Grand Rounds Ethambutol Toxicity Mark Sherman MD University of Louisville Department of Ophthalmology and Visual Sciences 11/21/2014

Subjective CC: Decreased vision OU x 4 months HPI: 77 year old white female referred to the neuro-ophthalmology clinic with complaint of progressively worse decreased vision OU for the past four months. No other complaints. Patient had been 20/20 OU after cataract surgery 12 months prior POH: PCIOL OU, POAG on Timolol BID OU PMH: Arthritis, Colon CA s/p resection in 2012, Pneumonia (around time of initial visual decline) Meds: Aspirin, Ethambutol, Clarithromycin

Exam OD OS OD OS BCVA: Pupils: 5  3 5  3 No APD No APD IOP: EOM: Full OU CVF: Constricted OU

SLE: ODOS L/L WNLWNL L/L WNLWNL Conjunctiva WNLWNL Conjunctiva WNLWNL K WNLWNL K WNLWNL AC WNLWNL AC WNLWNL I/L PCIOLPCIOL I/L PCIOLPCIOL DFE: c/d: 0.4 OU +PPA; MVP WNL OU Exam

HVF 24-2

Optic Nerve OCT

OCT

MRI Brain/Orbits Impression: 1. No acute intracranial findings 2. Nonspecific findings likely secondary to chronic small vessel disease

Assessment/Plan Assessment: 77 year old female with significantly decreased vision OU x 4 months with constricted visual fields OU and otherwise normal exam and imaging Dx:Toxic optic neuropathy secondary to ethambutol Plan:Discontinue ethambutol

Toxic Optic Neuropathy Characterized by Characterized by Gradual, progressive bilateral vision loss Gradual, progressive bilateral vision loss Painless Painless Central vision loss Central vision loss Decreased color vision Decreased color vision Absent APD due to symmetric visual loss Absent APD due to symmetric visual loss Ophthalmic exam findings may be minimal or subtle Ophthalmic exam findings may be minimal or subtle Optic atrophy can develop if the cause is not corrected Optic atrophy can develop if the cause is not corrected Can present with mild to moderate disc edema Can present with mild to moderate disc edema

Toxic Optic Neuropathy Common etiologies: Common etiologies: Ethambutol (occurs in up to 6% of patients) Ethambutol (occurs in up to 6% of patients) Amiodarone Amiodarone Isoniazid Isoniazid Chloramphenicol Chloramphenicol Antineoplastic agents: cisplatin and vincristine Antineoplastic agents: cisplatin and vincristine B12, thiamine, or folate deficiency B12, thiamine, or folate deficiency Methanol Methanol Ethylene glycol Ethylene glycol

Toxic Optic Neuropathy Diagnosis of exclusion made with a detailed history and work up to rule out other etiologies Diagnosis of exclusion made with a detailed history and work up to rule out other etiologies Differential diagnosis includes subtle maculopathies and hereditary, compressive, demyelinating, or infiltrative optic neuropathies Differential diagnosis includes subtle maculopathies and hereditary, compressive, demyelinating, or infiltrative optic neuropathies Neuroimaging is routinely performed to rule out any compressive etiology Neuroimaging is routinely performed to rule out any compressive etiology

Toxic Optic Neuropathy Treatment is aimed at stopping the inciting medication, substance abuse, or replacement of dietary deficiencies Treatment is aimed at stopping the inciting medication, substance abuse, or replacement of dietary deficiencies Prognosis for visual recovery is good unless optic atrophy has occurred Prognosis for visual recovery is good unless optic atrophy has occurred Visual recovery is slow, usually 3-9 months Visual recovery is slow, usually 3-9 months Patients with ethambutol toxicity will often have a worsening of vision and visual fields for several months after stopping the medication before improvement begins Patients with ethambutol toxicity will often have a worsening of vision and visual fields for several months after stopping the medication before improvement begins

The protective effects of caffeic acid phenethyl ester (CAPE) in isoniazid and ethambutol-induced ocular toxicity in rats CAPE: a natural phenolic compound found in plants used in a variety of cancer treatment studies for its anti- inflammatory effects CAPE: a natural phenolic compound found in plants used in a variety of cancer treatment studies for its anti- inflammatory effects Study of 8 groups, each including 10 rats: Study of 8 groups, each including 10 rats: Control, isoniazid alone, ethambutol alone, CAPE alone, isoniazid +CAPE, ethambutol +CAPE, isoniazid with ethambutol, isoniazid with ethambutol and CAPE Control, isoniazid alone, ethambutol alone, CAPE alone, isoniazid +CAPE, ethambutol +CAPE, isoniazid with ethambutol, isoniazid with ethambutol and CAPE After 30 days the eyes underwent histopatholoic evaluation and retinal ganglion cell count After 30 days the eyes underwent histopatholoic evaluation and retinal ganglion cell count Isoniazide alone, ethambutol alone, and ethambutol with isoniazid groups all had significantly decreased retinal ganglion cell counts compared to the groups that had CAPE Isoniazide alone, ethambutol alone, and ethambutol with isoniazid groups all had significantly decreased retinal ganglion cell counts compared to the groups that had CAPE

References BCSC: Neuro-Ophthalmology. Toxic/Nutrinitional optic neuropathy. Pgs: BCSC: Neuro-Ophthalmology. Toxic/Nutrinitional optic neuropathy. Pgs: Grzybowski A, Zulsdorff, et al. Toxic optic neuropathies: An updated review. Acta Opthahlmol August. Grzybowski A, Zulsdorff, et al. Toxic optic neuropathies: An updated review. Acta Opthahlmol August. Kumar A, Sandramouli S, Verma L, et al. Ocular ethambutol toxicity: is it reversible? J Clin Neuro-Ophthalmol.1993; 13(1)15-17 Kumar A, Sandramouli S, Verma L, et al. Ocular ethambutol toxicity: is it reversible? J Clin Neuro-Ophthalmol.1993; 13(1)15-17 Mascaluso DC, Shults ET, et al. Features of Amiodarone- induced optic neuropathy. Am J Ophathalmol. 1999;127(5): Mascaluso DC, Shults ET, et al. Features of Amiodarone- induced optic neuropathy. Am J Ophathalmol. 1999;127(5): Sahin A, Kursat, et al. The protective effects of caffeic acid phenethyl ester in isoniazid and ethambutol-induced ocular toxicity in rats. Cutan Ocul Toxicity Sep;32(3) Sahin A, Kursat, et al. The protective effects of caffeic acid phenethyl ester in isoniazid and ethambutol-induced ocular toxicity in rats. Cutan Ocul Toxicity Sep;32(3)