Polyneuropathies
Mononeuropathies
Motoneuron diseases
Zsuzsanna Arányi
Peripheral nerve
Motor, sensory and autonomic fibers
Fiber types according to diameter:
• A fibers- 1-17 μm in diameter; myelinated motor and sensory fibers
• B fibers- 1-3 μm in diameter; myelinated autonomic fibers
• C fibers- 0.3-1.3 μm in diameter; non-myelinated autonomic and pain fibers
Types of peripheral nerve damage
Demyelination


Slowed conduction: no symptoms
Conduction block: weakness and sensory
loss, but no atrophy
Axonal damage (axonotmesis)


Degeneration of axons distal to the lesion
(denervation)
Weakness, sensory loss, atrophy
Neurotmesis



Damage to axons and epineurium
Weakness, sensory loss, atrophy
No regeneration without nerve suture
Nerve regeneration – reinnervation
Remyelination
2-12 weeks
Proximo-distal
axon regeneration
1 mm/day
Intact basal
lamina/endoneurium
is needed
Collateral reinnervation
(in case of partial nerve
damage)
Starts within 4-6 weeks
Polyneuropathies


Generalised disease of the peripheral
nervous system (nerve roots and peripheral
nerves)
Usually the longest nerves are affected first


Symptoms start on the toes, feet
Usually the symptom of an underlying
systemic disease

Search for etiology!
Classification of polyneuropathies

Clinical presentation



Time course




Symmetric
Asymmetric
Acute
Chronic
Etiology
Pathology



Axonal
Demyelinative
Small-fiber
Clinical forms of polyneuropathies





Chronic, symmetric, distal and
predominantly sensory polyneuropathies
Mononeuropathy multiplex
Purely motor or sensory polyneuropathies
Autonomic polyneuropathies
Acute polyneuropathies
Typical symptoms of
polyneuropathies






Chronic course
Symmetric, distal paraesthesia,
pain and hypaesthesia in stocking
– glove distribution; feet are
affected first
Allodynia
Depressed or absent tendon
reflexes
Distally pronounced muscle
weakness, with wasting,
fasciculation
Gait disorder



Sensory ataxia
Weakness
Autonomic dysfunction (reduced
sweating, tachycardia, urinary
disturbances, gastroparesis etc.)
Typical complaints of patients with
polyneuropathies








Tingling, pin-prick, numbness, burning or cold sensation,
burning pain (especially during the night)
‘Ants crawling on my legs’
‘As if I had tight boots on’
‘As if I were walking on a duvet’
‘As if I had stockings on when really not’
‘As if my skin were thick on my soles’
Unstable gait, ‘dizziness’
Loss of dexterity of the hands: ‘I drop objects’
Causes of polyneuropathy




Metabolic-endocrine disturbances: diabetes mellitus, uremia etc.
Vitamin deficiencies: vitamin B1 -alcoholism, malabsorption,
malnutrition, vitamin B12
Toxic causes: heavy metals, industrial solvents, drugs, alcohol
Dysimmune polyneuropathies







With manifestation only in the peripheral nervous system: acute
inflammatory demyelinative polyneuropathy (Guillain-Barré syndrome),
chronic inflammatory demyelinative polyneuropathy (CIDP), multifocal motor
neuropathy (MMN)
Systemic diseases: vasculitis (polyarteritis nodosa, SLE etc.),
paraproteinaemias
Paraneoplasia
Infectious: lepra, Lyme-disease, HIV
Hereditary: Charcot-Marie-Tooth disease etc.
Other: critical illness polyneuropathy, small-fiber neuropathy
Idiopathic
Investigation of polyneuropathies











ENG-EMG
Blood tests: We, blood count, glucose, hepatic and renal function
Vitamin B12
Thyroid function
Se electrophoresis, autoanti-bodies, cryoglobulin
Serological examinations (HIV, Lyme, HCV)
Search for tumors
CSF
Toxicological investigations
Sural nerve biopsy
Genetic tests
Treatment of polyneuropathies



