, enlarged optic nerve sheath, globe flattening score ≥ 2, Yuh Score ≥ 3, cervical skin folding and cervical fat thickness ≥ 10.5 mm. The model correctly classified 93.5% of cases (sensitivity 94.4%, specificity 92.6%, AUC 0.965). Evaluating a combination of vertical tortuosity of the optic nerve, enlarged optic nerve sheath, globe flattening, Yuh Score, cervical skin folding and cervical fat thickness optimally predicts IIH. New MRI features are validated for the diagnosis of IIH and the optimal combination for diagnosis is established.

Dual lateral flow assay using quantum nanobeads for quantitative detection of BDNF and TNF-α in tears.

Glaucoma is a group of neurodegenerative eye diseases characterized by progressive damage to the optic nerve which is typically asymptomatic until irreversible vision loss has occurred. Early screening is essential for timely treatment to prevent visual impairment. However, existing detection methods struggle to achieve a balance between accuracy, time efficiency, and portability. The lateral flow assay (LFA) is a well-established immunoanalytical tool for point-of-care (POC) analysis. Here, we have developed a unique dual-testing, quantum nanobeads-based fluorescence LFA, allowing for the simultaneous and quantitative detection of two glaucoma biomarkers: tumor necrosis factor-α (TNF-α) and brain-derived neurotrophic factor (BDNF). By coating quantum dots on the surface of a SiO2 core, the fluorescent intensity of the quantum nanobeads was enhanced enabling an accurate, efficient, and high-throughput bioanalytical performance, with low detection limits of 3.39 pg mL-1 for TNF-α and 4.13 pg mL-1 for BDNF. The LFA also demonstrated superior selectivity, reproducibility, and stability to the standard enzyme-linked immunosorbent assay (ELISA). Using a 3D-printed readout box, the analysis of the LFA requires only a readily accessible smartphone and image processing software, making it an ideal POC detection tool. This ultrasensitive, economical, and user-friendly LFA demonstrates significant potential as an alternative for glaucoma screening.

Optimizing outcome in radiosurgery for spheno-orbital meningioma: the critical role of planning quality. Illustrative case.

Spheno-orbital meningiomas (SOMs) pose significant challenges due to their proximity to critical structures, such as the optic nerve. This report underscores the pivotal role of meticulous planning in achieving favorable outcomes with Gamma Knife radiosurgery (GKRS). A 54-year-old woman with a left SOM encasing the optic nerve underwent GKRS after being deemed unsuitable for surgery. The radiosurgical plan was meticulously tailored to balance effective tumor control with optic nerve sparing. A prescribed dose of 10 Gy at the 50% isodose line ensured a maximum optic nerve dose of 9.6 Gy, remaining within safe limits. Metrics such as high target coverage (0.96) and conformity (Paddick index: 0.83) highlighted the precision of the approach. A 12-year follow-up demonstrated stable tumor volume and preserved visual function without adverse effects, confirming the long-term efficacy and safety of this strategy. This case underscores the critical importance of comprehensive dose planning, particularly for perioptic lesions, where the therapeutic margin is narrow. GKRS offers a minimally invasive alternative for SOMs ineligible for surgery, emphasizing the need for individualized treatment strategies. This case highlights how tailored radiosurgical planning can optimize outcomes, preserve function, and improve quality of life for patients with complex skull base tumors. https://thejns.org/doi/10.3171/CASE2530.

Primary Vitreoretinal Lymphomas: A Diagnostic Challenge. Report of two recent cases with retinal biopsies and molecular investigations in Halifax, Nova Scotia.

