• Late adult onset: - Welander - Markesbery/Udd • Early adult onset: - Nonaka - Miyoshi (dysferlinopathy) - Laing - Desmin (myofibrillar) myopathy - Centronuclear myopathy - Myotonic dystrophy - Debrancher deficiency - Miyoshi (dysferlinopathy)

Myopathy, myasthenia and neuropathy Flashcards by Luke Bonavia

10 patterns of myopathies

Proximal “Limb‐Girdle” Weakness
Distal Weakness
Proximal Arm/Distal Leg (Scapuloperoneal) Weakness
Distal Arm/Proximal Leg Weakness
Ptosis with or without Ophthalmoplegia
Prominent Neck Extensor Weakness
Bulbar Weakness
Episodic Weakness/Pain/Rhabdo
Episodic Weakness Unrelated to Exercise
Stiffness/Inability to Relax

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Sites of myopathic pathology

Muscle Channel

Muscle Structure
Membrane proteins
Sarcomere proteins
Nuclear proteins
Muscle Metabolism

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6 questions to address myopathy

Patient’s symptoms and signs?
Temporal evolution?
Family history of a myopathic disorder?
Precipitating factors that trigger episodic weakness or myotonia?
Associated systemic signs or symptoms?
Distribution of weakness?

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Types of hereditary myopathies

Muscular dystrophies
Congenital myopathies
Myotonias
Channelopathies
Metabolic myopathies
Mitochondrial myopathies

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Types of acquired myopathies

Inflammatory/Immune myopathies
Myopathies associated with systemic illness
Endocrine myopathies
Drug‐induced/toxic myopathies

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Distal myopathies

• Late adult onset:

Welander
Markesbery/Udd

• Early adult onset:

Nonaka
Miyoshi (dysferlinopathy)
Laing
Desmin (myofibrillar) myopathy
Centronuclear myopathy
Myotonic dystrophy
Debrancher deficiency
Miyoshi (dysferlinopathy)

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Stiffness/inability to relax

Improves with exercise:

-Myotonia – Na++ or Cl‐ channelopathies

Worsens with exercise:

Paramyotonia congenita – Na++ channelopathy

With fixed weakness:

Myotonic dystrophy (DM1)
Proximal myotonic myopathy (DM2)
Becker’s disease (AR Cl‐ channelopathy)

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Myopathy genetics - X linked diseases

X‐linked - Duchenne MD, Becker MD, Emery‐Dreifuss

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Myopathy genetics - Autosomal dominant disease

Autosomal dominant - FSH, LGMD, OPMD, Myotonic dystrophy, PP, PC, Thomsen’s disease, Central core myopathy

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Myopathy genetics - Autosomal recessive disease and maternal transmissioon

Autosomal recessive: LGMD, Metabolic myopathies, Becker’s myotonia

Maternal transmission: Mitochondrial myopathies

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Clinical features of myotonic dystrophy

CTG triplet repeat genetic mutation with anticipation with each generation

Myotonia

Weakness distal > proximal

Sternomastoid and temporalis wasting

Frontal balding

Diabetes/insulin resistance, hypogonadal, hypopituitary

Cataracts

Intellectual impairment, avoidant personality

Cardiac conduction defects-arrhythmias-yearly ECG

Cardiomyopathy- late

Respiratory and Swallowing difficulties

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Differentials for recurrent weakness

Myasthenia, periodic paralysis, CIDP, (porphyria)

Metabolic defects

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Differentials for recurrent myalgia

Connective tissue/rheumatoid disease, CIDP, myositis, metabolic defects

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Differentials for recurrent rhabdomyolysis

Toxic, viral myositis, dystrophy, metabolic defects

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Types of metabolic myopathies

Lipid storage disorder - develops with prolonged sustained exercise and fasting; most common familial form - Carnitine Palmitoyl Transferase; biopsy may be normal or have lipid accumulation

Glycogen storage disorder- occurs with brief intense exercise- McArdle’s myophosphorylase deficiency

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Genetics of spinomuscular atrophy

Autosomal recessive gene due to loss of SMN1 on chromosome 5q

Variable penetrance with more severe disease due to loss of “back up” SMN2 genes

4 clinical phenotypes

SMA 1 (2 or 3 copies SMN2) -Severe, neonatal, respiratory failure, death in infancy

SMA 2 (3 copies) - never stand, death after 2yo

SMA 3 (4-8) - stand, death in adulthood

SMA 4 (less marked mutation) - can be adult onset, can ambulate lifelong, normal life expectancy

Genetic therapies for DMD and SMA

Nusinersen, mRNA antisense for interon 7(SMA)

AVXS101 - viral vector replacement of SMA gene

Eteplirsen - mRNA antisense for exon 51, prevent splicing

Clinical features of inflammatory myopathies

F>M
Weakness: proximal
Onset: subacute
Muscle enzymes: elevated
EMG: irritable myopathy
MRI: evidence of inflammation
Muscle biopsy: inflammation, necrosis, etc…
Responsive to immunosuppressive therapy

