CASE CONFERENCE Ap. 박신혜 / R3 박민지

CASE 1

F/58 김OO Past Hx. C/C Binocular horizontal diplopia UL ptosis (OU) since 1 month ago Past Hx. DM/HBP (-/-) Hypothyroidism – Hormone Tx. Ocular op/trauma(-/-) 2007, Lt. orbital myositis diagnosed at local Gls (-) Eye drop (-) Local 경유 신경외과 brain evaluation 이후 본과 내원함. no diunrnal fluctuation.

Ocular Examination VA OD 0.8 OS 0.63 IOP 17/17 mmHg Lid UL ptosis, bilateral Conj not injected Cornea clear Pupil round & nl sized, RAPD(-/-) Lens mild cortical opacity / OU 우안의 내전, 상전, 외전, 하전 장애 모두 관찰됨.

10XT l 14XT, 5 RHT - 10XT, 3 RHT - 14XT, 3RHT 10XT, 10RHT 특히 심한 우안의 ptosis 와 우안의 확연한 하전장애, 외전, 내전장애가 있으며 좌안도 mild 한 ptosis와 함께 내전, 외전장애가 관찰된다.

Cue list XT with RHT OD : Infraduction Abduction, Adduction Sudden onset Diplopia Bilateral upper lid ptosis Ophthalmoplegia Underlying Hypothyroidism Orital Myositis Hx. OD : Infraduction Abduction, Adduction OS : Abduction, Adduction

Differential diagnosis #1 Thyroid associated strabismus #2 Myositis related myopathy #3 Myasthenia gravis #4 Pupil spared 3rd n. palsy #5 Chronic XT

Orbit CT Thyroid ophthalomopathy 감별위해 촬영했는데 정상 Brain MRI 는 정상

Differential diagnosis #1 Thyroid associated strabismus #2 Myositis related myopathy #3 Myasthenia gravis #4 Pupil spared 3rd n. palsy #5 Chronic XT Combined with 6th n palsy? Not explained as only cranial palsy Sudden onset, diplopia symptom(+)

Diagnostic plan 1) Hx taking -> symptom : variable and fatigable diurnal fluctuation+ 2) ICE test ICE test 도 괜찮고, Ach receptor 도 정상범위였지만 임상적으로 MG 강력히 의심되어 추가 검사 위해 신경과 의뢰함.

Diagnostic plan 1) Hx taking -> symptom : variable and fatigable diurnal fluctuation+ 2) ICE test : suspicious 3) Ach Receptor Ab test ICE test 도 괜찮고, Ach receptor 도 정상범위였지만 임상적으로 MG 강력히 의심되어 추가 검사 위해 신경과 의뢰함.

Second Visit Ach Receptor Ab : 0.11 (<0.5) 18XT l 20XT, 5 RHT - 18XT, 5 RHT - 20XT, 5RHT 18XT, 10RHT 2번째 내원당시 우리가 시행했던 Ach Ab는 음성이였다 Ptosis는 심해졌고 사시각도 이전보다 커졌다. 임상적으로는 ~~~ 의뢰했다

Differential diagnosis #1 Thyroid associated strabismus #2 Myositis related myopathy #3 Myasthenia gravis #4 Pupil spared 3rd n. palsy #5 Chronic XT → Neurology consultation

Neurology consultation 1) Neostigmine test : positive 2) Jolly test (repetitive nerve stimulation) <Right orbicularis orculi > At 3 Hz stimulation: decremental response Post exercise(10 sec) stimulation at minutes: recover decremental response Post exercise(10 sec) stimulation at 1, 2 minutes: reappearance of decremental response -> other muscle : no decremental response 4mm/7mm 6mm/8mm 7mm/9mm Thyroid H 는 정상, TPO ab 만 2571.61 Chest CT : 정상 Start PO Mestinon tab. 90mg (Pyridostigmine)

