is it mg crisis?
DESCRIPTION
Is it MG Crisis?. Dr Chan Yan Fat Alfred Caritas Medical Center 20/01/2009. Background history. 82-year-old woman, ex-smoker Mother of 6 children Resident in Canada and being FU at there Post-radioactive-iodine hypothyroidism Asthma with nil attack for years Essential hypertension - PowerPoint PPT PresentationTRANSCRIPT
Background history
• 82-year-old woman, ex-smoker
• Mother of 6 children
• Resident in Canada and being FU at there
• Post-radioactive-iodine hypothyroidism
• Asthma with nil attack for years
• Essential hypertension
• Ocular myasthenia gravis (MG) since 2002
Long term medication
• L-thyroxine 75 microgram daily
• Candesartan 8mg daily
• Ventolin 2 puffs Qid PRN
• Becotide 2 puffs BD
• Pyridostigmine (Mestinon) 60mg BD
History of present illness
• Visit Hong Kong since one week ago• Upper respiratory infection since arrival• Fever and sputum for 3 days, and put on oral Levo
floxacin 100mg BD + Romilar• Subjective double vision for one day, with bilatera
l upper limb weakness + numbness, but still able to walk
• While at Precious blood Hospital, developed choking and SOB
To CMC AED 9/3/08 at 1900
• BP 202/89, pulse 72, SaO2 88% room air
• GCS 15/15, Fever 38.0 degree
• Speak full sentence, SaO2 96% at 2L O2
• “muscle weakness” at 4/5
• Chest clear; PFR 170 170 150
• Impression: mild MG
• Decision: consult ICU
Direct ICU admission
• Failed bedside swallowing test
• Impaired abduction of eyes at both side
• No facial weakness or fatigability
• Power: bilateral upper limb 4-/5
bilateral LL 4/5 proximal; 5/5 distal
• Bilateral down-going plantar
• Normal deep tendon reflex
Differential diagnosis
• Generalized myasthenia gravis (MG) with ocular and bulbar involvement
• Thyroid ophthalmopathy + myopathy
• Brainstem pathology
• Motor cranial nerve pathology
• Pharyngeal-cervical-brachial variant of Gullain-Barre Syndrome
Famous MG precipitating causes
• Antibiotics: aminoglycosides; macrolides; fluoroquinolone; tetracyclines
• Anesthetic: lidocaine; procaine; NMB• Cardiac: betablocker; CCB; procainamide• Steroids• Anticonvulsant: phenytoin; gabapentin• Others: Opiods; thyroxine; diuretics; anti-ch
olinergics; iodinated contrasts; URI
Management by on-call MO
• Keep NPO for possible intubation later
• Increase Mestinon 60mg tds
• Insert RT for medication
• Check CBP/RFT/LFT/INR/ABG/ESR
• Blood, sputum and urine for culture
• Serum viral titre
• Urgent plain CT brain
Blood test
• WCC 15.4 (Neutrophil 85.4%)
• Hemoglobin 13.5 with MCV 89.9
• ESR 87
• CK 145; albumin 37, globulin 42
• RFT and LFT normal
• TSH 1.79 (0.50-4.70)
• pH 7.41, CO2 42.6, O2 176, HCO3 26
Progress on 10/3/08 at ICU D2
• Subjective deterioration and require frequent suction of oral secretion/ sputum
• Examination in AM around:Hoarseness and weak coughDrooling of salivaPoor AE over both chest
• Impression: MG crisis
Bronchoscopy
• Very poor cough effort
• Continuous aspiration of saliva and upper airway secretion into lower tract
• BAL done at right lower lobe for virus study and bacterial culture
Management at ICU day 2
• Endotracheal intubation
• Start IV Augmentin for chest infection
• Start iv Intragram (IVIG) 21g (BW 53kg), plan daily dose for 5 days
• Trace old record from Canada family doctor about the diagnosis and previous workup of myasthenia gravis
Progress at ICU day 4
• All ocular movement is full, no ptosis• Hand-grip 3/5; right wrist flexion 2/5; rest o
f upper limb power 0/5 !• Both thigh 3/5, both ankle 4/5• Absent deep tendon reflex of lower limb, m
arkedly decreased at upper limb• Paraesthesia over 4 limb, nil sensory level• BP 100/55, fever down
Can it be due to MG crisis
Pros• Symmetrical proximal
muscle weakness
• Previous ocular MG
• Bulbar symptom
• Precipitating factors of crisis seen
Cons• Different symptom a
nd sign from past
• Severity of physical sign not fluctuating
• Global areflexia
• Sensory symptoms
Management at ICU day 4
• Stop Intragram
• Off Mestinon plan to have more MG workup first e.g. electrophysiology
• Urgent MRI cervical spine to upper thoracic spine to look for cord lesion
• Trace again past medical record from Canada doctor by relative
Urgent MRI report
• Serpentine intradural extramedullary flow-related signals and flow voids are demonstrated from C5 to T9 level, but no definite intramedullary involvement.
