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Unit III Disorders of the Peripheral Nervous System part 1: Overview, radiculopathies, neuropathies C.E. Pringle MD, FRCPC Division of Neurology

Describe the normal histology of peripheral nerve. slides 8,9 slides 8,9 List axon types found in peripheral nerves, relating diameter to function. slide 13 slide 13 Compare and contrast electrical conduction in myelinated and unmyelinated axons. slide 10 slide 10 Describe the clinical approach to the characterization of neuropathy. slides 30, slides 30, Describe degenerative disk disease and radiculopathic syndromes. slides slides Define and give examples of entrapment and traumatic neuropathies slides slides Prepare an outline of the classification of polyneuropathies. slides slides Discuss the clinical syndrome, pathophysiology and management of Guillain‐Barré syndrome. slides slides Review the mechanism and different clinical syndromes of diabetic neuropathy. slides 41-44, 28 slides 41-44, 28 Objectives: Peripheral nerve Unit III – Disorders of the Peripheral Nervous System – Pringle

Unit III – Disorders of muscle and neuromuscular junction – Pringle skeletal muscle sensory receptors

What is the peripheral nervous system? Neurologists divide the nervous system into 2 broad categories: – the Central Nervous System (CNS) brain + spinal cord – the Peripheral Nervous System (PNS) everything else Unit III – Disorders of the Peripheral Nervous System – Pringle

Neuromuscular Disorders disorders affecting anterior horn cells, spinal nerve roots,plexus, peripheral nerve, neuromuscular junction, muscle. – motor neuron disease – radiculopathies – plexopathies – neuropathies – NMJ disorders – myopathies Unit III – Disorders of the Peripheral Nervous System – Pringle

Anatomy of Peripheral Nervous System spinal roots organize into plexuses (brachial, lumbosacral) plexuses become individual nerve trunks (eg ulnar, median)

Anatomy of Peripheral Nervous System individual nerve trunks are made up of many nerve fascicles which in turn are composed of axons some axons are wrapped in myelin (“insulation”) perineurium epineurium

Myelinated & Unmyelinated Nerve Fibres Nodes of Ranvier Unit III – Disorders of the Peripheral Nervous System – Pringle “Teased Fibre” nerve biopsy

axon Saltatory Conduction myelin (internode) myelin Nodes of Ranvier (rich in sodium channels, poor in potassium channels) The purpose of myelin is to speed up conduction (myelinated fibres conduct faster than unmyelinated fibres because they employ saltatory conduction as opposed to continuous spread of current along unmyelinated fibres)

PNS – Schwann cells CNS - Oligodendrocytes Unit III – Disorders of the Peripheral Nervous System – Pringle 1:1 50:1

Unit III – Disorders of the Peripheral Nervous System – Pringle Central vs Peripheral Myelin

Physiology of Peripheral Nerve Function Nerve fibre diameter and myelination correlate with function Unit III – Disorders of the Peripheral Nervous System – Pringle afferent (ie sensory) efferent (ie motor)

Nerve Pathophysiology functional block demyelination – conduction slowing – conduction block Wallerian (axonal) degeneration Unit III – Disorders of the Peripheral Nervous System – Pringle

Symptoms of Neuromuscular Disorders motor symptoms (ie weakness) – pattern important proximal vs distal single nerve or root pattern vs symmetric – temporal aspects acute, subacute, chronic fixed/progressive vs fluctuating sensory symptoms (ie numbness, tingling, etc) – presence takes muscle and NMJ “off the list” – pattern & temporal aspects again important Unit III – Disorders of the Peripheral Nervous System – Pringle

Signs of Neuromuscular Disorders: motor exam neurogenic processes (“Lower Motor Neuron signs”) – prominent atrophy (wasting) – fasciculations – tone normal or hypotonic (vs UMN spasticity) – reflexes diminished/absent (vs UMN hyper) – weakness pattern depends on specific nerve involved – sensory symptoms & signs myopathic processes – little/no atrophy* – normal tone – reflexes usually normal until late – symmetric proximal muscle weakness – no sensory signs NMJ – no sensory symptoms/signs – weakness variable & fatiguable Unit III – Disorders of the Peripheral Nervous System – Pringle

Signs of Neuromuscular Disorders: sensory exam pattern – anatomic symmetric, distal “glove & stocking” vs nerve or root distribution large vs small fibre Unit III – Disorders of the Peripheral Nervous System – Pringle

