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CASE REPORT
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Ethambutol-Induced bilateral retrobulbar neuritis with cecocentral scotoma in cervical tuberculous lymphadenitis patient: A case report with estimated plasma level consideration


1 Department of Clinical Pharmacy, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India
2 Department of Pulmonary Medicine, Bharati Vidyapeeth (Deemed to be University) Medical College and Hospital, Pune, Maharashtra, India
3 Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India

Date of Submission29-Mar-2021
Date of Decision28-May-2021
Date of Acceptance02-Jun-2021
Date of Web Publication19-Jul-2022

Correspondence Address:
Sathiyanarayanan Lohidasan,
Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune - 411 046, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_231_21

  Abstract 


Ethambutol is considered to be safest first-line antitubercular drug, and patient acceptability is rather good in both intensive and continuation phase of the tuberculosis treatment with daily regimen. The important adverse effect associated with ethambutol is optic neuritis, resulting in loss of visual acuity, color vision, and field defects. The incidence of optic neuritis is generally directly proportional to the dose and duration of ethambutol therapy and rarely reported in a low standard dose. Here, we report a case of a 40-year-old female patient with complaints of progressive diminished vision (especially during day time) with a low daily dose (15 mg/kg/day) of ethambutol. She got diagnosed with cervical tuberculous lymphadenitis and was receiving isoniazid, rifampicin, ethambutol, and levofloxacin. In rare instances, ethambutol ocular toxicity may present with cecocentral scotoma. In rare instances, plasma levels are performed. An estimated plasma level of ethambutol was found to be in higher end (5.6 μg/ml) of the reported therapeutic range (2–6 μg/ml). Bilateral retrobulbar neuritis with cecocentral scotoma adverse effect due to ethambutol can be seen in plasma therapeutic range.

Keywords: Bilateral retrobulbar neuritis, cecocentral scotoma, ethambutol, plasma levels



How to cite this URL:
Panda BK, Bargaje M, Suryawanshi VR, Lohidasan S. Ethambutol-Induced bilateral retrobulbar neuritis with cecocentral scotoma in cervical tuberculous lymphadenitis patient: A case report with estimated plasma level consideration. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2022 Dec 6]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=351330




  Introduction Top


Ethambutol (E) is regarded as the least toxic compared to other first-line antitubercular agents, with a low incidence of ocular toxicity.[1] Incidence of ethambutol causing bilateral retrobulbar neuritis with cecocentral scotoma with its recommended dose (15 mg/kg/day) within >2 weeks is <1%.[2] We hereby report a case focused on rare ethambutol-induced reversible bilateral retrobulbar neuritis with cecocentral scotoma at a dose of 15 mg/kg/day and attempt to estimate the plasma levels of ethambutol in the patient who was on a self-administered daily antitubercular therapy (ATT). Comparison of presenting case with published case reports (Indian) with pharmacotherapy decisions regarding ATT was made.


  Case Report Top


A 40-year-old female 56 kg body weight presented to pulmonary outpatient department complaining left-sided neck pain which did not resolve with analgesics. Upon physical examination, nodules were felt. She was advised for ultrasonogram (USG) examination, tuberculin test, chest X-ray, hemogram, erythrocyte sedimentation rate, blood sugar level-random, serology, and histopathological examination biopsy of left cervical node. Her USG report specified left-sided cervical lymphadenopathy and tuberculin test came positive. Chest X-ray showed no abnormalities, and other laboratory tests were also within the normal limits. Histopathology report showed lymph node with thickened capsule, infiltrated by coalescent epithelioid histiocytic granuloma, suggestive of cervical tuberculous lymphadenitis.

She was advised for ATT with 4 tablet/day of Akurit-4® containing isoniazid 75 mg, rifampicin 150 mg, ethambutol 275 mg, and pyrazinamide 400 mg. After 10 days of therapy, she reported back with complaints of fatigue and pain in the right upper quadrant of abdomen. Physical examination confirmed abdominal tenderness and hepatomegaly. She was advised for liver function tests (LFTs). Her LFTs showed elevated aspartate aminotransferase (7–8 times [362 IU/L]) and elevated alanine aminotransferase (5–6 times [232 IU/L]). Suspecting drug-induced (isoniazid and rifampicin) hepatitis, Akurit-4® was discontinued. Combutol® (ethambutol) 800 mg/day and L-CIN® (levofloxacin) 500 mg/day were prescribed. After a month, her LFTs got resolved, rifampicin 450 mg/day followed by isoniazid 300 mg/day were reinitiated to the existing therapy. She had no complaints for subsequent 2 months.