• No hemorrhage or abnormal signal in cord• No mass effect on cervical/ thoracic cord• Impression: spinal vascular malformation, li
kely spinal dural AV fistula
Can it be spinal cord insult?!
Pros• Tetraparesis
• Areflexia
• Hypotension
• Normal cognitive function all along
• MRI showed vascular lesion around cord
Cons• Proximal affected pref
erentially
• No sensory level
• Bulbar symptoms
• Ophthalmoplegia, though improved
• Normal cord signal
Progress at ICU day 5
• Orthopedics intramedullary lesion better be managed by neurosurgery
• Neurosurgery no evidence of acute element for intervention, suggest to transfer patient when nil airway problem
• ICU noted good respiratory effort with spontaneous tidal volume >400ml. Failed extubation because of aspiration problem
Progress at ICU day 6 (1)
Medical summary from Canada• Patient presents as ptosis and diplopia in Ju
ne 2002. Nil peripheral/ bulbar or respiratory involvement
• Nil Tensilon test, nil anti-acetylcholine receptor antibody checked
• Prompt effect with Mestinon• CT thorax showed no thymoma
Progress at ICU day 6 (2)
• Proximal muscle power 2/5, distal 4/5
• Double-blinded Tensilon test
no significant change in limb power
• Bedside EMG: no typical decrement of amplitude with repetitive stimulation
• Acetylcholine receptor binding antibody
10.57 (<0.45, ELIZA method)
Neurologist (ICU Day 7)
• All along no cognitive impairment
• No objective sensory deficit
• Diplopia on presentation, though remitted
• Bulbar symptom: choking/ hoarseness
• Both shoulder and hip power 2/5
• Both ankle/wrist and hand power 4/5
• Global areflexia + withdrawal plantar
• Impression: Miller Fisher syndrome
BP/P
240
220
200
180
160
140
120
100
80
60
Temp
40
39
38
37
SBP
Temp
Pulse
8P 9/3 8A 10/3 8P 10/3 8A 11/3 8P 11/3
ICU intubation
Off sedation
On sedation
Off sedation
Management at ICU day 7 (1)
• Contrast CT brain nil significant lesion• Lumbar puncture
Protein 1.85, glucose 4.0 (serum 9.0) unfit for cell count PCR for HSV/ VZV not detected
• Check ANF/ANCA/Anti-cardiolipin/ lupus anticoagulant/ cold agglutinin/ atypical pneumonia titer/ CMV and EBV serology
Management at ICU day 7 (2)
• Check Anti-Ganglioside Q1b antibody by private lab
• Give 3 more days of Intragram 21g daily
• Plan perform nerve conduction test on working day to detect any features of polyneuropathy, and to differentiate demyelinating/ axonal degeneration if any
Progress at ICU day 9
• Shoulder/ elbow power 4-/5; hand 5/5
• Hip/ knee power 3/5; ankle 4/5
• Nerve conduction test bedsideAbsent F wave response in 5 nervesProlonged distal latencyAmplitude and velocity within normalNo conduction block; sural nerve sparedAxonal degeneration; motor dominant
Progress at ICU day 10
• Proximal power 4/5, distal power 5/5
• Right brachioradialis reflex intact, right knee jerk has minimal response
• Complained of severe headache and low back pain. ?neck stiffness on exam
• ?Mechanical injury of AVM during LP
CT brain + C-spine + L-spine
• Brain showed nil significant abnormality
• No abnormal vasculature in cervical cord
• Small enhancing vessels along surface of thecal sac at level down to L2
• No evidence of bleeding from vessel
Further progress
• Off RT and oral diet tolerated since day 11
• Discharge to general ward on day 15
• Anti-Ganglioside Q1b 105 (<20)
• ANF 1: 80; Anti-ds DNA 13 (<35)
• C-ANCA weak +ve; PR3-ANCA 6 (<20)
• Cold agglutinin 8 (<32)
• Lupus anticoagulant not detected
