Neurology JC032: Generalised Muscle Weakness: Myasthenia Gravis, Myopathy And Myositis, Neuropathy, Neurophysiology 2

Question 1

Definition of terms in Positive sensory symptoms

Answer 1

1. Allodynia (無痛覺得痛)
   - pain due to a stimulus that does not normally provoke pain
2. Hyperalgesia
   - ↑ response to stimulus that is normally painful
3. Hypoalgesia
   - ↓ pain in response to a normally painful stimulus
4. Analgesia
   - absence of pain in response to stimulation that would normally be painful
5. Hyperaesthesia
   - ↑ sensitivity to stimulation, excluding the special senses
6. Hypoaesthesia
   - ↓ sensitivity to stimulation, excluding the special senses
7. 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

Question 2

Generalised weakness

Answer 2

Weakness: Dysfunction of anywhere along motor system

Causes:
1. Nerves —> Polyneuropathies, Motor neuron disease
2. Muscles —> Myopathies
3. NMJ —> Neuromuscular junction disorders

Question 3

1. Polyneuropathies / Generalised peripheral neuropathies

Answer 3

Clinical features:
1. Motor problems
- Weakness
- Wasting (if chronic)
- Fasciculations
- Hyporeflexia
—> S/S of LMN lesions
- Severe: **Bulbar, **Respiratory weakness

2. 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
3. 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)

Question 4

Classification of Polyneuropathies / Generalised peripheral neuropathies

Answer 4

1. Time course
   - acute / subacute / chronic / relapsing
2. Distribution + Pattern of deficits
   - generalised / focal
3. Types of functional fibres involved
   - motor / sensory / autonomic / mixed
   - some can affect one modality more, most are mixed
4. **Axonal (↓ amplitude) / **Demyelinating (↓ conduction velocity) / Mixed

Question 5

Etiologies of Polyneuropathies / Generalised peripheral neuropathies

Answer 5

Very diverse (>100)
1. Systemic disease
- **DM (commonest in developed countries)
- **CTD (self notes)

2. Infectious and Granulomatous neuropathy
   - ***Leprosy (commonest)
3. Inflammatory demyelinating neuropathy
   - **Guillain-Barré syndrome (medical emergency)
   - **Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (self notes)
4. Ischaemic neuropathy
5. Metabolic neuropathy
   - ***Vit deficiency (commonest)
6. ***Hereditary neuropathy (appear in OSCE)
   - Charcot-Marie-Tooth disease (HMSN, SMA)
7. ***Toxins (chemotherapy, environmental toxins)

Question 6

Investigations of Polyneuropathies / Generalised peripheral neuropathies

Answer 6

1. Look for systemic disease
2. ***Electrophysiological studies
3. **CSF
   - CSF protein: good for suspected **inflammatory causes
4. ***Nerve biopsy (seldom indicated)
5. Genetic tests

Question 7

Inflammatory demyelinating neuropathy: Guillain-Barré syndrome

Answer 7

• ***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

2. 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

Question 8

Hereditary neuropathies: Charcot-Marie-Tooth disease

Answer 8

• ***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)

2. **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.

Question 9

Motor neuron disease / Amyotrophic lateral sclerosis (ALS)

Answer 9

• 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)

2. General supportive care
   - **nutritional support
   - **Riluzole, Endaravone?
   - euthanasia vs long-term ventilation

Question 10

2. Myopathies

Answer 10

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

Question 11

***Etiologies of Myopathies

Answer 11

Inherited
1. ***Muscular dystrophies
- Dystrophinopathies (Duchenne, Becker)
- Facioscapulohumeral dystrophy (FSHD)
- Limb-girdle dystrophies (LGMD)

2. Metabolic
   - Mitochondropathies
   - Glycogenoses
   - Lipid myopathies
3. Congenital myopathies
4. Channelopathies
   - Myotonic disorders
   - Periodic paralysis
   - Malignant hyperthermia

Acquired (mostly treatable)
1. ***Inflammatory
- Polymyositis
- Dermatomyositis
- Inclusion body myositis
- Infection-related

2. Complicating systemic diseases
   - **Connective tissue diseases
   - **Endocrinopathies (e.g. Hypo/Hyperthyroidism)
   - Sarcoidosis
   - Critical illness myopathy
3. Toxic myopathies
4. ***Rhabdomyolysis
   - Drug-induced (e.g. Statin myopathy)

Question 12

Investigations of Myopathies

Answer 12

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

Question 13

***Muscular dystrophies

Answer 13

***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)

Question 14

X-linked muscular dystrophies

Answer 14

ONLY in boys, girls are asymptomatic carrier
- ***Gowers’ sign: proximal weakness

