Continuing Education Activity

White-centered retinal hemorrhages, or Roth spots, are retinal hemorrhages distinguished by central pale areas observed on fundoscopic examination. These lesions most commonly occur in the setting of infective endocarditis, particularly subacute bacterial endocarditis, in which prevalence reaches approximately 80%. Additional associations include hematologic disorders such as leukemia and anemia, vascular conditions including hypertensive retinopathy and preeclampsia, and metabolic disorders such as diabetic retinopathy. Risk factors reflect underlying systemic disease, including immunosuppression, coagulopathy, and uncontrolled hypertension or hyperglycemia.

Roth spots arise from localized vascular injury, with central fibrin-platelet aggregates or leukocyte collections indicating microvascular ischemia and necrosis. Clinically, these lesions are often asymptomatic but may signal severe systemic illness.

Diagnosis relies on careful ophthalmoscopic examination, frequently complemented by systemic evaluation for causative conditions. Management focuses on addressing the underlying disorder, with ophthalmic findings typically resolving following systemic treatment. Complications are uncommon but may reflect severe vascular or hematologic pathology. Prognosis is determined primarily by the underlying systemic disease rather than the retinal lesions themselves.

This activity for healthcare professionals is designed to sharpen learners' skills in evaluating and managing Roth spots. Participants will broaden their grasp of the symptom's etiologies, risk factors, pathophysiology, clinical presentation, and evidence-based diagnostic and therapeutic strategies. Improved competence will equip clinicians to collaborate with interprofessional teams providing care for affected individuals.

Objectives:

• Differentiate Roth spots from diabetic, hypertensive, and hematologic retinal lesions on fundoscopic examination.
• Determine the etiology of Roth spots based on clinical presentation and diagnostic findings to guide the appropriate therapeutic strategy.
• Implement evidence-based, individualized approaches for managing Roth spots and their underlying cause.
• Collaborate with the interprofessional team to educate, treat, and monitor patients with Roth spots to improve health outcomes.

Introduction

White-centered retinal hemorrhages, also known as Roth spots, were first described by Moritz Roth, a Swiss physician, in 1872. The eponym was introduced in 1878 by Moritz Litten, who reported that white-centered retinal hemorrhages were present in approximately 80% of cases of subacute bacterial endocarditis (SBE). Roth spots are most frequently associated with infective endocarditis but may also occur in hematologic, vascular, metabolic, and obstetric conditions such as leukemia, anemia, hypertensive retinopathy, preeclampsia, diabetic retinopathy, and anoxia.[1][2][3]

Roth spots comprise distinctive retinal lesions characterized by pale or white centers within areas of hemorrhage. These lesions are often identified incidentally during fundus examination. Historically considered pathognomonic for SBE, Roth spots are now recognized as nonspecific indicators of systemic vascular injury. The classical retinal finding consists of a retinal hemorrhage secondary to ruptured capillaries, with the central pale region containing fibrin-platelet aggregates, ischemic necrosis, or leukocyte collections. These lesions usually localize in the posterior pole near the vascular arcades and may appear round or flame-shaped, depending on the retinal layer affected. Recognition of Roth spots is clinically significant, as their presence may serve as an early ophthalmic marker of underlying systemic disease.[4]

The historical origins of Roth spots date to the 19th century, when Moritz Roth first described these lesions in association with septicemia. Subsequent refinements by Moritz Litten and later investigators clarified their histopathologic composition, disproving the early assumption that the white center represented bacterial microabscesses. Modern histologic and clinical evidence demonstrates that the pale center consists primarily of fibrin and platelet aggregates, occasionally interspersed with inflammatory cells, reflecting localized capillary rupture and thrombosis. This reinterpretation expanded the clinical relevance of Roth spots beyond endocarditis, establishing them as retinal manifestations of microvascular injury arising from diverse systemic disorders.[5]

Roth spots develop when retinal capillaries sustain endothelial disruption, resulting in extravasation of red blood cells into surrounding retinal tissue. Platelet activation and fibrin deposition at the site of vascular injury generate the characteristic white center. Multiple mechanisms may precipitate this process, including septic embolization, immune complex deposition, hypoxia, and increased vascular fragility.

In infective endocarditis, circulating immune complexes and septic emboli lodge within retinal arterioles, initiating localized vasculitis and hemorrhage. In hematologic disorders such as leukemia and anemia, reduced oxygen delivery and altered blood viscosity impair vascular integrity. Metabolic and vascular diseases, including diabetes mellitus and hypertension, promote chronic microangiopathy. Collectively, these mechanisms illustrate that Roth spots represent a final common pathway of retinal microvascular injury resulting from systemic disease.[6]

Clinically, Roth spots appear as round or oval retinal hemorrhages with a central pale area, typically located along the posterior pole or near the major vascular arcades. On ophthalmoscopy, superficial lesions often assume a flame-shaped configuration, whereas deeper hemorrhages appear round. Advances in multimodal retinal imaging, including spectral-domain optical coherence tomography (OCT) and fundus fluorescein angiography (FFA), have enhanced the understanding of their morphology. OCT reveals hyperreflective foci within the inner retinal layers corresponding to fibrin deposits, while FFA demonstrates hypofluorescence caused by blocked fluorescence and, in some cases, adjacent capillary nonperfusion.[7]

The spectrum of systemic diseases associated with Roth spots is broad. SBE is the classic cause, where these lesions signify systemic embolization and immune-mediated vasculitis. Hematologic disorders such as leukemia, anemia, and thrombocytopenia feature Roth spots secondary to vascular fragility and coagulopathic abnormalities. In chronic metabolic and vascular diseases, including diabetes mellitus and hypertension, Roth spots may coexist with other microvascular changes such as cotton-wool spots and microaneurysms, both markers of focal retinal ischemia.

Autoimmune diseases, notably systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APLS), produce similar findings through immune-complex vasculopathy. Less commonly, Roth spots are associated with HIV retinopathy, meningococcal infection, septicemia, trauma, and Valsalva maneuvers.[8]

From a diagnostic perspective, the identification of Roth spots necessitates a comprehensive systemic evaluation rather than isolated ophthalmic management (see Image. Management Pathway for Roth Spots). Baseline investigations should include a complete blood count (CBC), erythrocyte sedimentation rate, C-reactive protein, and blood cultures when infection is suspected. Echocardiography is warranted if SBE is a consideration, particularly in the presence of systemic manifestations such as fever, cardiac murmurs, or embolic events.

Hematologic assessment, including peripheral smear and bone marrow examination, may reveal anemia, leukemia, or thrombocytopenia. In metabolic or autoimmune disorders, evaluation should include fasting glucose, renal function tests, and serologic markers such as antinuclear antibody, anti-double-stranded DNA, antineutrophil cytoplasmic antibody (ANCA), and antiphospholipid antibodies. Therefore, the presence of Roth spots functions as a clinical biomarker prompting coordinated evaluation among ophthalmologists, internists, and cardiologists.[9]

Roth spots are typically asymptomatic and seldom impair vision, yet their systemic significance is considerable. In SBE, the occurrence of these ocular lesions reflects embolic dissemination and correlates with disease severity. In hematologic disorders, the presence of Roth spots may parallel disease activity or recurrence, rendering serial fundus examinations a useful adjunct for systemic monitoring. The lesions generally resolve following treatment of the underlying condition, although recurrence may signify persistent vascular injury or inadequate systemic control.[10]

Advances in retinal imaging technology have substantially improved the detection and interpretation of Roth spots. OCT and OCT angiography (OCTA) have delineated their structural and vascular features, revealing inner retinal hyperreflectivity and localized perfusion deficits. Adaptive optics and confocal imaging further enhance cellular-level visualization, allowing detailed characterization of the lesions. Recent developments in artificial intelligence (AI) have enabled automated detection of Roth spots and other hemorrhagic retinal signs, supporting integration of ocular imaging into systemic health assessment through teleophthalmology.

Although historically linked to diseases such as endocarditis, Roth spots remain clinically relevant in modern medicine. These lesions exemplify the interconnection between systemic vascular integrity and retinal microcirculation. The recognition of these retinal abnormalities should prompt consideration of systemic pathology, as they may indicate underlying processes with life-threatening potential. Awareness of the nonspecific nature of Roth spots prevents diagnostic overinterpretation while emphasizing their function as sentinel indicators of microvascular injury.

Roth spots represent a distinctive interface between ophthalmology and systemic medicine. The presence of these retinal hemorrhages reflects microvascular compromise due to infection, hematologic imbalance, autoimmune inflammation, or metabolic stress. Advances in imaging and the renewed focus on systemic retinal markers have reinforced their diagnostic value. While not pathognomonic for any single condition, Roth spots are critical clinical indicators guiding comprehensive systemic evaluation. For the modern clinician, identifying a Roth spot extends beyond ophthalmic observation, as it signifies the need to explore deeper systemic disease, underscoring the principle that the eye mirrors overall health.[11]

Etiology

Historically, Roth spots were regarded as pathognomonic for SBE, attributed to septic emboli within the retina. However, recent histopathologic evidence indicates that these lesions result from retinal capillary rupture and intraretinal hemorrhage. Roth spots occur across various systemic diseases involving retinal vascular injury and hemorrhage. A unifying feature among these conditions is endothelial dysfunction predisposing to capillary disruption. Microscopic examination demonstrates that the pale centers of these lesions consist primarily of fibrin, representing a fibrin-platelet plug at the site of vascular rupture.[12]

Roth spots are multifactorial, reflecting a final common pathway of vascular and hematologic disturbances rather than a discrete disease entity (see Image. Etiology of Roth Spots). These ocular abnormalities represent retinal hemorrhages with a central white or pale focus arising from microvascular injury, endothelial damage, and impaired hemostasis within the retinal circulation. The pale center typically corresponds to fibrin-platelet aggregates, inflammatory infiltrates, or foci of ischemic necrosis surrounded by extravasated erythrocytes. These lesions are nonspecific and occur secondary to diverse systemic processes that induce vascular fragility, immune complex deposition, or hematologic dysregulation.[13]

