Neuromuscular Disease Flashcards
Associated features of neuromuscular disease
MOTOR: muscle weakness/wasting (diploplia, dyspnoea, dysphagia), stiffness, cramps, fasciculation, clumsiness, poor balance, falls
SENSORY: numbness, burning, tingling
NON-SPECIFIC: fatigue
Give 3 examples of conditions causing diplopia and ptosis
Myasthenia gravis
Ocular nerve palsy
Thyroid eye disease (although more commonly proptosis, not ptosis)
Give 2 examples of conditions causing dysphagia and dysarthria
Myasthenia gravis
MND
Clinical features of MND
Muscle wasting including tongue
Fasciculations
Tone
Generalised weakness (no pattern)
Reflexes preserved until late or exaggerated
Plantars may be upgoing
No sensory loss (may have sensory symptoms but on testing no signs)
Cranial nerves (except bulbar) spared
How is MND diagnosed?
On the basis of symptoms and signs, consistent laboratory findings (EMG) and the exclusion of other diagnoses
What is MND?
Gradually progressive disorder with evidence of upper and lower motor neuron involvement and intact sensation
Prognosis of MND
Life expectancy bulbar onset: 6-12 months
Life expectancy limb onset: 2-5 years
What are neuromuscular disorders?
Conditions that affect:
a) peripheral nervous system (motor and/or sensory nerves, including anterior horn and dorsal root ganglion cell disorders)
b) neuromuscular junction
c) muscle
What are the important features on Hx in neuromuscular disease?
Time course: are symptoms acute or chronic?
FHx of similar complaints (e.g. hereditary neuropathies, muscular dystrophy)
What symptoms are typically seen in carpal tunnel syndrome?
Affecting median nerve supplied digits (thumb, index and middle fingers)
Worse at night; have to shake hand to stop symptoms
What is a unilateral foot drop indicative of?
L5 radiculopathy or peroneal neuropathy
What is the best diagnostic test for carpal tunnel syndrome?
Nerve conduction studies
What is the distribution of symptoms and signs in neuromuscular disease?
Generalised
Distinguish between anterior horn cell diseases, neuropathy, myaesthenia gravis and myopathy in terms of muscle wasting, fasciculations, weakness, reflexes and sensation
Ix for suspected NM problem
Electrophysiology: distinguishes neuropathy from myopathy, axonal from demyelinating, sensory vs motor, NMJ disorder
Laboratory: FBE, ESR, vit B12, CXR, BSL, HbA1c, UEC, TFT, LFT, PEP (protein electrophoresis), anti-NF, ANCA, ENA, HIV, CK, heavy metal screen, VDRL (for syphilis), genetic tests
LP
Muscle biopsy, muscle MRI
And for difficult cases, consider: nerve biopsy, MRI of nerve
55 year old previously well building surveyor, on no medications, 6/12 ago noticed cramps in both legs worse after exercise
Increasing leg weakness over past 3/12 months with L foot drop; had noticed twitching in the muscles of both legs but no sensory complaints
No FHx of weakness
What are the clinical features of MND?
Non-specific cramps after exercise
Fasciculations (usually presents with weakness not twitching; remember twitchig is common normally, esp in calves)
Subacute progressive problem
55 year old previously well building surveyor, on no medications, 6/12 ago noticed cramps in both legs worse after exercise
Increasing leg weakness over past 3/12 months with L foot drop; had noticed twitching in the muscles of both legs but no sensory complaints
O/E: cranial nerve examination normal, no tongue wasting or fasciculations, few scattered fasciculations in UL muscles (deltoid and periscapular), no muscle wasting or weakness, brisk reflexes, no sensory loss, thin leg muscles, fasciculations in thighs only after exercise, weakness of hi flexion 4/5 and ankle dorsiflexion 3/5, plantars downgoing, normal sensation
What is the significance of the brisk reflexes?
Ix?
