1. Polyneuropathies Mononeuropathies Motoneuron diseases
Zsuzsanna Arányi

2. Peripheral nerve Motor, sensory and autonomic fibers
Fiber types according to diameter:
A fibers μm in diameter; myelinated motor and sensory fibers
B fibers- 1-3 μm in diameter; myelinated autonomic fibers
C fibers μm in diameter; non-myelinated autonomic and pain fibers

3. 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
No regeneration without nerve suture

4. Nerve regeneration – reinnervation
Remyelination
Proximo-distal
axon regeneration
Collateral reinnervation
(in case of partial nerve
damage)
2-12 weeks
1 mm/day
Intact basal
lamina/endoneurium is needed
Starts within 4-6 weeks

5. 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!

6. Classification of polyneuropathies
Clinical presentation
Symmetric
Asymmetric
Time course
Acute
Chronic
Etiology
Pathology
Axonal
Demyelinative
Small-fiber

7. Clinical forms of polyneuropathies
Chronic, symmetric, distal and predominantly sensory polyneuropathies
Mononeuropathy multiplex
Purely motor or sensory polyneuropathies
Autonomic polyneuropathies
Acute polyneuropathies

8. 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.)

9. 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’

10. 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

11. 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

12. 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

13. Polyneuropathies associated with diabetes mellitus
Distal symmetric sensory polyneuropathy
Mononeuropathies- carpal tunnel syndrome, ulnar nerve lesion
Cranial nerve lesions- oculomotor nerve palsy
Autonomic neuropathy- sexual and urinary disturbance, gastroparesis and diarrhoea etc.
Diabetic amyotrophy- painful, asymmetric, proximal weakness (plexopathy?)
Radiculopathy- lumbar, thoraco-abdominal

14. 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

15. 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

16. 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

17. 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)

18. Diabetic foot
Related to diabetic sensory neuropathy and peripheral artery disease
Diabetic foot ulcers precede 85% of non-traumatic lower limb amputations
Life-time prevalence of foot ulcers is 15% in diabetic patients

19. 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: / /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

20. Pathomechanism of GBS

21. 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

22. 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.)

23. Guillain-Barré syndrome- diagnosis
Normal neurography Segmental demyelination
Conduction block Temporal dispersion

24. Guillain-Barré syndrome- diagnosis and treatment
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!

25. Chronic inflammatory demyelinative polyneuropathy (CIDP)
Autoimmune disease
Prevalence: 1-2/
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%)

26. 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 Schwann-cell proliferation (‘onion bulb’ formation)
infiltration of inflammatory cells
MRI: hypertrophy of peripheral nerves and nerve roots, contrast enhancement

27. CIDP- nerve biopsy
‘onion bulbs’

28. CIDP- MRI
Hypertrophied trigeminal nerves

29. CIDP treatment IVIG Corticosteroids Plasmapheresis
2 g/kg bw in 2-5 days, monthly for 3 months
maintanance treatment
Corticosteroids
methylprednisolon 1 mg/kg bw, later gradual reduction
Plasmapheresis

30. Mononeuropathies- causes
Trauma
cutting, laceration and stretching of the nerve
Compression
often iatrogenic
Tunnel syndromes
Ischemia

31. 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

32. Median nerve

33. Distal median nerve damage: carpal tunnel syndrome
Incidence: / /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

34. Proximal median nerve damage1.
1. Weakness of all median nerve muscles ‘oath hand’ 2.
2. Weakness of flexion of the distal phalanx of digit no sensory loss

35. Ulnar nerve

36. Ulnar nerve lesion at the elbow- two types
Extension
Flexion
Retroepicondylar lesion (more common)
Compression, elbow fracture, arthrosis, diabetes
Real cubital tunnel syndrome

37. 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

38. Radial nerve

39. 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

40. 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

41. Common peroneal nerve

42. 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?

43. 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

44. ALS First described by Jean Martin Charcot in 1874
Incidence: 2 / / year
Prevalence: 6 /
‘Lou Gehrig’s disease’

45. ALS- Clinical forms Classic ALS Sporadic ALS Familial ALS (5-10%)
Progressive muscular atrophy (PMA)
Primary lateralsclerosis
Progressive bulbar paralysis
Progressive pseudobulbar palsy
Familial ALS (5-10%)
Autosome dominant
SOD1 mutations
No SOD1 mutations
Autosome recessive
SOD1 mutation
Chronic juvenile ALS
X-linked
Frontotemporal dementia + ALS (ubiquitin positive)
Progressive
muscular
atrophy (PMA)
Lower
motoneuron
onset
Classic ALS
Upper
motoneuron
onset
Bulbar onset
Progressive
bulbar
paralysis
Primary
lateralsclerosis

46. 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

47. ALS- Clinical syndromes at onset
Asymmetric small hand muscle atrophy and weakness (segmental distribution) %
Diff. dg.: radiculopathy, ulnar nerve lesion
Proximal arm muscle atrophy and weakness (‘flail’ arm)
Diff. dg.: radiculopathy
Bulbar onset %
Dysarthria and dysphagia
Diff. dg.: myasthenia gravis, pseudobulbar paresis
Spastic paraparesis
Diff. dg: spinal disease

48. ALS symptoms

49. 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:
Muscle relaxants
Antidepressants, anxiolytic drugs
PEG in case of severe dysphagia
Assistive devices
Ventilation??? (moral issue)
Riluzol trials

50. Infantile and juvenile spinal muscular atrophies (SMA I-III)
1 / live births
Autosome recessive
In 95% of patients the mutation is found in the SMN (survival motoneuron) gene (chr. 5)

51. 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 years: proximal, symmetric weakness in the legs
Progression is variable
Differential diagnosis: muscle dystrophies
Dg.: EMG (chronic neurogenic findings), genetic testing

52. Adult onset spinal muscular atrophies / lower motoneuron diseases
SMA IV: 'adult onset' proximal spinal muscular atrophy
Onset: 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

53. Adult onset spinal muscular atrophies / lower motoneuron diseases
dSMA V: 'adult onset' distal spinal muscular atrophy
Onset: years of age
Inheritance : AD
Gene is unknown
Symptoms : slowly progressive distal weakness and atrophy
Differential diagnosis: polyneuropathies

54. 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