Neurology JC032: Generalised Muscle Weakness: Myasthenia Gravis, Myopathy And Myositis, Neuropathy, Neurophysiology 2 Flashcards
Definition of terms in Positive sensory symptoms
- Allodynia (無痛覺得痛)
- pain due to a stimulus that does not normally provoke pain - Hyperalgesia
- ↑ response to stimulus that is normally painful - Hypoalgesia
- ↓ pain in response to a normally painful stimulus - Analgesia
- absence of pain in response to stimulation that would normally be painful - Hyperaesthesia
- ↑ sensitivity to stimulation, excluding the special senses - Hypoaesthesia
- ↓ sensitivity to stimulation, excluding the special senses - Hyperpathia (越黎越痛)
- a painful syndrome characterised by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an ↑ threshold
Generalised weakness
Weakness: Dysfunction of anywhere along motor system
Causes:
1. Nerves —> Polyneuropathies, Motor neuron disease
2. Muscles —> Myopathies
3. NMJ —> Neuromuscular junction disorders
- Polyneuropathies / Generalised peripheral neuropathies
Clinical features:
1. Motor problems
- Weakness
- Wasting (if chronic)
- Fasciculations
- Hyporeflexia
—> S/S of LMN lesions
- Severe: **Bulbar, **Respiratory weakness
- Sensory problems
- Negative (cannot perceive what they should be perceiving)
- Positive (perceive something that they should not be perceiving)
- **Length-dependent process: Longest nerve will be symptomatic first —> Stocking —> **Glove pattern of sensory disturbance - Autonomic problems
- CVS: **tachycardia, exercise intolerance, cardiac denervation, painless MI, **postural hypotension, heat intolerance, alterations in skin blood flow
- GI: **esophageal dysfunction, gastroparesis diabeticorum, diarrhoea / constipation, **faecal incontinence
- Genitourinary: **erectile dysfunction, retrograde ejaculation, cystopathy, **neurogenic bladder
DDx (SpC Medicine):
- Cervical myelopathy (e.g. cervical spondylosis)
- Different etiologies of Polyneuropathies (DM, Vit deficiency, Drug-induced, Inflammatory)
Classification of Polyneuropathies / Generalised peripheral neuropathies
- Time course
- acute / subacute / chronic / relapsing - Distribution + Pattern of deficits
- generalised / focal - Types of functional fibres involved
- motor / sensory / autonomic / mixed
- some can affect one modality more, most are mixed - **Axonal (↓ amplitude) / **Demyelinating (↓ conduction velocity) / Mixed
Etiologies of Polyneuropathies / Generalised peripheral neuropathies
Very diverse (>100)
1. Systemic disease
- **DM (commonest in developed countries)
- **CTD (self notes)
- Infectious and Granulomatous neuropathy
- ***Leprosy (commonest) - Inflammatory demyelinating neuropathy
- **Guillain-Barré syndrome (medical emergency)
- **Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (self notes) - Ischaemic neuropathy
- Metabolic neuropathy
- ***Vit deficiency (commonest) - ***Hereditary neuropathy (appear in OSCE)
- Charcot-Marie-Tooth disease (HMSN, SMA) - ***Toxins (chemotherapy, environmental toxins)
Investigations of Polyneuropathies / Generalised peripheral neuropathies
- Look for systemic disease
- ***Electrophysiological studies
-
**CSF
- CSF protein: good for suspected **inflammatory causes - ***Nerve biopsy (seldom indicated)
- Genetic tests
Inflammatory demyelinating neuropathy: Guillain-Barré syndrome
- ***Acute / Subcute
- ***Generalised
- Mixed (some pure motor / sensory)
- Demyelinating / Axonal forms
- **Rapidly progressive Flaccid paralysis, Areflexia, **Raised CSF protein ***without ↑ in cells
- Not uncommon: 10-20 cases per year, incidence 1-2 per 100,000 per year
Dysimmune disorder
- **Immune-mediated, Inflammatory PN
- Preceded by mild **viral / bacterial infection (URTI, GE) (2/3 of cases)
