Healthy and unhealthy nmj

Healthy and Unhealthy NMJ
PRESENTER-DR.PALLAV JAIN
DM RESIDENT(NEUROLOGY)
GMC,KOTA

Introduction
• Neuromuscular Junction is a chemical Synapse
• Anatomically & functionally differentiated for the transmission of a signal from
the motor nerve terminal to muscle fibre.
• Alterations in the structure and function of NMJ causes disorders.

Presynaptic structure and function
• The nerve terminal contains
synaptic vesicles which contains-
ACh
• Vesicles are held in an actin
framework close to the active
zones
• Action potential-opening of the
VGCC channels
• Arranged in regular parallel arrays
at the active zones
 N. P. Hirsch. Neuromuscular junction in health and diseas.Br J Anaesth 2007

Trans synaptic alignment
• Active zones are regularly organized presynaptic microdomains
• Embedded in the nerve terminal membrane
• Implicated in the docking and exocytosis of synaptic vesicles
The openings of synaptic folds at the postsynaptic membrane are aligned directly
opposite to active zones.

• Increase in free Calcium ions
• Mobilization of the vesicles from their
actin matrix
• Docking at the active zones
• Release of their quanta of ACh into the
synaptic cleft.

QUANTA
• Primary, or immediately available, store consists of approximately 1,000 quanta
located just beneath the presynaptic nerve terminal membrane.
• Secondary, or mobilization, store consists of approximately 10,000 quanta that can
resupply the primary store after a few seconds
• Tertiary, or reserve, store of more than 100,000 quanta exists far from the NMJ in
the axon and cell body

Synaptic cleft structure and function
• The synaptic cleft is the space between the nerve terminal and the postsynaptic
membrane
• Measures 50 nm.
• ACh diffuses within a few microseconds across the synaptic cleft to the postsynaptic
membrane

• 50% of the released Ach is hydrolysed by acetylcholinesterase (AChE)-before it
reaches its target.
• High concentration of AChE-preventing it from activating the postsynaptic
nicotinic acetylcholine receptors (nAChRs) more than once.
• Number of complex proteins that maintain the integrity, the formation, and the
clustering of the postsynaptic ACh receptors

Postsynaptic membrane structure and function
• The postsynaptic membrane is folded into secondary synaptic folds
• Top of which are clustered the nAChRs(20,000 receptors mm.)

Junctional fold
• Increase the surface area of the postsynaptic
membrane
• Amplify signals that derive from neurotransmission
Two domains-
• Edges of crests that contain AChRs together with
the molecular machinery that mediates their
clustering or signaling
• Depths of folds that contain high concentrations
of VGSC
 Daniel J Ham and Markus A Rueeg.Current Opinion in Physiology 2018

nAChR
• Transmembrane protein consisting of five
subunits arranged in a pentameric unit.
• Synaptic surface they provide the binding
sites for ACh.
• Central pore remains impermeable to the
flow of cations.
• The pore opens in response to two
molecules of Ach.

Achr microdomains
Achr clustering is promoted by Agrin
Agrin binds LRP4 at the postsynaptic
membrane
Increases affinity of the complex for muscle
specific kinase (musk)
Adaptor protein DOK7 is recruited to musk
Activation of the kinase and recruitment of
the scaffold protein rapsyn

Rapsyn interacts directly with Achrs,
clustering them at the cell surface.
The growing receptor assembly is
stabilized by the dystroglycan
complex (DGC).
The DGC is a multiprotein complex
that binds rapsyn and AChRs

Peri-junctional zone
• Area of muscle immediately beyond the junctional area
• Critical to the function of the neuromuscular junction.
• Smaller density of nAchrs and high density sodium channels.
• Enhances the capacity of the peri-junctional zone to respond to the depolarization.
 Daniel J Ham and Markus A Rueeg. Current Opinion in Physiology 2018

Nerve AP invades
Depolarizes the presynaptic junction, voltage-gated calcium channels are activated LEMS
Influx of calcium
release of ACH from the presynaptic terminal
Released ACH bind to AchR on post synaptic membrane
MG
This binding opens sodium channels – local depolarization
Produces end plate
potential(EPP)
MFAP

Properties contribute to NMJ transmission
efficiency
• Nerve terminal size
• ACh vesicle release (size, number and stores)
• AChR number and density
• Postsynaptic fold structure

