Neuroanatomy

Neuromuscular Junction
CLARA NOVENA
NEUROMUSCULAR JUNCTION MG
• Receptors • What is MG
• What can affects NMJ? • Epidemiology
• Neurotransmitter • Pathophysiology
BOTULISM • Modified Osserman Classification
• Transmission • Clinical features
• Signs and symptoms • Diagnosis of MG
• Mechanism of Action of Botulinum Toxin • Precipitating factors
• Diagnostic methods • Treatment
• Treatment • MG Crisis
LEMS • Cholinergic crisis
• What is LEMS • Prognosis
• Signs and Symptoms DRUGS
• Mechanism Lain-lain
• Diagnostic Methods Bahan\bahan2\Cogan's lid twitch sign.mp4
• Treatment Bahan\bahan2\Neuromuscular Junction (Anatomical
Structure).mp4
NEUROMUSCULAR JUNCTION
 Receptors
• Nicotinic receptors are cation-permeable ion channels
activated by the neurotransmitter acetylcholine
• The muscle type receptor mediates all fast synaptic excitation
on voluntary muscle
• Muscarinic acetylcholine receptors, or mAChRs,
are acetylcholine receptors that form G protein-receptor
complexes in the cell membranes of certain neurons and
other cells. They play several roles, including acting as the main
end-receptor stimulated by acetylcholine released
from postganglionic fibers in the parasympathetic nervous
system
 Neurotransmitter
• Also known as chemical messengers,
are endogenous chemicals that enable neurotransmission
• Catecholamine Neurotransmitters
– Derived from amino acid tyrosine
• Dopamine [Parkinson’s], norepinephrine, epinephrine
• Amine Neurotransmitters
– acetylcholine, histamine, serotonin
• Amino Acids
– aspartic acid, GABA, glutamic acid, glycine
• Polypeptides
– Include many which also function as hormones
– endorphins
Examples of important neurotransmitter :
• Acetylcholine It activates skeletal muscles in the somatic
nervous system and may either excite or inhibit internal organs
in the autonomic system
• Dopamine has a number of important functions in the brain;
this includes regulation of motor behavior, pleasures related to
motivation and also emotional arousal
• Epinephrine which is synthesized from tyrosine takes part in
controlling the adrenal glands
• GABA is used at the great majority of fast inhibitory synapses
in virtually every part of the brain
• Glutamate is used at the great majority of fast excitatory
synapses in the brain and spinal cord
• Norepinephrine which focuses on the central nervous system,
based on patients sleep patterns, focus and alertness
• Serotonin most is produced by and found in the intestine
(approximately 90%), and the remainder in central nervous
system neurons
 What can affects NMJ?