—> trigger immune response **misdirected against **peripheral nervous system
—> Subacute / Acute neuritis onset over a few **days
—> peaks / plateau about 2-*4 weeks
- Inflammatory demyelination
—> impaired nerve function - Aka: AIDP (Acute Inflammatory Demyelinating Polyneuropathy)
- Other variants:
—> AMAN (Acute motor axonal neuropathy), AMSAN (Acute motor and sensory axonal neuropathy) (axonal forms affecting motor fibres + sensory fibres)
—> Ataxic form (affect mainly sensory fibres)
—> MFS (Miller Fisher syndrome), Polyneuritis cranialis (affect mainly cranial nerves)
Clinical features:
1. Ascending weakness with facial involvement (CN neuropathy (SpC Medicine))
- respiratory failure 30%
2. **Sensory symptoms
3. Hypo / Areflexia
4. **Muscle ache
5. ***Autonomic dysfunction (>2/3 patients) (e.g. BP variations, cardiac arrhythmias) (worse prognosis if present (SpC Medicine))
(6. Usually affect lower limb first before upper limb (SpC Medicine))
Investigations:
1. **↑ CSF protein **without pleocytosis
2. **Electrophysiology
3. **Anti-gangliocyte Ab (some cases)
Treatment:
1. General supportive measures
- **Monitor FVC, ABG, BP, ECG, bulbar function
- **Mechanical ventilation for respiratory failure
- General care for immobility, **nutritional support
- Treat complications
—> prevention, monitoring, detection, treatment of complication e.g. **respiratory failure, ***aspiration pneumonia, sepsis, cardiac, haemodynamic events during acute course of illness
- Specific immunotherapy
- **Plasmapheresis (SpC Medicine: Gold standard)
- **High dose IVIG (SpC Medicine: Convenient, additional benefit of preventing infection since bedbound)
Prognosis:
- Mortality: 2 (with appropriate treatment) - 12%
- 20% permanent disability
- 10% severe
Hereditary neuropathies: Charcot-Marie-Tooth disease
- ***Chronic
- Mixed / Motor
- Demyelinating / Axonal forms
- Hereditary condition(s)
- **Early onset, **Slowly progressive neuropathy
- ***Distal wasting
- Deformities: **Foot drop, **Pes cavus (high foot arch) (indicate childhood disease / onset during development —> also seen in poliomyelitis, cerebral palsy etc. (vs late onset disease e.g. diabetic neuropathy))
Charcot-Marie-Tooth disease is NOT just one disease —> many hereditary neuropathies
1. ***Hereditary motor-sensory neuropathies (HMSN)
- Demyelinating / Hypomyelination form
- Axonal degenerative form
- Autosomal dominant / recessive, X-linked
- Different identifiable mutations: PMP22, MPZ, MFN2, GJB1 etc.
- HMSN-1 (demyelinating PN): AD, AR, X-linked
- HMSN-2 (axonal PN): AD, AR, X-linked
- HMSN-3 (DSD)
- HMSN-4 (Refsum disease)
- HMSN-5 (axonal PN with pyramidal signs)
- HMSN-6 (with optic atrophy, HMSN-2a)
- HMSN-7 (with retinitis pigmentosa)
-
**Hereditary motor neuropathies
- **Spinomuscular atrophies (SMA)
—> SMA type 1 (60%), type 2 (30%), type 3 (20%), type 4
- Different identifiable mutations: UBA1, DYNC1H1, VAPB etc.
Motor neuron disease / Amyotrophic lateral sclerosis (ALS)
- Chronic
- Generalised
- Motor
- Axonal
- ***Idiopathic motor neuropathy
-
**Progressive degeneration of **α motor neurons:
1. **Anterior horn cells (LMN deficits)
2. **Corticospinal tract (UMN deficits)
Types:
1. ***ALS
2. PLS (Primary lateral sclerosis)
3. PMA (Progressive muscular atrophy)
4. PBP (Progressive bulbar palsy)
5. Pseudobulbar palsy
- ***NO sensory involvement
- Onset: middle to old age (peak ***6th decade)
- Incidence: 1 per 100,000 per year
- M:F = 3:2
- ***~10% Familial (SOD1, C9orf72, TARDBP, FUS)
Treatment:
1. ***No specific treatment
- die within 3 years (aspiration, respiratory failure, death)
- General supportive care
- **nutritional support
- **Riluzole, Endaravone?
