Erythropoietin in Treatment of Methanol Optic Neuropathy

Methanol poisoning can cause an optic neuropathy that is usually severe and irreversible and often occurs after ingestion of illicit or homemade alcoholic beverages. In this study, we evaluated the potential neuroprotective effect of erythropoietin (EPO) on visual acuity (VA) in patients with methanol optic neuropathy. In a prospective, noncomparative interventional case series, consecutive patients with methanol optic neuropathy after alcoholic beverage ingestion were included. All patients initially received systemic therapy including metabolic stabilization and detoxification. Treatment with intravenous recombinant human EPO consisted of 20,000 units/day for 3 successive days. Depending on clinical response, some patients received a second course of EPO. VA, funduscopy, and spectral domain optical coherence tomography were assessed during the study. Main outcome measure was VA. Thirty-two eyes of 16 patients with methanol optic neuropathy were included. Mean age was 34.2 years (±13.3 years). The mean time interval between methanol ingestion and treatment with intravenous EPO was 9.1 days (±5.56 days). Mean follow-up after treatment was 7.5 months (±5.88 months). Median VA in the better eye of each patient before treatment was light perception (range: 3.90-0.60 logMAR). Median last acuity after treatment in the best eye was 1.00 logMAR (range: 3.90-0.00 logMAR). VA significantly increased in the last follow-up examination (P < 0.0001). Age and time to EPO treatment after methanol ingestion were not significantly related to final VA. No ocular or systemic complications occurred in our patient cohort. Intravenous EPO appears to improve VA in patients with methanol optic neuropathy and may represent a promising treatment for this disorder.

Original Contribution Erythropoietin in Treatment of Methanol Optic Neuropathy Farzad Pakdel, MD, Mostafa S. Sanjari, MD, Asieh Naderi, PhD, Niloofar Pirmarzdashti, MD, Anousheh Haghighi, MD, Mohsen B. Kashkouli, MD Background: Methanol poisoning can cause an optic neuropathy that is usually severe and irreversible and often occurs after ingestion of illicit or homemade alcoholic beverages. In this study, we evaluated the potential neuroprotective effect of erythropoietin (EPO) on visual acuity (VA) in patients with methanol optic neuropathy. Methods: In a prospective, noncomparative interventional case series, consecutive patients with methanol optic neuropathy after alcoholic beverage ingestion were included. All patients initially received systemic therapy including metabolic stabilization and detoxification. Treatment with intravenous recombinant human EPO consisted of 20,000 units/day for 3 successive days. Depending on clinical response, some patients received a second course of EPO. VA, funduscopy, and spectral domain optical coherence tomography were assessed during the study. Main outcome measure was VA. Results: Thirty-two eyes of 16 patients with methanol optic neuropathy were included. Mean age was 34.2 years (±13.3 years). The mean time interval between methanol ingestion and treatment with intravenous EPO was 9.1 days (±5.56 days). Mean follow-up after treatment was 7.5 months (±5.88 months). Median VA in the better eye of each patient before treatment was light perception (range: 3.90-0.60 logMAR). Median last acuity after treatment in the best eye was 1.00 logMAR (range: 3.90-0.00 logMAR). Department of Ophthalmology (FP, MSS, MBK), Eye Research Center, Tehran University of Medical Sciences, Rassoul Akram Hospital, Tehran, Iran; Department of Ophthalmology (FP), Eye Research Center, Farabi Hospital, Tehran University of Medical Sciences, Tehran, Iran; Eye Research Center (AN, NP), Farabi Hospital, Tehran University of Medical Sciences; and Department of Internal Medicine (AH), Rassoul Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran. Presented at the 2013 Annual Meeting of the American Academy of Ophthalmology, New Orleans. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Mostafa S. Sanjari, MD, Department of Ophthalmology, Eye Research Center, Tehran University of Medical Sciences, Rasool Akram Hospital, Sattarkhan Street, Niayesh Street, Tehran, Iran, postal code 1336616351; E-mail: [e-mail] Pakdel et al: J Neuro-Ophthalmol 2018; 38: 167-171 VA significantly increased in the last follow-up examination (P , 0.0001). Age and time to EPO treatment after methanol ingestion were not significantly related to final VA. No ocular or systemic complications occurred in our patient cohort. Conclusions: Intravenous EPO appears to improve VA in patients with methanol optic neuropathy and may represent a promising treatment for this disorder. Journal of Neuro-Ophthalmology 2018;38:167-171 doi: 10.1097/WNO.0000000000000614 © 2017 by North American Neuro-Ophthalmology Society M ethanol intoxication