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 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 56  |  Issue : 3  |  Page : 191-193

Left middle cerebral artery territory infarction due to intravitreal injection of ranibizumab


Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India

Date of Web Publication23-Oct-2018

Correspondence Address:
Ms. Shatavisa Mukherjee
Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata - 700 073, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjosr.tjosr_80_18

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  Abstract 


Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is increasingly used for the treatment of a wide variety of retinal diseases including age-related macular degeneration, diabetic retinopathy and retinal vascular occlusions, and retinopathy of prematurity. Despite encouraging results in halting the disease and improving the vision, intravitreal injection of anti-VEGF agents may be associated with marked side effects. The present case describes a 75-year-old female with known complications of hypertension, Type II DM, and hypothyroidism, who received intravitreal injections of Lucentis (ranibizumab) due to diabetic macular edema. After 10 days, the patient admitted with chief complaints of slurred speech. Further, radiological and clinical investigations conferred the case to be a left middle cerebral artery territory infarct with right-sided hemiparesis and aphasia. Although well-designed randomized clinical trials have shown the efficacy of these agents in visual improvement in various retinal diseases, each intravitreal injection poses the risk of postinjection- and drug class-associated adverse events. Clinicians should be more vigilant as patients receiving intravitreal injections are at a small risk of developing complications, which is often unrecognized or underreported.

Keywords: Adverse effects, anti-vascular endothelial growth factor agents, ranibizumab, thromboembolic complications


How to cite this article:
Samajdar SS, Mukherjee S, Roy SS, Tripathi SK. Left middle cerebral artery territory infarction due to intravitreal injection of ranibizumab. TNOA J Ophthalmic Sci Res 2018;56:191-3

How to cite this URL:
Samajdar SS, Mukherjee S, Roy SS, Tripathi SK. Left middle cerebral artery territory infarction due to intravitreal injection of ranibizumab. TNOA J Ophthalmic Sci Res [serial online] 2018 [cited 2018 Dec 15];56:191-3. Available from: http://www.tnoajosr.com/text.asp?2018/56/3/191/243779




  Introduction Top


Vascular endothelial growth factor (VEGF), a homodimeric glycoprotein, is a key regulator of physiologic and pathologic angiogenesis. VEGF consists of seven families- are as follows: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and placental growth factor. Isoforms of VEGF-A have been shown to be the most important promoters of intraocular neovascularization and hyperpermeability.[1] Upregulation of VEGF is the prime contributor to choroidal neovascularization in neovascular age-related macular degeneration (AMD) and for retinal neovascularization and macular edema (ME) in diabetic retinopathy (DR) and retinal vein occlusion (RVO). VEGF has thus become the target for the treatment of these conditions, and the emergence of intravitreal VEGF inhibitors has revolutionized the management of neovascular AMD, diabetic ME (DME) and ME following central RVO, and branch RVO.[2] Ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA, USA/Roche, Basel, Switzerland) is a humanized monoclonal antibody fragment that binds with high affinity to the VEGF-A isoforms (e.g., VEGF110, VEGF121, and VEGF165), thereby preventing the binding of VEGF-A to its receptors VEGF receptor (VEGFR)-1 and VEGFR-2.[3] Once VEGF-A is bound to its receptors, it promotes endothelial cell proliferation and neovascularization and leads to vascular leakage by affecting the tight junction proteins. Vascular leakage is the main mechanism that contributes to the development of DME.

Intravitreal injection of anti-VEGF agents has revolutionized the treatment of common retinal diseases, including neovascular AMD, DR, and RVOs.[4] Moreover, promising results were reported with intravitreal injection of anti-VEGF agents for other ocular diseases such as neovascular glaucoma, retinopathy of prematurity, and intraocular tumors. Currently, several anti-VEGF drugs, including pegaptanib, ranibizumab, bevacizumab, and aflibercept, are available.

Since its approval by the US Food and Drug Administration (FDA) for the treatment of diabetic ME in August 2012,[5] there have been numerous well-designed randomized clinical trials assessing the efficacy of intravitreal ranibizumab in visual improvement in various retinal diseases. However, each intravitreal injection poses the risk of injection-related adverse events. The repeated and long-term injections that are commonly needed may increase the chance of ocular and systemic complications. Adverse events following intravitreal anti-VEGF injections are sometimes unrelated to the underlying ocular disease, which mandates the exertion of caution. The present case describes thromboembolic complication postranibizumab therapy in a 75-year-old female. To the best of our knowledge, such case is the first of its kind from this part of the country.


  Case Report Top


A 75-year-old hypertensive, diabetic, hypothyroid female patient presented with slurring of speech weakness in the left-sided upper and lower limbs and admitted to the hospital. Medication history conferred that for the past 1 year, the patient was on once-daily dosing of sitagliptin 50 mg, glimepiride 2 mg, amlodipine 5 mg, losartan 50 mg, L-thyroxine 25 mcg, and trihexyphenidyl 2 mg; twice-daily dosing of metformin 500 mg, and thrice-daily dosing of levodopa carbidopa-fixed dose combination 125 mg.