- euthanasia vs long-term ventilation
- Myopathies
Clinical features:
1. **Proximal weakness
2. **Waddling gait (unable to stabilise pelvis when walking —> pelvic tilting)
3. **Bulbar, Respiratory weakness
4. **Muscle tenderness (inflammatory myopathies)
5. Sensory disturbance, Sphincter dysfunction (Pure myopathies does not involve sensory disturbance)
DDx of Proximal muscle weakness:
1. **Metabolic (e.g. DM)
2. **Electrolyte imbalance (e.g. HypoK)
3. **Drug induced (e.g. Steroid —> Cushing, Statin)
4. **Paraneoplastic
5. ***Neuropathy
***Etiologies of Myopathies
Inherited
1. ***Muscular dystrophies
- Dystrophinopathies (Duchenne, Becker)
- Facioscapulohumeral dystrophy (FSHD)
- Limb-girdle dystrophies (LGMD)
- Metabolic
- Mitochondropathies
- Glycogenoses
- Lipid myopathies - Congenital myopathies
- Channelopathies
- Myotonic disorders
- Periodic paralysis
- Malignant hyperthermia
Acquired (mostly treatable)
1. ***Inflammatory
- Polymyositis
- Dermatomyositis
- Inclusion body myositis
- Infection-related
- Complicating systemic diseases
- **Connective tissue diseases
- **Endocrinopathies (e.g. Hypo/Hyperthyroidism)
- Sarcoidosis
- Critical illness myopathy - Toxic myopathies
- ***Rhabdomyolysis
- Drug-induced (e.g. Statin myopathy)
Investigations of Myopathies
To identify reversible causes
1. Look for systemic diseases
2. **Electrophysiological studies
3. **Muscle enzymes (e.g. creatine kinase)
4. ***Muscle biopsy (not cause irreversible loss of function vs nerve biopsy)
5. Genetic tests
***Muscular dystrophies
***Hereditary myopathies
Old definition:
- Inherited disease
- All symptoms due to **muscle weakness
- **Progressive
- No histopathological abnormalities other than degeneration and regeneration
***Clinical classification:
X-linked recessive:
1. Duchenne (DMD)
2. Becker (BMD)
AD / AR:
3. Facioscapulohumeral (FSHD)
4. Limb-girdle (LGMD)
5. Myotonic dystrophy (MyoD)
X-linked muscular dystrophies
ONLY in boys, girls are asymptomatic carrier
- ***Gowers’ sign: proximal weakness
- Duchenne
- Mild delay in motor milestones
- **Progressive weakness (from 3-5) —> wheelchair-bound (9-12) —> respiratory failure + death (by late teens)
- **Cardiomyopathy
- Mild mental impairment
- ***No / Few dystrophin-positive fibres - Becker
- Mild form of Duchenne, more prolonged survival
- **Partial dystrophin deficiency
- Continue to ambulate beyond 15 —> death between **40-60
Facioscapulohumeral muscular dystrophy (FSHD)
Dystrophy in Facial, Scapular, Humeral muscles:
1. Facial
- SCM
- ***facial weakness
- ptosis
- Scapular
- neck muscles
- ***scapula winging
- spinati, pectoralis, trapezii - Humeral
- brachio-radialis
- ***biceps
- deltoid (compensatory hypertrophy)
May be additional involvement of Femoral / Peroneal muscles
Limb-girdle muscular dystrophy (LGMD)
- Pectoral girdle
- **pseudohypertrophy of deltoids
- **neck muscle - Pelvic girdle
- **hip flexors
- **glutei
- medial quadriceps
- tibialis anterior
- ***pseudohypertrophy of calves, lateral quadriceps
Classification of Muscular dystrophies
- ***Phenotypic (clinical features)
- FSHD, LGMD - Immunohistochemical
- **Dystrophin-opathies
- Sarcoglycan-opathies
- Laminin, caveolin, calpain, dysferlin
—> Muscle proteoglycans —> Genetic deficit —> Deficiency of these —> **Muscle breakdown —> Muscular dystrophy - Genetic
- X-linked (DMD, BMD) —> Now classified as ***Deletion in dystrophin gene
