neuromuscular disorders Flashcards
what hormone is released within the NMJ
ACh
examples of disorders at each of the following parts of the LMN pathway:
o Anterior horn cell
o Peripheral nerve
o NMJ
o Muscle
o Anterior horn cell eg. SMA
o Peripheral nerve eg. CMT
o NMJ eg. myasthenia
o Muscle eg. myopathies, muscular dystrophies
myopathy vs dystrophy vs neuropathy
myopathy = FUNCTIONAL
disorder of the contractile apparatus
proximal
static dysfunction
can be a/w pain
tendon stretch reflex preserved
CK normal/elevated
dystrophy:
disorder of the supporting apparatus
proximal
dysfunction more progressive
no pain
tendon stretch reflex preserved
CK classically ++++
neuropathy:
DISTAL
tendon stretch reflex LOST
characteristic feature of NMJ problems
fatiguability!
floppy infant - two best discriminators
Floppy weak and ARREFLEXIC – neuromuscular: no or reduced antigravity movements
Floppy strong – central: can move against gravity (may have mild weakness)
phasic vs postural tone
phasic = appendicular tone i.e. tone in extremities
postural = axial tone (neck/trunk)
arreflexia vs hyporreflexia in LMN problems - points to where in the LMN?
arreflexia = anterior horn cell, neuropathy
hyporreflexia = NMJ, muscular
what must you never forget in floppy infant examination
EXAMINE MOTHER - ask them to squeeze your hands! subclinical presentation of myotonic dystrophy
what do these gait examination findings suggest?
waddling gait
gower’s sign
ability to go up and down one foot per step
cannot heel toe walk/hop
waddling gait = proximal weakness
gower’s sign = proximal weakness
ability to go up and down one foot per step = proximal intact
cannot heel toe walk/hop = imbalance / distal weakness
fasciculation means what?
denervation - classically anterior horn problem
NCS: electro-decrement vs increment suggestive of what?
electro-decrement = NMJ like myasthenia
electro-increment = post-synaptic NMJ like botulism
NCS: reduced conduction vs amplitude means what?
conduction = myelin problem e.g. CMT
amplitude = less nerve fibres / less muscle fibres responding
EMG vs NCS
NCS = detects problem with nerve
EMG = stick probe in muscle and test whether its working properly
main aetiologies to consider for myopathies
- congenital
- endocrine: TH, PTH, GH
- iatrogenic e.g. steroid
- metabolic
most common manifestations of congenital myopathies
- floppy infant with bady resp
- later presentation with delayed milestones
main types of congenital myopathy we care about, their key exam features and which is most common.
- Nemaline myopathy (most common)
- ACTA1 most common
- neonatal most common, infantile presentation possible
- muscle biopsy with nemaline rods is diagnostic - Centronuclear/ myotubular myopathy
- no facies!
- bad neonatal common - Congenital fiber type disproportion
- neonates floppy no resp - Central core disease
- ryanodine (RYR1) mutations
- typically walk for a few years
- malignant hyperthermia, no volatile anaesthetics!
thyrotoxicosis vs hypothyroid myopathy
both symmetric proximal weakness and muscle wasting ++
hypothyroid: hypotonia also, and necrosis on biopsy
pattern of myopathy in steroid-induced myopathy
painless, symmetrical, progressive proximal weakness
mostly reversible
inheritance pattern of the following muscular dystrophies:
- myotonic dystrophy
- LGMD
- DMD/BMD
- congenital muscular dystrophies
- EDMD
- FSHD
i. AD – myotonic dystrophy, FSHD, LGMD type 1
ii. AR – congenital muscular dystrophies, LGMD type 2
iii. X-linked – DMD/BMD, EDMD
BMD vs DMD
DMD:
nonsense frameshift > no dystrophin
<5yo onset, wheelchair dependent <13yo
death ~21yo
BMD:
missense, normal reading frame > dysfunctional dystrophin
>5yo onset, wheelchair dependent >16yo
preservation of neck flexor muscles
DCM causing HF more common
death ~40s-50s
what does dystrophin do?
stabilises sarcolemma by connecting the actin cytoskeleton to the muscle membrane
DMD inheritance pattern
70% X-linked
30% de novo
DMD - explain mums with negative test who can still have kids with DMD
gonadal mosaicism - some eggs have it, some don’t, but blood tests won’t show
key complications of DMD
contractures
scoliosis
cardiomyopathy
ID, learning problems
resp failure
key features of DMD exam
gower’s sign and trendelenberg
pseudohypertrophy of calves
weak neck flexors (cf BMD)
lordosis
facial and extra-ocular muscle sparing (cf other dystrophies e.g. FSHD)
what can help ambulation in dmd and bmd
glucocorticoids (not dexa):
offer at time of decline and frequent falls 4-6yo
prolongs ambulation by 2-3y, preserves resp/cardiac function a little
female heterozygotes for DMD - what to remember?
