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Incidence of ocular complications in patients with multibacillary leprosy after completion of a 2 year course of multidrug therapy
  1. E Daniel1,2,
  2. T J ffytche3,
  3. J H Kempen4,
  4. P S S Sundar Rao5,
  5. M Diener-West6,
  6. P Courtright7,8
  1. 1Schieffelin Leprosy Research and Training Centre, Vellore, Tamil Nadu, India
  2. 2Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
  3. 3Department of Ophthalmology, The Hospital for Tropical Diseases, London, UK
  4. 4Department of Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
  5. 5Research Resource Center, The Leprosy Mission, New Delhi, India
  6. 6Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
  7. 7Kilimanjaro Centre for Community Ophthalmology, Tumaini University, Moshi, Tanzania
  8. 8BC Centre for Epidemiologic and International Ophthalmology, University of British Columbia, Vancouver, Canada
  1. Correspondence to: Dr Ebenezer Daniel Division of Ocular Immunology, Department of Ophthalmology, The Johns Hopkins University School of Medicine, 1620 McElderry Street, Reed Hall, 4th Floor, Baltimore, MD 21205, USA; edaniel4{at}jhmi.edu

Abstract

Aim: To evaluate the incidence of and risk factors for ocular complications in multibacillary (MB) leprosy patients following completion of 2 year, fixed duration, multidrug therapy (MDT).

Methods: Biannual eye examinations were conducted prospectively on a cohort of MB patients who had completed MDT and followed up for 5 years. The incidence of ocular pathology was calculated as the number of events per person year of event free follow up of patients who did not have the specific finding before completion of MDT.

Results: 278 patients had one or more follow up visits after completion of MDT. The incidence of lagophthalmos was 0.24%/patient year (95% CI 0.10% to 0.37%); corneal opacity, 5.35%/patient year (95% CI 4.27% to 6.70%); uveal involvement, 3.78%/patient year (95% CI 2.96% to 4.83%); and cataract that reduced vision to 6/18 or less, 2.4%/patient year (95% CI 1.77% to 3.26%). Overall, 5.65%/patient year (95% CI 4.51% to 7.09%) developed leprosy related ocular disease and 3.86%/patient year (95% CI 3.00% to 4.95%) developed leprosy related, potentially blinding ocular pathology during the period following MDT. Age and other disability also predicted incident eye disease.

Conclusions: Every year, approximately 5.6% of patients with MB who have completed MDT can be expected to develop new ocular complications of leprosy, which often (3.9%) are potentially vision threatening. Because many of these complications cannot be detected without slit lamp examination, periodic monitoring, particularly of older patients and those with other disability, is recommended, in order to detect and treat ocular complications satisfactorily.

  • LROP, leprosy related ocular pathology
  • MB, multibacillary
  • MDT, multidrug therapy
  • PBLROP, potentially blinding leprosy related ocular pathology
  • eye manifestations
  • leprosy
  • risk factors
  • LROP, leprosy related ocular pathology
  • MB, multibacillary
  • MDT, multidrug therapy
  • PBLROP, potentially blinding leprosy related ocular pathology
  • eye manifestations
  • leprosy
  • risk factors

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It is estimated that by the end of the year 2005, more than 14 million leprosy patients will have completed a standard course of anti-leprosy multidrug therapy (MDT).1 Although the incidence of leprosy is declining in some areas, approximately half a million new patients are diagnosed with leprosy each year. Recent changes in the epidemiology of leprosy include a gradual shift in the proportion of the type of leprosy from the paucibacillary to the multibacillary (MB) form, as well as a shift to an older age at diagnosis of disease.2 Improving health care and socioeconomic conditions predict increasing survival, with the fortunate result that there will be an ever increasing number of antimicrobially “cured” leprosy patients than ever existed in history.

There is evidence that even after adequate treatment with MDT, a sizeable proportion of cured leprosy patients continue to manifest progressive impairment of nerve function.3,4 Although the pathophysiology of this process is not fully understood, it is thought to be related to continuing immunological reactions and slow evolution of pre-existing nerve damage.5,6 Ocular complications are frequently observed in newly diagnosed leprosy patients and in patients who are undergoing MDT.7–9

However, little information exists on the incidence of ocular complications after completion of MDT in MB patients who have completed the recommended course of MDT. Knowledge of the risk and nature of ocular morbidity in leprosy patients after treatment with MDT is needed to prevent and/or manage such complications promptly and effectively in programmes worldwide. Such information potentially could identify risk factors that may be amenable to intervention and help prioritise groups for more active follow up.