- AD (LGMD1, FSHD) —> Now classified by underlying genetic mutations —> Genetic heterogeneity
- AR (LGMD2) —> Now classified by underlying genetic mutations —> Similar phenotypic but Different genotypes —> Genetic heterogeneity
***Inflammatory myopathies / Autoimmune myopathies (AIM)
- Immune-mediated conditions —> some will respond to immune therapy
- ***Inflammatory infiltration (or necrosis) of skeletal muscle
- **Limb-girdle pattern of weakness, occasionally **myalgia
- Some have associated ***Extra-muscular manifestation: Lung, Skin, Eye disease e.g. Dermatomyositis
- Incidence: 5 / 100,000
Big 5:
1. ***Polymyositis (PM)
- Endomysial inflammation
- ***Dermatomyositis
- Perimysial (sheath of connective tissue that groups muscle fibers into bundles) / Perifascicular inflammation
- Extra-muscular manifestations - ***Overlap myositis (OM)
- ***Inclusion body myositis (IBM)
- Inclusion body seen - ***Necrotising autoimmune myopathy
- Muscle fibre necrosis
(6. Non-specific myositis
- cannot be clearly classified histologically)
- Polymyositis
- ***Symmetric proximal myositis + absence of histopathological signs of other myopathies / typical rash of DM
- ***Endomysial mononuclear inflammatory infiltrates
- Previously considered relatively prevalent
—> Heterogenous group of disorders: many PM cases in fact sIBM / OM
—> True idiopathic PM rare
—> Similarities with other AIM —> diagnosis of exclusion
- Dermatomyositis
- Heterogenous group of Inflammatory myopathies
- F > M, particularly adult cases
- ***Subacute / Insidiously progressive proximal weakness, sometimes with myalgia
- ***Skin manifestations (heliotrope rash, malar, V + shawl rash, Gottron papules, mechanic’s hands, periungal erythema, gingival and oral involvement)
- ***Interstitial lung disease, Polyarthritis
- Juvenile: Calcinosis, GI involvement
- ***associated with neoplasia in 6-45% cases (breast, lung, pancreas, colon, cervix, NPC, 2 years before, 3 years after)
- Complement-mediated microangiopathy: **Perimysial + **Perivascular inflammation (macrophages, B cells, CD4+ plasmacytoid dendritic cells), Perifascicular atrophy, Capillary depletion
—> Anti-TIF-1γ: neoplasia, dysphagia
—> Anti-NXP-2: neoplasia in adults, calcinosis in children
—> Anti-Mi2: rapid onset, but low risk neoplasia, ILD, good response to immunotherapy
—> Anti-MDA-5: amyopathic DM, polyarthritis, severe ILD
—> Anti-SAE: amyopathic DM, in Asians associated ILD
- Overlap myositis
- Troyanov classification: Myositis with overlap features (other than rash) / Overlap AutoAb
- With other connective tissue diseases:
—> Anti-U1RNP (SLE/MCTD-OM)
—> Anti-PM/Scl, Anti-Ku, Anti-U3RNP (SSc-OM)
—> Heterogeneous / Non-specific muscle histology - Anti-synthetase syndrome:
—> Acute myopathy, fever, ILD, polyarthritis, Raynaud’s, mechanic’s hand
—> Anti-Jo1 (anti-tRNA-synthetase)
—> Anti-PL-7, Anti-PL-12 (amyopathic variant), Anti-OJ, Anti-KS, Anti-EJ, Anti-Zo, Anti-Ha-YRS
- Inclusion body myositis
- Commonest AIM >=50 yo
- M > F
- Quadriceps, Volar muscles, Dorsiflexors —> Axial muscles
- Slowly progressive, life expectancy not significantly affected
- CK normal / up to 10x above ULN
- **Inflammatory infiltrates (CD8+ T cells, macrophages) invading **non-necrotic muscle fibres, Rimmed vacuoles, Congophilic inclusions (amyloidogenic proteins)
- Anti-cytosolic 5’-nucleotidase 1A (cN1A)
