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Is it MG Crisis? Dr Chan Yan Fat Alfred Caritas Medical Center 20/01/2009.

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Presentation on theme: "Is it MG Crisis? Dr Chan Yan Fat Alfred Caritas Medical Center 20/01/2009."— Presentation transcript:

1 Is it MG Crisis? Dr Chan Yan Fat Alfred Caritas Medical Center 20/01/2009

2 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

3 Long term medication L-thyroxine 75 microgram daily Candesartan 8mg daily Ventolin 2 puffs Qid PRN Becotide 2 puffs BD Pyridostigmine (Mestinon) 60mg BD

4 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 Levofloxacin 100mg BD + Romilar Subjective double vision for one day, with bilateral upper limb weakness + numbness, but still able to walk While at Precious blood Hospital, developed choking and SOB

5 To CMC AED 9/3/08 at 1900 BP 202/89, pulse 72, SaO 2 88% room air GCS 15/15, Fever 38.0 degree Speak full sentence, SaO 2 96% at 2L O 2 “muscle weakness” at 4/5 Chest clear; PFR 170  170  150 Impression: mild MG Decision: consult ICU


7 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

8 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

9 Impression at ICU Generalized MG with bulbar involvement Precipitated by……

10 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- cholinergics; iodinated contrasts; URI

11 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

12 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, CO 2 42.6, O 2 176, HCO 3 26


14 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 cough  Drooling of saliva  Poor AE over both chest Impression: MG crisis

15 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

16 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

17 Progress at ICU day 4 All ocular movement is full, no ptosis Hand-grip 3/5; right wrist flexion 2/5; rest of upper limb power 0/5 ! Both thigh 3/5, both ankle 4/5 Absent deep tendon reflex of lower limb, markedly decreased at upper limb Paraesthesia over 4 limb, nil sensory level BP 100/55, fever down

18 Atypical presentation of MG! Deterioration with iv Ig Other pathology?

19 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 and sign from past Severity of physical sign not fluctuating Global areflexia Sensory symptoms

20 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



23 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, likely spinal dural AV fistula

24 Can it be spinal cord insult?! Pros Tetraparesis Areflexia Hypotension Normal cognitive function all along MRI showed vascular lesion around cord Cons Proximal affected preferentially No sensory level Bulbar symptoms Ophthalmoplegia, though improved Normal cord signal

25 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

26 Progress at ICU day 6 (1) Medical summary from Canada Patient presents as ptosis and diplopia in June 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

27 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)

28 Every sign must have explanation

29 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

30 Retrospectively, look at the graph of vital signs…….

31 BP/P 240 220 200 180 160 140 120 100 80 60 Temp 40 39 38 37 SBP Temp Pulse 8P 9/38A 10/38P 10/38A 11/38P 11/3 ICU intubation Off sedation On sedation Off sedation

32 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

33 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

34 Progress at ICU day 9 Shoulder/ elbow power 4-/5; hand 5/5 Hip/ knee power 3/5; ankle 4/5 Nerve conduction test bedside  Absent F wave response in 5 nerves  Prolonged distal latency  Amplitude and velocity within normal  No conduction block; sural nerve spared  Axonal degeneration; motor dominant

35 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

36 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

37 Our decision

38 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)

39 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

40 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 HA is ELIZA, may not be specific enough Decision: check AChR binding antibody (RIA) + AChR modulating antibody + AChR blocking antibody


42 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

43 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

44 Bedside diagnostic test of MG Tensilon test:  Sensitivity is 0.92 for ocular;  Sensitivity is 0.88 for generalized  False +ve: MND; brainstem tumor Ice-pad test:  Best use for ocular MG  Sensitivity: 0.94 for ocular;  Sensitivity: 0.82 for generalized Neuromuscular disorders 2006; 16: 459-67

45 Ice test 2 min ice Ophthalmology 1999: 106:1282

46 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

47 30 seconds post-exPost-activation exhaustion Normal MG

48 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 antibody 3. Modulating  Increases sensitivity only ~5% to binding antibody Neurology 1997; 48 (5): S23-27

49 Other antibodies 1. Striational antibody (anti-striated muscle)  Present in 30% of MG only, but 80% in those thymoma-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


51 Our patients had all three AchR antibodies positive, with titre high or very high at OPD

52 Evaluation of 550 patients with MG Saunders 2001

53 History of Guillain Barre Syndrome Landry’s ascending paralysis 1859 Landry described 10 cases of weakness which ascended 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

54 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…...

55 Guillain BarreStrohl

56 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

57 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

58 BP/P 240 220 200 180 160 140 120 100 80 60 Temp 40 39 38 37 SBP Temp Pulse 8P 9/38A 10/38P 10/38A 11/38P 11/3 ICU intubation Off sedation On sedation Off sedation

59 Atypical GBS features Meningism Papilloedema Vocal cord palsy Hearing loss Mental state change e.g. hallucination, delusion and vivid dream has been reported in a cohort of 139 patients of GBS in ICU Brain 2005; 128: 2535

60 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

61 Possible antecedent infections Campylobacter jejuni  Generate antibody to specific ganglioside GM1  60% of AMAN/ AMSAN  Axonal degeneration  worse prognosis CMV/ Epstein-Barr virus/ Mycoplasma HIV ?VZV/ HSV/ H influenzae

62 Diagnostic criteria (NINDS) Required features  Progressive weakness >1 limb, ranging from minimal LL to complete tetraparesis, bulbar/facial muscles and ophthalmoplegia  Areflexia. Typiclly global areflexia, but distal areflexia + hyporeflexia at knee/ biceps will suffice

63 Diagnostic criteria (NINDS) Supportive features  Progression of symptoms over days to 4/52  Symmetrical involvement  Bilateral facial nerve weakness  Autonomic dysfunction  Mild sensory symptoms/ signs  Raised CSF protein with normal white cell Ann Neurol 1978; 3: 565

64 Nerve conduction test Early change (~1 week)  Signify nerve root demyelination  Absent or prolonged F waves  Absent H reflexes Intermediate change (~1-2 weeks)  Increased distal latency  Temporal dispersion of motor response Late change (> 3-4 weeks)  Slowing of conduction velocity


66 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

67 Differential diagnosis for GBS Acute polyneuropathies Vasculitis Spinal cord: compression; myelitis Neuromuscular junction: MG; Eaton- Lambert; botulism Muscle: polymyositis; CIM

68 Miller Fisher syndrome Triad: ophthalmoplegia, ataxia and areflexia 20% patient may have extremities weakness Anti-Ganglioside q1b antibody present in 85-90% of cases NCT shows absent or diminished sensory response, and may show similar change of AIDP for cases with weakness CSF has similar change with GBS


70 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

71 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

72 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

73 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 reported Brain 2007; 130: 2245-2257


75 Prognosis Median time to walk unaided 53-85 days 5-10% patients with prolonged ventilator dependency, and incomplete recovery Overall mortality 5%; 20% ventilator cases Poor prognosis indicator: old age; rapid onset; diarrhoea preceded; ventilator need; reduced distal motor response amplitude <20% of normal; axonal degeneration

76 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

77 Wish you happy lunar new year

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