Introduction Primary vitreoretinal lymphomas (PVRL) are a type of central nervous system lymphoma that arise in the retina, vitreous, or optic nerve without initial brain involvement. The clinical diagnosis can be a challenge since the disease mimics uveoretinitis in its presentation and initial treatment response to steroids. Diagnostic confirmation with vitreous cytology has been the gold standard for diagnosis. However, there are limitations of vitreous cytology such as low volume of sample, low number of lymphoma cells within the sample, and poor preservation of cells due to shearing forces of vitrectomy. There has been a long-standing need for alternative options to improve the diagnostic yield of PVRLs. Recently, MYD88 gene mutations (myeloid differentiation response gene 88) have been found in 69-82.4% of PVRLs. Case Presentations Case 1: 89-year-old male with a retinal detachment post cataract surgery. He had subsequent surgical repair but continued to have poor and worsening vision and developed constitutional symptoms including weight loss and decreased appetite. A vitreous sample submitted for molecular studies, demonstrated MYD88 L265P mutation and a retinal biopsy showed large B lymphocytes infiltrating the retina. Case 2: 62-year-old female referred to the Uveitis Clinic for assessment of chronic right eye panuveitis and left eye anterior uveitis. The patient developed symptoms (blurry vision and photophobia) 9 months prior to the referral. A vitreous biopsy was conducted and was negative for MYD88 mutations and large B cells were not seen on vitreous cytology. The fundus view post-vitrectomy revealed an area of necrotizing retinitis. The patient was started on empiric treatment for herpetic and parasitic etiologies and on high dose oral prednisone shortly after. She had a further decline in her right eye vision with significant extension of the necrotizing retinitis into the macula and optic disc. A retinal biopsy then revealed atypical large B-cells infiltrating the retina. Conclusion PVRLs are rare and establishing the diagnosis is difficult. The traditional use of vitreous cytology has its limitations. Recent molecular advances, in particular the detection of MYD88 mutation is extremely helpful to confirm the diagnosis, but in certain cases retinal biopsies may still be required.

Clinical and immunological differences between primary and autoimmune-associated neuromyelitis optica spectrum disorders: a retrospective study

IntroductionNeuromyelitis optica spectrum disorder (NMOSD) is a rare immune-mediated disease affecting the spinal cord and optic nerves. While NMOSD has been widely studied, limited data exist on the subset associated...

Assessment of optic nerve sheath enlargement and Frisen classification in idiopathic intracranial hypertension: Implications for estimating intracranial pressure and grading chronic papilledema

Abstract: PURPOSE: This study aimed to investigate the correlation between ONSD measured by USG and opening cerebrospinal fluid (CSF) pressure in cases of IIH. MATERIALS AND METHODS: This study employed a prospective observational design. It included 47 patients diagnosed with IIH. ONSD was measured using USG while opening CSF pressure was measured using LP. The study analyzed the correlation between ONSD, CSF opening pressure, and other variables. RESULTS: The study discovered a significant positive association between the measurements of right and left ONSD. However, the ONSD and opening CSF pressure were not significantly correlated. The axial length showed a negative correlation with ONSD. The study determined that an ONSD cutoff value of 5.67 mm was optimal for the prediction of high ICP. CONCLUSION: The investigation concluded that there is no significant relationship between ONSD distension and opening CSF pressure in IIH cases, suggesting that USG may not be reliable for estimating ICP. Frisen classification may have limited application in patients with chronic papilledema.

Rapid Reversal of Optic Nerve Cupping in Steroid-Induced Glaucoma.

Rapid Reversal of Optic Nerve Cupping in Steroid-Induced Glaucoma.

Tauroursodeoxycholic Acid Protects Retinal Ganglion Cells and Reduces Inflammation in Mice Following Optic Nerve Crush

