Ocular Manifestations among Systemic Tuberculosis Cases: A Hospital Based Study from Nepal

Aim: To study the frequency of various ocular manifestations in diagnosed cases of active pulmonary and extra pulmonary tuberculosis in two different major hospitals in Nepal. Method: A hospital based, cross sectional descriptive study was conducted in the National Tuberculosis Centre, Bhaktapur and BP Koirala Lions Center for Ophthalmic Studies (BPKLCOS), Tribhuvan University Teaching Hospital (TUTH), Kathmandu, Nepal during a period of 18 months from February 2010 to August 2011. Diagnosed cases of systemic tuberculosis were evaluated by ophthalmologists for any ophthalmic manifestations. Results: There were 585 cases in the study. 399 (68%) were cases of pulmonary tuberculosis and 186 (32%) were that of extra pulmonary tuberculosis. Ocular manifestations were seen in 2.6% (15 patients) of the study population; 1.25% (6 patients) in cases of pulmonary tuberculosis and 5.37% (9 patients) in extra pulmonary tuberculosis cases. Uveitis (40%) followed by papilloedema (33%) were the two most common ocular manifestations. Of the 25 affected eyes of 15 patients, 2 eyes of patients with choroiditis involving the macular area were legally blind. Majority of the affected cases (67%) had bilateral involvement. Conclusion: Ocular manifestations in tuberculosis vary greatly ranging from mild episcleritis to potentially blinding posterior uveitis, clinical acumen being of great importance in timely diagnosis and treatment so that vision threatening complications can be prevented. Ocular manifestations are more common in extra pulmonary tuberculosis cases.


Introduction
Tuberculosis is an infectious disease of chronic pathology caused by one of the members of the Mycobacterium tuberculosis complex that includes M. tuberculosis, M. bovis, and M. africanum (most commonly by M. tuberculosis). This disease is characterized by formation of granulomas. M. tuberculosis is an obligate aerobic slow growing, non-spore forming, and non-motile bacterium. The disease is spread through airborne aerosol gaining access in the lung, resulting in a latent or dormant infection in susceptible hosts. Globally, there is an estimated 9.6 million new cases and 1.5 million deaths are attributed to TB. About 58% of cases are in the South-East Asia and Western Pacific regions. In Nepal alone there are 44,000 new cases and 60,000 people living with TB, with 4900 death a year [1].
Ocular tuberculosis encompasses any infection by Mycobacterium tuberculosis complex involving the eye. Terms as "primary" and "secondary" ocular tuberculosis are often used in literatures. There is difference in opinion regarding definition of primary ocular tuberculosis (TB). Some literatures use it to describe isolated ocular disease without systemic involvement, while others use the term when eye is the initial port of entry of the bacilli. The term, secondary ocular tuberculosis is reserved for those cases where there is ocular involvement from seeding by hematogenous spread from primary sites as lungs and lymph nodes. There can also be direct invasion from surrounding areas like paranasal sinus or cranial cavity. Difficulty in obtaining ocular tissue for biopsy often makes it difficult to establish a conclusive diagnosis by demonstrating tuberculosis bacteria in tissue and hence the diagnosis is frequently presumptive [2] [3]. Delayed hypersensitivity reaction to tuberculosis bacteria without the presence of any infectious agent can lead to ocular disease. This makes the evaluation of ocular fluid sample less sensitive to any laboratory examinations. There is also lack of uniform diagnostic criteria in addition to the difficulties in confirming the diagnosis with traditional laboratory methods [3]. Hence epidemiological data on the true prevalence of ocular TB is scanty and varied in different parts of the world [4] [5] [6].
Consequences of tuberculosis in eye can lead to permanent blindness in patients. It's therefore necessary to identify the ocular manifestations of early stages of the disease. In spite of vast developments in diagnostic tools, evidence of systemic tuberculosis disease along with suggestive clinical ocular findings is still considered the major diagnostic criteria for ocular tuberculosis, more so over in a developing country like Nepal where such modern diagnostic facilities are often limited. Thus the knowledge about frequency and clinical features of ocular tuberculosis in Nepalese population can be of huge benefit in diagnosing such cases early and providing the patient with proper treatment. As to our knowledge, no study has yet been reported from Nepal evaluating the ocular manifestations in tuberculosis patients. Hence this study was done to evaluate ocular findings in diagnosed cases of pulmonary and extra pulmonary tuberculosis so as to find out the frequency and types of ocular manifestations seen in tubercu-Journal of Tuberculosis Research losis.