TOXIN
• Botulinum toxin
• Botulinum toxin (aka botulinum neurotoxin, BoNT, and sold under the trade
name Botox) inhibits the release of acetylcholine at the neuromuscular junction
by interfering with SNARE proteins. This toxin crosses into the nerve terminal
through the process of endocytosis and subsequently interferes with SNARE
proteins, which are necessary for ACh release. By doing so, it induces a transient
paralysis and chemical denervation localized to the striated muscle that it has
affected. The inhibition of the ACh release does not set in until approximately
two weeks after the injection is made. Three months after the inhibition occurs,
neuronal activity begins to regain partial function, and six months, complete
neuronal function is regained
• Tetanus Toxin
• Tetanus toxin, also known as Tetanospasmin is a potent
neurotoxin produced by Clostridium Tetani and causes the
disease state, tetanus.
• It functions very similarly to botunlinum neurotoxin (BoNT) by
attaching and endocytosing into the presynaptic nerve
terminal and interfering with SNARE protein complexes. It
differs from BoNT in a few ways, most apparently in its end
state, wherein tetanospasmin demonstrates a rigid / spastic
paralysis as opposed to the flaccid paralysis demonstrated with
• Latrotoxin
• Latrotoxin (α-Latrotoxin) found in venom of widow spiders also
affects the neuromuscular junction by causing the release of
acetylcholine from the presynaptic cell
• Mechanisms of action include binding to receptors on the presynaptic
cell activating the IP3/DAG pathway and release of calcium from
intracellular stores and pore formation resulting in influx of calcium
ions directly. Either mechanism causes increased calcium in
presynaptic cell, which then leads to release of synaptic vesicles of
acetylcholine. Latrotoxin causes pain, muscle contraction and if
untreated potentially paralysis and death
• Snake Venom
• Snake venoms act as toxins at the neuromuscular junction and can induce weakness
and paralysis. Venoms can act as both presynaptic and postsynaptic neurotoxins
• Presynaptic neurotoxins, commonly known as β-neurotoxins, affect the presynaptic regions
of the neuromuscular junction. The majority of these neurotoxins act by inhibiting the
release of neurotransmitters, such as acetylcholine, into the synapse between neurons.
However, some of these toxins have also been known to enhance neurotransmitter release.
Those that inhibit neurotransmitter release create a neuromuscular blockade that prevents
signaling molecules from reaching their postsynaptic target receptors. In doing so, the
victim of these snake bite suffer from profound weakness.
• Such neurotoxins do not respond well to anti-venoms. After one hour of inoculation of
these toxins, including notexin and taipoxin, many of the affected nerve terminals show
signs of irreversible physical damage, leaving them devoid of any synaptic vesicles
• Postsynaptic neurotoxins, otherwise known as α-neurotoxins, act
oppositely to the presynaptic neurotoxins by binding to the
postsynaptic acetylcholine receptors. This prevents interaction
between the acetylcholine released by the presynaptic terminal and
the receptors on the postsynaptic cell. In effect, the opening of
sodium channels associated with these acetylcholine receptors is
prohibited, resulting in a neuromuscular blockade, similar to the
effects seen due to presynaptic neurotoxins. This causes paralysis in
the muscles involved in the affected junctions
• Unlike presynaptic neurotoxins, postsynaptic toxins are more easily
affected by anti-venoms, which accelerate the dissociation of the
toxin from the receptors, ultimately causing a reversal of paralysis
AUTOIMMUNE
1. Myasthenia gravis
2. Neonatal MG
Neonatal MG is an autoimmune disorder that affects 1 in 8 children
born to mothers who have been diagnosed with Myasthenia gravis (MG). MG
can be transferred from the mother to the fetus by the movement of AChR
antibodies through the placenta
-Signs of this disease at birth include weakness, which responds to
anticholinesterase medications, as well as fetal akinesia, or the lack of fetal
movement
-This form of the disease is transient, lasting for about three months
3. Lambert-Eaton myasthenic syndrome
4. Neuromyotonia
Neuromyotonia (NMT), otherwise known as Isaac’s syndrome, is unlike many
other diseases present at the neuromuscular junction. Rather than causing
muscle weakness, NMT leads to the hyperexcitation of motor nerves
- NMT causes this hyperexcitation by producing longer depolarizations by down-
regulating voltage-gated potassium channels, which causes greater
neurotransmitter release and repetitive firing. This increase in rate of firing leads
to more active transmission and as a result, greater muscular activity in the
affected individual. NMT is also believed to be of autoimmune origin due to its