Diagnostic Tests for Neuromuscular Disorders nerve conduction studies (NCS) electromyogram (EMG) nerve biopsy – rarely helpful except in vasculitis or amyloidosis muscle biospy Unit III – Disorders of the Peripheral Nervous System – Pringle

Some Specific Examples of Neuromuscular Disorders motor neuron disease – ALS, polio radiculopathies – disc herniations – Guillain-Barre syndrome plexopathies – diabetic amyotrophy, radiation plexopathies neuropathies – Polyneuropathies (eg diabetic neuropathies, toxic neuropathies, nutritional neuropathies), mononeuropathies (eg carpal tunnel syndrome, ulnar neuropathy, peroneal neuropathy) neuromuscular junction disorders – myasthenia gravis, Lambert-Eaton, botulism myopathies – myositis, muscular dystrophies, steroid myopathy, statin myopathy Unit III – Disorders of the Peripheral Nervous System – Pringle

Unit III – Disorders of muscle and neuromuscular junction – Pringle

Motor Neuron Diseases classified according to relative degree of upper and lower motor neuron features – both UMN + LMN = ALS (amyotrophic lateral sclerosis; Lou Gehrig’s disease) – pure UMN = PLS (primary lateral sclerosis) – pure LMN = SMA (spinal muscular atrophy) LMN UMN ALS SMA PLS Unit III – Disorders of the Peripheral Nervous System – Pringle

Amyotrophic Lateral Sclerosis a clinical diagnosis combination of UMN + LMN signs – spasticity, hyper-reflexia, Babinski signs – weakness, wasting, fasciculations* *distinguish from benign fasciculations – weakness! – weight loss absence of significant sensory abnormalities bulbar symptoms (dysphagia, speech abnormalities) pseudobulbar affect (“emotional incontinence”) denervation on EMG Unit III – Disorders of the Peripheral Nervous System – Pringle

Unit III – Disorders of muscle and neuromuscular junction – Pringle

Radiculopathies Unit III – Disorders of the Peripheral Nervous System – Pringle

Degenerative Disc Disease commonest cause of isolated radiculopathy cervical, thoracic, lumbar, sacral "radicular pain" – radiates in sensory distribution of that particular nerve root associated numbness/paresthesiae in dermatome of nerve root loss of strength in myotome – eg C7 myotome= triceps, wrist extensors, finger extensors diminution of or loss of relex supplied by that nerve root Unit III – Disorders of the Peripheral Nervous System – Pringle

Plexopathies THE BRACHIAL PLEXUS Unit III – Disorders of the Peripheral Nervous System – Pringle

Brachial Plexopathies inflammatory – brachial plexitis – neuralgic amyotrophy – Parsonage-Turner Syndrome traumatic – especially after shoulder dislocations malignant – especially with apical lung cancer – painful+++ – lower trunk, associated Horner’s syndrome Unit III – Disorders of the Peripheral Nervous System – Pringle

Diabetic Lumbosacral Plexopathies “diabetic amyotrophy” abrupt onset of unilateral leg pain (usually thigh) weakness follows pain – L3, L4 muscles most commonly involved – proximal and distal muscles weak in most cases frequently affects other leg after latency of days to months believed to be ishaemic often good recovery but residual weakness common Unit III – Disorders of the Peripheral Nervous System – Pringle

Unit III – Disorders of muscle and neuromuscular junction – Pringle

Disorders of Peripheral Nerves mononeuropathies – compression/entrapment – traumatic polyneuropathies (aka generalized neuropathies, peripheral neuropathies) – usually due to some metabolic or toxic process – multiple classifications schemes Unit III – Disorders of the Peripheral Nervous System – Pringle

Common Mononeuropathies: UE wrist – Carpal tunnel syndrome elbow spiral groove – "Saturday night palsy" wrist drop usually these are “compression neuropathies” (aka “entrapment neuropathies”) due to direct pressure on the nerve at characteristic sites of vulnerability but any peripheral nerve can also be injured traumatically at any point in its course Unit III – Disorders of the Peripheral Nervous System – Pringle

Common Mononeuropathies: LE lateral femoral cutaneous – "meralgia paresthetica“ fibular head – foot drop “steppage gait”

Polyneuropathies classified by – the type of nerve involved sensory, motor, sensorimotor, autonomic, generalized – mechanism of damage axonal, demyelinating, mixed – distribution length-dependent (aka "dying-back") mononeuritis multiplex – time course acute, subacute, chronic Unit III – Disorders of the Peripheral Nervous System – Pringle

Approach to Neuropathies 2 A Practical Unit III – Disorders of the Peripheral Nervous System – Pringle