• Anti-cardiolipin IgG 9.5 (weak +ve)
At rehabilitation
• Repeated NCT on day 19 showed improving polyneuropathy. Yet EMG showed equivocal MG features
• Repeated Tensilon test on day 25 Still NEGATIVE result
• Neurology opinion not to resume Mestinon since MG not the dominant illness
• Home on day 48
Neurology FU
• No ocular/ bulbar or peripheral symptom• Private MRI brain and brain stem
bilateral frontal lobe atrophy only• Imp: assay for AChR binding antibody in H
A is ELIZA, may not be specific enough• Decision: check AChR binding antibody (R
IA) + AChR modulating antibody + AChR blocking antibody
Myasthenia Gravis overview
• Autoimmune disease
• Antibodies against post-synaptic acetylcholine receptor (AChR), or receptor associated protein (muscle-specific TK)
• Fluctuating weakness of muscles in various combination of ocular; bulbar; limb; resp
• Two clinical form: Ocular vs. Generalized
Presenting symptoms
• Ocular: >50%. Among ocular presentation, >50% progress to generalized in 2 years
• Bulbar: 15%. Dysarthria/ dysphagia and fatigable chewing
• Proximal limb: <5% as presenting symptom
• Rare: isolated neck; isolated resp; isolated distal limb weakness
Bedside diagnostic test of MG
• Tensilon test:Sensitivity is 0.92 for ocular; Sensitivity is 0.88 for generalizedFalse +ve: MND; brainstem tumor
• Ice-pad test:Best use for ocular MGSensitivity: 0.94 for ocular; Sensitivity: 0.82 for generalized
Neuromuscular disorders 2006; 16: 459-67
Electrophysiological studies
Repetitive nerve stimulation (RNS)
• Motor nerve is stimulated 6-10 times under low frequencies (2-3 Hz)
• Positive result if decrement in compound muscle action potential >10% within 4-5 stimuli
• Post-activation exhaustion
• Post-tetanus potentiation
• Sensitivity: 50% if ocular
• Sensitivity: 75% if generalized
Acetylcholine receptor antibodies 1. Binding antibody
Most sensitive: 0.93 in severe generalized MG False +ve in Eaton-Lambert; MND; myositis Positive in SLE; PBC; thymoma; relative of MG
2. Blocking Found in 50% of generalized disease May be seen in 1% of MG with negative binding a
ntibody
3. Modulating Increases sensitivity only ~5% to binding antibody
Neurology 1997; 48 (5): S23-27
Other antibodies
1. Striational antibody (anti-striated muscle) Present in 30% of MG only, but 80% in those thy
moma-assocated MG Useful marker of thymoma at age 20-50
2. Muscle-specific receptor TK (MuSK) Present in 50% of Ach-R Ab negative case ?Different pathogenesis with seropositive Oculobulbar rather than pure ocular Nil thymoma or even ?thymic atrophy Respond less to cholinesterase inhibitor
Semin Neurol 2004; 24:31
History of Guillain Barre Syndrome
Landry’s ascending paralysis 1859• Landry described 10 cases of weakness which asce
nded from lower limb to become generalized, and one of died of asphyxia
• “usually a motor disorder characterized by a gradual diminution of muscular strength with flaccid limbs and without contractures, convulsions or reflex movements”
• “weakness spreads rapidly from the lower to the upper parts of the body with a universal tendency to become generalised”
• Landry offered no explanation of disease
• Guillain and Barre spotted two soldiers in WWI becoming partially paralyzed, but then recovered spontaneously
• With Strohl, a paper was published in 1916, reporting educed reflexes and CSF finding of raised protein without high WCC
• In 1927, Guillain Barre syndrome was introduced, but Strohl…...
