RECENT ADVANCES OF MYASTHENIA GRAVIS

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INTRODUCTION

            ‘MG’ the commonest neuromuscular junction (NMJ) disorder caused by Auto antibodies against the Nicotinic  AChRs on post synaptic membrane (PSM) and characterized by weakness and fatiguability of voluntary muscles.

  • Being very disabling often fatal, a relatively obscure condition is now best characterized and understood autoimmune disorder with greatly improved understanding in pathogenesis/ immunology/ Molecular Biology over last 3 decades.
  • The practical mortality rate is ‘o’ with newer advancements.

EPIDEMIOLOGY

Prevalence Rate: 1/7,500 (2-7 /10,000 population in UK) and 1.5/10,000 population in (Central   /West Virginia)

Sex: W> M (~3:2), Almost equal in aged population

Age :Higher incidence > 40 years age group. It has bimodal peak distribution  (a) 2nd – 3rd decade, young women, mean age 28 years (b) 6th – 8th decade, older man,    mean age – 42 years, Childhood – upto 30% (China & Japan), Rare  below 10years & > 70 years. 10-20% infants born to myathenic mother ® Neonatal MG

GENETIC ASSOCIATION

Not directly  inherited in young women – HLA B8 & DR3

Old men – HLA B7 & DR2, Ocular MG – HLABW 46, North Indian population - HLA  BW21 & HLA BW 35 are the genetic association.

CLASSIFICATION

Based upon onset of age / Anti Ach R antibodies/severity /etiology.

  1. Age of onset:
  • Transient Neonatal MG (10-20%). Due to passage of Anti AchR – Abs through placenta to newborn baby. Presents with Hypotonia , Resp.difficulty in 1st few hours of life. Symptoms disappears within 1-3 hours . May require temporary supports , pyridostigmine.
  • Adult Autoimmune MG
  1. Presence or absence of Anti AChR – Abs :
  • Seropositive MG: Commonest acquired autoimmune MG. 85% general MG, 50-60% ocular MG
  • Seronegative SNMG (10-20%): No Anti AchR – Abs detectable by RIA, Involve antibodies against one or more components of NMJ (not detectable by current Anti AchR – RIA), One subgroup (40%) of SNMG contains anti MuSK Abs , humoral factors IgG, Non IgG (Possibly IgM) antibodies, which reversibly & indirectly inhibits AchR function.

 
  1. Severity        

A. Modified Osserman Scale:

a.       Ocular myasthenia

b.       Mild generalized - Symptoms sparing oculopharygeal muscles

c.       Moderate generalized- Weakness with mild to moderate oropharyngeal symptoms

d.       Severe - Disability (generalized) including oropharyngeal/ Respiratory muscles

e.       Myasthenic crisis

B. Modified form by American Committee of mg foundation

                                  i.           Any ocular weakness (may have weakness of eye closure with all other muscle strength – normal)

                                 ii.           Mild weakness other than ocular muscles… ± ocular muscle weakness of any severity

IIa – Prominent limb/axial involvement,

IIb – Predominant oropharyngeal / Respiratory involvement

                               iii.           Moderate weakness other than OM, may have ocular weakness

IIIa­ – Predominant limb/Axial involvement

IIIb – Predominant oropharyngeal /Respiratory involvement

                               iv.           Severe Weakness other than OM, May have ocular weakness

IVa – Predominant limb/Axial involvement

IVb – Predominant oropharyngeal /Respiratory involvement

                                v.           Intubation with or without mechanical ventilation

(Except when patient kept during post operative management)

  1. Etiology

a)             Acquired autoimmune MG

b)             Transient Neonatal MG

c)             Drug induced Mg – ‘D Penicillamine’

d)             Congenetal Myasthenic syndrome – exacerbated with curare /Aminoglycosides/quinine /procainamide /Ca+2 blocker

NORMAL ANATOMY & PHYSIOLOGY OF NMJ

Role of NMJ:

  • Amplification of weak N. impulse to strong – capable of producing muscle contraction
  • Components: (a) Presynaptic (b) Synaptic(c) Post Synaptic

Presynaptic :

Arrival of N. impulse

¯

Stimulus – Secretion coupling

            ¯

Release of 150 – 200 quanta (each with 8000-13000 AChmol)

 

Exocytosis – help in relasing ACh

 

Pinocytosis – Recapturing of PSM, vesicles are remade, being repleted with ACh.