Safety factor
• Ability of neuromuscular transmission to remain effective under various
physiological conditions and stresses.
• Amount of transmitter released per nerve impulse being greater than that
required to trigger an action potential in the muscle fibre
• Safety factor is crucial-quantal content, and thus EPP, runs down during
prolonged higher frequency stimulations

Schwan cells
• Indispensable for normal innervation of muscle
• Promotion of synaptogenesis
• Mediation of synapse elimination after the establishment of NMJ
• Reinnervation of NMJ after nerve injury
• Coordinating postsynaptic development

Effect of exercise on NMJ
• Exercise-boosting mitochondrial
function, increasing ATP levels and
decreasing ROS.
• More efficient recycling of nAChRs on
the postsynaptic membrane
Daniel J Ham and Markus A Rueeg. Current Opinion in Physiology 2018

• Exercise elevates the number
of active zones on the
presynapse
• Increases levels of beneficial
growth factors-BDNF and IGF-1.
 Daniel J Ham and Markus A Rueeg. Current Opinion in Physiology 2018

Unhealthy NMJ
Alterations in the structure and function of NMJ.
Physiological
• Age
• Injury
Pathological
Acquired
• Mysthenia gravis
• LEMS
• Drugs
• Toxins
(Botulism, Arthropod,
Snake-venom,OPC)
Congenital
• Congenital mysthenic
syndromes
• Transient Neonatal
myasthenia gravis

Ageing on NMJ
• Junctional folds of the postsynapse
become shallow
• nAchrs are less concentrated along the
peaks of the folds
• nAchrs are found in extra-synaptic areas
of the muscle fiber membrane
• Mitochondria are damaged and fewer in
the Postsynaptic region of the muscle
fiber
 Lei Li .Annual Review of Physiology 2017.Neuromuscular Junction Formation, Aging, and Disorders

• Active zones are lost in the motor axon
terminal.
• Aggregation of vesicles containing
acetylcholine near the terminal membrane is
lost
• Vesicles are present away from the terminal
along the axon.
• Ensheathment of the NMJ by perisynaptic
Schwann cells is lost
 Lei Li .Annual Review of Physiology 2017.Neuromuscular Junction Formation, Aging, and Disorders

Changes in injury
• Loss of synaptic vessels
• Disruption of pre-synaptic membrane
• Degeneration of mitochondria
• Increase in extra junctional receptors
Recovery of structures may be regulated by schwann cells
T.tomboy.Ultrastructures changes in NMJ in reperfusion injury.Cell tissue organ 2002.

Mysthenia Gravis
• Decrease in the number of available AChRs at NMJ due to an antibody mediated
autoimmune attack
• Morphological damage to the endplates and postsynaptic folds
• Important as the VGSC responsible for initiating the action potential are located
at the bottom of the folds
 Disorders of neuromuscular transmission. Bradley’s Neurology in clinical practice 7th edition

0verview of symptoms of Myasthenia Gravis
Symptoms of MG
(fatigable weakness is
diagnostic)
Change in voice
& difficulty to
lift the objects
Deep tendon reflexes and
pupils are normal
Weakness of eye
muscles:
Ptosis
Double vision
Dropping of head &
facial weakness
Breathing
difficulty
Difficulty to
chew and
swallow

Diagnosis
Anti acetylcholine receptors
• Detectable in 70-80% of patients
• 50% of patients with weaknes confined to ocular muscles
• MuSK - 50% AChR negative MG.
• Female predominant
• Associated with neck exterior weakness and respiratory crisis
• Thymus: normal.
• Poor prognosis

LRP4 antibody MG
• Anti-low density lipoprotein receptor related protein-4 antibodies seen in 50%
cases of AChR & MuSK antibody negative MG.
• Adult onset
• Weakness: generalized and moderate to severe
• Thymoma: none

Diagnostic clues
• Pharmacological test- Edrophonium test
• CT Neck- To r/o thymoma
• Ice pack test
• RNS
• Single fibre EMG

Guidelines for management of MG
Symptomatic and Immunosupressive treatment
• Pyridostigmine should be part of the initial treatment in most patients with MG.
• Pyridostigmine dose should be adjusted as needed based on symptoms.
• Corticosteroids or Immunosupressive therapy should be used in all patients with
MG who have not met treatment goals after an adequate trial of pyridostigmine
 International consensus guidance for management of myasthenia gravis. 2016 American Academy of
Neurology