associations with autoimmune symptoms in the individual affected
GENETIC
• Congenital myasthenic syndromes
Congenital myasthenic syndromes (CMS) are very similar to both MG and LEMS in their functions,
but the primary difference between CMS and those diseases is that CMS is of genetic origins.
Specifically, these syndromes are diseases incurred due to mutations, typically recessive, in 1 of at
least 10 genes that affect presynaptic, synaptic, and postsynaptic proteins in the neuromuscular
junction. Such mutations usually arise in the ε-subunit of AChR,thereby affecting the kinetics and
expression of the receptor itself. Single nucleotide substitutions or deletions may cause loss of
function in the subunit. Other mutations, such as those
affecting acetylcholinesterase and acetyltransferase, can also cause the expression of CMS, with
the latter being associated specifically with episodic apnea.These syndromes can present
themselves at different times within the life of an individual. They may arise during the fetal phase,
causing fetal akinesia, or the perinatal period, during which certain conditions, such
as arthrogryposis, ptosis, hypotonia,ophthalmoplegia, and feeding or breathing difficulties, may be
observed. They could also activate during adolescence or adult years, causing the individual to
develop slow-channel syndrome.
Treatment for particular subtypes of CMS (postsynaptic fast-channel CMS) is similar to treatment for
other neuromuscular disorders. 3,4-Diaminopyridine, the first-line treatment for LEMS, is under
development as an orphan drug for CMS in the US, and available to eligible patients under an
expanded access program at no cost.
BOTULISM
 Botulism
• also known as botulinus intoxication
• is a rare but sometimes fatal paralytic illness caused by
botulinum toxin which is a protein produced under anaerobic
conditions by the bacterium Clostridium botulinum, and
affecting a wide range of mammals, birds and fish
• C. botulinum is an anaerobic, Gram positive, spore-forming
rod
 Transmission
• by colonization of the digestive tract by the bacterium in
children (infant botulism) or adults (adult intestinal
toxemia),
• by ingestion of toxin from foods (foodborne botulism) or
• by contamination of a wound by the bacterium (wound
botulism).
• Person to person transmission of botulism does not occur.
• 3 main kinds of botulism
– The classic (food-borne) botulism
• Ingestion of toxin in food contaminated with toxin-
producing bacteria.
– Infant botulism
• Ingestion of spores that then germinate and produce
toxin in the infant’s gastrointestinal tract.
– Wound botulism
• Wound infected with Clostridium botulinum
• IVDU
Mechanism of Action of Botulinum Toxin
• All forms lead to paralysis that typically starts with the
muscles of the face and then spreads towards the limbs.
In severe forms, it leads to paralysis of the breathing
muscles and causes respiratory failure. In light of this life-
threatening complication, all suspected cases of botulism
are treated as medical emergencies, and public health
officials are usually involved to prevent further cases from
the same source
• Pathogenic bacterium that found in the soil.
• Proliferates under anaerobic and alkaline conditions
• The spores can survive extreme weather and temperature
conditions (>120c may be required to kill the spores).
• Toxin is heat labile (>85c inactivates the toxin)
• Toxins A,B,C1,C2,D,E,F,G
Foodborne botulism can be prevented by :
• use of pressure cooking or autoclaving at 121 °C (250 °F)
for 30 minutes when canning to kill the spores
• by providing conditions that prevent the spores from
growing.
• Additional precautions for infants include not feeding them
honey.
 Triad Botulism
• Bulbar palsy and descending paralysis,
• lack of fever
• clear senses and mental status ("clear sensorium")
 Signs and symptoms
Kelemahan otot-otot yang disarafi saraf kranial
• Otot penggerak bola mata
• Otot wajah
• Otot pengunyah dan penelan
• Dobel vision
• Ptosis
• Hilangnya ekspresi wajah
• Sulit menelan
• Sulit bicara
• Lengan  bahu, lengan, tungkai
• Cranial nerve palsies (2-36hr)
– Diplopia, ptosis, blurred vision
– Dysarthria, dysphagia
• Descending weakness of the limbs
– Upper limbs  Lower limbs
– Usually bilateral but can be asymmetric.
• Respiratory paralysis
• Autonomic dysfunction
 Autonomic dysfunction
• Dilated pupils (<50% of patients)
• Constipation, diarrhea
• Nausea and vomiting
• Dry mouth
• Postural hypotension
• Urinary retention
• Heart rate R-R interval variation
• Recovery of autonomic function may take longer than NM
transmission/
 Diagnostic methods
• NCV and EMG
– Small CMAP amplitude
– Decremental response of the MAP to slow rated of
nerve stimulation (2-3 Hz)
– Posttetanic facilitation (PTF) (50Hz) or post isometric
exercise  incremental response to 30-100%