Historically, Roth spots were first described in association with infective endocarditis, in which immune complex-mediated vasculitis and septic emboli induce localized vascular occlusion and leakage. In bacterial endocarditis, deposition of circulating immune complexes within retinal capillaries initiates complement activation, endothelial injury, and subsequent hemorrhage. The central white spot, previously attributed to leukocytic infiltration, is now recognized to consist primarily of fibrin and platelet aggregates formed at the site of vascular disruption. Beyond endocarditis, septicemia, particularly from streptococcal or staphylococcal infection, can similarly produce immune-mediated retinal microinfarctions, underscoring the immunopathologic and embolic mechanisms involved in Roth spot formation.[14]

Hematologic disorders comprise another major etiologic group. In anemia and thrombocytopenia, reduced oxygen delivery and defective hemostasis contribute to capillary hypoxia, fragility, and intraretinal hemorrhage. Conversely, in leukemia, particularly acute forms, Roth spots arise through leukostasis, anemia, and endothelial infiltration by malignant cells. Leukemic retinopathy reflects the combined effects of hyperviscosity, tissue hypoxia, and microvascular occlusion. Likewise, aplastic and megaloblastic anemias compromise marrow function and impair vascular repair, further predisposing to retinal hemorrhagic manifestations.[15]

Vasculitic and immune-mediated disorders play a significant role in the development of Roth spots. Conditions such as SLE, Behçet disease, and APLS induce immune complex-mediated endothelial injury, whereas hypertension and diabetes mellitus cause direct microangiopathic damage. In diabetic retinopathy, capillary basement membrane thickening and pericyte loss weaken the vascular wall, predisposing to hemorrhage. In hypertensive crises, abrupt arteriolar constriction and rupture may produce Roth-like hemorrhagic lesions. Autoimmune vasculitides, including granulomatosis with polyangiitis (GPA) and polyarteritis nodosa (PAN), can cause focal capillary necrosis with hemorrhagic exudation and fibrin deposition, resulting in retinal findings that mimic Roth spots (see Image. Systemic Pathways Leading to Roth Spots).[16]

Systemic embolic phenomena constitute another important etiologic group. In SBE, septic emboli originating from valvular vegetations occlude retinal arterioles, leading to focal infarction and hemorrhage. Noninfectious embolic states, such as marantic endocarditis, atrial myxoma, or prosthetic valve thrombosis, produce comparable retinal changes through sterile microemboli. The ensuing microinfarction promotes local necrosis and fibrin-platelet aggregation, generating the characteristic pale center. These manifestations underscore the value of Roth spots as ophthalmic indicators of systemic embolic disease.[17]

Metabolic and nutritional disorders also contribute to the development of Roth spots. Diabetes mellitus, uremia, and hyperlipidemia induce endothelial dysfunction and increase vascular permeability. Chronic kidney disease (CKD), through the accumulation of uremic toxins, impairs platelet function and weakens capillary integrity, predisposing to retinal hemorrhages with central pale foci. Similarly, deficiencies of vitamin B12 and folate produce megaloblastic changes in the bone marrow and ineffective erythropoiesis, which compromise vascular stability. Vitamin C deficiency (scurvy) results in defective collagen synthesis, diminishing vascular wall strength and rendering capillaries susceptible to rupture under minimal hemodynamic stress.[18]

Additional precipitating factors include trauma, hypoxia, and systemic stress states. Retinal venous congestion from elevated intracranial pressure or the Valsalva maneuver may cause rupture of fragile retinal vessels. In neonates, birth trauma and perinatal hypoxia have been reported as rare causes of Roth-like retinal hemorrhages. Similarly, exposure to high altitude can induce hypoxia-mediated endothelial dysfunction, leading to microvascular rupture and focal fibrin deposition.[19]

Recent histopathologic investigations have refined the understanding of Roth spot composition. The central pale region, historically attributed to leukocytic infiltration, is now identified as a platelet-fibrin thrombus encircled by extravasated erythrocytes and necrotic cellular debris. Immunohistochemical staining demonstrates the presence of fibrin and platelet markers, confirming a thrombohemorrhagic rather than purely inflammatory origin. In infective etiologies such as endocarditis, inflammatory infiltrates and bacterial antigens may also be detected, indicating overlapping mechanisms involving thrombosis, immune-mediated endothelial injury, and microbial invasion.[20]

Roth spots may also occur in iatrogenic and drug-related contexts. Chemotherapeutic agents, anticoagulants, and immunosuppressive drugs can induce hematologic suppression or coagulopathy, predisposing to retinal microhemorrhage. Methotrexate and cytarabine commonly give rise to pancytopenia, whereas warfarin and heparin therapy may accentuate bleeding risk. In bone marrow transplant recipients, graft-versus-host disease and profound thrombocytopenia further increase susceptibility to retinal vascular injury.

In contemporary clinical practice, Roth spots are recognized not as pathognomonic for a specific disease but as nonspecific retinal biomarkers of systemic microvascular injury. These microvascular markers indicate underlying systemic pathology—infectious, hematologic, embolic, or immune-mediated—that necessitates comprehensive evaluation. Detection during fundus examination should prompt systemic assessment for SBE, anemia, leukemia, vasculitis, or coagulopathies, particularly when accompanied by constitutional symptoms such as fever, pallor, or petechiae.

The etiology of Roth spots reflects the convergence of vascular injury, endothelial dysfunction, and coagulative imbalance. Each lesion represents localized capillary rupture with subsequent fibrin deposition at the site of endothelial compromise. Although historically associated with infective endocarditis, current understanding establishes Roth spots as the final common expression of diverse systemic disorders that impair microvascular integrity. Identification of these lesions serves as a critical diagnostic cue, guiding timely systemic evaluation and management of potentially life-threatening underlying disease.[21]

Epidemiology

White-centered retinal hemorrhages are nonspecific ophthalmologic findings that occur in a wide range of systemic disorders with diverse etiologies. On fundoscopic examination, Roth spots are typically located along the posterior pole or in the retinal periphery. Retinal endothelial dysfunction appears to represent the unifying mechanism among the various causes of white-centered retinal hemorrhage.

Although relatively uncommon, Roth spots are clinically significant retinal findings that function as sentinel markers of systemic disease rather than primary ocular pathology. The epidemiologic distribution of these lesions parallels that of the systemic disorders with which they are associated, including infective endocarditis, hematologic malignancies, severe anemia, and systemic vasculitides. While these retinal abnormalities may occur at any age, they are most frequently identified in adults aged 30 to 60, corresponding to the peak incidence of infective endocarditis and hematologic disease. Reports in pediatric and neonatal populations are rare but have been documented in association with birth trauma, sepsis, and congenital heart disease.

Historically, Roth spots were regarded as pathognomonic for SBE, with reported prevalence ranging from 2% to 10% in earlier clinical series. Advances in antimicrobial therapy and improvements in diagnostic accuracy have led to a marked decline in the incidence of ocular manifestations, including Roth spots, among patients with endocarditis. Despite this decline, ocular abnormalities remain a classic clinical sign that should prompt consideration of septic embolization, particularly in undiagnosed or subacute presentations. In cases caused by Staphylococcus aureus or Streptococcus viridans, the microembolic and immunologic mechanisms responsible for Roth spot formation are well established.[22]

Within the spectrum of hematologic diseases, Roth spots occur in approximately 30% to 40% of patients with acute leukemia, most frequently in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), where retinal hemorrhages result from anemia, thrombocytopenia, and leukostasis. These retinal lesions may also appear in aplastic anemia, megaloblastic anemia, or iron deficiency anemia (IDA), though with lower frequency. In such contexts, the presence of Roth spots often signifies severe systemic hypoxia or bone marrow failure, underscoring their diagnostic and prognostic significance.[23]

From an immunologic and vasculitic perspective, conditions such as SLE, APLS, PAN, and GPA contribute to the epidemiologic spectrum of Roth spots. In these disorders, immune complex deposition and complement activation lead to capillary wall necrosis and intraretinal hemorrhage. Epidemiologic studies indicate that retinal findings, including Roth spots, occur in approximately 5% to 15% of patients with SLE, particularly during active systemic disease.[24]

Roth spots have also been documented in metabolic and systemic disorders, notably diabetes mellitus, hypertensive crises, and uremia, where microangiopathic injury compromises retinal capillary integrity. In CKD, platelet dysfunction and the accumulation of uremic toxins exacerbate vascular fragility, accounting for the occasional occurrence of Roth spots in this population. Likewise, severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and thrombotic microangiopathies may give rise to Roth spot-like retinal hemorrhages.[25]

In patients with HIV/AIDS, opportunistic infections and immune thrombocytopenia increase susceptibility to retinal hemorrhage, with reported prevalence ranging from 5% to 8% in untreated or advanced cases. Recent case series in COVID-19 have described Roth spot-like lesions attributed to systemic endothelial injury, coagulopathy, and microthrombus formation, suggesting a potential role for these findings as ocular indicators of systemic hypercoagulability.[26] 

Geographically, Roth spots are observed worldwide, although their reported prevalence varies with healthcare accessibility and diagnostic vigilance. Routine fundoscopic evaluation during systemic illness facilitates early identification in high-income regions, whereas underrecognition is more common in low-resource settings. Epidemiologic discrepancies also reflect differences in diagnostic criteria. Some clinicians restrict the term “Roth spots” to retinal hemorrhages with a distinct central white core, while others include pale-centered hemorrhages of broader etiology.

No consistent sex predilection has been established. Rather, the occurrence parallels the distribution of the underlying systemic diseases. In infective endocarditis, a male predominance corresponds to the higher incidence of valvular disease and intravenous drug-associated infections, whereas autoimmune etiologies such as SLE demonstrate a clear female preponderance, particularly among women of reproductive age.

The underlying cause influences laterality and lesion distribution. Bilateral and multifocal involvement is typical of endocarditis and vasculitis, while unilateral presentation is more characteristic of traumatic or embolic events. The number of lesions may range from a few discrete foci to numerous scattered spots, particularly in leukemic or septic conditions. Lesion size and localization are variable but most often confined to the posterior pole, occasionally extending toward the midperipheral retina.[27]

Modern epidemiologic investigations employing fundus photography and OCT have enhanced the characterization and documentation of Roth spots. These imaging modalities have revealed that subtle lesions may be overlooked during routine ophthalmoscopic examination.

