Recent eLetters

Dear Editor,

RE: Non-arteritic anterior ischaemic optic neuropathy and the treatment of erectile dysfunction.

McGwin et al.[1] suggest that treatment of erectile dysfunction with sildenafil (Viagra®) or tadalafil (Cialis®), two phosphodiesterase inhibitors (PDE5-I), may increase the odds of non-arteritic anterior ischaemic optic neuropathy (NAION) in men with a history of myocardial infarction (MI) or hypertension (HTN). We believe, however, that this study is fraught with significant limitations (as the authors acknowledge) that preclude drawing any conclusions about this relationship.

Case-control studies are susceptible to several biases that must be carefully considered and controlled for in the study design, implementation, and analysis.[2] For example, accurate and complete ascertainment of exposure is critical in a retrospective case-control study because both disease and exposure occur prior to study initiation. The authors note that the interviewers were not blinded to the case or control status of the patient, making it possible that the interviewer may, even unconsciously, probe cases differently from controls for exposure to a PDE5-I (interviewer bias). Another obstacle is that patients were not consistently interviewed at the time of NAION event (or index date for controls) about their PDE5-I usage. Hence, NAION patients may have been more likely to remember drug usage (recall bias). Furthermore, exposure misclassification may have occurred as timing, dose, and duration of drug use relative to event onset were not captured (exposure bias). This information is crucial for drugs used as needed such as PDE5-I and particularly for short half-life drugs like sildenafil.

Perhaps, the most troublesome weakness of the study was the limited sample size and differential participation rates of cases and controls, likely resulting in selection bias that distorts the conclusion. The authors note that almost one-fifth of the cases and one-third of the controls refused to participate. The baseline cardiovascular characteristics, while not significantly different (with the exception of MI) between cases and controls, were consistently more prevalent in the NAION group. This finding is not surprising given that these cardiovascular conditions, especially in combination, are also risk factors for NAION.[3] Thus, the MI and HTN subgroup analyses presented in Table 3 should be interpreted with skepticism.

Exacerbating the inherent problems are subgroup analyses that had no a priori hypothesis. The dangers of unplanned subgroup analyses in research are well documented.[4] Compounding matters is the sparse number of patients, reflected in the exceptionally wide confidence intervals (Table 3). The robustness of such extremely small cell numbers must also be questioned, as the observed statistical significance for patients with MI can be eliminated if only one or two patients are switched to an alternative category. The authors also did not provide individual patient totals by exposure group with and without MI, rendering it impossible to replicate their results. Furthermore, there appear to be errors in the numbers/percentages and crude odds ratios presented in Table 2.

In summary, the methodological limitations call into serious question the authors’ conclusions. For men with a history of MI or HTN, therefore, this study does not provide any valid evidence that the use of Viagra or Cialis may increase the risk of NAION.

Rachel E. Sobel, MPH,
Pfizer Inc,
150 E 42nd St., MS#150-3-72,
New York, NY 10017.
Rachel.Sobel@pfizer.com

Joseph C. Cappelleri, PhD, MPH,
Pfizer Inc,
Global Research and Development,
Groton, CT.

References

1 McGwin G, Vaphiades MS, Hall TA, Owsley C. Non-arteritic anterior ischaemic optic neuropathy and the treatment of erectile dysfunction. Br J Ophthalmol 2006; 90:154-157.

2 Rothman KJ, Greenland S. Modern Epidemiology. Philadelphia, PA: Lippincott-Raven Publishers, 1998.

3 Hatzichristou, D. Phosphodiesterase 5 Inhibitors and Nonarteritic Anterior Ischemic Optic Neuropathy (NAION): Coincidence or Causality? J Sex Med 2005; 2:751–758.

4 Assman SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000; 35:1064- 1069.

Keywords: NAION, phosphodiesterase-5 inhibitors.

Dear Editor,

We read with great interest the clinical report by Pate et al. in which bacterial conifection in keratomycosis was reported by smear, culture or both. We have seen in our own practice in a series of 110 cases of infectious keratitis (unpublished data) between year 2001-2005, six cases of bacterial co infection in keratomycosis. Five of them were smear positive and one case was only culture positive for bacteria. In all these cases, the mycotic element was septate fungus - Fusariunm sps and not yeast as reported by these authors. We had suspected polymicrobial keratitis clinically in all these cases due to certain distinctive features at presentation. The typical raised dry infiltrate with hyphate margins which is so characteristic of keratomycosis was modified into wet looking necrotic infiltate in some areas; epithelial defect overlying the infiltrate showed extension beyond the infiltrate in some areas. Treatment in all these cases is incomplete if thorogh microbiological work up is not done. Clinical judgement does suffice to treat microbial keratitis in many cases, rather we advocate laboratory support.

