In the United States, gastrointestinal stromal tumors (GISTs) have an incidence of 4500 to 6000 new cases per year.1 Surgical resection is the first line of treatment, although up to 80% of the tumors reoccur or metastasize after definitive surgical resection. In addition, cytotoxic chemotherapy and radiation are generally ineffective.2–4 Before 2002, tumor resection was the mainstay for GISTs, and the estimated survival after resection was reported to be only 15 months.4 On February 1, 2002, outcomes dramatically improved when imatinib mesylate (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland) was approved by the US Food and Drug Administration for treatment of GISTs.5 Patients with advanced tumors receiving imatinib mesylate were reported to survive for up to 48 months.4 All medications have potential risks and side effects, and imatinib mesylate is no exception. Imatinib mesylate's most common systemic side effects are fluid retention (superficial systemic and periorbital), gastrointestinal side effects (i.e., nausea, cramps, diarrhea), fatigue, muscle or bone pain, and rash.6–9 There are also ocular side effects reported; however, the most common is periorbital edema.7–9 Moreover, other serious ocular side effects are very rare but have been reported, including optic nerve edema, optic nerve damage, and glaucoma.6–11 Hence, it is important that Optometrists be familiar with imatinib mesylate and its potential sight-threatening complications. The following is a challenging case of such a rare ocular side effect of imatinib mesylate treatment.
A 66-year-old white male presented to the Optometry clinic at West Haven VA Medical Center for an emergent eye examination. His chief complaint was sudden decrease in vision left eye for 3 weeks, with no associated flashes or eye pain, and he felt the visual symptoms were now starting in his right eye also. Medical history was positive for smoking, hypertension, and hyperlipidemia. His medications included prazosin, felodipine, lisinopril, and pravastatin. He was also recently diagnosed with a duodenal GIST with hepatic metastases treated with imatinib mesylate for 4 months, the dosage had been increased from the initial 200 to 400 mg 3 months before this visit.
The examination revealed a stable visual acuity of 20/20 right eye and a reduction in acuity left eye from 20/20 11 months earlier to 20/70. In addition, a positive left afferent pupillary defect and decreased color vision of the left eye 1/11 were noted (Table 1). Color vision of the right eye was normal 11/11. Confrontation visual fields were full to finger count right eye, superior field restriction left eye. Extraocular muscle motility was unrestricted with full range of motion in all gazes both eyes. Cover test showed orthophoria at distance and near. Anterior segment evaluation by slit lamp examination was unremarkable. Intraocular pressure was 15 mm Hg for right eye and 15 mm Hg for left eye with Goldmann applanationtonometry. A dilated fundus assessment revealed syneresis of the vitreous body of both eyes. Optic nerve heads are average size in both eyes, small cup-to-disc ratio of 0.25, with healthy neuroretinal rim tissue right eye and 0.20 elevated edematous optic nerve left eye (Fig. 1). Both maculae were flat without edema and/or thickening. The posterior poles of both right and left eyes were clear with normal vasculature. The peripheral retina was flat and intact, with no pathology noted in both eyes. Humphrey visual field 24–2 examination confirmed a significant superior and mild inferior field defect in the left eye and normal field in the right eye (Fig. 2).
Differential diagnoses included optic neuritis, papilledema, hypertensive disc edema, arteritic anterior ischemic optic neuropathy, nonarteritic ischemic optic neuropathy (NAION), optic nerve compression, and toxic optic neuropathy. Optic neuritis is most commonly caused by multiple sclerosis. However, less common causes include the following: autoimmune disorders (i.e., lupus), granulomatous inflammation (i.e., tuberculosis, sarcoidosis), infection (bacterial, viral, or fungal), or idiopathic.12 Optic neuritis was an unlikely diagnosis based on the patient's age, gender, lack of pain on eye movement, no evidence of infection, or any diagnosis of autoimmune or granulomatous diseases. Papilledema was also unlikely due to the unilateral nature of the presentation, no preceding symptoms of transient vision loss, and no other neurological signs or symptoms. Uncontrolled hypertension can cause disc edema, but it is usually bilateral and accompanied by bilateral arteriovenous crossing changes, cotton-wool spots, and flame-shaped hemorrhages. The patient did not exhibit any of these findings except for the unilateral disc edema, and his blood pressure was under control; therefore, this differential was eliminated. Because of the patient's lack of headache, jaw claudication or scalp tenderness, moderate (not severe) vision loss, and no progression of vision loss OS or loss of vision in the other eye arteritic anterior ischemic optic neuropathy was very doubtful.