at risk of DCM - need to have cardiac evaluation
exercise and neuromuscular conditions - comment
Exercise not dangerous in any neuromuscular condition
don’t exercise past the point of pain
key features of limb girdle muscular dystrophy for exams - and what to not confuse it with
progressive pelvic weakness > down
early adulthood onset
pseudohypertrophy of calves but not common - don’t confuse with BMD
not all limb girdle weakness is LGMD - think SMA3 and 4
key features of FSMD for exams
AD
late childhood onset
face, shoulder blades, upper arms and ABDO weakness - can walk initially
mask-like facies, beevor sign positive
key features of emery-dreifuss muscular dystrophy
X-linked, 5-15yo
1. early onset contractures
2. weakness in scapulo-humeral distribution
3. DCM*!!
myotonic dystrophy: DM1 vs DM2 genetics
DM1 = expansion of trinucleotide repeat CTG in DMPK gene
- >35 repeats = worse, >50 = worst.
DM2 = expansion of tetranucleotide repeat CCTG
- no correlation between repeat length and severity
explain the concept of anticipation in DM1.
Pathogenic alleles (>35) unstable and may expand in length during gametogenesis > transmission of a longer trinucleotide repeat allele associated with earlier onset and more severe disease (esp if from mum)
DM1 vs DM2 clinical manifestation
DM1 = can occur from neonate > adult; more severe
DM2 = adult onset; less severe
differentiate DM1 phenotypes
- congenital (>1000 repeats) = worst
- childhood onset (>800): <10y, involvement of other organs besides skeletal muscle
- classical (most common): adolescence
- mild adult (>50): cataracts + myotonia
- premutation (<50 repeats) - no signs
clinical manifestations of myotonic dystrophy
- cranial muscle problems e.g. face/speech/ptosis
- CNS: mental retardation
- eyes: cataracts
- cardiac
- resp
- GI: megacolon, dysphagia, constipation/incontinence
- endocrine: DM + hypogonadism
- DISTAL to proximal weakness
- myotonia
what is myotonia
Delayed relaxation of muscle after voluntary or involuntary contraction (e.g. percussion)
key features of congenital myotonic dystrophy
- resp failure
- profound hypotonia
- poor feeding
- arthrogryposis
- facial diplegia with inverted v lips
- polyhydramnios
congenital muscular dystrophy distinguishing feature from congenital myotonic dystrophy
congenital muscular dystrophy - high association with brain malformations e.g. lissencephaly
anaesthetics in neuromuscular disorders - key points
- risk of cardio-resp failure
- hypersensitivity to sedative agents
- major AE: malignant hyperthermia, rhabdo, hyperkal
pathogenesis of myasthenia gravis
AI disease from anti-AChR antibodies blocking receptor activity at the post-synapse terminal
classic myasthenia gravis clinical manifestations
- rapid fatigue of muscles
- weakness worse at end of day
- ptosis, ophthalmopegia, diplopia WITHOUT acuity issues
- NO fasciculations, myalgias, sensory symptoms
natural history of childhood myasthenia gravis
50% ocular MG will be generalised in 2 years
maximal disease severity in 2y
spontaneous remission possible, more common in younger
what is a myasthenic crisis?
acute or subacute severe increase in weakness in patients with MG precipitated by stress/physical stress, which can be severe enough to require IV cholinesterase, IVIG, plasma exchange, vent support
key Ix for myasthenia gravis
- Anti-AChR
- Anti-MusK (usually young bulbar females, not pure ocular)
- electro-decremental response in nerve conduction study ONLY in affected muscles, but velocity remains normal
- administration of short acting cholinesterase inhibitor e.g. edrophonium / neostigmine - ptosis and ophthalmoplegia improve in a few seconds
management options for MG
- 1st line anti-cholinesterase e.g. neostigmine
- short term - exchange / IVIG
- long term - roids / AZA
- surgical - thymectomy
distinguish between acquired and congenital myasthenia
acquired not autoimmune at all, no anti-ACh-Ab
permanent static disorder WITHOUT remission
most do NOT experience myasthenic crisis
how does botulism work to cause paralysis?
