Mitochondrial optic neuropathy R3 박율리/ AP. 신선영

Case 1 M/27 1달 전 좌안 시력저하 경주 동국대학교병원에서 retrobulbar optic neuritis 로 진단 5.13일부터 3일간 IV steroid pulse 시행 후 tappering 중 further evaluation 위해 내원. DM/HBP (-/-) Ocular op/trauma(-/-) Gls (-) Eye drop (-)

VA OD 1.0 OS 0.02 IOP OD 18 OS 15 mmHg Ortho at N&F Lid OU no swelling Conj. OU not injected Cornea OU clear AC OU deep & cell(-) Pupil OU Round and normal sized, LR(+/+), RAPD(-/+) Lens OU clear * Ishihara :OD 17/17 OS 10/ 17 * HRR: OD:WNL OS: Mild R-G Defect * 외부 Brain MRI & MRA : N-S

2개월 후 VA 1.0/0.02 Ishihara :OD 17/17 OS 13/ 17 HRR: OD:WNL OS: Mild R-G Defect

3개월 후 VA 1.0/0.02 엄마 : 11778A (+) HRR: OD:WNL OS: Mild R-G Defect

1년 후 “ 혼자 운전도 하고 다니고 일상생활에 문제가 없다.” VA 0.1/0.4 Ishihara test OU 20/21 HRR OD WNL OS mild R-G defect

Case 2 F/8 6개월전에 정기 검진 위해 새빛안과 방문, 안경 처방 받음. 우안 약시 진단 받고 상담 원하여 내원 산동 검사에서 특이 소견 없다고 알고 계심 PHx) No systemic disease, developmental delay(-) BHx) 40wks-3.15kg-NSD Ocular trauma/op(-/-) gls(+) for 6m Eye drop (-)

VA OD 0.125(0.125) OS 0.63(N-C) Ortho at N&F Lid OU no swelling Conj. OU not injected Cornea OU clear AC OU deep & cell(-) Pupil OU Round and normal sized, LR(+/+), RAPD(+/-) Lens OU clear 외부 Brain MRI : N-S Lang II E (- ) C (- ) M (- ) Titmus Fly(high ) Animal ( 3/3) Circle ( 4/9) W4D N' G3 D G3(OD suppression) Ishihara OD 2/17 OS 2/17 HRR mild R-G defect (OU)

5개월 후 VA (0.1)/0.8 Ishihara OD 1/17 OS 1/17 HRR OD strong R-G defect OS medium R-G defect

1년 후 VA 0.125/0.8 Ishihara OD 1/17 OS 1/17 HRR OD mild R-G defect OS mild R-G defect 어머니, 오빠 G11778A mutation

Case 3 F/78 Dec VA(OU) o/s 7개월 전 2009년 7월부터 8개월간 결핵약 복용하셨다고 함. (영남대학교에서 ethambutol induced optic neuropathy 결핵약 stop한 상태.) DM/HBP(-/-) Ocular trauma/op(-/+) 2005.3.4 cat.op(OS) a local 2010.1.25. cat.op(OD) at local gls(+) Eye drop (-)

VA OD 0. 25 OS 0. 04 Ortho at N&F Lid OU no swelling Conj VA OD 0.25 OS 0.04 Ortho at N&F Lid OU no swelling Conj. OU not injected Cornea OU clear AC OU deep & cell(-) Pupil OU Round and normal sized, LR(+/+), RAPD(-/-) Lens OU PCL in situ * Ishihara OD 5/17 OS 3/17 * H.R.R OD mild B-Y defect OS Strong R-G defect, mild B-Y defect * Amsler OD central scotoma(-) OS central scotoma(+) * 외부 Brain MRI : N-S * 외부 FAG, Fd-photo : seemed to be normal

2 달 후 VA 0.63/0.2 Ishihara OD 17/17 OS 10/17 H.R.R OD WNL OS medium R-G defect RAPD (-/-)

6달 후 VA 0.63/0.2 Ishihara OD 19/19 OS 18/19 H.R.R OD WNL OS Medium R-G defect RAPD (-/-)

Case 4 F/64 폐결핵으로 2008년 10월부터 ethambutol 처방 받아 복용하던 중 시력저하 소견 보여, 외래 방문함. 이와 관련한 소송 진행중 DM/HBP(-/+) for 3 yrs Ocular trauma/op(-/-) Gls(-) Eye drop (-)

VA OD HM(N-C) OS HM(N-C) IOP 13/12 mmHg Lid OU no swelling Conj VA OD HM(N-C) OS HM(N-C) IOP 13/12 mmHg Lid OU no swelling Conj. OU not injected Cornea OU clear AC OU deep & cell(-) Pupil OU Round and normal sized, LR(+/+), RAPD(-/-) Lens OU mild cortical opacity

4달 후 VA HM/HM

REVIEW

Mitochondrial Optic Neuropahty Congenital Acquired LHON, DOA Syndromic Toxic Nutritional

Introduction Mitochondrial genetic disease characterised by bilateral subacute loss of central vision owing to focal degeneration of optic nerve. Typically affect males at ages of 15 and 35 1 in 25,000 in the north east of England Maternally inherited mitochondrial DNA mutation, most notably 11778.

