Transcript Clinical Features

Neuromuscular
Junction Disorders
Abdullah Al-Salti R3
AHD 9 march 2011
Neuromuscular junction
Myasthenia Gravis
Myasthenia Gravis:
a chronic autoimmune neuromuscular disease characterized by varying
degrees of weakness of the skeletal (voluntary) muscles of the body.
Age and Gender:

Myasthenia gravis presents at any age. Female incidence peaks in the
third decade of life, whereas male incidence peaks in the sixth or seventh
decade.
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The female-to-male ratio is said classically to be 6:4, but as the
population has aged, the incidence is now equal in males and female
Inheritance:
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1st degree relatives have 1000x the rest of general population
inc. jitter on SFEMG demonstrated in 33-45% of asymptomatic 1st
degree relatives
Inc. titres of AChR antibodies in up to 50%
Pathophysiology
Immunoglobulin G (IgG) directed attack on the NMJ, aimed specifically
at the nicotinic acetylcholine (ACH) receptor.
Damage to the ACH receptor and postsynaptic membrane involves several
steps.
 First, binding of the antibody to the receptor can directly
block the binding of ACH.
 Second, there is a complement-directed attack, with
destruction of the ACH receptor and post junctional folds.
 Third antibody binding can result in an increase in the
normal removal of ACH receptors from the postsynaptic
membrane.
Resulting in a smaller endplate potential and a reduced safety factor of
NMJ transmission.
Pathophysiology

The MuSK
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maintains the normal functional integrity of the NMJ
anti-MuSK antibodies may alter the normal maintenance of a high
density of AChRs at the NMJ
leading to reduced numbers of functional AChRs.
Thymus gland.
greater than 50% of anti– AChR-positive patients having
thymic hyperplasia and 10% to 15% having a thymic tumor.
1. HLA-DRW3, -B8, and -A1 predispose
2. a-subunit is the major T cell antigen
Etiology
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Acquired autoimmune
Drug-induced : D-penicillamine
Transient neonatal (passive transfer of maternal
anti-AChR antibodies)
Congenital myasthenic syndrome
Clinical presentation

most commonly presents with weakness of extraocular muscles
ptosis and/or diplopia, +/- photophobia

can mimic any pattern of ophthalmoplegia including pupil sparing
IIIrd nerve palsy, internuclear ophthalmoplegia (INO) or sixth
nerve palsy

Bulbar involvement common eventually dysphagia, dysarthria,
dysphonia (hypernasal or hoarse)