Summary Patient with Diagnosed as Ocular Myasthenia Gravis 1) XT combined HT 2) UL ptosis 3) Symptom : variability, fatigability 4) AchR Ab : negative 5) Ice test : suspicious 6) Neostigmine test, Jolly test : positive Diagnosed as Ocular Myasthenia Gravis This case is about the paie

CASE 2

M/21 장OO Past Hx. C/C Binocular diplopia since 7 month ago DM/HBP (-/-) Hyperthyroidism – Hormone Tx. Hx. (poorly controlled) Ocular op/trauma(-/-) Gls (+) Eye drop (-) Diurnal fluctuation. +

Ocular examination VA OD (0.8) OS (1.0) IOP OD 14 mmHg OS 13 mmHg Conj. not injected(OU) Cornea clear(OU) AC deep & cell(-)(OU) Pupil round & nl sized, LR(+)(OU) Lens clear(OU)

30XT, 6RHT l 25XT, 4RHT----- 30XT, 6RHT------35XT, 6RHT 25XT, 10RHT

Cue list XT with RHT OD : Adduction Infraduction, Abduction Sudden onset Diplopia Ophthalmoplegia Underlyng Hyperthyroidism OD : Adduction Infraduction, Abduction

Differential diagnosis #1 Thyroid associated strabismus #2 Myasthenia gravis #3 Chronic XT

Orbit CT

Differential diagnosis #1 Thyroid associated strabismus #2 Myasthenia gravis #3 Chronic XT Sudden onset, Diplopia symptom (+)

Diagnostic plan 1) Hx taking : variability, fatigability diurnal fluctuation + 2) AchR Ab test

→ Neurology consultation Second visit 1) AchR Ab level : 1.31 (above normal range) 2) Prism cover test 35 XT l 25XT ----- 25 XT, 5 RHT -----35 XT, 6 RHT 25 XT, 10 RHT =>variability (+) → Neurology consultation

Neurology consult Start PO Mestinon tab. 90mg (Pyridostigmine) 1) Neostigmine Test : positive Upward gaze 안검열 거리 (mm) Baseline : 15secs Baseline : 9 / 9 Neostigmine inj. 15mins : 40secs Neostigmine inj. 15mins : 10 / 10 Neostigmine inj. 30mins : 25secs Neostigmine inj. 30mins : 11 / 11 Neostigmine inj. 45mins : 20secs Neostigmine inj. 45mins : 11 / 11 2) Jolly test : positve - Rt. orbicularis oculi muscle : NMJ disorder 시사하는 전기생리학적 이상소견 + - other muscle : WNL 내분비내과는 consult 해서 MTZ 복용시작 Chest CT는 정상 Rt. abductor digiti minimi, Rt. trapezius and Rt. orbicularis oculi muscles Start PO Mestinon tab. 90mg (Pyridostigmine)

After po medication 1month Symptom : nearly disappeared Occasionally diplopia occured X(T) 40 PD, RHT 4 PD /sc X(T)' 20 PD , RHT 4 PD /sc

Summary Patient with 1) XT combined HT 2) Symptom : variability, fatigability 3) AchR Ab : positive 4) Neostigmine test, Jolly test : positive Diagnosed as Ocular Myasthenia Gravis

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REVIEW OCULAR MYASTHENIA GRAVIS

Introduction Autoimmune disorder Vs. Cranial palsy ptosis and or diplopia weakness of the EOM, levator palpebrae superioris, orbicularis oculi, without dysfunction of other muscles. Vs. Cranial palsy - variable and fatigable ocular muscle weakness - presence of normal pupillary function

EPIDEMIOLOGY Incidence : 0.04 to 5/100 000/year Prevalence : 0.5–12.5/100 000/year No racial or geographic predilection Any age group : first decade or >70 yrs – less common Onset <40 years, women predominate (mean,28 years) Onset >40 years, men predominate (mean, 42 years)

PHYSIOLOGY Ach : stimulates nicotinic AChRs but not muscarinic AChRs at the postsynaptic junction * The pupillary sphincter muscle is devoid of nicotinic AChRs -> the pupils are unaffected in MG motor nerve axon의 termination membrane 에서 action potential depolarizing 으로 neurotransmition 이 시작되고, calcium permeability가 증가되고 Ach 이 분비 된다.

