PolyneuropathiesMononeuropathies

Motoneuron diseases

Zsuzsanna Arányi

Peripheral nerve

Motor, sensory and autonomic fibersFiber 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 – reinnervationRemyelination Proximo-distal

axon regenerationCollateral reinnervation(in case of partial nervedamage)

2-12 weeks 1 mm/dayIntact basallamina/endoneuriumis needed

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

Symmetric Asymmetric

Time course 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 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

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 antibodiesFibrous 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 non-traumatic 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 Schwann-

cell 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

2 g/kg bw in 2-5 days, monthly for 3 months maintanance treatment

Corticosteroids methylprednisolon 1 mg/kg bw, later gradual reduction

Plasmapheresis

Mononeuropathies- causes Trauma

cutting, laceration and stretching of the nerve Compression

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.

2.

1. Weakness of all median nerve muscles ‘oath hand’

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

• Retroepicondylar lesion (more common)• Compression, elbow fracture, arthrosis, diabetes

• Real cubital tunnel syndrome

Extension 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

ALSFirst described by Jean Martin Charcot in 1874

Incidence: 2 / 100 000 / year Prevalence: 6 / 100 000

‘Lou Gehrig’s disease’

ALS- Clinical forms

Classic ALS

Lowermotoneurononset

Progressivemuscularatrophy (PMA)

Bulbar onset

Progressivebulbarparalysis

Uppermotoneurononset

Primarylateralsclerosis

Sporadic ALS Classic ALS 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)

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

Riluzol trials

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