Optic neuritis R2 김은영/Ap.박신혜

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1 Optic neuritis R2 김은영/Ap.박신혜
The Catholic University of Korea St. Mary’s Hospital Department of Ophthalmology

2 Case 1 C.C 27/M 김 O 인 Decreased VA(OU) Onset : 3주전 (내원일 :2013.02.27)
상기 27세 남환 3주전부터 Dec.VA(OU)(교정시력 0.5정도/양안)증상 발생하여 local안과에서 R/O Optic neuritis(OU) 소견하에 po steroid 8~9 알( 40~45mg)정도 복용하였으며 호전되었다고 함. 4일 후 서울대병원 안과 방문하여 시신경염에 관한 안과검사 시행하였으나 특이소견 없었다고 함 .당시 시력 1.5/1.5 였다함. 3일전부터 양안 시력저하 심해져 (교정시력 양안 > 0.1정도) 이에 대한 검사 본원에서 원하여 내원함.

3 Present Illness 상기 27세 남환 3주전부터 Dec.VA(OU) 증상 발생하여 local안과에서 R/O Optic neuritis(OU) 소견하에 po steroid 복용후 증상 호전되었으며, 2주전 분당 서울대 병원 안과 ,신경과 진료시 양안 시력 1.5/1.5 체크되고 특이소견 없어 경과관찰 하던 중 약 3일전부터 다시 양안 시력저하 발생하여 본원 내원함. Ocular pain (OU) 동반함

4 History Past History Medication History (+) :신경과두통약
DM/HTN (-/-) recent URI(-) Medication History (+) :신경과두통약 Surgical History (-) Trauma Hx(-) Eye drop use (-) Gls(-) C.L.(-) FHx(-)

5 Ocular Examination VA OD ; 0.1 (N-C) OS ; 0.02(N-C)
MR OD : -0.75Ds-0.25Dc Ax132 OS : -0.25Ds -0.75Dc Ax144 IOP(by air) OD ; 11mmHg OS ; 14mmHg Ocular muscles straight at primary position, LOM(-) /OU Orbit & adnexa no exophthalmo/OU Lid no swelling, no ptosis/OU Cornea & sclerae clear /OU Ant. Chamber Deep & cell(-) /OU Iris & pupil round & nl sized/OU RAPD(+-/+-) Lens & vitreous clear Fundus OD disc swelling,flat OS disc swelling,flat Ishihara 1/17(OD) 0/17(OS) HRR 모든 plate 보이지 않음 양안 통증 동반 Hardy-Rand-Rittler (HRR)

6 Impression & Initial plan
Initial Impression R/O Bilateral Optic neuritis (OU) R/O LHON Diagnostic plan F-Photo, Disc photo VF Brain imaging FAG , RNFL OCT LHON gene study [응급] Total Cholesterol [응급] [응급] HDL-Cholesterol [응급] [응급] LDL-Cholesterol [응급] [응급] Triglyceride [응급] MRA Neck (enhance) Plan 신경과 Consultation Addmission ->Steroid pulse therapy

7 Fundus photo

8 Fds OD sl. elevated, hyperemic optic disc, temporal pallor(+)
OS sl. elevated optic disc, temporal pallor(+)

9 VF – VF : OS) Altitudinal defect .아래쪽 시야결손이 더 심함.

10 RNFL OCT – FAG – WNL

11 Neurology Consultation
Evaluation. Brain MRI (enhance) SEP Vasculitis & Autoimmune battery lab NMO Ab. CSF study 시행. Brain MRI (Enhance) Brain parenchyme에 특별히 의심되는 lesion은 보이지 않았고, Rt. optic nerve enhancement소견이 의심되나 fat suppressed MRI이 필요함.

12 Neurology Consultation
CSF Study Oligoclonal (IgG) Band Negative NM0-AB--정상+ OCB-OK NMO ab--OK 각종 항체-모두 정상++ BP 128/78-77 BP 114/63-94 NM0-AB--정상+ 모든검사 -- OCB-OK NMO ab--OK 각종 항체-모두 정상++ MRI orbit E (안과 시행) no definite brain parechymal lesion pit. gl. 는 특이소견 없음(영상 verbal 판독) CSF tapping was done without complication Pr 19.2cmH2O WBC RBC protein Glu/ Alb/ IgG/

13 Progress note Admission and steroid pulse therapy start
1000mg #4/day x3days HD #1 VA OD (0.1 x -0.75Ds) OS (0.08 x ) IOP OD 16 OS mmHg at 8:00 AM by NCT RAPD(-/-) Fds OD sl. elevated, hyperemic optic disc, temporal pallor(+) OS sl. elevated optic disc, temporal pallor(+) HD #2 VA OD 0.08(N-C x -0.75Ds) OS 0.16(N-C x ) IOP OD 15 OS mmHg at 8:00 AM by NCT .