Dear Editor,

We read with great interest the article titled 'Characteristic clinical features as an aid to the diagnosis of suppurative keratitis caused by filamentous fungi' by Thomas and associates1. We would like to congratulate the authors on this attempt to validate the signs of fungal keratitis, which would be helpful to the ophthalmologists of developing nations. We would like to make following comments:

In the light of the fact that in the tropics laboratory facilities are rare and the diagnosis and treatment of cases is based on clinical characteristics, the authors conclusion that "the probability of fungal etiology in a case of microbial keratitis is 63% if one of the 3 clinical signs are present (serrated margin, raised slough and coloration other than yellow) and at least 85% if all of three are present" becomes very important. However, before applying this conclusion in clinical practice we will have to take into account following facts of the study:

In this study the authors excluded cases with mixed infection (1.4% and 5.5% in Ghana and India respectively), acanthamoeba keratitis (0.3% & 0.9%), unconfirmed laboratory diagnosis (49.7% & 31.1%), and small infiltrates (11.7% overall) 2. Since the score is designed for application in community practice, it would have been better to apply the scores to all cases (290) from Ghana rather than a subset of patients.

Since this study aims at ophthalmologists at the primary health care level, including cases that had small infiltrate i.e. less than 4 mm would have been very useful because clinicians at the primary care level are likely to see early cases.

The predictive value of a positive test depends on relative pretest probability or prevalence of the disease in the group of individuals tested. Therefore, the "score" will be useful only in countries with a high prevalence of fungal keratitis. At a prevalence of 30% the positive predictive value of even a high score will not allow a conclusive diagnosis.

Therefore, the statement that the three signs described by the authors allow the diagnosis of fungal keratitis with 85% confidence can be misleading. Rather, this study further highlights that there are no exclusive clinical signs in microbial keratitis to diagnose the etiological agent.

To address this difficulty, addition of simple, cost effective microbiology tests such as microscopic examination of smears using 10% potassium hydroxide or lactophenol cotton blue will help ophthalmologist to be surer of diagnosis and to start initial treatment with more certainty.

References

1 Thomas P A, Leck A K and Myatt M. Characteristic clinical features as an aid to the diagnosis of suppurative keratitis caused by filamentous fungi. Br. J. Ophthalmol 2005;89;1554-1558

2 Leck AK, Thomas PA, Hagan M, et al. Aetiology of suppurative corneal ulcers in Ghana and south India, and epidemiology of fungal keratitis. Br J Ophthalmol 2002;86:1211-15.

Dear Editor,

We read with interest the paper by Hamada et al 1, which draws a number of conclusions from a five year follow up study of 69 periocular BCCs treated by conventional surgery, and in particular suggests that there is no place for Mohs micrographic surgery (MMS) in patients with periocular BCCs. MMS is the serial saucerisation excision with mapped horizontal tissue sections examining 100% of the surgical margins to produce histological evidence of tumour negative margins. Unfortunately, the data included in the paper are incomplete and if such conclusions are to be considered, then further clarification is required.

Risk of BCC recurrence relates directly to the nature of the tumours treated2. The principle risk factors for recurrence include previous treatment, large tumour size, and an infiltrative or micronodular histological growth pattern. No information is given on the first 2 factors and the histological subtype was non-specified in approx 45% of cases. We calculate from the data provided that the authors experienced a 19% 5 year recurrence rate in patients with a histologically infiltrative BCC.

If most of the “non-specified” tumours in Hamada’s series were small nodular tumours, as the paper implies, then Hamada’s series also differs significantly from other larger series in that it represents a group of patients with an inherently better prognosis. Other comments hint at this, in that 76% of BCCs were on the lower eyelid and 72% were amenable to direct closure. If the majority of the tumours in this series were not in a high- risk group then only one recurrence would be anticipated. In contrast, the Australian Mohs’ database series3 reported on a much higher incidence of high-risk tumours (50% were infiltrative, morphoeic, basosquamous or superficial), of which only 54% were on the lower eyelid while 41% affected the medial canthus, a site with a proven higher risk of recurrence. Despite this, they reported a 0% recurrence rate for primary BCCs of all histological subtypes treated by MMS surgery.

Hamada also concludes that 4mm margins are justified for well-defined nodular tumours, on the basis of the 5-year recurrence rates and the fact that most eyelids can still be directly repaired after such excisions. It is of interest however that 16% of the patients reported had incomplete tumour excision at the first attempt, although we do not know what margins were used for this group. As conventional pathological sectioning examines less than 1% of the margins4, it is likely that the actual incomplete excision rate was higher. Hamada argues that MMS is not necessary for periocular tumours on the basis that it is difficult to obtain true MMS sections. Unless either periosteum or anterior orbital septum are breached by the tumour, then there is no evidence for the former statement. What about cost benefit? MMS histology costs are greater than routine sections. However, when the other advantages of MMS are taken into account MMS is cost-effective in comparison to traditional surgical excision5.

The current best evidence shows that recurrence rates are lower with MMS than with any other technique, with MMS for recurrent or high-risk tumours showing the greatest advantage over conventional surgery. Furthermore, Hamada acknowledges that the tissue sparing quality of MMS is an important issue in that 36% of patients will develop a second BCC within 5 years.

Although we believe that MMS is the treatment of choice for optimal cure rates in periocular BCC, we would agree with Hamada that is currently impractical for all tumours because of the patchy availability of the service in the UK. However we believe the current evidence shows that MMS remains the optimal treatment for all high risk tumours based on treatment status, site, size and histological subgroup and do not feel that the data presented warrant a different conclusion.

