Neuro-Ophthalmic Manifestations of Carotid Cavernous Fistulas: A Systematic Review and Meta-Analysis

Carotid-cavernous fistulas (CCFs) are pathologic, arteriovenous communications between the carotid artery and cavernous sinus. They cause various complex neuro-ophthalmic symptoms by shunting the flow of arterial blood into the venous system. In this study, a systematic review is conducted on the neuro-ophthalmic presentations associated with CCFs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines were followed during the systematic review. We searched PubMed, Scopus, and Web of Science from inception to December 31, 2023. Articles written in English on patients with confirmed CCFs reporting clinical features, diagnostic modalities, treatment approaches, and outcomes were included. Abstracted data included demography, clinical presentations, venous flow dynamics, trauma history, investigative methodology, approaches to treatment, and outcomes. Overall, 33 studies with a total number of 403 patients were included. The mean age at presentation was 42.99 years for patients with direct CCFs and 55.88 years for those with indirect CCFs. Preponderance was observed in male patients with direct CCFs, constituting 51.56%, while females predominated in those with indirect CCFs, at 56.44%. The clinical symptoms in all patients with CCFs were proptosis in 58 cases (14.39%), conjunctival congestion in 29 patients (7.20%), diplopia in nine patients (2.23%), vision blurring in four patients (0.99%), eyelid swelling in five patients (1.24%), pain in the eye in three patients (0.74%), and an upper lid mass in one patient (0.25%). Endovascular treatments, including coil and Onyx embolization, have been effective in relieving clinical symptoms and arresting the progression of these symptoms. In conclusion, the common clinical features in CCFs usually underline proptosis, congestion, and diplopia, necessitating a comprehensive neuro-ophthalmological review. Prompt identification of the symptoms of blurred vision is crucial to avoid permanent damage. Lid swelling, ocular pain, and an upper lid mass are less common but equally essential presentations for comprehensive evaluation. The recognition of these variable presentations is essential not only for timely intervention but also for the improvement in patient outcomes, thus emphasizing the role of clinician awareness in managing CCF cases.


Introduction And Background
Carotid cavernous fistulas (CCFs) are abnormal connections that form between the carotid artery and the cavernous sinus.This anomaly allows arterial blood to flow directly into the venous system.The high rate of abnormal blood flow through the fistula can result in neuro-ophthalmic symptoms due to increased venous pressure and subsequent ocular and orbital congestion.Patients may experience proptosis, chemosis, diplopia, and other visual disturbances as a consequence [1,2].
CCFs can be classified into two main types: direct and indirect.Direct CCFs typically present as high-flow fistulas, often resulting from trauma or the spontaneous rupture of intra-cavernous aneurysms.This form involves a direct connection between the internal carotid artery and the cavernous sinus.On the other hand, indirect CCFs, also known as dural arteriovenous fistulas, are generally low-flow and tend to occur spontaneously.They are frequently associated with underlying conditions such as hypertension, atherosclerosis, and connective tissue disorders [3,4].
The neuro-ophthalmic symptoms of CCFs can vary widely depending on the type and size of the fistula, the direction of venous drainage, and any underlying conditions.These symptoms can be severe, often providing crucial diagnostic clues.Patients may exhibit ocular and cranial nerve abnormalities, such as proptosis, chemosis, and cranial nerve palsies that affect ocular motility.The increased venous pressure caused by abnormal venous drainage can lead to characteristic signs like ocular redness, reduced visual acuity, and pulsatile exophthalmos.Additionally, involvement of the third, fourth, fifth, and sixth cranial nerves, either directly or due to proximity to the cavernous sinus, can result in diplopia, ptosis, and facial pain or numbness.The varied presentation of these symptoms necessitates a high level of suspicion and thorough clinical evaluation [5].

Study Selection
Studies were included if they: (1) involved patients with clinically confirmed CCFs; (2) reported on clinical features, diagnostic methods, treatment approaches, and outcomes of CCFs; and (3) were written in English.Exclusions were made for studies that: (1) were reviews, book chapters, or animal and cadaver studies; (2) 2024 Al-shalchy et al.Cureus 16 (7): e65821.DOI 10.7759/cureus.65821focused on CCFs from non-traumatic etiologies without clear clinical implications; or (3) provided insufficient clinical data on CCFs.Two reviewers (Y.A. and M.H.) independently screened the titles and abstracts of collected articles and assessed the full texts of studies meeting inclusion criteria.Any disagreements were resolved by a third reviewer (M.I.).