14 HD #3 2013.3.2 A P S&O VA OD 0.125 (0.16 x -1.50Ds = -0.50Dc Ax 175)
OS 0.16 (0.5 x -1.25Ds = -0.50Dc Ax 160) IOP OD 15 OS mmHg at 8:00 AM by NCT Ishihara OD 1/17 OS 2/17 HRR OD strong R-G defect, strong B-Y defect OS mild R-G defect, strong B-Y defect EOM pain (-) Fds OD disc swelling 감소, temporal pallor(+) OS disc swelling 감소, temporal pallor(+) A R/O bilateral Optic neuritis (OU) R/O LHON less likely P VF24-2 : f/u H-LON 75 mg (15T#1) for 11days -> tapering 없이 stop F/U 11days later 상환 ~ 일간 Steroid pulse therapy 후 tolerable state로 퇴원함.

15 Progress note : 2013.03.13 A S&O P Keep PO steroid VA OD 0.8 OS 0.8
shihara 14/17 (OD), 15/17 (OS) HRR mild R-G defect, medium B-Y defect (OU) A R/O bilateral Optic neuritis (OU) R/O LHON less likely P Keep PO steroid 모든검사 -- OCB-OK NMO ab--OK 각종 항체-모두 정상++

16 Progress note : 2013.04.10 A S&O P F/U 2013.3.13 LHON gene : negative
VA OD1.0 OS 0.8 신경과 lab - 모두 정상임. Ishihara 17/17 (OD), 17/17 (OS) RNFL thickness : WNL (OU) disc swelling (-) A R/O bilateral Optic neuritis (OU) R/O LHON less likely P F/U 모든검사 -- OCB-OK NMO ab--OK 각종 항체-모두 정상++

17 Fundus photo

18 VF – VF – VF : OS) Altitudinal defect .아래쪽 시야결손이 더 심함.

19 Progress note : 2013.07.20 Recurrence C.C
양안 (우안>좌안) 시력이 3일전 부터 다시 안좋아요. Ocular pain (+) Ocular Examination VA OD OS 0.5 IOP 10/12 Ishihara OD 10/17 OS 8/17 RAPD (-/-) Fds OD nl. optic disc c flat post.pole, no disc swelling OS nl. optic disc c flat post.pole, no disc swelling Recurrence 모든검사 -- OCB-OK NMO ab--OK 각종 항체-모두 정상++ 7/22 ~ 7/25 ★ 퇴원 후 약 복용 잘 설명 해주세요 ★ 1. 처음 11일동안 50mg/일 (아침 식후 30분에 50mg 모두 복용) 2. 그 다음 1일은 20mg/일 (아침 식후 30분에 20mg 모두 복용) 3. 그 다음 1일은 10mg/일 (아침 식후 30분에 10mg 모두 복용) 4. 그 다음 1일은 쉬고 5. 그 다음 1일은 10mg/일 (아침 식후 30분에 10mg 모두 복용) -- 끝

20 Fundus photo

21 VF – Central scotomas

22 RNFL OCT –

23 Case 2 C.C 51/M 김O섭 2013.07.08 Decreased VA(OS) Onset : 2013.06.30
갑자기 좌측 눈이 까맣게 안보임 ( 분) - 이후 이전보다 시력이 더 나빠진 듯. local 내원 os optic disc swelling 으로 의뢰. 수차례 뇌경색 37세 최초 뇌경색 - 양측 마비 ? 전신 쇠약 10년 후 및 2년 전 및 작년 (총 4회) 뇌경색 - 복시, 말 어둔함 등 다양한 증상

