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
 Senso
Sensory Diame
ry Velocity
&
Fiber
ter
(m/s) Functions
Motors* (nm)
s**
Motor: alpha motor neurons
A-α Ia 10-20 50-120
Sensory: muscle spindle afferents
Sensory: Golgi tendon organs,
A-α Ib 10-20 50-120
touch, pressure
Motor: motor neurons to
intra/extrafusal muscle fibers
A-β II 4-12 25-70
Sensory: secondary muscle spindle
afferents, touch, pressure, vibration
 Senso
Sensory Diame
ry Velocity
and
Fiber
ter
(m/s) Functions
Motoers* (nm)
s**
Motor: Small gamma motorneurons
A-γ III 2-8 10-50
to intrafusal muscle fibers
Sensory: small touch, pain,
A-δ III 1-5 3-30
temperature fibers
Motor: small unmyelinated
B III 1-3 3-15
preganglionic autonomic fibers
Motor: postganglionic ANS fibers
C IV <1 <2
Sensory: pain, temperature
Anatomy of peripheral nervous system
Principal components of Peripheral nervous system
 Clinical syndrome
Brain Motor
Spinal cord
Sensory
Nerve
Reflex
NMJ
ANS
Muscle
weakness
Brain
Spinal cord
Nerve
NMJ
Muscle
 Cortex lesion –
cortical sensation,
other cortical signs

Spinal Cord –
LMN at level ,
UMN below level ,
Root – proximal Suspended sensory
muscle weakness, level
winging scapula

Peripheral nerve –
motor, sensory, autonomic,
reflex
 Clinical syndrome
Peripheral Motor
Nerve

Neuro
Sensory
Muscular
Reflex
Junction
ANS
Muscle
 Nerve NMJ Muscle

Motor

Sensory

Reflexes

ANS
 Nerve NMJ Muscle

Motor Proximal
Distal
Focal
Sensory Pain
Numbness

Reflexes Decreased /
Normal

ANS Small fiber

ANS
Neuropathy
 Nerve NMJ Muscle

Motor Proximal

Sensory Mild S/S

Reflexes Normal /
Decreased

ANS Presynaptic
 Nerve NMJ Muscle

Motor Proximal

Sensory Normal

Reflexes Normal/
Decreased

ANS Normal
 Distribution of weakness
Cranial musculature
Extremities
Axial musculature
Combination
• Symmetrical - Asymmetrical
 Nerve NMJ Muscle

Motor Proximal Proximal Proximal

Distal
Focal
Sensory Numbness Mild S/S Normal
Pain Pain
Cramp Cramp

Reflexes Decreased / Normal / Normal/

Normal Decreased Decreased

ANS Small fiber Presynaptic Normal

Pattern of PNS lesion
• Polyneuropathy
• Radiculopathy
• Polyradiculopathy
• Plexopathy
• Mononeuropathy
• Mononeuropathy multiplex
 Nerve NMJ Muscle

Motor Proximal

Sensory Mild S/S

Reflexes Normal /
Decreased

ANS Presynaptic
 Nerve NMJ Muscle

Motor Proximal Proximal Proximal

Distal
Focal
Sensory Numbness Mild S/S Normal
Pain Pain
Cramp Cramp

Reflexes Decreased / Normal / Normal/

Normal Decreased Decreased

ANS Small fiber Presynaptic Normal

 Nerve NMJ Muscle

Motor Proximal Proximal Proximal

Distal
Focal
Sensory Pain /cramp Mild S/S Normal
Numbness Pain/cramp

Reflexes Decreased / Normal / Normal/

Normal Decreased Decreased

ANS Small fiber Presynaptic Normal

ANS
Neuropathy
 Nerve NMJ Muscle

Motor Proximal Proximal Proximal

Distal
Focal
Sensory Pain Mild S/S Normal
Numbness

Reflexes Decreased / Normal / Normal/

Normal Decreased Decreased

ANS Small fiber Presynaptic Normal

ANS
Neuropathy
 The neuromuscular synapse
Rich in ion channels and associated proteins
vulnerable to antibody-mediated attacks
Voltage-gated Blood brain barrier
Potassium
Voltage-gated
channel (VGKC)
Sodium
Voltage- channel
gated
Calcium
channel
(VGCC)
Acetyl choline
acetylcholine
receptor
(AChR)

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 & Myopa
thy
• 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 & myopat
hy
• 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 & Myopa
thy
• Hereditary
– Debrancher deficiency
– Lamin A/C mutations
– Congenital muscular dystrophy: Merosin defic
iency
– 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 symptom
atic in legs
–Pain: Low back & legs
–Paresthesias: Distal
 "Classic" Guillain-Barré syndrome

• Cranial Nerves (70%)

– VII
• Symmetric: Occurs early in parallel with weakn
ess
• 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 Congenial and familial

Myasthenia gravis Congenital Myasthenic Syndrome

Sero Positive Pre synaptic
Anti AChR Positive CMS with episodic apnea
Anti MuSK Positive Paucity of synaptic vescicles
Drug induced (pencillamine) Simulating Lambert Eaton
MG with Thymoma Synaptic
Neonatal MG AChE deficiency
Sero Negative Post synaptic
AChR Negative 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

