1. Myasthenia Gravis

3. Pathophysiology
The presynaptic membrane (on the nerve), postsynaptic membrane (on the muscle membrane), and the synaptic cleft (the space between the 2 membranes) together constitute the NMJ 

4. activate the acetylcholine receptors.
Pathophysiology
The vesicles fuse with the neural membrane and empty their acetylcholine into the synaptic cleft
activate the acetylcholine receptors.
triggering muscle contraction.
The process is rapidly terminated by hydrolysis of ACh by acetyl cholinesterase (AChE), which is present within the synaptic fold
synaptic cleft
ACH vesicles
acetylcholine
muscle fiber membrane
acetylcholinesterase (AChE),
acetylcholine receptors
nerve fiber forms a complex of branching nerve terminal

5. Pathophysiology
decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue

6. Pathology
the postsynaptic muscle membrane is distorted and simplified, having lost its normal folded shape
The concentration of AChRs on the muscle endplate membrane is reduced
antibodies and complement are attached to the membrane
pathological changes

7. autoimmune disorders of the neuromuscular junction
MYASTHENIA GRAVIS
autoimmune disorders of the neuromuscular junction
The basic defect is a loss of available postsynaptic AChRs at the neuromuscular junction
Women are affected more in the second and third decades
Men in the sixth decade
Auto antibodies to acetylcholine receptors in the post- junctional membrane of the neuromuscular junction. These antibodies block neuromuscular transmission and initiate a complement-mediated inflammatory response which reduces the number of acetylcholine receptors and damages the end plate

10. Clinical Presentation
Weakness typically fluctuates during the day, usually being least in the morning and worse as the day progresses
Ptosis or diplopia
Difficulty chewing, swallowing, or talking
Neck flexors
muscles.
Any limb muscle may be affected, most commonly those of the shoulder girdle
Respiratory muscles may be involved
Factors that worsen myasthenic symptoms are
emotional upset, systemic illness (especially viral respiratory infections), hypothyroidism or hyperthyroidism,
pregnancy, the menstrual cycle, drugs affecting neuromuscular transmission
neuromuscular blocking agents (e.g., curare-like compounds); local anesthetics (and antiarrhythmics (quinine, quinidine, procainamide, verapamil); aminoglycoside, quinolone, and
macrolide antibiotics; beta blockers; calcium channel blocking agents). D-penicillamine

12. Pregnancy - 1/3 stable, 1/3 worsen, 1/3 improve in pregnancy
- higher risk of relapse in post-partum period
- In 1/8 pregnancies, neonatal MG will occur secondary to transplacental passage of AchR antibodies
- Cholinesterase inhibitors, steroids, and IVIg are safe in pregnancy. Azathioprine also appears to be safe. PLEX can be done but care must be taken to avoid volume shifts.
- Magnesium sulfate for treatment of ecclampsia may worsen MG
- C-section not routinely planned but should be considered in severe disease

13. generalized MG shows widespread skeletal muscle weakness
pure ocular MG if presenting in isolation for more than 12 months
myasthenic crisis’. weakness of respiration or swallowing
becomes so severe as to require mechanical support------
cholinergic crisis

14. Fatigability testing
looking upward and sidewards for 30 seconds: ptosis and diplopia.
looking at the feet while lying on the back for 60 seconds
keeping the arms stretched forward for 60 seconds
10 deep knee bends
walking 30 steps on both the toes and the heels

16. 4. Radiological test : CT- scan of the thymus
Investigation
Pharmacological testing (Tensilon test)
Electrophysiological study (RNS) Titanic decrement
Seriological test : antibodies
anti acyteyl choline receptor
anti muscle serin kinase musk
anti striated muscle :not diagnostic but indicate presence of thymoma
4. Radiological test : CT- scan of the thymus

19. Edrophonium chloride (Tensilon)
is used as a short-acting cholinesterase inhibitor (duration 3 to 10 min). Atropine (1-2 mg) should be available to antagonize possible muscarinic side effects. The rapid action after intravenous administration allows repeated interaction between ACh and AChR, and partially compensates for the functional deficit
positive in more than 90% of patients with MG

