DISEASES OF NEUROMUSCULAR JUNCTION , MYASTHENIA GRAVIS

1. MYASTHENIA GRAVIS
-Dr CHETAN

2. MAJOR DISORDERS OF NEUROMUSCULAR JUNCTION
• MYASTHENI
C
SYNDROME
S
• PRESYNAPT
IC
• BOTULISM
• LAMBERT-
EATON
SYNDROME
• SYNAPTIC
• INSECTICID
ES
• POST -
SYNAPTIC
• MYASTHENI
A GRAVIS
• SNAKE
VENOM
TOXINS

3. MYASTHENIA GRAVIS
• Erb (1878), characterized this disease as a bulbar palsy without any anatomic lesion: Erb –
Goldflam syndrome & later Jolly (1895) used the term Myasthenia gravis.
• It is referred to as myasthenia , a fluctuating weakness of certain voluntary(skeletal)
muscles, particularly those innervated by motor nuclei of brainstem i.e ocular, masticatory ,
facial, deglutitional, lingual
• It manifests as :
1. weakness during continued activity,
2. quick restoration of power with rest,
3. dramatic improvement in strength following administration of anticholinesterase
drugs like neostigmine
• Myasthenia is an autoimmune disease in which circulating antibodies against components
of the motor synaptic membrane & subsequent structural changes in membrane explain
most of the features of the disease.

4. EPIDEMIOLOGICAL FEATURES
• Its prevalence is estimated to be 43 – 84 per million persons & the annual rate is
approximately 1 per 300,000.
• The disease can begin at any age, first decade is relatively rare.
• The peak age of first symptoms is between 20 – 30 years in woman & between 50 –
60 years in men.
• Under the age of 40 , women are more affected than males whereas in later life the
incidence in males is higher 3: 2
• Of the thymomas , the majority is older 50 -60 years & male predominate.

5. IMMUNOPATHOLOGY
• * 80- 85 % weakness
• *Type II hypersensitivity
• *antibodies bind to AChR on
terminal expansions of
junctional folds
• Cause complement mediated
destruction of folds
• Accelerated internalization
and degradation of AChR
• Distortion & simplification of
postsynaptic region
• NMJ failure & muscle
weakness
• * 10% if MG have circulatory
Ab to MuSk ( a surface
membrane component
essential in the development
of neuromuscular junction)
• *these antibodies
• Adversely effect the
maintenance of AChR
clustering at the muscle end
plate
• Decrease in number of AChR
• *remaining so called double
seronegative patients have no
known antibodies by
conventional assays
• *they have antibodies against
a protein at NMJ – low density
lipoprotein receptor related
protein(lrp4) important in
clustering of ACh
• *the patients improve with
immunosuppressive
treatments,plasma exchange
,thymectomy
• *Recently, low affinity IgG
antibodies have been about
2/3 of MG who were
seronegative for both
antibodies of anti-AChR & anti
-MUsK
ANTIBODIES TO AChR ANTIBODIES TO MuSK DOUBLE
SERONEGATIVE

7. THYMUS AND SYSTEMIC DISORDERS ASSOCIATED WITH
MYASTHENIA GRAVIS
• Thymus is abnormal in most MG patients, 65% have lymphoid follicular hyperplasia , 10%
have thymoma
• Hyperplasia is even more frequent in younger patients , cells in centers of follicles are
histiocytes surrounded by helper T lymphocytes, B lymphocytes , plasma cells ,immunoglobulin
G.
• Neoplastic epithelial cells in thymomas express numerous self like antigens, including AChR ,
titin & ryanodine receptor like epitopes
• Myasthenia associated thymomas are also rich in autoreactive T cells .

8. CLINICAL PRESENTATION
• MYASTHENIA
GRAVIS
• LIMB
MUSCLES
• OCULAR
MUSCLES
• OROPHARYNGEAL
MUSCLES

9. OCULAR FINDINGS
• Weakness usually involves one or more ocular muscles, without pupillary
abnormality.
• Ptosis & diplopia
• Weakness is typically variable , fluctuating & fatiguible
• Ptosis that shifts from one eye to other is virtually pathognomic of myasthenia
gravis
• If weakness remains restricted to extraocular muscles for 3 years without
becoming generalized, patients are said to have ocular MG.

10. OROPHARYNGEAL MUSCLES
• Weakness causes changes in voice, difficulty in chewing, swallowing ,
inadequate maintainance of upper airway which may develop in the form of ,
❑Nasal intonation
❑Nasal regurgitation of liquids
❑Weakness of laryngeal muscles – h/o frequent choking, throat clearing &
coughing after eating

11. LIMB MUSCLES
• Weakness in limb or axial muscles
begins in 20 % MG patients,usually
proximal & asymmetric
• Neck flexors are usually weaker than
neck extensors i.e deltoids + triceps +
extensors of wrist + fingers & ankle
dorsiflexors are frequently weaker
than other limb muscles
• Despite of the weakness DTRs are
preserved.
• In untreated patients with long
standing disease the weakness can be
fixed, severely involved muscles may
be atrophic.