A Practical Approach to Neuropathies “usual” neuropathies – chronic, sensorimotor, axonal, length dependent single commonest cause = diabetes other things to think about – toxic (esp chemo, anti- retrovirals) – Alcoholic – B12 deficiency – uremic – thyroid – paraproteinemic “weird” neuropathies – mononeuritis multiplex vasculitis – pure motor lead – pure sensory xs B6, paraneoplastic, platinum- derived chemo – hereditary (HMSN, HSAN etc) Charcot-Marie Tooth – acquired demyelinating* GBS, CIDP Unit III – Disorders of the Peripheral Nervous System – Pringle

Symptoms of Polyneuropathy motor symptoms – weakness – loss of muscle bulk – muscle cramps sensory symptoms – numbness, loss of feeling – tingling, “pins & needles” – burning, pain – poor balance autonomic symptoms Unit III – Disorders of the Peripheral Nervous System – Pringle

Clinical Findings in “Usual” Neuropathies: Inspection wasting of intrinsic muscles of feet if chronic: – hammering of toes – arches pes cavus distal tapering of forelegs Unit III – Disorders of the Peripheral Nervous System – Pringle

Clinical Findings in “Usual” Neuropathies graded loss of sensation distally (“stocking”) loss of vibration sense or increased threshold weakness of distal muscles (esp toe flexors) hypo-active/absent distal DTR’s Unit III – Disorders of the Peripheral Nervous System – Pringle

NCS in Neuropathies determine which nerves are involved – mononeuropathy – polyneuropathy – establish pattern symmetric vs asymmetric length dependent mononeuritis multiplex determine sensory and/or motor involvement large fibre vs small fibre axonal vs demyelinating – acquired vs hereditary acute vs chronic (with EMG) Unit III – Disorders of the Peripheral Nervous System – Pringle

Unit III – Disorders of muscle and neuromuscular junction – Pringle

Diabetic Neuropathy occurs in both type I & type II most diabetics will have some detectable neuropathy after 10 years – subclinical in many – symptomatic 5 years 25 years multiple factors believed to contribute to pathophysiology – microvascular disease – elevated intracellular glucose disrupts protein functions activation of protein kinase C polyol pathway activation (reactive oxygen species) Unit III – Disorders of the Peripheral Nervous System – Pringle

Diabetic Neuropathy several different clinical patterns by far the commonest is chronic, length-dependent sensory>motor axonal – distal tingling & numbness “Like I’m walking on wadded up sock.” frequent muscle cramps distally – small fibre predominant burning dysesthetic pain prominent in some often autonomic neuropathy as well NCS may be relatively normal early on – large fibre predominant very little/no pain prominent ataxia (“diabetic pseudotabes”) Unit III – Disorders of the Peripheral Nervous System – Pringle

Diabetic Autonomic Neuropathy resting tachycardia and loss of sinus arrhythmia postural hypotension erectile dysfunction/impotence bladder dysfunction sweating abnormalities pupillary abnormalities gastroparesis Unit III – Disorders of the Peripheral Nervous System – Pringle

 diabetic 3 rd nerve palsy  ptosis, diplopia  spares the pupil (vs compressive) Other Diabetic Neuropathy Syndromes Unit III – Disorders of muscle and neuromuscular junction – Pringle

Guillain Barre Syndrome acute inflammatory demyelinating polyradiculoneuropathy (AIDP) autoimmune attack on the myelin sheaths of peripheral nervous system molecular mimicry usually classified with neuropathies but is really a polyradiculoneuropathy Unit III – Disorders of the Peripheral Nervous System – Pringle

Epidemiology of GBS incidence 1-2/100,000 annually – most common cause of acute flaccid paralysis in the Western world since eradication of polio can affect any age male:female 1.5:1 no seasonal variation 2/3 have history of antecedent illness in 2-3 weeks before onset of neuro symptoms – usually respiratory or diarrheal Unit III – Disorders of the Peripheral Nervous System – Pringle

Clinical Features of GBS acute monophasic illness developing over days- weeks – nadir usually in 3 weeks weakness +/- sensory complaints autonomic instability areflexia Unit III – Disorders of the Peripheral Nervous System – Pringle

GBS Clinical Features: Motor weakness! “ascending” paralysis a bad term – legs usually before arms 10% begin in arms – often more striking proximally don’t rely on grip strength – facial weakness (usually bilateral) in 50% fairly symmetric respiratory failure requiring ventilation in approx. 25% Unit III – Disorders of the Peripheral Nervous System – Pringle

