Siwaporn Chankrachang MD Chiang Mai University

How to Approach Peripheral Neurology
(Nerve ,Neuromuscular junction & Muscle)

Siwaporn Chankrachang Chiang Mai University

31 May 2011

Over view
‡ Anatomy & physiology ‡ Clinical manifestation

Anatomy of peripheral nervous system
‡ Cell body
± Anterior horn cell ± Sensory ganglion cell ± Autonomic ganglion cell ± Cranial nerve ganglion cell

‡ Nerve fiber
± Axon ± Myelin

‡ Sensory and autonomic end organ ‡ Neuromuscular junction ‡ Muscle

Cell body
Anterior horn cell Sensory ganglion cell Autonomic ganglion cell Cranial nerve ganglion cell

‡Nerve fiber
±Axon ±Myelin

Sen Dia Sensory sor met Velo y & er city Motors Fib Functions (nm (m/s) ers * ) ** Motor: alpha motor 10- 50- neurons AIa 20 120 Sensory: muscle spindle afferents 10- 50- Sensory: Golgi tendon AIb 20 120 organs, touch, pressure Motor: motor neurons

Sen Dia Sensor sor met Velo y and y er city Motoe Fib Functions (nm (m/s) ers rs* ) ** Motor: Small gamma AIII 2-8 10-50 motorneurons to intrafusal muscle fibers Sensory: small touch, AIII 1-5 3-30 pain, temperature fibers Motor: small unmyelinated

Anatomy of peripheral nervous system

Principal components of Peripheral nervous system

Clinical syndrome
Brain Spinal cord Nerve NMJ Muscle

Motor

Sensory
Reflex ANS

weakness
Brain Spinal cord Nerve NMJ

Muscle

Cortex lesion ±
cortical sensation, other cortical signs

Spinal Cord ±
LMN at level , UMN below level , ± proximal muscle weakness, winging scapula

Root

Suspended sensory level

Peripheral nerve ±
motor, sensory, autonomic, reflex

Clinical syndrome
Peripheral Nerve Neuro Muscular Junction Muscle

Motor

Sensory
Reflex ANS

Nerve
Motor

NMJ

Muscle

Sensory Reflexes ANS

Nerve
Motor
Proximal Distal Focal Pain Numbness Decreased / Normal Small fiber ANS Neuropathy

NMJ

Muscle

Sensory Reflexes ANS

Nerve
Motor

NMJ
Proximal

Muscle

Sensory

Mild S/S

Reflexes ANS

Normal / Decreased Presynaptic

Nerve
Motor

NMJ

Muscle
Proximal

Sensory Reflexes ANS

Normal Normal/ Decreased Normal

Distribution of weakness 
Cranial musculature Extremities Axial musculature Combination

‡ Symmetrical - Asymmetrical

Nerve
Motor
Proximal Distal Focal Numbness Pain Cramp Decreased / Normal Small fiber ANS

NMJ
Proximal

Muscle
Proximal

Sensory

Mild S/S

Normal Pain Cramp Normal/ Decreased Normal

Reflexes ANS

Normal / Decreased Presynaptic

Pattern of PNS lesion
‡ Polyneuropathy ‡ Radiculopathy ‡ Polyradiculopathy ‡ Plexopathy ‡ Mononeuropathy ‡ Mononeuropathy multiplex

Nerve
Motor

NMJ
Proximal

Muscle

Sensory Reflexes ANS

Mild S/S Normal / Decreased Presynaptic

Nerve
Motor
Proximal Distal Focal Numbness Pain Cramp Decreased / Normal Small fiber ANS

NMJ
Proximal

Muscle
Proximal

Sensory

Mild S/S

Normal Pain Cramp Normal/ Decreased Normal

Reflexes ANS

Normal / Decreased Presynaptic

Nerve
Motor
Proximal Distal Focal Pain /cramp Numbness Decreased / Normal Small fiber ANS Neuropathy

NMJ
Proximal

Muscle
Proximal

Sensory Reflexes ANS

Mild S/S

Normal Pain/cramp Normal/ Decreased Normal

Normal / Decreased Presynaptic

Nerve
Motor
Proximal Distal Focal Pain Numbness Decreased / Normal Small fiber ANS Neuropathy

