Weakness (myopathies and neuropathies) Flashcards
What makes up muscles?
Muscle fibre
- multiple myofibrils made up from contractile proteins that include myosin II, actin, tropomyosin and troponin (I, T, C)
Motor unit is made up of
- motor neurone cell bodies (ventral horn) and axons and neuromuscular junction and all muscle fibres innervated by same nerve
What is the difference between myopathy / dystrophy / neuropathy?
myopathy
- contractile unit involved
- static
dystrophy
- support tissue involved
- progressive
Myopathy causes proxiMal weakness (except myotonic dystrophy) as opposed to neuropathy, which causes distal weakness (except SMA)
How does ‘weakness’ present?
Non-specifically as
- developmental delay
- difficulty walking / poor at sports / frequent falls / fatigue
- IUGR / decreased foetal movements
Possible symptoms / signs Head and neck weakness - ptosis - diplopia - difficulty chewing - facial weakness - can't suck / blow / smile - head nod (neck) - drooling (bulbar) - dysphagia
Limbs and trunk weakness
- can’t put things on shelves (shoulder girdle)
- poor writing (hands / forearms)
- can’t go up stairs (hips / thighs)
- tripping over self (legs)
- undescended testes - weakness of gubernaculums (striated and smooth muscles)
What are main differentials for hypotonia in an infant?
Cerebral (biggest group)
- benign congenital hypotonia
- chromosomal disorder (T21, ch15q11-13 del prada-willi / angelman)
- malformations
- HIE
- sepsis
- metabolic disorder (Zellweger, neonatal leukodystrophy, hypothyroidism)
Spinal cord
- injury
Ant. horn cell
- spinal muscular atrophies
What are causes for weakness in older children?
Progressive proximal weakness: Motor neuron - juvenile spinal muscular atrophy NMJ disease Muscle - Duchenne / Becker - facioscapulohumeral - limb-girdle - inclusion body myopathy - inflammatory: dermatomyositis / polymyositis / viral myositis - metabolic myopathies: carnitine deficiency, mitochondrial myopathies - endocrine myopathies: adrenal, parathyroid, thyroid
Progressive distal weakness Motor neurone - Spinal muscular atrophy Neuropathies - Hereditary motor-sensory neuropathies: Charcot-Marie Tooth - Systemic disease: drugs, vasculitis, toxins, uraemia Idiopathic - chronic axonal neuropathy - chronic demyelinating neuropathy Myopathies - inclusion body myopathies - myotonic dystrophy - sacpulo-peroneal syndrome
What are indications to investigate when patient presents with ?weakness?
Family history of dystrophy
Male not walking by 18 months
Unexplained motor dev regression / abnormal gain or language delay
What are investigations for weakness?
CK [MM (skeletal muscle), MB (cardiac muscles), BB (brain)]
Interpretation:
>1000
- DMD, BMD, limb girdle MD, congenital myopathy
200-800
- pompe (glycogen storage disease II) - accumulation of glycogen in lysosomes due to acid alpha-glucosidase enzyme
normal or upper limits of normal - congenital myopathy - endocrine / metabolic myopathy - myotonic dystrophy - dermatomyositis - SMA - motor neuropathy Normal - myasthenia
Nerve conduction studies
- reduced amplitude = reduced numbers of axons / muscle
- reduced conduction velocity = demyelination
- reduced repetitive on stimulation
- –> pre-synaptic: botulism (increased response due to inc Ach in NMJ)
- –> post-synaptic: myasthenia gravis (decreased response as used up Ach in NMJ)
EMG
- records electrical potentials (needle inserted into muscle belly)
- invasive
- neuropathy: denervation leads to increased motor unit amplitude, decreased recruitment, increased fibrillation
- myopathy: decreased motor unit amplitude, early recruitment
- NMJ: repetitive –> fatiguability
Muscle biopsy
- sample weak muscle (but not too weak)
- usually vests lateralis
- avoid deltoid as 60-80% type 1 fibres makes it difficult to interpret)
- no EMG in last 6 months as causes fibrosis / scarring
Nerve biopsy
- usually dural nerve
- regenerates in 90%
What clinical features would you expect from spinal muscular atrophies?
Degenerative disorders of anterior horn cells
- lower motor neuron signs
- hypotonia and weakness, atrophy, fasciculations, reduced / absent reflexes
2nd most common neuromuscular disease after DMD
What types of SMA are there?