In the era of teleophthalmology, incidental identification of Roth spots during systemic screening programs for diabetes and hypertension has expanded understanding of their prevalence across varied populations. Such findings emphasize the importance of advanced imaging in detecting early or subclinical retinal changes.

Overall, the epidemiology of Roth spots reflects the intersection of systemic vascular, hematologic, and infectious disorders. Although relatively uncommon, the detection of these lesions carries substantial diagnostic and prognostic significance. With widespread adoption of digital fundus imaging and improved systemic monitoring, Roth spots continue to serve as a valuable indicator of systemic disease, reinforcing the importance of comprehensive ocular evaluation in patients with suspected microvascular pathology.[28] The table below outlines key epidemiologic and clinical features of Roth spots categorized by their underlying etiologies.

Table

Table. Epidemiology and Clinical Associations of Roth Spots by Etiologic Category.

Note: AML = acute myelogenous leukemia; ALL = acute lymphoblastic leukemia; SLE = systemic lupus erythematosus; APLS = antiphospholipid antibody syndrome; PAN = polyarteritis nodosa; GPA = granulomatosis with polyangiitis

Pathophysiology

Multiple theories have been proposed to explain the pathogenesis of white-centered retinal hemorrhages, but the most widely accepted mechanism involves retinal capillary rupture leading to intraretinal hemorrhage. Endothelial dysfunction weakens the capillary wall, predisposing it to rupture and subsequent extravasation of erythrocytes. Activation of the coagulation cascade follows, resulting in the formation of a platelet-fibrin plug at the site of endothelial injury. Histopathologic analyses demonstrate that the central white area primarily consists of platelet-fibrin thrombi (see Image. Pathophysiology of Roth Spots).

Roth spots represent a distinct retinal manifestation characterized by hemorrhages containing a central pale or white spot, indicative of complex microvascular injury within the retinal capillary plexus. The pathophysiology is multifactorial, involving vascular occlusion, endothelial disruption, immune-mediated inflammation, and hematologic abnormalities. Initially described in association with SBE, Roth spots are now recognized as nonspecific indicators of systemic microangiopathic or inflammatory disease. These lesions develop when fragile retinal capillaries rupture under vascular or hemodynamic stress, producing flame-shaped or round hemorrhages within the nerve fiber layer. The pale center reflects localized fibrin, platelet aggregates, or leukocytic infiltration trapped within the hemorrhage, representing a focal site of active microvascular injury.

At the microscopic level, the sequence of events begins with capillary endothelial injury. The retinal circulation, an end-arterial system devoid of collateral pathways, is particularly vulnerable to embolic, infectious, and immunologic insults.

In conditions such as SBE, circulating immune complexes composed of bacterial antigens and host antibodies deposit within the retinal vessel wall, initiating complement activation. This cascade promotes neutrophil chemotaxis and endothelial disruption, leading to breakdown of the blood-retinal barrier. Septic microemboli may lodge within terminal arterioles concurrently, producing focal ischemia and intraluminal thrombosis. Subsequent endothelial necrosis permits erythrocyte extravasation into the retinal nerve fiber layer, giving rise to intraretinal hemorrhages. Within these hemorrhages, localized activation of the coagulation cascade results in fibrin deposition, forming the pale central zone characteristic of a Roth lesion.

The underlying mechanisms differ in hematologic disorders but culminate in comparable microvascular injury. Severe anemia and thrombocytopenia, as observed in AML, ALL, and aplastic anemia, reduce oxygen delivery and impair platelet plug formation, increasing susceptibility of the retinal vasculature to rupture from minor hemodynamic stress.

Hyperviscosity and leukostasis in AML further impede retinal blood flow, promoting capillary obstruction and regional hypoxia. The ensuing ischemic insult stimulates the release of pro-inflammatory mediators such as tumor necrosis factor α and interleukin 1β, amplifying endothelial permeability and vascular leakage. In this context, the central pale focus may represent leukemic blast aggregation or fibrin-platelet complexes rather than fibrin alone. Therefore, Roth spots in hematologic malignancies reflect both mechanical obstruction and metabolic compromise of the retinal microcirculation.

Immune-mediated vasculitides, including SLE and APLS, produce Roth spots through immune complex-mediated capillaritis. Circulating antigen-antibody complexes deposit along retinal vessel walls, triggering complement activation and inflammatory cell recruitment. This cascade culminates in fibrinoid necrosis of the vessel wall, increased permeability, and intraretinal hemorrhage. In SLE, antiphospholipid antibodies further induce a prothrombotic state that promotes microvascular occlusion and focal infarction of the inner retina. The central pale spot in such lesions often represents coagulated fibrin surrounded by hemorrhagic exudate, reflecting combined vasculitic and thrombotic mechanisms. In PAN and GPA, necrotizing inflammation of arterioles similarly compromises capillary integrity, resulting in hemorrhages with pale centers.[29]

Microangiopathic disorders such as diabetes mellitus, hypertension, and uremia likewise contribute to Roth spot formation through chronic endothelial injury and basement membrane thickening. Hyperglycemia promotes the formation of advanced glycation end-products, leading to oxidative stress and pericyte apoptosis. Loss of pericyte support destabilizes the capillary wall, while persistent hypertension induces shear stress and microaneurysm formation. Rupture of these fragile vessels produces retinal hemorrhage, with the characteristic central white spot arising from fibrin accumulation or platelet aggregation. Platelet dysfunction, prolonged bleeding time, and circulating endothelial toxins generate comparable retinal findings in patients with uremia.[30]

Infectious and septic conditions, including meningococcemia, HIV, and COVID-19, produce Roth spots secondary to systemic inflammatory and thrombotic mechanisms. Disseminated intravascular coagulation (DIC) and microthrombus formation obstruct retinal capillaries during sepsis, resulting in ischemic hemorrhages. In COVID-19-associated coagulopathy, endothelial activation and a cytokine-mediated inflammatory cascade induce capillary leakage and perivascular fibrin deposition. In these settings, the central white focus may represent microinfarction with necrotic cellular debris rather than fibrin exudate alone. Such findings reinforce the concept that Roth spots reflect intravascular injury rather than a disease-specific manifestation, serving as indicators of systemic microvascular dysfunction.[31]

Traumatic and mechanical factors may also precipitate Roth spot formation. In Valsalva retinopathy, birth trauma, or sudden venous pressure surges, abrupt hemodynamic shifts cause rupture of superficial capillaries within the nerve fiber layer. The ensuing hemorrhages may entrap fibrin and cellular material centrally, producing a Roth-like appearance. Similarly, high-altitude retinopathy results from hypobaric hypoxia-induced endothelial stress, leading to increased vascular permeability, intraretinal bleeding, and pale-centered hemorrhages caused by ischemic coagulation necrosis.[32]

At the molecular level, hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) play central roles in the development of Roth spots. Hypoxic injury stimulates the upregulation of hypoxia-inducible factor 1α (HIF-1α), which, in turn, induces the release of VEGF. This cascade enhances vascular permeability and fragility within the retinal capillary network. Concurrently, oxidative stress and dysregulation of nitric oxide signaling disrupt endothelial tight junctions, compromising vascular integrity. The combined effect of these mechanisms culminates in hemorrhagic exudation and intraretinal clot formation. The central pale area represents a localized focus of coagulative necrosis, fibrin deposition, or immune cell aggregation within a hemorrhagic background.[33]

Resolution of Roth spots typically occurs spontaneously as the intraretinal hemorrhage resorbs, and the fibrin core undergoes enzymatic degradation. However, persistent or recurrent lesions indicate continuing systemic pathology. Therefore, the identification of Roth spots should prompt a comprehensive evaluation for underlying etiologies, including infective endocarditis, leukemia, vasculitis, or severe anemia, as ocular findings may precede systemic diagnosis.

Overall, the pathophysiologic framework of Roth spots integrates infectious, immunologic, hematologic, and vascular mechanisms into a unified endpoint characterized by capillary rupture, hemorrhage, and focal coagulative reaction. The retinal microvasculature, by virtue of its transparency and accessibility, provides direct visualization of systemic microvascular injury. Thus, Roth spots exemplify the concept of the eye as a reflection of systemic health, translating invisible vascular pathology into observable clinical evidence.[34]

Histopathology

Microscopically, Roth spots are characterized by retinal hemorrhages with a pale or whitish center, typically observed during fundus examination. Histopathologically, these lesions are intraretinal hemorrhages containing a central area of fibrin-platelet aggregation, surrounded by extravasated erythrocytes. The pale center was initially thought to represent septic emboli, but later studies confirmed that it primarily consists of fibrin, leukocytes, and focal ischemic necrosis of the retinal nerve fiber layer (see Image. Microscopic Components of a Roth Spot).

The lesion originates within the superficial retinal capillary plexus, where endothelial damage leads to capillary rupture and localized hemorrhage. The central pale region reflects fibrinoid necrosis, leukocyte infiltration, and, occasionally, microbial or immune complex deposition in infectious or immune-mediated causes. In infective endocarditis, histology may show microabscesses or bacterial colonies embedded within the fibrin core, confirming septic embolization as an underlying mechanism. In such cases, neutrophilic infiltration and localized necrosis are prominent features, indicating intense inflammatory activity. In septicemic conditions, bacteremia-related embolization produces comparable lesions characterized by inflammatory debris, vascular thrombosis, and necrosis.

In systemic conditions such as leukemia, anemia, or diabetes, the Roth spot center may contain aggregates of degenerated leukocytes and fibrin plugs, indicating vascular occlusion secondary to endothelial injury or hyperviscosity. In hypertensive or diabetic retinopathy, perivascular leakage and localized ischemia contribute to the formation of a pale ischemic focus. In cases related to diabetes, microaneurysm formation and pericyte loss further weaken the capillary wall, predisposing to focal hemorrhage.