Data Extraction
One reviewer (M.H.) extracted the data, while two reviewers (Y. A. and M.I.) independently verified the extractions.The extracted data included authors, sample size, age, gender, clinical manifestations, venous flow dynamics, trauma history, diagnostics, treatment modalities, and outcomes.Clinical manifestations were categorized based on venous flow direction (anterior vs. posterior).Treatment responses were evaluated based on the resolution of symptoms and complications.

Data Synthesis and Analysis
Due to the heterogeneity across studies, we performed a meta-analysis in order to systematically synthesize multiple results.The main outcomes of interest were clinical presentations, diagnostic methods, treatment approaches, and patient's outcome.Table 1 details a synthesis of the key findings from all studies to offer readers an in-depth understanding of available knowledge.Our approach enables incisive knowledge of the complex and wide-ranging data characteristic of neuro-ophthalmic manifestations with CCFs through appropriate representation and analysis.
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Clinical Manifestations
The clinical manifestations varied significantly between direct and indirect CCFs.For direct CCFs, common symptoms included proptosis in 49 cases (24.87%), eye redness in 21 patients (10.66%), double vision in seven patients (3.55%), blurred vision in three patients (1.52%), eyelid swelling in three patients (1.52%), and eye pain in three patients (1.52%) (Table 1).These symptoms are due to abnormal venous pressure and congestion in the orbital area (Figure 2).Indirect CCFs presented with proptosis in nine patients (5.03%), eye redness in eight patients (4.47%), diplopia in two patients (1.12%), blurred vision in one patient (0.56%), eyelid swelling in two patients (1.12%), and an upper lid mass in one patient (0.56%) (Table 1).Overall, combined manifestations among all patients with CCFs included proptosis in 58 cases (14.39%), eye redness in 29 patients (7.20%), diplopia in nine patients (2.23%), blurred vision in four patients (0.99%), eyelid swelling in five patients (1.24%), eye pain in three patients (0.74%), and an upper lid mass in one patient (0.25%).Patients with anterior venous flow primarily exhibited proptosis and eye redness due to the arterialization of the superior and inferior ophthalmic veins.In contrast, those with posterior venous flow often experienced cranial nerve VI (abducens) palsy, resulting in double vision, and cranial nerve V (trigeminal) involvement, causing facial pain or headache.1).

Trauma History
A significant factor for direct CCFs was trauma history, with 67 out of 197 patients (34.01%) having experienced trauma.Conversely, indirect CCFs were frequently associated with trauma history, observed in 6 out of 179 patients (3.35%) (Table 2).

Diagnostic Modalities
The primary diagnostic techniques used included CT, MRI, and cerebral angiography, which is considered the gold standard.These imaging methods were crucial for confirming the diagnosis and devising treatment plans (Table 1).

Treatment Approaches
Patients were treated by conservative, surgery and endovascular methods.Fistula closure was achieved using endovascular techniques such as coil and Onyx embolization, allowing the blood flow to return into its normal pathway.These methods are where patient results have been drastically improved in the treatment of CCFs.Management is multimodal and it depends on various factors including CCF features and patientrelated health issues (Table 1).

Outcomes
Outcomes for patients varied; some experienced spontaneous improvement, while others reported a progression of symptoms.Those who underwent endovascular therapy generally showed significant clinical improvement, without deterioration of symptoms.Significant outcomes included enhanced visual acuity, reduced conjunctival vessel corkscrewing, decreased proptosis, and resolved diplopia (Table 1).

Key Findings
Direct CCFs were more common in younger males with a history of trauma, while indirect CCFs were prevalent in older females with hypertension.Endovascular treatment proved effective for managing symptoms and halting the progression of CCFs.Early diagnosis and intervention are critical for achieving better patient outcomes (Table 1).

TABLE 1 : Clinical Characteristics, Diagnostic Modalities, Treatment Approaches, and Outcomes of Patients with Carotid Cavernous Fistulas (CCFs) from Selected Studies. Results Study Selection
This comprehensive analysis includes 33 studies involving 403 individuals with CCFs (Table1).The reviewed studies covered clinical aspects, diagnostic methods, treatment techniques, and outcomes.The mean age of patients with direct CCFs was 42.99 years, whereas those with indirect CCFs averaged 55.88 years.Direct CCFs were more prevalent in males, with 102 out of 197 patients (51.56%) being male and 95 (48.11%) females.Conversely, indirect CCFs were more common in females, comprising 101 out of 179 patients (56.44%) compared to 78 (43.56%) males.Detailed demographics and clinical characteristics are presented in Table 2.