References

1. Hamada S, Kersey T, Thaller VT. Eyelid basal cell carcinoma: non- Mohs excision, repair and outcome. Br J Ophthalmol 2005;89:992-994

2. Lawrence CM. Mohs surgery - A critical review. Br J Plast Surg 1993, 46, 599-606

3. Malhotra R, Huilgol SC, Huynh NT, Selva D. The Australian Mohs Database, part II: Periocular basal cell carcinoma outcome at 5 year follow up. Ophthalmol 2004, 111, 631-636.

4.Abide JM, Nahai F, Bennet RG. The meaning of surgical margins. Plast Reconstr Surg 1984;73:492-6

5. Cook J, Zitelli JA. Mohs micrographic surgery: a cost analysis. J Am Acad Dermatol. 1998; 39:698-703.

EA Barnes¹, AJ Dickinson¹, J AA Langtry² and CM Lawrence²

¹Department of Ophthalmology Royal Victoria Infirmary Newcastle-upon-Tyne, NE1 4LP

²Department of Dermatology Royal Victoria Infirmary Newcastle-upon-Tyne, NE1 4LP

Competing interests: None to declare

Dear Editor,

We want to congratulate Drs. S.L. Liao, et al., on their excellent paper entitled "Surgical coverage of exposed hydroxyapatite implant with retroauricular myoperiosteal graft". 1 In the paper they described "a newly developed technique with an autogenous retroauricular myoperiosteal graft" to repair defects with exposed hydroxyapatite implants.

However, they did not mention our retrospective, multicentered work published in 1999 in The American Journal of Ophthalmology. 2 In this paper we discussed a technique very similar to that of Dr. Liao and coworkers in which we covered exposed hydroxyapatite implants with a retroauricular muscle complex graft (complex refers to muscle, fascia, and vascular tissues). As with Dr. Liao's, et al., technique, we placed our retroauricular graft between the implant and the overlying Tenon's capsule and conjunctiva and the latter tissues migrated over the graft within several weeks.

We also used the thicker, stronger, retroauricular tissues anteriorly combined with the thinner tissues overlying the pinna for additional volume post-enucleation. This also facilitated the insertion of the spicular hydroxyapatite into the orbit post-enucleation. Additionally, we used only the thicker tissue between the mastoid and the overlying dermal flap anteriorly as a "cap graft" post-enucleation. Our techniques involved 83 patients with a mean follow-up of 36 months.

One difference in our technique and that of Dr. Liao and associates was that they used periosteum in their retroauricular complex graft for added strength and vascularity. We were reluctant to use periosteum in our grafts for fear of unduly compromising the vascularity of the underlying mastoid bone and the overlying dermal flap. The authors do not state that this occurred in their series of 9 patients in the duration of over one year. Accordingly, this may be a non-problem and it would appear that both techniques are efficacious. However, incorporation of the periosteum in the retroauricular myoperiosteal graft may not be necessary because of the strong, thick complex of muscle and fascia and vascular tissues between the underlying periosteum and overlying dermal flap.

Another difference in our technique is that we did not have to encounter active infections at the time of surgery and did not find it necessary to burr down the implant anteriorly. By undermining conjunctiva and Tenon's capsule the approximate distance of the equator of the globe, we have found that there is sufficient space for the graft to fit "flush tight" in the recipient bed.

The authors and readers might read with interest an article entitled "Variability of the postauricular muscle complex - analysis of 40 hemi-cadaver dissections" by Guerra, et al., including myself. 3 This article identifies and analyzes variations in the patterns of the posterior auricular muscle complex and the relations of the fascial contributions.

In our opinion, a signature thought would be to wrap a hydroxyapatite orbital implant with a strong autogenous graft of the surgeon's choice anteriorly to create a barrier between the implant and the overlying conjunctiva and Tenon's capsule to significantly decrease the chance of implant exposure.

Our technique has been discussed in a presentation of the 9th annual meeting of the European Society of Ophthalmic Plastic and Reconstructive Surgery in Dublin, Ireland, 1991, a presentation at the 23rd annual Scientific Symposium of the American Society of Ophthalmic, Plastic, and Reconstructive Surgery in Dallas, Texas, 1992, and discussed as a scientific video presentation at the annual meeting of the American Academy of Ophthalmology, 1994.

References

1. Liao S.L., Kao S.C.S, Tseng J.H.S., et al. Surgical coverage of exposed hydroxyapatite orbital implants with retroauricular myoperiosteal graft. Br J Ophthalmol 2005;89:92-95.

2. Naugle T.C., Lee A.M., Haik B.G., et al. Wrapping hydroxyapatite orbital implants with posterior auricular muscle complex grafts. Am J Ophthalmol 1999;128:495-501.

3. Guerra A.B., Metzinger S.E., Metzinger R.C., et al. Variability of the postauricular muscle complex - analysis of 40 hemicadaver dissections. Arch Facial Plast 2004;6:324-344.

Thomas C. Naugle Jr, M.D.
Department of Ophthalmology,
Tulane University School of Medicine,
New Orleans, LA, USA.