is associated with a severe and irreversible optic neuropathy and neurologic deficits (1). It is a common additive solvent in washing fluids, antifreeze formulations, photocopying fluids, perfumes, and paint removers. Illegal alcoholic beverages may contain toxic levels of methanol and can be a significant cause of optic neuropathy (2). Poisoning may occur after ingestion, dermal application, or inhalation (1,3). Methanol is metabolized by dehydrogenation to formaldehyde and then to formic acid. Formic acid likely inhibits mitochondrial function, increases oxidative stress, which leads to neurologic damage (1-4). The cytokine erythropoietin (EPO), long known as a hematopoietic agent, also has neuroprotective effects. It has been shown to be neuroprotective in experimental models of mechanical trauma (5-8), neuronal inflammation (9), cerebral and retinal ischemia (10), oxidative stress (11), optic nerve transection (12-14), human studies of traumatic optic neuropathy (15), and ischemic optic neuropathy (16). We conducted a prospective study to evaluate the use of EPO in patients with methanol optic neuropathy. METHODS From November 2010 to January 2013, patients with acute visual loss secondary to methanol toxicity were recruited 167 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution into our study. All patients underwent toxicology evaluation and appropriate systemic treatment for methanol poisoning. Ophthalmology assessment included visual acuity (VA) (Landolt-C), pupillary testing, extraocular movements, slit-lamp examination, and ophthalmoscopy. Retinal nerve fiber layer thickness was measured with spectral domain optical coherence tomography (SD-OCT, Heidelberg Spectralis; Heidelberg Engineering, Dossenheim, Germany). Diagnosis of acute methanol optic neuropathy was based on the history of decreased VA within 24-48 hours after alcoholic beverage ingestion and toxicologist report of methanol intoxication. Those meeting the inclusion criteria were patients with acute visual loss after ingesting methanol; completion of detoxification treatments; less than 3 weeks since methanol ingestion; no improvement in VA for at least 3 days; absence of systemic disease; and serum anion gap below 11 mEq/L before admission. The exclusion criteria included pregnancy; breastfeeding; elevated blood pressure; history of thromboembolic events; malignancy; history of seizure disorder; hemoglobin concentration .16 gm/dL; history or clinical findings of previous ophthalmic disease; previous intervention for optic neuropathy such as corticosteroid or EPO treatment; and history of recent head trauma. Eligible patients were hospitalized and underwent comprehensive physical examination and hematologic studies including complete blood count, liver enzymes, blood urea nitrogen, creatinine, potassium, sodium, and magnesium. Patients received a treatment course of intravenous human recombinant EPO 20,000 international units (Eprex; Janssen Cilag, Berchan, Belgium) as a daily infusion for 3 successive days. They were evaluated by an internal medicine specialist before, during, and after treatment for potential adverse events. Ophthalmologic and systemic assessments were performed at 1, 2, 3, 7, and 14 days, 1 month, 3 and every 6 months, thereafter. Additional treatment was offered to some patients. The criteria for an additional treatment course included 1) none or poor initial response within at least 1 week of EPO treatment and 2) patient gave consent. This study was approved by the ethics committee of Rassoul Akram Eye Research Center of Tehran University of Medical Sciences. It was conducted according to the tenets of Declaration of Helsinki. The purpose of the study, potential outcomes, and possible adverse events were explained to all participants, and written informed consent was obtained from all patients. Statistical analysis was performed by SPSS version 15. We considered 3.9 and 3.6 logarithm of the minimum angle of resolution (logMAR) for VAs of no light perception and light perception (LP), respectively. Wilcoxon on signed-rank test and linear-mixed models were used to compare VA. A P value ,0.05 was considered statistically significant. RESULTS Sixteen consecutive patients with recent methanol optic neuropathy were enrolled in the study (Table 1). All had a history of drinking homemade or illicit alcoholic beverages within 24 hours of onset of systemic and/or visual symptoms. All had already undergone toxicology evaluations and hemodialysis. Mean age was 34.2 years (±13.3, TABLE 1. Demographics and VA before and after treatment with intravenous EPO Case No. Age, yrs/Sex 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 21/m 13/m 38/m 48/m 42/m 38/m 29/m 36/m 18/m 48/m 20/m 36/m 46/m 23/m 29/f 60/m Time Between Methanol Ingestion and Treatment With EPO, d No. of Treatment Courses Initial VA OD OS 14 17 7 4 13 35 7 16 7 3 21 15 3 7 7 5 3 1 3 3 3 2 2 2 2 1 3 3 2 2 2 2 NLP HM NLP NLP LP NLP NLP NLP HM HM NLP 20/400 2 m CF NLP HM NLP NLP HM HM HM HM NLP NLP LP HM LP NLP 20/400 20/80 NLP HM NLP Final VA (At least 3 mo) OD 20/20 20/40 HM 20/25 1 m CF 1 m CF NLP 20/32 1.5 m CF 20/120 20/32 20/300 2 m CF 20/32 20/160 20/32 OS 20/20 20/30 20/400 20/25 20/25 1 m CF NLP 20/25 1.5 m CF 1 m CF HM 20/200 20/50 20/40 HM 20/25 Follow-up, mo 23 18 5 8 5 3 4 3 6 5 4 15 3 7 7 5 CF, counting fingers; d, days; EPO, erythropoietin; f, female; HM, hand movement; LP, light perception; m, male; mo, months; NLP, no light perception; OD, right eye; OS, left eye; VA, visual acuity. 