- ***Immunotherapy NOT beneficial
Investigations of inflammatory myositis
- ***Myositis-AutoAb (80-80% AIM)
- Immunoprecipitation / Immunodot
- ELISA / ALBIA - PET scan (malignancy in 20% AIM)
- ***Electromyography
- increased insertional activity, fibrillation, CRD, spiky, polyphasic MUAP - Muscle MRI
- fat suppression / STIR: signal changes in muscle and fascia from inflammation, edema / ***muscle replacement by connective tissue
- guiding biopsy site (also EMG) and monitoring disease activity / treatment response
- NMJ disorders
2 types:
1. Pre-synaptic (of motor end plate)
2. Post-synaptic (of motor end plate)
Clinical features (similar for both types):
1. Fluctuating weakness, **Fatigability
2. **Extra-ocular muscles manifestation (affected first)
3. Limb, **Bulbar, **Respiratory weakness (more severe disease)
4. Sensory disturbance, Sphincter dysfunction (Pure NMJ disorder does not involve sensory disturbance)
Post-synaptic NMJ disorder: Myasthenia gravis
Post-synaptic NMJ disorder
- Ab binding + ***blocking ACh receptor —> Motor dysfunction
- Prevalence 5 per 100,000
Clinical features:
1. Fluctuating weakness
2. **Fatigability
3. Ocular (first) —> **Ptosis, Diplopia, **Ophthalmoplegia
4. +/- Generalised involvement (*Generalised MG)
2 populations of MG by age:
1. Young
- predominantly female
- associated other autoimmune disorder e.g. **Graves’, Thyrotoxicosis
- might have **Thymic hyperplasia
- Older
- Paraneoplastic condition —> associated with ***Thymoma
- M:F = 1:1
Investigations:
1. **Anti-AChR Ab —> confirm diagnosis of MG
(Other Ab: Anti-MuSK Ab, Anti-Striated muscle Ab)
2. Electrophysiology **Tensilon test —> demonstrate impairment of motor functions
- IV injection of **Edrophonium (short acting AChE inhibitor —> transiently ↑ synaptic ACh level to overcome blocking effect of Anti-AChR Ab —> reversing weakness in MG)
3. CT thorax —> Thyroid / Thymus
4. **Thyroid function +/- other AutoAb
5. ***Thymic pathologies
(6. Ice pack tests)
Treatment:
1. Supportive measures
2. Specific treatment
- AChE inhibitor (Pyridostigmine (Mestinon): longer acting) (for mild cases)
- **Thymectomy (refractory cases / if thymoma identified)
- **Immunotherapy (severe cases)
—> Corticosteroids
—> Steroid-sparing agents e.g. **Azathioprine, Rituximab, Mycophenolate mofetil
—> **Plasmapheresis / ***High dose IVIG (very severe / acute exacerbation of MG which impair Respiratory + Bulbar function)
Pre-synaptic NMJ disorder: Lambert-Eaton myasthenic syndrome (LEMS), Botulism
- ***Pre-synaptic NMJ disorder
- both result in motor weakness
- Lambert-Eaton myasthenic syndrome (LEMS):
- Ab against **Voltage-gated Ca channel —> blockage causes failure of **ACh release at pre-synaptic motor end plate
- associated with ***SCLC - Botulism:
- Clostridium botulinum toxin (food, wound, gut) —> irreversibly block **SNARE protein (required for **presynaptic ACh release)
Floppy infant syndrome
Etiologies:
**UMN pattern of weakness (also result in floppiness ∵ CNS not yet fully developed in infants i.e. also LMN signs)
1. Cerebral hypotonia
- Chromosomal disorders
—> Trisomy
—> Partial chromosome deletion / duplication
—> **Prader-Willi syndrome
- Static encephalopathy
—> **Cerebral malformation
—> Perinatal distress
—> **Postnatal cerebral injury
—> Idiopathic disorders - Single gene disorders
—> Zellweger’s syndrome
