motoneuron betegségek mononeuropathiák izomdystrophiák
TRANSCRIPT
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