Optimizing treatment in MG - PSU

Optimizing treatment in myasthenia gravis

Pat Korathanakhun, MD.

Neurology, PSU

Outline

• Case management in patients with MG

– Diagnosis

– OMG vs GMG

– Conversion from ocular to generalized

– When to start prednisolone

– When to start immunosuppressive

– When to consider Sx

Case 41 YOF, Teacher

• CC: หนงตาซายตก 2 เดอน

• 2 เดอน – หนงตาซายตก เปนๆหายๆ ตนเชามาอาการด นงท างาน สอนคอมพวเตอร 3 ชวโมงแลว รสกลา นกเรยนทกวาหนงตาซายตก เหนภาพซอนนดหนอย ไปนงพก หลบตา โปะผาเยน สกพก กดขน

ไมมออนแรง ไมมชา ไมมกลนตดกลนล าบากหรอส าลก

Physical examination

• Conscious

• Pupil 3 mm BRTL,

no anisocoria

• No ptosis

• Palpebral fissure 8 mm both

• Levator function 12 mm both

• Induced ptosis – positive

• Enhanced ptosis – positive

• EOM full

• Normal pinprick sensation V1-3

• No facial palsy

• No dysarthric speech

• No nasal voice

• Neck flexor power – MRC Gr V

• Motor power – MRC Gr V all

• Fatigability test – negative

• DTR 2+ all

PTOSIS: How to Approach

Local eye diz

Horner syndrome

CN III pathway

NMJ Muscle

Local eye signs

Miosis Ptosis

Endophthalmos Anhidrosis

All or none laws

nucleus fascicle nerve

Bilat. ptosis

Fluctuation Systemic signs

In this case

• Clues = history of fluctuation + signs of fatigability

• Dx Possible Ocular MG

Continuum Lifelong Learning Neurol 2009;15:13–34.

Continuum (Minneap Minn) 2016;22:1978–2005.

Lancet Neurol 2015; 14: 1023–36

Confirmation test for MG

Case 41 YOF with ocular MG

Rx

• Mestinon

PYRIDOSTIGMINE

• Pyridostigmine (60 mg) 1-2 tablets tid to q 4 hrs

• Increased strength in the weak muscles

• Symptomatic Rx

• Do not change the disease process

• After Rx with Mestinon

1x2 -> 1x3 -> 1x4

• Progressive ptosis and bulbar symptoms with fluctuation over 2 months

• Nasal voice

• No limbs or axial muscle weakness

• What should you do ?


Immunosuppressive Rx

Corticosteroid

Cochrane Database Syst Rev 2005; CD002828.

• Rx Mestinon 1x4 + Prednisolone 30 mg/d

• Progressive weakness over 6 months

• Neck flexor power MRC Gr IV

• Proximal muscle weakness

• Nasal voice

• Does this Pt. have generalized MG ?

• What should you do ?


Natural history of ocular MG

50-60% develop generalized weakness in 1-2 years

40% remain ocular MG

~50% will develop

generalized MG in 1 year

Patients with pure

ocular symptoms for

2 years have less

chance to develop generalized MG

Confirmation test for MG

Sero-subtype in MG

Lancet Neurol 2015; 14: 1023–36

Continuum (Minneap Minn) 2016;22(6):1978–2005.

Case 41 YOF with GMG

• AChR Ab positive

• RNS = positive decremental response

• Rx: ↑ Mestinon 2x4

• Progressive weakness

• TFT: TSH = 0.005

FT4 = 12

FT3 = 9

DID WE FORGET ANYTHING ?

DO NOT FORGET !!!

• DO NOT FORGET TO LOOK FOR OTHER COMORBIDITIES

– Hyperthyroidism -> TFT

– Autoimmune disease -> ANA

– Thymoma screening -> CXR vs CT chest

Case 41 YOF with GMG

• AChR Ab positive

• RNS = positive decremental response

• Hyperthyroidism

• CXR – no thymoma

• Rx: ↑ Mestinon 2x4 + MMI for hyperthyroid

-> Progressive weakness

DID WE FORGET ANYTHING ?

Immunosuppressive drugs

Seminars in Neurology 2004;24:41-8.