reduced facial expression, jaw fatigue

generally progresses over time so that within 2 years of onset of
ocular MG, 90% have bulbar and proximal symmetric limb
weakness
Clinical presentation
Early Symptoms
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frequent purchase of new eyeglasses to correct blurred vision
sleepy or sad facial appearance
avoidance of difficult to chew foods
cessation of activities requiring specific muscles (e.g. singing)
Presenting Symptoms
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ptosis or diplopia (2/3 of patients)
 present in almost all within 2 years of onset
difficulty chewing, swallowing, talking (1/6)
limb weakness (1/10)
 Rarely limited to single muscle group
Diurnal Variation
Exacerbating Factors
Clinical presentation
Natural History
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Restricted to ocular muscles in 10% of patients.
90% have progressive weakness over two years involving oropharyngeal and
limb muscles.
2/3 of patients reach remission within 1 year
Spontaneous remission can occur, usually early
Stages
1.
2.
3.
Active stage
1.
brief period of fluctuation
2.
more severe
Inactive stage
1.
fluctuations attributable to fatigue, intercurrent illness
Burnt out stage (15-20 years)
1.
2.
fixed weakness
atrophic muscles
Physical Findings
Ocular Muscles
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Ptosis
assymetrical
covering ptotic lid may relieve contraction of opposite frontalis
passively lifting ptotic lid may cause opposite lid to fall
varies during sustained activity
may shift from eye to eye - pathognomonic
edrophonium response
EOMs
 ³N muscle without pupil involvement
 variable, fluctuating, and fatigable
 most severe in medial rectus
 “pseudo-INO”
 edrophonium may improve only one of several weak ocular
muscles
Physical Findings
Oropharyngeal Muscles
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altered facial appearance – depressed , snarl/sad
examiner can manually open jaw against resistance
impaired strength of eye closure
nasal regurgitation
difficulty swallowing
hoarseness (larynx)
nasal voice, especially after prolonged talking
Limb Muscles
 neck flexors > extensors
 deltoids, triceps, wrist extensors, finger extensors especially affected
 ankle dorsiflexors preferentially affected
 fatigability
Diagnostic Procedures
Tensilon test
Measures
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ptosis, limitation of eye movement, or nasal speech preferred
limb muscles (requires maximum effort)
Administration
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2mg then wait 60s then 8mg then wait 60s
total dose 0.15mg/kg in children
sc administration in newborns and infants (delayed 2-5 minutes)
Test Characteristics
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90% sensitivity not 100% specificity
motor neuron disease
oculomotor nerve palsies
Alternative Agents
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im neostigmine (longer duration of action)
therapeutic trial of pyridostigmine
Tensilon test
Antibodies Against Acetylcholine
Receptors
Value
confirm diagnosis but cant predict severity neither predict thymoma
Test Characteristics
 80% sensitivity for generalized myasthenia (range 74-99%)
 55% sensitivity for ocular myasthenia
 may rise with disease progression
 generally specific
 rare DDx
SLE
Inflammatory neuropathy (CIDP)
ALS
RA
Thymoma without MG
Normal relatives of patients with MG
Ocular cooling
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Specificity??
Positive 80%, no positive response in patients with
ptosis not due to myasthenia
Alternative to tensilon test
Improvement in lid ptosis after the eye is cooled with
ice pack 2 minutes
Repetitive nerve stimulation
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(CMAP) should be normal in patients with MG.
With a small CMAP, LEMS should be considered.
Reproducible 10% decremental in amplitude when the
first stimulus is compared to fourth or fifth
skin temperature (i.e. 32ºC – 34ºC) before beginning
RNS.
hold anticholinesterases before test
more common in proximal muscles (facial, biceps,
deltoid, trapezius)
may get some repair with exercise, but not an
increment (unlike LEMS)
RNS in hand/shoulder has sensitivity of 61%
1.
76% in generalized myasthenia
2.
48% in ocular myasthenia
Repetitive nerve stimulation
SFEMG
(MUAP) abnormalities suggestive of a NMJ disorder,unstable MUAP, small,
short-duration.
 At least one symptomatic muscle
 Increased jitter and blocking
 Jitter is greatest in weak muscles
 Measure 2 time locked motor units
 SENSITIVE: 99% sensitive for generalized and 97% sensitive for ocular
 NONSPECIFIC
 any other motor unit disease
 must perform EMG and NCS to exclude neuronopathy, neuropathy,
myopathy
 limb jitter DOES NOT predict development of generalized myasthenia
 should examine 20 pairs in each muscle
Sensitivity
test
ocular
generalized
tensilon
60-95%
72-95%
Ach rec. Ab1
50-75%
70-95%
Anti-Musk
50% of AchR -