Types 1 to 3
Actually exists on a continuum
SMA 1
- Werdnig-Hoffmann
- severe infantile form
- 80%
- never sits
- reduced fetal movement and born with joint deformities
- alert face
- bulbar dysfunction - poor suck
- severe hypotonia with frog-leg position, claw hand, arreflexic
- SMN 1 deletions
SMA 2
- intermediate
- late infantile form, onset < 18 months
- can sit, but misses milestone for standing/ walking (only 5% still standing at 20)
- able to suck, swallow at infancy then progressive weakness, late speech and swallow problems
- normal intellect, develops scoliosis and severe handicap (wheelchair), die at 2nd decade
- missense mutations and multiple copies SMN II
SMA 3
- Kugelberg-Welander
- mild juvenile form, onset usually 5-15y
- proximal > distal weakness with muscular hypertrophy
- walks until 40’s, death in adulthood
- normal intelligence
- missense mutations and multiple copies SMN II
What’s the pathogenesis and genetics behind SMA?
Usually primitive neuroectoderm produces more neuroblast than our body needs so half of these will have limited cell cycle and degenerate
In SMA
- mutation in survival motor neurone gene causes apoptosis of neuroblast BEYOND fetal life
Autosomal recessive Deletion in 5q11 2 genes identified: - SMN 1 - telomeric —> lost in SMA - SMN 2 - centromeri —> less functional
How do you investigate / treat SMA?
Investigations
- SMN gene panel (pre-natal diagnosis available)
- muscle biopsy: groups of giant type 1 fibres, mixed with fascicles of severely strophic fibres of both types
- CK: normal (helps distinguish from myopathy / dystrophy)
- EMG: fibrillation, large motor unit potentials
- Sural nerve biopsy: mild sensory changes
Treatment: nil available
Monitoring
- respiratory compromise: annual FVC, chesty physical therapy or positive pressure ventilation
- scoliosis
- other complications: wt gain, osteoporosis, PE, constipation
What drugs can cause neuropathies?
Antibiotics - isoniazid, nitrofurantoin Anti-arrhythmic - amiodarone Anti-cancer - vincristine, cisplatin Anti-seizure - phenytoin
What nutritional deficiencies / metabolic conditions can cause neuropathies?
Vitamin B1, B6, B12 deficiencies
Hypothyroidism
Porphyria
What is Charcot-Marie tooth disease?
Hereditary motor and sensory neuropathy I and II
- Progressive diseases of peripheral nerves
- Motor > sensory > autonomic
HSMN I
- hypertrophic neuropathy due to demyelination followed by re-myelination giving onion bulb appearance on nerve biopsy
- automsone dominant with incomplete penetrance
- abN gene is 17p11.2 (70% duplicatio) causing peripheral myelin protein over-expression resulting in demyelination
- onset early childhood
- distal wasting weakness (loss of dorsiflexion, eversion) with pes cavus / hammer toe / stork legs with pressure sensation (shoes too tight) then gradual loss of position, vibration sense and loss of ankle then knee jerks
- has abnormal gait (toe walking, clumsy running style) but doesn’t lose ability to walk
- vitamin C may have a role in management - increases myelination
- normal CK
- EMG (not necessary) but will show cycles of re-innervation and denervation
HSMN II
- also autosomal dominant
- due to axonal degeneration
- onset late childhood - adulthood
- clinical features similar to type 1 but milder weakness and more prominent sensory loss
HSMN III is Dejerine-Sottas disease
- AD
- onset infancy, much more severe disease
- hypotonic, motor delays, lacks pupillary response to light, enlarged palpable nerves
HSMN IV is Refsum disease
- heterogeneous group of neuropathies with combination of findings including: spastic paraplegia, retinitis pigmentosa
What is the most common cause of acute flaccid paralysis in healthy children?
Guillain-Barré syndrome
- acute inflammatory demyelinating poly-radiculopathy
- affects cranial nerves, spinal roots and peripheral nerves
Forms
- Primarily motor: progressive symmetrical ascending LMN paralysis and affects longest nerve fibres first
- pure sensory or pure autonomic forms are possible
- miller-fisher syndrome: triad of ataxia, ophthalmologist, areflexia a/w papillodema, urinary retention
What is the cause of GBS?
Triggering event occurs in 2/3 of children
1) viral infection ~ 2 weeks prior
- GI: campylobacter (pure motor form strongly a/w)
- Resp: mycoplasma pneumoniae, EBV, CMV, varicella
2) Vaccination
3) Hodgkin’s lymphoma
What’s the pathogenesis of GBS?
Humoral mechanism
- antibodies to gangliosides (GM1 / GD1) resulting in axonal neuropathy
Cellular mechanism
- monocytes destroy myelin insulating axons —> demyelination
Presents with
- symmetrical LMN weakness, ascending over 2-4 weeks
- bulbar involvement in 50% —> risk of aspiration
- sensory sx mainly pain
- autonomic sx labile BP, HR, sweating, urinary retention / constipation
- plateaus for 4 weeks then improves over 1 year
- resolution of symptoms are in reversed order
What would you find in the LP of patient with MS?
Oligoclonal bands and increased polymorphonucleated neutrophils
What causes myasthenia gravis and what are the clinical features, ix methods and complications?
