Download Neuromuscular Emergencies - S Derghazarian 07 28 10

NEUROMUSCULAR EMERGENCIES
July 28, 2010
Sandra Derghazarian
Outline
• Approach to rapidly progressing LMN
weakness
• Myasthenic crisis
• GBS
Intro
• Three major tasks:
– Assess stability, signs of imminent resp failure
– Generate differential diagnosis
• Knowledge of localisation
• Knowledge of major disorders
– Determine management
Brief Review of Anatomy
• Motor unit anatomy
– Anterior horn cell
– Its motor axon
– The synaptic cleft
– The muscle fibers it innervates
• Remember sensory and autonomic systems
– Many disorder with rapidly progressing peripheral
neuropathic weakness will have sensory loss and
dysautonomia
Classification
• Motor neuron
– Loss of anterior horn cells
• Motor axon
– Disruption of myelin sheath
– Axonal degeneration
• Neuromuscular junction
– Pre-synaptic (e.g. Release of Ach)
– Post-synaptic (e.g. Abnormalities of Ach receptor)
• Muscle
– Membrane, contractile elements
– Genetic or acquired secondary (infex, inflamm, vasc.)
Approach to Determining Cause of
Weakness
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Knowledge of some of the possible disorders
Focused history
Physical exam
Lab studies
Major Disorders
Level of motor unit
Disorders causing rapidly progressing weakness
Motor neuron
ALS
Poliomyelitis, West Nile virus
Peripheral nerve
Guillain-Barre syndrome/AIDP
Tick paralysis
Diphtheric, porphyric, arsenic neuropathy
Shellfish poisoning
Neuromuscular
junction
Myasthenia gravis
Botulism
Lambert-Eaten myasthenic syndrome
Hypermagnesemia
Muscle
Acquired: Dermato- and polymyositis, Myoglobinuric
myopathy, Hypokalemic paralysis, Toxic myopathy,
Acute myopathy of intensive care
Genetic disorders: X-linked dystrophies, myotonic
dystrophy, acid maltase deficiency, mitochondrial
History – Key Elements
• Pre-existing NM disorder?
– MG – exacerbation 2ary systemic illness, medication
– ALS – accelerated phase, decompensation 2ary pneumonia
• Pre-existing systemic disorder?
– Malignancy, CTD, sepsis
• What drugs is pt taking?
• Any recent illness?
• Diet in last 48 hours?
– Shellfish (saxitoxin, brevetoxin)
– Home-canned goods (botulinum toxin)
• Any possible exposure to tick bite, snake bite?
• Any sensory or autonomic symptoms?
Drugs
• Diuretics
– Hypokalemia
• Corticosteroids, statins, colchicine, cyclosporine,
cocaine, chloroquine, L-tryptophan, penicillamine,
zidovudine
– Myotoxic effect
• Amiodarone, cytarabine, streptokinase
– Demyelinating neuropathy
• Magnesium-containing antacids with pre-existing renal
insufficiency
– Hypermagnesemia
Physical Exam
• Vital signs
– Unstable?
– Dysautonomia?
• Respiratory status
Signs of impending NM resp failure
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Tachypnea, sinus tachycardia
Staccato speech
Inability to count to 20
Profound weakness of neck flexion
Use of accessory muscles (visible, palpable)
Orthopnea
Paradoxical breathing pattern
Signs of bulbar dysfunction (nasal voice,
accumulation of saliva, weak cough)
–  think about aspiration!
Physical Exam
Physical Exam
• Vital signs
• Note any dysautonomia
• Presence and pattern muscle weakness
• Proximal (myopathy), distal (peripheral neuropathy)
• Symmetric, asymmetric
• Involvement of cranial muscles
• Reflexes
• Sensory changes
• Dysautonomia
Localisation of the Disorders
• Clinical picture varies depending on which part of
motor unit is involved
Level of motor unit
Key Clinical Feature
Motor neuron
Predominantly motor signs
Often asymmetric
Occasional sensory signs
DTRs may be increased if ALS
Peripheral nerve
Weakness and sensory signs
+/- autonomic signs
+/- cranial muscles
DTRs reduced or lost
Localisation ctn’d
Level of motor unit
Key Clinical Features
Neuromuscular junction
Involve cranial, limb girdle, proximal
muscles
+/- respiratory muscles
Normal sensation
(If presynaptic: +ve autonomic signs and
post-exercise increase in strength
If post-synaptic: fatigability)
Muscle
Predilection for neck, limb girdle,
proximal muscles
Normal sensation
Possible cardiomyopathy
Occasional resp muscle involvement
Possible risk of myoglobinuria
Regroup
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Is respiratory failure imminent?