·          ‘ACh – release sites’ – located opposite to the peaks of folds of PSM where ‘AchR” are clustered  in high concentration.

Synaptic Cleft:

Space – 70nm wide, length equal to pre-synaptic membrane, Communicates to extracellular space , No. lateral boundary. Primary cleft: Space separating pre & post synaptic membrane. Secondary cleft: Space between junctional fold of synaptic membrane. ‘AchE’ highly concentrated in secondary cleft . ‘ACh’ released into the space before it acts on ‘AchR’ and hydrolysed by ‘AchE’ to terminate NMT, so that muscle fibre can be stimulated again. ACHE inhibitors increase availability of ‘Achs’ and increases NMT in “MG”

Post synaptic:

Surface of muscle cell membrane, present itself with junctional folds having slender (Stalk) & terminal expansion (Peak).  ‘AchRs’ mostly concentrated in ‘Peaks of these folds.

AchReceptor & Its structure

A glycoprotein with five subunits around a central channel. Subunits are : Two ‘a’ , one ‘b’ , one ‘d’ one ‘Î’/’g’. ‘Î’ subunit is replaced by ‘g’ in an immature /denervated muscle. In resting stage ion channels remain closed.

NORMAL PHYSIOLOGY

Once a-subunits occupied by ACh® slight twisting of AchR like Chineese purse ® opening of ion channel  ® rapid entry of Na+ ions into interior of muscle cells  ® partial depolarization of PSM at end plate region ® generation of Excitatory Post Synaptic Potential (EPSP).

**  - When number of opening channels reaches threshold ® self propagating action potential triggers muscle contraction.

** - ‘Synaptic Run Down’ (SRD) – progressive decreases in ACh release on repeated Nerve Stimulation (NS).

** ‘Safety Factor’ (SF) – Higher amplitude of End Plate Potential (EPP) than potential required to trigger Muscle Action Potential (MAP).

NMJ abnormality in “MG”:

Reduced SF with normal SRD ® progressive decline in muscle power on Repeated Nerve Stimulation (RNS). Fundamental defect: decreased AchRs at Post Synaptic Membrane (PSM) (<1/3rd) . Flattened & simplified Post Synaptic (PS) folds ® Decreased NMT. Production of small EPP ® Failure in triggering ® Weak muscles contraction

Major post synaptic abnormalities:

Decrease in AChRs causing reduction in PSM length. Shortening of synaptic fold due to destruction of terminal expansion. Widening of synaptic cleft by shortening of junctional folds.

IMMUNOPATHOGENESIS IN MG

Evidence in favor of immunoattack:- ‘AChR- abs’ found in 80-90% patients (Lindstrom et al , 1976). Circulating anti ‘AChR- abs’ found in transient Neonatal MG that declines when patient recovers. Passive transfer of IgG to mice produce similar disease (Vincent & Newson, 1985) Plasmapheresis lowers ‘AchR’ level resulting improvement. IgG abs bind to AchR being localized at the crest of PSM folds (Engel et al, 1979). Experimental model of MG can be produced with purified ‘AchR’

MECHANISM OF DESTRUCTION of ‘AchRs’:

            Blockade of the active sites of ‘AchR’. Accelerated turn over with alteration in ‘AchR’ with rapid endocytosis & degradation by muscle cells. Antibody and complement mediated Destruction of Junctional folds of PSM (Engel et al, 1977). Serum AchR concentration does not correlate with severity, rather depends upon. (a) Antibody activity – Accelerated degradation, blocking of AchR ability to bind complements. (b) Difference in NMJ – of different patients / of different muscles of same patient.

Immunopathology & seronegative MG

Circulating Abs not detectable by RIA can destroy AchR in culture system. Produce similar illness when transferred to MICE.  Few SNMG patients shows abtibody against MUSK (Muscle Specific Kinase) the protein of anchoring & clustering of AChRs at PSM. Interference in anchoring & clustering impair NMT. Other group of SNMG patients shows undetectable ‘antibodies (abs)’ against other components of NMJ.