NMJ
Proximal

Muscle
Proximal

Sensory Reflexes ANS

Mild S/S

Normal

Normal / Decreased Presynaptic

Normal/ Decreased Normal

The neuromuscular synapse
Rich in ion channels and associated proteins vulnerable to antibody-mediated attacks
Voltage-gated Potassium channel (VGKC) Voltagegated Calcium channel (VGCC)

Blood brain barrier Voltage-gated Sodium channel

Acetyl choline receptor (AChR)

acetylcholine

Muscle pecific kinases (MUSK

rapsyn

Normal NMJ
Action Potential

Ca2+ Ca2+ Ca2+

Presynaptic

Acetylcholine receptor

Postsynaptic

Action Potential

Ca2+

Presynaptic
Acetylcholine

Acetylcholine receptor

Postsynaptic

Characteristic signs in M gravis

Neck flexor Test

Test for Fatiguability

Enhancing test

Give diagnosis

It¶s fun to hide
hahahaaaa

Give diagnosis

Describe Abnormal Findings

Let me die sir«..

Botulism exotoxin action

Low rate stimulation

Immediate storage depleted quickly

End Plate Potential

High rate stimulation
> 10 Hz

Ach quanta Released by Ca++ which was previously blocked by toxin becomes more important

Repetitive nerve stimulation test 2 weeks after
30 stimulation 30 HZ

Syndromes with Neuropathy & Myopathy
‡ Drugs & Toxins
± ± ± ± ± ± ± ± ± ± ± ± Amiodarone Chloroquine Chlorphenoxy Clofibrate: Risk factor - renal failure Colchicine: Risk factor - renal failure Doxorubicin Eosinophilia-myalgia syndrome Ethanol: Risk factor - fasting Hydroxychloroquine Organophosphates Perhexiline Vincristine

Syndromes with neuropathy & myopathy
‡ Paraneoplastic (with weight loss > 15%)
± Neuropathy: Distal; Sensory > Motor ± Myopathy: Proximal with type II muscle fiber atrophy

‡ Inclusion Body Myositis ‡ Systemic disorders
± ± ± ± ± Uremia Acromegaly Collagen vascular disorders Sarcoid HIV Infection
‡ Myopathy: Inflammatory; ‡ Several types of neuropathy

Syndromes with Neuropathy & Myopathy
‡ Hereditary
± Debrancher deficiency ± Lamin A/C mutations ± Congenital muscular dystrophy: Merosin deficiency ± Marinesco-Sjögren ± Mitochondrial: MNGIE Syndrome ± Tyrosinemia

Periodic paralysis
‡ Symmetric weakness that reverses within 1 day
± Asymmetrical weakness may occur due to excessive utilization ± No respiratory failure ± Periodic attack is very common ± Attack may related to over exercise or high carbohydrate intake ± Normal CSF and CK ± Associated with hyperthyroidism in young oriental male ± Associated with renal tubular acidosis in north-eastern Thailand ± Positive family history may occur

Guillain-Barré syndrome
± Symmetric weakness ± Generalized areflexia ± Distal tingling with little sensory loss ± Extraocular weakness ± Respiratory failure ± Elevated cerebrospinal fluid (CSF) protein ± Anteccdent infection

"Classic" Guillain-Barré syndrome

Clinical features
‡ Onset
±Weakness: Most often symptomatic in legs ±Pain: Low back & legs ±Paresthesias: Distal

"Classic" Guillain-Barré syndrome
‡ Cranial Nerves (70%)
± VII
‡ Symmetric: Occurs early in parallel with weakness ‡ Asymmetric
± Occurs later in disease course ± Other weakness may be stable or improving

± Extra-ocular: Overlap with Miller-Fisher ± Tongue: Symmetric; Common (50%)

"Classic" Guillain-Barré syndrome
‡ Tendon reflex loss
± Early in most (70%) but not all patients ± Progressive reduction during 1st week ± Distribution: Ankles most frequently lost; Biceps most frequently spared ± Spared reflexes all during disease course suggests another diagnosis