The surrounding hemorrhage demonstrates intact and lysed erythrocytes, macrophages containing hemosiderin, and varying degrees of retinal edema. Under light microscopy, the pale area appears as a sharply demarcated acellular eosinophilic focus within the hemorrhage. Electron microscopy may reveal disrupted capillary basement membranes, platelet clumps, and fibrillar fibrin networks. Immunohistochemical staining for fibrinogen and von Willebrand factor confirms endothelial disruption, whereas CD68+ macrophages indicate active phagocytosis at the lesion periphery.

In immune-complex-mediated diseases such as SLE, deposition of immunoglobulins (IgG, IgM) and complement components (C3, C4) occurs around damaged capillaries, consistent with vasculitic pathology. Perivascular lymphocytic infiltration may also be observed, reflecting ongoing immune-mediated inflammation. In hematologic malignancies, infiltration of blast cells or atypical leukocytes may accompany hemorrhage, further compromising retinal microvascular integrity.[35][36]

Toxicokinetics

Although Roth spots are not inherently toxic lesions, their occurrence is closely associated with systemic toxic or metabolic disturbances that disrupt vascular homeostasis, compromise endothelial integrity, and alter coagulability. Toxicokinetics in this context describes the absorption, distribution, metabolism, and elimination of circulating toxins, metabolites, or immune complexes, and how these processes contribute to retinal microvascular injury, culminating in the formation of hemorrhagic lesions with pale central foci.[37]

Systemic Toxin Exposure and Retinal Microangiopathy

Circulating toxins, including bacterial endotoxins, immune complexes, and uremic metabolites, preferentially affect small-caliber vessels, such as retinal capillaries. The retina’s high metabolic demand and dense capillary network increase susceptibility to hypoxic and toxic insults. In SBE, sepsis, and severe viremia, elevated systemic levels of immune complexes and endotoxins bind endothelial receptors, triggering oxidative stress, cytokine release, and complement activation. Progressive endothelial injury results in capillary rupture, microaneurysm formation, and extravasation of erythrocytes, producing the pale-centered hemorrhagic lesions characteristic of Roth spots.[38]

Pharmacologic and Metabolic Toxins

In iatrogenic or metabolic states, accumulation of uremic metabolites, hyperglycemia-induced glycation end-products, and oxidative stress mediators alters the toxicokinetic environment of the retinal circulation. In uremia, impaired renal clearance prolongs systemic exposure to guanidines, indoxyl sulfate, and p-cresol, increasing vascular permeability and inducing endothelial apoptosis. Diabetic ketoacidosis produces glucose-mediated nonenzymatic protein glycation and basement membrane cross-linking, enhancing retinal vascular fragility. In toxin-mediated infections such as SBE, streptococcal exotoxins and superantigens activate macrophages and T cells, amplifying local inflammation and microvascular injury.[39]

Immune Complex Deposition and Complement Activation

Immune-mediated mechanisms involve circulating antigen-antibody complexes that deposit within the retinal microvasculature. Complement activation releases C3a and C5a, recruiting neutrophils that secrete proteases and reactive oxygen species, causing endothelial lysis. Focal hemorrhages encapsulate fibrin and necrotic leukocytes centrally, producing the white foci histologically characteristic of Roth spots.[40]

Drug-Induced Retinopathy and Oxidative Stress

Prolonged exposure to systemic drugs, such as chemotherapeutic agents (cyclophosphamide, methotrexate), interferon, and anticoagulants, alters retinal perfusion and induces microhemorrhages resembling Roth spots. Toxicokinetic processes involve drug accumulation in retinal tissue, mitochondrial dysfunction, and induction of endothelial apoptosis. Agents affecting platelet aggregation or coagulation pathways (warfarin, heparin, antiplatelets) exacerbate bleeding tendencies, predisposing to microvascular hemorrhages under mild stress conditions.[41]

Hypoxia and Ischemia-Related Toxin Dynamics

Systemic hypoxia in severe anemia, leukemia, or hypoxic encephalopathy triggers anaerobic metabolism and lactate accumulation, shifting the acid-base balance and impairing detoxification pathways. Accumulated metabolic intermediates injure the endothelium. HIFs, particularly HIF-1α, upregulate VEGF, increasing permeability and fragility of retinal vessels, thereby potentiating Roth spot formation.

Toxicokinetic Phases of Retinal Injury

Toxic-induced retinal injury occurs through interrelated kinetic phases. Absorption involves the entry of circulating toxins or immune complexes into the retinal vasculature. Distribution reflects preferential localization within capillary-rich retinal layers, particularly around the macula and posterior pole. Metabolism encompasses local enzymatic or oxidative processing within endothelial cells, generating reactive species. Elimination failure occurs when systemic dysfunction—renal, hepatic, or hematologic—impairs clearance, resulting in cumulative endothelial injury. These processes disrupt the blood-retinal barrier, precipitate microvascular rupture, and promote intraluminal thrombus formation, culminating in the characteristic white-centered hemorrhages.[42]

History and Physical

Clinical Presentation

Retinal hemorrhage is frequently observed in patients with underlying conditions that predispose to endothelial dysfunction and capillary rupture. Roth spots may be detected during routine ophthalmologic examination in asymptomatic individuals, prompting further systemic evaluation. In other cases, patients present with clinical manifestations of systemic illness, with retinal hemorrhages identified during acute assessment. The presence of Roth spots on examination should trigger evaluation for underlying systemic disease, including a thorough history and meticulous physical examination.[43][44]

A detailed history, combined with a comprehensive review of systems, can help narrow the differential diagnosis and identify the causative pathology. Symptoms associated with common etiologies of Roth spots must be assessed. For suspected SBE or infectious processes, the review should include fever, chills, and night sweats. Hematologic disorders warrant evaluation for unexplained weight loss, fatigue, abnormal bleeding or bruising, and dyspnea. Past medical history and family history may provide additional insight into the underlying etiology.

Roth spots are visualized on fundoscopic examination. A complete ophthalmologic assessment should be performed, as additional retinal abnormalities may coexist. Systemic evaluation is essential following identification of Roth spots, including assessment of vital signs such as blood pressure, temperature, and pulse. Multiple etiologies of white-centered retinal hemorrhages exhibit characteristic physical findings, necessitating a high index of suspicion. In cases concerning endocarditis, careful examination for additional stigmata, such as Janeway lesions, Osler nodes, splinter hemorrhages, petechiae, and cardiac murmurs, is warranted. Evaluation of digital clubbing, splenomegaly, and respiratory abnormalities may provide further diagnostic insight.[45]

Roth spots are often discovered incidentally during fundus examination or the investigation of visual complaints. The presence of these ocular abnormalities indicates microvascular injury and capillary rupture, frequently secondary to infectious, hematologic, cardiovascular, or metabolic disorders.

The ophthalmologic history should emphasize the onset and duration of visual disturbances, including blurring, scotomas, or transient visual loss. Roth spots often present asymptomatically, usually detected incidentally during routine ophthalmic evaluation, prompting a systemic workup. The lesions may also produce symptoms in the context of acute illness, such as infective endocarditis, leukemia, hypertensive crisis, or severe anemia, where retinal findings coexist with systemic manifestations.

Attention should focus on constitutional symptoms, such as fever, chills, malaise, or night sweats, and on any history of dental procedures, intravenous drug use, or valvular heart disease, which may indicate endocarditis. Signs of hematologic disorders include fatigue, pallor, easy bruising, bleeding gums, petechiae, or recurrent infections, suggesting leukemia, anemia, or thrombocytopenia.

Vascular stress or poor glycemic control may be inferred from headaches, dizziness, vision changes, polyuria, or polydipsia, indicative of hypertensive or diabetic retinopathy. Autoimmune or vasculitic conditions, including SLE, may manifest with arthralgia, rashes, Raynaud phenomenon, or hematuria. Systemic inflammatory symptoms, rigors, or features of toxic shock raise suspicion for septicemia or disseminated infections, while dietary insufficiencies, alcohol use, or chronic renal or hepatic disease may compromise coagulation and retinal vessel integrity.[46]

Physical Examination

A comprehensive physical examination is essential when Roth spots are identified, with careful attention to both vital signs and stigmata of systemic disease. Temperature, heart rate, and blood pressure should be recorded, as fever may indicate infection or endocarditis, while hypertension may predispose to vascular rupture. Cardiac auscultation should assess for new murmurs, particularly aortic or mitral regurgitation, which are suggestive of infective endocarditis. Peripheral signs of endocarditis, including Janeway lesions, Osler nodes, splinter hemorrhages, and mucosal petechiae, should be sought.

Respiratory and abdominal evaluation may reveal crackles, hepatosplenomegaly, or tenderness, reflecting embolic phenomena or systemic involvement. Hematologic abnormalities, such as pallor, ecchymosis, bruising, or gum hypertrophy, may indicate leukemia or other marrow disorders. Neurologic assessment is warranted for altered mental status, focal deficits, or seizures, raising concern for cerebral emboli or hemorrhagic stroke. Dermatologic and rheumatologic signs, including rash, purpura, or livedo reticularis, can suggest vasculitis or connective tissue disease. Examination of the extremities should note digital clubbing, cyanosis, or peripheral embolic changes. A dilated fundus examination using slit-lamp biomicroscopy or indirect ophthalmoscopy is required to evaluate retinal findings, including Roth spots.[47]

Fundoscopic findings

On fundoscopy, Roth spots appear as round or oval retinal hemorrhages with a central white core composed of fibrin, platelets, or leukocytes, surrounded by extravasated erythrocytes. Lesions are most commonly located at the posterior pole or along the vascular arcades but may appear throughout the retina. Additional ocular findings may include flame-shaped or dot-blot hemorrhages, cotton wool spots reflecting localized ischemia, vascular sheathing or venous tortuosity, exudates, and, in severe cases, papilledema or retinal edema. In infective endocarditis, Roth spots may coexist with embolic phenomena or retinal artery occlusion. In leukemia, these lesions may be accompanied by retinal infiltrates, venous dilation, or perivascular sheathing.[48]

Evaluation

Roth spots suggest systemic pathology. Therefore, every patient should undergo detailed clinical, laboratory, and imaging investigations to determine the root cause.