20. Electromyography. (EMG)
Abnormal decrement at
low rates[5-10] of stimulation may be present.
High rate stimulus/sec
Single fiber EMG will be abnormal in almost all cases

21. SERIOLOGICAL : antibodies
80% of patients with generalized MG and in more than one half of patients with ocular myasthenia
Ach Receptor antibodies
half of the “seronegative”
patients
antibodies to a muscle serine kinase MuSK
90% of patients with MG and thymoma
Striated muscle antibodies
One third of patients with MG without thymoma

22. Thymus imaging
10 % of patients with MG have a thymoma tumor, and 70% have hyperplasia

25. Treatment Anticholinesterase (AChE) agents
Pyridostigmine bromide (Mestinon) and neostigmine bromide (Prostigmin)
Glucocorticosteroids:
10 percent of patients show a transient steriod-induced exacerbation of myasthenic weakness
Immunosuppressive drugs:
Azathioprine Cyclosporine A (Sand immune®
for refractory MG is the much less toxic compound mycophenolate mofetil
(CellCept

26. Intravenous immunoglobulin:.
Plasmapheresis:
Intravenous immunoglobulin:
Thymectomy:
Most studies report better responses when thymectomy is performed early in the disease and a trans-sternal surgical approach is preferred.
patients between 10 and 50 years of age with relatively recent onset of MG (within 3-5years)

27. Lambert-Eaton Myasthenic syndrome
paraneoplastic (P-LEMS), associating with small cell lung cancer and occasionally lymphoma, or non-paraneoplastic
The physiological abnormality in LEMS is
a reduced quantal release of acetylcholine
cause by antibodies to voltage-gated calcium channels
CLINICAL FEATURES
TRIADE OF 1- difficulty walking Autonomic features (dry mouth, constipation The tendon reflexes are depressed
investigations :
post-tetanic potentiation Electromyography. The EMG shows a small compound muscle action potential and a striking (>100%) post-tetanic potentiation
Serology. Antibodies to voltage-gated calcium channels (VGCCs) can be
detected in > 90% of patients
Treatment
3,4-diaminopyridine

29. motor neuron disease
is a relatively rare disorder characterized by progressive degeneration of upper and lower motor neurons
In the USA, "ALS" is often used to refer to all forms or motor neuron disease
In the UK "motor neuron disease" is used as a generic term to describe all forms of the motor neuron degeneration.
MND is largely a disease of middle and elderly life presenting in the sixth and seventh decades although can present much earlier. A younger presentation is more often seen in familial MND which accounts for approximately 5 percent of cases.
Clinical presentations
1.ALS
combination of upper and lower motor neurone signs with progression
Limb onset
Bulbar onset
respiratory muscles
live 2-4 years following diagnosis

30. Primary lateral sclerosis
a degenerative disorder of the motor system in which the abnormalities
are confined to the upper motor neurones.
Progressive muscular atrophy
present with LMN only lower motor neurone disease accounts for
approximately 10% of MND
fasciculation and wasting
progressive spinal muscular atrophy and adult onset SMA/SMA type IV are synonymous with PMA.
(20-40%) finding of sub-clinical frontal lobe dysfunction
ALS-Dementia
El Escorial and Airlie House Diagnostic Criteria for Diagnosis of ALS

31. Pure upper or pure lower motor neurone syndrome
Clinical features that should lead to re-consideration of the diagnosis of ALS
Failure to progress History of poliomyelitis
Family history with no affected females and no male to male transmission Symmetrical Signs
Pure upper or pure lower motor neurone syndrome
Upper motor signs caudal to lower motor neurone signs, with no bulbar involvement
Development of sensory signs
Development of sphincter disturbances

32. Neuroimaging
MRI brain (in patients with predominantly upper motor neurone signs)
MRI spine (in patients with upper motor neurone signs caudal to lower motor
neurone signs, and no bulbar features)
Neurophysiology
Extensive nerve conduction studies (in patients with predominantly lower motor
neurone sign EMG of 4 limbs and bulbar musculature
Muscle biopsy (if EMG is atypical or unusual myopathy is suspected))
reduced levels transthyretin and cystatin C and increased levels of carboxy-terminal fragment of neuroendocrine protein 7B2)
Heavy metal screen
The only evidence-based therapy is Riluzole