24 Present Illness 상기 51세 남환 환자 진술상 약 30여분 가량 좌안 안보이는 현상 발생한 이후 점점 시력저하 증상 있어 local clinic 경유 Disc swelling (OS) 있어 further evaluation 및 proper management 위해 내원. Painless 수차례 뇌경색 37세 최초 뇌경색 - 양측 마비 ? 전신 쇠약 10년 후 및 2년 전 및 작년 (총 4회) 뇌경색 - 복시, 말 어둔함 등 다양한 증상

25 History Past History Surgical History (-) Medication History (-)
DM/HTN (+/+) for 2yrs on medication . ASA(+) stroke Hx (+) 12년전 , 3-4년전 총 4회 . (37세 최초 뇌경색) Recent ex-smoker Surgical History (-) Medication History (-) Trauma Hx(-) Eye drop use (-) Gls(-) C.L.(-) FHx(-) 수차례 뇌경색 37세 최초 뇌경색 - 양측 마비 ? 전신 쇠약10년 후 및 2년 전 및 작년 (총 4회) 뇌경색 - 복시, 말 어둔함 등 다양한 증상 (아스피린 복용 중 재발 여부는 잘 모름) 갑자기 좌측 눈이 까맣게 안보임 ( 분) - 이후 이전보다 시력이 더 나빠진 듯BP: 85/61 mmHg - 74/min

26 외부 MRI (2013.7.3) r/o TMB with Lt cavenous ICA stenosis (2013. 6. 30)
Multiple recurrent infarction (최초 뇌경색은 37세) - Old MRI: cerebellar, Rt frontal, Lt parietal etc Old MRA: Lt M1 focal stenosis local안과에서 좌측 시신경부종 발견되어 의뢰되었습니다. 타병원에서 찍은 orbit MRI에서 좌측 시신경을 따라 이상 소견은 없습니다. 현재로서는 좌안의 optic nerve의 ischemic change 일 가능성이 높아 Cervical ICA - 영상 없음 =>MRA( ): Rt VA occlusion / both cavernous ICA stenosis / Lt MCA/ACA stenosis HTN/DM on tx (HbA1C = 7.1%) Recent ex-smoker

27 Ocular Examination VA OD ; 0.8 OS ; 0.5(0.63 x -0.75 Ds -0.50Dc Ax125)
IOP(by air) OD ; 11mmHg OS ; 14mmHg Ocular muscles straight at primary position, LOM(-) /OU Orbit & adnexa no exophthalmo/OU Lid no swelling, no ptosis/OU Cornea & sclerae clear /OU Ant. Chamber Deep & cell(-) /OU Iris & pupil round & nl sized/OU RAPD(uncheckable ) – 산동상태로 내원 Lens & vitreous clear Fundus OD nl disc c flat post pole OS disc swelling c disc hm Ishihara 17/17(OD) 11/17(OS) EOM movement 통증 없음

28 Fundus photo

29 Impression & Initial plan
Initial Impression R/O Ant. Ischemic optic neuropathy(OS) Diagnostic plan VF FAG 신경과 Consultation 　Total Cholesterol 　Triglyceride ▲ 　HDL-Cholesterol ▼ 　LDL-Cholesterol MRA Neck (enhance) Plan 2주뒤 F/U ( VF 예약) O-BMDP x2 /OU start 신경과 : Lipid profile , MRA Neck(enhance)

30 Imaging Study FAG - 시신경/황반 주변으로 초기 저형광 (+)

31 VF – VF : OS) Altitudinal defect .아래쪽 시야결손이 더 심함.

32 Progress note : 2013.07.29 A S&O P steroid pulse 고려
더 잘 안 보인다. 눈주변통증, 두통동반. VA OD OS 0.06 BP: 79/60 mmHg - 82/min optic disc 주변으로 edema (++) (OU) -increased macula- sparing A R/O Ant. Ischemic optic neuropathy(OS) P steroid pulse 고려 Keep O-BMDP x2/OU & 2wks later F/U 같은날 신경과 LDL-C = 85 / TG = 225 【원외】Pregrel tab. 75mg (Clopidogrel) 1T #1 ⅹ 30days 【원외】Mevalotin tab. 40mg (Pravastatin) 1T #1 ⅹ 30days 【원외】Diabex xr tab. 500mg (Metformin) 1T #1 ⅹ 30days 【원외】Aspirin protect tab.100mg (Aspirin) 1T #1 ⅹ 30days Neck MRA 판독 Short segmental irregular stenosis involving Lt MCA M1 segment. Also noted focal stenosis involving proximal A1 segment, and distal A2/3 segments of Lt ACA. RO azygous ACA. Irregular contours of both distal ICAs,  V4 segments of Lt VA, basilar arteries and Rt PCA, and distal M2/3 branches of both MCAs.  - Atherosclerotic changes. Hypoplastic Rt VA. Chronic infarction with encephalomalacic change involving Rt frontal and Lt occipitotemporal lobe. Chronic ischemic changes along the both periventricular white matters.