More likely differentials were optic nerve compression, NAION, and toxic optic neuropathy. According to his medical history of metastatic cancer, magnetic resonance imaging of the brain was obtained, and it was negative for central nervous system metastases that could cause compressive optic neuropathy. This left the two most likely differentials NAION or toxic optic neuropathy caused by imatinib mesylate. NAION was a high suspicion due to the patient's multiple risk factors, including history of smoking, hypertension, hyperlipidemia, peripheral vascular disease along with small optic nerve cupping. This diagnosis was less likely due to the patient's risk factors being well controlled. Toxic optic neuropathy also had to be considered based on the timeline of increased dosage of imatinib mesylate and the patient's symptoms. Immediate comanagement was also done with the patient's oncologist regarding the ocular findings and the possibility of it being caused by imatinib mesylate. Based on an extensive literature review, including cases of imatinib mesylate-related optic nerve edema, retrobulbar optic neuritis, and macular edema, the oncologist discontinued his imatinib mesylate.
The patient returned for an 8-day follow-up per his oncologist request. The oncologist had discontinued the patient's imatinib mesylate 2 days before this follow-up visit. Although the patient was only off the imatinib mesylate for only 2 days, he reported a subjective improvement in his left eye vision. His visual acuity remained stable; however, his visual field was repeated and did show some improvement. The optic disc swelling decreased from baseline when viewed stereoscopically with indirect biomicroscopy, this was supported by the optical coherence tomography that showed a decrease in retina nerve fiber layer thickening (Fig. 3). The patient was again seen 2 weeks later with continued improvement of the optic disc edema. Based on the improvement of clinical findings, visual acuity, and literature research providing similar presentations, the diagnosis of unilateral optic disc edema caused by imatinib mesylate was confirmed. The toxicity level of imatinib mesylate that could potentially cause the optic disc edema in majority of patients is unknown at this time. The patient was continually reevaluated by his oncologist and was subsequently restarted on imatinib mesylate at 50% dose reduction because of its prior effectiveness in controlling the patient's GISTs. There is no standard whether to reinitiate treatment or not at this time. Literature research documents cases of both reoccurrence of the adverse effects after reinitiating treatment and other cases of no reoccurrence.6, 10,11
Five weeks after initial presentation, the patient's acuity had improved from 20/70 to 20/30, and his optic nerve edema was continuing to improve along with the visual field. The patient was followed closely for 3 months where he stabilized with an acuity of 20/40 OS, resolved optic nerve edema, subsequent optic nerve pallor, and reduction in retinal nerve fiber layer thickness (Fig. 4).
Optic neuropathy is a broad term used to describe optic nerve damage caused by any of the following etiologies: infectious, inflammatory, demylinating, traumatic, infiltrative, compressive, glaucomatous, ischemic, hereditary, nutritional, and toxic.12 Determining the etiology of the optic neuropathy is imperative to providing the best management and potential outcome.
This case presents a challenging presentation because of the many potential factors that could have caused or been associated with the patient's optic neuropathy. History of smoking, hypertension, hyperlipidemia, peripheral vascular along with small optic nerve cupping, all represent risk factors in themselves for NAION and when combined create an even higher risk. However, a review of the patient's medical record revealed the coincidence of imatinib mesylate being increased in dosage from 200 to 400 mg 3 months before the onset of the blurry vision, which falls into the documented timeline (5–12 weeks) for the most common ocular side effect, periorbital edema, to arise.7 Based on this timeline of the patient's symptoms, the increased dosage of imatinib mesylate, and the improvement of clinical signs when the medication was discontinued, a diagnosis of toxic optic neuropathy induced by imatinib mesylate, as opposed to NAION, was entertained although it was unilateral.
