Journal of Neuro-Ophthalmology, March 2013, Volume 33, Issue 1

Is Pentoxifylline Plus Vitamin E an Effective Treatment for Radiation-Induced Optic Neuropathy?

woman. In the last case, concomitant nutritional deficiency (vitamins B1 and B6) may have been responsible for the optic neuropathy because her vision stabilized with appropriate supplementation. In the case reported by Traber et al (1) MRI showed enhancement of both optic nerves. Their patient developed rapid onset of decreased vision, and the MRI was performed 2 weeks after the onset. In contrast, our patient's visual loss was more chronic, and MRI was obtained approximately 2 months after the onset of visual failure. We believe that the late occurrence of optic neuropathy in our patient may, in part, be the result of strict control of his disease since birth. Fasting, the stress of the surgical procedure, and hyperammonemia that developed during surgery may have triggered optic nerve damage. Susana Noval, PhD, MD Ophthalmology Department, La Paz University Hospital, IdiPaz, Madrid, Spain, [e-mail] Mónica López-Rodríguez, MD Internal Medicine Department, La Paz University Hospital, IdiPaz, Madrid, Spain Eugenia González-Sánchez, MD Ophthalmology Department, La Paz University Hospital, IdiPaz, Madrid, Spain Inés Contreras, PhD, MD Ophthalmology Department, Ramón y Cajal University Hospital, Madrid, Spain Arancha Royo, MD Radiology Department, La Paz University Hospital, IdiPaz, Madrid, Spain Ana Boto-De-los-Bueis, MD, PhD Ophthalmology Department, La Paz University Hospital, IdiPaz, Madrid, Spain The authors report no conflicts of interest. REFERENCES 1. Traber G, Baumgartner MR, Schwarz U, Pangalu A, Donath MY, Landau K. Subacute bilateral visual loss in methylmalonic acidemia. J Neuroophthalmol. 2011;31:344-346. 2. Salbert BA, Astruc J, Wolf B. Ophthalmologic findings in biotinidase deficiency. Ophthalmologica. 1993;206:177-181. 3. Rahman S, Standing S, Dalton RN, Pike MG. Late presentation of biotinidase deficiency with acute visual loss and gait disturbance. Dev Med Child Neurol. 1997;39:830-831. 4. Puertas Bordallo D, Martin Reyes C, Ruiz-Falcó Rojas ML, Duat Rodríguez A, Valls Ferrán MI. [Optic neuropathy in biotinidase deficiency]. Arch Soc Esp Opthalmol. 2004; 79: 393-396. 5. Costeff H, Elpeleg O, Apter N, Divry P, Gadoth N. 3-Methylglutaconic aciduria in "optic atrophy plus". Ann Neurol. 1993;33:103-104. 6. Patton N, Beatty S, Lloyd IC, Wraith JE. Optic atrophy in association with cobalamin C (cblC) disease. Ophthalmic Genet. 2000;21:151-154. 7. Wolf B, Hsia YE, Sweetman L, Gravel R, Harris DJ, Nyhan WL. Propionic acidemia: a clinical update. J Pediatr. 1981;99: 835-846. 8. Harker HE, Emhardt JD, Hainline BE. Propionic acidemia in a four-month-old male: a case study and anesthetic implications. Anesth Analg. 2000;91:309-311. 9. Ianchulev T, Kolin T, Moseley K, Sadun A. Optic nerve atrophy in propionic acidemia. Ophthalmology. 2003;110: 1850-1854. 10. Williams ZR, Hurley PE, Altiparmak UE, Feldon SE, Arnold GL, Eggenberger E, Mejico LJ. Late onset optic neuropathy in methylmalonic and propionic acidemia. Am J Ophthalmol. 2009;147:929-933. Is Pentoxifylline Plus Vitamin E an Effective Treatment for Radiation-Induced Optic Neuropathy? We read with great interest the article, "Novel treat-ment of radiation optic neuropathy with intravenous bevacizumab" by Farooq et al (1). We recently evaluated a patient with radiation optic neuropathy (RON) who also experienced dramatic visual recovery after treatment with corticosteroids, pentoxifylline, and vitamin E. A 42-year-old woman reported acute, painless loss of vision in the right eye 3.5 months following gamma knife therapy for a partially resected pituitary tumor. Treatment consisted of 23 Gy to the right sellar region in a single treatment, with the right optic nerve receiving a marginal point maximum dose of 10.5 Gy (Fig. 1A). Visual acuity was counting fingers in the right eye and 20/20 in the left eye, with a right relative afferent pupillary defect. Automated visual