33 Fundus photo 좌안 악화됨.

34 VF – 좌안 VF 소견 악화됨.

35 Progress note : 2013.08.12 A S&O P VF 예약
VA OD OS 0.63 RAPD (-/+) A R/O Ant. Ischemic optic neuropathy(OS) P VF 예약 Keep O-BMDP x2/OU & 2wks later F/U 같은날 신경과 LDL-C = 85 / TG = 225 【원외】Pregrel tab. 75mg (Clopidogrel) 1T #1 ⅹ 30days 【원외】Mevalotin tab. 40mg (Pravastatin) 1T #1 ⅹ 30days 【원외】Diabex xr tab. 500mg (Metformin) 1T #1 ⅹ 30days 【원외】Aspirin protect tab.100mg (Aspirin) 1T #1 ⅹ 30days Neck MRA 판독 Short segmental irregular stenosis involving Lt MCA M1 segment. Also noted focal stenosis involving proximal A1 segment, and distal A2/3 segments of Lt ACA. RO azygous ACA. Irregular contours of both distal ICAs,  V4 segments of Lt VA, basilar arteries and Rt PCA, and distal M2/3 branches of both MCAs.  - Atherosclerotic changes. Hypoplastic Rt VA. Chronic infarction with encephalomalacic change involving Rt frontal and Lt occipitotemporal lobe. Chronic ischemic changes along the both periventricular white matters.

36 Progress note : 2013.08.27 A S&O P Keep O-BMDP x2/OU & 2mo later F/U
시력은 많이 좋아졌어요. 굴절되어 보이는 증상 (+) VA OD OS 0.63 VF : inf. altitudinal defect (+) A R/O Ant. Ischemic optic neuropathy(OS) P Keep O-BMDP x2/OU & 2mo later F/U 같은날 신경과 LDL-C = 85 / TG = 225 【원외】Pregrel tab. 75mg (Clopidogrel) 1T #1 ⅹ 30days 【원외】Mevalotin tab. 40mg (Pravastatin) 1T #1 ⅹ 30days 【원외】Diabex xr tab. 500mg (Metformin) 1T #1 ⅹ 30days 【원외】Aspirin protect tab.100mg (Aspirin) 1T #1 ⅹ 30days Neck MRA 판독 Short segmental irregular stenosis involving Lt MCA M1 segment. Also noted focal stenosis involving proximal A1 segment, and distal A2/3 segments of Lt ACA. RO azygous ACA. Irregular contours of both distal ICAs,  V4 segments of Lt VA, basilar arteries and Rt PCA, and distal M2/3 branches of both MCAs.  - Atherosclerotic changes. Hypoplastic Rt VA. Chronic infarction with encephalomalacic change involving Rt frontal and Lt occipitotemporal lobe. Chronic ischemic changes along the both periventricular white matters. VF : OS : inf. altitudinal defect (+)

37 Fundus photo 2013.08.12 Fundus photo 2013.08.27 좌안 시신경부종 감소함.
9.27 금일 오후 신경과..안과 예약 진료 예정입니다.

38 F/U Neurology (2013.08.27) BP: 137/101 mmHg - 73/min Plan
LDL-C = 85 / TG = 225 HbA1C = 6.2% BP: 137/101 mmHg - 73/min Plan Add Olmesartan Clopidogrel. 75mg 1T #1 ⅹ 60days Pravastatin 1T #1 ⅹ 60days Aspirin 1T #1 ⅹ 60days

39 Optic neuritis The Catholic University of Korea St. Mary’s Hospital
Department of Ophthalmology

40 Types of optic neuropathy
Inflammatory (optic neuritis) Vascular (ischemic optic neuropathy) Compressive/ infiltrative Hereditary Toxic/nutritional Raised ICP (papilledema) Glaucomatous Anomalous optic nerve