Toxic Optic Neuropathies
Toxic optic neuropathies can be due to any substance that causes a loss of function of the visual pathway. The ocular symptoms that usually accompany toxic optic neuropathy are slowly progressive bilateral loss of central vision and loss of color vision. Clinically, the only findings are either swelling of the nerve fiber layer or pallor of the optic nerve later in the disease process.13 In this case report, the symptoms and clinical findings were unilateral likely due to the patient presenting to clinic shortly after symptoms arose and the swift discontinuation of imatinib mesylate. If imatinib mesylate had been left at a dose of 400 mg, it would likely have progressed to bilateral presentation. To understand how imatinib mesylate can cause a toxic optic neuropathy, we must understand how and where it can affect the eye. Imatinib mesylate is a selective tyrosine kinase inhibitor that targets v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (c-KIT) and platelet-derived growth factor (PDGF).14,4,15–17 Therefore, for imatinib mesylate to affect the eye KIT and PDGF receptors has to be present. Specifically for this case report, we will concentrate on the retina and optic nerve. At this time, we are unaware of any studies or case reports documenting KIT playing a role in any dysfunction of the retina or optic nerve. PDGF is expressed in pericytes that are found in the endothelium of many capillaries and arteries.18,19 It is well documented that if PDGF is inhibited, it results in edema.7–11,18,20 PDGF receptors have also been found in the retinal ganglion cells of the retina and optic nerve.20 In the other case reports of optic disc edema, retinal edema, and macular edema, the proposed mechanisms include inhibition of PDGF results in edema, and there are no proposed molecular mechanisms behind how this occurs.10,11,21 Biswas et al. closely observed at the role of PDGF and the retinal ganglion cell; they found that the selective tyrosine kinase inhibition of PDGF by imatinib mesylate has potential to cause retinal ganglion cell apoptosis.20 It is then presumed that the apoptosis of many ganglion cells produces the dysfunction of the retina/optic nerve. The mechanism for the resultant edema, which was seen clinically, may solely be related to the inhibited PDGF on the pericytes or a combination of the apoptosis of the retinal ganglion cells and the pericytes. This same study also evaluated whether insulin, a neuroprotective agonist, could prevent the apoptosis created by the inhibition of PDGF; this was not found to be protective.20 Further research is warranted to determine doses of imatinib mesylate sufficient to cause apoptosis of retinal ganglion cells or inhibition of PDGF on pericytes to lead to clinically significant toxicity to the eye.
GISTs are mesenchymal tumors that arise from a mutation of either the cell surface transmembrane receptor KIT or the PDGF.1,15,16 The annual incidence in the United Sates is between 4500 and 6000 new cases.1 They affect both men and women, with >75% occurrence in patients aged >50 years.1 Prognosis is greatly impacted by tumor size and mitotic count.1,17 Also, if there is recurrence or metastases, the prognosis is usually poor (estimated survival is <20 months).1,4,5,15 The most common locations for metastases are the abdominal cavity, lungs, ovaries, or the liver.1,4,17 Treatment is primarily surgical resection; however, this is not always possible.1,17 Even if surgical resection is possible up to 80% of tumors to reoccur or metastasize after definitive surgical resection, and cytotoxic chemotherapy and radiation have not been proven effective in treatment.2–4 Up until 2002, medication treatment was very limited, this changed when imatinib mesylate was approved by the US Food and Drug Administration.14,1,5,16,17
Imatinib mesylate is the standard treatment in advanced GIST patients when surgical resection is not an option.4,5,16,22 Imatinib mesylate was originally developed to treat chronic myelogenous leukemia and was later to be found effective on reducing the size and number of metastases in GISTs.1 Imatinib mesylate is a selective tyrosine kinase inhibitor that targets KIT and PDGF, and it has been found that GISTs are extremely sensitive to this action.14,4,15–17 The standard dose of imatinib mesylate is 400 mg, but it has been shown to be effective in an increased dose of 600 to 800 mg in patients who are initially not responsive to 400 mg.4,15,16 Blanke et al. reported patients on imatinib mesylate 400 mg had a 2-year survival rate of 76%, and Zhu et al. reported patients on imatinib mesylate 400 mg had a median overall survival time of 48 months.4,16