In the 1st week of 3rd month, she presented with painless bilateral defective vision worsening during day time. She was facing this problem from the past 10 days. Only ethambutol was discontinued immediately suspecting ethambutol ocular toxicity (EOT). She was treated with Vitamin B-complex supplementation and pyridoxine 100 mg once daily for 15 days. [Table 1] describes the investigations performed for the diagnosis of cervical tuberculous lymphadenitis.
Table 1: Impressions of investigations performed for cervical tuberculous lymphadenitis diagnosis in patient

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Investigations

Automated perimetric visual fields [Figure 1] performed for both eyes, revealed 60% and 36% visual field index with bilateral homonymous quadrantanopia and cecocentral scotoma. Her best-corrected visual acuity finger counting at a distance of 3 m was disturbed in bilateral eyes and was not improving through pinhole. Goldmann applanation tonometry revealed increased intraocular pressure (left eye 12 mmHg < right eye 14 mmHg). Ishihara color vision test showed defective color vision (red–green dyschromatopsia). Fundoscopy revealed mild hyperemia of optic disc with normal macular examination. Amsler grid examination and optic coherence tomography were also performed to measure central visual fields and retinal nerve fiber layer (RNFL) thickness, respectively. These were found to be normal. Pupils were reactive in both eyes with no relative afferent pupillary defect. Diagnosis of bilateral retrobulbar neuritis with cecocentral scotoma secondary to ethambutol was confirmed.
Figure 1: Automated perimetry test for left and right eye

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As a daily routine, the patient usually takes medicines at 7:00 am and breakfast after 1 h. The day she visited the outpatient department, her venous blood (5 ml) was withdrawn at 10 am without delay. The duration of drug intake and blood withdrawal was approximately 3 h. Separated plasma was centrifuged and immediately frozen at −80°C. The plasma concentrations of ethambutol were quantified six times to identify intraday variation using a simple and validated liquid chromatography tandem mass spectrometry developed in collaboration with Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Pune, Maharashtra, India.[3] Plasma concentration reference range for ethambutol (E) was 2–6 μg/ml.[4] This range represents the expected (average) concentrations (Cmax in μg/ml) in adults with standard daily doses of ethambutol used to treat tuberculosis.[3],[4] Her ethambutol plasma (mean ± standard deviation) concentration was 5.6 ± 0.34 μg/ml. [Figure 2] is the representative Multiple Reaction Monitoring (MRM) chromatogram for ethambutol in patient plasma collected 3 h of postdose.
Figure 2: Representative MRM chromatogram for ethambutol in patient plasma after 3 h of dose

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Within 2 months of ethambutol discontinuation, her peripheral and color vision gradually restored.


  Discussion Top


The reported incidence of retrobulbar neuritis when ethambutol is taken for more than 2 months is 18% in subjects receiving more than 35 mg/kg/day, 5%–6% with 25 mg/kg/day, and <1% with 15 mg/kg/day.[2] This suggests that there is no safe dose for ethambutol in the clinical practice. The time of onset for EOT cannot be predicted from the literature, as it varies from few days to 2 years of therapy initiation with ethambutol.[1],[2]

A comparative study with Indian case reports was carried out [Table 2]a and [Table 2]b. Cecocentral scotomas were commonly reported [Table 2a], whereas, in case series [Table 2b],[10] it was not reported. EOT was reported even after completion of ATT.[8],[11] Therefore, late onset of EOT may occur, so history taking regarding ATT must be considered. Blurring of temporal margins in macula and pigmentary changes are uncommon but can be seen in EOT. Pretreatment visual testing was performed in three cases.[5],[10],[11] Optic coherence tomography was performed post-EOT only in our case to measure RFNL thickness, however, was found to be normal. Measurement of RFNL thickness at the peripapillary regions can be done in the patients receiving ethambutol for the detection of subclinical EOT as, mean temporal RFNL thickness increases after ethambutol, and medication duration of 5–6 months seems to be the strong risk factor.[9],[12]


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For ethambutol, Cmax of 2–6 μg/ml after daily doses of 15–25 mg/kg is required. Plasma levels of ethambutol were estimated in the present case report to understand the relation between plasma concentration and ocular adverse effect. With the best of our knowledge, none of the published studies or reports considered ethambutol plasma estimation. Ethambutol usually reaches Cmax 2–3 h postdose. As per literature, the toxic concentration reported is 10 μg/ml. In our patient, the mean plasma levels of ethambutol were on the higher side of therapeutic range and the concentration achievement shows no malabsorption. The plasma estimation of ethambutol in this patient suggests that EOT may happen even in therapeutic range and may not be a useful assessment tool in low-resource health-care settings. Isoniazid is considered to cause ocular toxicity but is advised to stop if less severe optic neuritis does not improve within 6-week postethambutol withdrawal.[5] Our patient showed a sign of improvement within a month and complete recovery within 2 months.