Brisk reflexes are an UMN sign and suggests amyotrophic lateral sclerosis (commonly upper AND lower MND)
Ix: CK, NCS/EMG
55 year old previously well building surveyor, on no medications, 6/12 ago noticed cramps in both legs worse after exercise
Increasing leg weakness over past 3/12 months with L foot drop; had noticed twitching in the muscles of both legs but no sensory complaints
CK 859 (N is 50-200)
NCS/EMG: normal nerve conduction in motor and sensory nerves, but evidence of active and chronic denervation on needle EMG and fasciculations
Why is CK elevated in MND?
Due to the trophic effect of nerves on muscle; if this trophic effect is removed due to the death of the neuron, the CK will rise
What is the most common MND?
Amyotrophic lateral sclerosis (disorder of upper and lower motor neurons)
What clinical syndrome is amyotrophic lateral sclerosis associated with in some patients?
Fronto-temporal dementia (FTLD)
What is the peak age of onset for FTLD?
55-70 years
How does FTLD arise?
90% sporadic
10% familial (in some families linked to a mutation of the SOD1 gene on Ch 21; recently discovered link in some families to mutations in the gene responsible for the production of the protein TDP 43 and in others to C9orf72)
How is MND diagnosed?
Based on characteristic symptoms and signs: gradually progressive disorder with evidence of upper and lower motor neuron involvement and intact sensation
Consistent laboratory findings: EMG
But ultimately, Dx of EXCLUSION
What is the most common mimic for MND?
Widespread radiculopathies of the spine
What is the prognosis for MND?
Terminal illness in most cases
Course depends on presentation: average life expectancy bulbar onset is 6-12/12, average life expectancy with limb onset is 2-5 years
Common clinical manifestations of MND
Can affect all skeletal muscles causing weakness, dysphagia, anarthria, dyspnoea and respiratory failure
What is hereditary spastic paraplegia?
Inherited disorder caused by mutations in the spastin gene (although many other mutations exist)
What is adrenomyeloneuropathy?
X-linked disorder which results in the deposition of excess LCFAs in the CNS
What is primary lateral sclerosis?
Similar to ALS but with no LMN signs
Best prognosis but very difficult to diagnose (no EMG markers)
Clinical features include progressive UMN weakness
35 year old previously well lawyer, on no medications, 6/12 ago began noticing episodic diplopia which was worse towards the end of the day, now increasing exertional dyspnoea over past 1/12 but no sensory complaints
No FHx of weakness
O/E: mild ptosis (L>R) with failure to adduct the L eye, speech becomes slurred during latter part of Hx taking, proximal weakness in shoulder girdle muscles not evident initially but appears with repetitive trials
List 2 post-synaptic and 2 pre-synaptic disorders of NMJs
Post-synaptic: myasthenia gravia (Abs against ACh receptors), MuSK myasthenia (Abs against MuSK)
Pre-synaptic: Lambert Eaton Myasthenic Syndrome (LEMS; Abs against Ca2+ channels), botulism
What neoplasm is associated with LEMS? What is the mechanism?
Small cell lung Ca (it is a paraneoplastic syndrome)
In what patient populations is botulism seen? How does it present?
IVDUs (abscess with botulinum spores)
Presents with acute neuromuscular weakness which usually starts at the top and works down; neurological emergency (must be recognised early)
How long does it take for botulinum toxin to break down?
~6/12
How is botulism treated?
Anti-botulinum toxin, THEN debride
Metronidazole
List 6 clinical features that should make you suspect myasthenia gravis
Hx of fatigueability
Early involvement of EOMs and lid-opening muscles
Dysarthria
No muscle wasting
Weakness increasing with repetitive exercise
Reflexes and sensation unaffected
Describe the pathophysiology of myasthenia gravis
AutoAbs which cross react with ACh receptors at NMJs
High association with thymic hyperplasia or thymoma
Describe the pathophysiology of MuSK myasthenia?
