Advances in myasthenia gravis

Dr Parag MoonSR1, Neurology

Myasthenia Gravis

•Myasthenia gravis is a disease of skeletal muscle acetylcholine receptors.

•Acetylcholine (ACh) is unable to bind to the receptors (AChR) on the postsynaptic membrane

•Transmit the nerve impulse to muscle fibers to produce a muscle contraction

MG occurs at any age, involves either sex and begins insidiously

Second and third decades commonest age of onset in women. Seventh and eighth decades in men

Patients complain of specific muscle weakness

Presentation

Ptosis or diplopia – initial symptoms in 65% of patients

Oropharyngeal muscle weakness – difficulty in swallowing and talking initial symptoms in 17% of patients

Limb weakness presenting symptom in only 10% of cases

Presentation

Ocular myasthenia – if progressing to generalized MG usually does so within the first two years after onset

After 15 to 20 years, weakness becomes fixed. The Burnt-Out-Stage + muscle atrophy

Presentation

Myasthenia GravisClinical Classification

I. Ocular alone

IIa. Mild generalized

IIb. Moderately severe generalized plus usually some bulbar involvement

III. Acute severe over weeks-months with severe bulbar involvement

IV. Late severe with marked bulbar involvement

Early onset MG- AChR antibody positive, non-thymoma, generalized MG with onset before 50 yr.

Thymus hyperplasia 65% of all MG. Females (male/female ratio: 1:4) AChR antibodies high, titin and ryanodine

receptor (RyR) muscle antibodies only very rarely High frequency of autoimmune diseases. HLA A1, B8, DQB1, DR3, DR52a; in Japanese HLA

DPB1, DQB1, DR9

Subgroups

Late-onset MG –AChR antibody positive, non-thymoma, generalized MG with onset at 50 yrs or later.

Thymus atrophy is predominant Equal in men and women Peak between 70 and 80 yrs AChR antibodies is usually lower. One half have titin and RyR antibodies HLA-A3, B7, DR2, HLA-DR4, and in titin

antibody positive patients HLA-DR7

Ocular MG- AChR antibody positive, non-thymoma MG with purely ocular (non-generalized) symptoms.

More common in children and in late-onset males. HLA-DQ6

Thymoma MG –MG patients with thymoma regardless of the extent of muscular involvement.

Usually have AChR antibodies. 15% of MG patients, is of cortical type. Peak of onset around 50 years In addition to AChR antibodies,frequent

occurrence of titin and RyR antibodies. Thymoma and non-thymoma MG patients have

similar MG long-term prognosis. HLA DR2 mostly in women

Seronegative MG - AChR antibody negative, no evidence of thymoma

Occurrence of muscle specific kinase (MuSK) antibodies in 10–40% of AChR antibody negative MG patient.

Seronegative MG patients lacking MuSK antibodies appear to have less severe MG than seropositive MG patients

AChR antibodies –85% with generalized MG,70% with ocular MG

Main immunogenic region (MIR) for the AChR antibodies is located on the a-subunit.

MOA-complement-mediated focal muscle membrane damage, accelerated degradation of AChR, and also direct blockade of AChR ligand binding.

C3 and C4 is low Polyclonal, mainly IgG, IgG1 and IgG3

subclasses

Immunological

Ab against titin and rynodin receptor MIR of titin is called myasthenia gravis titin-30

(MGT-30) and situated near the A/I band junction Two forms of RyR, skeletal (RyR1) and cardiac

(RyR2). RyR antibodies from MG patients react with both Titin and RyR antibodies occur more often in

severe MG Antibodies against rapsyn (a 43-kDa

postsynaptic protein essential for anchoring and clustering AChR) .