Role of T Cells

Thymic ‘T’ cells – more responsive than peripheral blood T cells (Sommer et al, 1990). Thymus contain more ‘B’ cell & produce more abs against ‘AChR’ than control (Scadding et al, 1981). Presence of myeloid cells (Striated /Multinucleated/Muscle like cells) (Vande Velde & Friedman, 1970) having ‘AChR’ on their surface (Kao & Drachman , 1977) surrounded by (CD4+) T cells (Kirchner et al , 1988). Molecular mimicry of myeloid & skeletal muscle AChR & association with immunocompetent cells altogether constitute the important mechanistic hypothesis causing MG.

CLINICAL FEATURES

Presentation: History of cardinal features – ‘weakness & fatiguability’ of muscles on sustained /repeated activity with sudden /gradual onset. Improves after rest. Variation: Diurnal & timely variation. Factors affecting – exertion , hot temperature, infection , emotion, surgery, menstruation, pregnancy, drugs (aminoglycosides, phenytoin). Remission : Rarely complete & permanent. Tendency to long term spontaneous remission & relapse (lasting for weeks). Distribution of weakness (decreased order). Levator palpabrae superioris. Extraocular muscles (initially in 50%, eventually in 90%). Proximal limb muscles (Triceps , deltoid, illospoas). Muscles of facial expression , mastication & speech. Neck extensors. Progression: ocular ® facial ® lower bulbar ® truncal ® limb muscles

 

SIGNS & SYMPTOMS

Ocular

Presenting symptoms  is more than  one half of patients. Pupil never involved. Ptosis & diplopia: Initial symptom in 2/3 cases , all develop within 2 years. Fluctuating & shifting in nature. Asymmetric when B/L. Increases with repeated closure & prolonged upward gaze. Due to weakness of levator palpabrae superioris . Not pathognomonic for MG.  Worsens after TV watching /Driving /Bright Light

Bulbar

Dysarthria , dysphagia, weak mastication. ‘Hanging jaw sign’, jaw opening is > stronger than closing. Low fading, MUSHY voice – on hasty, laborious , continuous talk, dysphonia (laryngeal weakness).Nasal twang and Nasal timbre (hypernasal speech) (palatal weakness). Nasal regurgitation, poor gag reflex, weak tongue . Difficult swallowing and aspiration of foods. A flurry of weak & ineffective cough.

Facial

Bifacial weakness. Loss of facial expression ‘myasthanic face”. ‘Sleepy’ or ‘sorry face’ pitiable appearance. Horizontal smile – depressed grin (myasthenic snarl). Upper lips elevates transversely in an apparent snarl, smile is limited , showing only the canines as the corners are not drawn up.  Difficulty in smoking and whistling. Women complain difficulty in applying lipstick as unable to purse & roll their lips.

Muscles Of Neck

Extensor > flexors. ‘HEAD PTOSIS’ – FLOPPY HEAD SYNDROME, head drops forward in older patients with selective weakness of extensors. Attentive appearance - hand supporting the dropped jaw and falling head with thumb under chin, middle finger curled under bottom lip & the index finger up the check.

Diaphragmatic & intercostals muscles: Isolated respiratory failure, Exertional stridor

Limbs & trunk:

Proximal > distal ( difficulty in rising from chairs , lifting the arms over hand , climbing stairs, combing hairs , walking , running ).  Arms> legs, Symmetric involvement.

Deep tendon jerks:  Preserved , BRISK in week muscles .

Muscle Wasting :  Uncommon except when chronic & untreated

Sensory:  Normal.

STAGES OF WEAKNESS: Maximum Weakness In 1st Year In 2/3rd Patients

Active Stage:  Fluctuating symptoms over short period – progress to severity

Inactive stage: Fluctuation in strength still occurs (attributable to fatigue /illness),  Burnt out stage: Most severily affected muscles become atrophied.