Motor neuron diseases
Amyotrophic lateral sclerosis ± asymmetric weakness proximal or distal ± Weakness with atrophy and fasciculations ± Upper motor neuron signs ± Preservation of reflexes unless severe weakness Spinal muscular atrophy ± Symmetrical weakness ± Associated features
‡ Kenedy syndrome
± gynecomastia, diabetes

‡ Madras pattern
± Deafness

Gynecomastia & neuromuscular
Bulbospinal muscular atrophy Adrenomyeloneuropathy Myasthenia gravis and macromastia Recovery from severe malnutrition & weight loss ‡ Pectoral muscle hypertrophy ‡ ‡ ‡ ‡

Neuromuscular Junction Disease

Neuromuscular Junction Disease

‡ Myasthenia gravis ‡ Lambert-Eaton myasthenic syndrome ‡ Congenital myasthenic syndrome ‡ Drug-induced myasthenic syndrome

Classification of Myasthenia gravis and Congenital myasthenic syndrome
Acquired NMJ disorders Myasthenia gravis Sero Positive Anti AChR Positive Anti MuSK Positive Drug induced (pencillamine) MG with Thymoma Neonatal MG Sero Negative AChR Negative Congenial and familial Congenital Myasthenic Syndrome Pre synaptic CMS with episodic apnea Paucity of synaptic vescicles Simulating Lambert Eaton Synaptic AChE deficiency Post synaptic Kinetic abnormalities with Normal, reduced or Increased AChR MuSK,Rapsyn,Agarin, Plectin mutations

Differentiating features of Myasthenia gravis and Congenital Myasthenic syndrome
Distinctive Features Myasthenia Gravis Congenital Myasthenic Syndrome Common Mostly Autosomal recessive Favours diagnosis Unknown below 2 years,except transient neonatal myasthenia gravis Can occur Favours diagnosis Nil Neonatal period to adulthood

Familial occurrence Pattern of inheritance Consanguinity Age of onset

Extremely rare(2-5%)

Spontaneous remission Association of other autommune disease Characteristic facial appearance apart from ptosis

Does not occur Not seen Elongated face, prongnathism,high arched palate Nil

Response to immuno modulatory treatment

Positive

Diagnosis of neuromuscular junction disorders
Pharmacologic tests Edrophonium Neostigmine Pyridostigmine Electrophysiologic tests Repetitive nerve stimulation Single-fiber electromygraphy

Diagnosis of neuromuscular junction disorders
Immunologic tests
Myasthenia Gravis Acetylcholine receptor antibodies (binding,blocking,modulating) Antistriational antibodies Anti-titin,Antiryanodine receptor antibodies Antibodies to muscle-specific receptor tyrosine kinase Lambert-Eaton Myasthenic Syndrome Antibodies to the voltage-gated calcium channel

Miscellaneous
Ice-pack tasts Muscle biopsy

Selection of diagnostic tests based on clinical features
Distribution of Weakness Ocular Bedside Test Edroph onium Ice pack Oropharyngeal. None Sensitivity, % 60-95 89 RNS (limb/cran ial) SFEMG (limb/faci al) Generalized (reflexes normal,no autonomicsigns)sus pectMG None RNS (limb/cran ial) 60 AChR-Ab
85

Edx Test (muscle) SFEMG (facial)

Sensitivity % 90

Immunologi c AChR-Ab

Sensitivity, % 50

99

MuSK-Ab (if above negative) AChR-Ab

40-50

60

85

Edx,electrodiagnostic;SFEMG,singlr-fiber electromyography;AChR-Ab,acetlcholine receptor antibody;RNS,repetitive nerve stimulation;MuSK-Ab,muscle-specific receptor tyrosine kinase antibody;MG, myasthrnia gravis;LEMS,Lambert-Eaton myasthenic syndrome;VGCC-Ab, voltage-gated calcium channel antibody;CMS,congenital myasthenic syndrome.

Selection of diagnostic tests based on clinical features
Bedside Test Sensitivity, % Edx Test (muscle) Sensitivity % Immunologi c
Sensitivity, %

Ocular

Distribution of Weakness

Edrophoni um Ice pack Oropharyn None geal.

