Myasthenia Gravis is an autoimmune disorder of the neuromuscular junction where antibodies block neuromuscular transmission, reducing acetylcholine receptors. Clinical features include weakness of the eye muscles, face, neck, and limb muscles that worsens with activity and improves with rest. Diagnosis involves fatigue testing, pharmacological testing with edrophonium, electrical studies showing decremental responses, and serological testing for antibodies. Treatment includes anticholinesterases, steroids, immunosuppressants, IVIG, and plasmapheresis. Thymectomy may be considered for some patients.
2. nerve fiber forms a complex of
branching nerve terminal
muscle fiber membrane
synaptic cleft
The vesicles fuse with the neural membrane and
empty their acetylcholine into the synaptic cleft
activate the acetylcholine receptors.
acetylcholine receptors
ACH vesicles
acetylcholine
triggering muscle contraction.
The process is rapidly terminated by hydrolysis of ACh
by acetylcholinesterase (AChE), which is present within
the synaptic fold
acetylcholinesterase
(AChE),
3. MYSTHENIA GRAVIS
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
4. • 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
Pathology
5. MYASTHENIA GRAVIS
Women are affected more in the second and
third decades
men in the sixth decade
autoimmune disorders of the neuromuscular junction
The basic defect is a loss of available postsynaptic
AChRs at the neuromuscular junction
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
6.
7. Clinical Presentation
۞ Ptosis or diplopia
۞ Difficulty chewing, swallowing, or talking
۞Neck flexors limb proximal weakness
muscles.
۞Any limb muscle may be affected, most commonly those of the shoulder
girdle
۞Respiratory muscles may be involved
Weakness typically fluctuates during the day, usually being least in the
morning and worse as the day progresses
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
8.
9. 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 disea
10. pure ocular MG if presenting in isolation for more than
12 months
generalized MG shows widespread skeletal muscle
weakness
myasthenic crisis’. weakness of respiration or swallowing
becomes so severe as to require mechanical support------
cholinergic crisis
11. Fatigue 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
12. 4-RADIOLOGICAL : CT MRI thymus
screen for CT disease
1. Pharmacological testing (Tensilon test)
2. Electrical study (RNS) TETANIC
DECREMENTAL
3. SERIOLOGICAL : antibodies
1. anti acyteyl choline receptor
2. anti muscle serin kinase musk
3. anti striated muscle :not diagnostic but indicate
presence of thymoma
Investigation
13. 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 of receptors .
positive in more than 90% of patients with MG
14. Electromyography. Abnormal decrement at
A.low rates[5-10] of stimulation may be present.
B.High rate 30-100 stimulus/sec
C.Single fiber EMG will be abnormal in almost all
cases
15. Striated muscle antibodies 90% of patients with MG and thymoma
One third of patients with MG without thymoma
Ach Receptor antibodies 80% of patients with generalized MG and
in more than one half of patients with
ocular myasthenia
antibodies to a muscle serine kinase MuSK half of the “seronegative”
patients
16. Thymus
imaging
10 % of patients with MG
have a thymoma tumor, and
70% have hyperplasia
Thyroid function tests
17.
18. Anticholinesterase (AChE) agents
Pyridostigmine bromide (Mestinon) and neostigmine bromide (Prostigmin)
Treatment
Glucocorticosteroids:
10 percent of patients show a transient GS-induced exacerbation of myasthenic
weakness
Immunosuppressive drugs:
Azathioprine Cyclosporine A (Sand immune®
for refractory MG is the much less toxic compound mycophenolate mofetil
(CellCept
19. Intravenous immunoglobulin:
myasthenic crisis when therapeutic plasmapheresis is contraindicated, or when
vascular access is problematic.
Plasmapheresis:
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)
20. 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
+ TRIADE OF 1- difficulty walking 2- Autonomic features (dry mouth,
constipation 3- The tendon reflexes are depressed
+ in v e s t i g a t i o n s :
+ 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..
3,4-diaminopyridine
Immunosuppressive therapy IVIg treatment and plasmapheresis
CLINICAL FEATURES
21. 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.
Limb onset
Clinical presentations
Bulbar
onset
respiratory muscles
combination of upper and lower motor neurone signs with progression
I. ALS
live 2-4 years following diagnosis
22. II. Primary lateral sclerosis
a degenerative disorder of the motor system in which the abnormalities
are confined to the upper motor neurones.
III. 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
23. 1. Failure to progress History of poliomyelitis
2. Family history with no affected females and
no male to male transmission Symmetrical
Signs
3. Pure upper or pure lower motor neurone
syndrome
4. Upper motor signs caudal to lower motor
neurone signs, with no bulbar involvement
5. Development of sensory signs
6. Development of sphincter disturbances
Clinical features that should lead to re-consideration of the diagnosis of ALS
24. Routine Hematology and Biochemistry
Serum Calcium and Phosphate
Thyroid Function Tests
Lumbar Puncture
Analysis for trinucleotide expansion within the androgen receptor gene (in males
lower motor neurone syndrome of bulbar and proximal musculature)
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 signs)
EMG of 4 limbs and bulbar musculature
Muscle biopsy (if EMG is atypical or unusual myopathy is suspected)
Hexosaminidase A and B activity (in susceptible Ashkenazi Jewish population)
Very long chain fatty acids (in patients with positive family history and predominantly
upper motor neurone signs)
The only evidence-based therapy is Riluzole
Heavy metal screen
reduced levels transthyretin and cystatin C and
increased levels of carboxy-terminal fragment of
neuroendocrine protein 7B2)