Initial evaluation begins with a thorough history and physical examination, guiding targeted laboratory and imaging studies. A CBC with differential count is essential to detect anemia, leukocytosis, thrombocytopenia, or blast cells suggestive of leukemia. If leukemia or aplastic anemia is suspected, further evaluation should include a peripheral smear, bone marrow aspiration or biopsy, flow cytometry for immunophenotyping of malignant cells, and cytogenetic analysis to detect chromosomal abnormalities. These investigations help confirm the diagnosis and guide subsequent management.

Inflammatory and infectious processes may be assessed with erythrocyte sedimentation rate, C-reactive protein, and blood cultures, particularly in febrile patients or suspected bacterial endocarditis cases. An autoimmune panel, including antinuclear antibody, rheumatoid factor, and ANCA, may be performed to evaluate for underlying vasculitides. Coagulation studies (prothrombin time, activated partial thromboplastin time, D-dimer, and international normalized ratio) evaluate for coagulopathy or DIC. Viral serology, including HIV and hepatitis B and C testing, may be indicated in immunocompromised individuals.[49] 

Screening for diabetes mellitus should include fasting plasma glucose or hemoglobin A1c, while renal and liver function tests provide insight into systemic metabolic status.[50] A lipid profile may be indicated to identify dyslipidemic conditions that contribute to retinal microvascular compromise.

OCT can delineate the retinal hemorrhage layers, revealing hyperreflective intraretinal deposits surrounded by hyporeflective hemorrhagic zones. FFA may show blocked fluorescence corresponding to the hemorrhage, while OCTA allows assessment of microvascular ischemia. Incidentally discovered Roth spots should prompt referral to internal medicine or hematology for systemic evaluation.[51]

Magnetic resonance imaging or computed tomography may be indicated if neurologic symptoms such as headache, confusion, or seizures suggest central nervous system vasculitis or microembolic phenomena. Carotid Doppler ultrasonography may be performed when embolic disease is suspected. Echocardiography, either transthoracic or transesophageal, remains essential for detecting vegetations or valvular abnormalities in cases of infective endocarditis.

An electrocardiogram should be performed to detect cardiac rhythm abnormalities resulting from endocardial involvement. Roth spots may also be observed in conditions such as preeclampsia, high-altitude retinopathy, or shock, underscoring the importance of clinical correlation.[52]

Treatment / Management

Most white-centered retinal hemorrhages resolve spontaneously without direct intervention. Management focuses on identifying and treating the underlying systemic disorder, as addressing the primary etiology prevents potential ocular and systemic complications. Follow-up with an ophthalmologist is recommended, particularly in patients in whom Roth spots are identified during acute illness.[53]

Roth spots represent nonspecific retinal findings arising from capillary rupture and intraretinal hemorrhage with fibrin-platelet deposition. These lesions generally resolve once the primary disease is controlled. Therefore, the ophthalmologist’s role is crucial in recognizing these lesions as indicators of systemic pathology and facilitating appropriate interprofessional evaluation and management.

Etiology-Based Management

Roth spots do not comprise a primary disease but rather a manifestation of microvascular injury secondary to systemic pathology. These lesions typically regress within weeks with appropriate therapy, leaving no permanent retinal damage.

In patients with infective endocarditis, management involves prolonged intravenous antibiotic therapy tailored to blood culture sensitivities. Surgical intervention, including valve repair or replacement, may be required in cases of valvular destruction, abscess formation, or refractory infection. Retinal lesions usually resolve following control of the systemic infection.[54] For hematologic malignancies such as leukemia, treatment targets the primary disorder through chemotherapy, bone marrow transplantation, or targeted agents. Supportive transfusions may be necessary for anemia or thrombocytopenia, and corticosteroids or immunomodulators may be employed when vascular fragility contributes to hemorrhage.[55]

In nutritional anemias, particularly those due to vitamin B12 or folate deficiency, supplementation restores vascular integrity and promotes resolution of Roth spots. In cases of aplastic anemia or bone marrow failure, supportive interventions, including erythropoietin, transfusion, or immunosuppressive therapy, are indicated to address the underlying hematologic compromise.[56] In patients with diabetes mellitus, strict glycemic control is essential to prevent recurrence or progression of microvascular retinal changes, with optimization of insulin or oral hypoglycemic therapy and concomitant management of blood pressure and lipids.[57]

Roth spots arising from hypertensive emergencies require urgent blood pressure reduction using agents such as labetalol or nicardipine, with careful monitoring to avoid optic nerve ischemia.[58] In cases related to trauma or Valsalva retinopathy, conservative management is preferred, as vision generally recovers spontaneously with hemorrhage resolution. For septicemia or sepsis-related microangiopathy, aggressive treatment with broad-spectrum antibiotics, fluid resuscitation, and source control is essential, with Roth spots improving gradually as systemic inflammation resolves.[59]

Emerging Therapeutic Perspectives

Novel strategies aimed at vascular stabilization are under investigation. Angiogenesis inhibitors and anti-inflammatory agents targeting microvascular permeability may provide adjunctive benefit in selected conditions, including diabetic and septic retinopathy. Additionally, machine learning-assisted analysis of fundus images has the potential to improve early detection of microvascular alterations, facilitating prompt systemic evaluation.[60]

Ophthalmic Follow-Up and Monitoring

Baseline fundus photography should be performed to document the presence and distribution of Roth spots. Follow-up imaging at intervals of 2 to 4 weeks is recommended to assess lesion resolution. No local ocular therapy is indicated in the absence of progression. Intravitreal anti-VEGF therapy or focal laser treatment may be considered in rare cases of vision-threatening hemorrhage or macular involvement, although supporting evidence remains limited.[61]

Differential Diagnosis

Roth spots should not be considered isolated ocular findings. Rather, these microvascular anomalies are important diagnostic indicators of underlying systemic disease. Accurate differentiation among potential etiologies necessitates careful correlation of fundoscopic features with systemic history and targeted diagnostic investigations. Early recognition of conditions that mimic Roth spots facilitates timely intervention, thereby reducing the risk of systemic complications and vision loss.

Roth spots were originally described in association with SBE. In this condition, circulating immune complexes and microemboli lodge in retinal capillaries, producing localized ischemia and hemorrhages with central fibrin deposition. Systemic signs such as fever, heart murmurs, Osler nodes, and Janeway lesions support the diagnosis.

Severe anemia predisposes to retinal hypoxia and capillary fragility, resulting in hemorrhages resembling Roth spots. In IDA or megaloblastic anemia, microvascular ischemia and altered blood viscosity contribute to vascular rupture, with fundoscopic examination often revealing flame-shaped hemorrhages with pale centers in the posterior pole.[62]

Systemic anoxia or hypoxia, as seen in cardiopulmonary failure, chronic obstructive pulmonary disease, and high-altitude exposure, similarly induces endothelial dysfunction, increasing vascular permeability and promoting fibrin and leukocyte exudation within intraretinal hemorrhages.[63] Carbon monoxide poisoning reduces hemoglobin’s oxygen-binding capacity, causing retinal ischemia and capillary fragility. White-centered hemorrhages may arise secondary to vascular occlusion and tissue hypoxia, serving as an early diagnostic clue in undetected toxic exposure.[64]

Retinal hemorrhages resembling Roth spots have been reported following complicated labor, particularly in cases of Valsalva retinopathy. Sudden increases in venous pressure during delivery can cause capillary rupture and focal ischemia, producing pale-centered hemorrhages that are typically self-limiting and resolve postpartum.[65] In preeclampsia and eclampsia, retinal hemorrhages with white centers may arise from microvascular ischemia, DIC, or fibrinoid necrosis. Visual symptoms, hypertension, and proteinuria help distinguish these conditions from other etiologies.[66]

In diabetes, chronic hyperglycemia induces microangiopathy, pericyte loss, and vascular leakage, leading to intraretinal hemorrhages that may mimic Roth spots. Differentiation relies on identifying microaneurysms, hard exudates, and neovascularization, which are characteristic of diabetic retinopathy.[67] Chronic hypertension induces arteriosclerotic changes, endothelial damage, and vascular leakage, producing flame-shaped hemorrhages with central pallor that can mimic Roth spots. Associated findings such as arteriovenous nicking, cotton-wool spots, and optic disc edema aid in differentiating hypertensive retinopathy.[68]

HIV infection can produce white-centered hemorrhages through immune-mediated vasculitis or opportunistic infections, often accompanied by cotton-wool spots and microvascular occlusions. Coexisting cytomegalovirus retinitis should be considered, as it presents with hemorrhagic necrotizing lesions at the posterior pole.[69]

Raised intracranial pressure or subarachnoid hemorrhage can cause retinal venous congestion and secondary hemorrhages. In Terson syndrome, subarachnoid blood extends into the vitreous and retina, producing lesions resembling Roth spots and warranting neuroimaging to exclude intracranial pathology.[70] In infants, multiple retinal hemorrhages with pale centers are hallmark findings of shaken baby syndrome (SBS), resulting from shearing forces that rupture retinal vessels. Subdural hematomas often accompany these lesions and necessitate urgent interprofessional evaluation.[71]

Pertinent Studies and Ongoing Trials

Etiology-Based Approach to Roth Spots: Evidence and Recommendations

The literature consistently demonstrates that identification and treatment of the underlying cause leads to resolution of Roth spots and improved outcomes. This finding emphasizes the need for systemic evaluation and etiology-directed therapy rather than ocular intervention.

In infective endocarditis, ocular signs, including Roth spots, are observed in a minority of patients but correlate with embolization and increased inflammatory burden. Early blood-culture-guided intravenous antibiotics, with or without valve surgery, reduce embolic complications, and Roth spots typically resolve in parallel. Echocardiography, particularly early transesophageal imaging, facilitates rapid source control and improved outcomes, supporting prompt systemic evaluation in patients presenting with Roth spots alongside fever or cardiac murmurs. No ocular intervention is required beyond documentation and follow-up photography.[72]

In hematologic disorders such as leukemia, severe anemia, and thrombocytopenia, Roth spots occur in up to 1/3 of patients at diagnosis, correlating with anemia, thrombocytopenia, and leukostasis. Retinal hemorrhages regress and vision improves following induction chemotherapy and hematologic remission. Similarly, in IDA or megaloblastic anemia, transfusion or hematinic therapy normalizes hemoglobin and platelet counts, leading to resolution of Roth spots.[73] A CBC-first approach and referral to hematology are recommended to address the underlying disorder promptly.

