PATIENTS WITH MYASTHENIA GRAVIS AND ANAESTHESIA.pptx

myasthenia gravis

1. PATIENTS WITH MYASTHENIA GRAVIS AND ANAESTHESIA MODERATOR – DR. MANU VARSHANEY PRESENTER- DR PRATIMA SINGH

2. Introduction Myasthenia gravis : chronic acquired autoimmune disorder Characterized by fatiguable weakness of skeletal muscles Weakness results from an antibody mediated immunological attack directed at acetylcholine receptor or receptor associated protein in the post synaptic membrane of the neuromuscular junction Improvement following rest Type 2 Hypersensitivity reaction

3. Incidence • 2.1 to 5.0 per 100000 people in India • More common in females • M:F 4:6 • Peak incidence 2 nd /3rd decade – female 5 th decade - male Associated autoimmune disorders • Rheumatoid arthritis • SLE • DM • Autoimmune thyroid disease • SIADH • Cushing Syndrome • RBC aplasia • Hypogammaglobinemia

4. Etiopathogenesis • Autoimmune disorder • Autoantibodies to n-ACH receptor or muscle membrane proteins TK/Rapsyn/ Agrin ) • Autoantibodies damage NMJ by • Activation and damage to muscle membrane • Degrade n- ACH –R • Blockade of ACH -R

5. In around 80–90% of generalised patients, this is due to autoantibody formation against the acetylcholine receptor ( AChR ). Around 50–70% of generalised MG patients who do not produce antibodies against AChR are seropositive for antibodies against the muscle-specific receptor kinase ( MuSK ), which mediates the clustering of AChRs during synapse formation and is essential for the formation and maintenance of the neuromuscular junction (NMJ ). The thymus gland, the central organ in T-cell mediated immunity, is also an important factor in the pathogenesis of MG with AChR autoantibodies.

6. Role of Thymus • Majority of patients with acetylcholine receptor abnormalities have thymic abnormalities • Hyperplasia : 60-70 % • Thymoma : 10-12 % • Thymus contains myeloid cells which poses acetylcholine receptor on their surface The auto immunity cells attack acetylcholine receptor units on the myeloid cells leading to creation of germinal centres in the thymus containing : 1 . Myeloid cells 2 . Complement proteins 3 . Autoantibodies These auto antibodies in germinal centre mature to recognise acetylcholine receptors

7. Mass effect of MG associated with Thymoma • Cough • Dyspnea • SVC syndrome • Cardiovascular involvement - • Focal myocarditis • LVDD • Atrial fibrillation • AV conduction delay

8. Clinical Features - • Muscles weakness • Fluctuating • Worsens on exertion, improves with rest (hallmark) • Ocular- • 1 st manifestation • Ptosis and diplopia • Ptosis : symmetrical/ unsymmetrical , u/l or b/l • Diplopia : nystagmus • Pupil spared Limb Muscles • Proximal muscles > distal • Difficulty in climbing • Weakness of neck extensors • Dyspnea – resp muscles involvement • Diaphragmatic involvement : reduced forcefulness to cough • Difficulty to produce voice • Bulbar Muscles • Dysarthia / dysphagia • Difficulty in chewing • Nasal regurgitation and Nasal twang (palatal involvement) • Involvement of facial muscle • Myasthenic Snarl

9. Diagnosis- Clinical Examination- Fatigue after prolonged upward gaze and holding outstretched hand in abduction Decreased vital capacity Absence of other neurological signs Electrophysiological Tests- • Peripheral nerve stimulated • Decrease in twitch response of 10% between 4th and 1st twitch • Diagnostic Repetitive Nerve Stimulation Test- • Rapid decrease in amplitude of CMAP • Single dose of edrophonium decrease decremental response

10. ICE PACK TEST • Cooling improves neuromuscular transmission • Placing ice pack for 2 min over eyelids causes resolution of ptosis Serological tests • Anti-ACH R antibodies • 80% with generalized MG • Preop level > 100nmol/l a/w postop myasthenic crisis • MUSK antibodies (muscle specific receptor kinase) Single Fiber Electromyography • More sensitive EPT • Evaluates time interval between 2 muscles fiber AP in the same motor unit TENSILON TEST • IV Edrophonium 1.2 mg (test dose ) given followed by 8mg iv • Onset : 30 sec • Duration : 10 min • Patient with MG : drastic improvement