Pathophysiology Approximately 95% of individuals with LHON have one of three point mutations of mitochondrial DNA (mtDNA) m.3460G>A, m.11778G>A, or m.14484T>C

Why should this mitochondrial insufficiency be so selective for RGCs & their axons that from ON? Axonal transport : highly energy dependent RGCs with their long axon : particularly vulnerable RGCs axon of papillomacular fiber bundle Narrow caliber : High surface area to volume ratio favors energy consumption over energy production early and preferential involvement of axons that form papillomacular bundle, anatomical substrate for central and color vision. .Mitochondria가 pre-laminar unmyelinated portion of optic disc 와 under the nodes of Ranvier in the post-laminar portion of the myelinated optic nerve 에 많다. .RGC axon을 따라 mito의 non-homogenous distribution은 이 segment의 에너지요구와 비례한다. Axon의 Myelinated posterior portion은 salvatory conduction으로도 충분하기 때문에 mitochondria가 거의 없다

Presentation Bilateral acute or subacute, severe, painless loss of central vision during young adult life. The fellow eye become similarly within weeks or months In an estimated 25% of cases, visual loss is bilateral at onset Males are approximately four times more likely to be affected than females. Visual acuity is severely reduced to counting fingers or worse. Early impairment of color perception In many cases, pupillary reflexes are preserved Patients usually report no pain on eye movement.

Diagnosis Fundus Exam - disc swelling with obscuration of the disc margin - edema of the peripapillary nerve fiber layer - increased vascular tortuosity - Telangiectatic microangiopthy may be present in asymptomatic female relatives - 20% of LHON cases, optic disc looks entirely normal in acute phase. - optic discs become atrophic

Diagnosis FAG Visual field Electrophysiologic studies Cranial imaging - absence of dye leakage Visual field - Enlarging central or centrocecal scotoma Electrophysiologic studies - VEP to confirm optic nerve dysfunction Cranial imaging - to exclude other compressive, infiltrative, and inflammatory causes of a bilateral optic neuropathy. MRI is often normal but may reveal a high signal within the optic nerves Difficult to exclude other possible causes of optic atrophy, especially if there is no clear maternal family history.

Treatment - Generally ineffective (steroids, hydroxocobalamin and surgical intervention) - Antioxidant : CoeZ Q-10, Idebenone -Smoking and excessive consumption of alcohol : discouraged -> to minimize potential stress on mitochondrial energy production

ETHAMBUTOL-INDUCED OPTIC NEUROPATHY

Introduction Chelating metal ions involved in prokaryotic ribosomes Similarity of mammalian mitochondrial DNA & ribosome to those of bacteria Protein synthesis inhibited Chronic impairment of energy production & accumulation of ROS Apoptosis & optic nerve degeneration mitochondria - provide most of ATP accumulate at nodes of Ranvier and other unmyelinated regions along axons ochondria가 pre-laminar unmyelinated portion of optic disc 와 under the nodes of Ranvier in the post-laminar portion of the myelinated optic nerve 에 많다. .RGC axon을 따라 mito의 non-homogenous distribution은 이 segment의 에너지요구와 비례한다. Axon의 Myelinated posterior portion은 salvatory conduction으로도 충분하기 때문에 mitochondria가 거의 없다 The mitochondrial pathway to apoptosis. Accumulation of reactive oxygen species (ROS) leads to a decrease in the electrical potential across the mitochondrial membrane, which allows for an opening of the mitochondrial permeability transition pore (MPTP), releasing cytochrome c (Cyt c) into the cytosol. Cytochrome c binds to apoptosis activating factor-1 (APAF-1), which activates procaspase-9, which triggers the caspase cascade and apoptosis. Each time an axon undergoes action potential propagation, sodium/potassium pumps must restore the resting membrane potential. This step requires large quantities of ATP. Not surprisingly, mitochondria, the primary source of ATP, accumulate at the nodes of Ranvier and other unmyelinated regions along axonsEach time an axon undergoes axons

Risk Factors for Ethambutol Visual Loss Too high dosage (do NOT stay on 25mg.kg for more than 1 m.) Small people Kidney problems (urinary clearance) Old people (have poor cr. cl.) Failure to adequately monitor vision

Clinical manifestations Usually bilateral Acute or chronic onset (3days ~ 8mon.) Decreased visual acuity Dyschromatopsia – may be the earliest sign blue–yellow color changes(m/c) or acquired red–green color vision loss Central or cecocentral scotoma, or bilaterally temporal (peripheral) field defect

Assessment No relative afferent pupillary defect, but bilaterally slugged light reflex Fundus - normal optic disc or temporal disc pallor visual acuity color vision central visual fields (such as Amsler grid or HVF) pattern visual evoked potentials

Management CESSATION of drug as soon as visual symptom occurs CIx. : pts who cannot describe visual symptoms Identification of pts at risk - Renal dysfunction, Diabetes mellitus, poor nutrition Adjusting dose regimen for impaired renal function, Bwt, and age regular monitoring for early signs of ocular toxicity, and pt education.

J Neuro-Ophthalmol 2008;