Severe Guillain-Barre syndrome induced by intravitreal injection of ranibizumab for branch retinal vein occlusion: a case report

Introduction

Guillain-Barré syndrome (GBS) is an acute, inflammatory, demyelinating, polyradiculoneuropathy resulting from immune system damage to the peripheral nervous system, leading to acute muscle paralysis. It is commonly triggered by infections, with rare cases reported following surgery or vaccination (1). Ranibizumab is a recombinant humanized monoclonal antibody fragment that binds and inhibits vascular endothelial growth factor (VEGF), preventing the formation of new blood vessels. It is widely used in diseases such as macular degeneration and retinal vein occlusion (RVO). While it is effective, the systemic safety of intravitreal injection of anti-VEGF drugs is also a concern. Common systemic adverse reactions to VEGF inhibition include arterial thromboembolic events, hypertension, non-ocular bleeding, proteinuria, urinary tract infections, and pneumonia (2,3). However, ranibizumab-induced GBS is exceedingly rare. The exact pathogenic mechanism remains elusive. We report a case of GBS that occurred after intravitreal injection of ranibizumab in a patient with left branch RVO. The patient’s condition was severe but improved after treatment with immunoglobulin. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-23-107/rc).

Case presentation

On December 5, 2019, a 53-year-old female was admitted to The Fifth Affiliated Hospital of Sun Yat-sen University, due to sudden loss of vision in her left eye. Fluorescein angiography revealed early vascular dilation of the optic disc in the left eye with late hyperfluorescence; delayed venous drainage in the temporal branch of the retina, accompanied by extensive areas of hyperfluorescent hemorrhages, and late leakage of fluorescein in the macular area (Figures 1,2), leading to a diagnosis of “left eye retinal branch vein occlusion”. Starting from December 14, 2019, she received ranibizumab injections every 2 weeks. On January 17, 2020, the patient underwent her third transconjunctival intravitreal injection of ranibizumab under local anesthesia, after which numbness gradually intensified in the fingertips, followed by numbness and weakness in the lower limbs. Neurological examination revealed grade 4 muscle strength in the lower limbs, reduced pain sensation in the palms and soles, and weakened tendon reflexes in all limbs. Weakly positive results were obtained for anti-GD1b, GD2, GD3, GT1a, GT1b IgG, and GM2 IgM antibodies. On January 20, 2020, the patient experienced respiratory muscle paralysis and a decrease in blood oxygen saturation (SPO₂ 31–36%). She was immediately transferred to the intensive care unit for mechanical ventilation and intravenous immunoglobulin (IVIG) therapy at a dose of 0.4 g/kg per course for 5 days, totaling two courses. On the 20th day, cerebrospinal fluid analysis showed protein-cell separation. Nerve conduction studies (NCS) indicated demyelinating polyneuropathy (Table 1). The diagnosis of GBS was confirmed (a summary of the timeline is shown in Figure 3). After one month of treatment, the patient’s limb weakness improved, and she was discharged, transferred to a rehabilitation facility for further rehabilitation therapy. Follow-up at three months showed that the patient could walk short distances with crutches, and after one year, the patient was living independently without disease recurrence.

Figure 1 Color fundus photograph of the right eye (left panel) and the left eye (right panel), showing branch retinal vein occlusion in the left eye (white arrow).

Figure 2 The temporal branch of the retinal vein in the left eye has delayed venous return, with extensive hemorrhage and fluorescence masking in the corresponding area, and late-phase fluorescein leakage in the macular region (white arrow).

Figure 3 Progression timeline of the illness, insertion of treatment time points for the patient. ICU, intensive care unit; IVIG, intravenous immunoglobulin; irAEs, immune-related adverse events.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

RVO is the prominent vascular-driven eye diseases leading to vision loss and blindness (4). Anti-VEGF drugs are considered the main regulatory factor in inhibiting ocular neovascularization caused by retinal hypoxia, with ranibizumab, bevacizumab, and aflibercept being representative drugs. Neurological complications are rare; diagnosis of GBS is typically symptom-based, ruling out other conditions, and supported by auxiliary tests such as electromyography and cerebrospinal fluid examination. In this case, a patient developed limb weakness and numbness progressing rapidly to respiratory muscle paralysis after the third intravitreal injection of ranibizumab. The patient had no chronic diseases like diabetes or thyroid disorders, nor evident infectious factors or recent vaccination records. Hematologic tests for cytomegalovirus, Epstein-Barr virus (EBV), influenza virus, and human immunodeficiency virus (HIV) antibodies were negative, excluding infectious or metabolic causes. With typical protein cell separation in cerebrospinal fluid and positive ganglioside antibody, and consistent neurophysiological changes indicative of GBS on day 20 of onset, a diagnosis of GBS was established. Therefore, GBS may represent a rare but rapidly progressive neurological complication of intravitreal ranibizumab therapy.