—> Neonatal adrenoleukodystrophy
—> Oculocerebral renal syndrome
—> Acid maltase deficiency
—> Carbohydrate-deficient glycoprotein syndrome
- Spinal cord disorders
- Hypoxic-ischaemic myelopathy
- Trauma
- Congenital malformation
**LMN pattern of weakness (i.e. floppiness)
3. Motor neuronopathies
- **Spinal muscular atrophy
- Congenital cervical spinal muscular atrophy
- Infantile neuronal degeneration
- Neurogenic arthrogryposis
- Vaccine-associated poliomyelitis
- Incontinentia pigmenti
- Polyneuropathies
- ***Congenital hypomyelinating polyneuropathy
- Dejerine-Sottas syndrome
- Idiopathic motor sensory polyneuropathies - Myopathies
- Genetic myopathies
- Central core disease
- Congenital fibre-type disproportion myopathies
- X-linked myotubular myopathy - Disorders of neuromuscular transmission
- Congenital defect of NMJ
- In-utero passive transfer of maternal antijunction Ab
- Autoimmune MG
- Infantile botulism
Implications: Extensive investigations required + Diagnosis very difficult
Neurophysiology: Electrodiagnostic (EDx) studies
By recording electrical activities in excitable tissues:
- Objective assessment of ***PNS function (CNS cannot)
- Generate quantitative + reproducible information
- Non-invasive (majority)
Depolarisation of a peripheral nerve induced by a small electric current
—> propagating membrane action potential recorded directly over Sensory / Mixed nerve / Muscle for motor nerves
—> estimate conduction velocity in a nerve segment by latency differences
- Problems affecting myelin (i.e. **Demyelinating neuropathy) (e.g. Inflammatory neuropathies) —> **Velocity slowing
- Problems causing axonal loss (i.e. **Axonal neuropathy) —> Attenuation of action potential **amplitudes
EMG (Electromyography)
EMG (Electromyography) (Peripheral electrode diagnostic test) (CNS cannot):
1. Nerve conduction test
- assessment of ***large fibre conduction function
- analysis of neuronal signals generated by electrical activation
- Needle EMG
- analysis of ***bioelectric activities of skeletal muscles - Special techniques for NMJ conduction
Inserting a needle electrode into muscle being tested
—> Subject asked to contract a muscle
—> Signal within pickup area will summate to form a ***motor unit action potential
Neuropathies: Denervated muscle fibres
—> reinnervated by surviving neighbours
—> **expanding motor unit territory by up to 40%
—> activation of **enlarged motor unit
—> formation of ***large, bizarre looking signal
Myopathies: **Reduced no. of muscle fibres per motor unit
—> **less summation effect
—> ***small, spiky signal
Indications of electrodiagnostic test
- Exclude / Confirm peripheral neuropathy / myopathy
- Distinguish between neuropathy / myopathy
- Define Peripheral neuropathy clinically
- Define Myopathy clinically
- Cervical myelopathy
- Diagnosing focal / multifocal neuropathies
- Demyelinating vs Axonal degenerative neuropathies
- Assess severity of neuropathy
- Monitor progress of neuropathy / myopathy
- Monitor response to treatment
- Prognosis after nerve trauma + guide intervention
- EMG-guided BTx therapy
- Localising focal neuropathy e.g. radiculopathy, plexopathies, lesions at more distal site
- Locating specific muscle for injection
CANNOT demonstrate underlying cause of peripheral neuropathy / myopathy —> require further investigations e.g. biochemical markers, genetic markers, histopathology