 

DIAGNOSIS

Firm diagnosis is must as MG requiring thymectomy  /long term immuno therapy. To avoid inappropriate treatment, unwanted side effects in patients who do not have the disease. Non pharmacological clinical tests , Pharmacological , serological & electrodiagnostic tests are to be done.

Strategy:

Diagnosis based upon (1) Characteristic history & physical examination (2) Two +ve diagnostic tests (serological & electrodiagnostic)

Diagnostic test must include: Testing for “Serum’ Anti AChR –antibody and RNS study

 

Physical Examination

Detection of Ptosis : (Ocular examination)

On prolonged upward gaze or repeated closure of eye lid, Test showing ‘seesaw’ phenomenon & Herring’s law of equal innervation. Test for eye lid twich response ‘Cogans Lid Twitch’. Evidence for spontaneous eye lid retraction ‘pesudointernuclear ophthalmoplegia’ in patients of MG. Myasthenic sustained gaze fatigue. Test for ‘orbicularis oculi’ strength. Test for ‘orbicularis oculi’ fatigue ‘peak sign’. Sleep test : no ptosis after few minutes rest. Safe, moderately sensitive & specific way to confirm  improvement lasts for 2-5 mins. (Odel et al, 1991).

Ice Test:

Local Cooling: (from 35 – 360 C to 280C)

Decreases decremental response,  NM gitter , weakness ® ptosis improves, Positive response in 80% of MG patients.

PHARMACOLOGICAL METHODS:

Tensilon Test

Drug: Edrophonium (10mg)

Action: Inhibits AchE, Prolongs presence of ‘ACh’ in NMJ, increases muscle strength

Time Course: Rapid onset within 30-45 seconds, short acting. Result last for 2 minutes

Procedure:      Initially 2mg IV, Observe for 2 minutes – No response – Add 8 mg, Look for weakness of Extra Ocular Muscles (EOM), Impairment of speech, Length of time patient can keep arms forwards in abduction, Fight with 0.6 mg atropine when troublesome

Utility: Useful only in patients with objective , preferable , measurable findings, Sensitivity for MG –relatively low - 60%, Should not be used in dose adjustment of pyridostigmine, False +ve  - In LES, localized intracranial mass lesion, ALS (Amyotropic lateral Sclerosis).

Prostigmin Test :

Utility: In diagnosis of MG in patients with diplopia without ptosis, in non-co-operative children where IV tensilon is unsuitable

Procedure:      Inject 0.6 mg atropine + 1.5 mg prostigmine ® IM into deltoid

Result :Change in ocular motility & ptosis within 15 seconds, most obvious in 30 seconds,

Dose in Children: 0.04 mg/kg  not > 1.5 mg ( total dose ). Negative result does not ruleout the disease

SEROLOGICAL:

a. Anti AChR Antibody Test:

Gold standard diagnostic, highly specific. It is +ve in 80-85% of Gen. MG , 50-60% in ocular MG, 50% in childhood MG, 100% in MG with thymoma.

Procedure : Detection through RIA by ACh – receptor labeled by I 125 or  a  Bungarotoxin

Interpretation : High titre does not correlate with severity, Mild disease can have high titre, Decreases Titre (>50%) indicate favorable response to treatment, Negative test does not exclude the disease, False +ve in - ALS, LES (13%), Primary Lung cancer , Older patients (> 70 years) , Neuromyotonia

b. Anti MuSK Antibodies:

 +ve in few group in SNMG patients, ‘Abs’ not seen in sera of normal person nor concurrently with Anti-AChR antibodies.

ELECTROPHYSIOLOGICAL DIAGNOSIS

A. RNS (Repeated N. Stimulation):

Most frequently used electro diagnostic (ED) test.

Caution : Withdrawal of AChE medication 6-24 hour before

Muscle choice : Weak muscles or proximal muscle group.

Procedure: Electrical N. stimulation 6-10 times @ 2-3 Hz and recording of Compound Muscle Action Potential (CMAP) with surface electrodes over muscle.

Result: Progressive rapid reduction /Decremental response of ‘CMAP’ > 10-15% from  4th response onwards.

Interpretation: CMAP is normally unchanged or 4th response is slightly smaller than 1st (7%),  Significant when decreases > 10%.

