Paracentral acute middle maculopathy with occlusive retinal vasculitis in presumed intraocular tuberculosis and hyperhomocysteinemia

Abstract

A male patient presented with a sudden visual decline in the right eye (OD). Fundus revealed bilateral vasculitis; OD also showed an occluded inferior retinal vein and a wedge-shaped retinal opacification of the inferior macula and nasal retina. Fluorescein angiography revealed occlusive retinal vasculitis, while optical coherence tomography showed paracentral acute middle maculopathy (PAMM) in the OD. A thorough systemic evaluation revealed hyperhomocysteinemia and a positive Mantoux test. A diagnosis of PAMM with occlusive retinal vasculitis in presumed intraocular tuberculosis and hyperhomocysteinemia was made. Retinal vasculitis improved with oral corticosteroid, intravitreal anti-vascular endothelial growth factor and laser photocoagulation. However, the patient declined antitubercular therapy despite recommendations. This unique report indicates that PAMM may complicate tubercular retinal vasculitis, especially in the presence of systemic hypercoagulable states.

Background

Tubercular retinal vasculitis (TRV) is characterised by occlusive retinal vasculitis (ORV) that preferentially involves the retinal veins with clinical or angiographic evidence of peripheral retinal ischaemia.^{1 2} Heterogeneous presentations, lack of specific diagnostic tests and difficulty obtaining histopathological confirmation make the diagnosis of intraocular tuberculosis (IOTB) most often presumed.^{1 3}

Paracentral acute middle maculopathy (PAMM) occurs due to ischaemia of retinal capillary plexuses and is associated with various retinal vascular diseases as well as systemic vasculopathic risk factors.^4–6 In this report, we describe a case of presumed IOTB with incidentally detected hyperhomocysteinemia who presented with ORV and PAMM. To the best of our knowledge, such phenotypical presentation of TRV has not been reported in the ophthalmic literature.

Case presentation

A male patient in his mid-30s presented with a sudden painless decrease in vision in the right eye (OD) since 1 day with a superior hemifield loss. His medical history was negative for diabetes mellitus, hypertension, coronary artery disease or drug abuse. He was a known smoker (15 pack-year) with occasional alcohol consumption for the last 15 years. Ocular examination revealed best-corrected visual acuity (BCVA) of 20/1200 in the OD and 20/20 in the left eye (OS), normal intraocular pressures, a relative afferent pupillary defect in the OD and absence of anterior segment inflammation. Fundus examination of the OD (figure 1A) revealed hyperemic optic disc oedema, dilated retinal veins with perivenular sheathing in all quadrants, scattered superficial retinal haemorrhages and two distinct yellowish-white patches of wedge-shaped retinal opacification—in the inferior macula and at the nasal equator. OS fundus (figure 1B) revealed a normal optic disc, multifocal areas of perivenular sheathing with few retinal haemorrhages along the inferotemporal arcade.

Figure 1.

Fundus photograph of the right eye (A) showing dilated and tortuous retinal veins with perivenular sheathing, retinal haemorrhages, disc oedema, and a creamy patch of wedge-shaped retinal opacification in the inferior macular and nasal quadrant. Fundus of the left eye (B) revealing tortuous and dilated retinal veins, and focal areas of perivenular sheathing and infiltrate. Optical coherence tomography (OCT) of the right eye (C) showing intraretinal oedema, subfoveal neurosensory detachment and a temporal parafoveal hyper-reflective area involving middle retinal layers (yellow arrow) suggestive of paracentral acute middle maculopathy. OCT of the left eye (D) demonstrating normal foveal contour.

OD spectral-domain optical coherence tomography (OCT; figure 1C) demonstrated disorganisation of retinal architecture, subfoveal fluid and an ill-defined area of middle retinal layer hyper-reflectivity temporal to the fovea, corresponding to the area of retinal opacification. OS OCT (figure 1D) was normal. Fundus fluorescein angiography (FFA; figure 2A–F) showed bilateral active periphlebitis with marked capillary non-perfusion areas in the OD along with disc leakage. A clinical diagnosis of bilateral retinal periphlebitis with OD ORV and PAMM was made.

Figure 2.

Fundus fluorescein angiography (FFA) of the right eye (A–C) showing blocked fluorescences due to retinal haemorrhages, marked capillary non-perfusion areas, staining of the superotemporal vein and intense disc hyperfluorescence. FFA of the left eye (D–F) revealing few block fluorescences, mild disc hyperfluorescence, perivenular staining and focal leakages.