• Detection of toxin
– Serum (30-40%)  (<30% after day 2)
– Stool (60%)  (36% after day 3)
– wound
• Otot2 pernafasan  dispnea, gagal nafas  koma
• Sist. Saraf otonom 
produksi saliva ↓ mulut & tenggorokan
kering
postural hipotensi
peristaltik ↓  konstipasi
mual, muntah
 Electrophysiologic Studies
• Should be performed on clinically-involved muscles.
• Tensilon test -normal (differentiates botulism from
myasthenia gravis).
• Nerve conduction velocity - normal Repetitive nerve
stimulation at 50 Hz -facilitation of the compound muscle
action potential (rates 20-50 per second)(EMG shows an
incremental response to repetitive stimulation).
• These studies may support the diagnosis of
botulism. However, a normal electromyogram does not
rule out disease.
• Defective release of Ach from nerve terminals.
• It cleaves synaptic vesicle protein.
• Extra ocular and bulbar weakness  limb and respiratory
weakness.
• Blurred vision, dilated pupil, constipation, urinary
retention.
• Electro physiologically resemble LEMS
• Reduced CMAP in at least two muscles
• At least 20 percent CMAP amplitude facilitation on tetanic
stimulation
• Persistance of facilitation atleast 2 minutes after activation
• No postactivation exhaustion
 Treatment
• Supportive care (weeks – months)
• Antitoxin
– Dose not reverse paralysis when the toxin is
internalized and bound at the nerve terminal.
– Lack of efficacy in some cases
– Allergic reactions and serious side effect 20%
 Treatment
• Supportive care combined with the rapid administration of
botulinal antitoxin are the keys to successful management
of botulism.
• With improvements in intensive care support and early
administration of antitoxin, mortality rates for botulism
have been approximately 6% in recent years.
• Respiratory failure due to paralysis of respiratory muscles
is the most serious complication as well as the most
common cause of death.
 Botulinum Antitoxin
• Uncontrolled studies, use of antitoxin has been
associated with lower mortality rates and, if administered
early after onset of symptoms, a shorter course of illness
• Contrary to the package insert directions, current
recommendations are to administer ONE 10 ml vial of
antitoxin per patient, intravenously in a normal saline
solution over 20 minutes.
• Antitoxin need not be repeated since the circulating
antibodies have a half-life of 5 to 8 days.
• Skin testing is performed by injecting 0.1 ml of a 1:10
dilution (in sterile physiologic saline) of antitoxin
intradermally in the patient's forearm with a 26 or 27
gauge needle. The injection site should be monitored and
the patient observed for allergic reactions for 20 minutes.
LAMBERT EATON MYASTHENIC
SYNDROME
 What is LEMS
• A rare autoimmune disease
• Symptoms and origins similar to MG.
• LEMS interferes with ACh release from nerve cells, While
MG targets the Ach receptors on muscle cells.
• 85 %  positive for antibodies against the P/Q type
voltage-gated calcium channel (VGCC).
• This protein is a pore that allows calcium entry into nerve
cells, which is required for ACh release.
• 60 % of cases, LEMS is associated with small-cell lung
cancer (and more rarely with other types of cancer), which
might be diagnosed at the same time as LEMS or years
later.
• There’s evidence that the cancerous cell inappropriately
make VGCC, triggering the immune system to make anti-
VGCC antibodies.
• The trigger for LEMS without cancer is unknown.
 Signs and Symptoms
• LEMS symptoms usually begin with leg weakness, often followed by
weakness in the muscles of the eyes, face and throat
• Sometimes the weakness temporarily improves after exertion
• Leg weakness and difficulty walking
• Oculobulbar weakness (affecting the muscles of the eyes, face and
throat) may occur later, causing ptosis, speech impairment and
swallowing problems
• Unlike weakness in MG, weakness in LEMS temporarily improves after
exertion. (It’s thought that, with repeated activity, calcium gradually builds
up in the nerve cells, increasing the amount of Ach released)
• Because ACh regulates many bodily functions, LEMS sometimes causes
autonomic (involuntary) symptoms such as dry mouth, constipation,
impotence and bladder urgency
• Because ACh regulates many bodily
– Proximal limb weakness (Leg>arms)
– Rarely, cranial nerve symptoms
– Rarely, respiratory failure
– Autonomic dysfunction (75%)
•Dry mouth, constipation,dilated pupils with poor reactive
to light, impair sweating, orthostatic hypotension,
impotence
– Lambert’s sign
•Grip becomes more powerful over several seconds
– Absent DTR but obtainable after exercise
Mechanism
 Diagnostic Methods
• NCV and EMG
– Low amplitude of CMAP
– Decremental response to slow rated of nerve
stimulation (2-3 Hz)
– Posttetanic facilitation (PTF) (50Hz) or post isometric
exercise  incremental response to >200 %
 Repetitive Nerve Stimulation