Abs binding to MuSK cause the subunits of the ACh receptor to deaggregate and lose function
Ix for Dx of myasthenia gravis and MuSK myasthenia, and expected findings
Tensilon test: short acting ACh-ase antagonist
Blood test for autoAbs to ACh receptor, MuSK (positive in 50% of cases of pure ocular myasthenia gravis, positive in 90% of cases of generalised myasthenia gravis, 70% of seronegative cases positive for anti-MuSK Abs)
CT chest: look for thymoma
EMG studies: repetitive stimulation, single fibre EMG, post-exercise facilitation (post-tetanic potentiation)
What is the relationship between thymoma and myasthenia gravis?
Poorer; even if thymus is normal, removal improves prognosis if done when patient is young
MuSK
Muscle-specific kinase
How is the Tensilon test performed?
IV injection of short-acting drug (edrophonium) increases ACh concentration at the NMK and can temporarily reverse weakness due to myasthenia gravis
Good idea to be blinded: use a dummy saline syringe as well
SEs of tensilon
Can become bradycardic
Distinguish between electrophysiology study findings with repetitive stimulation in myasthenia gravis vs normal
Normal: no decrement in amplitude of muscle response with repetitive nerve stimulation
NMJ disorder: decrement
Distinguish between electrophysiology study findings with post-exercise facilitation in LEMS and normal patients
Exercise consists of 10 secs maximal contraction of the target muscle and then electrophysiological readings are taken
Normal: no change in compound muscle action potentials (CMAP) post-exercise
LEMS: change in amplitude (wider) of CMAP post-exercise
Mx of myasthenia gravis
ACh antagonists
Plasma exchange
IVIG
Immunosuppression with steroids, azathioprine
Thymectomy
65 year old type 2 diabetic, on no medications, complains of poor balance and feelings in soles of feet like “walking on cotton wool”
O/E: poor balance on walking, wide-based gait, Romberg’s positive, weakness of dorsiflexion bilaterally, absent ankle reflexes, stocking loss of pain and temperature sensation with sensory level just below both knees
How are neuropathies categorised?
Inherited or acquired
Acute or chronic
Mononeuropathy, multifocal, generalised
Motor, sensory or mixed
What is the most common type of neuropathy? How do they present?
Focal mononeuropathies
Symptoms are consistent with anatomy of neve involved
What are the main categories of causes of focal mononeuropathies? Give examples of each
Compressive (most common): carpal tunnel syndrome, ulnar neuropathy
Infection: leprosy
Inflammatory: Bell’s palsy
Infiltrative: cancer, amyloid
Ischaemic: diabetes (3rd nerve palsy)
Dx of focal mononeuropathies
NCS/EMG to localise lesion and confirm Dx
Presentation of focal mononeuropathies
Focal symptoms and signs
What is mononeuritis multiplex? Include definition, cause
Multifocal neuropathies (multiple mononeuropathies)
Multiple peripheral nerves affected rather than generalised (e.g. ulnar and tibial)
Cause almost always ischaemic (e.g. DM, vasculitis including Churg-Strauss syndrome) but occasionally infective (e.g. AIDS, CMV, sarcoid, leprosy)
How are generalised peripheral neuropathies classified?
Acute or chronic
What is the most common neurological defect in generalised peripheral neuropathy?
Sensorimotor: distal weakness and glove and stocking sensory loss (can be accompanied by severe pain, esp in diabetics, amyloid, etc)
List 3 causes of acute demyelinating polyneuropathy
Guillain-Barre syndrome
AIDS seroconversion phase (can also cause GBS)
Lymphoma
List 4 causes of acute axonal polyneuropathy
Glue sniffers neuropathy (due to N-hexane toxicity)
Vasculitis
Thiamine deficiency
Acute intermittent porphyria
How does an acute polyneuropathy present?