Purpose: The aim of this study was to investigate the protective effects of systemically administered tauroursodeoxycholic acid (TUDCA) in an optic nerve crush (ONC) mouse model of retinal ganglion cell (RGC) death. Methods: C57BL/6J mice were injected intraperitoneally (i.p.) three times per week with TUDCA (500 mg/kg) for two weeks, after which unilateral ONC was performed. A control cohort was identically treated with a drug vehicle (phosphate buffered saline; PBS). A separate cohort did not undergo any injections or surgeries (this was termed the “Naïve” group). Pattern electroretinography (PERG) was recorded 3 days after ONC. Retinas were harvested for whole-mount immunofluorescence staining with an antibody against RGC marker Brn3a and imaged by fluorescent confocal microscopy. Apoptotic cells in the ganglion cell layer (GCL) were detected by Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling (TUNEL) performed on fixed retina sections. Glial fibrillary acidic protein (GFAP) immunostaining on fixed retina sections was conducted to detect the activation of Müller cells. Total RNA was extracted from retinas and expression of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-10 was determined by digital droplet PCR (ddPCR). Results: TUDCA treatment preserved visual function as assessed by PERG. P1 and N2 amplitudes from the PBS-treated ONC group were significantly diminished compared to those of the Naïve group (p &lt; 0.001). TUDCA treatment prevented this diminution. The amplitudes of P1 and N2 in the TUDCA-treated ONC group were statistically indistinguishable from those of the Naïve group and were higher than the PBS-treated ONC group (TUDCA+ONC vs. PBS+ONC, P1: 6.99 ± 0.89 µV vs. 3.60 ± 0.69 µV, p &lt; 0.01; N2: −9.30 (IQR: −13.43–−6.44) µV vs. −4.47 (IQR: −10.26–−2.17) µV). TUDCA treatment preserved RGCs. The ONC-vehicle-only group had 25% fewer RGCs (Brn3a-positive cells) than Naïve eyes (p &lt; 0.0001). TUDCA treatment nearly completely prevented this loss, preserving all but 7.7% of the RGCs, and the number of RGCs in the TUDCA-treated ONC group was significantly higher than in the PBS-treated ONC group (TUDCA+ONC vs. PBS+ONC, 1738.00 ± 14.43 cells per field vs. 1454.00 ± 6.55 cells per field, p &lt; 0.0001). The number of TUNEL-positive cells in the GCL (Naïve vs. PBS+ONC group: 1.00 (IQR: 0.00–2.00) % vs. 37.00 (IQR: 8.50–48.50) %, p &lt; 0.05) and GFAP-positive fibers transversing retina sections (Naïve vs. PBS+ONC group: 33.00 ± 1.15 vs. 185.70 ± 42.37 fibers/retina, p &lt; 0.05), and the expression of IL-6, TNF-α were significantly greater in the PBS-treated ONC group compared to that of the Naïve group (Naïve vs. PBS+ONC group, IL-6: 0.07 (IQR: 0.06–0.31) vs. 0.99 (IQR: 0.56–1.47), p &lt; 0.05, TNF-α: 0.19 ± 0.069 vs. 1.39 ± 0.23; p &lt; 0.01), an increase not observed with TUDCA treatment. Conclusions: Systemic TUDCA treatment significantly preserved RGC function and survival in the mouse ONC model of RGC damage. TUDCA treatment prevented RGC apoptosis, Müller glial cell activation, and retinal expression of several inflammatory cytokines. These data suggest that TUDCA is a promising therapeutic candidate for preserving RGC numbers and function.

Myeloid lineage C3 induces reactive gliosis and neuronal stress during CNS inflammation

Complement component C3 mediates pathology in CNS neurodegenerative diseases. Here we use scRNAseq of sorted C3-reporter positive cells from mouse brain and optic nerve to characterize C3 producing glia in experimental autoimmune encephalomyelitis (EAE), a model in which peripheral immune cells infiltrate the CNS, causing reactive gliosis and neuro-axonal pathology. We find that C3 expression in the early inflammatory stage of EAE defines disease-associated glial subtypes characterized by increased expression of genes associated with mTOR activation and cell metabolism. This pro-inflammatory subtype is abrogated with genetic C3 depletion, a finding confirmed with proteomic analyses. In addition, early optic nerve axonal injury and retinal ganglion cell oxidative stress, but not loss of post-synaptic density protein 95, are ameliorated by selective deletion of C3 in myeloid cells. These data suggest that in addition to C3b opsonization of post synaptic proteins leading to neuronal demise, C3 activation is a contributor to reactive glia in the optic nerve.