Classification of MG (3) Transient neonatal myasthenia gravis (1) General form (2) Ocular form If myasthenia gravis remains ocular for 1 year, -> the progression to generalized MG is 16%, If disease remains localized for 3 years, -> the progression to generalized MG is only 6% (3) Transient neonatal myasthenia gravis (4) Congenital myasthenia gravis (5) Drug induced myasthenia gravis (6) Neuromuscular junction blockade

Diagnosis Diagnosing MG – can be difficult because the disease may mimic any pupil-sparing pattern of ocular misalignment When History of weakness and fatigability, especially involving the eyelids and extraocular muscles, raises the suspicion of MG * Clinical symtom & sign / Testing

Clinical symptom & Sign ① Lid ptosis a. Enhanced ptosis. ‘curtaining’ : valuable diagnostic sign b. Upgaze for 2 min : ptosis often worsens c. Lid hopping or small amplitude movements of the lid during lateral gaze d. Cogan’s lid twitch or Reverse’ Cogan’s lid twitch e. nystagmus : unilaterally or bilaterally in MG without an apparent ophthalmoparesis a. 상방향 주시시 피로 (‘정면’ vs. ‘상방향 주시 2분 후 정면 주시’에서의 위눈꺼풀의 위치) b. 눈꺼풀 움찔 수축(Cogan’s lid twitch) (5초 하방 주시 후 정면 주시시, overshoot(위로치켜떠짐)→다시 쳐지면서 ‘twitch’) ‘Reverse’ Cogan’s lid twitch, a similar small downward movement of the lid elicited by a saccade to primary position from upgaze, c. 눈꺼풀 떨림 (hopping) (한쪽 지속적 주시시, 짧게 떨림.) d. 증강된 눈꺼풀 처짐 ( enhanced ptosis. ‘curtaining’ 징후) (더쳐진 눈꺼풀을 들어올리면 눈꺼풀올림근을 올리려는 흥분이 줄어 덜 처졌던 눈꺼풀이 처지게 됨. 특징적이지는 않음. 진정한 한눈 눈꺼풀처짐과 구별(ex.Horner)) e. 눈꺼풀 뒤당김 (한눈 처짐시, 반대 눈에 / 아래 보게 하면 없어짐(vs. 갑상샘 눈병증))

Clinical symptom & Sign ② Diplopia a. Paralysis of the CN VI.> CN III or IV. 등처럼 보일 수 있음. b. EOM weakening : MR, IR, SO – commonly involved c. Limitation of EOM : supraduction> Infraduction> Abduction a. paralysis of the CN VI.> CN III or IV. 등처럼 보일 수 있음.  마비사시 환자 볼 때 근육무력증의 가능성 고려 (경과관찰 중 약화된 근육이 자주 바뀐다는 점이 신경마비와 구분되는 점) b. 외안근의 약화 : 내직근, 하직근, 상사근 자주 침범 우리나라 눈근무력증 어린이: 외사시(+/- 수직사시) c. 눈운동 장애 : 상전장애> 하전장애> 외전장애 ③ Weakening of Orbicularis oculi 눈 꽉 감고 상대방이 억지로 눈을 벌렸을 때 저항이 적음. - peek 징후 – 눈을 감고 있으면 피로로 오히려 눈이 뜨여짐. - afternoon ectropion : 오후되면 아래눈꺼풀이 늘어짐. ③ Weakening of orbicularis oculi a. Peek sign b. Afternoon ectropion