 

Single Fibre Electromyography (SF- EMG):

Most sensitive (95%) in both General and Ocular MG

Principle :  Muscle fibres innervated by single axon., Normally activated with consistent latencies, ‘Jitter ‘ the mean inter potential difference between 2 fibres, Increase variability seen in NMJ disorder, Normally < 55ms. But >100ms in MG

Interpretation: Abnormal Jitter may not be specific for MG, Also seen in the ALS, LEM , Polymyositis, More specific with large degree Jitter

 

OTHER DIAGNOSTIC TESTS:

Ø      CT, MRI, X-ray : Screening of Thymic tumor.  Greater yield in > 40 years age.

Ø      CBC, ESR, TFT, PFT, FBS , Montoux, RA Factor , ANA etc., to screen associated disorders.

OTHER ASSOCIATED AUTOIMMUNE DISORDER:

Ø      Thyroid disorder (13% of MG)

Ø      Rheumatoid- Arthritis , SLE, Sarcoidosis , polymyositis, Ulcerative. Collitis, Pemphigus

DIFFERENTIAL DIAGNOSIS

A. Lambert Eaton Syndrome

A presynaptic disorder (Autoantibodies against Ca+2 channels at Motor N. Terminals). Never begins with ocular weakness. Weakness in legs > arms. Depressed & absent reflexes. Shows autonomic changes  - dryness, dry mouth , impotence. Increment RNS response

B. Neurasthenia

‘Jerky release’ or ‘Give away weakness’ in muscle testing. C/o tiredness or apathy or decreased muscle power on repeated use.

C. Botulisim

Generalised weakness, Internal & External ophthalmoplegia, Respiratory  paralysis. Dilated pupil and incremental response on RNS

D. Hyperthyroidisim : Abnormal ‘TFT’

E. Inherited “MG’: Persistence weakness begins in infancy /early childhood, Muscle biopsy changes don’t explain degree of weakness

F. Intracranial Mass Lesion : Example-Sphenoid ridge meningioma’

Procedures ‘DIPLOPIA” mimicking ‘MG’ illness, Detected by CT/MRI

TREATMENT

Ø      Modern treatment is highly effective with ‘0’ practical mortality rate (30% before 1958).

Available Tx modalities:

1.      AChE inhibitors                       2. Plasmapheresis     

3.      Corticosteroids                       4. IV immunoglobulins

5.      Immunosupressants               6. Thymectomy

Principle: To minimize the ACh activity at the remaining AChR in the NMJ, To limit/abolish immunological attack on motor end plate.

ACHE INHIBITORS:

Pyridostigmine (MESTINON):Usual 1st line treatment to tie up the progressive MG

Regular Mestinon pills:

·         60mg tabs /(Syp 60mg/5ml)

·         Dose: Started with 30 mg , increased gradually, Tailored as per individual requirement, Higher dose –ineffective, more S/E. increases weakness

Time span pills: Sustained release ’90-180mg , used at bedtime , acts over 12 hrs

Advantage: Few Side effects

Disadvantage:

Cholinergic crisis, (symptoms increases with ACh), Effective only in some patients, Muscarinic crisis (Abdominal pain, Diarrhoea) - managed with propanthelene /Diphenoxylate

CORTICOSTEROIDS:

Used for moderate to severe type of MG. Needs prior discussion with patient about S/E & long duration of treatment. Started with low dose 10-20 mg/day to avoid early worsening (48%) on high dose regimen. Increased 5mg every 3rd day upto 60mg. After 3 months higher dose treatment, dose modified to alternate day regimen then gradually tapered. Need months to years to determine the minimal effective dose. Patient may require additional dose on OFF days. Disadvantage: S/E - weight gain/HT/OP/Aseptic necrosis of hip /cataract/ immuno suppression. Needs regular monitoring of BP, FBS, Sr. K+, Bone density (during long term treatment)

IMMUNOSUPRESANTS:

(Azathioprine/cyclophosphamide /cyclosporin /mycofenolate mofetil)

Azathioprine : (Imuran)

1st choice drug because of relative ‘safety’

Dose : 2.5 –3 mg/kg/qd – initial dose