Posttetanic facilitation - incremental response >200%

• Distal muscles RNS preferred
• 3 pattern recognized
• Low normal CMAP amplitude, decremental response at
low rate RNS, normal at high rate.
• Low CMAP amplitude, decremental response at low rate,
and incremental response at high rate RNS (>100%)—
classical triad.
• Low CMAP amplitude, decremental low rate RNS, initial
decrement at high rate RNS.
 Treatment
• Treating the cancer
– Screened for small cell lung CA every 6 months with
chest imaging for at least 2 years
• Pyridostigmine alone is usually ineffective
• 3,4 Diaminopyridine is usually beneficial, and usually
enhanced by pryidostigmine
• Plasma exchange/ IVIg temporary improveme
MYASTHENIA GRAVIS
 What is MG
• An autoimmune disorder caused by autoantibodies against the nicotinic
acethycholine receptors on the postsynaptic membrane at the NM junction
• Characterised by weakness and fatigability of the voluntary muscles

Epidemiology
• The commonest disorder in NMJ
• Annual incidence 0.25-2/100,000
• Present in any age
– A bimodal peak
• First peak in 3rd decade ( women > men )
• Second peak in 6th-7th decade
( men > women )
Epidemiology
Pathophysiology
 Anti AChR antibodies reduce number of available AChRs
by :
 Accelerated turnover of AChRs (cross-linking & rapid
endocytosis of receptors)
 Blockade of active site of AChR (site that normally binds
ACh)
 Damage to postsynaptic muscle membrane by antibody in
collaboration with complement.
 Decreased efficiency of neuromuscular transmission
combined with presynaptic rundown results in activation
of fewer & fewer muscle fibres by successive nerve
impulses & hence increasing weakness / myasthenic
fatigue
 An immune response to MuSK - result in MG, by
interfering with AChR clustering.
 Antibodies are IgG & T cell dependent
 Modified Osserman Classification
• Class I: Ocular weakness
• Class II: Mild weakness
– IIa : limb and/or axial involvement
– IIb : oropharyngeal and/or respiratory involvement
• Class III: Moderate weakness
– IIIa : limb and/or axial involvement
– IIIb : oropharyngeal and/or respiratory involvement
• Class IV: Severe weakness
– IVa : limb and/or axial involvement
– IVb : oropharyngeal and/or respiratory involvement
• Class V: Defined by intubation c/s mechanical ventilator
Quantitative MG Score
 Clinical features
• Weakness and fatigability of muscles on sustained or repeated
activity that improves after rest
• Insidious onset
• Often fluctuation
• Progression
– Craniocaudal direction
• The most commonly affecting muscles
– Levator palpebrae (ptosis)
– Extraocular muscles (diplopia)
– Muscle of facial expression (“Snarl” face)
– Neck muscles (drop neck myopathy)
– Bulbar muscles (dysphagia, nasal voice)
– Proximal limb muscles
• Can first present during
– Pregnancy or post natally
– Post general anesthesia
– ICU care
• Diaphragmatic weakness
• Weakness can remain localized to one group of muscle for many
years eg. Ocular MG
 Severity of weakness fluctuates during the day least
severe in the morning & worse as the day progresses,
especially after prolonged use of affected muscles.
 Patient usually gives h/o
 Worsening of ocular symptoms while reading, watching
television, driving.
 Worsening of jaw muscle weakness on prolonged
chewing – meat / chewy candy.
• Also give h/o :
 Frequent purchase of new eyeglasses to correct blurred vision
 Avoidance of foods that became difficult to chew or swallow
 Cessation of activities that require prolonged use of specific
muscles
 Course of disease is variable but often progressive
 Symptoms fluctuate over a short period & then become more
severe for several years ( Active Stage )
 Followed by a period in which fluctuations in strength still occurred (
Inactive Stage )
 After 15-20 yrs, weakness becomes fixed & most severely involved