botulism binds to peripheral cholinergic nerve endings, neurotoxin damages SNARE proteins > prevents fusion of vesicles with pre-synaptic membrane to release ACh
key features of lambert eaton syndrome and differences with myasthenia gravis
auto-abs to Ca channels at pre-synaptic neuron > no ach release
a/w malignancy + paraneoplastic syndrome (SCC)
improves temporarily after repeated use of muscle
name the 4 anterior horn diseases we care about
polio
enterovirus (polio-like)
ALS
SMA
key features of SMA for exams
prox to distal weakness symmetrical - SNS and PNS affected
areflexia / hyporeflexia
hypotonia
fasciculations from denervation
resp insufficiency
heart and IQ are fine
genetics of SMA
AR mutation of telomeric SMN1, leaving centromeric SMN2 to do the job - number of SMN2 copies left determines severity of SMA
differentiate the types of SMA
SMA 0: prenatal onset, death by 6mo
SMA 1: infantile <6mo onset. never sit, feeding problems, death by 2yo
SMA 2: late infantile 6-18mo onset, never walk can sit, can live to 20y
SMA 3: >2y onset, walk ok. slower progression, can hypertrophy not atrophy.
SMA 4: adult onset, pretty much normal.
diagnostic Ix of SMA
genetic SMN test
new therapy for SMA
nusinersan = antisense oligonucleotide binds SMN2 pre-mRNA to prevent exon 7 from being removed > making more SMN protein
what are the two exceptions to prox to distal weakness?
DISTAL to proximal weakness:
SMARD (cf SMA1)
myotonic dystrophy MD1
when is myelination of peripheral nerves complete
2-3yo
CMT also known as
hereditary motor sensory neuropathy (HMSN)
key points of CMT pathophys
- GROUP of disorders causing chronic motor AND sensory polyneuropathy
- defective proteins in myelin sheath (CMT1A most common) OR axon (CMT2)
key features of CMT diseases
- Length-dependent muscle wasting and weakness = distal > proximal + LL > UL
- reduced DISTAL reflexes
- impaired DISTAL sensation; vibration affected EARLIER than pin-prick
- foot deformity – reflection of chronicity
CMT genetics - most common?
mostly from AD of CMT1A = duplication of PMP22
diagnostic study of CMT
Sural nerve biopsy: large and medium size myelinated fibres are reduced in formation, collagen is increased and characteristic onion bulb formations of proliferated Schwann cell cytoplasm surrounds axons
earliest and most severely affected nerves in CMT
peroneal and tibial nerves > walking runnning issues with ortho issues
which is better for CMT - nerve conduction or EMG
nerve conduction (both motor and sensory velocity slower)
key features of CMT1 vs CMT2 vs CMT3
CMT1:
demyelination
first-second decade
CMT2:
axonal damage
second-third decade
variable foot deformity
CMT3 = Dejerine-Sottas Disease
demyelination
<2y
foot deformity common
name three common exam drugs causing peripheral neuropathy
Vincristine, cisplatin and paclitaxel
infections vs vaccines particularly associated with guillan-barre
Infections
i. GIT = campylobacter jejuni, H pylori
ii. Respiratory = Myocoplasma pneumoniae
Vaccines particularly associated with GBS
i. Rabies
ii. Influenza
iii. Oral polio
iv. Conjugated menincoccal C vaccine
key features of Guillan Barre for exams
- acute inflammatory polyneuropathy
- rapidly progressive symmetric weakness - prox=dist, LL > UL
- acutel no progression past 4 weeks
- areflexia
- CN involvement (facial, bulbar, ophthalmoplegia)
- autonomic instability
- sensory - pain/dyasthesia
key CSF findings in guillan-barre
WCC <10 cells/mm3 and protein >0.45 g/L (cytoalbuminologic dissociation)
what key investigations should be considered if suspecting guillan barre
- csf cytoalbuminologic dissociation
- nerve conduction studies: slow
- MRI: nerve root enhancement
- stool: for polio and campylobacter
- bloods:
- Anti-GM1: campylobacter associated GBS
- Anti-GQ1b: Miller Fisher syndrome
(and bc, etc)
Mx options in guillan barre
- resp support
- IVIG 2g/kg over 2 days if bad - help speed recovery not change outcome
- neuropathic pain: gaba/nsaids/*steroids- don’t change outcome
outcome for guillan-barre in kids
90% of children fully recover – small number have mild weakness
Relapses uncommon
d. Very small percentage later develop CIDP
chronic inflammatory demyelinating polyradiculopathy (CIDP) - key features for exam
like long-term guillan barre
but CN/bulbar uncommon
course is different - either relapsing/remitting or progressive
key features of miller-fisher syndrome
ophthalmoplegia, ataxia and areflexia
do not have significant lower extremity weakness
first test for DMD and why
60% have deletion - so first do a microarray