168 Pakdel et al: J Neuro-Ophthalmol 2018; 38: 167-171 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution range: 13-62 years). The mean time interval between methanol ingestion and treatment with intravenous EPO was 9.1 days (±5.56, range: 3-21 days). Mean follow-up time after treatment was 7.5 months (±55.88, range: 3-23 months). Median VA in the better eye of each patient before treatment with EPO was LP (3.60 logMAR, range: 3.90- 0.60 logMAR). Median last VA after treatment in the best eye was 1.00 logMAR (range: 3.90-0.60 logMAR). Median last VA after treatment in the better eye was 1.00 logMAR (range: 3.90-0.00 logMAR). VA was significantly better in the last follow-up examination compared with initial acuity (P , 0.0001) (Fig. 1). Visual improvement was significantly better in participants with baseline VA of hand movement or better (t = 2.36, P = 0.025, 95% confidence interval: 0.15-2.08). Fourteen patients (excluding Cases 2 and 10) received more than 1 course of intravenous treatment when they showed a rapid but partial impairment after the first EPO treatment. In patients who received repeated injections, a stepwise increment in VA occurred; however, it was not statistically significant (P = 0.6). All patients except 1 (Case 7) showed improvement in VA within 1-3 days after starting intravenous EPO (Table 1). One patient (Case 4) showed a modest decrement in VA 3 months after an initial remarkable improvement. He denied new consumption of any alcoholic beverages and drugs and head trauma. All patients developed optic disc pallor with increased cupping. In 6 patients, SD-OCT data were available over a 3-month follow-up period. Average peripapillary nerve fiber layer thickness was 85.04 mm (±28.19) and 76.88 mm (±23.77) in the right eye (OD) and left eye (OS), respectively. There was no significant difference in VA in patient age or time interval between methanol ingestion and starting intravenous EPO in OD (P = 0.63) and OS (P = 0.80). FIG. 2. Case 2. Axial T2 MRI shows areas of abnormal increased and decreased signal in the basal ganglia bilaterally. Also, there was no significant correlation between final VA and peripapillary nerve fiber layer thickness) in the OD and OS (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A291). One patient (Case 2) developed ataxia, tremor, and muscle rigidity. Brain MRI revealed putaminal abnormalities (Fig. 2). Tremor and motor impairment started to improve approximately 3 weeks after treatment with EPO, and the patient was able to walk without assistance within 3 months. Brain MRI was unremarkable in all other patients. There were no adverse drug events during and after treatment with EPO. DISCUSSION FIG. 1. Mean visual acuity before (pre-) and after intravenous erythropoietin treatment in the right and left eyes. Error bars represent standard deviation. mo, months; OD, right eye; OS, left eye. Pakdel et al: J Neuro-Ophthalmol 2018; 38: 167-171 Histopathologic findings in patients with methanol toxicity have shown demyelination in the retrobulbar portion of the optic nerve (17,18). This likely results from histotoxic effects of formic acid on oxidative metabolism in watershed areas of the cerebral and optic nerve circulations. Formic acid can inhibit cytochrome C oxidase activity in mitochondria and prevent oxidative metabolism because of its affinity for ferric iron moiety (19,20). Inhibition of adenosine triphosphate leads to interruption of axoplasmic flow, intraaxonal swelling, and optic disc edema. Sodium-potassium adenosine triphosphatase inhibition interferes with nerve conduction (17,19). Also, mitochondrial inhibition may 169 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution increase the production of reactive oxygen species, resulting in cell death (4). Methanol ingestion can cause dysfunction in Muller cells and photoreceptors (21,22). Baumbach et al (23) reported lesions of the inner segment of photoreceptors in methanol poisoning, especially in rods, which are known to be more sensitive to metabolic insults than cones. Currently, treatment of methanol toxicity includes correction of metabolic acidosis with intravenous sodium bicarbonate, elimination of methanol and its