In our previous reports, we have described a cohort of newly diagnosed MB leprosy patients who were followed for ocular complications during 2 year fixed MDT.8,10 These patients were followed up for a further 5 years. In this paper, we report information on ocular complications that were incident during the post-MDT period.

MATERIAL AND METHODS

All new clinically diagnosed MB patients starting on a 2 year MDT and living within the leprosy control area of the Schieffelin Leprosy Research and Training Centre in southern India were invited to participate. Recruitment began in 1991 and was completed in 1997. Consenting patients received a baseline ocular examination followed by biannual examinations during MDT and for a period of at least 5 years after completion of MDT. Based on sample size calculations taking into account possible losses to follow up resulting from migration and mortality, 301 MB leprosy patients were enrolled over a period of 6 years. Research methods and protocols were approved by the institutional review board of the Schieffelin Leprosy Research and Training Centre. All patients were examined and given treatment free of charge.

At enrolment the following leprosy characteristics were recorded; the type of MB leprosy, based on the clinical classification of Ridley and Jopling11; deformity grading of hands and legs, based on the WHO classification12; the bacterial index, calculated from the results of the acid fast staining of smears from specific skin sites13; presence or history of type 1 (reversal reaction) or type 2 (erythema nodosum leprosum) reactions; and history of hypopigmented or erythematous patches on the face.

At each visit, the following ophthalmic characteristics were recorded: visual acuity (with and without correction); presence of orbicularis oculi weakness; lagophthalmos; ectropion; entropion; trichiasis; corneal opacity; corneal ulcer; episcleritis; scleritis; clofazamine crystals in the cornea or conjunctiva; anterior chamber flare and/or cells; posterior synechiae; small pupil size; pupillary reaction to light; iris atrophy; and cataract. When synechiae or cataracts were suspected, mydriatic drops were instilled and the patient was re-examined to confirm the diagnosis. For purposes of the analyses reported here, cataract was defined as the presence of lens opacity observed by slit lamp examination consistent with a measured corrected visual acuity of 6/18 or worse. Patients free of cataract at enrolment who underwent cataract surgery during follow up also were considered to have developed cataract, as of the midpoint between visits before and after cataract surgery was performed.

Best corrected visual acuity was measured by a trained examiner using a Snellen chart. After examination of the ocular adnexae, slit lamp biomicroscopy was carried out on all patients. Goldmann applanation tension was recorded in the upright position. Direct ophthalmoscopy without dilatation was performed in all cases during each visit; patients with decreased vision or with intraocular complications underwent pupil dilatation and indirect ophthalmoscopy.

Among patients free of each condition studied upon completion of MDT, the incidence of ocular complications of leprosy was calculated as the number of each kind of event observed per person year at risk during follow up after MDT. In addition, compound outcomes to describe the incidence of complications were created, as follows. Leprosy related ocular pathology (LROP) was defined as the presence of one or more of the following: lagophthalmos, corneal nerve beading, corneal opacity, punctate keratitis, and observations indicative of uveal involvement (flare and cells, keratic precipitates, and/or iris atrophy). This grouping was created to encompass all leprosy related ocular conditions. Potentially blinding leprosy related ocular pathology (PBLROP) was defined as the presence of lagophthalmos and/or uveal involvement—constituting those leprosy related conditions associated with substantial risk of vision loss. Corneal opacity was not included under PBLROP as no cases were associated with a drop in visual acuity. Cataract was not included in this group on the conservative assumption that cataract is not a uniquely leprosy induced condition.

Statistical analysis was conducted with the unit of observation being the individual rather than the eye. Univariate and multivariate Cox proportional hazards regression models were used to analyse the incidence of specific findings, and evaluate their relation to demographic and clinical characteristics. p Values, hazard ratios (HR), and 95% confidence intervals (CI) were generated.

RESULTS

Among all newly diagnosed MB patients eligible for the study, 15 (13 males and two females) opted not to participate and a total of 301 patients were enrolled. The characteristics of this cohort have previously been reported.10 During the 2 year MDT treatment period there were 14 deaths and nine migrations; thus, the analysis after completion of MDT is based on 278 patients (92%), who were followed until their last examination visit in 2004 or until death or migration, whichever occurred earliest. Between completion of MDT and the last examination visit in June 2004, a further 28 (9.3%) patients died and 30 (10%) migrated to distant places. These patients contributed follow up time to the analysis until they were lost. Thus, from the time of enrolment to the last visit in 2004, a total of 42 patients died and 39 migrated and were lost to follow up. During 2004, additional efforts were made to contact and examine all patients from the original cohort, and 41 patients were seen in 2004 who had not been seen for 3 years or more before the final visit.