Investigations

An extensive work-up was initiated for the patient in conjunction with a physician. Positive laboratory findings included slightly elevated haemoglobin (173 g/L), mild dyslipidaemia, mild transaminitis, raised serum homocysteine level (89.3 umol/L), elevated ACE level (123 U/L) and positive Mantoux test (induration size of 15×15 mm). Ultrasound of the abdomen findings and transaminitis were attributed to fatty liver disease. His blood sugar levels, renal function tests, urinalysis, venereal disease research laboratory test, Treponema pallidum hemagglutination assay, reverse transcription PCR (RT-PCR) from nasopharyngeal and oropharyngeal swabs for COVID-19 were unremarkable. The 24-hour ambulatory blood pressure monitoring, echocardiogram, carotid Doppler ultrasound, contrast-enhanced CT (CECT) of the chest, basic autoimmune work-up and coagulation profile were unremarkable.

Diagnosis and treatment

A provisional diagnosis of presumed IOTB with hyperhomocysteinemia was made. He was started on 60 mg oral prednisolone and received an intravitreal ranibizumab (0.5 mg/0.05 mL) injection. As he was a young phakic patient with bilateral involvement (and sight-threatening in one eye), systemic corticosteroids were preferred over periocular or intravitreal corticosteroids. Intravitreal ranibizumab was given as an adjunct to reduce the load of vascular endothelial growth factor (VEGF), stabilise the blood–retinal barrier and decrease the subretinal fluid before performing laser photocoagulation. He was also started on oral folic acid (5 mg daily) and pyridoxine (100 mg daily) for hyperhomocysteinemia, as advised by the general physician. He did not consent to antitubercular treatment (ATT), despite extensive counselling regarding the same.

Outcome and follow-up

Over the following 6 weeks, BCVA in the OD improved to 20/400 with a reduction of retinal haemorrhages, optic disc swelling, macular oedema and perivenular exudation (figure 3A–C). OS showed resolution of perivenous sheathing with normalisation of fundus appearance. At this time, he underwent FFA-guided inferior scatter laser photocoagulation in the OD along with tapering of oral steroids (10 mg every 2 weeks) over the next 8 weeks. Serial OCT scans of the OD over the next few weeks (figure 3D–I) showed a progressive reduction of middle retinal layer hyper-reflectivity with the development of inner nuclear layer (INL) atrophy of the temporal parafoveal area, signalling resolution of PAMM. At 4-month follow-up, BCVA in the OD improved to 20/200 with complete resolution of periphlebitis and macular oedema with development of temporal disc pallor, few macular hard exudates and thread-like inferior retinal vessels. OS maintained a BCVA of 20/20 with the restoration of fundus appearance. He was advised to continue oral folic acid+pyridoxine tablets and 3-month follow-up to look for recurrences or neovascular complications.

Figure 3.

Fundus photograph of the right eye in subsequent visits at 6 weeks (A), 9 weeks (B) and 12 weeks (C) showing gradual resolution of retinal haemorrhages, disc swelling and macular oedema. Corresponding optical coherence tomography scans (D–F) and their magnified views (G–I) showing gradual atrophy of inner nuclear layer in the previous hyper-reflective area. Atrophic and normal inner nuclear layer have been represented with green and yellow arrows, respectively; the transition between the two zones is marked with white arrowhead.

Discussion

PAMM is a lesion causing hyper-reflectivity of the INL of the retina on OCT due to ischaemia of the intermediate and deep capillary plexuses.^{4 5} Acute macular neuroretinitis (AMN), initially described by Bos and Deutman, was further subclassified by Sarraf et al into type-1 AMN (also known as PAMM) and type-2 AMN.^{4 7} Venkatesh et al recently reported a case of IOTB presenting as type-2 AMN with central retinal vein occlusion (CRVO), who was successfully treated with ATT and oral steroids.⁸ PAMM (type-1 AMN) is associated with various retinal diseases like diabetic retinopathy, hypertensive retinopathy, retinal vascular occlusions, sickle-cell crisis, Purtscher’s retinopathy, migraine, post-H1N1 vaccine, following respiratory tract infection and others.⁶ It has also been reported in isolation with a few ORV diseases, including Behcet’s disease, ulcerative colitis and systemic lupus erythematosus.^9–11 However, PAMM, as a presenting feature of TRV, has never been reported to the best of our knowledge. PAMM lesions are characterised by a hyper-reflective band at the level of the outer plexiform layer/INL region in the acute stage with eventual INL thinning.⁵ Although a wedge-shaped area of retinal whitening and corresponding middle layer hyper-reflectivity on OCT were evident at presentation in our patient, the characteristic hyper-reflective band at the level of INL was inconspicuous due to significant intraretinal fluid. As the retinal oedema subsided with oral steroids and following anti-VEGF injection, INL atrophy ensued in the distribution of the previous retinal infarct, confirming the diagnosis of PAMM.