60-95 SFEMG (facial)

90

AChR-Ab

50

89 RNS (limb/crania l) SFEMG (limb/facial) 60 AChR-Ab
85

99

MuSK-Ab (if above negative)

40-50

Selection of diagnostic tests based on clinical features
Distribution Bedsid Sensitivity of Weakness e Test , % Generalized None (hyporeflexia, autonomic signs),suspect LEMS Suspect botulism Suspect CMS None None Edx Test (muscle) RNS(hand) SFEMG (limb) Sensitivity, % 98 100 Immunol Sensiti vity, ogic
%

VGCC-Ab

90

RNS(limb) RNS(limb)

? ?

None None*

Edx,electrodiagnostic;SFEMG,singlr-fiber electromyography;AChR-Ab,acetlcholine receptor antibody;RNS,repetitive nerve stimulation;MuSK-Ab,muscle-specific receptor tyrosine kinase antibody;MG, myasthrnia gravis;LEMS,Lambert-Eaton myasthenic syndrome;VGCC-Ab, voltage-gated calcium channel antibody;CMS,congenital myasthenic syndrome. *Muscle biopsy

MGFA clinical classitication of myasthenia gravis

Jaretzki et al Neurology 2000 Class I-Ocular Class II-Mild general IIa-Predominantly limb/axial muscles IIb-Predominantly oropharyngeal/respiratory muscles Class III-Moderate general IIIa- Predominantly limb/axial muscles IIIb- Predominantly oropharyngeal/respiratory muscles ClassIV- Severe general IVa- Predominantly limb/axial muscles IVb- oropharyngeal/respiratory muscles (feeding tube)

MGFA clinical classitication of myasthenia gravis Jaretzki et al Neurology 2000 Class I-Ocular Class II-Mild general IIa-Predominantly limb/axial muscles IIb-Predominantly oropharyngeal/respiratory muscles Class III-Moderate general IIIa- Predominantly limb/axial muscles IIIb- Predominantly oropharyngeal/respiratory muscles ClassIV- Severe general IVa- Predominantly limb/axial muscles IVb- oropharyngeal/respiratory muscles (feeding tube)

Myasthenia gravis: treatment recommendattions
Before 2007

1st Line

Mestinon Prednisone Thymectomy

Mestinon Prednisone Thymectomy Azathioprine Cyclosporine IVIg Myocphenolate mofetil Plasmapheresis Tacrolimus Rituximab cyclophophamide

2 nd Line

Azathioprine Myocphenolate mofetil Cyclosporine

3 rd Line

IVIg Plasmapheresis

4 th Line 5 th Line

Myasthenia gravis: treatment recommendattions
Before 2007

1st Line

Mestinon Prednisone Thymectomy

Mestinon Prednisone Thymectomy Azathioprine
Cyclosporine IVIg

2 nd Line

Azathioprine
Myocphenolate mofetil Cyclosporine

Myasthenia gravis: treatment recommendattions
Before 2007

3 rd Line

IVIg Plasmapheresis

Myocphenolate mofetil Plasmapheresis Tacrolimus Rituximab cyclophophamide

4 th Line 5 th Line

MGFA : M gravis Foundation of America

History

Pain testing (1)

Sensory testing (2)

Reflexes

Question
‡ Where is the lesion?
1.Nerve 2.Neuromuscular lesion 3.Muscle

Syndrome in peripheral nerve 
Weakness Muscle pain Decreased muscle tone Decreased deep tendon reflex

What is the pattern of PNS lesion ? ‡ Polyneuropathy ‡ Radiculopathy ‡ Polyradiculopathy ‡ Plexopathy ‡ Mononeuropathy ‡ Mononeuropathy multiplex

Symmetrical involvement
Neuropathic skin change Pain & Numb Decreased reflexes

Radiculopathy

Motor predomi nate Less sensory s/s

Plexopathy

Mononeuropathy Multiple mononeuropathy / mononeuropathy multiplex

Radiculopathy

Dorsal scapular to rhomboid

Long thoracic nerve to seratus anterior

Motor predomi nate Less sensory s/s

Plexopathy

1 and 2

3

3 and 4

for brachial plexus lesion 1. Supraspinatous 2. Infraspinatous 3. Pectoraris major 4. Pectoraris minor 5. Subscapularis 6. latissimus dorsi

Muscles to test

6

5

Mononeuropathy Multiple mononeuropathy / mononeuropathy multiplex

Median N.