41 Classification of optic neuritis
Ophthalmoscopic classification 1.Retrobulbar neuritis 2.papillitis 3.Neuroretinitis Etiological classification 1.demyelinating 2.parainfectious 3.infectious 4.non-infectious

42 Diagnosis-Clinical characteristics
Young women(14-45yrs)(3F:1M) usually monocular Rarely binocular (particularly in children) Acute to subacute onset :usually rapidly progressive over a few days Decreased VA(variable) , URI Hx. (+) Pain with eye movements(in>90% of cases) Decreased color vision(usually red ones) Exacerbation with heat or exercise(Uhthoff’s phenomenon) Strong association with multiple sclerosis(MS) A 10-year f/u-> MS is diagnosed in 38% Worsening beyond one week or failure of recovery to begin within four weeks : ->consider other diagnoses

43 Diagnosis-Physical examination
1.RAPD: almost always present in affected eye 2.Visual field loss 1) Central scotomas: classic 2) diffuse defects, focal defect 3.Optic disc 1)Papillitis(swelling): 1/3 2)Retrobulbar optic neuritis: normal in 2/3 3) After weeks :Optic disc pallor (if at least 4 to 6wks after onset) :Thinning of the nerve-fiber layer of the surrounding retina Normal macula and retina(no exudates, no hemorrhages)

44 INTRODUCTION The most common form of optic neuritis is acute demyelinating optic neuritis

45 DIAGNOSIS TEST Ocular exam Brain MRI and orbit MRI for MS Color vision
Visual field : cecocentral scotoma Fundus exam : Normal or swollen optic disc Complete ophthalmic & neurologic exam

46 Retroabular optic neuritis: normal
Mild and diffuse: no hemorrhage, cotton-wool spots, retinal exudates(lipid deposits) Peripapillary hemorrhage: AION에서 발견됨, 이것이 발견되면 multiple sclerosis 가생길 위험이 상대적으로 더 적다

47 Diagnosis-MRI Enhancement of the optic nerve
Enlargement of the optic nerve

48 Diagnosis-Brain MRI Routinely performed Preferably within 2 weeks
3mm or larger in diameter ovoid located in periventricular areas of the white matter Radiating toward the ventricular spaces

49 SYSTEMIC ASSOCIATIONS
Acute demyelinating optic neuritis occurs most often in MS(50%) Brain MRI - most powerful predictor of subsequent CDMS White matter lesion RISK( after 5 years) two or more 51% 1 or 2 lesion 37% nomal 16%

50 Ten-year risk of development of clinically definite multiple sclerosis (MS)
There was a strong association between the presence of one or more baseline MRI T2 lesions and the future development of clinically definite MS (Fig. 1). In patients who had isolated optic neuritis and one or more baseline MRI lesions, the 10- year risk of MS was 56%; the number of demyelinating lesions (greater than one) on the baseline MRI was not correlated with the subsequent risk of developing MS (Fig. 1). Optic neuritis patients with a normal baseline MRI had a 10-year risk of MS of 22%.

51 Diagnosis-VEP/OCT/CSF
<Visual evoked potentials> Increased latencies Reduced amplitudes of waveform <Optical coherence tomography> Determine the thickness of retinal tissues Thinning of the nerve-fiber layer of the retina Not used routinely in practice <Cerebrospinal fluid> Oligoclonal banding of proteins

52 Diagnosis-CSF study A recent study suggested that the presence of oligoclonal bands in the CSF of patients with a clinically isolated syndrome and abnormal MRI was highly specific and sensitive for early prediction of conversion to MS Indication of a lumbar puncture bilateral cases childhood If an infectious or systemic inflammatory disorder is suspected

53 Optic neuritis Associated with demyelinating ds
Idiopathic Multiple sclerosis Neuromyelitis optica(Devic ds.) Acute disseminated encephalomyelitis Associated with infection Syphilis, Herpes zoster, Toxoplasmosis, etc. Postvaccination (HBV) Associatated with other inflammatory disorders Sarcoidosis, SLE Isolated recurrent optic neuritis (Autoimmune optic neuritis) Classification

54 Retrobublar&demyelinating
Retrobulbar neuritis optic disc appearance is normal most frequent type in adult frequent associated with MS Demyelinating optic neuritis Isolated optic neuritis: no clinical evidence of generalized demyelination Multiple sclerosis: most common Devic disease: bilateral optic neuritis Schilder disease