1. 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
2. Becker
   - Mild form of Duchenne, more prolonged survival
   - **Partial dystrophin deficiency
   - Continue to ambulate beyond 15 —> death between **40-60

Question 15

Facioscapulohumeral muscular dystrophy (FSHD)

Answer 15

Dystrophy in Facial, Scapular, Humeral muscles:
1. Facial
- SCM
- ***facial weakness
- ptosis

2. Scapular
   - neck muscles
   - ***scapula winging
   - spinati, pectoralis, trapezii
3. Humeral
   - brachio-radialis
   - ***biceps
   - deltoid (compensatory hypertrophy)

May be additional involvement of Femoral / Peroneal muscles

Question 16

Limb-girdle muscular dystrophy (LGMD)

Answer 16

1. Pectoral girdle
   - **pseudohypertrophy of deltoids
   - **neck muscle
2. Pelvic girdle
   - **hip flexors
   - **glutei
   - medial quadriceps
   - tibialis anterior
   - ***pseudohypertrophy of calves, lateral quadriceps

Question 17

Classification of Muscular dystrophies

Answer 17

1. ***Phenotypic (clinical features)
   - FSHD, LGMD
2. Immunohistochemical
   - **Dystrophin-opathies
   - Sarcoglycan-opathies
   - Laminin, caveolin, calpain, dysferlin
   —> Muscle proteoglycans —> Genetic deficit —> Deficiency of these —> **Muscle breakdown —> Muscular dystrophy
3. 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

Question 18

***Inflammatory myopathies / Autoimmune myopathies (AIM)

Answer 18

• 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

2. ***Dermatomyositis
   - Perimysial (sheath of connective tissue that groups muscle fibers into bundles) / Perifascicular inflammation
   - Extra-muscular manifestations
3. ***Overlap myositis (OM)
4. ***Inclusion body myositis (IBM)
   - Inclusion body seen
5. ***Necrotising autoimmune myopathy
   - Muscle fibre necrosis

(6. Non-specific myositis
- cannot be clearly classified histologically)

Question 19

1. Polymyositis

Answer 19

• ***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

Question 20

2. Dermatomyositis

Answer 20

• 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

Question 21

3. Overlap myositis

Answer 21

• 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

Question 22

4. Inclusion body myositis

Answer 22

• 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

Question 23

Investigations of inflammatory myositis

Answer 23

1. ***Myositis-AutoAb (80-80% AIM)
   - Immunoprecipitation / Immunodot
   - ELISA / ALBIA
2. PET scan (malignancy in 20% AIM)
3. ***Electromyography
   - increased insertional activity, fibrillation, CRD, spiky, polyphasic MUAP
4. 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

Question 24

3. NMJ disorders

Answer 24

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)

Question 25

Post-synaptic NMJ disorder: Myasthenia gravis

Answer 25

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

2. 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)

Question 26

Pre-synaptic NMJ disorder: Lambert-Eaton myasthenic syndrome (LEMS), Botulism

Answer 26

• ***Pre-synaptic NMJ disorder
• both result in motor weakness

1. 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
2. Botulism:
   - Clostridium botulinum toxin (food, wound, gut) —> irreversibly block **SNARE protein (required for **presynaptic ACh release)

Question 27

Floppy infant syndrome

Answer 27

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

2. 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

4. Polyneuropathies
   - ***Congenital hypomyelinating polyneuropathy
   - Dejerine-Sottas syndrome
   - Idiopathic motor sensory polyneuropathies
5. Myopathies
   - Genetic myopathies
   - Central core disease
   - Congenital fibre-type disproportion myopathies
   - X-linked myotubular myopathy
6. 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

Question 28

Neurophysiology: Electrodiagnostic (EDx) studies

Answer 28

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

Question 29

EMG (Electromyography)

Answer 29

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

2. Needle EMG
   - analysis of ***bioelectric activities of skeletal muscles
3. 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

Question 30

Indications of electrodiagnostic test

Answer 30

1. Exclude / Confirm peripheral neuropathy / myopathy
2. Distinguish between neuropathy / myopathy
3. Define Peripheral neuropathy clinically
4. Define Myopathy clinically
5. Cervical myelopathy
6. Diagnosing focal / multifocal neuropathies
7. Demyelinating vs Axonal degenerative neuropathies
8. Assess severity of neuropathy
9. Monitor progress of neuropathy / myopathy
10. Monitor response to treatment
11. Prognosis after nerve trauma + guide intervention
12. EMG-guided BTx therapy
13. Localising focal neuropathy e.g. radiculopathy, plexopathies, lesions at more distal site
14. Locating specific muscle for injection

CANNOT demonstrate underlying cause of peripheral neuropathy / myopathy —> require further investigations e.g. biochemical markers, genetic markers, histopathology