RNS
50%
75%
SFEMG
90-95%
98-100%
Ocular cooling2
89%
89%
Comparison of Diagnostic
Techniques
Tensilon test diagnostic if positive in patients with
ptosis or ophthalmoparesis
 AChR Ab specific
 RNS confirms DNMJ transmission but
nonspecific; often normal in mild or ocular disease
 SFEMG sensitive but not specific
Other Diagnostic Procedures
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CT chest
TFTs
TB test prior to immunosupression
Treatment
Treatment
Cholinesterase Inhibitors
Roles
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diagnostic
early, symptomatic treatment
adjunct to immunomodulatory and immunosuppressive therapy.
RARELY can be used as chronic treatment
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usually effect diminishes with time
Dosing
Pyridostigmine
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longer duration of action
initially 30-60mg q4-8 hours
1.0mg/kg in infants and children
available in serum (60mg/5ml)
available as nebulizer
RARELY produces normal strength and RARELY completely
corrects diplopia
Treatment
Cholinesterase Inhibitors
Neostigmine
 initially 7.5-15.0mg q4-8h
 0.3mg/kg in infants and children
 available as IV and nebulizer
Side Effects
Smooth Muscle (muscarinic)
 NxVx
 cramps
 diarrhea
 Rx with loperamide, propantheline, glycopyrrolate,
diphenozylate
Autonomic (muscarinic)
bronchial/oral secretions
Treatment
Cholinesterase Inhibitors
Skeletal Muscle (nicotinic)
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weakness
Bromism (from Mestinon)
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acute psychosis
rash
measure bromine level
Drug Interactions
succinylcholine metabolized by acetylcholinesterase
impaired metabolism can lead to potential arrythmias
Corticosteroids
Efficacy
marked improvement or complete relief in 75%
 some improvement in 25%
 most improvement in 6-8 weeks
 may become total remission even later
 best response if treated early
 severity does not predict response
 respond better with shorter disease duration and younger <50
Initiation - standard
 begin with 1.5-2.0mg/kg/day
 given until sustained improvement (2 weeks) then changed to 100-120mg alternate
days
Initiation - alternative
 begin at 20mg qd
 increase in 10mg increments q1-2 weeks
 then maintain constant until improvement is maximum
 used in ocular myasthenia
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Corticosteroids
Taper
decrease to lowest dose necessary to maintain improvement
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by 20mg each month until dose is 60mg
by 10mg each month until dose is 20mg
by 5mg each 3 months until 10 every other day
if weakness occurs, increase prednisone or add another
immunosuppressant
 do not d/c altogether
Initial Worsening
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1/3 of patients
within 1st 7-10 days and lasts 6 days
cover with ChE inhibitors
use initial PLEX and do in hospital if oropharyngeal weakness or
respiratory insufficiency
Immunosupressants
Azathioprine
Regimen
 start 50mg/d
 +50mg/d q7d
 target 150-200mg/d
Efficacy
 improvement maintained
 ?synergistic with steroids
 may start simultaneous with steroids and taper steroids when azathioprine
kicks in
 effect takes 4-8 months
 maximum improvement within 12 months
 70-90% response rate – similar to steroids
Immunosupressants
Azathioprine
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severe allergic reaction (required discontinuation)
 2 weeks after initiation
 15-30%
 flu-like symptoms and rash
GI irritation (use divided doses after meals or decrease dose)
leucopenia (monitor CBC q1wk x1m, q1m x1y, q3-6m after)
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Transaminitis
 stop only if >2x normal and can restart at lower dose once
normalize
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no proven increase in malignancy in MG patient specifically (unlike in
SLE)
Immunosupressants
Cyclosporine
Regimen
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begin at 5-6mg/kd div q12h
trough levels after 1 month (allows tissue saturation) - aim for
75-150ng/ml
Efficacy
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improvement in most patients taking CYA
improve within 1-2 months
maximum improvement at >6months
SFX
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Renal toxicity .
HTN (monitor q1month until steady state)
++drug interactions
Immunosupressants
Cyclophosphamide
Use
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severe, refractory MG
Regimen
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200mg/m2 q1month
titrate to changes in strength and side effects
150-200mg/d po to total of 5-10g to relieve Sx
SFX
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alopecia
cystitis
leucopenia
NxVx anorexia
Immunosupressants
Mycophenolate Mofetil
Mechanism
 Selectively inhibits proliferation of B- and T- lymphocyte clones responding to
antigenic stimulation
 Suppresses formation of antibodies