field testing demonstrated dense, global field loss in the right eye (Fig. 2A) and was normal in the left eye. The remainder of the examination, including ophthalmoscopy, was unremarkable. Magnetic resonance imaging of the brain revealed en-hancement of the canalicular segment of the right optic nerve (Fig. 1B). Cerebrospinal fluid analysis and serologic studies to rule out demyelinating, infectious, and autoimmune causes were normal. Thought to have RON, the patient was treated with 6 mg of dexamethasone, 400 mg of pentoxifylline, and 400 IU of vitamin E, each given 3 times per day. Two weeks after initiating therapy, the patient reported a dramatic improvement in her vision. Visual acuity was 20/40 in the right eye, with marked improvement in her right visual field (Fig. 2B). She was tapered off dexa-methasone over 6 weeks but continued on pentoxifylline and vitamin E. Chahal et al: J Neuro-Ophthalmol 2012; 33: 90-95 91 Letters to the Editor Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Six weeks after initiating treatment, vision remained 20/40 in the right eye, but there was further improvement in the visual field (Fig. 2C). After 4.5 months, visual acuity was 20/25 in the right eye, and the patient remains on pentoxifylline and vitamin E. In the patient reported by Farooq et al, the remarkable recovery of vision was attributed to intravenous bevacizu-mab. Any possible synergistic effect of corticosteroids was not discussed, and the potential contribution of pentoxifyl-line was dismissed, claiming that there is "little evidence that pentoxifylline has any significant effect on radiation therapy." This is based on a report by Nieder et al (2) review-ing the role of pentoxifylline in radiation injury. These inves-tigators noted that there is "little evidence . . . to prove that pentoxifylline reduces the acute side effects of radiotherapy." However, with respect to the late sequelae of radiation expo-sure, they state, "numerous non-randomized clinical trials described healing of soft tissue necrosis and improvement of . . . fibrosis after several weeks of pentoxifylline or pentox-ifylline plus vitamin E." FIG. 1. A. Stereotactic radiosurgery map outlining distribution of radiation isodose curves. B. Axial fluid-attenuated inversion recovery (FLAIR) image demonstrates hyper-intensity of the canalicular segment of the right optic nerve (arrow). FIG. 2. Automated visual fields of the right eye. A. At presentation, there is dense global field loss. B. Two weeks after starting treatment, there is marked improvement with a residual central scotoma. C. Follow-up at 6 weeks shows an intact visual field. 92 Chahal et al: J Neuro-Ophthalmol 2012; 33: 90-95 Letters to the Editor Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. While unproven in the nervous system, there is substantial evidence that pentoxifylline is efficacious in treating delayed-onset radionecrosis of various soft tissues (3-5). Pentoxifylline improves blood viscosity and flow, decreases fibroblast pro-liferation and wound healing, and mitigates the production of inflammatory mediators, such as tumor necrosis factor (6-8). Pentoxifylline in combination with vitamin E, a powerful antioxidant, has been proposed as an even more potent, tar-geted approach. Using this combination, in vivo studies of irradiated cells have demonstrated reduced generation of re-active oxygen species and impaired fibrosis (3,9) and histo-logic normalization of irradiated tissues in animal models (10,11). Promising results of using pentoxifylline and vitamin E in humans have been reported anecdotally (12,13) and in one randomized placebo-controlled trial (14). Both our patient and the patient reported by Farooq et al (1) demonstrated potential reversibility of radiation-induced injury to the anterior visual pathways by targeting underlying etiologic mechanisms. Pentoxifylline is gaining credibility in the treatment of radiation-induced injury to nonneural tissues, is less expensive than bevacizumab, and is established as safe based on