In microangiopathic diseases such as diabetes, hypertension, and uremia, white-centered retinal hemorrhages may occur alongside cotton-wool spots and microaneurysms. Strict glycemic and blood pressure control reduces the risk of new hemorrhages, while dialysis or kidney transplantation in CKD or uremia improves platelet dysfunction-related retinal bleeding. Ophthalmic intervention is generally observational unless macula-threatening edema is present, emphasizing the need to optimize systemic risk factors.

In autoimmune and vasculitic disorders, including SLE, APLS, and ANCA-associated vasculitis, white-centered hemorrhages reflect immune-complex-mediated vasculopathy. Disease-specific immunosuppression and antithrombotic therapy improve both ocular and systemic outcomes, and an autoimmune panel should be pursued when clinical history suggests systemic involvement.[74]

Retinal hemorrhages resembling Roth spots are also reported in sepsis, HIV, and COVID-19, often reflecting microthrombi or endothelial injury. Outcomes improve with source control, hemodynamic stabilization, antiretroviral therapy, or anticoagulation as appropriate, and retinal monitoring with photography is recommended to document resolution.[75]

In pediatric and neurotrauma contexts, including SBS and intracranial hemorrhage (Terson syndrome), multilayer retinal hemorrhages with white centers frequently accompany subdural bleeds. Management focuses on urgent systemic and neurocritical care, with delayed vitrectomy considered only if a nonclearing vitreous hemorrhage threatens vision. Retinal lesions are secondary indicators of systemic or neurological injury.

Evidence From Ocular Imaging

OCT and OCTA characterize Roth spots as hyperreflective inner retinal cores surrounded by hemorrhage, occasionally with focal capillary nonperfusion. These imaging modalities are valuable for baseline assessment and follow-up but do not alter acute management. Teleophthalmology fundus photography programs enhance detection and facilitate timely systemic referrals.[76]

Although no randomized trials specifically target Roth spots, several active or recent trials inform systemic management. Endocarditis care pathways, including early transesophageal echocardiography, rapid diagnostics (polymerase chain reaction and next-generation sequencing on blood cultures), and optimized antibiotic timing, reduce embolic complications, with retinal signs serving as secondary outcomes. Hematology trials in AML and ALL incorporating induction therapy and supportive care track ocular hemorrhages as safety and efficacy markers.

Biologic and steroid-sparing studies in vasculitides and SLE, including complement inhibitors and rituximab or cyclophosphamide, consider retinal ischemic lesions as exploratory endpoints. Trials on systemic risk factor control demonstrate that intensive blood pressure and glycemic management reduce microvascular injury, decreasing retinal hemorrhage burden. Imaging and AI registries using OCT or OCTA automate the detection of hemorrhagic lesions, triggering systemic evaluation.

Treatment Planning

As mentioned, the management of Roth spots focuses on identifying and treating the underlying systemic cause rather than the retinal lesion itself (see Image. Treatment Planning for Roth Spots). A thorough history and comprehensive ophthalmologic examination, supplemented by diagnostic tools such as fundus photography or OCT, are conducted to correlate retinal findings with underlying systemic conditions. Systemic evaluation, including vital signs and cardiovascular risk assessment, guides early interprofessional consultation.

Management includes antibiotics for infective endocarditis, chemotherapy or hematologic-directed therapy for leukemia, glycemic and blood pressure control for diabetes and hypertension, antiretroviral therapy for HIV with management of opportunistic infections, and nutritional supplementation for anemia. Preeclampsia requires blood pressure control and postpartum reassessment, while SBS mandates child protection and neurologic evaluation, with documentation for medicolegal purposes. Ophthalmic intervention is generally observational unless vision-threatening complications arise.[77]

Radiation therapy has no role in the management of Roth spots. However, toxicity surveillance parallels systemic adverse effect monitoring. Hematologic toxicity should be assessed via CBCs in patients with leukemia or sepsis, while renal and hepatic function must be monitored during antibiotic or chemotherapeutic therapy. Ophthalmic evaluation is important to detect secondary complications such as macular edema or neovascularization. Long-term follow-up serves as a posttreatment assessment, confirming both systemic resolution and retinal recovery.[78]

Prognosis

The visual prognosis for isolated Roth spots is generally favorable, as lesions typically resolve following treatment of the underlying systemic condition. However, failure to identify and manage the causative disease can result in significant morbidity or mortality. For instance, untreated endocarditis may lead to embolic stroke, heart failure, or death. Consequently, the overall prognosis is primarily determined by the effective control of systemic pathology rather than the retinal findings themselves.[79]

Complications

Roth spots rarely produce direct ocular complications and generally resolve without permanent retinal damage. Visual impairment is uncommon and typically transient, except in cases with macular involvement or extensive hemorrhage. Clinically significant complications are primarily related to the underlying systemic condition, such as embolic events in endocarditis, bleeding in cytopenic states, or vascular compromise in severe hypertension, rather than the retinal lesion itself.

Deterrence and Patient Education

Patients should be counseled that Roth spots represent manifestations of underlying systemic pathology rather than a primary ocular disease, and adherence to systemic therapy is essential for optimal outcomes. Preventive strategies include lifestyle modifications such as dietary optimization for anemia, glycemic control in diabetes, and regular cardiovascular monitoring. Coordinated interprofessional care among ophthalmologists, internists, and other specialists facilitates timely diagnosis and integrated management, particularly in life-threatening conditions such as endocarditis or hematologic malignancies.

Pearls and Other Issues

Roth spots are primarily markers of systemic disease, and management should focus on addressing the underlying etiology rather than the retinal lesion itself. Across conditions, these lesions resolve with etiology-directed systemic therapy, such as antibiotics for infective endocarditis, chemotherapy or transfusion for hematologic disorders, blood pressure and glycemic control for microangiopathy, and immunosuppression or anticoagulation for autoimmune or vasculitic conditions. Prompt systemic evaluation is critical, as delays in diagnosing conditions like infective endocarditis or leukemia significantly increase morbidity. The detection of Roth spots should expedite cultures, echocardiography, CBC, and targeted laboratory panels.

Direct ocular intervention is rarely necessary, with high-quality imaging primarily used for documentation and follow-up. Invasive ocular procedures are reserved for uncommon cases of vision-threatening, unresolved hemorrhages. Interprofessional care consistently improves outcomes, with coordinated management involving ophthalmology, cardiology, hematology, infectious disease, and rheumatology recommended.

Emerging data aim to clarify the true prevalence of Roth spots in modern infective endocarditis and leukemia cohorts using standardized imaging. These studies also assess their potential prognostic value as independent markers after adjustment for systemic disease severity.

Enhancing Healthcare Team Outcomes

Management of Roth spots requires a staged, coordinated approach across specialties, analogous to fractionated therapy. Initial evaluation focuses on identifying the underlying systemic pathology, including cardiac, hematologic, or metabolic disorders. Definitive therapy is then initiated under specialist supervision, followed by ocular monitoring every 4 to 6 weeks until lesions resolve. Long-term prevention relies on controlling the systemic disease to minimize recurrence. Collaboration among ophthalmologists, cardiologists, hematologists, infectious disease specialists, and internists ensures comprehensive care, with treatment directed at the primary etiology, including antibiotics for infective endocarditis, chemotherapy for leukemia, or optimization of glycemic and blood pressure control.[80]

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References

1.

Wang L, Petrak M, Holz FG, Müller A, Krohne TU. Retinal Hemorrhages in Shaken Baby Syndrome. J Pediatr. 2019 Apr;207:256. [PubMed: 30922497]

2.

Ścisłowicz A, Piejko P, Nowak M, Renke P, Chaniecki P, Rucka A. [Infective endocarditis in a patient with vision disorders]. Pol Merkur Lekarski. 2018 Nov 28;45(269):198-200. [PubMed: 30531670]

3.

Sabrane I, Belkhadir K, Saoudi S, Benchekroun S, El Ikhloufi M, Cherkaoui O. [Roth spots suggestive of myeloid leukemia: Case report]. J Fr Ophtalmol. 2018 Nov;41(9):e423-e424. [PubMed: 30458927]

4.

Ling R, James B. White-centred retinal haemorrhages (Roth spots). Postgrad Med J. 1998 Oct;74(876):581-2. [PMC free article: PMC2361020] [PubMed: 10211348]

5.

Fred HL. Little black bags, ophthalmoscopy, and the Roth spot. Tex Heart Inst J. 2013;40(2):115-6. [PMC free article: PMC3649782] [PubMed: 23678206]

6.

Kothari M, Chiwhane A, Kumar S, Wanjari A, Reddy H. Roth Spots: A Rare Finding in Sickle Cell Anemia. Cureus. 2024 Apr;16(4):e59047. [PMC free article: PMC11128069] [PubMed: 38800292]

7.

Benazzi F, Mazzoli M. Psychotic affective disorder after nicotine withdrawal. Am J Psychiatry. 1994 Mar;151(3):452. [PubMed: 8109663]

8.

Arora N, Dhibar DP, Bashyal B, Agarwal A. Roth's Spots, a clinical diagnostic clue for Infective Endocarditis. Perm J. 2020;24 [PMC free article: PMC7417078] [PubMed: 33183500]

9.

Ceglowska K, Nowomiejska K, Kiszka A, Koss MJ, Maciejewski R, Rejdak R. Bilateral Macular Roth Spots as a Manifestation of Subacute Endocarditis. Case Rep Ophthalmol Med. 2015;2015:493947. [PMC free article: PMC4709653] [PubMed: 26839725]

10.

Macauley M, Nag S. Roth spots in pernicious anaemia. BMJ Case Rep. 2011 Apr 19;2011 [PMC free article: PMC3082065] [PubMed: 22696623]

11.

Alsalem N, Al-Ali A. Unilateral Roth spots secondary to uterine leiomyoma. BMJ Case Rep. 2025 Jul 18;18(7) [PMC free article: PMC12272332] [PubMed: 40681178]

12.