Evidence
 Open label pilot study demonstrated role as adjunctive therapy in refractory MG
Dosing
 2g/d div bid
Efficacy
 Improvement as early as 2 weeks and usually seen within 2 months
Role
 Refractory MG
 Steroid sparing agent when imuran intolerable or ineffective
Side Effects
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Diarrhea
leukopenia
Plasma Exchange
Roles
 sudden worsening of myasthenic symptoms for any reason
 rapidly improve strength before surgery
 concomitantly with high dose steroids
 chronic intermittent Rx in refractory MG
Protocol
2-3L of plasma 3x per week until improvement plateaus (usually after 5-6
exchanges)
Adverse Effects
 cardiac arrhythmias
 Lightheadedness
 Chills
 Obscured vision
 Pedal edema
 Hemorrhage (removal of coagulation factors)
 Hypercoagulation (removal of antithrombin III)
 Coagulation defects corrected within24h
IVIG
Indications
 Similar to PLEX
Mechanisms
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blocks Fc receptors on macrophagesm
anti-idiotype Ab against AChR antibodies
Protocol
2g/kg over 2-5 days
SFX
Headache , fever and chills, alopecia, aseptic meningitis, leucopenia
retinal necrosis, renal failure.
Treatment
Other Types Of Myasthenia
Gravies
Transitory Neonatal Myasthenia
clinical features
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hypotonic
onset within hours of birth but can be delayed up to 3
days
feed poorly in 1st 3 days
can get weak cry and lack of facial expression in 50%
15% have limited EOM and ptosis
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respiratory insufficiency rare
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worsens for first few days then improves
last 2-12 weeks (usually 2 weeks)
 neonatal antibodies have half life of 2-3 weeks and
not detected after 5 months
recovery is complete
Transitory Neonatal Myasthenia
diagnosis
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tensilon test OR RNS
high AChR in neonate blood
treatment
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ChE for swallowing or breathing - just before
feeding
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neostigmine im before feeding
can also give via NG tube at 10 times parenteral level
PLEX if respiratory weakness (rare).
Anti-Musk Myasthenia
Epidemiology
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25% of all MG patients are seronegative
40% of seronegative MG patients are MuSK positive (about 10% overall)
M=F
Same age of onset as usual myasthenia
Normal Function of MuSK
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Tyrosine kinase
Regulates and maintains AChR at NMJ
Clinical Features – Differences from Typical Myasthenia
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More involvement of neck, shoulder, respiratory
Less limb
More bulbar
Increased risk of myasthenic crisis in 1st 2 years
Greater proportion in more severe category
Outcome similar, but require more steroids
Treatment
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Treatment generally the same
Can respond to thymectomy
Less likely to have thymic hyperplasia
Genetic Myasthenic Syndromes
Congenital Myasthenia
Genetics
several genetic defects
Epidemiology
2:1 male predominance
Causes
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Deficiency of muscle acetylcholine receptors at the end plate
 Some have AChR mutations
 Some have deficiency of rapsyn (receptor-associated protein at the
synapse)
Abnormalities of acetylcholine resynthesis or immoblilization
Reduced end plate acetylcholinesterase
Impaired AChR function
Genetic Myasthenic Syndromes
Congenital Myasthenia
Clinical Features
 ophthalmoparesis and ptosis developing in infancy
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incomplete at onset
progresses to complete paralysis during infancy or childhood
mild facial paresis
limb weakness mild compared to opthalmoplegia
respiratory distress unusual
symptoms may not fluctuate much
Genetic Myasthenic Syndromes
Congenital Myasthenia
Diagnosis
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subcutaneous injection of edrophonium  transitory
improvement in ocular motility
RNS
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Decrement found in some limb muscles
May be necessary to test proximal or facial muscles if limbs normal
SFEMG
Treatment
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ChE inhibitors improve limb weakness in many forms
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Ocular muscle weakness less responsive
Some children respond to DAP
Congenital Myasthenic Syndrome with
Episodic Apnea (Familial Infantile
Myasthenia)
Clinical Features
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Similar problems in other siblings
generalized hypotonic at birth +/- arthrogryposis
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respiratory insufficiency and feeding difficulty at birth
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repeated episodes of life-threatening apnea and feeding difficulty