decades of systemic administration. Further study is war-ranted for its potential role in managing patients with RON. Harinder S. Chahal, MD Department of Ophthalmology, University of California, Davis, Sacramento, California. [e-mail] Alexander Lam, BS School of Medicine, University of California, Davis, Sacramento, California S. Khizer Khaderi, MD, MPH Department of Ophthalmology, University of California, Davis, Sacramento, California REFERENCES 1. Farooq O, Lincoff NS, Saikali N, Prasad D, Miletich RS, Mechtler LL, Novel treatment for radiation optic neuropathy with intravenous bevacizumab. J Neuroophthalmol. [published ahead of print August 3, 2012] doi:10.1097/WNO.0b013e3182607381. 2. Nieder C, Zimmermann FB, Adam M, Molls M. The role of pentoxifylline as a modifier of radiation therapy. Cancer Treat Rev. 2005;31:448-455. 3. Futran ND, Trotti A, Gwede C. Pentoxifylline in the treatment of radiation-related soft tissue injury: preliminary observations. Laryngoscope. 1997;107:391-395. 4. Delanian S, Lefaix JL. Current management for late normal tissue injury: radiation-induced fibrosis and necrosis. Semin Radiat Oncol. 2007;17:99-107. 5. Chiao TB, Lee AJ. Role of pentoxifylline and vitamin E in attenuation of radiation-induced fibrosis. Ann Pharmacother. 2005;39:516-522. 6. Adams JG Jr, Dhar A, Shukla SD, Silver D. Effect of pentoxifylline on tissue injury and platelet-activating factor production during ischemia-reperfusion injury. J Vasc Surg. 1995;21:742-748; discussion 8-9. 7. Needham D, Armstrong M, Hatchell DL, Nunn RS. Rapid deformation of "passive" polymorphonuclear leukocytes: the effects of pentoxifylline. J Cell Physiol. 1989;140:549-557. 8. Sonkin PL, Sinclair SH, Hatchell DL. The effect of pentoxifylline on retinal capillary blood flow velocity and whole blood viscosity. Am J Ophthalmol. 1993;115:775-780. 9. Berman B, Wietzerbin J, Sanceau J, Merlin G, Duncan MR. Pentoxifylline inhibits certain constitutive and tumor necrosis factor-alpha-induced activities of human normal dermal fibroblasts. J Invest Dermatol. 1992;98:706-712. 10. Lefaix JL, Delanian S, Vozenin MC, Leplat JJ, Tricaud Y, Martin M. Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study. Int J Radiat Oncol Biol Phys. 1999;43:839-847. 11. Dion MW, Hussey DH, Osborne JW. The effect of pentoxifylline on early and late radiation injury following fractionated irradiation in C3H mice. Int J Radiat Oncol Biol Phys. 1989;17:101-107. 12. Delanian S, Balla-Mekias S, Lefaix JL. Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol. 1999;17:3283-3290. 13. Fischer M, Wohlrab J, Marsch W. Crux medicorum ulcerated radiation-induced fibrosis - successful therapy with pentoxifylline and vitamin E. Eur J Dermatol. 2001;11:38-40. 14. Delanian S, Porcher R, Balla-Mekias S, Lefaix JL. Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol. 2003;21:2545-2550. Spontaneous Resolution of Optic Perineuritis Optic perineuritis (OPN) is a clinical entity characterized by painful visual loss and a distinctive neuroimaging sign of optic nerve sheath enhancement (1). It may be a manifesta-tion of a systemic disease as recently reported by McClelland et al (2). OPN may be severe and recurrent and typically requires treatment with systemic corticosteroids. While steroids are thought to be essential in the management of OPN, we recently evaluated a patient with OPN, which resolved com-pletely without treatment. A 60-year-old African American woman reported a 2-week history of visual loss, severe pain around both eyes, and headache worsened when lying down. She denied nausea, vomiting, photophobia, sonophobia, pulsatile tinnitus, or diplopia. Medical history was significant for well-controlled hypertension and glucose intolerance. Surgical history included cholecystectomy, appendectomy, and hysterectomy. She took only multivitamins, calcium, and omega-3. She denied use of tobacco, alcohol, or recreational drugs. Tung et al: J Neuro-Ophthalmol 2012; 33: 90-95 93 Letters to the Editor Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.