Zhang J, Chen Y, Yu Z, Liu L. Bilateral Hemorrhagic Retinopathy with Roth Spots in Pediatric-Onset Systemic Lupus Erythematosus and Associated Thrombocytopenia: A Case Report and Review of Literature. Ocul Immunol Inflamm. 2018;26(8):1150-1153. [PubMed: 29020480]

13.

Lee S, Kim J. Floaters as the First Manifestation of Chronic Myeloid Leukemia: A Case Report. Int J Mol Sci. 2025 Sep 11;26(18) [PMC free article: PMC12469411] [PubMed: 41009410]

14.

Gan EJY, Yap JF, Patrick S, Binson C, Mary Alexander S. A Rare Case of Subretinal Abscess Secondary to Methicillin-Sensitive Staphylococcus aureus Bacteremia. Ocul Immunol Inflamm. 2025 Oct;33(8):1865-1868. [PubMed: 40550014]

15.

Kabataş EU, Aydoğan S, Bilgiç AA, Dinlen Fettah N, Kabataş N, Dilli D, Zenciroğlu A. Retinal Hemorrhages and Long-Term Ocular Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy. Medicina (Kaunas). 2025 May 16;61(5) [PMC free article: PMC12113395] [PubMed: 40428864]

16.

Ponce-de-León Á, Miranda-Sánchez A, Valverde-Megias A. Early Recognition of Retinal Signs in Waldenström's Macroglobulinemia: Implications for Therapeutic Plasma Exchange. J Clin Apher. 2025 Jun;40(3):e70031. [PubMed: 40329702]

17.

Kildahl HA, Brenne EL, Dalen H, Wahba A. Systemic embolization in infective endocarditis. Indian J Thorac Cardiovasc Surg. 2024 May;40(Suppl 1):40-46. [PMC free article: PMC11139814] [PubMed: 38827555]

18.

Cunha RSD, Santos AF, Barreto FC, Stinghen AEM. How do Uremic Toxins Affect the Endothelium? Toxins (Basel). 2020 Jun 20;12(6) [PMC free article: PMC7354502] [PubMed: 32575762]

19.

Di Fazio N, Delogu G, Morena D, Cipolloni L, Scopetti M, Mazzilli S, Frati P, Fineschi V. New Insights into the Diagnosis and Age Determination of Retinal Hemorrhages from Abusive Head Trauma: A Systematic Review. Diagnostics (Basel). 2023 May 12;13(10) [PMC free article: PMC10217069] [PubMed: 37238204]

20.

Katz FN, Rothman JE, Knipe DM, Lodish HF. Membrane assembly: synthesis and intracellular processing of the vesicular stomatitis viral glycoprotein. J Supramol Struct. 1977;7(3-4):353-70. [PubMed: 211348]

21.

Wang X, He B. Endothelial dysfunction: molecular mechanisms and clinical implications. MedComm (2020). 2024 Aug;5(8):e651. [PMC free article: PMC11261813] [PubMed: 39040847]

22.

Rana V, Singh K, Tripathi AN, Goenka R, Markan A, Mondal R. Roth spots in acute myeloid leukemia: unveiling the ocular window to systemic disease. QJM. 2025 Oct 01;118(10):770-771. [PubMed: 40244818]

23.

Mulcahy LT, Choudhry A, O'Leary F, Crockett MT, McAnena L. Spot the Connection: A Case of Unilateral Roth Spots and Postflow Diversion Microhemorrhage. J Neuroophthalmol. 2026 Mar 01;46(1):e4-e6. [PubMed: 39690459]

24.

Hinge S, Tagare S, Sindal MD. Unrecognized chronic myeloid leukemia manifesting as hemorrhagic complications in proliferative diabetic retinopathy: A case report. Eur J Ophthalmol. 2025 Jul;35(4):NP68-NP72. [PubMed: 40232275]

25.

Kasumovic A, Matoc I, Rebic D, Avdagic N, Halimic T. Assessment of Retinal Microangiopathy in Chronic Kidney Disease Patients. Med Arch. 2020 Jun;74(3):191-194. [PMC free article: PMC7406003] [PubMed: 32801434]

26.

Bomhof G, Mutsaers PGNJ, Leebeek FWG, Te Boekhorst PAW, Hofland J, Croles FN, Jansen AJG. COVID-19-associated immune thrombocytopenia. Br J Haematol. 2020 Jul;190(2):e61-e64. [PMC free article: PMC7276755] [PubMed: 32420612]

27.

Slouha E, Al-Geizi H, Albalat BR, Burle VS, Clunes LA, Kollias TF. Sex Differences in Infective Endocarditis: A Systematic Review. Cureus. 2023 Dec;15(12):e49815. [PMC free article: PMC10758535] [PubMed: 38169615]

28.

Nanegrungsunk O, Patikulsila D, Sadda SR. Ophthalmic imaging in diabetic retinopathy: A review. Clin Exp Ophthalmol. 2022 Dec;50(9):1082-1096. [PMC free article: PMC10088017] [PubMed: 36102668]

29.

Atanassova PA. Antiphospholipid syndrome and vascular ischemic (occlusive) diseases: an overview. Yonsei Med J. 2007 Dec 31;48(6):901-26. [PMC free article: PMC2628175] [PubMed: 18159581]

30.

Mauricio D, Gratacòs M, Franch-Nadal J. Diabetic microvascular disease in non-classical beds: the hidden impact beyond the retina, the kidney, and the peripheral nerves. Cardiovasc Diabetol. 2023 Nov 15;22(1):314. [PMC free article: PMC10652502] [PubMed: 37968679]

31.

Ceriz T, Lagarteira J, Alves SR, Carrascal A, Terras Alexandre R. Disseminated Intravascular Coagulation in COVID-19 Setting: A Clinical Case Description. Cureus. 2023 Jun;15(6):e39941. [PMC free article: PMC10319425] [PubMed: 37409194]

32.

Woszczek D, Górska A, Sirek S, Wyględowska-Promieńska D. A Case of Spontaneously Resolving Valsalva Retinopathy in a 29-Year-Old Patient. Cureus. 2025 Apr;17(4):e82906. [PMC free article: PMC12103179] [PubMed: 40416192]

33.

Du Y, Ge Y, Xu Z, Aa N, Gu X, Meng H, Lin Z, Zhu D, Shi J, Zhuang R, Wu X, Wang X, Yang Z. Hypoxia-Inducible Factor 1 alpha (HIF-1α)/Vascular Endothelial Growth Factor (VEGF) Pathway Participates in Angiogenesis of Myocardial Infarction in Muscone-Treated Mice: Preliminary Study. Med Sci Monit. 2018 Dec 08;24:8870-8877. [PMC free article: PMC6295139] [PubMed: 30531686]

34.

Dell'Arti L, Barteselli G, Pinna V, Invernizzi A, Mapelli C, Viola F. Sudden occurrence of Roth spots and retinal hemorrhages following endoscopic adhesiolysis: an SD-OCT evaluation. Eur J Ophthalmol. 2015 Dec 01;26(1):e11-3. [PubMed: 26428215]

35.

Pan L, Lu MP, Wang JH, Xu M, Yang SR. Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr. 2020 Feb;16(1):19-30. [PMC free article: PMC7040062] [PubMed: 30796732]

36.

Jidigam VK, Singh R, Batoki JC, Milliner C, Sawant OB, Bonilha VL, Rao S. Histopathological assessments reveal retinal vascular changes, inflammation, and gliosis in patients with lethal COVID-19. Graefes Arch Clin Exp Ophthalmol. 2022 Apr;260(4):1275-1288. [PMC free article: PMC8553591] [PubMed: 34714382]

37.

De Pablo-Moreno JA, Serrano LJ, Revuelta L, Sánchez MJ, Liras A. The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V. Int J Mol Sci. 2022 Jul 27;23(15) [PMC free article: PMC9425441] [PubMed: 35955419]

38.

Lee SJV, Goh YQ, Rojas-Carabali W, Cifuentes-González C, Cheung CY, Arora A, de-la-Torre A, Gupta V, Agrawal R. Association between retinal vessels caliber and systemic health: A comprehensive review. Surv Ophthalmol. 2025 Mar-Apr;70(2):184-199. [PubMed: 39557345]

39.

Stinghen AE, Massy ZA, Vlassara H, Striker GE, Boullier A. Uremic Toxicity of Advanced Glycation End Products in CKD. J Am Soc Nephrol. 2016 Feb;27(2):354-70. [PMC free article: PMC4731113] [PubMed: 26311460]

40.

Saavedra Torres JS, Annamaraju P. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Sep 15, 2025. Type III Hypersensitivity Reaction. [PubMed: 32644548]

41.

Liu X, Chang Y, Li Y, Liu Y, Song W, Lu J, Chen N, Cui J. Oxidative stress and retinopathy: evidence from epidemiological studies. J Transl Med. 2025 Jan 21;23(1):94. [PMC free article: PMC11748554] [PubMed: 39838377]

42.

Allen KA, Brandon DH. Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments. Newborn Infant Nurs Rev. 2011 Sep 01;11(3):125-133. [PMC free article: PMC3171747] [PubMed: 21927583]

43.

Lin AL, Burnham JM, Pang V, Idowu O, Iyer S. OCULAR MANIFESTATIONS OF PRIMARY MYELOFIBROSIS. Retin Cases Brief Rep. 2016 Fall;10(4):364-7. [PubMed: 26836259]

44.

Furtado JM, Toscano M, Castro V, Rodrigues MW. Roth Spots in Ocular Toxoplasmosis. Ocul Immunol Inflamm. 2016 Oct;24(5):568-70. [PubMed: 26472315]

45.

Singh R, Singh SP, Mittal SK, Rana SK. Roth Spots in Chronic Myeloid Leukaemia. J Assoc Physicians India. 2014 Sep;62(9):836-7. [PubMed: 26259322]

46.

Gurnani B, Kaur K. Predicting Prognosis Based on Regional Prevalence, Ulcer Morphology and Treatment Strategy in Vision-Threatening Pythium insidiosum Keratitis. Clin Ophthalmol. 2023;17:1307-1314. [PMC free article: PMC10167989] [PubMed: 37181081]

47.