GBS Clinical Features: Sensory tingling paresthesiae & pain often the first symptoms – deep aching pain in lower back may radiate – tingling, burning, shock-like sensory symptoms often out of proportion with demonstrable sensory findings sensory level demands MRI to rule out spinal cord lesion Unit III – Disorders of the Peripheral Nervous System – Pringle

GBS Clinical Features: Autonomic up to 65% – more frequent in severely affected blood pressure lability cardiac arrhythmias urinary retention constipation Unit III – Disorders of the Peripheral Nervous System – Pringle

Diagnosis of GBS primarily a clinical diagnosis nerve conduction studies – often normal or minimally/nonspecifically abnormal early in course conduction slowing conduction block temporal dispersion lumbar puncture (albuminocytologic dissociation) – CSF protein elevated but cells not elevated – often normal early in course Unit III – Disorders of the Peripheral Nervous System – Pringle

Pathophysiology of NCS Abnormalities in GBS normal (saltatory) conduction slowed conduction velocity conduction block

Treatment of GBS immunomodulatory supportive Unit III – Disorders of the Peripheral Nervous System – Pringle

Immunomodulatory Therapies plasmapheresis intravenous immunoglobulin (IVIg) –N–NO role for corticosteroids initiate treatment quickly! –e–earlier treatment = better outcome Unit III – Disorders of the Peripheral Nervous System – Pringle

General Medical Management close monitoring of respiratory status – bedside spirometry – DON’T rely on oximetry or ABG’s autonomic instability DVT prophylaxis stress ulcer prophylaxis nosocomial infections bowel routine urinary catheter swallowing issues/nutrition pain control SIADH psychological issues Unit III – Disorders of the Peripheral Nervous System – Pringle

The Single Biggest Threat to the GBS Patient? the inexperienced physician! do NOT rely on arterial blood gases or oximetry to judge imminence of respiratory failure – bedside spirometry – FREQUENT reassessments (hourly) beware the “insufficient effort” “anxious” “functional” labels when to be pushy: – bedside spirometry trending downwards – ICU should be assessing patient when FEV 1 < 2.0 litres – intubation at 1.5 litres – elective intubation always preferable to crash intubation Unit III – Disorders of the Peripheral Nervous System – Pringle

Prognosis in GBS mortality 3-6% most patients make a complete functional recovery – usually over 6-12 months 10-15% significant residual deficits – footdrop, paresthesiae, permanent weakness, gait difficulties persistent fatigue in 67%

Break time! 59 Unit III – Disorders of the Peripheral Nervous System – Pringle

ELSEWHERE

Nerve Conduction Studies motor ncs sensory ncs – orthodromic – antidromic Unit III – Disorders of the Peripheral Nervous System – Pringle

Nerve Conduction Study Parameters latency – time (in msec) to response onset conduction velocity ( in m/sec) a derivative stim latency Unit III – Disorders of the Peripheral Nervous System – Pringle

Nerve Conduction Study Parameters conduction velocities (CV) can be derived from latencies at different points of stimulation – CV= distance between stimulation points/(latency 2 - latency 1 ) 1 2 Stimulating at wrist Stimulating 30 cm (0.3m) proximal to wrist 4msec 10msec CV = 50m/sec CV = 0.3m/6msec =.05 m/msec Unit III – Disorders of the Peripheral Nervous System – Pringle

Nerve Conduction Study Parameters response amplitude – usually mV in motor studies – uV in sensory studies npa ppa npa = negative peak amplitude; ppa = peak to peak amplitude Unit III – Disorders of the Peripheral Nervous System – Pringle

Electromyography (EMG) examines electrical signals of motor units differentiates myopathic & neurogenic processes helps differentiate axonal from demyelinating – denervation changes in axonal helps establish chronicity Unit III – Disorders of the Peripheral Nervous System – Pringle NormalNormal EMG

Clinical Spectrum of GBS acute inflammatory demyelinating polyradiculoneuropathy (AIDP) axonal variants – acute motor axonal neuropathy (AMAN) – acute motor & sensory axonal neuropathy (AMSAN) without predominant weakness – Miller-Fisher variant – acute pandysautonomia – pure sensory neuronopathy Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) – progression over 8 weeks

Upper Motor Neuron vs Lower Motor Neuron UMN runs as single axon from cell body in the motor cortex to synapse on the anterior horn cell via the corticospinal pathway LMN cell body is the anterior horn cell leaves the cord via spinal root and travels to synapse on muscle at the neuromuscular junction Unit III – Disorders of the Peripheral Nervous System – Pringle