Treat the cause!
Immune therapy
 plasmapheresis: Guillain-Barré syndrome, CIDP
 immunoglobulins: MMN, Guillain-Barré syndrome, CIDP
 corticosteroids: CIDP, systemic vasculitis
Symptomatic treatment of paraesthesias and neuropathic
pain




antiepileptic medications (carbamazepine, gabapentin, pregabalin)
tricyclic antidepressants (amitriptilin, clomipramin)
SNRI antidepressants (duloxetin, venlafaxin)
Vitamin B1: alcoholism, malabsorption, malnutrition
Polyneuropathies associated with
diabetes mellitus






Distal symmetric sensory
polyneuropathy
Mononeuropathies- carpal
tunnel syndrome, ulnar nerve
lesion
Cranial nerve lesionsoculomotor nerve palsy
Autonomic neuropathysexual and urinary
disturbance, gastroparesis and
diarrhoea etc.
Diabetic amyotrophy- painful,
asymmetric, proximal
weakness (plexopathy?)
Radiculopathy- lumbar,
thoraco-abdominal
Diabetic chronic distal symmetric
sensory polyneuropathy

The most common form of diabetic neuropathy








Prevalence among diabetic patients: 20-60%
Present at the diagnosis of diabetes in 20% of patients
May be the only manifestation of impaired glucose tolerance
Severity is usually proportional to the duration and severity
of hyperglycemia
Prevalence increases with age and duration of diabetes
Small fibers (pain, temperature, light touch) are
preferentially affected → painful diabetic neuropathy in
about 20-35%
Autonomic dysfunction
Trophic alterations → diabetic foot
Small fiber neuropathy- skin
biopsy
Normal
Small fiber neuropathy
Epidermal nerve fibers (arrow): anti PGP 9.5 antibodies
Fibrous tissue and basal lamina: anti collagen IV antibodies
Symptoms of sensory diabetic
neuropathy I.






Length-dependent: first symptoms on
the toes and feet
Later stocking-gloves distribution
Usually doesn’t go above the knees
and elbows
If symptoms appear on the hands first
→ carpal tunnel syndrome
Areflexia
Trophic changes
Symptoms of sensory diabetic
neuropathy II.

Positive sensory symptoms:




burning pain (pronounced during the night)
hyperesthesia, allodynia
paresthesia
Negative sensory symptoms:

hypesthesia (loss of sensation)
Diabetic foot



Related to diabetic
sensory neuropathy and
peripheral artery disease
Diabetic foot ulcers
precede 85% of nontraumatic lower limb
amputations
Life-time prevalence of
foot ulcers is 15% in
diabetic patients
Guillain-Barré syndrome





Acute immunmodulated poly-radiculo-neuro-pathy
Pathology: perivascular lymphocyte-macrophage infiltration
in the peripheral nervous system leading to macrophage
mediated segmental demyelination
Incidence: 1.5-2.0/100 000/year
In most cases preceded by an infection (upper respiratory
tract infection, diarrhoea)
Infectious agents associated with Guillain-Barré syndrome:
CMV, EBV, HIV, Campylobacter jejuni, Mycoplasma
pneumoniae

The infectious agent is usually unidentified
Pathomechanism of GBS
Guillain-Barré syndrome- symptoms

Acute, symmetric ascending flaccid paralysis







Variable severity
Respiratory insufficiency
Bilateral facial palsy
Ascending numbness to a lesser degree
Radicular pain
Areflexia
Autonomic symptoms- tachycardia,
cardiovascular instability
Guillain-Barré syndrome- time course




Symptoms evolve over 1-2 weeks
Plateau is reached within 2-3 weeks
Spontaneous recovery within a few months
Good prognosis

Prognosis is determined mainly by complications
of being bed-bound (infection, thrombosis etc.)
Guillain-Barré syndrome- diagnosis
Normal neurography
Segmental demyelination
Conduction block
Temporal dispersion
Guillain-Barré syndrome- diagnosis
and treatment

Diagnosis




Clinical symptoms
Electroneurography- confirms segmental
demyelination
Cerebrospinal fluid examination: elevated protein
content with normal cell count (starting from the
2nd week)
Treatment