4 Types of immune mediated myopathies

Polymyositis (PM)

Dermatomyositis (DM)

Immune-mediated necrotizing myopathy (IMNM)

Inclusion body myositis (IBM):

Anti-HMG-CoAR induced myopathies

Biopsy: necrotizing in 80%

Nearly 100% proximally weak

75% with myalgias

Maximum CK ~10,000

Requires immunosuppressive therapy to treat

Myopathy associated with statin exposure (~70%)

Progresses despite discontinuing statins

Diagnosis of inclusion body myositis

Degenerative disease of muscle due to cytoplasmic aggregates TDP43

Inclusions 20% of histology; mostly perifascicular inflammation

Anti-NTC51 abs highly specific, titre predicts severity also

Poor response to steroid therapy

Cancers commonly associated with dermatomyositis

Ovarian

Lung

Pancreas

NHL

Stomach

Diagnosis of cancer in DM

anti-p155 antibody has high specific and good NPV for cancer detection in DM

Treatment for myasthenia gravis

IVIg for exacerbation

Pyridostimine (Not effective in MuSK positive patients)

Corticosteroids

Plasmapheresis for crisis

Thymectomy

Other immunosuppressives (marginally effective)

Differentials for myasthenia gravis

CNIII, CNIV and/or CNVI palsies - PCOM aneurysm, diabetes, cavernus sinusitis/thrombosis, lymphatomous meningitis, sarcoid etc. Miller fischer variant of Guillain Barre syndrome Thyroid ophthmalopathy Myotonic dystrophy and occulopharyngeal muscular dystrophy Chronic progressive external ophthalmoplegia (CPEO) or Kearns Sayre syndrome

Diagnosis of myasthenia gravis

Presentation of variable ptosis and ophthalmoplegia, facial, jaw and neck weakness and proximal limb weakness (including respiratory muscles) with demonstrated fatiguability EMG - decrement in amplitude in repetitive muscle stimulation - Ice pack test and Tensilon testing ACh-R- antibodies- specific, not sensitive, titre does not reflect severity Anti-MuSK antibodies- present in absence of ACh-R antibodies, specific to non-occular, generalised MG

10 Types of neuropathy presentation

Symmetric proximal and distal weakness with sensory loss Asymmetric proximal and distal weakness with sensory loss Asymmetric distal weakness with sensory loss Asymmetric distal weakness without sensory loss Symmetric distal weakness without sensory loss Focal proximal weakness without sensory loss Symmetric sensory loss with distal LMN weakness and UMN weakness Symmetric distal sensory loss without weakness Asymmetric proprioceptive sensory loss without weakness Additional autonomic symptoms and signs

Differentials for distal and proximal motor weakness with sensory loss

CIDP or GBS Lead poisoning, botulism, acute intermittent porphyria Possible paraproteinaemic neuropathy (MM, Waldenstrom's, POEMs, lymphoma, amyloid) NCS - motor slowing, conduction block with dispersion, increased F wave latencies, reduced sensory nerve action potentials (SNAP)

Symmetric distal motor and sensory or sensory only neuropathy differentials

Diabetes Mellitus Alcohol Drugs Toxins Amyloidosis Metabolic disorders (Fabry's, etc.) CMT Cryptogenic sensory neuropathy HSAN (hereditary)

Asymmetric distal weakness with sensory loss mononeuropathy differential (single nerve)

Compression/entrapment mononeuropathies and radiculopathies

Asymmetric distal weakness with sensory loss multifocal mononeuropathy

Vasculitis Cryoglobulinaemia Amyloidosis Sarcoidosis Infectious (Hep B, C, HIV,CMV, lyme disease, leprosy) Hereditary neuropathy with pressure palsies (HNPP) Tumour infiltration

Distal symmetric motor and sensory neuropathy with UMN signs

Sub-acute degeneration of the spinal cord (B12, copper deficiency/zinc excess, vitamin E deficiency) Inherited disorders - Freiderich's ataxia, adrenmyeloneuropathy, MLD

Asymmetric distal proprioceptive loss (ganglionopathy/neuronopathy)

B6 Toxicity Sjogrens Paraneoplastic?/cancer HIV sensory neuronopathy Cisplatin based chemotherapeutics

Asymmetric distal motor only pattern

Progressive muscular atrophy Multifocal motor neuropathy Multifocal acquired motor axonopathy (MAMA) Juvenille monomelic amyotrophy

Distal and proximal motor only pattern

Spinal musclar atrophy

Neuropathies with associated autonomic disturbance

Diabetes Mellitus Amyloidosis Guillain Barre syndrome Vincristine induced Porphyria HIV associated autonomic neuronopathy Hereditary sensory autonomic neuropathy Idiopathic pan dysautonomia