Anti MuSK-41% of AChR antibody negative patients with generalized MG have autoantibodies against MuSK

MuSK antibodies may correlate with MG severity in AChR antibody negative MG

Thymoma MG patients have higher titers of anti-myosin and anti-actomyosin antibodies than MG patients without thymoma

Muscle groups involved at onset

Ocular alone 34%

Bulbar alone 8%

Extremities alone 15%

Ocular and bulbar 7%Ocular and extremities 7%Bulbar and extremities 6%Ocular, bulbar and extremities 21%

Co-existing autoimmune diseases◦ Hyperthyroidism

Occurs in 10-15% MG patients Exopthalamos and tachycardia point to

hyperthyroidism Weakness may not improve with treatment

of MG alone in patients with co-existing hyperthyroidism

◦ Rheumatoid arthritis◦ Scleroderma◦ Lupus

Physical examination

Myasthenic Crisis VS. Cholinergic Crisis

Myasthenic CrisisUnder medication

Increased HR/BP/RR Bowel and bladder

incontinence Decreased urine output Absent cough and

swallow reflex May need mechanical

ventilation Temporary improvement

of symptoms with administration of Tensilon

Cholinergic CrisisOvermedication

Decreased BP Abd cramps N/V, Diarrhea Blurred vision Pallor Facial muscle twitching Constriction of pupils Tensilon has no effect Symptoms improve with

administration of anticholinergics (Atropine)

Lab studies◦Anti-acetylcholine receptor antibody

Positive in 74% 80% in generalized myasthenia 50% of patients with pure ocular myasthenia

◦Anti-striated muscle Present in 84% of patients with thymoma who

are younger than 40 years

Work-up

Lab studies◦ Interleukin-2 receptors

Increased in generalized and bulbar forms of MG

Increase seems to correlate to progression of disease

Work-up

Imaging studies◦Chest x-ray

Plain anteroposterior and lateral views may identify a thymoma as an anterior mediastinal mass

◦Chest CT scan is mandatory to identify thymoma

◦MRI of the brain and orbits may help to rule out other causes of cranial nerve deficits

Work-up

Edrophonium (Tensilon test)◦ Edrophonium is a short acting Acetylcholine

Esterase Inhibitor.◦ Onset within 30secs ◦ Evaluate weakness (i.e. ptosis and

opthalmoplegia) before and after administration

WorkupPharmacological testing

Edrophonium (Tensilon test)◦ Steps

0.1ml(1-2mg) of a 10 mg/ml edrophonium solution is administered as a test

If no unwanted effects are noted (i.e. sinus bradychardia), the remainder of the drug is injected

Keep atropine ready

WorkupPharmacological testing

Sensitivity 71.5- 95% Specificity: not clear but can be positive in

many other condition False positive= ALS, poliomyelitis, and some

peripheral neuropathies

Neostigmine testLonger acting1.5 mg im or 0.5 mg ivAction begins in 15-20 mins

Ice pack test Apply ice pack to ptotic lid Sensitivity

◦ 89% Specificity

◦ 100% (!?)

Work-up Electrodiagnostic studies

◦ Repetitive nerve stimulation◦ Single fiber electromyography (SFEMG)

◦ SFEMG is more sensitive than RNS in MG

Electrodiagnostic studies:Repetitive Nerve Stimulation

During RNS EPSP’s may not reach threshold and no action potential is generated Results in a decremental decrease in the

compound muscle action potential Any decrement over 10% is considered

abnormal Should not test clincally normal muscle Proximal muscles are better tested than

unaffected distal muscles

Repetitive nerve stimulation Most common employed stimulation rate is 3Hz

◦ Lower temperature increases the amplitude of the compound muscle action potential Many patients report clinically significant

improvement in cold temperatures◦ AChE inhibitors prior to testing may mask the

abnormalities and should be avoided for atleast 1 day prior to testing

Electrodiagnostic studies:Single-fiber electromyography

Concentric or monopolar needle electrodes that record single motor unit potentials

Increased jitter and normal fiber density

Electrodiagnostic studies:Single-fiber electromyography

◦ Generalized MG Abnormal extensor digiti minimi found in 87% Examination of a second abnormal muscle will

increase sensitivity to 99%◦ Occular MG

Frontalis muscle is abnormal in almost 100% Sensitive(60%)

Treatment AChE inhibitors Immunomodulating therapies Immunoglobulins Plasmapheresis Thymectomy

◦ Patients should be advised to be as active as possible but should rest frequently and avoid sustained activity

◦ Educate patients◦ Speech therapy◦ Speech assistive/communicative devices

If dysphagia develops, liquids should be thickened Thickened liquids decrease risk for

aspiration

TreatmentBehavioral modifications

Treatment AChE inhibitor Indicated for mild to mod. disease

◦ Pyridostigmine bromide Starts working in 30-60 minutes and lasts 3-6 hours Individualize dose Adult dose:

30-60mg every 4 hrly. 2mg IV/IM q2-3h Pediatric=7mg/kg/day

MuSk positive MG respond poorly Mestinon- 180 mg timed release

Neostigmine- shorter actingAdult dose-15mg every 3-4 hrly0.5-2.5mg iv/im/sc every 1-3 hrsPediatric dose-2mg/kg/day Side effects- Muscarinic (nausea, vomiting, salivation,

bronchospasm, abdominal cramps, diarrohea) Nicotinic- cholinergic crisis

Immunomodulating therapies

1)Prednisone Most commonly used High starting dose-60-80mg/day Early remission Worsens weakness in half Given for 3-6 months then tapered 5mg per

week Low starting dose-15-20mg/day Increased by 5mg every 3 day till remission

(60-80mg) Trial showed that steroid decrease incidence of

disease generalisation.

2) Azathioprine inhibits T and B cell proliferation by interaction

with purine metabolism Steroid sparing agent Effect may take 6-12 months Dose-1mg/kg/day increased to 2-3mg/kg/day Effect monitored by MCV = >100 fl or >16fl

increase over baseline

Monitor CBC, LFT every week for first 3-4 months 3 fold elevation requires dose reduction Pregnancy cat D drug Side effects-hepatotoxicity, p Bone marrow suppression, pancreatitis Rare risk of lymphoreticular malignancy

3) Cyclosporine Inhibits T helper cell mediated synthesis of

cytokines Indicated in severe steroid and thymectomy

resistant MG Response seen in <7 months Dose- 4-10mg/kg/day divided in 2-3 doses Trough levels= 100-200mcg/ml Side effects-nephrotoxicity, hypertension,

infection, BM depression, neoplasm

4) Mycophenolate mofetil IMPDH inhibitor Add on drug in generalised MG Dose- 500 mg twice day for 4wks f/b increase till

1gm twice a day C/I in Lesch-Nyhan and kelley seegmiller

syndrome Not co-administered with azathioprine

5) Tacrolimus- indicated in steroid and cyclosporine resistant MG in dose 0.1mg/kg/day

Less nephrotoxic than cyclosporine 6)Cyclophosphamide- 500mg/m2 monthly pulseNot indicated7) Rituximab (anti CD20)

Elliminates autoantibodies Treatment of choice for myasthenic crisis,

preparation for thymectomy, other surgery Short lived effect (2-3wks) 5-6 exchanges alternate day with 2-4 litre

per exchange Replacement with 5% albumin

Plasma exchange

Techniques Plasma filtration Plasma seperation Antigen specific immuno-adsorptionSide effects Platelet depletion Citrate toxicity Electrolyte disturbances Line related S/E

MOA-modulation of autoantibody response, inhibition of complement activation, decrease membrane attack complex formation, decrease cytokine response, interference with antigen recognition

More effective QMG score >11 73% favourable response within 4-5 days Dose-0.4 mg/kg /day for 3-4 days Maintainance- 1gm/kg/ day for 1- 2 days

Immunoglobulins

C/I in IgA defeciency (use IgA depleted immunoglobulins)

Side effects-flu like, transient HTN, renal failure, thrombotic events, serum sickness

High cost Cockrane review- similar efficacy of PE vs IvIg

Indicated in non thymomatous pts with generalised autoimmune MG of age group 10-55yrs

All pts with thymomaTechniques1. Transcervical 2. Transternal extended thymectomy- standard

procedure used3. Videoendoscopic including robotic assisted

Thymectomy

Remission rate-40-60% maximum with transternal

Young pt. with short duration of disease with no thymoma but with hyperplasia do best

Complication Perioperative Myasthenic crisis(6%) Infection(11%) Recurrent laryngeal or phrenic nerve injury(0-2%)

Etanercept-TNF alpha receptor antibodyConcerns abt worsening MG Methotextrate-17.5 mg/week Terbutaline-beta 2 agonist 2.5 mg 3 times a day Complement inhibitors

Other drugs

Drugs that unmask or exacerbate MG

Myasthenia gravis: clinical, immunological, and therapeutic advances; Acta Neurol Scand 2005: 111: 134–141 DOI: 10.1111

Seminars in neurology vol 32 july 2011;Neuromuscular therapy

Current treatment options in neurology vol 35 may 2010: myasthenia gravis

References

Thank you!