Pharmacotherapy for EOT remains the same in all of the case reports which includes Vitamin B-complex supplementation and pyridoxine 100 mg. Two cases reported [Table 2] the use of oral steroids (1 mg/kg) for 11–14 days.[7],[9] Zinc deficiency has been linked with EOT in patients, so zinc supplementation may improve recovery.[6],[7],[13] The mechanism EOT is unknown but hypothesized that mitochondrial disturbance, the zinc-chelating effect, and its metabolite are the possible underlying mechanisms. Malnourishment of B-complex vitamins, particularly thiamine (Vitamin B1), and cyanocobalamin (Vitamin B12) could result in nutritional optic neuropathy. Deficiency of riboflavin (Vitamin B2), niacin (Vitamin B3), pyridoxine (Vitamin B6), and folic acid also seems to play a vital role in optic neuropathy.[14] Furthermore, EOT is dependent on the patient's age, duration of therapy, dose, and renal clearance of ethambutol. But remains highly unpredictable. Hence, monitoring of ocular manifestations is warranted and advised.


  Conclusion Top


Bilateral retrobulbar neuritis with cecocentral scotoma secondary to ethambutol can occur at the lowest standard dose of ethambutol having plasma concentration within therapeutic range.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Prasad R, Singh A, Gupta N. Adverse drug reactions in tuberculosis and management. Indian J Tuberc 2019;66:520-32.  Back to cited text no. 1
    
2.
Garg P, Garg R, Prasad R, Mishra AK. A prospective study of ocular toxicity in patients receiving ethambutol as a part of directly observed treatment strategy therapy. Lung India 2015;32:16-9.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Panda BK, Bargaje M, Sathiyanarayanan L. A simple and reliable analytical method for simultaneous quantification of first line antitubercular drugs in human plasma by LCMS/MS. Anal Methods 2020;12:3909-17.  Back to cited text no. 3
    
4.
Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002;62:2169-83.  Back to cited text no. 4
    
5.
Kodan P, Kariappa A, Hejamady MI. Ethambutol induced acute ocular toxicity: A rare case report. J Med Trop 2014;16:32-4.  Back to cited text no. 5
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6.
Divya G, Ranganayakulu D. A rare case report on ethambutol induced optic neuritis. Int J Basic Clin Pharmacol 2015;4:172-4.  Back to cited text no. 6
    
7.
Undrakonda V, Yashodhara BM, Gonsalves S, Shashikiran U, Kapoor S. Bilateral retrobulbar neuritis following cessation of ethambutol. Int J Case Rep Images 2015;6:76-80.  Back to cited text no. 7
    
8.
Monika, Kumar J, Rathi M, Dua M, Sachdeva S. Ethambutol induced optic neuropathy: A rare case report. Int J Res Rev 2020;7:13-7.  Back to cited text no. 8
    
9.
Addoor KR, Nishant V, Raju J, Bhandary S, Menon D, Gupta A. Optic neuropathy induced by low dose of ethambutol: A rare presentation. Asian J Pharm Clin Res 2017;10:12-3.  Back to cited text no. 9
    
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Sruthi N, Anuradha M. Ethambutol induced optic neuritis: A case series. Int J Basic Clin Pharmacol 2020;9:207-10.  Back to cited text no. 10
    
11.
Kho RC, Al-Obailan M, Arnold AC. Bitemporal visual field defects in ethambutol-induced optic neuropathy. J Neuroophthalmol 2011;31:121-6.  Back to cited text no. 11
    
12.
Kim KL, Park SP. Visual function test for early detection of ethambutol induced ocular toxicity at the subclinical level. Cutan Ocul Toxicol 2016;35:228-32.  Back to cited text no. 12
    
13.
Jhamaria JP, Rajput VS, Luhadia SK, Bansal PP, Ved ML, Gandhi VC. Ocular toxicity of ethambutol and its correlation with serum zinc levels. Lung India 1989;7:183-5.  Back to cited text no. 13
  [Full text]  
14.
Sharma P, Sharma R. Toxic optic neuropathy. Indian J Ophthalmol 2011;59:137-41.  Back to cited text no. 14
[PUBMED]  [Full text]  


    Figures

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    Tables

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