muscles become atrophic ( Burnt-out Stage )
 Ocular Manifestations
 Weakness of levator palpebrae & extraocular muscles – initial
manifestation in ½ cases.
 Ocular palsies, ptosis usually accompanied by weakness of eye
closure – always myopathic & not neuropathic in origin
 Diplopia- due to asymmetric weakness of muscles in both eyes.
 Sustained upgaze for 30 or more seconds – induce / exaggerate ptosis
& uncover myasthenic motor weakness
 Lid-twitch sign : twitching of upper eyelid appears a moment after the
patient moves the eyes from downward to primary position
 After sustained upward gaze, 1or more twitches are observed with
closure of eyelids
• Unilateral painless
ptosis without
ophthalmoplegia or
pupillary abnormality
 Combined weakness of extraocular muscles, levators &
orbicularis oculi combined with
 Normal pupillary response to light
 Normal accomodation is virtually diagnostic of
myasthenia.
 Bright light aggravates ocular signs
 Cold ( application of ice pack ) improves them
 Oropharyngeal Manifestations
 Voice may be nasal after prolonged talking
 Weakness of laryngeal muscles – hoarseness
 Frequent choking due to difficulty in swallowing &
chewing after eating for a while.
 Characteristic facial appearance
 At rest, b/l lid ptosis,
downward curve of
corners of mouth, giving pt
a sad appearance
 Smiling: myasthenic snarl
– resulting from upward
movement of medial
portion of upper lip &
horizontal contraction of
corners of mouth
 Jaw weakness – shown by manually opening the jaw
against resistance, which is not possible in normal
people.
 Patient holds
jaw closed with thumb under chin,
middle finger curled under nose/lower lip
index finger extended up the cheek
producing studious appearance
 Neck flexors are weaker than neck extensors
 Bulbar weakness is prominent in MuSK antibody positive
MG.
 Limb weakness is often proximal & asymmetric
 Tendon reflexes are unaffected
 Even repeated tapping of tendon does not tax muscles to
the point where contraction fails
 Associated disorder
• Thymic hyperplasia 50-70%
• Thymoma 10-15%
• Thyroid disease 10%
• Rheumatoid arthritis
• Pernicious anemia
• SLE
 Diagnosis of MG
• Serology:
– Anti-AchR (sensitivity 80%, high specificity)
• EMG: Repetitive nerve stimulation
– CMAP decremental >10% at 3 Hz (sensitivity 75%)
• SFEMG:
– increase jitter +/- blocking (most sensitive but not specific)
• Edrophonium/ Tensilon test
– (sensitivity 80%, not specificity)
• Ice test
– (80% sensitivity, high specificity)
 Anticholinesterase Test /
Edrophonium Chloride ( Tensilon )
Test
 Positive in > 90 % of patients with MG
 Initially 2mg Edrophonium IV given, response monitored
for 60 sec - if definite improvement of muscular
weakness occurs, it is + & test is terminated.
 If no change, additional 8mg IV is given in 2 parts ( 3mg &
5 mg ) , if improvement is seen within 60 sec after any
dose, no further injections are given.
 Anticholinesterase Test /
Edrophonium Chloride ( Tensilon )
Test
 10 mg of Edrophonium does not weaken normal muscle &
occurrence of weakness indicates neuromuscular
transmission weakness.
 IM Neostigmine can be used ( infants & children )
 False positive in neurologic disorders like Amyotropic
lateral sclerosis
 Now reserved for those with clinical features suggestive
of MG but antibody & electromyographic tests are
negative
 Antibodies to AChR , MuSK :
 Anti-AChR Radioimmunoassay :
 85 % positive in generalized MG
 50 % positive in ocular MG
 Presence of Anti-AChR antibodies is virtually diagnostic
 But negative result does not rule out MG
 Antibodies to MuSK – 40 % of AChR antibody negative
pts with generalized MG.
Acetylcholine Receptor Antibodies
75% of cases generalized MG
54% with ocular MG have antibodies
10% MG cases with no binding antibodies have
other antibodies