metabolites from the body by hemodialysis and preventing the formation of toxic metabolites by competitive inhibition of alcohol dehydrogenase by ethyl alcohol or fomepizole (1,24). Generally, patients with established methanol optic neuropathy respond poorly to this regimen (17), although there are a few case reports of visual improvement after treatment with corticosteroids and vitamin B1 (16,25,26). Pakravan and Sanjari (27) have reported 2 patients with methanol optic neuropathy who experienced dramatic improvement in their vision after multiple injections of EPO combined with the use of corticosteroids. Our study demonstrated that administration of EPO may exert a beneficial effect in patients with methanol optic neuropathy. EPO is a pleiotropic cytokine originally characterized as a hematopoietic growth factor (28). However, EPO also has been shown to have neuroregenerative, proangiogenic, anti-inflammatory, antioxidative, and antiapoptotic actions in the brain (29). These effects may result from the activation of one or more signal transduction pathways such as those involving P13K/Akt, STAT-5, or MAPK/ERK (9,11,30-32). EPO seems to have multiple effects on both optic nerve and retinal survival. EPO may increase retinal ganglion cell (RGC) and axon survival by its neuroregenerative properties and upregulating growth-associated protein-43 expression (14,33). In addition, EPO has a neuroprotective effect on RGCs against glutamate-induced cytotoxicity and nitric oxide toxicity likely through its potential effect to increase the Bel-2 expression (34). Junk et al (35) showed that systemic administration of EPO before or immediately after retinal ischemia could both reduce the histopathological damage and promote functional recovery. Another potential contributing biologic property of EPO is through protecting the cells against oxidative damage and inflammatory cytokines. Several experiments have shown that oxidative stress disrupts the barrier integrity of retinal pigment epithelial (RPE) cells, increasing intracellular reactive oxide species and activating caspase-3, leading cells to apoptosis (36). EPO inhibits lipid peroxidation by increasing the activities of intracellular antioxidant enzymes such as glutathione peroxidase and superoxide dismutase (37). EPO can protect the RPE cells against hydrogen peroxide-induced mitochondrial dysfunction and oxidative damage by activating the P13KAkt pathway, modulating mitochondrial membrane potential, reactive oxygen species level, and cysteine protease 170 activity, and downregulating inflammatory cytokines (38). EPO is known to be expressed in retinal tissue (38). By increasing retinal EPO and its receptor, RPE-cultured cells have been protected against light-induced oxidatively mediated retinal apoptosis (39). In a rat model or cerebral ischemia, administration of EPO attenuated the influx of inflammatory cells into the damaged region and decreased the production of proinflammatory cytokines, including tissue necrosis factors and interleukin-6 (10,40). One of our patients had severe gait disturbance and signs of parkinsonism secondary to putamen necrosis, but improved within 3 months after treatment with EPO. Parkinsonian movement disorder has been reported in methanol toxicity and is assumed to be associated with predilection of formic acid to concentrate in putamen and impairment of dopaminergic pathways and increase enzymatic activity of dopa-B-hydroxylase (41,42). It has been shown that EPO may be effective in ischemic and toxic damage of central nervous system (43,44). Also, EPO could protect neural tissues after metabolic stress (45). Furthermore, it may protect or improve function of dopaminergic neurons in substantia nigra (44,46). In conclusion, intravenous EPO showed a relatively rapid increase in VA when used within 3 weeks of ingestion of methanol. EPO may be a promising modality of treatment for methanol-associated optic neuropathy. The precise mechanism by which EPO exerts its protective effects on the visual system remains unclear but may have beneficial effects on both the optic nerve and retina. Limitations of our study include lack of a control group, lack of significant visual field data, and relatively small number of patients. Clinical trials need to answer the questions regarding dosage, timing, to establish the magnitude of effects of EPO treatment. Also, optic nerve structural effects of EPO require further study. REFERENCES 1. Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol. 2002;40:415-446. 2. Givens M, Kalbfleisch K, Bryson S. Comparison of methanol exposure routes reported to Texas Poison Control Centers. West J Emerg Med. 2008;9:150-153. 3. International Programme on Chemical Safety (IPCS). Methanol. Environmental Health Criteria 196. Geneva, Switzerland: WHO, 1997. 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