optimizing treatment in mg - psu
TRANSCRIPT
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Optimizing treatment in myasthenia gravis
Pat Korathanakhun, MD.
Neurology, PSU
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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
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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
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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
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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
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In this case
• Clues = history of fluctuation + signs of fatigability
• Dx Possible Ocular MG
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Continuum Lifelong Learning Neurol 2009;15:13–34.
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Continuum (Minneap Minn) 2016;22:1978–2005.
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Lancet Neurol 2015; 14: 1023–36
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Confirmation test for MG
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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
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• 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 ?
Case 41 YOF with ocular MG
Immunosuppressive Rx
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Corticosteroid
Cochrane Database Syst Rev 2005; CD002828.
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• 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 ?
Case 41 YOF with ocular MG
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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
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Confirmation test for MG
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Sero-subtype in MG
Lancet Neurol 2015; 14: 1023–36
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Continuum (Minneap Minn) 2016;22(6):1978–2005.
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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 ?
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DO NOT FORGET !!!
• DO NOT FORGET TO LOOK FOR OTHER COMORBIDITIES
– Hyperthyroidism -> TFT
– Autoimmune disease -> ANA
– Thymoma screening -> CXR vs CT chest
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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
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Seminars in Neurology 2004;24:41-8.
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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)
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Prednisolone in mild to moderate case
Start 10-20 mg/d
alternate day regimen
Maintain 2-4 months
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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
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Longterm steroid side effect
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Though steroid works rapidly, side effects are intolerable.
Should we start other immunosuppressant concurrently with prednisolone?
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Seminars in Neurology 2004;24:41-8.
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Strategy for immunosuppressive Rx
time
prednisolone Other immunosuppressant
Ther
apeu
tic
effe
ct
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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.
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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
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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?
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Postgrad Med J2004;80:690–700.
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Case 41 YOF with AChRAb +ve GMG with hyperthyroidism without thymoma
• Rx:
– Mestinon 2x4
– MMI -> euthyroid
– Pred 15 mg/d
– AZA 150 mg/d [for 6 months]
[total AZA Rx = 1 yr]
– Fluctuated Clinical symptoms
Should we change immunosuppressant
right now?
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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.
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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.
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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.
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Case 41 YOF with AChRAb +ve GMG with hyperthyroidism without thymoma
• Rx:
– Mestinon 2x4
– MMI -> euthyroid
– Pred 15 mg/d
– AZA 150 mg/d [for 6 months]
[total AZA Rx = 1 yr]
– Fluctuated Clinical symptoms
Did we forget anything else?
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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.
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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.
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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
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SUMMARY [2]
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QUIZ
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Richard Gere Kieth Richard
Richard Harris