Download reducing ACh release

Disorders of the Peripheral
Nervous System.
Divisions of the
Nervous System
Spinal Cord
Sensory axons ONLY
(afferents)
Autonomic
Mixed sensory & motor
axons
(afferents & efferents)
Somatic
Motor axons ONLY
(efferents)
Origins of PNS Disorders
Presynaptic
Lesions of the:
Soma
Axon
Schwann Cells
Neuromuscular Junction (NMJ)
Postsynaptic
Neuromuscular junction (NMJ)
Sign of PNS Lesions
Negative signs (Loss of normal function): due to degeneration or
demyelination of axon.
Muscle weakness (paresis)
Reduced conduction
Loss of reflexes
Impaired sensations – Cutaneous and/or joint and/or muscle
Autonomic Deficits – e.g. lack of sweat
Positive signs (‘More’ than normal):
Parestheasia – ephaptic transmission between adjacent damaged sensory
axons that become hyperexcitable.
Brief periods of pain (eg trigeminal neuralgia) – due to acute compression of
nerves causing them to briefly become hyperexcitable, thought to be due to
activation of stretch-activated channels.
CV Measurements – Clinical Correlates
Mean conduction velocities (CV) for sensory and motor axons are 55 - 60 m/s.
Lesion Site
Motoneurone soma, but axon
still intact
Motoneurone soma with axon
degeneration
Peripheral nerve:
Compression
Demyelination
Axonal degeneration
CV Observation
Little or no reduction in motor
Reduction or no conduction in motor
No change in sensory
Slowing of motor and sensory at site
Marked slowing of motor and sensory
Reduction or no conduction of motor and
sensory
NMJ
No change in motor or sensory
Muscle
No change in motor or sensory
Trauma to Nerve
Damaged Last
•Epineurium
•Perineurium
•Endoneurium
•Axon
Damaged First
Endoneurium (around
each axon)
Axotomy and Degeneration
Axotomy and Degeneration
Axotomy –
Regeneration by
regrowth and
remyelination
Nerve growth factor (released from
Schwann Cells), laminins and adhesion
molecules promote regrowth.
Last stage is the remyelination of the
‘new’ axon.
Axon Reinnervation of Muscle
Basal lamina intact – axon reinnervates muscle at same point.
Basal lamina lost – No reinnervation
Critical components of basal lamina are laminins and agrin.
e.g. Laminin 11 – expressed at synaptic junction. Prevents Schwann
Cell invasion.
Basal Lamina
Lesions of the Soma
Causes:
Toxins
Drugs
Trauma
Unknown
Symptoms:
Paralysis or paresis (weakness) of muscle.
Rapid onset muscle atrophy. Can lead to loss of muscle fibres being replaced
by fibrous connective tissue.
Fasciculation & fibrillations.
Hyporeflexia/Areflexia (partial or complete loss of reflexes).
Lesions of the Soma (and/or Axon)
Fasciculation & fibrillation.
Sign that muscle fibres are undergoing denervation.
Fasciculation
Spontaneous irregular contraction of muscle fibres associated to a skeletal
motor unit. Visible twitches can be seen on surface of body.
Fibrillation
EMG activity associated with spontaneous contraction of single skeletal
muscle fibres.
Cause:
Denervation of skeletal muscle fibre leads to de-aggregation of nicotinic ACh
receptors, so that they lie randomly on the surface. They become
supersensitive to small amounts of ACh, which leads to muscle fibre activation.
Poliomyelitis
Viral infection with the poliovirus.
Destroyed motoneurones do not regenerate and the affected motor units will not
be able to contract. (Some sprouting of surviving neurones may reinnervate the
denervated muscle restoring some function).
Affected limbs become floppy and poorly controlled – acute flaccid paralysis (AFP).
Extensive paralysis of the muscles of the trunk, abdomen and thorax may occur.
If Cervical regions 3, 4 & 5 of the spinal cord are affected then diaphragm paralysis
can occur and patient requires ventilation. Key nerves are phrenic and those
related to swallowing.
A Tank Respirator (Iron Lung) is best known piece of equipment associated with
this disease. It is still in use by a few patients, though more common to use
positive pressure applied through a tracheostomy.
Treatable with Polio immunization (vaccine).
Diabetic Neuropathy
Most insulin-dependent diabetics show signs of
polyneuropathy.
Two types may coexist: sensory (usually
symmetric), motor (usually asymmetric) and
autonomic neuropathy.
Sensory symptoms usually begin in both legs
and the losses are caused by abnormalities of
unmyelinated axons carrying pain and
temperature in a ‘stocking distribution’.
The sensory endings and axons of small
unmyelinated dorsal root ganglion cells are
vulnerable to hyperglycemia. The problem may
originate in failure of the cell body to supply its
distant parts with nutrients and essential proteins
for its cytoskeleton.
Lesions of the Nerve (axon)
Axon
Carpel Tunnel Syndrome
Transection
Causes:
Compression, Stretching
Crush
Axotomy
Symptoms vary according to severity and cause of problem but may included:
Paralysis or paresis (weakness) of muscle.
Rapid onset muscle atrophy. Can lead to loss of muscle fibres being replaced by
fibrous connective tissue.
Fasciculation & fibrillations.
Hyporeflexia/Areflexia (partial or complete loss of reflexes).
Trauma to Nerve
Damaged Last
•Epineurium
•Perineurium
•Endoneurium
•Axon
Damaged First
Endoneurium (around
each axon)
Compression – Carpal Tunnel Syndrome
Occurs due to reduction in tunnel size,
such as swelling of tendon sheaths or
swelling of soft tissue due to odema.
Occurs spontaneously often in middleaged women, pregnancy and
hypothyroidism.
Pain and/or tingling sensation in
cutaneous distribution to the thumb,
index and middle fingers.
Difficulty in handling small objects, due
to muscle weakness of thenar
eminence.
http://www.carpaltunnelattorney.com/ima
ges/hand1.jpg
Lesions of Schwann Cells
Causes:
Toxins
Autoimmune disease
Symptoms:
Conduction slowing or block due to demyelination
Guillain-Barré Syndrome
Incidence – 2:100,000
XY > XX
First symptoms of motor and sensory loss
occur 2-3 weeks after a viral respiratory or
gastrointestinal illness. Thought to be
autoimmune.
Losses are due to demyelination of axons.
http://www.monografias
.com/trabajos37/sindro
me-guillainbarre/Image8645.jpg
Treatment – immunoglobulin
Patients may make a good recovery
following remyelination of axons.
NB Not to be confused with Multiple Sclerosis, which is demyelination within CNS
Nerve ending & NMJ (ACh related derangements)
Neuromuscular junction (NMJ) – basic structure
Neuroscience – Exploring the Brain, 3rd Ed., Bear, Connors & Paradiso. Copyright © 2007, Lippincott, Williams & Wilkins.
Activation of NMJ and Muscle
Ca2+
Depolarizing
muscle cell
membrane
Depolarization
Ca2+
Na+
 Ca2+
Na+
Na+
Nerve terminal
Muscle fibre
Nerve ending & NMJ (ACh related derangements)
Botulism Nerve toxin, botulin, from Clostridium botulinum.
Beta-bungarotoxin Venom toxin from snake.