Due to the rarity of adverse events of GBS induced by intravitreal injection of ranibizumab, the underlying mechanisms deserve exploration. A search of the database found that anti-VEGF drugs can cause systemic adverse events. One report of systemic adverse events showed that out of 610 patients, 161 experienced at least one serious adverse events (SAEs) during the trial, and 25 participants experienced immune-related adverse events (irAEs) (5). Ranibizumab, as an anti-VEGF drug, has the advantage of smaller molecular weight, better tissue penetration, and potential elimination of the safety impact of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (6,7). However, anti-VEGF compounds can pass through the blood-retinal barrier, enter the systemic circulation, and inhibit serum VEGF levels, which may be a key factor in inducing systemic immune reactions in eye administration (8,9). Therefore, the possibility of ocular administration inducing autoimmune reactions and resulting in neurological complications should not be overlooked.

GBS is a post-infectious syndrome, autoimmune-mediated peripheral nerve damage disease (6). The main mechanism of GBS is the molecular mimicry theory, where certain components of the pathogen have a similar structure to certain components of the peripheral nerves. This stimulates the immune system to produce ganglioside antibodies, which then leads to an erroneous identification by the immune system. Both cellular and humoral immunity are abnormally activated, and the ganglioside antibodies bind to GM1 or GD1a gangliosides (in the Ranvier nodes), activating the complement system and causing demyelination (6,7). In GBS patients, serum inflammatory markers such as VEGF-A, bFGF, and soluble FMS-like tyrosine kinase-1 (SFLT-1) can recruit and migrate macrophages and other cytokines, leading to inflammation and neuronal damage (10). Under normal physiological conditions, VEGF has a regulatory effect on the immune system, including inhibiting T cell activation and increasing immune suppressor cells (such as regulatory T cells and macrophages). VEGF-A is an important initiator of intraocular neovascularization and increased intraocular permeability in the VEGF family. Ranibizumab specifically binds to VEGF-A, and it is speculated that it may affect plasma VEGF concentration and cause immune imbalance.

The mechanism of action of ranibizumab is similar to that of bevacizumab, and they have similar efficacy and safety in the treatment of wet macular degeneration. Previous clinical studies have shown that the incidence of SAEs in the ranibizumab group (20.29%) is significantly higher than that in the bevacizumab group (1%) (11). Bevacizumab can bind to Fc and FcRN receptors expressed on the retinal pigment epithelium (RPE) (12). The Fc region slows down the drug clearance rate and prolongs the drug half-life, while the Fc receptor protects IgG from elimination from the circulation and tissue distribution (13). The Fc component on the antibody molecule has the potential to regulate immune responses, and under certain conditions, these conditions may create conditions for immune sensitization in the body (14).

We are contemplating whether the patient’s receipt of three intravitreal injections of ranibizumab within the span of about a month elevated the risk of GBS onset. This meta-analysis investigated the correlation between the frequency of anti-VEGF injections and mortality rate, which included a study of 1.12 injections within 7 months and another study of 6.24 injections within 11 months (15). More frequent anti-VEGF injections did not significantly increase the risk of death. But Ziemssen et al. (16) pointed out that adverse events after ranibizumab injection mostly occurred after the third or fourth injection. For moderate to severe cases of GBS, IVIG is the preferred treatment, with plasma exchange as an option if available (17). Approximately 24% of patients may require mechanical ventilation, and up to 12% may die from disease-related complications. Although appropriate interventions can lead to complete recovery in about 85% of cases, approximately 15% may experience varying degrees of sequelae (18). Close monitoring of the disease course is crucial. In this patient, mechanical ventilation therapy prevented respiratory failure, and prompt IVIG therapy initiated within two days of onset improved prognosis, resulting in no residual sequelae.

Conclusions

Due to the rarity of GBS cases associated with intravitreal injections of ranibizumab, our analysis of the mechanism of GBS caused by ranibizumab is limited, but it may be related to factors such as the number of injections, pharmacokinetics, and plasma VEGF concentration. Given the high risk and rapid progression of GBS, it is important for clinicians to identify GBS early, provide timely treatment, and standardize management when using anti-VEGF drugs to prevent irreversible damage to the central nervous system, which is crucial for improving long-term prognosis.

Acknowledgments

Funding: This work was supported by Science and Technology Projects of Social Development in Zhuhai (No. ZH22036201210052PWC).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-23-107/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-23-107/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-23-107/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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