TRV can have various phenotypical presentations. The presence of pigmented perivascular choroiditis scars with ORV has been strongly associated with tubercular aetiology with a positive predictive value of 94.58% and a negative predictive value of 95.09%.¹² Despite the absence of perivascular choroiditis and any associated intraocular inflammation in our patient, the presence of bilateral periphlebitis with marked occlusive features in the OD and Mantoux positivity in a young man from a highly TB-endemic country made us consider presumed IOTB as the most likely diagnosis. In a large multinational review involving 251 patients with TRV by the Collaborative Ocular Tuberculosis Study group, the majority of the patients were male (66.5%), had Asian ethnicity (70.7%) and displayed occlusive features (61.1%).¹ In another study involving patients with inflammatory retinal vascular occlusions from two tertiary institutes of different geographical regions (India and USA), 96 eyes had occlusive features among 346 patients with retinal vasculitis, and IOTB was the most common aetiology. ORV was predominantly venular (68.7%), unilateral and more common in Asian Indians. IOTB presenting with retinal vein occlusion has also been reported in a few case reports.^12–14

Our patient presented during the peak of the COVID-19 pandemic, and thromboembolic phenomena are well documented following this infection; we considered this a differential as well. Retinal vascular occlusions and PAMM have been reported in patients with COVID-19.^{15 16} However, our patient did not have any symptoms of COVID-19 and had a negative RT-PCR along with an unremarkable chest CT scan. Other autoimmune and prothrombotic disorders were actively ruled out in this patient.

Fundus presentation of ORV in the OD of our patient simulated CRVO. Various mechanisms have been hypothesised to explain retinal venous occlusions in IOTB. Direct blockage of the central retinal vein by Mycobacterium tuberculosis, compression from an adjacent choroidal/retinal tubercle, inflammatory disc swelling leading to secondary venous occlusion and hypersensitivity to M. tuberculosis have been incriminated.¹⁷ Besides the above possible mechanisms, hyperhomocysteinemia in our patient might also have contributed to vascular occlusion, which is also an independent risk factor for retinal vascular occlusion. Being a highly reactive amino acid, it is endothelio-toxic. Endothelial insult causes the liberation of free radicals and creates a thrombophilic environment.¹⁸ Chronic smoking and associated dyslipidaemia in our patient might have further potentiated oxidative stress and vascular injury. All these factors cumulatively resulted in an ischaemic insult to the capillary plexuses as well as larger retinal vessels. Microvascular ischaemia involving intermediate and deep capillary plexuses resulted in the development of PAMM, while the involvement of retinal veins led to occlusive periphlebitis.

There are regional variations in the recommendation of ATT in patients with presumed TRV. Some studies suggest a good response with few recurrences when ATT is combined with oral steroids, especially in the presence of ORV.¹ However, a better therapeutic effect and less treatment failure with ATT could not be established in a large multicentric study of patients with TRV.¹ Our patient, despite being advised ATT, did not consent to the same. Although he responded well to oral steroids, intravitreal anti-VEGF injection and scatter laser photocoagulation, he was cautioned about the chance of recurrence in the same or fellow eye. As TRV has been related to a delayed hypersensitivity reaction to tubercular antigen without active replication of tubercular bacilli, oral corticosteroids without ATT have a negligible risk of aggravating systemic infection in the presence of an unremarkable CECT of the chest.

In conclusion, IOTB can present as inflammatory occlusive retinal periphlebitis with PAMM, indicating ischaemic insult at both the macrovascular and microvascular level of the retinal circulation. Hyperhomocysteinemia, smoking and dyslipidaemia are important risk factors, which can further aggravate the vascular compromise.

Patient’s perspective.

Following sudden drop in vision in my right eye, I was subjected to various laboratory investigations. I noticed some improvement in vision following oral medicines, and treatment with laser and injection in the eye. I did not want to take anti-tubercular treatment for possible side-effects despite knowing the possibility of future recurrence of my eye problem.

Learning points.

• Paracentral acute middle maculopathy may be seen in patients with intraocular tuberculosis associated with retinal vasculitis, indicating both macrovascular and microvascular ischaemic involvement.

• Additional risk factors like hyperhomocysteinemia, smoking and dyslipidaemia may contribute to the vascular insult.

Ethics statements

Patient consent for publication

Obtained.