Prednisolone in severe case

Therapeutic effect 2-8 wk

Alternate day regimen to decreased side effect

Start 60-100 mg/d (1-1.5 MKD)

Prednisolone in mild to moderate case

Start 10-20 mg/d

alternate day regimen

Maintain 2-4 months

How to decrease prednisolone KEY = Slowly titrate with maintaining motor function

Decrease dose 5mg/d Every 2 wks or more

At dose 20 mg/d More slowly taper

Most patients require pred 5-10 mg

for longterm Rx

Longterm steroid side effect

Though steroid works rapidly, side effects are intolerable.

Should we start other immunosuppressant concurrently with prednisolone?

Seminars in Neurology 2004;24:41-8.

Strategy for immunosuppressive Rx

time

prednisolone Other immunosuppressant

Ther

apeu

tic

effe

ct

AZATHIOPRINE

• RCT : – [AZA + pred] vs [placebo + pred] – [AZA + pred] vs [pred]

• Benefit – AZA claims the better clinical remission – Rx with AZA can reduce

dose of prednisolone at 3 yr

– Therapeutic effect was observed at 18 months

Neurology 1998; 50: 1778–83. J Neurol Neurosurg Psychiatry 1993;56:1157-1163.

HOW TO USE AZATHIOPRINE

Drug titration

Side effect monitoring

Start 25 mg/d Slowly increase

Target 2-3 MKD

MCV rising > 10%

Idiosyncrasy reaction Fever, anroexia, N/V,

Flul-ike symptoms -> stop AZA

Side effect Leucopenia If WBC < 4000 -> reduce ½ dose If WBC < 3000 -> hold drug + F/U Hepatitis If liver enz rising – hold drug + work up other causes

Case 41 YOF with AChRAb +ve GMG with hyperthyroidism without thymoma

• Rx:

– Mestinon 2x4

– MMI -> euthyroid

– Pred 60 -> slowly tape over period to 15 mg/d

– AZA 100 mg/d [for 6 months]

– Clinical stable 3 months

• 2 wks pelvic pain, foul-odor vaginal discharge

• Dx PID

• Rx clindamycin 2700 mg/d + Gentamicin 240 mg/d

• -> worsening weakness

What happens?

Postgrad Med J2004;80:690–700.


• Rx:

– Mestinon 2x4


– Pred 15 mg/d


[total AZA Rx = 1 yr]

– Fluctuated Clinical symptoms

Should we change immunosuppressant

right now?

Cyclosporine

• RCT : GMG moderate to severe

– [Cyclosporine 6MKD] vs [Placebo]

– [Cyclosporine5MKD + Pred] vs [Placebo + Pred]

• Benefit

– Improved function [QMG score] after Rx 6 months

– No significant change in pred dose

N Engl J Med 1987;316:719–724. Ann N Y Acad Sci 1993;681:539–551

Cochrane Database Syst Rev 2007; CD005224.

Mycofenolate mofetil

• RCT: GMG mild to moderate symptoms

– [MMF 2g/Kg/d + pred] vs [placebo + pred]

– [MMF 2.5g/kg/d + pred20/d] vs [placebo + pred20]

• Benefit

– No clinical significance

– Comment: might be too early to evaluate

Neurology 2008;71:400-6. Neurology 2008;71:394-9.

Other

• RCT evidence

– MTX – might help in pred dose reduction

– Tacrolimus – no significant change

– Eculizumab – no significant change

• Rituximab – no RCT

Neurology 2016;87:57-64. Neurology 2017;88:417-418. Eur Neurol 2005; 53: 146–50.

J Neurol Neurosurg Psychiatry 2011; 82: 970–77. Lancet Neurol 2017;16:976-986.


• Rx:

– Mestinon 2x4


– Pred 15 mg/d


[total AZA Rx = 1 yr]

– Fluctuated Clinical symptoms

Did we forget anything else?

Thymectomy

GMG • RCT

– [Thymectomy+pred] vs [pred alone]

• Benefit

– thymectomy helps in pred dose reduction

– Reduce admission rate

OMG • No evidence

N Engl J Med 2017;376:511-521.

Thymectomy : opinion

GMG • All GMG should

undergo thymectomy within 2 years regardless of thymic status.

OMG • Thymectomy should be

considered in OMG with evidence of thymoma.

SUMMARY [1]

• Clinical evaluation

• OMG vs GMG

• Sensitivity of confirmation test

• DDx of OMG and GMG

• Conversion rate of OMG to GMG

• Searching for comorbidities [ANA, TFT]

• Searching for aggravating factors

SUMMARY [2]

Richard Gere Kieth Richard

Richard Harris

Optimizing treatment in MG - PSU

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