Essential features of GBS
• Progressive symmetrical muscle weakness associated with depressed deep tendon reflexes, usually begins at proximal legs
• Severity varies a lot from mild difficulty in walking to complete paralysis and respiratory failure
• Extremities, facial, bulbar and respiratory muscles are affected in combination
Other features of GBS
• Facial weakness >50%• Oropharyngeal weakness 50%• Oculomotor weakness 15%• Respiratory failure ventilation 30%• Begins from face and UL 10%• Paresthesias in hand/feet 80% (Yet nil sign)• Prominent severe back pain • Dysautonomia 70% (e.g. HT alt with shock)
NEJM 1992; 326: 1130
BP/P
240
220
200
180
160
140
120
100
80
60
Temp
40
39
38
37
SBP
Temp
Pulse
8P 9/3 8A 10/3 8P 10/3 8A 11/3 8P 11/3
ICU intubation
Off sedation
On sedation
Off sedation
Atypical GBS features
• Meningism• Papilloedema• Vocal cord palsy• Hearing loss• Mental state change e.g. hallucination, delu
sion and vivid dream has been reported in a cohort of 139 patients of GBS in ICU
Brain 2005; 128: 2535
GBS Pathogenesis
• Heterogenous syndrome caused by immune-mediated peripheral nerve damage after being evoked by antecedent infection
• Acute inflammatory demyelinating polyradiculoneuropathy (AIDP): epitopes in Schwann cell surface membrane
• Acute motor axonal neuropathy (AMAN): epitopes in axonal membrane
Possible antecedent infections
• Campylobacter jejuniGenerate antibody to specific ganglioside GM160% of AMAN/ AMSANAxonal degeneration worse prognosis
• CMV/ Epstein-Barr virus/ Mycoplasma
• HIV
• ?VZV/ HSV/ H influenzae
Diagnostic criteria (NINDS)
• Required featuresProgressive weakness >1 limb, rangin
g from minimal LL to complete tetraparesis, bulbar/facial muscles and ophthalmoplegia
Areflexia. Typiclly global areflexia, but distal areflexia + hyporeflexia at knee/ biceps will suffice
Diagnostic criteria (NINDS)
• Supportive featuresProgression of symptoms over days to 4/52Symmetrical involvementBilateral facial nerve weaknessAutonomic dysfunctionMild sensory symptoms/ signsRaised CSF protein with normal white cell
Ann Neurol 1978; 3: 565
Nerve conduction test
• Early change (~1 week)Signify nerve root demyelinationAbsent or prolonged F wavesAbsent H reflexes
• Intermediate change (~1-2 weeks)Increased distal latencyTemporal dispersion of motor response
• Late change (> 3-4 weeks)Slowing of conduction velocity
GBS variant
• Acute motor axonal neuropathy (AMAN)
• Acute motor and sensory axonal (AMSAN)
• Pharyngeal-cervical-brachial
• Paraparesis only
• Acute pandysautonomia
• Miller-Fisher syndrome
• Bickerstaff encephalitis
Differential diagnosis for GBS
• Acute polyneuropathies
• Vasculitis
• Spinal cord: compression; myelitis
• Neuromuscular junction: MG; Eaton-Lambert; botulism
• Muscle: polymyositis; CIM
Miller Fisher syndrome
• Triad: ophthalmoplegia, ataxia and areflexia• 20% patient may have extremities weakness• Anti-Ganglioside q1b antibody present in 8
5-90% of cases• NCT shows absent or diminished sensory re
sponse, and may show similar change of AIDP for cases with weakness
• CSF has similar change with GBS
Differential diagnosis for MFS
• Brainstem stroke
• Myasthenia gravis
• Wernicke encephalopathy
• Other neuromusclar junction disease e.g. Eaton-Lambert, botulism
• Bickerstaff encephalitis: ophthalmoplegia + ataxia + hyper-reflexia + anti-G Q1b +ve
Treatment of MFS
• Supportive care including ventilatory support, DVT prophylaxis, pain control
• Cardiovascualar monitoring and control
• Cholinesterase inhibitor not useful
• Immunomodulating therapy: IVIG; plasmapheresis
• Steroid has not been shown beneficial
Plasma exchange
• Maximal benefit when given within 7 days
• ?Optimal number of exchange. Possibly lying between 4-6 exchanges
• Dose of volume: 200-250ml/kg weight
• Shorten median time to recover walking by 40-50% compared to supportive treatment
• May be a problem in hemodynamics
IV IG
• Five days of IVIG of 0.4g/kg body weight
• No inferiority compared to plasmapheresis
• Common minor side-effect: headache
• Other effects: aseptic meningitis; allergy; skin rash; acute renal failure
• Life-threatening anaphylaxis reportedBrain 2007; 130: 2245-2257
Prognosis
• Median time to walk unaided 53-85 days• 5-10% patients with prolonged ventilator de
pendency, and incomplete recovery• Overall mortality 5%; 20% ventilator cases• Poor prognosis indicator: old age; rapid ons
et; diarrhoea preceded; ventilator need; reduced distal motor response amplitude <20% of normal; axonal degeneration
In summary, our patient
• Past history of ocular MG
• Symptom and sign suggest MFS
• MRI shows bystander vascular malformation around spinal cord
• NCT showed axonal degeneration
• Improved rapidly
• Presence of anti-gangliose Q1b antibody
• Anti-AchR antibodies signify underlying MG