Acute inflammatory demyelinating polyneuropathy shortly after administration of intravitreal ranibizumab

Dear Editor:

Ranibizumab is a recombinant humanized IgG1 monoclonal antibody fragment that binds and inhibits vascular endothelial growth factor (VEGF), an angiogenesis promoter.¹ Its use by intravitreal injection was initially approved by the Food and Drug Administration (FDA) in 2006 as a therapy for wet age-related macular degeneration (wet AMD) and has subsequently been approved in diabetic retinopathy and diabetic and ischemic macular oedema.² Its most frequently reported adverse effects (AE) are conjunctival hemorrhage, pain, decreased visual acuity, retinal detachment, and increased intraocular pressure.³ Anti-VEGF drugs have been associated with serious adverse reactions and systemic toxicity not only with systemic use but also with intravitreal administration. Recently an Italian study that analyzed a database of spontaneous reports⁴ identified 2472 cases of AE related to the use of these drugs in the areas of oncology and ophthalmology. However, systemic AEs were exceptional: single cases of cerebral hemorrhage, transient ischemic attack, and acute coronary syndrome. Additionally, other less severe and more frequent AEs related to parenteral administration have been described in the field of oncology such as hypertension and renal involvement.⁵ None of the currently available anti-VEGFs have been associated with dysimmune neuropathies such as AIDP (acute inflammatory demyelinating polyneuropathy). Nevertheless, cases have been described with other monoclonal antibodies such as Nivolumab,⁶ Ipilimumab,⁷ Pembrolizumab,⁸ Adalimumab.⁹ VEGF has been implicated in neuroregeneration functions in the Central and Peripheral Nervous Systems (CNS and PNS) stimulating remyelination in NPS through its effects on Schwann cells.¹⁰ It also promotes anatomic and functional recovery of injured peripheral nerves regardless of their angiogenic effects.¹¹

AIDP is an acute, often severe, fast-onset autoimmune polyradiculoneuropathy. Nowadays it represents the most common cause of acute or subacute generalized paralysis, having been compared in frequency with poliomyelitis.¹² We present the first report of AIDP after intravitreal injection of Ranibizumab.

Case report

50-Year-old-male patient, photographer, no family history of interest. Previous personal history of epilepsy in remission, treated with Carbamazepine and seizure free for more than 20 years. After experiencing deterioration of his visual acuity over two months he sought an ophthalmological consultation, and a diagnosis of wet AMD was made. Intravitreal Ranibizumab was administered in the left eye and oral ciprofloxacin was prescribed for five days as prophylaxis. After three days the patient developed tingling in the lower limbs, unsteadiness, and sinus tachycardia. He underwent an ENG (Fig. 1) that proved diagnostic of AIDP. All other ancillary tests were normal, including cerebrospinal fluid analysis, viral screen and antiganglioside antibodies. He underwent a 5-day cycle of intravenous immunoglobulins (0.4 mg × kg × day) with excellent clinical outcome and complete symptom resolution.

Fig. 1.

Electroneurography performed four days from clinical onset. Electrophysiological examinations of the following motor nerves (scanning speed: 2 ms/D, sensitivity: 5 mV/D) are shown: right median nerve (A), left tibial nerve (B), and right peroneal nerve (C); whit no remarkable findings. Right peroneal nerve F-waves showed increased latency (D). Electrophysiological examinations of sensory waves (scanning speed: 1 ms/D, sensitivity: 20 μV/D): both superficial peroneal nerves sensory waves were absent (not shown). Right median nerve (E), left ulnar nerve (F) and right and left sural nerves sensory wave amplitudes were decreased. Left median nerve and right ulnar nerve sensory waves were not induced. These results fulfil the electrodiagnostic criteria for acute inflammatory demyelinating polyneuropathy.

Discussion

Safety data reported in ophthalmology trials and pharmacokinetic and pharmacodynamic data provide strong evidence that systemic events after intravitreal injection are very unlikely. A possible explanation could be found in the minimal dose used in ophthalmological disease (400 times less) and in the fact that the eye barrier implies a local sequestration of the drug and a delay in its systemic absorption. Nonetheless, it should be noted that this retinal blood barrier is altered in ophthalmological processes, and elimination is systemic even if the administration is local.¹³ Reported systemic AEs associated with this agent are related to toxicity on the vascular system. In addition, no cases of dysimmune diseases secondary to anti-VEGF have been described. Still, considering the neuromodulatory functions attributed to VEGF, these drugs could be a triggering factor in demyelinating diseases in some cases.

We describe a case of AIDP after use of intravitreal Ranibizumab. Our patient developed AIDP three days after treatment, with no history of infection or recent vaccinations. Other causal entities such as viral infections with Campylobacter Jejuni, Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and HIV were ruled out. There was also simultaneous use of ciprofloxacin, as fluoroquinolones (CF) have been exceptionally associated with AIDP.¹⁴ New users are at highest risk of developing CF-associated neuropathy¹⁵ but the patient does not remember if this was his first treatment.

Although this may be the first case of AIDP related to intravitreal Ranibizumab, we cannot establish a causal relationship because of confounding factors. Further clinical evidence is needed. Therefore, these conclusions should be interpreted with caution given the inherent limitations of spontaneously occurring AEs.

Disclosure

The author reports no funding or disclosures.

Authors’ contribution

Drs. Fuerte-Hortigón, Sánchez-Sánchez and García-Campos, contributed equally to this work.