Plasmapheresis, immunoglobulin (IVIG)
Supportive treatment!
Chronic inflammatory demyelinative
polyneuropathy (CIDP)



Autoimmune disease
Prevalence: 1-2/100 000
Course:






chronic monophasic (15%)
chronic relapsing-remitting (34%)
step-wise progressive (34%)
continuously progressive (15%)
Symptoms: proximal and distal motor and sensory
symptoms, cranial symptoms (not a length-dependent
neuropathy)
Rarely associated with central nervous system
demyelination (3%)
Diagnosis of CIDP

ENG/EMG: segmental (non-uniform) demyelination
CSF: protein >45 mg/dl, cell count <10

Histology (biopsy): not obligatory, may be normal




chronic demyelination-remyelination may lead to Schwanncell proliferation (‘onion bulb’ formation)
infiltration of inflammatory cells
MRI: hypertrophy of peripheral nerves and nerve
roots, contrast enhancement
CIDP- nerve biopsy
‘onion bulbs’
CIDP- MRI
Hypertrophied trigeminal nerves
CIDP treatment

IVIG



Corticosteroids


2 g/kg bw in 2-5 days, monthly for 3 months
maintanance treatment
methylprednisolon 1 mg/kg bw, later gradual reduction
Plasmapheresis
Mononeuropathies- causes

Trauma


Compression



cutting, laceration and stretching of the nerve
often iatrogenic
Tunnel syndromes
Ischemia
Localisation of focal nerve lesions
• A partial proximal nerve lesion may
selectively affect only one nerve fascicle →
clinically the lesion appears more distal
• The longer axons are more sensitive to
compression → distal symptoms are more
pronounced
Median nerve
Distal median nerve damage: carpal
tunnel syndrome


Incidence: 200-500/100 000/year, 3
times more common in women
Symptoms:





Painful paraesthesia of the hand during
the night, pain in the whole arm
First the dominant hand is affected, but
bilateral involvement in most cases
Advanced symptoms: sensory loss on
digits 1-3, thenar atrophy and weakness
Causes: idiopathic, overuse, change
of tunnel anatomy (fracture, arthrosis,
oedema etc.), diabetes
Treatment:


Splinting of the hand during the night
Surgery
Proximal median nerve damage
1.
1. Weakness of all median nerve muscles
‘oath hand’
2.
2. Weakness of flexion of the distal phalanx of digit 1-2
no sensory loss
Ulnar nerve
Ulnar nerve lesion at the elbow- two
types
Extension
• Retroepicondylar lesion (more common)
• Compression, elbow fracture, arthrosis,
diabetes
• Real cubital tunnel syndrome
Flexion
Ulnar nerve lesion




Numbness of digit 4-5 and
ulnar edge of the hand
Atrophy and weakness of
hypothenar, interosseus
muscles and adductor
pollicis muscle
Tinel-sign at the elbow
Claw hand
Radial nerve
Radial nerve lesion on the upper arm

‘Saturday night palsy’:
nerve compression
during sleep


common in alcoholics
Symptoms: weakness of
wrist and finger extension
(wrist drop); triceps is
normal;
loss of sensation on the
dorsal-radial aspect of
the hand
Radial nerve lesion on the forearm
• Weakness of finger extension (‘finger drop’),
extension of the wrist is only sightly weak,
oftens starts on digit 4-5 → may be confused with
ulnar nerve lesion
• No sensory loss
• Causes: supinator tunnel syndrome due to overuse
Common peroneal nerve
Peroneal nerve damage at the fibular
head




Foot drop, steppage gate
Supination (inversion) and
plantarflexion is normal
Sensory loss on the lateral
aspect of the leg and dorsal
aspect of the foot
Causes: compression






During sleep, in coma
During surgery
Cast
Crossed legs
Squatting (strawberry pickers)
Peroneal tunnel syndrome?
Motoneuron diseases