12. MYASTHENIA GRAVIS CLINICAL SUBTYPES

13. DIAGNOSIS
1. EDROPHONIUM CHLORIDE TEST (TENSILON TEST )
Edrophonium & other choline esterase inhibitors impede an
enzymatic breakdown of acetylcholine by inhibiting the action of
acetylcholinesterase , thus allowing ACh to spread more diffusely
through ought the synaptic cleft.
• Its given at a dose of 3.3 mg for ptosis, 2- 6 mg for
ocular muscle dysfunction
• Lowest effective dose can be determined by injecting
small incremental doses of 2 mg & monitor
responses for 60s.
• If clear response is seen within 60 s after any dose
the test is positive .
• Side effects: increased salivation, sweating , nausea,
stomach cramps, fasciculations, bradyarrhythmias (
Inj . Atropine 0.4 – 2 mg should be available)
• Neostigmine (long acting drug can be used ) 15 mg
PO.

14. 2. OCULAR COOLING
• Myasthenic weakness typically improves with muscle cooling .
• Asses the improvement after placing an ice pack over ptotic eyelid usually after 2 mins
• Positive responses can also occur when edrophonium test is negative.
3. ELECTRODIAGNOSTIC TESTING IN MG
• Repetitive nerve stimulation (RNS ) is done at 3 Hz , at low rates of stimulation it depletes the store of
readily releasable ACh at diseased motor end plates causing failure of NMJ. Anti- AChE medications
have to be stopped 6- 24 hours before.
• In MG, there is decrementing response of at least 10 % to trains of 2-3 Hz stimulation.
• For maximal yield test several muscles , if RNS comes normal then proceed with SFEMG (single fiber
electromyography).
• SFEMG is most sensitive clinical test of NMJ & shows increased jitter in almost all patients with
MG
• Increased jitter is a non specific sign of abnormal NMJ and can also occur in other motor unit diseases,
R/o : neuropathy & myopathy.

16. • TREATMENT
ANTICHOLINESTERASE DRUGS:
PYRIDOSTIGMINE: PO 30 -60mg every 6th
hourly(long acting effect it must be given at
night)
Max dose 120mg given every 3 hr
NEOSTIGMINE : 7.5 – 45 mg given every 2-
6th hourly, both are given at bedtime or early
morning hours
1.5 mg IM or 0.5 mg IV has immediate onset
CORTICOSTEROIDS: Small doses of
corticosteroids : Prednisolone 15- 25 mg daily alone
or in combination with azathioprine in an alternate
day schedule
Can be increased upto 50 – 60 mg (with higher
doses worsening of weakness can occur in 1few
weeks)
Potassium supplements & antacids must be given in
case of chronic corticosteroid regime.
Antibiotics prophylaxis in C/o Pneumocystis infection
Bisphosponate for osteoporosis
Upon outset of steroids ,anticholinesterase drugs
must be given simultaneously
AZATHIOPRINE:
Used as an adjunct to steroids in those who
cannot tolerate or fail to respond to prednisolone
Rx: 50mg (1 tab) BD for few days, if this is
tolerated then its raised to 2-3mg /kg/day (150-
250 mg daily)
LFT & blood cell count must be measured
regularly
AZT is metabolized by thiopurine
methyltransferase (TPMT), absence of this
enzyme can cause bone marrow suppression
IMMUNOSUPPRESSIVES:
CYCLOSPORINE:6mg /kg in 2 divided doses.(HTN,
nephrotoxicity, expensive)
MYCOPHENOLATE: 1-1.5 g BD ,adjunct to
corticosteroids ,diarrhea is main side effect.
CYCLOPHOSPHAMIDE: IV pulses 50mg /kg/day for
4 days followed by a GSF to reboot immune system
in refractory cases(used if all methods have failed)

17. TREATMENT
PLASMA EXCHANGE(PLEX) :used for short term
treatment in severe MG , myasthenic crisis, before
surgery
5-6 exchange administered on alternate day schedule,
2-3L of plasma is removed
Benefits wears off by 4 weeks , repetitive exchanges
don’t have cumulative effect
Side effect – paresthesia, from citrate induced
hypocalcemia, hypotension, transitory arrhythmias,
nausea, lightheadedness, chills & pedal edema, SABE
,pneumothorax
IV IMMUNOGLOBULINS :
Improvement occurs in 50 – 100% MG patients after
infusion of high dose (IVIG) 2mg /kg given over 2-5
days
Induces rapid improvement in severe disease crisis,
reduces perioperative morbidity
Side effects: headaches, chills , fever, nephrotoxicity,
stroke, leukopenia & aseptic meningitis
THYMECTOMY:
• Guidelines and consensus statements
recommend early thymectomy for:
• Early-onset MG
• MG in children
• Late onset generalized MG who have
anti-AChR antibodies
EVOLVING TREATMENTS:
RITUXIMAB :375 mg/m2, given IV in 4 weekly
infusions or 1g given IV in 2 occasions 2 weeks apart
ETANERCEPT
COMPLEMENT INHIBITION is still in clinical trials
AUTOLOGOUS STEM CELL TRANSPLANTATION
in refractory MG