 The amount of Ab in the serum does not

predict the severity of the disease in
individual patients

http://www.library.med.utah.edu/NOVEL
Repetitive Nerve Stimulation

“Decrement response”
Decrement > 15 % at 3Hz is highly probable
 Single Fiber Electromyography
 Most sensitive clinical test of neuromuscular transmission
& shows increased jitter in some muscles in almost all pts
with MG.
 It is confirmatory but not specific
 Pts with mild / purely ocular muscle weakness may have
increased jitter only in facial muscles.
 When jitter increases, EMG should be done.
• Most commonly used test, easy.
• RNS is relatively insensitive,10-50% in ocular
myastenia,75% in generalised MG
• RNS is relatively specific(90%)
• SFEMG is Most sensitive.(90% in ocular,95% in MG)
• Normal baseline CMAP
• Greater than 10% decremental response at rest and post
exercise
• No role for high frequency stimulation
 Precipitating factors
• Physical exertion • Drugs induced MG
• Hot temperature – Aminoglycoside
– Fluoroquinolones
• Emotional upsets – B-blockers
• Infections – Ca Channel blocker
• Hyperthyroidism – High dose steroid
• Surgery – D-penicillamine
• Menstruations – Chloroquine
– Quinine
• Pregnancy (1st trimester) – Quinidine
• Postpartum – Lithium
• Hypokalemia – Clopromazine
– Procainnamide
 Treatment
• Improve neuromuscular transmission
– Acethycholineaterase inhibitors : Mestinon
• Suppress immune response
– Corticosteroid
– Immunosuppressant: AZA, MTX, MM etc.
– IVIg
• Remove antibodies
– Plasmapheresis
• Thymectomy
 Acethycholinesterase inhibitors
• Pyridostigmine bromide (Mestinon ®)
– Start low, titrate up
– 30 mg qid to 60-90 mg qid
– Rapid onset : 15-30 minutes
– Duration : 4 hours
– Side effects : Muscarinic effects
• Abdominal pain
• Diarrhea
• Salivation, lacrimation
• Only partial remission
• Reduce/ discontinue when possible
• Cholinergic crisis
– Worsening weakness + side effects
How to use
• In hospital
– Maintain patient’s home schedule
– Order for specific times
– Keep at bedside, if necessary
• In crisis
– Discontinue in intubated patients
– Resume at lower dose, titrate up
 Cholinesterase Inhibitors
 Pyridostigmine Bromide
initial dose 30 – 60 mg TID / QID
 Dose to be tailored according to pts need
 Used as diagnostic test
 Early symptomatic treatment
 May be satisfactory chronic treatment in some.
 Neostigmine, Mestinon, Ambenonium chloride
are also used.
 Thymectomy
• Recommended for most pts with MG
• Maximal favourable response occurs 2 - 5yrs after
surgery
• Best response is seen in young people operated early in
the course of disease
• But improvement can occur even after 30 yrs of
symptoms.
• Improvement is also seen in seronegative MG pts.
 Thymectomy
• Indicated in all pts with generalized MG who are b/w ages
of puberty & 55 yrs.
• Thymectomy in children, > 55yrs, ocular MG – Still
a?
• Pts with MuSK antibody + MG may not respond to
thymectomy.
 Thymectomy
• Definite indications:
1. Generalized: puberty – 60 years
2. Thymoma (15%)

• OMG w/o thymoma: not rec

• Response: months-years
 Corticosteroids
 Produce rapid improvement in many
 Produce total remission / marked improvement in > 75 %
of patients
 Used as initial definite therapy
 Used as secondary treatment in who do not respond to
thymectomy / immunosuppressive therapy
 Initial dose prednisone 15 – 25 mg/day increased until
maximal improvement is seen or upto 50 – 60 mg/day
 PREDNISON cont..
• Patients with thymoma have an excellent response to
prednisone before or after thymectomy
 Prednisone

• OMG: good response

• Maintain high dose ~ 3 months or stable
• Lowest effective dose
– once determined alternate day
therapy
– majority need indefinitely
• Caution: steroid-induced exacerbation
 Immunosuppressants
 Produces marked & sustained improvement in many
 Azathioprine – initially 50 mg OD, which is increased in 50
mg/day increments every 7 days to total of 150-200
mg/day
 Cyclosporine – initially 5-6 mg/kg/day
 Cyclophosphamide – IV 200 mg/day-5days
150-200mg/day oral
Cyclosporine and Azathioprine
• Occasionally used in OMG