Immunosupressive agent should be used alone when corticosteroids are
contraindicated or refused
• Immunosupressive agent should be added to corticosteroids when:
a. Steroid side effects, deemed significant by the patient or the treating
physician, develop
b. Response to an adequate trial of corticosteroids is inadequate
c. The corticosteroid dose cannot be reduced due to symptom relapse
Neurology

• Azathioprine as a first-line agent in MG.
• Cyclosporine-potential serious adverse effects and drug interactions limit its use.
• Mycophenolate and tacrolimus does not support the use.
Neurology

Refractory MG
• Chronic IVIg and chronic PLEX
• Cyclophosphamide
• Rituximab, for which evidence of efficacy is building
Neurology

Duration of treatment
• Once patients achieve treatment goals, the corticosteroid dose should be
gradually tapered.
• In many patients, continuing a low dose of corticosteroids on long-term can help
to maintain the treatment goal.
Immunosupressive once treatment goals have been achieved and maintained for 6
months to 2 years
• Dose should be tapered slowly to the minimal effective amount.
• Dosage adjustments should be made no more frequently than every 3–6 months
Neurology

IVIg and PLEX
PLEX and IVIg- used as short term treatments
• MG with life threatening signs
• Preparation for surgery in patients with significant bulbar dysfunction;
• When a rapid response to treatment is needed
• When other treatments are insufficiently effective
Neurology

• The choice between PLEX and IVIg depends on individual patient factors
• IVIg and PLEX are probably equally effective in the treatment of severe
generalized MG.
• PLEX may be more effective than IVIg in MuSK-MG
Neurology

Thymectomy
• In non-thymomatous MG, thymectomy is performed as an option.
• Thymectomy should be considered in children with generalized AChR antibody–
positive MG:
a. If the response to pyridostigmine and immunosupressive therapy is unsatisfactory
b. Avoid potential complications of latter.
• Patients with MG with thymoma should undergo surgery to remove the tumor
 International consensus guidance for management of myasthenia gravis. 2016 American Academy of Neurology

• In elderly or multimorbid patients with thymoma, palliative radiation therapy
can be considered in the appropriate clinical setting.
• Generalized MG without detectable AChR antibodies- Thymectomy may be
considered in patients
• Current evidence does not support an indication for thymectomy in patients
with MuSK, LRP4, or agrin antibodies
 International consensus guidance for management of myasthenia gravis. 2016 American Academy of Neurology

Juvenile MG
• Children with acquired autoimmune ocular MG are more likely than adults to go
into spontaneous remission.
• Young children with only ocular symptoms of MG can be treated initially with
pyridostigmine.
• Immunotherapy can be initiated if goals of therapy are not met.
• Long-term treatment with corticosteroids should use the lowest effective dose to
minimize side effects.
• Maintenance PLEX or IVIg-alternatives to immunosupressive drugs in JMG
Neurology

MuSK antibodies
• Respond poorly to ChEIs
• Respond well to corticosteroids and to many steroid-sparing agents
• Responds well to PLEX, while IVIg seems to be less effective.
• Rituximab should be considered as an early therapeutic option
Neurology

Pregnancy
• Oral pyridostigmine-1st line
• IV ChEIs-should not be used.
• Thymectomy should be postponed.
• Prednisone is the agent of choice during pregnancy.
• Azathioprine and cyclosporine are relatively safe.
• PLEX or IVIg are useful when a prompt, although temporary, response is required
during pregnancy
Neurology

LAMBERT EATON MYASTHENIC
SYNDROME(LEMS)
• Immune-mediated attack against the P/Q type VGCC on presynaptic cholinergic
nerve terminals at NMJ and in autonomic ganglia
• Reduced release of Ach from the presynaptic terminal
• Reduced EPP on the postsynaptic membrane causing NMJ transmision failure
 (Sanders DB. Lambert- Eaton Myasthenic syndrome : Diagnosis and treatment. Ann N Y Acad Sci
2003;998:500-8)

Clinical features
• Affects adults> 40 yrs
• Male=Female
• Proximal muscle weakness(especially lower extremities) with less common and
mild bulbar symptoms.
• DTR-reduced or absent
• Autonomic symptoms(esp dry mouth),transient sensory paresthesias.
2003;998:500-8)

