Why Therapeutic Compliance in Optic Neuritis Deserves to be More Than Just a Footnote

Letters to the Editor Although the reason for the slow deterioration of vision in our patient is unclear, we suggest 3 possibilities. First, under metabolic conditions causing stress such as respiratory complex 1 dysfunction in LHON, the retinal ganglion cells may have been able to increase their mitochondrial copy number to compensate for insufficient ATP synthesis. Conceivably, our patient was able to upregulate her mitochondrial biogenesis against acute or subacute vision deterioration that occurs in LHON. Second, estrogens may have a protective effect against retinal ganglion cell damage in women with LHON mutations. It has been reported that LHON cybrids treated with 17b-estradiol demonstrated a significant reduction in reactive oxygen species levels and more efficient mitochondrial biogenesis (3-5). Retinal ganglion cell bodies, which are selectively damaged in patients with LHON, have a high concentration of estrogen receptors. This evidence suggests that the neuroprotective effect of estrogen may have played a role in the clinical course of our patient. Finally, we could not find any clinical or environmental factors known to trigger vision loss in our patient, so possibly this led to a slow decline in vision rather than one of abrupt onset. We are unaware of any similar reports of visual loss in patients with LHON occurring over many years. Our case emphasizes that the presentation and progression of LHON are variable, and clinicians should be aware of this clinical course. Bo Young Chun, MD, PhD Department of Ophthalmology, School of Medicine, Kyungpook National University, Daegu, Korea Department of Ophthalmology, Kyungpook National University Hospital, Daegu, Korea Brain Science & Engineering Institute, School of Medicine, Why Therapeutic Compliance in Optic Neuritis Deserves to be More Than Just a Footnote W e read with interest the Point Counter-Point by Morrow and Ko (1) discussing the use of oral corticosteroids to treat demyelinating optic neuritis. Despite their differences, both authors agreed, and we concur, that the treatment of typical optic neuritis with high-dose oral corticosteroids (at least 1,000-mg prednisone equivalents) is noninferior to intravenous methylprednisolone (IV-MP) (1,000 mg), and that there is no evidence of benefit and some evidence of risk with lower-dose corticosteroids. Both authors outlined and evaluated the relevant studies and 422 Kyungpook National University, Daegu, Korea Dai Woo Kim, MD, PhD Department of Ophthalmology, School of Medicine, Kyungpook National University, Daegu, Korea Department of Ophthalmology, Kyungpook National University Hospital, Daegu, Korea Byeong Jae Son, MD, PhD Department of Ophthalmology, Kyungpook National University Hospital, Daegu, Korea The authors report no conflicts of interest. REFERENCES 1. Ohden KL, Tang PH, Liley CC, Lee MS. Atypical Leber hereditary optic neuropathy: 18-year interval between eyes. J Neuroophthalmol. 2016;36:304-307. 2. Jorstad OK, Odegaard EM, Heimdal KR, Kerty E. Leber hereditary optic neuropathy caused by mitochondrial DNA 40663T˃C point mutation and its response to idebenone treatment. J Neuroophthalmol. 2018;38:129-131. 3. Yu-Wai-Man P. Therapeutic approaches to inherited optic neuropathies. Semin Neurol. 2015;35:578-586. 4. Pfeiffer ML, Hashemi N, Foroozan R, Lee AG. Late-onset Leber hereditary optic neuropathy. Clin Exp Ophthalmol. 2013;41:690-693. 5. Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Gheli A, Sadun AA, d'Amati G, Carelli V. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Brain. 2011;134:220-234. available evidence base, however, neither considered the crucial issue of therapeutic compliance. One major advantage of intravenous administration of any drug is that there can be little doubt that the patient is, indeed, receiving treatment. By contrast, with oral administration, unless patients take their medication in front of a witness (e.g., as is often required with methadone in the treatment of opioid dependence), drug intake cannot be guaranteed. Approximately 50% of patients do not take their medication as prescribed (2), and the likelihood of noncompliance is generally increased when there are wellknown and undesirable side effects, as is the case with corticosteroids. It is, therefore, likely that some patients prescribed oral corticosteroids may only take them initially, or at a reduced