Rapidly increasing diffuse weakness and/or sensory loss occurring over days
What are the 7 categories of causes of chronic axonal polyneuropathy? Provide at least one example for each
Genetic: HMSN type II
Metabolic: DM, hypothyroidism
Toxin: EtOH, drugs, prescription Rx, heavy metals (arsenic/As, Pb)
Nutritional: thiamine, B12 deficiency, B6 excess
Paraneoplastic: Anti-Hu
Immune: abnormal paraprotein, Sjogren’s
Ischaemic: DM, vasculitis
What are the 3 categories of causes of chronic demyelinating polyneuropathy? Provide at least one example for each
Genetic: HMSN type I, HNPP (Hereditary neuropathy with liability to Pressure Palsy)
Immune: inflammatory (e.g. CIDP - Chronic Inflammatory Demyelinating Polyneuropathy) or non-inflammatory (e.g. IgM anti-MAG neuropathy)
Paraneoplastic: POEMS syndrome
POEMS syndrome
Polyneuropathy
Organomegaly
Endocrinopathy
Monoclonal gammopathy
Skin changes (e.g. hyperpigmentation)
Classic changes on nerve conduction study in axonopathy, inherited demyelinating neuropathy and acquired demyelinating neuropathy
Axonopathy: low amplitude CMAPs, normal conduction velocity
Inherited demyelinating: slow conduction velocity, no block
Acquired demyelinating: slow conduction velocity, conduction block
What disease process is shown in this histopathology specimen?
Small fibre neuropathy
What disease process is shown in this histopathology specimen?
Axonal neuropathy
What disease process is shown in this histopathology specimen?
Demyelinating disease (e.g. chronic inflammatory demyelinating polyneuropathy, CIDP)
18 year old previously well young man, Hx of increasing weakness over last 6/12 which is most noticeable when getting out of chairs, walking up stairs and using the hair dryer
On no medications
No sensory complaints, does not fluctuate during the day
No FHx of weakness
O/E: waddling gait, can’t rise from squat without help, proximal weakness in shoulder girdle and hip girdle muscles
Dx? What are the different types?
Myopathy: inherited, metabolic, ion channel mutations or acquired
List 6 inherited causes of myopathy
Myotonic dystrophy
Facio-scapulo-humeral dystrophy
Duchenne’s dystrophy
Becker’s dystrophy
Limb-girdle dystrophies
PROMM (proximal myotonic myopathy)
List 2 metabolic causes of myopathy
Glycogen storage disease type V (McArdle)
Carnitine palmitoyltransferase II deficiency (CPT II deficiency)
What ion channel mutations can cause myopathy?
Periodic paralyses: hypo K+, hyper K+, paramyotonia
What are the 3 categories of causes of acquired myopathy? Give examples of each
Drugs: alcohol, statins
Endocrine/metabolic: hypothyroidism, hypokalaemia
Inflammatory: polymyositis, dermatomyositis, inclusion body myositis
18 year old previously well young man, Hx of increasing weakness over last 6/12 which is most noticeable when getting out of chairs, walking up stairs and using the hair dryer
Ix?
Electrophysiology: needle EMG for myopathy and myotonia
CK: if elevated almost always indicates a myopathy (can be 500-1000 in MND)
FHx (genetic testing): e.g. myotonic dystrophy has a triplet repeat at Ch 9, DMD has loss of dystrophin gene on X chromosome
Muscle biopsy
What findings on histopathology are characteristic of muscular dystrophies?
Varying muscle fibre size
Regenerating and degenerating fibres
Increased fibrosis
What muscle membrane proteins can be visualised with special stains and for what myopathies is this technique used to aid Dx?
Dystrophin: Duchenne’s, Becker’s
Dysferlin: limb girdle dystrophies
Sarcoglycans: limb girdle dystrophies
What features are seen on muscle biopsy in myositis?
Inflammatory cell infiltrate with T (polymyositis, inclusion body myositis) and B (dermatomyositis) lymphocytes
Degenerating and regenerating muscle cells