Progressive loss/degeneration of
motoneurons




Weakness
Atrophy
No sensory or autonomic symptoms
Two major types:


Amyotrophic lateralsclerosis (ALS): both upper
and lower motoneurons are affected
Spinal muscular atrophies / lower motoneuron
syndromes
ALS
First described by Jean Martin Charcot in 1874


Incidence: 2 / 100 000 / year
Prevalence: 6 / 100 000
‘Lou Gehrig’s disease’
ALS- Clinical forms

Sporadic ALS






Lower
motoneuron
onset
Familial ALS (5-10%)



SOD1 mutations
No SOD1 mutations
Autosome recessive



Classic ALS
Autosome dominant


Progressive
muscular
atrophy (PMA)
Classic ALS
Progressive muscular atrophy (PMA)
Primary lateralsclerosis
Progressive bulbar paralysis
Progressive pseudobulbar palsy
Bulbar onset
SOD1 mutation
Chronic juvenile ALS
Upper
motoneuron
onset
X-linked
Frontotemporal dementia
+ ALS (ubiquitin positive)
Progressive
bulbar
paralysis
Primary
lateralsclerosis
ALS- symptoms and course

Mixed signs of upper and lower motor neuron
lesion




Atrophy, fasciculation, cramps
Spasticity, increased reflexes, Babinski
Relentlessly and quickly progressive
Average survival: 2-5 years

Cause of death: respiratory insufficiency
ALS- Clinical syndromes at onset




Asymmetric small hand muscle atrophy and weakness
(segmental distribution)- 60-85%
 Diff. dg.: radiculopathy, ulnar nerve lesion
Proximal arm muscle atrophy and weakness (‘flail’ arm)
 Diff. dg.: radiculopathy
Bulbar onset- 15-40%
 Dysarthria and dysphagia
 Diff. dg.: myasthenia gravis, pseudobulbar paresis
Spastic paraparesis
 Diff. dg: spinal disease
ALS symptoms
ALS- treatment



No cure
Only drug approved for ALS:
riluzol (inhibits the presynaptic
release of glutamate), survival on
riluzol increases by 3-6 months
Supportive treatment:





Riluzol trials
Muscle relaxants
Antidepressants, anxiolytic drugs
PEG in case of severe dysphagia
Assistive devices
Ventilation??? (moral issue)
Infantile and juvenile spinal
muscular atrophies (SMA I-III)



1 / 6-20 000 live births
Autosome recessive
In 95% of patients the mutation is found in
the SMN (survival motoneuron) gene (chr.
5)
Infantile and juvenile spinal
muscular atrophies (SMA I-III)



SMA I: Werdnig-Hoffmann disease. Symptoms are present at birth‘floppy baby’. Death within 1-2 years.
SMA II.: Intermediate form
SMA III: Kugelberg-Welander disease




Symptoms start at age 12-15 years: proximal, symmetric weakness in
the legs
Progression is variable
Differential diagnosis: muscle dystrophies
Dg.: EMG (chronic neurogenic findings), genetic testing
Adult onset spinal muscular atrophies /
lower motoneuron diseases
SMA IV: 'adult onset' proximal spinal muscular atrophy





Onset: 20-40 years of age
Inheritance: 70% AR, 30% AD
Gene is unknown
Symptoms: very slowly progressive limb girdle weakness and
atrophy. May be asymmetric, the quadriceps muscle is very
often affected. No bulbar involvement.
Differential diagnosis: muscle dystrophies, ALS
Adult onset spinal muscular atrophies /
lower motoneuron diseases
dSMA V: 'adult onset' distal spinal muscular atrophy





Onset: 20-40 years of age
Inheritance : AD
Gene is unknown
Symptoms : slowly progressive distal weakness and atrophy
Differential diagnosis: polyneuropathies
Adult onset spinal muscular atrophies /
lower motoneuron diseases
Benign focal amyotrophy





Usually sporadic
More common in men
Starts in young adulthood,
slow progression over a
few years, then stagnation
Symptoms: small hand
atrophy on one side
Differential diagnosis:
ALS, ulnar nerve lesion