dose. The risk of noncompliance is Letters to the Editor: J Neuro-Ophthalmol 2018; 38: 419-425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor compounded where the regimen is onerous as would be the case with prednisone tablets. As Dr. Morrow explained "prednisone in 20-mg tablet form is generally the most available and least expensive alternative in the United States." A prescription of oral prednisone 1,250 mg (equaling methylprednisolone 1,000 mg) for 3 days would require a patient to take more than sixty 20-mg tablets in a day, which may prove too much for some patients. Methylprednisolone (at least in Europe) comes in 100-mg tablet form, and patients will no doubt find taking 10 tablets more palatable than taking 60. The acceptability to patients of a proposed treatment is vital in the case of demyelinative optic neuritis, where noncompliance with oral corticosteroids resulting in a patient taking lower doses will not only have no benefit but may even cause harm. In view of this, we would like to strongly encourage everyone prescribing oral treatment for optic neuritis to emphasize the importance of full compliance, and, where this seems unlikely at the outset, offer treatment with IV-MP, or avoid steroids altogether. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland James M. A. Ellison, BMedSci(Hons), BMBS, PGDip, MRCPsych Medical Education Unit, University of Nottingham School of Medicine, Nottingham, United Kingdom Nottinghamshire Healthcare NHS Foundation Trust, Nottingham, United Kingdom Jessica R. Chang, MD Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland USC Roski Eye Institute, Keck Medicine of USC, Los Angeles, California The authors report no conflicts of interest. REFERENCES Anna M. Gruener, BMedSci(Hons), BMBS, MSc, FRCOphth Department of Ophthalmology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom Why Therapeutic Compliance in Optic Neuritis Deserves to Be More Than Just a Footnote: Response I appreciate the comments of Dr. Gruener et al regarding oral steroid administration for optic neuritis (1). I certainly agree that compliance with a full course of therapy should be encouraged; medications are of no value unless a patient takes them. It is every physician's duty to carefully explain benefits and risks of any therapeutic undertaking. Fortunately, published data and personal experience indicate good compliance with a regimen similar to the one I suggested for optic neuritis. Sarah Morrow et al (2) surveyed patients treated with oral prednisone 1,250 mg daily for 5 days for multiple sclerosis relapse, identifying a compliance rate of at least 94%. Protocol deviations for noncompliance were rare in the similarly-dosed COPOUSEP study (3). Dr. Gruener et al expressed reasonable concern over the number of pills needed to deliver the suggested dose of prednisone (1,250 mg daily). Although I noted that 20-mg tablets are the most easily obtained, 50-mg tablets Letters to the Editor: J Neuro-Ophthalmol 2018; 38: 419-425 1. Morrow MJ, Ko MW. Should oral corticosteroids be used to treat demyelinating optic neuritis? J Neuroophthalmol. 2017;37:444-450. 2. Haynes RB, McDonald HP, Garg AX. Helping patients follow prescribed treatment: clinical applications. JAMA. 2002;288:2880-2883. were available at all large Los Angeles-area pharmacies I contacted in a telephone survey in response to this question. Cost for a 3-day course ranged from $33 to 55 if paying out of pocket, and even less with insurance. Another option is mixing the powdered intravenous preparation of methylprednisolone (MP) into a beverage and having the patient drink it as a slurry. This form of MP comes in 1000-mg vials, but is generally available only from inpatient pharmacies. Either way, one might note that these are uncommon steroid-dosing regimens; prescribers should be prepared to answer questions from incredulous pharmacists. There are certainly instances in which intravenous steroid administration might be preferred, including previous intolerance of oral dosing and noncompliance despite thoughtful discussion. There are also occasions when inpatient admission is necessary for management of severe diabetes exacerbation and other acute steroid complications, or for nursing needs of disabled patients. In my opinion, these much more costly interventions should be weighed carefully in view of the prevailing information on high-dose oral steroids. 423 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.