Testing AChR antibody assays Found in up to 87% of patients with generalized myasthenia gravis But only in 50–80% with OMG (correlate poorly with the clinical status) 2) Muscle-specific kinase (MuSK) antibodies 39-49% of patients with AChR-antibody-negative MG have positive MuSK MusK positive MG : Female dominant. Frequent oculobulbar weakness and crisis Seronegative MG : Ach receptor Ab(-), muscle specific kinase Ab (-) => high prevalence cranial & bulbar muscle involvement, result respiratory difficulty 10-30분의 휴식

Testing 3) Antibodies against skeletal muscle In almost all myasthenic patients with thymoma 30% of myasthenic patients without thymoma Do not appear to play a significant role in the pathogenesis of MG 4) Chest imaging with either computed tomography (CT) or MRI Thymic hyperplasia (as many as 70%) or thymoma (10–15%) 10-30분의 휴식

Testing 5) Thyroid studies Thyroid dysfunction : up to 13% of patients with MG Both are are common autoimmune diseases and may possibly share similar pathogenetic mechanisms Th17 cell lineage : involved in autoimmune thyroid disease key factor in the development of both MG and Graves disease TAO with exotropia consider superimposed OMG - TAOs are esotropic because of the preferential involvement of MR 10-30분의 휴식

Testing 6) Sleep/rest test : improved function after 10–30 min of rest or sleep 7) Ice test : quick & effective clinical method used in the evaluation of ptosis - for 2 min improved ptosis in 80% of patients with MG 10-30분의 휴식

Testing 8) IV edrophonium (Tensilon) or IM Prostigmine (neostigmine) test main side effect : bradyarrhythmias 9) Electromyography (EMG) and nerve conduction excellent diagnostic test confirming the diagnosis in seronegative myasthenia gravis patients

Management 1) Cholinesterase inhibitors : first line of treatment - Improve more often in ptosis than diplopia - Do not affect the natural history of the disease 2) Corticosteroids : very effective in controlling symptoms - Lowering the risk of progression from OMG to generalized MG - Safety of chronic low-dose prednisone therapy (<10mg/day) : serious complications with a 2-year risk of approximately 1% less serious complications had a 2-year risk of approximately 39%

Management 3) IV immunoglobulin and plasma exchange : Useful for acute exacerbations including myasthenic crisis or in the perioperative period after thymectomy - suppressing antibody production and neutralizing autoantibodies (accelerating the catabolism of IgG) 4) Prism or occlusion therapy : Viable option for remained diplopia 5) Strabismus surgery : Very select group of patients (stable strabismus)

Oral corticosteroids on control of ocular symptoms. Effects of oral corticosteroids showed a benefit in terms of reducing the risk of progression to generalized MG . Effects of azathioprine showed a beneficial effect on the risk of progression to generalized MG Effects of thymectomy showed no benefit in terms of improvement in ocular symptoms or risk of progression to generalized MG

MuSK : form and maintain neuromuscular junction, including clustering of AChRs. IgG anti-MuSK Ab : deplete MuSK from postsynaptic membrane

MuSK MG : Female, Acute, Aggrasive LPr4 MG :not detect in AchR MG Rituximab: IgG1 monoclonal Ab - Good effect - but, multifocal leukoencephalopathy Tacrolimus : combined Tx with Steroid MMF : no effective MTX New Treatment

TAKE HOME MESSAGE 어떤 증상의 환자에게서 MG를 의심해야 하는가? 1. 복시와 눈꺼풀처짐이 동반되는 경우 2. 증상이 아침 .저녁 변화가 있는 경우 3. 성인의 복시가 동반되는 사시(특히 외사시) 의 경우 급성 사시를 의심해야 하며, 이때 MG를 감별해야 함 3. 사시(특히 외사시)와 수직사시가 동반된 경우 4. 사시와 함께 한눈운동/동향운동의 제한이 있는 경우 5. 경과관찰 중 한눈운동/동향운동의 변화가 있는 경우

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