55 Treatment(Short-term)
1.IV methylprednisolone 250mg q 6hrs for 3 days -> Oral prednisone 1mg/kg for 11days -> Subsequent tapering over a period of 4 days Hastens recovery of visual function No better effect of long-term visual outcome(6 months) Reducing the risk of MS within 2 yrs after onset 2. Oral prednisone alone Association with increased risk of recurrent episode Treatment with intravenous methylprednisolone followed by an oral corticosteroid regimen provided a short-term reduction in the rate of development of MS, particularly in patients with brain MRI changes consistent with demyelination; however, by 3 years of follow-up, this treatment effect was no longer clinically detectable.22 Although intravenous corticosteroids hastened visual recovery, visual outcome at 6 months was the same for all treatment gro

56 Treatment(Long-term)
1. Interferon beta-1a(Avonex) Reduced 3-yr cumulative probability of MS Lower rate of new lesions 2. Interferon beta01a(Rebif) Significantly less likely to develop MS 3. Befateron/Betaseron

57 AION When there is acute visual loss and unilateral optic disc swelling, both optic neuritis and AION must be considered AION - typically painless - over 50 years of age - may be associated with optic disc hemorrhages

58 DIFFERENTIAL DIAGNOSIS
Differential diagnosis of Acute Unilateral Optic Neuropathy Anterior ischemic optic neuropathy Tumor Aneurysm Vasculitis Neuroretinitis Metastatic carcinoma Lymphoreticular disorder Sinusitis Granulomatous inflammation Leber’s hereditary optic neuropathy

59 Ischemic Optic Neuropathy
Anterior / Posterior Nonarteritic/ Arteritic Nonarteritic AION Arteritic AION Age Older(>50 yrs) Elderly(>65) Visual loss / Color Acute/Spared Acute severe loss/Abnormal Pain infrequent common VF Hemifield defect Any defect Optic disc Disk edema, Small CDR Segmental pallor Disk edema Diffuse pallor clue Systemic sx. ESR↑ Systemic ds HBP, DM GCA Tx No PO steroid Prognosis Variable Poor Ischemic optic neuropathy는 disc edema가 동반된 AION과 optic nerve가 정상 모습인 PION으로 구별할 수 있다.

60 Ischemic Optic Neuropathy
Post ciliary a.의 해부학적 특성상 대개 시신경의 위아래 반쪽에만 시신경창백 소견이 관찰되며 이로 인해 시야검사에서 altitudinal defect가 흔하게 보입니다.

61 Demyelinating optic neuritis
Course - Vision worsens over several day to 2 weeks - begines to recover within 2-4 weeks Prognosis - 75% : recover visual acuity to 0.63 or better - color vision contrast sensitivity and light brightness appreciation : often remain abnormal - 10% : chronic optic neuritis characterized by slowly progressive visual loss

62 Visual prognosis AION Optic neuritis
Prognosis : poor becausc visual loss is usually permanent. second eye may become involved in 25’% of cases despite early and adequate steroid administration. Treatment is aimed at preventing blindness of the fellow eye Spontaneous visual recovery begins rapidly (within 3 weeks) in in ~80% of patients with idiopathic acute optic neuritis and continues to improve for up to 1 year Optic neuritis

63 NAION sudden, painless, mostly irreversible, and generally nonprogressive visual loss results from inadequate blood supply to the posterior ciliary arteries(inadequate perfusion of the optic nerve head) - leading to infarction, swelling, compression, ischemia and more infarction accompanied by nerve fiber bundle field defects and a relative afferent pupillary defect Risk factors Arterial HTN, DM, hypercholesterolemia, IHD, CVD, migraine, sleep apnea syndrome and anterior segment surgeries ischemic heart disease, cerebrovascular disease, migraine, sleep apnea syndrome and anterior segment surgeries have been identified as risk factors for NAION

64 Optic neuritis/AION DDx

65 Leber’s hereditary ON Sudden loss of central vision in young men with a family history of blindness neurological symptoms : numbness and tingling cardiac conduction anormality mitochondrial diseases, inherited through the mother Diagnosis : genetic analysis (Mitochondria DNA) No treatment has been proven effective in controlled trials for LHON

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