• Distinctive clinical finding- Muscle facilitation.
• After a brief period(10 seconds) of intense exercise of a muscle, the power and
the DTR to that muscle are transiently increased
2003;998:500-8)

• Underlying malignancy-Small cell lung carcinoma(SCLC) expresses VGCCs.
• May be discovered years before or years after the onset of symptoms.
• Immunoprecipitation assay demonstrates VGCC antibodies.
• Presence of SOX1 antibodies-marker for an underlying cancer in LES patients
2003;998:500-8)

Electrodiagnostic
• CMAPs with low amplitude, which increases during 20 to 50 Hz stimulation and
after brief maximum voluntary muscle activation.
• Low frequency RNS produces a decrementing response.
2003;998:500-8)

Treatment
• Once the diagnosis of LES is established, an extensive search for underlying malignancy,
especially SCLC, is mandatory.
• 3,4-diaminopyridine —potassium channel blockade(80 mg/day,20 mg four times daily)
• Pyridostigmine-only marginally effective
• Guanidine hydrochloride-toxicity limited its use- Not recommended
 (Sanders DB. Lambert- Eaton Myasthenic syndrome : Diagnosis and treatment. Ann N Y Acad Sci 2003;998:500-8)

Refractory weakness
• IVIg improve muscle strength scores and CMAP amplitudes in patients with LES.
• Corticosteroids and immunosuppressive agents
• Rituximab may be of benefit in some patients

Transient Neonatal Myasthenia Gravis (TNMG)
• 10% to 20% of newborns
• Affected newborns are typically hypotonic and feed poorly during the first 3 days.
• Symptoms usually last less than 2 weeks but may persist for as long as 12 weeks
• Correlates with the half-life of neonatal antibodies

Diagnosis
• Detection of AChR-abs- strong evidence
• Improvement following injection of 0.1 mg/Kg edrophonium .
• A decremental response to RNS.
 Disorders of neuromuscular transmission.Bradley’s Neurology in clinical practice 7th edition

Treatment
• Affected newborns require symptomatic treatment with ChEIs if
swallowing or breathing is impaired.
• Exchange transfusion if respiratory weakness is severe.
• Examine all infants born of myasthenic mothers carefully at birth.
• Consider prophylactic treatment with PLEX and/or steroids in a woman
with a previously affected child, as the risk of recurrent TNMG is high

CONGENITAL MYASTHENIC SYNDROMES (CMS)
• Group of NMJ diseases caused by genetic defects of muscle endplate molecules.
• Symptoms are present at birth in most forms, but may go unrecognized until
adolescence or adulthood.
• 2 : 1 male predominance.
• Not immune mediated and thus are not associated with autoantibodies in blood
 Andrew G. Engel. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol.
2015 April

Clinical Features
• Ophthalmoparesis and ptosis.
• Mild facial paresis.
• Generalized fatigue and weakness but limb weakness is usually mild.
• High-arched palate, facial dysmorphism, arthrogryposis, and scoliosis.
• Episodic respiratory crises may- choline acetyl transferase (ChAT) deficiency
2015 April

AChR Deficiency
• AChR subunit or rapsyn mutations.
• Respond variably to symptomatic therapy with pyridostigmine or 3,4-DAP.
Choline Acetyl Transferase (ChAT) Deficiency
• Mutations in the CHAT gene, which codes for endplate choline acetyltransferase
(ChAT)
• ChEIs improve strength
Congenital Acetylcholinesterase (AChE) Deficiency
• Endplate AChE deficiency results from a recessive mutation of COLQ.
• ChEIs typically make symptoms worse
2015 April

Slow-Channel Congenital Myasthenia Syndrome
• Autosomal dominant
• Defect is a prolonged open time of the ACh channel.
• Quinidine sulfate and fluoxetine- may improve strength.
• ChEIs worsen the weakness.
Fast Channel Syndrome
• ε subunit mutations-abnormally brief opening of the AChR ion channel.
• Patients respond to ChEIs and 3,4-DAP but the improvement from ChEIs may wane over
time.
Rapsyn Mutations
• Rapsyn is a post-synaptic protein involved in clustering AChR at the muscle endplate.
• The response to ChEIs and 3,4-DAP is good
 Andrew G. Engel. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015 April