Subjects and Methods
A hospital based, cross sectional descriptive study was conducted in National tuberculosis Centre, Bhaktapur, Nepal (center for tuberculosis control in South East Asia region) and BP Koirala Lions Center for Ophthalmic Studies (BPKLCOS), Tribhuvan University Teaching Hospital (TUTH), Kathmandu Nepal during a period of 18 months from February, 2010 to August 2011 after approval from institutional review board of Institute of Medicine.
The study was explained to all eligible people in their own language, and consent was obtained. Patients with history suggestive of tuberculosis were first examined by general physicians. Clinical examination was done, followed by relevant investigations. Three morning samples of sputum for AFB staining were taken along with a chest X-ray posterio-anterior view. Diagnosis of pulmonary TB was made on the basis of at least 2 sputum samples staining positive for AFB or one sample positive with suggestive X-ray findings. Smear negative pulmonary tuberculosis was diagnosed on the basis of relevant history, suggestive X-ray findings and positive Mantoux test with no improvement after a week of appropriate antibiotic therapy. Extra pulmonary tuberculosis was diagnosed by direct tissue cytology in most cases. In those cases where tissue wasn't accessible for cytology evaluation, findings suggestive of tuberculosis on relevant imaging studies and positive supporting evidences as Mantoux test, IgM Quantiferon Gold and serum immunoglobulin IgG and IgM assay were taken into consideration in making a diagnosis.
Detail ocular evaluation of the cases was then conducted by an ophthalmologist. Visual acuity was assessed by Snellen Vision Chart with multiple optotypes. Any evidence of ocular misalignment and abnormality of extra ocular movement was evaluated with extra ocular motility and cover tests. Periorbital area and anterior segment was first examined with diffuse torchlight. Haag Streit 900 slit lamp was used in appropriate magnification and illumination for further evaluation of anterior and posterior segment. Posterior vitreous and fundus were evaluated under dilatation using 90 diopters and 20 diopters Volk aspheric lenses. Gonioscopy was done as required. Fundus fluorescein angiography and optical coherence tomography were done in cases with choroidal manifestations. Uveitis cases were evaluated for signs of granulomatous or non-granulomatous inflammation with recording of type and distribution of keratic precipitates, anterior chamber reaction, posterior synechiae and iris nodules. Vitreous was examined for cells and exudates. Snow balls, snow banking and peripheral sheathing were also looked for. Any evidence of posterior uveitis like choroidal tubercles, tuberculoma, subretinal abscess, serpiginous-like choroiditis or endophthalmitis was noted. Any signs of retinal vasculitis and optic nerve abnormalities like papilloedema or optic neuropathy were also evaluated. Cases of uveitis were further evaluated by a uveitis specialist. Data was analysed using SPSS 14 software. The frequencies of ocular manifestations were evaluated with chi square test sta-

Results
The mean age of presentation was 35.76 years with the range of 3 -78 years.
There were total of 585 cases enrolled in the study. 60% (349) of the cases were males and 40% (236) were females. 68% (399) of enrolled patients were cases of pulmonary tuberculosis and 32% (186) were extra pulmonary cases. Lymph node TB (26%) was the most common presentation among extra pulmonary cases followed by pleural effusion (21%) and TB meningitis (17%).
Cases with Ocular Manifestations: Among 585 cases of tuberculosis, 2.56% (n = 15) were found to have some form of ocular manifestations. Among those with ocular manifestations, 47% percent of manifestations were observed in cases with tubercular meningitis. Table 3 shows the visual acuity of affected eye in snellen acuity. 67% (n = 10) of the affected cases had bilateral involvement. Of the 25 affected eyes of 15 patients, 84% (n = 21) had best corrected visual acuity (BCVA) between 6/6-6/18. 12% (n = 3) of affected eyes had BCVA less than 6/60. BCVA was less than 3/60 in 2 eyes with posterior uveitis involving the macular area.    Papilloedema was the second most common ocular manifestation seen in 33% of cases. All of those cases were of tubercular meningitis. Two cases of LR paresis (1 case of unilateral and 1 case of bilateral LR paresis) with associated raised intracranial pressure were also seen. There was a case each of recurrent nodular scleritis and episcleritis. The distribution of patients with type of ocular manifestation is given in Figure 1.