After completion of MDT, among 225 patients (1631 patient years) who had visual acuity better than 6/18 at the time of completion of their MDT, 49 (3%/patient year, 95% CI 2.27% to 3.97%) developed reduction of visual acuity to 6/18 or worse. Among these, 20 patients (1%/patient year, 95% CI 0.6% to 1.5%) became severely visually impaired (less than 6/60 vision in one or both eyes). Age at enrolment (HR = 1.08 95% CI 1.03 to 1.13 p = 0.003) and grade 2 deformity in all limbs (HR = 5.91 95% CI 0.97 to 36.23 p = 0.05) were associated with severe visual impairment. Vision was reduced to less than 3/60 in 21 eyes (0.5%/patient year, 95% CI 0.3% to 0.7%). Five patients became blind (vision <3/60 in both eyes) during this period (0.2%/patient year, 95% CI 0.1% to 0.5%) and cataract was the cause of blindness in all of these patients.

Table 1 summarises the incidence of various ocular morbidity that occurred after completion of MDT. Lagophthalmos developed in only five patients (0.0024/patient year). Except for grade 2 deformity (HR = 10.2, 95% CI: 1.1 to 92.5, p = 0.039) none of the demographic or leprosy related characteristics were significantly associated with incident lagophthalmos. Corneal opacity occurred in 76 patients (0.0535/patient year; see table 2). Multiple regression confirmed corneal opacity to be significantly associated with grade 2 deformity (HR = 1.86, 95% CI: 1.15 to 3.00), sex (female v male) (HR = 0.50, 95% CI: 0.29 to 0.87), and PBLROP (HR = 2.55 SE 0.87 95% CI 1.30 to 4.99 p = 0.007). Table 3 summarises the risk factors associated with incident uveal involvement. Multiple regression confirmed a higher risk of uveal involvement with increasing age (HR (for each decade) = 1.57, 95% CI: 1.32 to 1.86) and grade 2 deformity (HR = 3.03, 95% CI: 1.08 to 8.53). Smear positivity at enrolment had a borderline association (HR = 2.32, 95% CI: 0.99 to 5.44).

Table 1

 Incidence of ocular morbidity after completion of 2 year fixed MDT, by patient

Table 2

 Risk factors for corneal opacity

Table 3

 Risk factors for uveal involvement

Table 4 summarises risk factors associated with LROP. Multiple regression revealed that only higher age for each decade (HR1.20 95% CI 1.03 to 1.41, p = 0.021) was significantly associated with LROP. Multiple regression confirmed that age (for each decade) (HR1.50 95% CI 1.27 to 1.78, p = <0.001), smear positivity (HR2.37 95% CI 1.01 to 5.55, p = 0.048), and grade 2 deformity (HR3.20 95% CI 0.98 to10.42, p = 0.054) were associated significantly with PBLROP (table 5). Cataract with reduced vision and PBLROP were seen in 60 out of 194 patients at risk, occurring over 1352 patient years, giving an incidence rate of 0.44/patient year (95% CI 0.034 to 0.057). Reactions and face patches, past and/or at enrolment, were not associated with any of the ocular complications. Cataract was not associated with the cumulative corticosteroid dose (given for neuritis). Corneal ulcers developed in three patients, which did not provide sufficient information to conduct a risk factor analysis.

Table 4

 Risk factors for leprosy related ocular pathology

Table 5

 Risk factors for potentially blinding leprosy related ocular pathology

DISCUSSION

This is the first systematic prospective study evaluating the incidence of ocular complications among MB patients after completion of 2 year fixed dose MDT. Findings from the study suggest that leprosy related ocular complications occur at a substantial rate, over 5% per year, in the years following completion of their MDT, with approximately 4% per year developing potentially blinding leprosy related ocular complications. In addition, cataract associated with visual impairment occurred in 2.4% per year and some of it occurred in patients with PBLROP. Thus, the overall incidence of vision threatening eye disease is 4.4% per year following presumed microbiological cure of leprosy. Comparison of results among other ocular studies in MB patients who have been released from anti-leprosy treatment are limited by the short supply of data available from population based ocular leprosy studies with extended follow up, as well as by the different classification systems and definitions used. Good participation of patients in this study for an extended period of time after completion of their therapeutic regimen adds strength to this population based study of MB patients.

Although visual acuity dropped to less than 6/60 in one or more eyes in 1% of patients per person year, only five patients (0.2%) became bilaterally blind (worse than 3/60 in both eyes) during this period. Blindness and severe loss of vision were the result of the progressive development of cataract. Results of cataract surgery in this population will be reported separately. Risk of cataract is likely to increase with age; access to good cataract surgical services will be important in reducing ocular morbidity in this high risk population. Uveal involvement (4%), corneal opacities (5%), and punctate keratitis (1%) were not major contributors to vision loss, perhaps because of treatment, which patients received free of charge during the study. Each of the other complications was less than 1%.