Imatinib mesylate is a well-tolerated medication; however, the majority of patients develop mild or moderate side effects.5,15,22 It has also been shown that treatment with higher doses of imatinib mesylate correlates to increased incidence of its side effects.5,16 It is well documented that superficial edema (most commonly in the legs) is the most common side effect of imatinib mesylate present in >50% of patients (Table 2).5,7,15,22 The most common ocular side effects include periorbital edema and epiphora, which are caused by the inhibition of the PDGF receptors found on dermal dendrocytes in the periorbital skin creating the perioribital edema.7,8 Other documented side effects include extraocular muscle palsy, ptosis, blepharoconjunctivitis, glaucoma, retinal hemorrhages, increased intraocular pressure, abnormal vision, photosensitivity, and conjunctival hemorrhages.6–9,23 Moreover, rare serious ocular side effects have been reported such as optic nerve edema, retrobulbar optic neuritis, and macular edema.6,10,11 In the reported cases, the onset of the more serious ocular side effects was between 1 and 3 months after starting imatinib mesylate 400 mg or more, such as in our case.6,10,11
It is always challenging to restart imatinib mesylate after a serious ocular side effect has occurred. In the few documented cases of patients who were restarted on imatinib mesylate after an ocular adverse effect, only some had a reoccurrence of these complications. In a specific case of optic disc edema, the imatinib mesylate was restarted at the same dose without sequelae. Conversely, in a case of imatinib mesylate-induced optic neuritis, the patient developed symptoms 6 days after restarting the medication on the same dose.6,11 The struggle behind this decision is weighing the efficacy of imatinib mesylate to control metastatic disease from an incurable tumor against the recurrent ocular side effects of the drug that may lead to marked decreases in quality of life from loss of vision. This example represented patient-directed decision making, as the oncologist held extensive discussions with the patient regarding the potential additional ocular toxicity from treatment vs. controlling a life-threatening malignancy on dose-reduced imatinib mesylate with close ocular follow-up examinations. The patient agreed to proceed with this proposed treatment strategy. Indeed, future research evaluating the probability of reoccurrence of ocular side effects and the efficacy of dose reductions of imatinib mesylate on the overall effect on controlling GISTs is warranted.
This case exemplifies the importance of systemic medication review, especially in cases where visual acuity or ocular health has been compromised. The patient's presentation was complicated by the other risk factors for his optic disc edema, vision loss, and visual field defects. However, based on the time frame between initiation of imatinib mesylate treatment and vision loss in addition to the start of resolution after discontinuation of this medication, the symptoms experienced by our patient are most likely a side effect of imatinib mesylate.
Another key point demonstrated by this case is the importance of comanagement with other health care practitioners especially when systemic medication or diseases are contributory to the ocular findings. For this patient, comanagement with oncology was essential in the management and optimization of his visual and oncologic medical care.
Veteran Administration Nebraska
Western Iowa Health Care System-Lincoln
600 S 70th St
Lincoln, NE 68510
In no way does this medical case report reflect the views of the Department of Veterans Affairs, its agents or assigns. This report is published as a factual medical history for educational purposes only and meant to neither endorse nor condemn any medical manufacturer, facility, or provider. In addition, this case report does not serve as a replacement for personal health care from a licensed professional practitioner. As such, any lay reader should beware of misinterpreting this case report, which is written and edited for health care professionals and which may be easily misconstrued without the benefit of professional health care training and experience. This case report was presented as a poster on June 19, 2010, during the American Optometry Association Annual Meeting, Orlando, Florida.
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