• Indications:
– resistant to steroids
– need to reduce steroid dose
• >50 mg qod
• significant SE
 Plasma exchange
• Produces rapid improvement
• Mainly used as adjunctive treatment
• As treatment in those who have not responded to other
forms of treatment
IV Ig
 MG Crisis
• Occur 15-20% of MG patients
• Plamapheresis is the treatment of choice except
– Hemodynamic instability
– Sepsis
– Coagulopathy
– Unavailable
– First trimester of pregnancy
• Then  IVIg
 An exacerbation of weakness sufficient to endanger
life , usually consists of respiratory failure caused by
diaphragmatic & intercostal muscle weakness.
 Usually have precipitating event such as infection
(most common), surgery, rapid tapering of
immunosuppression
 Cholinergic crisis
 Respiratory failure from overdose of cholinesterase
inhibitors
 It was more common before the introduction of
immunosuppressive therapy
 Possibility that deterioration could be due to cholinergic
crisis is best excluded by temporarily stopping the
anticholinesterase drugs.
 Management
• Admit in intensive care unit
• Discontinue all cholinesterase inhibitors
• Ventilate the patient
• Cholinesterase inhibitors should be resumed at low doses
& slowly increased as needed
• Treat the intercurrent infection
 Prognosis
• Ocular MG 10%  90% turn to Generalized (usually in 2
years)
• Untreated weakness  fixed and atrophic
• Spontaneous remission rate 20%
• 20-30% will die within 10 years without treatment
 MG crisis vs Cholinergic crisis
• Myasthenic crisis • Cholinergic crisis
– Respiratory distress – Abdominal cramps
– Increased pulse and – Diarrhea
blood pressure – Nausea and vomiting
– Poor cough – Excessive secretions
– Secretion aspiration – Miosis
– Dysphagia – Fasciculations
– Weakness – Weakness
– Improve with – Worse with edrophonium
edrophonium
DRUGS
 Cholinesterase Inhibitors
They inhibit the
Acetylcholinesterase
enzyme from breaking
down Ach, thereby
increasing the level and
duration of action of
neurotransmitter
Acetylcholine.
 Mestinon (Pyridostigmine Bromide)

• Pyridostigmine bromide is 3-
hydroxy-1-methylpyridinium
bromide dimethylcarbamate
• Preventing the breakdown
of a certain natural
substance (acetylcholine)
 Side Effects
serious side effects:
• extreme muscle weakness, muscle twicthing;
• slurred speech, vision problems;
• severe vomiting or diarrhea;
• cough with mucus;
• confusion, anxiety, panic attacks;
• seizure (convulsions); or
• worsening or no improvement in your symptoms of
myasthenia gravis.
Less serious side effects may include:
• cold sweat, pale skin;
• urinating more than usual;
• watery eyes;
• mild nausea, vomiting, or upset stomach;
• warmth or tingly feeling; or
• mild rash or itching.
 Usage in Pregnancy
• The safety of Mestinon (pyridostigmine) during pregnancy
or lactation in humans has not been established.

• Therefore, use of Mestinon (pyridostigmine) in women

who may become pregnant requires weighing the drug's
potential benefits against its possible hazards to mother
and child.
• verdosage of Mestinon (pyridostigmine) may result in
cholinergic crisis

• according to Osserman and Genkins, calls for the prompt

withdrawal of all drugs of this type.

• The immediate use of atropine in cholinergic crisis is also

recommended.
 Contraindications
• mechanical intestinal or urinary obstruction,
• patients with bronchial asthma.

Care should be observed in the use

of atropine for counteracting side
effects
 Pharmacology
• Mestinon (pyridostigmine) inhibits the destruction of
acetylcholine by cholinesterase and thereby permits freer
transmission of nerve impulses across the neuromuscular
junction.
• Pyridostigmine is an analog of neostigmine (Prostigmin®),
but differs from it in certain clinically significant respects;
• pyridostigmine is characterized by a longer duration of
action and fewer gastrointestinal side effects.
Lain-lain
Botulism vs LEMS vs MG
MG vs LEMS