neonatally
 may require ventilation
 usually improves within weeks of birth, allowing weaning from
ventilation
 episodes may persist throughout infancy and even into adulthood
 sudden bouts of respiratory distress with intercurrent illness
ocular function usually normal
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Congenital Myasthenic Syndrome with
Episodic Apnea (Familial Infantile
Myasthenia)
Diagnosis
 edrophonium test - 0.15mg/kg
 decremental RNS
Treatment
 ChE inhibitors improve strength in most children - long term to
prevent episodes of apnea at time of intercurrent illness
 DAP + pyridostigmine works for children from several families
 many require mechanical ventilation
Slow-Channel Congenital Myasthenic
Syndrome
Epidemiology
RARE
Genetics and Molecular Biology
 AD
 Prolonged open time of Ach channel
Clinical Features
 Normal at birth
 Onset always after infancy
 onset may be delayed until adult life
 can present in 20’s
 begins with weakness of cervical and scapular muscles
 slowly progressive weakness of arm leg neck facial muscles
 exercise intolerance
 ophthalmoparesis
 Rare to have ptosis, bulbar dysfunction, leg weakness
 atrophy of affected muscles
Slow-Channel Congenital Myasthenic
Syndrome
Course
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progresses slowly
many patients do not present until after age 10
Diagnosis
 decremental RNS
 repetitive discharges after nerve stimulation (like ChE
inhibitor toxicity)
 muscle Bx – type I predominance, group atrophy,
tubular aggregates, abrnomal end-plate configurations
Slow-Channel Congenital Myasthenic
Syndrome
Treatment
 not effective
ChE inhibitors
 Thymectomy
 Immunosuppression
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May be effective
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Quinidine sulfate improves strength
Fluoxetine equally effective
Fast Channel Myasthenic Syndromes
Pathophysiology
 Ach receptor/channel complex does not let in
sufficient sodium
 Mechanisms
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Channel open for too short a time
Channel takes long time to open up
Ach does not bind sufficiently long to receptor
Channel requires too much energy to switch from inactive to
active state
Treatment
 Responds well to 3,4 DAP and anticholinesterases.
 Ephedrine may help
LEMS
Epidemiology
 usually after 40’s
 has been reported in children
 M=F
 50% have underlying malignancy (80% of these SCLC)
Immunopathology
 antibodies to VGCCs
 disorganization of motor nerve terminal active zone particles
 SCLC cells contained high concentrations of VGCCs and SCLC VGCC are
inhibited by LEMS sera
Clinical Features
Weakness
 proximal muscles, especially legs
 oropharyngeal and ocular relatively spared (although can be affected)
 objective weakness mild compared to severity of symptoms
 weakness improves briefly after exercise, then returns with sustained activity
 absent DTR which are enhanced by repeated muscle contraction or repeated tapping
of tendon
 can present as prolonged paralysis following use of neuromuscular blocking agents in
surgery
LEMS
Clinical Features
Autonomic Features
 dry mouth common
 impotence
 postural hypotension
Temperature Dependence
 worse in heat
 avoid hot showers or baths
Diagnosis
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edrophonium not as effective as seen in MG
EMG/NCs – most sensitive in distal muscles
Neoplastic Workup
bronchoscopy
PET scan
LEMS
NCS
CMAP amplitudes low
Repetitive Nerve Stimulation and Exercise Testing
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>10% decrement in CMAP amplitude on slow repetitive nerve
stimulation (3Hz) between 1st and 4th potential
>40% (often >100%) increase in distal CMAP amplitude after 10
seconds of maximal voluntary exercise.
>40% (often>100%) increase in distal CMAP amplitude after high
frequency (30-50Hz) repetitive nerve stimulation
EMG
generally normal
 motor unit action potentials may be unstable; may be
short, small, or polyphasic (i.e. myopathic); may have
normal or early recruitment
SFEMG
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increased jitter and blocking
LEMS
Treatment
ChE Inhibitors
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may work in occasional patients
pyridostigmine 30-60mg q6h x several days
major benefit is relief of dry mouth
Guanidine Hydrochloride
 increases release of Ach
 add on agent to mestinon
 temporary improvement in strength in many patients with LEMS
 start 5-10mg/kg/d div 4-6h apart
 increase to maximum of 30mg/kg/d q3d
SFX
BM suppression ,RTA ,Chronic interstitial nephritis ,Cardiac arrhythmia ,Hepatic
toxicity ,Pancreatic dysfunction ,Paresthesiae ,Ataxia .Confusion ,Mood changes
LEMS
Treatment
DAP
 5-25mg tid-qid
 facilitates release of Ach from motor nerve terminals
 synergistic with pyridostigmine
PLEX and IVIG
 can provide transitory improvement
(Immunosupression ,prednisone,azathioprine ,cyclosporine)