Discussion
Tuberculosis is one of the major causes of morbidity and mortality in Nepal.
This disease has serious public health implications. Survey suggests that a significant number of people in productive age group suffer from Tuberculosis in Nepal [7]. In this study of 585 cases of tuberculosis, majority (68%) of cases were of pulmonary tuberculosis; however the number is lower than that of national statistics [1]. The higher number of extra pulmonary cases in the study compared Uveitis (40%) followed by papilledema (33%) was the most common ocular manifestation in our study. Tuberculosis was observed to be the second most common identifiable cause of uveitis in a large review looking at reports from several countries [11]. Uveitis is the most common ocular manifestation in tu- berculosis as uvea receives the most share of blood supply in eye [12]. In a case series from Srilanka, eighteen out of twenty-three patients with symptomatic ocular TB had tuberculous uveitis [13]. In a study by Biswas et al.; the most common ocular finding was bilateral healed focal choroiditis (50%) [4]. In another study from India where 55 cases of ocular tuberculosis were evaluated, the most common ocular finding was acute anterior uveitis (21.8%) [8]. reported choroiditis in 6 (10.90%) cases and anterior uveitis in 12 (21.81%) cases [8]. In Malawi, Africa, 2.8% incidence of choroidal granuloma was reported among 109 patients with fever and tuberculosis [17].
Choroidal tubercles are common findings among tuberculosis manifestations Of five patients with papilloedema in our study, all were below 20 years of age, the youngest being three years of age. The findings of papilloedema as second common ocular manifestation in tuberculosis in our study can be explained on the basis of relatively large number of complicated tubercular meningitis cases especially children, referred to us from different centers. In a study from Malawi; out of 109 patients with TB, two patients had papilloedema, one with pulmonary tuberculosis and one with TB meningitis [17]. Tuberculosis is one of the common etiologies of meningitis in Nepal, more so in children. In persons who develop tubercular meningitis, there is hematogenous seeding of bacilli to the meninges or brain parenchyma. This results in formation of subpial or subependymal foci of metastatic caseous lesions which have propensity to enlarge and rupture into the subarachnoid spaces, leading to meningitis. Basal meningitis can lead to obstructive hydrocephalus from obstruction of basilar cisterns leading to papilloedema. In children, primary optic atrophy and blindness can result from direct involvement of the optic nerves and chiasma by basal exudates (i.e., opticochiasmatic arachnoiditis). In adults, long standing papilledema will commonly lead to secondary optic atrophy. Papilloedema is considered to be poor prognostic factor for tuberculous meningitis [18].
Basal meningitis leads to cranial nerve pathologies resulting in paresis or palsy. Sahu et al. described 1 (1.81%) case of cranial nerve palsy out of 55 cases of ocular tuberculosis [8]. In our study, out of 31 cases of tubercular meningitis, we had two cases of cranial nerve paresis (14% of all cases with ocular involvement), both with involvement of VI nerve, one of them having bilateral lateral rectus paresis. Sharma et al. also reported CN VI to be most commonly affected cranial nerve in tubercular meningitis [19]. Anterior non necrotizing nodular scleritis was observed in a case of lymph node tuberculosis in our study. There was nodular episcleritis in a patient with pulmonary tuberculosis with history of multiple recurrences even after treatment with topical steroids. Sahu et al. reported scleritis and episcleritis to be common occurrences among cases of ocular tuberculosis with 12 cases (21%) of scleritis and 2 cases (4%) of recurrent episcleritis among 55 cases of ocular tuberculosis [8]. A case series of ocular Tuberculosis from Srilanka also reported a case of episcleritis and inflammatory scleral nodule [13]. Tuberculous scleritis may lead to scleromalacia [20] Tuberculosis is one of the existing pandemic diseases in the world that can affect almost every organ of the body. Despite the low percentage of ocular manifestation in TB, ocular morbidity due to tuberculosis is still in significant numbers because of high prevalence of tuberculosis among people in developing countries. Newer diagnostic tools as PCR showing mycobacterial load in intraocular fluids in combination with ophthalmic features of tuberculosis help in diagnosis of ocular tuberculosis [21]. As sophisticated diagnostic tools are still not available in most of the developing countries and they too cannot alone make a definitive diagnosis; clinical features are still the most important criteria for making a diagnosis of ocular tuberculosis. This study helps in outlining some of the common manifestations that patients with ocular tuberculosis can present with. It is very important for clinicians to be well aware of these different manifestations of tuberculosis in eye so as to make an early diagnosis and start the correct treatment before the patient suffers from irreversible loss of vision. As tuberculosis is mainly a disease of young people, proper ophthalmic examination of tuberculosis patients is recommended for early diagnosis and treatment; preventing significant years of productivity that can be lost due to visual disability having a tremendous impact on wellbeing of a society.