Median N.
Pronator Teres Flexor Carpi Radialis Palmaris Longus Flexer Digitorum superficialis

Anterior interosseous nerve Flexer digitorum profundus Flexer pollicis longus

APB FPB Opponen Lumbrical 1&2

Median N.
Anterior interosseous nerve Flexer digitorum profundus Flexer pollicis longus APB FPB Opponen Lumbrical 1&2

Sensory Changes in Median Nerve lesion

Ulnar Nerve

Sensory Changes in Ulnar Nerve lesion

Lumbosacral

Lumbosacral plexus

Nerve & Muscle
Median Ulnar Radial Femoral Peroneal Sciatic Thumb and thenar eminence Little finger and hypothenar eminence Wrist-drop (weak hip flexion & knee extension) Foot-drop Weak gastrocnemius

Nerve
Motor

NMJ

Muscle

Sensory

Numbness Pain Cramp

Mild S/S

Normal / Pain Cramp

Reflexes ANS

Sensory symptoms
Pain
‡ Nerve ‡ Muscle ‡ NMJ

Pain (1)
‡ Inflammatory process
±Inflammatory myopathies
‡ Systemic connective tissue disease ‡ Childhood dermatomyositis

±Muscle infections
‡ Viral myositis ‡ Pyomyositis ‡ Toxoplasmosis ‡ Trichinosis

Pain (2)
‡ Denervation muscle pain symmetrical or asymmetricle with weakness
±Guillain Barre syndrome ±Acute anterior horn cell disease
‡

‡ Rhabdomyolysis ± Metabolic disorder

Pain (3) 
Infections 
Viral & post-viral syndromes  Brucellosis; Leptospirosis; Falciparum malaria 

Systemic connective tissue disorders: Sjögren's  Drugs & Toxins  Polyneuropathy: Small fiber

Cramp
‡ Nerve
Motor system disorders
‡ Amyotrophic Lateral Sclerosis ‡ Motor neuropathies ‡ Hereditary motor neuron disorders

Other denervation
‡ Spinal stenosis ‡ Polyneuropathies

Cramp
‡ Nerve
Spontaneous activity syndromes
‡ Episodic ataxia 1 (EA1) ‡ Neuromyotonia (Isaac's syndrome) ‡ Stiffman syndrome ‡ Cramp-fasciculation syndromes

‡ Muscle
± Becker muscular dystrophy ± Type II muscle fiber predominance

Fasiculations
‡ Along the course of the axon ‡ Causes
± Benign
‡ Common in gastrocnemius ‡ Normal strength ‡ Exacerbated by exercise, hyperventilation & tension ‡ May be associated with tendency to cramp

Fasiculations 2
±Motor neuron disorders & Motor neuropathies ±Metabolic disorders: Hyperparathyroid; Hyperthyroid; Hypomagnesemia ±Pharmacologic
‡ Anti-Cholinesterase; Caffeine; Theophylline; Terbutaline; Lithium

Primary reflexes
1. Ankle jerk 2. Knee jerk 3. Biceps 4. Triceps S1 L2,L3,L4 C5,C6 C7,C8 Gastrocnemius Quadriceps Biceps Triceps

Root & muscle
C5 C5 C5,C6 C6 C7 C8,T1 Deltoid Infraspinatus Biceps Extensor carpi radialis & ulnaris Extensors digitorum & triceps Inetrossei and lumbricals

Root & muscle
L2,L3,L4 L5 S1 Quadriceps & iliopsoas Anterior tibial and extensor hallucis Gastrocnemius

C5

C6

C6 C7

C7 T1

Nerve & Muscle
Median Ulnar Radial Femoral Peroneal Sciatic Thumb and thenar eminence Little finger and hypothenar eminence Wrist-drop Absent knee jerk (weak hip flexion & knee extension) Foot-drop Pain down lateral thigh and leg , absent ankle jerk

Deep tendon reflexes 1
‡ Reflexes are lost before weakness
±Demyelinating neuropathies ±Loss of large myelinated sensory axons: Ankle reflexes lost early

‡ Reflexes are lost with weakness
±Reflexes are generally lost in proportion to weakness in polyneuropathy