On detailed history elicitation, it was noted that the patient had received intravitreal injection of Lucentis (ranibizumab) for epiretinal membrane formation with ME 12 days before the presentation with the said problem. Laboratory investigations suggested glycated hemoglobin – 6.4%; blood urea nitrogen – 10 mg/dL; Cr – 0.6 mg/dL; Na – 137 mmol/L; TSH – 4.32 μIU/mL; total cholesterol – 144 mg/dL; TG – 131 mg/dL; low-density lipoprotein – 78 mg/dL; very LDL – 26 mg/dL; and urine albumin to creatinine ratio – 334.4 (urine pus cells – 20–30). Noninvasive cardiac diagnostic tests comprising of electrocardiogram and echocardiography were normal with ejection fraction 58%. Radiological investigations included computed tomography imaging of brain suggesting ischemic changes in the bilateral periventricular region and centrum semiovale, focal calcific focus in the right posterior thalamus, and diffuse cerebral atrophy. Magnetic resonance imaging of the brain inferred an acute infarct in the left posterior frontal and parietal region with lacunar infarct in the left basal ganglia. She was diagnosed with left middle cerebral artery territory infarction with right-sided hemiparesis and aphasia. After 10 days of hospital stay, she was discharged with advice of once-daily dosing of atorvastatin 40 mg, aspirin 75 mg, and pantoprazole 40 mg and thrice-daily dosing of piracetam 800 mg and levetiracetam 800 mg.

Causality assessment of the reaction conferred it to be “possible” with a score of 3 using Naranjo causality assessment algorithm,[6] while the WHO-UMC causality assessment scale [7] also graded it as “possible.” Severity assessment using Hartwig and Seigel Scale [8] conferred on it to be moderate (Level 4). The event was reported under the Pharmacovigilance Programme of India.


  Discussion Top


VEGF plays a pivotal role in the development of DME, the leading cause of vision loss among aged individuals. Several clinical trials have demonstrated that drugs that bind soluble VEGF to restore the integrity of the blood–retinal barrier, resolve ME, and improve vision in such patients.[9] Intravitreal anti-VEGF administration of pegaptanib, ranibizumab, bevacizumab, and aflibercept has been shown to effectively treat DME; however, among these, ranibizumab and aflibercept have received tUS FDA approval for the treatment of DME in the years 2012[5] and 2014,[10] respectively. Bevacizumab is commonly used as an off-label drug.[11]

Since effective treatment of DME necessitates repeated intravitreal injections of these agents, long-term safety is a major lookout. Each intravitreal injection poses the risk of postinjection-and drug class-associated adverse events. Increases in intraocular pressure have been noted in both the pre and postintravitreal injections.[12] Major injection-related risks include infective endophthalmitis, sterile endophthalmitis, and retinal detachment. Despite the well-established injection-related risks, the potential risk of arterial thromboembolic events such as stroke, transient ischemic attacks (TIA), and myocardial infarctions are of particular concern. There are some evidence that ranibizumab is associated with ATE, but this association requires further research.[13],[14],[15],[16] The mechanism involved, however, hints that VEGF inhibitors might cause cerebrovascular events either by elevating systemic blood pressure or by damaging the cerebral vascular endothelium.[17]

Clinicians should be more vigilant as patients receiving intravitreal injections are at a small risk of developing complications which is often unrecognized or underreported. Patients with a previous history of stroke, TIA, or multiple risk factors should thus be informed about the theoretically increased risk of stroke associated with this therapy prior treatment initiation. Patients should be well monitored after each intravitreal anti-VEGF administration and instructed to seek immediate medical advice on developing any cardiovascular complications.


  Conclusion Top


Intravitreal ranibizumab has revolutionized the treatment of diabetic maculopathy over the past decades, and it has proven its efficacy both in the multiple clinical trials and everyday clinical practices. However, its continued use in patients with ME should be well monitored for the incidences of adverse cardiovascular complications. Focused and continued pharmacovigilance for generation of robust evidence in this regard is warranted.

Acknowledgment

The authors would like to acknowledge and support the untiring efforts and contribution of Pharmacovigilance Programme of India towards ensuring better patient safety nationwide.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Niu G, Chen X. Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Curr Drug Targets 2010;11:1000-17.  Back to cited text no. 1
    
2.
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5.
Lucentis Approval History. Available from: https://www.drugs.com/history/lucentis.html. [Last accessed on 2018 Jun 30].  Back to cited text no. 5
    
6.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. Amethod for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 6
    
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The Use of the WHO-UMC System for Standardised Case Causality Assessment. Available from: http://www.who-umc.org/Graphics/24734.pdf. [Last accessed on 2017 Jun 03].  Back to cited text no. 7
    
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Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.  Back to cited text no. 8
    
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Stewart MW. Anti-VEGF therapy for diabetic macular edema. Curr Diab Rep 2014;14:510.  Back to cited text no. 9
    
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Kampougeris G, Spyropoulos D, Mitropoulou A. Intraocular pressure rise after anti-VEGF treatment: Prevalence, possible mechanisms and correlations. J Curr Glaucoma Pract 2013;7:19-24.  Back to cited text no. 12
    
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Wang W, Zhang X. Systemic adverse events after intravitreal bevacizumab versus ranibizumab for age-related macular degeneration: A meta-analysis. PLoS One 2014;9:e109744.  Back to cited text no. 13
    
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Bressler NM, Boyer DS, Williams DF, Butler S, Francom SF, Brown B, et al. Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials. Retina 2012;32:1821-8.  Back to cited text no. 14
    
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Pratt NL, Ramsay EN, Kemp A, Kalisch-Ellett LM, Shakib S, Caughey GE, et al. Ranibizumab and risk of hospitalization for ischemic stroke and myocardial infarction in patients with age-related macular degeneration: A self-controlled case-series analysis. Drug Saf 2014;37:1021-7.  Back to cited text no. 15
    
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Carneiro AM, Barthelmes D, Falcão MS, Mendonça LS, Fonseca SL, Gonçalves RM, et al. Arterial thromboembolic events in patients with exudative age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab. Ophthalmologica 2011;225:211-21.  Back to cited text no. 16
    
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