Should ICU be involved?
Where can I localise motor findings?
Does it fit with sensory findings?
Does it fit with autonomic findings?
Does it fit with the history?
Can the history help me narrow things down?
Major Disorders
Level of motor unit
Disorders causing rapidly progressing weakness
Motor neuron
ALS
Poliomyelitis
Peripheral nerve
Guillain-Barre syndrome
Tick paralysis
Diphtheric, porphyric, arsenic neuropathy
Shellfish poisoning
Neuromuscular
junction
Myasthenia gravis
Botulism
Lambert-Eaten myasthenic syndrome
Hypermagnesemia
Muscle
Acquired: Dermato- and polymyositis, Myoglobinuric
myopathy, Hypokalemic paralysis, Toxic myopathy,
Acute myopathy of intensive care
Genetic disorders: X-linked dystrophies, myotonic
dystrophy, acid maltase deficiency, mitochondrial
Laboratory Studies
• CBC
• Anemia or leukocytosis - systemic disease
• Eosinophilia - possibly elevated in vasculitic neuropathy, porphyria
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Lytes, Cr, BUN, Ca, Mg, PO4,
Liver enzymes (consider EtOH myotoxicity)
CK (myopathy if very elevated)
ESR (infectious or inflammatory disorders)
CXR (pneumonia, atelectasis, elevated hemidiaphragm)
EKG
– Changes associated with electrolyte imbalances
– Arrythmias 2ary to dysautonomia in GBS
– Axis deviation – may be suggestive of cardiomyopathy
Assess Respiratory Status
• Tests in ER
– MIP
– MEP
– FVC
– ABG
• 20/30/40 rule
– VC: 20 ml/kg
– MIP: -30cmH20
– MEP: +40cm H20
MYASTHENIC CRISIS
Myasthenia Gravis
• Disorder of transmission across NM junction
• Auto-immune and congenital form
• Epidemiology (auto-immune form):
– 200-400 cases per million population
– Women > men (3:2)
– Bimodal incidence
• F: 20s, 30s; M: 50s, 60s
– 5-10% co-association with other auto-immune
disorders
Classification
• Auto-immune – two forms
– Acquired anti-AChR Abs (85%)
– Acquired anti-MuSK Abs, a muscle-specific TK
• 40-50% of anti-AChR seronegative pts
• Congenital
– Heterogeneous group (pre or post-synaptic)
– Of note: do not affect respiratory muscles
therefore do not present with myasthenic crisis
Clinical Features
• Painless, fatigable weakness of voluntary muscles
– Repeated activity  progressive paresis
– Rest  restoration of strength (at least partial)
• Usually insidious onset
– May occur more rapidly after precipitant (stress,
infection)
• Association with thymic abnormalities
– 10-15% thymoma
– 50-70% thymic lymphoid hyperplasia
Clinical Features
• Presenting symptoms:
Diplopia
Ptosis
Generalised weakness
Leg weakness
50-64%
50-64%
35%
10%
Fatigue
Respiratory failure
9%
1%
• MuSK-MG
– Younger women
– Predominantly facial, bulbar and respiratory weakness
– Relatively mild limb weakness
Severity Classification
Myasthenic Crisis
• Myasthenic weakness leading to respiratory
failure and need for ventilatory assistance
• Severe weakness of respiratory muscles
and/or
• Severe weakness of upper airway muscles
(bulbar myasthenia)
Prevalence and Characteristics
• Life-time prevalence: 20-30%
– Early onset  younger pt, median onset w/in 8
mos, fast recovery
– Late onset  older pts, later in dz course, slower
recovery
• White pts respond more poorly than black pts
• Pregnancy aggravates MG in 30% of women
– High potential mortality of crisis
Precipitants
• Elements to look for in history/chart:
– Poor control of generalised disease
– Medical treatment for bulbar myasthenia
• Steroids and anti-cholinesterases
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Use of certain drugs (next slide)
Systemic infection, esp. of respiratory tract
Aspiration
Surgery
Others (in refractory myasthenia):
• Emotional stress
• Hot environment
• Hyperthyroidism
Drugs
• Anticholinesterases can also lead to myasthenic crisis
• Signs of excessive cholinergic activity
– Miosis, diarrhea, salivation, abdominal cramps, sweating, weakness
Investigations
• CBC, extended lytes, BUN, Cr, liver enzymes
• CXR, U/A +/- blood cultures
• Obtain VC, MIP, MEP – 20/30/40 rule
Investigations
• Repetitive motor nerve stimulation
– Stimulate motor nerve at 2-3 Hz and measure CMAP of stimulated
muscle
– Positive if >er 10% decrement in amplitude of CMAP from the 1st to
the 5th potential
– Positive in about 75% of patients with generalized MG, if
– Proximal & clinically involved muscles are tested
– Muscle is warm
– More than one muscle is tested
• Single fibre EMG
• Tensilon test not recommended in pt suspected of being in crisis
– False postive, false negative
– Risk of worsening muscle weakness in pts with anticholinesterase
overdose
– Worsening of bulbar and respiratory symptoms in MuSK-MG
Management
• Monitoring of respiratory status
– Recognition of impending resp failure
• Tachypnea, inability to count to 20, saliva pooling, nasal
voice, NF weakness, paradoxical breathing
– Deciding when to intubate
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(Code status)
20/30/40 rule
If in doubt, intubate
?BiPAP
– Limited experience. May reduce prolonged intubatn and trach
Management
• General
– Stop any meds that may be contributing
– Treat any infection
• Specific
– PLEX and IVIG comparable efficacy
• Based on clinical evidence, few RTCs
• Earlier response seen with PLEX
– More likely to extubate at 14 days, better 1-month functional
outcome (Qureshi, et al. Neurology, 1999).
