Myasthenia gravis MG

Myasthenia Gravis

Pathophysiology

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 acetyl cholinesterase (AChE), which is present within the synaptic fold
acetylcholinesterase (AChE),
Pathophysiology

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


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

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

Clinical Presentation

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

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


- 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
Pregnancy

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

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

4. Radiological test : CT- scan of the thymus

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
Investigation

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
Edrophonium chloride (Tensilon)


Electromyography. (EMG) Abnormal decrement at low rates[5-10] of stimulation may be present. High rate 30-100 stimulus/sec Single fiber EMG will be abnormal in almost all cases

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 Striated muscle antibodies
90% of patients with MG and thymoma
One third of patients with MG without thymoma
SERIOLOGICAL : antibodies

Thymus imaging

10 % of patients with MG have a thymoma tumor, and 70% have hyperplasia

Anticholinesterase (AChE) agents Pyridostigmine bromide (Mestinon) and neostigmine bromide (Prostigmin)
Treatment
Glucocorticosteroids:
10 percent of patients show a transient steriod-induced exacerbation of myasthenic weakness

for refractory MG is the much less toxic compound mycophenolate mofetil (CellCept

Intravenous immunoglobulin:
.
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)

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 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
CLINICAL FEATURES

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
1.ALS
live 2-4 years following diagnosis

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

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
Clinical features that should lead to re-consideration of the diagnosis of ALS

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))

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)