Loots FJ, Smulders D, Giesen P, Hopstaken RM, Smits M. Vital signs of the systemic inflammatory response syndrome in adult patients with acute infections presenting in out-of-hours primary care: A cross-sectional study. Eur J Gen Pract. 2021 Dec;27(1):83-89. [PMC free article: PMC8118397] [PubMed: 33978531]

48.

Feroze KB, Gurnani B, O'Rourke MC. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Aug 11, 2024. Transient Loss of Vision. [PubMed: 28613595]

49.

Shapiro SM, Young E, De Guzman S, Ward J, Chiu CY, Ginzton LE, Bayer AS. Transesophageal echocardiography in diagnosis of infective endocarditis. Chest. 1994 Feb;105(2):377-82. [PubMed: 8306732]

50.

Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in adults. Mayo Clin Proc. 2005 Jul;80(7):923-36. [PMC free article: PMC7127472] [PubMed: 16007898]

51.

Le PH, Kaur K, Patel BC. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Oct 6, 2024. Optical Coherence Tomography Angiography. [PubMed: 33085382]

52.

Aalbers AM, van den Heuvel-Eibrink MM, Baumann I, Dworzak M, Hasle H, Locatelli F, De Moerloose B, Schmugge M, Mejstrikova E, Nováková M, Zecca M, Zwaan CM, Te Marvelde JG, Langerak AW, van Dongen JJ, Pieters R, Niemeyer CM, van der Velden VH. Bone marrow immunophenotyping by flow cytometry in refractory cytopenia of childhood. Haematologica. 2015 Mar;100(3):315-23. [PMC free article: PMC4349269] [PubMed: 25425683]

53.

Mahroo OA, Graham EM. Images in clinical medicine. Roth spots in infective endocarditis. N Engl J Med. 2014 Jun 19;370(25):e38. [PubMed: 24941198]

54.

Charlesworth M, Williams BG, Ray S. Infective endocarditis. BJA Educ. 2023 Apr;23(4):144-152. [PMC free article: PMC10028394] [PubMed: 36960439]

55.

Habib G. Management of infective endocarditis. Heart. 2006 Jan;92(1):124-30. [PMC free article: PMC1861013] [PubMed: 16365367]

56.

Depuis Z, Gatineau-Sailliant S, Ketelslegers O, Minon JM, Seghaye MC, Vasbien M, Dresse MF. Pancytopenia Due to Vitamin B12 and Folic Acid Deficiency-A Case Report. Pediatr Rep. 2022 Mar 03;14(1):106-114. [PMC free article: PMC8951551] [PubMed: 35324819]

57.

Bin Rakhis SA, AlDuwayhis NM, Aleid N, AlBarrak AN, Aloraini AA. Glycemic Control for Type 2 Diabetes Mellitus Patients: A Systematic Review. Cureus. 2022 Jun;14(6):e26180. [PMC free article: PMC9304683] [PubMed: 35891859]

58.

Alley WD, Schick MA. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 24, 2023. Hypertensive Emergency. [PubMed: 29261994]

59.

Côté E, Micieli JA. Roth spot secondary to Valsalva retinopathy. BMJ Case Rep. 2020 Jun 17;13(6) [PMC free article: PMC7304636] [PubMed: 32554448]

60.

Semeraro F, Morescalchi F, Cancarini A, Russo A, Rezzola S, Costagliola C. Diabetic retinopathy, a vascular and inflammatory disease: Therapeutic implications. Diabetes Metab. 2019 Dec;45(6):517-527. [PubMed: 31005756]

61.

Ahn SJ, Kim YH. Clinical Applications and Future Directions of Smartphone Fundus Imaging. Diagnostics (Basel). 2024 Jun 30;14(13) [PMC free article: PMC11240943] [PubMed: 39001285]

62.

Venkatesh R, Gurram Reddy N, Jayadev C, Chhablani J. Determinants for Anemic Retinopathy. Beyoglu Eye J. 2023;8(2):97-103. [PMC free article: PMC10375210] [PubMed: 37521879]

63.

Drachmann J, Petersen L, Jeppesen SK, Bek T. Systemic Hypoxia Increases Retinal Blood Flow but Reduces the Oxygen Saturation Less in Peripheral Than in Macular Vessels in Normal Persons. Invest Ophthalmol Vis Sci. 2025 Jun 02;66(6):43. [PMC free article: PMC12173086] [PubMed: 40512486]

64.

Rose JJ, Wang L, Xu Q, McTiernan CF, Shiva S, Tejero J, Gladwin MT. Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy. Am J Respir Crit Care Med. 2017 Mar 01;195(5):596-606. [PMC free article: PMC5363978] [PubMed: 27753502]

65.

Al-Mujaini AS, Montana CC. Valsalva retinopathy in pregnancy: a case report. J Med Case Rep. 2008 Apr 07;2:101. [PMC free article: PMC2311321] [PubMed: 18394189]

66.

Gurnani B, Kaur K. Re: Dot et al.: Incidence of retinal detachment, macular edema, and ocular hypertension after neodymium:yttrium-aluminum-garnet capsulotomy: a population-based nationwide study-The French YAG 2 Study (Ophthalmology. 2022;130:478-487). Ophthalmology. 2023 Dec;130(12):e43. [PubMed: 37737811]

67.

Roy MS, Rick ME, Higgins KE, McCulloch JC. Retinal cotton-wool spots: an early finding in diabetic retinopathy? Br J Ophthalmol. 1986 Oct;70(10):772-8. [PMC free article: PMC1040826] [PubMed: 3778861]

68.

Tsukikawa M, Stacey AW. A Review of Hypertensive Retinopathy and Chorioretinopathy. Clin Optom (Auckl). 2020;12:67-73. [PMC free article: PMC7211319] [PubMed: 32440245]

69.

Kuo HT, Tseng H, Hsu AY, Wu BQ, Hsia NY, Lin CJ, Gonzales J. Human immunodeficiency virus ocular involvement and retinopathy: Clinical spectrum and management strategies. Taiwan J Ophthalmol. 2025 Apr-Jun;15(2):218-224. [PMC free article: PMC12204653] [PubMed: 40584190]

70.

Shukla UV, Gurnani B, Kaufman EJ. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Oct 6, 2024. Intraocular Hemorrhage. [PubMed: 33620856]

71.

Togioka BM, Arnold MA, Bathurst MA, Ziegfeld SM, Nabaweesi R, Colombani PM, Chang DC, Abdullah F. Retinal hemorrhages and shaken baby syndrome: an evidence-based review. J Emerg Med. 2009 Jul;37(1):98-106. [PubMed: 19081701]

72.

Fowler VG, Durack DT, Selton-Suty C, Athan E, Bayer AS, Chamis AL, Dahl A, DiBernardo L, Durante-Mangoni E, Duval X, Fortes CQ, Fosbøl E, Hannan MM, Hasse B, Hoen B, Karchmer AW, Mestres CA, Petti CA, Pizzi MN, Preston SD, Roque A, Vandenesch F, van der Meer JTM, van der Vaart TW, Miro JM. The 2023 Duke-International Society for Cardiovascular Infectious Diseases Criteria for Infective Endocarditis: Updating the Modified Duke Criteria. Clin Infect Dis. 2023 Aug 22;77(4):518-526. [PMC free article: PMC10681650] [PubMed: 37138445]

73.

Yan BJ, Luo LH, Shen J, Huang YX. Secondary Ocular Manifestations in Acute Leukemia: Clinical Patterns and Hematologic Correlates. J Multidiscip Healthc. 2025;18:3289-3297. [PMC free article: PMC12161144] [PubMed: 40510816]

74.

Md Noh UK, Zahidin AZ, Yong TK. Retinal vasculitis in systemic lupus erythematosus: an indication of active disease. Clin Pract. 2012 Mar 30;2(2):e54. [PMC free article: PMC3981295] [PubMed: 24765453]

75.

Al-Beltagi M, Saeed NK, Bediwy AS. COVID-19 disease and autoimmune disorders: A mutual pathway. World J Methodol. 2022 Jul 20;12(4):200-223. [PMC free article: PMC9350728] [PubMed: 36159097]

76.

Langlo CS, Amin A, Park SS. Optical coherence tomography retinal imaging: narrative review of technological advancements and clinical applications. Ann Transl Med. 2025 Apr 30;13(2):17. [PMC free article: PMC12106120] [PubMed: 40438521]

77.

Bazan JG, Khan AJ. Target Volume Delineation and Patterns of Recurrence in the Modern Era. Semin Radiat Oncol. 2022 Jul;32(3):254-269. [PubMed: 35688524]

78.

Takeda K, Umezawa R, Yamamoto T, Takahashi N, Suzuki Y, Kishida K, Omata S, Jingu K. Acute hematologic toxicity of radiation therapy - a comprehensive analysis and predictive nomogram. J Radiat Res. 2023 Nov 21;64(6):954-961. [PMC free article: PMC10665302] [PubMed: 37740569]

79.

Colcombe J, Mundae R, Kaiser A, Bijon J, Modi Y. Retinal Findings and Cardiovascular Risk: Prognostic Conditions, Novel Biomarkers, and Emerging Image Analysis Techniques. J Pers Med. 2023 Oct 31;13(11) [PMC free article: PMC10672409] [PubMed: 38003879]

80.

D'Aniello S, Rustici A, Gramegna LL, Godi C, Piccolo L, Gentile M, Zini A, Carrozzi A, Lodi R, Tonon C, Dall'Olio M, Simonetti L, Chieffo R, Anzalone N, Cirillo L. The Contribution of Vessel Wall Magnetic Resonance Imaging to the Diagnosis of Primary and Secondary Central Nervous System Vasculitis. Diagnostics (Basel). 2024 Apr 29;14(9) [PMC free article: PMC11083696] [PubMed: 38732340]

Disclosure: Bharat Gurnani declares no relevant financial relationships with ineligible companies.

Disclosure: Vijai Tivakaran declares no relevant financial relationships with ineligible companies.