Familial occurrence Extremely rare(2-5%) Common

Pattern of inheritance Mostly Autosomal recessive

Consanguinity Favours diagnosis

Age of onset Unknown below 2 years,except Neonatal period to adulthood

transient neonatal myasthenia
gravis

Spontaneous remission Can occur Does not occur

Association of other autommune disease Favours diagnosis Not seen

Characteristic facial appearance apart Nil Elongated face,

from ptosis prongnathism,high arched
palate

Response to immuno modulatory Positive Nil

treatment
 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 Bedsid Sensitivity, Edx Test Sensitivity Immunologi Sensitivity,

of Weakness e Test % (muscle) % c %

Ocular Edroph 60-95 SFEMG 90 AChR-Ab 50

onium (facial)
Ice 89
packα
Oropharyngeal. None RNS 60 AChR-Ab 85
(limb/cran
ial)
SFEMG 99 MuSK-Ab 40-50
(limb/faci (if above
al) negative)
Generalized None RNS 60 AChR-Ab 85
(reflexes normal,no (limb/cran
autonomicsigns)sus ial)
pectMG
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 Sensitivity, Edx Test Sensitivity Immunologi Sensitivity,

Test % (muscle) % c %

Ocular Distribution 60-95 SFEMG 90 AChR-Ab 50

of Weakness
(facial)
Edrophoni
um
Ice packα 89

Oropharyn None RNS 60 AChR-Ab 85

geal. (limb/crania
l)
SFEMG 99 MuSK-Ab 40-50
(limb/facial) (if above
negative)
 Selection of diagnostic tests based on clinical features
Distribution Bedsid Sensitivity Edx Test Sensitivity, Immunol Sensiti
of Weakness e Test , (muscle) % ogic vity,
% %

Generalized None RNS(hand) 98 VGCC-Ab 90

(hyporeflexia, SFEMG 100
autonomic (limb)
signs),suspect
LEMS
Suspect None RNS(limb) ? None
botulism
Suspect CMS None RNS(limb) ? 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 Mestinon

Prednisone Prednisone

Thymectomy Thymectomy

2 nd Line Azathioprine Azathioprine

Myocphenolate mofetil Cyclosporine

Cyclosporine IVIg

3 rd Line IVIg Myocphenolate mofetil

Plasmapheresis Plasmapheresis

4 th Line Tacrolimus

5 th Line Rituximab cyclophophamide

Myasthenia gravis: treatment recommendattions

Before 2007

1st Line Mestinon Mestinon

Prednisone Prednisone

Thymectomy Thymectomy

2 nd Line Azathioprine Azathioprine

Myocphenolate Cyclosporine

mofetil

Cyclosporine IVIg
Myasthenia gravis: treatment recommendattions

Before 2007

3 rd Line IVIg Myocphenolate mofetil

Plasmapheresis Plasmapheresis

4 th Line Tacrolimus

5 th Line Rituximab cyclophophamide

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 Muscles to test fo
r brachial plexus le
sion
1. Supraspinatous
3 2. Infraspinatous
3. Pectoraris major
3 and 4
4. Pectoraris minor
5. Subscapularis
6. latissimus dorsi
6 5
Mononeuropathy

Multiple mononeuropathy /
mononeuropathy multiplex
Median N.
 Median N.
Pronator Teres
Flexor Carpi Radialis
Anterior
Palmaris Longus
interosseous
Flexer Digitorum superficialis
nerve
Flexer digitorum
profundus
Flexer pollicis
APB
longus
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 Thumb and thenar eminence
Ulnar Little finger and hypothenar
eminence
Radial Wrist-drop
Femoral (weak hip flexion
& knee extension)
Peroneal Foot-drop
Sciatic Weak gastrocnemius
 Nerve NMJ Muscle

Motor

Sensory Numbness Mild S/S Normal /

Pain Pain
Cramp 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 disord
er
 Pain (3)
 Infections
 Viral & post-viral syndromes
 Brucellosis; Leptospirosis; Falciparu
m malaria
 Systemic connective tissue disord
ers: 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 & t
ension
• May be associated with tendency to cramp
 Fasiculations 2
–Motor neuron disorders & Motor neu
ropathies
–Metabolic disorders: Hyperparathyroi
d; Hyperthyroid; Hypomagnesemia
–Pharmacologic
• Anti-Cholinesterase; Caffeine; Theophyll
ine; Terbutaline; Lithium
 Primary reflexes
1. Ankle jerk S1 Gastrocnemius

2. Knee jerk L2,L3,L4 Quadriceps

3. Biceps C5,C6 Biceps

4. Triceps C7,C8 Triceps

 Root & muscle
C5 Deltoid

C5 Infraspinatus
C5,C6 Biceps

C6 Extensor carpi radialis &

ulnaris
C7 Extensors digitorum &
triceps
 Root & muscle

L2,L3,L4 Quadriceps & iliopsoas

L5 Anterior tibial and

extensor hallucis
S1 Gastrocnemius
C5
C6
 C6

C7
C7

T1
 Nerve & Muscle
Median Thumb and thenar eminence
Ulnar Little finger and hypothenar
eminence
Radial Wrist-drop
Femoral Absent knee jerk (weak hip
flexion & knee extension)
Peroneal Foot-drop
Sciatic 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 axo
ns: Ankle reflexes lost early
• Reflexes are lost with weakness
–Reflexes are generally lost in propor
tion 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 NMJ Muscle

Motor

Sensory

Reflexes Decreased / Normal / may Normal/

Fasciculation be increased Decreased
/Normal and may be
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
Clinical
• Reflexes Syndrome
• ANS
Onset
History of 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
Nerve
Peripheral 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 fibres-
distal 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.
I got you