Deep tendon reflexes 2
‡ Preserved after weakness in myopathy
‡ lost proximally in muscular dystrophies or severe proximal myopathy ‡ hyper-reflexia in myasthenia gravis ‡ hypo-reflexia in myasthenic syndrome ‡ Ankle reflexes preserved in porphyria

Nerve
Motor

NMJ

Muscle

Sensory Reflexes
Decreased / Fasciculation /Normal Normal / may be increased and may be decreased Normal/ Decreased

ANS

How to get Diagnosis ?
History taking Physical examination Lab investigations

History (1)
Course
±Acute: Days to Weeks ±Subacute : Weeks to months ±Chronic: Months to Years ±Episodic

History (2)
Age at onset 
Pediatric: Neonatal; Childhood  Adult: 20 to 60 years;  Geriatric

Hereditary: family history or examination of relatives

Physical examination

‡ Motor ‡ Sensory ‡ Reflexes ‡ ANS
History of

Clinical Syndrome
Onset progression location

Clinical syndrome
‡ Acute generalized weakness ‡ Subacute generalized weakness ‡ Acute or sunacute or chronic focal S/S ‡ Relapsing ‡ Fluctuating

Acute generalized weakness
‡ ‡ ‡ ‡ ‡ ‡ GBS Neuromuscular junction diseases Food-borne botulism Acute necrotizing myopathy Acute poliomyelitis syndrome Periodic paralysis

Subacute or chronic generalized weakness
‡ Motor neuron diseases ‡ Chronic demyelinating polyneuropathy ‡ Neuromuscular junction diseases ‡ Myopathies

Acute or subacute or chronic weakness or numbness limited to one limb
Radiculopathy ,  Plexopathy  Compressive neuropathy  Mononeuritis multiplex 

RELAPSING deficit
± Immune mediated disease
‡ CIDP

± Hereditary
‡ Neuropathy Liability to Pressure Palsy ‡ Brachial Plexopathy ‡ Porphyria

Fluctuation
Myasthenic syndrome

Investigations in Peripheral nerve disease

Types of Investigations Where is the lesion ? What is the lesion ?

Objectives
‡localization ‡Function components ‡Physiology ‡Pathology ‡Follow up

Investigation of Peripheral nerve
Nerve & Muscle Biopsy

‡ NCV ‡ EMG

MRI

MRI
painless. ‡ identify axonal damage ‡ identify a lesion site
‡

Magnetic resonance imaging of human peripheral nerve disease

EXAMINATION OF CSF
Helpful in demyelinating neuropathies.
‡ Guillain-Barre syndrome CSF protein rises during the first week. WBC count varies with the time of lumbar puncture and raised in 10% of cases. ‡ HIV infection or Lyme disease. increased white cell count ‡ CIDP CSF protein is also raised in and help to distinguish from hereditary demyelinating neuropathies.

A high CSF protein suggests inflammatory causes and demyelination of spinal roots or both.

Motor conduction velocity
Median nerve

CV = distance / time

Sensory conduction velocity
Ulnar nerve

Pathology
‡ Segmental demyelination ‡ Wallerain degeneration ‡ Axonal degeneration

Axonal degeneration
‡ most common pathology seen in systemic, metabolic, toxic, and nutritional disorders. ‡ It characteristically has a predilection for large diameter and long fibresdistal axonopathy or dying back neuropathy.

Segmental demyelination
‡ destruction of the myelin sheath leaving the axon intact, ‡ Although axonal degeneration may also be present in demyelinating neuropathies ‡ and secondary primary segmental demyelination may be seen in axonal degeneration.

Pathological diagnosis
3 major pathological processes ‡ axonal degeneration, ‡ segmental demyelination, ‡ neuronopathy.

Wallerian type degenrtation

Pathology

Chronic inflammatory neuropathy. Patchy loss of myelinated fibres in a fascicle of the sural nerve (Semi-thin resin section, toluidine blue). The lower rectangle is an area with a significant loss of large myelinated fibres. There are several other thinly myelinated and entirely demyelinated fibres. The upper rectangle is a more densely populated area.

‡ Vasculitis and severe axonal neuropathy in a peripheral nerve. CD68 immunohistochemical staining to visualize digestion chambers and macrophage in the acutely degenerating nerve.

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