18. MEDICATIONS THAT ADVERSELY EFFECT NMJ
1. INF Alpha , botulinum toxin, D- penicillamine, telithromycin (ketek) should never be used in myasthenic
patients.
2. Following drugs can produce worsening of myasthenic weakness in most of the patients who receive them,
• Succinylcholine, d- tubocurarine, or other neuromuscular blocking agents.
• Quinine , quinidine & procainamide
• Antibiotics: Aminoglycosides : Gentamicin, kanamycin, neomycin, tobramycin, & streptomycin
Fluoroquinolones
Macrolides
• Beta-blockers (systemic & ocular preparations) : propronolol , timolol maleate eye drops
• CCB
• Magnesium salts (including laxatives & antacids )
• Lithium
• Iodinated contrast agents
• Statin drugs (causal relationship is not clear)

19. MYASTHENIC CRISIS
• It is respiratory failure from myasthenic weakness.
• Precipitating event like infection, aspiration, surgery , medication change.
• Cholinergic crisis is respiratory failure from overdose of cholinesterase inhibitors.
SPECIAL SITUATIONS

20. CONDITIONS WHICH MIMIC MG
1. ALS : Asymmetrical muscle weakness & atrophy
2. Botulism : generalized limb weakness
3. GBS : ascending limb weakness, areflexia
4. Inflammatory muscle weakness : proximal symmetric limb weakness
5. Lambert – Eaton syndrome : proximal symmetric limb weakness
6. Multiple sclerosis : Bilateral internuclear ophthalmoplegia
7. Periodic paralysis: intermittent generalized muscle weakness
8. Intracranial mass lesion (sphenoid ridge meningioma)
9. Kearns – Sayre syndrome :oculocraniosomatic neuromuscular disease with
ragged red fibers. Has a triad of chronic progressive external ophthalmoplegia,
B/l pigmentary retinopathy, cardiac conduction abnormality & short stature &
ataxia.

21. LAMBERT-EATON SYNDROME
• It results from an immune –mediated attack against the P/Q – type voltage –gated
calcium channels (VGCC) on presynaptic cholinergic nerve terminals at
neuromuscular junction & in autonomic ganglia.
• Two groups: One with autoimmune disorder & other associated with SCLC.
• Gradual onset of lower extremity weakness sometimes with muscle tenderness
• Clinical features: Autonomic dysfunction like dry mouth, erectile dysfunction,
postural hypotension , constipation & dry eyes.
• Ocular & bulbar symptoms are not prominent.

22. • Symptoms begin after 40.
• Males & females are equally affected
• Tendon reflexes are always absent or diminished
• The response to edrophonium is not as evident as in MG , weakness is not
life threatening and resembles cachexia, polymyositis, or a paraneoplastic
neuromuscular disease.
• Response to neostigmine & pyridostigmine is poor or atleast unpredictable

24. • Conventional electrodiagnostic studies show no abnormality in
peripheral nerves .
• The defect lies in release of Ach quanta from the presynaptic nerve
terminals.
• Thymus is normal .
• Search occult tumor through PET scan.
• Approximately one half of the patients have underlying malignancy
small cell lung carcinoma, non SCLC, lymphosarcoma, malignant
thymoma, carcinoma of breast, stomach, colon, prostate, bladder
,kidney or gall bladder .

25. TREATMENT
• Includes plasmapheresis & immunosuppression.
• Most of them are benefited from 3,4 di-aminopyridine (3,4 DAP) an
agent that blocks the potassium channels in distal motor terminal thus
prolonging depolarization & enhancing the release of Ach vesicles.
Given as 20 mg up to 5 times a day either alone or in conjunction with
pyridostigmine.
• Alternate day administration of prednisone(25-60 mg/day) &
azathioprine(2-3mg/kg ) supplemented intermittently as needed by
IVIG
• Response to treatment tends to be slow, some may recover fully while
restoration of power is incomplete

26. BOTULISM
• Botulism is caused by toxin produced by
Clostridium botulinum .
• It blocks the release of Ach from the motor
nerve terminal.
• The intracellular target is the SNARE proteins
of the presynaptic membrane.
• Results in long lasting severe muscle paralysis
• Toxins block Ach release from nerve
terminal & parasympathetic & sympathetic
nerve ganglia
• Symptoms begin 12 – 36 hours after the
ingestion of contaminated food

27. CLINICAL FEATURES
• Autonomic features include paralytic ileus,
constipation, urinary retention, dry mouth, respiratory
paralysis
• Blurred vision(dilated pupils)
• Dysphagia ,
• Dysarthria ,
• Reduction in tendon reflexes,

28. • Diagnosis:
• PCR assays are available to detect bacteria.
• EMG :
Reduced CMAP amplitude in at least 2 muscles

29. TREATMENT
Administration of bivalent or trivalent antitoxin,
BIG –IVIG 2ml/kg body wt.
Antibiotic therapy is not effective
AChE inhibitors not useful, 3,4-DAP may improve strength but not respiratory
function.
Patient may need ventilator assistance.
Prognosis is excellent with Treatment .