The development of corneal nerve beading after presumed microbiological cure of leprosy in 19 patients was an unexpected finding. Nerve beading is believed to be due to calcified collections of large amounts of Mycobacterium leprae on the fine nerves that traverse the corneal stroma. They can be missed on perfunctory biomicroscopy but when diagnosed are much more distinct entities than the nerve enlargement or thickening often reported in ocular leprosy. The strong association of corneal nerve beading with high bacillary counts both at the time of enrolment and while receiving MDT9,10 was not seen following completion of MDT; neither was incident corneal beading following MDT associated with leprosy reactions. One potential explanation of this observation is that changes taking place in the unmyelinated corneal nerves are independent of reactions and high bacillary count.

Females were only half as likely as males to develop corneal opacities during this period. Corneal opacities were also more commonly observed among patients with severe limb deformities and those with other leprosy related ocular complications, particularly lagophthalmos; however, the corneal opacities observed were generally small, superficial, and peripheral and did not contribute to visual impairment. It could be speculated that the pathophysiology of these opacities is different from those that occur in MB patients during the time that they are taking MDT.10 They could result from minor injuries and ocular exposure: females do less outdoor work in rural India. Patients with fewer deformities were less likely to develop these opacities, consistent with the fact that patients with more deformed extremities are more likely to injure their eyes while rubbing them. Corneal conditions such as opacities, nerve beadings, punctate keratitis and ulcers are likely to be associated with impaired corneal sensation but this correlation could not be established in our cohort as the method of estimating corneal sensation used was subjective, and not consistently reproducible.

Leprosy related uveal involvement accounts for a large proportion of the complications observed and could reflect a para-infectious mechanism of autoimmune inflammation.14–18 For every decade increase in age, there appeared to be a 60% higher likelihood of having uveal involvement, for reasons that are unclear. Uveal involvement in this population was not related to type 2 leprosy reactions but was significantly associated with being smear positive at enrolment and having more severe limb deformities. Thus, the more severely infected MB patients and those with advanced deformity before treatment may be at a higher risk of ongoing para-infectious autoimmune disease. Previous studies have shown that patients who have nerve function impairment at the time of diagnosis have a higher risk of developing severe deformities during and after MDT.4,19 Elderly and highly bacilliferous MB patients with more severe limb deformities constitute a risk group for developing uveal involvement during the period after completion of MDT. Further observations of the outcomes and clinical course of uveal involvement are needed to assess the contribution of leprosy related uveal involvement to ocular morbidity, but it seems likely that such disease will require ongoing management. Because detection and management of uveal involvement requires slit lamp examination and specialised training, the input of an ophthalmologist would be necessary for satisfactory follow up and management.

What are the clinical and public health implications of the findings of this study? The most important issue, from our perspective, is to make known to all those involved in the care of leprosy patients that leprosy related ocular manifestations continue to occur in MB patients after completion of MDT, at a substantial rate. Cataract, with potentially recoverable visual acuity, was the leading cause of vision loss in this period. Uveal involvement occurred in a substantial proportion of patients, and often is not detectable on penlight examinations by field workers. The long term effects of uveal disease on vision and its contribution to other ocular morbidity have not been directly studied in patients with leprosy, but are likely to be substantial in the absence of appropriate management. Lagophthalmos, neurotrophic punctate keratitis, episcleritis, and corneal ulcers appear to be infrequent in our study.

It must be emphasised that the true “threat to sight” pathology observed in leprosy patients living among the general population may have been obscured by the early detection and treatment facilities afforded by the study environment. This study demonstrates that after completion of MDT, vulnerable groups should continue to be screened for ocular complications of leprosy, with the involvement of an ophthalmologist, in order to satisfactorily prevent or reverse ocular morbidity caused by leprosy.

Acknowledgments

This work was supported primarily by Lepra, UK. We are grateful for their support. The World Health Organization Leprosy Control Unit provided administrative support. Dr Kempen received support for his work on this project from the Paul and Evanina Mackall Foundation and from Research to Prevent Blindness. Many thanks to Mr Paramanandan Yowan for his excellent coordination of field activities and patient follow up. The authors declare no competing interests in the preparation and submission of this manuscript.

REFERENCES

Footnotes

  • Ethical approval: Research methods and protocols were approved by the Institutional Review Board of the Schieffelin Leprosy Research and Training Center, and were conducted in accordance with the principles of the Declaration of Helsinki.

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