Management
• PLEX
– Removal of anti AChR and antiMuSK Abs
– 1 session/day x 5
• No superiority of PLEX qd x 5 vs qod x 5
– Rapid onset of action (3-10 days)
– Need central line with associated complications
• PTX, hemorrhage, line sepsis
– Caution in pts with sepsis, hypotension; may lead
to increased bleeding and cardiac arrhythmias
Management
• IVIG
– 0.4gm/kg/day x 5 days
– Easily administered and widely available
– Long duration of action
• May last as long as 30 days
– Side effects
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Anaphylaxis in IgA deficiency
Renal failure, pulmonary edema
Aseptic meningitis
Thrombotic complications and stroke
MG – Overall Treatment Summary
• 1. Mild weakness: cholinesterase inhibitors
• 2. Moderate-marked localized or generalized weakness
– Cholinesterase inhibitors, and
– Thymectomy for patients under age 50-60 yrs
• 3. Symptoms uncontrolled on cholinesterase inhibitors
– Prednisone if severe or urgent
– Azathioprine
• Prednisone failure
• Excessive prednisone side-effects
• 4. Plasma exchange or IV Ig
– Impending crisis; crisis
– Pre-operative boost
– Chronic disease refractory to drug therapy
• 5. If above fails
– Search for residual thymus tissue
– Cyclosporine or mycophenylate mofetil
(Sem. Neurol., 2001;21:425-440)
Guillain-Barre Syndrome
GBS
• Most common cause of acute and subacute
generalised paralysis
• Incidence of 0.4 to 1.7/100 000 per yr
• Worldwide, all ages, both sexes
• Preceding mild resp or GI infection in 60% (1-3 wks)
– Campylobacter jejuni (26%),
– CMV, EBV, VZV
– Influenza, cocksackie, hepatitis A and B, HIV
• May also be preceded by:
– Surgery
– Immunisations
Typical Symptoms & Signs
• Sensory
– Paresthesias and slight numbness distally earliest Sx
– Reduced proprioception and vibration sense (1 wk)
• Motor
– Weakness
• Evolves symmetrically over days to 1-2 weeks
• Usually LE before UE, proximal + distal
• +/- trunk, intercostal, neck, cranial muscles
– Progresses to total motor paralysis and respiratory
failure in 5% of cases
Typical Symptoms & Signs
• Reflexes
– Reduced and then absent
• Autonomic dysregulation
– Sinus tachycardia/bradycardia, facial flushing,
labile BP, excess or loss of sweating, urinary
retention
– Usually do not persist for >er 1 wk
• Other
– Myalgias (50%) in hips, thighs, back
Variants
• Fisher syndrome
– Ophthalmoplegia, ataxia, areflexia
– +/- bilateral facial nerve paresis
– Associated with anti-GQ1b Ab
• Acute motor sensory axonal neuropathy (5% of GBS cases)
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Severe and diffuse axonal damage
Abrupt and explosive onset
Severe paralysis, minor sensory features
Slow and poor recovery
• Pandysautonomia
– Severe orthostatic hypotension, anhidrosis, dry eyes and mouth, fixed pupils,
arrhythmia, bowel/bladder dysfunction
– Areflexia without somatic motor/sensory involvement
• Other variants:
– Initial cervico-brachial-pharyngeal muscle involvement
– Generalised ataxia without dysarthria or nystagmus
– Facial and abducens weakness, distal paresthesias, proximal leg weakness
Laboratory Findings
• Most important: CSF, EMG
• CSF
– Normal pressure
– Protein
• Early (1st 2 days): Usually normal (>85%)
• Later: High (66% in 1st week, 82% in 2nd week)
• Amount not correlated with clinical course or prognosis
– Acellular or few lymphocytes
• 10% : 10-50 lymphocytes, decreases over 2-3 days; if not:
other Dx
– Oligoclonal bands (10-30%)
Laboratory Findings
• EMG
– Abnormalities seen within first week of sx
– Reduction in motor amplitude
– Slowed conduction velocities
– Conduction block in motor nerves
– Prolonged distal latencies (distal conduction block)
– Prolonged/absent F-responses (involvement of
proximal parts of nerves and roots)
Laboratory Findings
• Hematology
– Abnormal only with infection or other disorder
• Biochemistry
– Mild-severe SIADH in 7-26%
• Liver enzymes
– Elevated <10% reflecting CMV or EBV infection
• ESR: Normal unless co-existing process
Diagnostic Criteria
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National Institute of Neurological Disorders and Stroke (NINDS) criteria are based
on expert consensus.