Safety profile of faricimab: a multi-source pharmacovigilance analysis using FAERS and JADER

BackgroundFaricimab is a bispecific antibody targeting vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), offering a novel therapeutic approach for ocular diseases. However, its long-term safety profile remains under evaluation. This study analyzes its adverse events (AEs) using the U.S. FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER).MethodsAEs from FAERS (2004–2024) and JADER (2004–2024) were analyzed using disproportionality algorithms. Subgroup analyses assessed differences by age and sex. AE onset time was also assessed.ResultsSeveral newly identified adverse events (AEs) were observed, including macular ischemia, keratic precipitates, and optic nerve injury, with strong safety signals detected in both FAERS and JADER. For instance, macular ischemia showed a high association with faricimab use (ROR = 260.46), suggesting a potential risk of retinal circulation impairment. Similarly, keratic precipitates (ROR = 739.65) indicate a notable inflammatory response. All these findings highlight the need for closer monitoring of ocular complications, particularly in high-risk patient groups. The FAERS database mainly reported retinal occlusive vasculitis, ocular vasculitis, and keratic precipitates, while JADER predominantly featured retinal occlusive vasculitis and retinal vascular occlusion. Sex-based differences indicated a higher risk of inflammatory AEs in females (e.g., uveitis and eye inflammation) and a greater incidence of retinal vascular events in males (e.g., retinal vasculitis). Age-related differences showed that older patients (≥65 years) had lower inflammatory AE risks but were more prone to optic nerve damage and retinal atrophy, while younger patients (<65 years) exhibited a higher risk of vitreous hemorrhage and cataracts.ConclusionsThis study identified previously unreported safety signals, suggesting the need for potential updates to faricimab’s safety labeling. Faricimab’s dual-target mechanism presents unique safety concerns. Clinicians should monitor ocular inflammation and vascular complications, particularly in younger males and Asian patients. Further studies using real-world data are needed to validate these findings.

Preventive role of rottlerin in endotoxin-induced uveitic glaucoma in rats

BackgroundRottlerin is a natural polyphenolic compound obtained from dried ripe fruits of Mallotus philippinensis and is primarily used as a PKCδ inhibitor. The effectiveness of rottlerin was checked in the endotoxin-induced glaucoma models, focusing on its impact on intraocular pressure, inflammation, and optic nerve protection. For this study, both pure and extracted rottlerin were used. Extracted rottlerin was characterised by determining its melting point, conducting gas chromatography-mass spectrometry analysis, Nuclear magnetic resonance analysis, and measuring its wavelength and retardation factor. The acute toxicity study was carried out using Organization for Economic Co-operation and development guideline 405 (acute eye irritation test).ResultPure and extracted rottlerin showed decreased intraocular pressure and reduced inflammation, lenticular opacity, and retinal damage. These results are attributed to an increase in antioxidant levels, maintenance of lipid peroxidation, enzyme level (Na+ ATPase, K+ ATPase), ionic balance (Na+, K+), and a decrease in the level of nitric oxide.ConclusionRottlerin (pure) as well as rottlerin (extracted) has demonstrated potential in managing uveitic glaucoma. Its multifaceted mechanisms not only target inflammation and oxidative stress but also promote tissue regeneration and slow disease progression. This makes rottlerin a promising candidate for further clinical research as a potential treatment for uveitic glaucoma.

Cup and Disc Segmentation in Smartphone Handheld Ophthalmoscope Images with a Composite Backbone and Double Decoder Architecture

Glaucoma is a visual disease that affects millions of people, and early diagnosis can prevent total blindness. One way to diagnose the disease is through fundus image examination, which analyzes the optic disc and cup structures. However, screening programs in primary care are costly and unfeasible. Neural network models have been used to segment optic nerve structures, assisting physicians in this task and reducing fatigue. This work presents a methodology to enhance morphological biomarkers of the optic disc and cup in images obtained by a smartphone coupled to an ophthalmoscope through a deep neural network, which combines two backbones and a dual decoder approach to improve the segmentation of these structures, as well as a new way to combine the loss weights in the training process. The models obtained were numerically evaluated through Dice and IoU measures. The dice values obtained in the experiments reached a Dice of 95.92% and 85.30% for the optical disc and cup and an IoU of 92.22% and 75.68% for the optical disc and cup, respectively, in the BrG dataset. These findings indicate promising architectures in the fundus image segmentation task.