Both act by reducing ACh release from NMJ by acting on
presynaptic proteins involved in exocytosis.
Alpha-latrotoxin Venom of the black widow spider.

Causes massive release of ACh from NMJ by acting on presynaptic
proteins involved in exocytosis. Results in tetanus – a continuous
painful contraction.
Curare (d-tubocurarine) Found in the extract of Chondrodendron
tomentosum, a plant found in South American jungles.

Non-depolarising muscle relaxant, that ‘competitively’ blocks ACh
receptors on the post-synaptic membrane of the NMJ.
BOTOX treatment – benefits & pit falls
Can be used to treat conditions such as
Strabismus (cross-eyed), Hyperhidrosis
(excessive sweating), Muscle spasms,
Dystonia, Spasticity.
Also, cosmetic use for wrinkles.
All require successive treatment to maintain
‘benefits’.
Repetitive over use leads to sprouting of
NMJ axon and poor function of muscle.
Rogozhin, A.A., Pang, K.K, Bukharaeva, E., Young C. & Slater, C.R.
(2008). J. Physiol. 586: 3163-3182.
Lambert-Eaton Syndrome
Autoimmune disease – antibodies
against voltage-gated Ca2+ channels
Often found in patients with bronchial
(oat cell) carcinoma
Reduced ACh release
EPP due to single nerve stimulation is
reduced, often not reaching threshold
for muscle contraction.
(NB mEPP amplitude unchanged)
Muscle weakness
Weakness can be improved with
activity (facilitation).
Reduced reflexes
Synaptic Cleft/Postsynaptic Membrane Impairments
Congenital Myasthenias
There are several forms of Congenital Myasthenia
(muscle weakness). All are usually present at birth
and show signs and symptoms before the age of two
years.
Congenital Myasthenias
ACh-esterase deficiency
Accumulation of ACh in synaptic cleft
EPP amplitude is larger and prolonged
as compared to normal.
Single muscle nerve stimulation
delivered at long intervals produces a
single muscle twitch
Repetitive muscle nerve causes EPP
temporal summation, leading to a
depolarisation block of the muscle, and
reduced muscle twitch.
Neuroscience – Exploring the Brain, 3rd Ed., Bear,
Connors & Paradiso. Copyright © 2007, Lippincott,
Williams & Wilkins.
Congenital Myasthenias
Slow Channel Syndrome
ACh binding to nicotinic ACh receptors
(nAChR) causes prolonged opening of
channels.
Hence prolonged depolarisation and
EPP
Leads to depolarisation block of the
muscle and reduced muscle twitch.
Other forms
Abnormal binding of ACh to nAChR
Brief opening of ACh channels (Fast
Channel Syndrome).
Neuroscience – Exploring the Brain, 3rd Ed., Bear,
Connors & Paradiso. Copyright © 2007, Lippincott,
Williams & Wilkins.
Myasthenia Gravis
Chronic disease due to immune process. Can
be an acquired disorder, eg abnormal myoid
cells in thymus, or genetic abnormality.
Greater prevalence in females than males.
Antibodies form to nAChR
Symptoms:
Weakness of voluntary muscles, especially if
muscle is worked a lot, e.g. eye muscles.
Chronic fatigue
Not associated to denervation
Serum from patients can cause disease in
animals
Neuroscience – Exploring the Brain, 3rd Ed., Bear,
Connors & Paradiso. Copyright © 2007, Lippincott,
Williams & Wilkins.
Myasthenia Gravis
Antibody interaction with nAChR
Myasthenia Gravis - Endplate structural changes
Normal
Myasthenia Gravis
Myasthenia Gravis - Therapy
ACh-esterase inhibitors eg Neostigmine. This prolongs
presence of ACh in synaptic cleft and hence improves
ability to use muscles.
Immune suppressors eg Azathioprine. Blocks antibodies.
Plasma exchange can give temporary relief
Thymectomy