Required features include:
– Progressive weakness of more than one limb, ranging from minimal weakness of the legs to
total paralysis of all four limbs, the trunk, bulbar and facial muscles, and external
ophthalmoplegia
– Areflexia. While universal areflexia is typical, distal areflexia with hyporeflexia at the knees and
biceps will suffice if other features are consistent.
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Supportive features include:
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Progression of symptoms over days to four weeks
Relative symmetry
Mild sensory symptoms or signs
Cranial nerve involvement, especially bilateral facial nerve weakness
Recovery starting two to four weeks after progression halts
Autonomic dysfunction
No fever at the onset
Elevated protein in CSF with a cell count <10 mm3
Electrodiagnostic abnormalities consistent with GBS
Differential Diagnosis
• Features suggesting another diagnosis:
– Sensory level, severe bladder or bowel dysfunction 
Spinal cord syndrome
– Marked asymmetry  Mononeuritis
multiplex/vasculitis
– CSF pleocytosis  Infectious disorders: viral, HIV,
lyme, poliomyelitis
– Very slow nerve conduction velocities, multiple
relapses or chronic course -> CIDP
– Persistent abdominal pain and psychiatric signs 
Acute intermittent porphyria
Management
• General:
– Recommend admission for observation
• Can deteriorate rapidly in first days of presentation
• M&M: Respiratory failure, dysautonomia
• 25% will require mechanical ventilation
• Respiratory
– Measure MIP/MEP/FVC
• Decision to intubate should be based on downward trend
– Other measures of respiratory status same
• Counting to 20, strength of NF
Management
• Dysautonomia
– 10% develop hypotension
• Volume, +/- pressors
– Hypertension
• IV labetolol
• Other complications
– Adynamic ileus
– PE
– Aspiration
Management
• PLEX and IVIG
– No difference in efficacy between the two
– Indications for prompt initiation
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Respiratory failure
Bulbar involvement
Inability to walk without assistance
Usually see these signs day 5-10
May occur anywhere from day 1 – week 3
• Steroids
– No proven benefit
PLEX
• Regimen: 4-6 treatments on alternate days
• Established usefulness in evolving phase
• If treated within 2 wks onset
– Decrease in LOS, ventilation, time to independent
ambulation by approx. half
• Value less clear if started later than 2 wks after
initial symptoms
• Predictors of response
– Age
– Preservation of motor CMAP amplitudes pre-PLEX
IVIG
• Dose: 0.4 gm/kg/day x 5 consecutive days
• Cheaper, easier to administer
• Rare complications
– Renal failure, proteinuria, pulmonary edema
– Asceptic meningitis
– Anaphylaxis in IgA deficiency
Course and Prognosis
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Progressive symptoms : 1-4 weeks
Plateau: 2-4 weeks
Recovery: A few weeks to months
Recurrence: 5-10%
Mortality
– 3-5%
– Cardiac arrest, ARDS, PTX, HemoTX, PE
• Pronounced disability: 10%
– Clinical prognostic indicators
• Greater age
• Rapid evolution; early and prolonged ventilatory assistance, rapid course
• Lack of treatment with IVIG or plasma exchange
– Laboratory
• EMG: severely reduced CMAP and widespread denervation
Pathogenesis
• Most evidence points to cell-mediated
immunologic reaction directed at peripheral
nerve
– May be precipitated by antecedent infection
• Antibodies against myelin components with
complement-mediated damage
• T cells and macrophages become involved in
process and lead to destruction of
myelin/axon
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