Infantile Cerebellar-Retinal Degeneration Associated With Novel ACO2 Variants: Clinical Features and Insights From a Drosophila Model.

Infantile Cerebellar-Retinal Degeneration (ICRD) is an autosomal recessive neuro-disability associated with hypotonia, seizures, optic atrophy, and retinal degeneration. Recessive variants of the mitochondrial aconitase gene (ACO2) are a known cause of ICRD. Here, we present a paediatric male patient with ICRD, where whole genome sequencing of the family trio revealed segregating heterozygous variants of unknown significance in ACO2. At 4 months, he displayed generalised hypotonia, and by 6 years, visual electrophysiology indicated bilateral optic atrophy. Magnetic Resonance Imaging (MRI) at age seven confirmed optic nerve and cerebellar atrophy, and together with symptoms of developmental delay, align with ICRD. We established a Drosophila animal model to explore the impact of ACO2 loss- and gain-of-function. Manipulating the fly ortholog, mAcon1, through pan-neuronal knock-down or over-expression negatively affected longevity, locomotion, activity, whilst disrupting sleep and circadian rhythms. Mis-expression of mAcon1 in the eye led to impaired visual synaptic transmission and neurodegeneration. These experiments mirrored certain aspects of the human disease, providing a foundation for understanding its biological processes and pathogenic mechanisms, and offering insights into potential targets to screen for future treatments or preventive measures for ACO2-related ICRD.

How I do it: Optic nerve decompression in patient with osteopetrosis

BackgroundOsteopetrosis is a rare genetic disorder causing excessive skeletal density, with a predilection to affect the skull base. This commonly leads to optic canal stenosis, optic nerve compression, and atrophy and vision loss. Timely optic nerve decompression can be an effective surgical intervention to preserve vision.MethodsPterional approach combining both extra- and intradural optic nerve decompression was performed. Intradural optic nerve identification proved a helpful and safe way to facilitate adequate decompression while dissecting in the region of hypertrophic anterior clinoid process.ConclusionPrecise surgical technique and anatomical awareness are crucial for minimizing complications and aiding recovery.

A Case of Optic Disc Pit and Optic Nerve Cyst on MRI.

A Case of Optic Disc Pit and Optic Nerve Cyst on MRI.

Similar performance between modified retrobulbar and ultrasound-guided Peterson nerve blocks using computed tomography in bovine cadavers.

Description and performance of an ultrasound-guided Peterson (UP) block technique were compared to those of a conventional modified retrobulbar (RB) nerve block in bovine cadaver heads by use of CT. This was an original descriptive study using 10 normal orbits from 5 bovid cadavers between April 17 and 23, 2024. Standardized techniques for the modified RB and UP blocks were utilized, with each technique randomly performed on either orbit of each head. Blocks were performed with 9-cm, 18-gauge spinal needles and iopamidol as a contrast solution. Ultrasound guidance involved the use of a 12-MHz linear transducer, and subsequent imaging of contrast distribution was performed with a GE Lightspeed 16-slice CT scanner. Contrast deposition within the intraconal space was observed in 5 of 5 RB blocks and 5 of 5 UP blocks. No extraconal contrast deposition was observed in either block technique. Extension of contrast in close association with the optic nerve to the level of orbital foramen was observed in 5 of 5 RB orbits and 5 of 5 UP orbits. Extension of the contrast to the level of the foramen orbitorotundum was seen in 5 of 5 RB orbits and 3 of 5 UP orbits. Correct needle placement was observed in 5 of 5 UP orbits and confirmed on CT images. The RB and UP blocks performed similarly, demonstrating similar intraconal distribution of contrast medium and no inadvertent distribution to unintended anatomical locations. The performance of the ultrasound-guided technique in live cattle and ability to successfully achieve adequate blockade need further study.