DOK-7 Mutations
• DOK-7 is a muscle protein that activates MuSK and is critical in
endplate development and AChR aggregation.
• Ephedrine or albuterol is the first choice of treatment
• ChEIs should be avoided.
GFPT1 and DPAGT1 Mutations
• Affect enzymes in glycosylation pathways.
• ChEIs and 3,4-DAP benefit most patients
• Thymectomy and immunosuppression are not effective in any CMS
 Andrew G. Engel. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015 April

Electrophysiology
• RNS show decremental response in patients
• Decrement may be absent in
• Mild symptomatic disease
• Mutations in ChAT
• Rapsyn mutation
• An increment greater than 100% is s/o presynaptic defect
• Repetitive CMAP on single impulse is pathognomonic of
• Slow channel syndrome
• Acetylcholinesterase deficiency
2015 April

Approach to a case of CMS
Diagnostic strategy-
1. Association of a clinical & electrophysiological picture of a myasthenic
syndrome
2. Recognition of pathophysiological type based on
• Clinical data
• Hereditary transmission type
• Response to cholinesterse inhibitors
• Results of electrophysiology
• Molecular genetics
2015 April

BOTULISM
• Caused by exotoxin of Clostridium botulinum(mainly types A,E and F)
• Modes of transmission-
a)Improperly prepared food(canned vegetables or fish)
b)Wound infection
c) Infantile botulinum-GI tract becomes colonised with clostridia bacteria
 De Jesus et al.Neuromuscular physiology of Botulism.Arch Neurol 2003;29:425-31

Pathophysiology
Block ACh release from the presynaptic motor nerve terminal and the
parasympathetic and sympathetic nerve ganglia.
• The intracellular target is the SNARE proteins of the presynaptic membrane.
• block exocytosis of the vesicles

Clinical features
• Onset of symptoms-2 to 72 hrs.
• Nausea, vomiting, abdominal pain f/b blurred vision, diplopia and dysarthria.
• Rapid descending pattern of progression resulting in flaccid, areflexic,
quadriparesis with opthlamoplegia.
• Pupillary involvement.

Electrodiagnostic
• Low CMAP amplitude in at least two muscles – most consistent defect.
• Rapid RNS or CMAP following 10 sec of isometric exercise, results in a
modest increment of 30-100%.
• Slow RNS – normal or mild decrement(<10%)
• Needle EMG- increase in number of small,short & polyphasic MUAPs &
occasional fibrillation potentials

Treatment
• Administration of bivalent (type A and B) or trivalent (A, B, and E) antitoxin.
• Antibiotic therapy is not effective.
• In infantile botulism, IV human botulism immune globulin (BIG-IV) neutralizes the
toxin for several days after illness onset.
• ChEIs are usually not beneficial.
• Treatment is supportive
 De Jesus et al. Neuromuscular physiology of Botulism. Arch Neurol 2003;29:425-31

Other Toxins
Snake toxins act either presynaptically or post-synaptically.
• Pre-synaptic β-neurotoxins (β-bungarotoxin, notexin and taipoxin) impair ACh
release.
• Ptosis and opthalmoparesis, Weakness of neck flexion, proximal muscles
• Bulbar and respiratory muscles are also involved
Organophosphates impair transmission by irreversibly inhibiting
acetylcholinesterase
 Bradley’s Neurology in clinical practice 7th edition

Drugs
Antibiotics- Aminoglycosides
Quinolones
Macrolides
• Non depolarizing agents(Pancuronium,vecuronium)
• Quinine derivatives-Quinine,quinidine,choroquine
• Magnesium
• Penicillamine
• Beta blockers
 Bradley’s Neurology in clinical practice 7th edition

Conclusions
• Healthy NMJ is a chemical Synapse-transmission of a signal from the motor nerve
terminal to postsynaptic region on the muscle fiber.
• Much has been known about the physiology of NMJ.
• Unhealthy NMJ -Alterations in the structure and function of NMJ.
• More research will lead to us causes for various congenital syndromes.

References
• Daniel J Ham and Markus A Rueeg.Current Opinion in Physiology 2018
• Andrew G. Engel. Congenital myasthenic syndromes: pathogenesis, diagnosis, and
treatment. Lancet Neurol. 2015 April
• Lei Li .Annual Review of Physiology 2017.Neuromuscular Junction Formation,
Aging, and Disorders
• International consensus guidance for management of myasthenia gravis. 2016
American Academy of Neurology

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