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Disorders of the Peripheral Nervous System.. Divisions of the Nervous System.

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Presentation on theme: "Disorders of the Peripheral Nervous System.. Divisions of the Nervous System."— Presentation transcript:

1 Disorders of the Peripheral Nervous System.

2 Divisions of the Nervous System

3 Spinal Cord Motor axons ONLY (efferents) Mixed sensory & motor axons (afferents & efferents) Sensory axons ONLY (afferents) Somatic Autonomic

4 Origins of PNS Disorders Presynaptic Lesions of the: Soma Axon Schwann Cells Neuromuscular Junction (NMJ) Postsynaptic Neuromuscular junction (NMJ)

5 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.

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8 CV Measurements – Clinical Correlates Mean conduction velocities (CV) for sensory and motor axons are m/s. Lesion SiteCV Observation Motoneurone soma, but axon still intact Motoneurone soma with axon degeneration Little or no reduction in motor Reduction or no conduction in motor No change in sensory Peripheral nerve: Compression Demyelination Axonal degeneration Slowing of motor and sensory at site Marked slowing of motor and sensory Reduction or no conduction of motor and sensory NMJNo change in motor or sensory MuscleNo change in motor or sensory

9 Trauma to Nerve Damaged Last Epineurium Perineurium Endoneurium Axon Damaged First Endoneurium (around each axon)

10 Axotomy and Degeneration

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12 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.

13 Axon Reinnervation of Muscle Basal Lamina 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.

14 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).

15 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. Lesions of the Soma (and/or Axon)

16 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).

17 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.

18 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).

19 Trauma to Nerve Damaged Last Epineurium Perineurium Endoneurium Axon Damaged First Endoneurium (around each axon)

20 ges/hand1.jpg 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 middle- aged 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.

21 Causes: Toxins Autoimmune disease Symptoms: Conduction slowing or block due to demyelination Lesions of Schwann Cells

22 me-guillain- barre/Image8645.jpg 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. 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

23 Nerve ending & NMJ (ACh related derangements)

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25 Neuromuscular junction (NMJ) – basic structure Neuroscience – Exploring the Brain, 3 rd Ed., Bear, Connors & Paradiso. Copyright © 2007, Lippincott, Williams & Wilkins.

26 Activation of NMJ and Muscle Depolarization Ca 2+  Ca 2+ Na + Depolarizing muscle cell membrane Nerve terminalMuscle fibre

27 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. Nerve ending & NMJ (ACh related derangements)

28 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:

29 Lambert-Eaton Syndrome Autoimmune disease – antibodies against voltage-gated Ca 2+ 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

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31 Synaptic Cleft/Postsynaptic Membrane Impairments

32 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.

33 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. Congenital Myasthenias Neuroscience – Exploring the Brain, 3 rd Ed., Bear, Connors & Paradiso. Copyright © 2007, Lippincott, Williams & Wilkins.

34 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). Congenital Myasthenias Neuroscience – Exploring the Brain, 3 rd Ed., Bear, Connors & Paradiso. Copyright © 2007, Lippincott, Williams & Wilkins.

35 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 Myasthenia Gravis Neuroscience – Exploring the Brain, 3 rd Ed., Bear, Connors & Paradiso. Copyright © 2007, Lippincott, Williams & Wilkins.

36 Myasthenia Gravis Antibody interaction with nAChR

37 Myasthenia Gravis - Endplate structural changes Normal Myasthenia Gravis

38 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


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