Portable Non-Contact Device for Measurement of Home-Based Eye Measurement Tonometer

Glaucoma is a major cause of irreversible blindness, predominantly linked to elevated intraocular pressure (IOP), which damages the optic nerve. Early detection and management depend on regular IOP monitoring. Conventional tonometers that require direct contact with the cornea face challenges such as discomfort, infection risks, and dependence on clinical visits. To address these issues, this study introduces a portable, non-contact tonometer utilizing a Passive Infrared (PIR) sensor for improved accuracy in IOP measurement. Unlike traditional infrared (IR) sensors, which have precision limitations, PIR sensors detect infrared radiation variations more effectively, enhancing pressure estimation. The device also incorporates a Wi-Fi module for cloud- based data storage, facilitating remote monitoring by healthcare providers and improving patient accessibility. Designed as a cost-effective and user-friendly solution for home-based IOP measurement, this system aims to alleviate the burden on patients and healthcare facilities. Future research will focus on calibrating the device against gold- standard tonometry methods and conducting clinical validation to ensure reliability[1],[2]. Keywords: Glaucoma, Intraocular Pressure, Non-Contact Tonometer, PIR Sensor, IOT, Cloud Storage

Long-term Effects of Anti-VEGF Therapy versus Panretinal Photocoagulation on Retinal Vessel Caliber in Eyes with Proliferative Diabetic Retinopathy.

Long-term Effects of Anti-VEGF Therapy versus Panretinal Photocoagulation on Retinal Vessel Caliber in Eyes with Proliferative Diabetic Retinopathy.

Investigating Whether Dissemination in Time Is Essential to Diagnose Relapsing Multiple Sclerosis.

The diagnosis of multiple sclerosis (MS) requires evidence of both dissemination in space (DIS) and time (DIT); oligoclonal bands (OCBs) in the CSF can substitute for DIT on MRI. We investigated whether DIT (or positive CSF) is necessary to make a diagnosis of MS in patients who fulfil a high number of DIS criteria. We prospectively recruited patients with a first demyelinating event evaluated with brain and spinal cord MRI within 3 months of onset. The patients were followed up clinically and with MRI. We retrospectively applied DIS criteria requiring lesions in ≥2/4, ≥3/4, or 4/4 regions typically affected in MS (periventricular, cortical/juxtacortical, infratentorial, spinal cord) and ≥2/5, ≥3/5, ≥4/5, and 5/5 regions (including the optic nerve) to baseline assessments. We investigated the performance of each set of DIS criteria for a diagnosis of MS using the 2017 McDonald criteria, requiring both DIS (lesions in ≥2/4 regions) plus DIT on MRI (gadolinium-enhancing and nonenhancing lesions, new T2 lesions at follow-up) or CSF-specific OCBs, as the gold standard. We included 244 patients (mean age 32.5 years, 154 [63%] female); 187 (77%) patients were diagnosed with MS using the 2017 McDonald criteria over a mean follow-up of 11.2 years. DIS alone, requiring lesions in ≥2/4, ≥3/4, or 4/4 regions, exhibited reducing sensitivity (84%, 58%, and 26%, respectively) and increasing specificity (91%, 98%, 100%) for an MS diagnosis. In 112 (46%) patients with optic nerve assessment with orbital MRI or visual evoked potentials, DIS in ≥2/5, ≥3/5, ≥4/5, or 5/5 regions also resulted in reducing sensitivity (96%, 83%, 61%, 30%) and increasing specificity (44%, 83%, 100%, 100%) for MS diagnosis. We propose a diagnostic algorithm for MS in patients with a first demyelinating event based on the number of DIS regions fulfilled. In patients with a first demyelinating event, DIS in ≥4 regions typically affected in MS is highly specific, indicating an extremely low risk of false-positive results, and misdiagnosis. Using DIS in ≥4 regions would reduce the need for follow-up MRI or CSF examination in all patients with suspected MS, streamlining the diagnostic process. Limitations include an over-representation of patients with optic neuritis at onset, a low rate of CSF examination, and lack of optical coherence tomography data.