not as good as in MG
Severe Weakness
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PLEX/IVIG 1st
Prednisone and imuran added after improvement begins
Prognosis
variable
Botulism
Pathophysiology

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botulinum toxin block release of Ach from motor nerve terminal
8 types of toxin
 types A and B cause most occurrences of botulism in US
 type E transmitted in seafood
Clinical Features

Course
 NxVx 1st Sx of food-borne botulism
 Neuromuscular Sx begin 12-36h after exposure
Ocular : blurred vision and impaired pupillary reflexes
Motor : weakness and decreased DTRs

Autonomic : dry mouth ,constipation ,urinary retention
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Botulism
Diagnosis
Tensilon Test
 positive in 1/3 of patients
 do not distinguish botulism from other causes
Microbiological
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Botulinium toxin in stool
C. Botulinium culture from stool
Wound cultures and serum for Botulinium toxin
EMG/NCS
1.
2.
3.
4.
reduced CMAP in at least 2 muscles
at least 20% facilitation of CMAP amplitude during titanic stimulation
persistence of facilitation at least 2 minutes after activation
no postactivation exhaustion
SFEMG
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Jitter and blocking
Sensitivity 100% ,Poor specificity
Botulism
Treatment
 bivalent (type A, B) or trivalent (A, B, E) antitoxin
 antibiotics NOT effective
 supportive therapy
 ChE inhibitors NOT beneficial
 DAP improves strength but not respiratory function
Prognosis
 Most patients make complete recovery within 2-3 months
 If sever einvolvement, may not return to normal for a year
Venoms
Clinical Features
 progressive, symmetrical muscle weakness
 oculomotor/eyelids most often
 neck flexion, and pelvic and pectoral girdles next
 bulbar or respiratory if severe
 cognition and sensation preserved
 DTR preserved, or minimally diminished
Mechanisms
 initial augmentation of Ach release with subsequent depletion
 facilitation of Ach release without subsequent depletion of neurotransmitter
 depletion of Ach release
 blockade of post junctional Ach receptor
Specific Venoms
Funnel Web and Black Widow Spiders (latrodectism)
facilitation of neurotransmitter release by depolarization of presynaptic terminal
Venoms
Tick Paralysis
Microbiology

dermacentor andersoni ,dermacentor variabilis
Clincial Features

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
usually children <5yo
similar to GBS
ocular motor palsies and papillary abnormalities <GBS
Mechanism
postsynaptic blockade of neurotoxin
Diagnosis

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CSF protein normal
NCS normal or mild slowing of NCV
decreased CMAP
high frequency RNS may be normal or abnormal incremental response
Treatment

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remove tick usually lead to rapid recovery
Australian variant may have continued worsening for another 1-2 days
Other Neurotoxins Affecting The
NMJ

Marine neurotoxins
are rare and come primarily from poisonous fish (stonustoxin), a few
mollusks (conotoxins), and dinoflagellates.

Heavy metal intoxication
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is a rare cause of neuromuscular toxicity.
Ingestion of contaminated grain used for flour in bread.

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produced weakness with characteristic decremental responses
partial reversal with ChE inhibitors.
Organophosphates


impair neuromuscular transmission by irreversibly inhibiting
acetylcholinesterase.
producing a depolarizing neuromuscular block.
Neuromuscular
Junction Disorders