Autoimmune reaction against post-synaptic acetylcholine receptors. Types include:
- transient neonatal (maternal MG)
- congenital / familial (rare, usually due to Ach receptor channel abN)
- autoimmune (non-hereditary, majority of cases)
- occasionally secondary to Hashimoto’s thyroiditis
Clinical features
- Ptosis is earlier & most constant sign (worse if asked to maintain upward gaze i.e fatigability)
- Diplopia
- Difficult chewing / swallowing / slurred speech
- Poor head control
Ix
- acetylcholine receptor antibodies is only 50% reliable in childhood
- edrophonium (acetylcholinesterase inhibitor) test should improve weakness but watch out for cholinergic crisis w secretions, laryngospasm, low HR /BP, GI sx and sudden diarrhoea, and have atropine available
Complications
- Don’t tolerate NMJ blocking agents such as succinylcholine or pancuronium and may be paralysed for weeks after single dose
- aminoglycoside may make sx worse
Treatment
- symptomatic mx with neostigmine
- Corticosteroids (some role)
- Thymectomy (may provide cure, most effective in those with high titres of anti-Ach receptor abs and who are symptomatic for less than 2 years)
- Plamsaphereis
- Immunoglobulin
- Treat assoc hypothyroidism
Prognosis
- progressive if untreated
- potentially fatal when respiratory muscles involved
- sometimes remits in children
What are other causes of neuromuscular blockade?
Organophosphate poisoning
- used in insecticides
- cause myasthenia like syndrome
Botulism
- flaccid paralytic illness by botulinum neurotoxin A or B
- toxin binds to pre-synaptic nerve terminal —> enters nerve cell and blocks release of Ach irreversibly
- more common in mountain locales secondary to water boiling at lower temperatures in high altitude
- progressive spread top —> bottom (cranial —> trunk —> extremeties —> diaphragm when 90-95% synaptic receptors are occupied)
- not possible to have botulism w/o multiple bulbar palsies
- only affects motor neurons, paraesthesia not a feature
- duration usually 1-2 months but occasionally relapses
- 3 types
1) infant
- only in < 1y, caused by ingestion of c. Botulism spores which subsequently produce toxin in infants intestine
- honey often implicated cause
- presents with constipation, poor feeding then progressive hypotonia
2) food Bourne botulism
- caused from ingestion of food already containing c. Botulism like canned food
- abdominal symptoms (nausea, vomiting, diarrhoea, pain) precedes paralysis
3) Wound botulism
- rare
Investigations:
- send stool for toxin
Treatment:
- botulinum immune globulin (BIG): the earlier the better
Tick paralysis
- ticks can burrow deep into skin (usually scalp) and releases neurotoxin blocking depolarisation
- gives a picture of GBS plus papillary involvement and nystagmus
Treatment
- remove tick
- recovery within hours or days
What are the most common forms of congenital myopathy?
Nemaline Rod myopathy
- most common with wide variation of disease severity
- autosomal recessive in most common genetic cause (NEB)
- muscle biopsy: nemaline bodies / rods
- a/w cleft palate and thin muscles
Central core myopathy
- more prevalent due to longer term survival
- autosomal dominant
- a/w congenital hip dislocation and malignant hyperthermia (gene is at same locus)
- not usually severely debilitating
- autosomal
What’s the genetic cause of Duchenne’s and Becker dystrophy?
Xp21 deletion
- recessive
- 1/3 new mutation, consider gonadal mosaicism
- results in absence of dystrophin (frame shift mutation in Duchene’s) or less function dystrophin (in-frame mutation in Becker)
What are the clinical features of duchenne’s?
Abnormal gait (toe walking) Waddling (trendelenburg) gait Positive trendelenburg sign - when standing on one leg, pelvis on opposite side tilts down Lumbar lordosis - compensate for gluteal weakness Pseudo hypertrophy Gower sign positive - may be evident by age 3 and fully expressed by 5-6y Language delay / learning difficulty - 20%
Progress
- Knee jerks lost but ankle jerks retained till late
- Loss of mobility from age 8-13 and scoliosis rapidly progresses after confinement to wheelchair
- facial muscle weakness is late
- Myalgia and muscle spasm can result in pain
- Do baseline LFTs, sleep study, ECHO, X-ray of chest and thoracolumbar spine once wheelchair bound
increased risk of malignant hyperthermia
Death usually by respiratory failure (restrictive lung disease), pneumonia, aspiration or cardiac failure at about 18 years
What’s Emergy-Dreifuss muscular dystrophy?
Aka Scapulohumeral muscular dystrophy
- x-linked and rare
- Presents in middle of childhood with muscle wasting in scapulohumeroperoneal distributation
- No facial weakness
- Normal intellect
- contracture of elbows and ankles present
- Slow progress, often live into late adulthood
- May develop cardiac arrhythmia
- Mildly elevated CK