11. Clinical Classification • Pediatric MG • Neonatal transient MG • Babies born to mother with MG • Circulation Ach-r antibodies passively transferred • Present at 12-48 hrs after birth • c/f feeble, poor cry, poor feeding effort ptosis and facial weakness • Neonatal Persistent MG • Very rare • No detectable antibodies • Juvenile MG • Similar to adult MG

12. Adult MG ( Osserman and Genkin ) OCULAR MYASTHENIA • Involves ocular muscles only • Ptosis and diplopia is present • Electrophysiologic tests for other muscles are negative 2.GENERALISED MYASTHENIA 2A . MILD • Slow onset • usually ocular • spreading to bulbar and skeletal muscles • good response to therapy • No respiratory muscles are involved • Patient’s activity is limited • low mortality rate 2B. MODERATE • Slow onset • ocular with more involvement of peripheral muscles • dysphoria, dysphagia • Fair response to drug therapy • No respiratory muscle involvement • Patient’s activity limited • Low mortality rate

13. 3. ACUTE FULMINATING MYASTHENIA • Rapid onset • Progresses within 6 months • Severe bulbar and skeletal muscle involvement • poor response to treatment • involved respiratory muscles • Patient’s activities are limited • High mortality 4. LATE SEVERE MYASTHENIA • Develops 2 years after Group 1 or 2 symptoms • progression may be gradual or rapid • severe bulbar and skeletal muscle involvement • poor response to treatment • involved respiratory muscles • Patient’s activities are limited • High mortality

14.  MG-ADL scale assesses the impact of MG on your daily functions. Physicians use this tool to score a patient’s MG symptoms based on the patient’s recall of symptoms during the prior week. A person’s score can range from zero (normal) to 24 (most severe)."

15. TREATMENT 1 . ANTICHOLINESTERASES • Prolong the duration of action of acetylcholine post synaptic membrane • Eg : Pyridostigmine : usual dose 30-120 mg/day PO in 3-4 divided dose Max dose 120 mg every 4th hourly i.e. 720 mg/day. • Glycopyrrolate 1 mg is added with each dose to reduce cholinergic side effects • Children: 1mg/kg PO • Neostigmine : • Adult dose : 7.5-15 mg PO • Children : 0.3 mg/kg PO S/E : Cholinergic crisis • Weakness due to persistent depolarization

16. 2. CORTICOSTEROIDS • Use in patients responding poorly to Anticholinesterase •Causes immunomodulation • Reduce amount of acetylcholine receptor antibodies as well as anti ACH Receptor Activity of peripheral lymphocytes • Dose : PREDNISOLONE 0.5 mg/kg/day for pure ocular myasthenia and up to 1 mg/kg/day for generalised myasthenia, if using a daily regime. Some authors recommend alternate day dosing with a target of 0.75 mg/kg/alternate days for ocular and 1.5 mg/kg/alternate days for generalised patients . 3 . IMMUNOSUPPRESANTS • Azathioprine : 50-100 MG/DAY • inhibits purine metabolism, as well as T- and B-cell production • Require many months to show its effects • Cyclosporine : 3 MG/KG • mainly used in patients in whom azathioprine is not tolerated • Suppression of T and NK cells • S/E : Nephrotoxic and hepatotoxic • Other drugs : Cyclophosphamide, Tacrolimus, Rituximab, Mycophenolate mofetil

17. 4. PLASMAPHERESIS • Directly remove circulating antibody from plasma • Effect lasts only for 3 to 6 weeks • 5 Exchanges done on alternate days over 7 to 14 days • 3-5 L plasma is exchanged • Replacement fluid used is albumin • Use in conjunction with 5. IVIG • 2 gram per kg over 2 to 5 days • Neutralization of antibodies, suppression of B and T lymphocytes • Effect seen in one week and last 3 to 6 weeks

18. THYMECTOMY • 10 to 15% patients of myasthenia gravis have thymoma • Indication in patients of myasthenia gravis without thymoma : 1 . Age less than 60 years 2 . Generalised myasthenia gravis 3 . Presence of ACHR antibody • CI : Pre pubertal children Patients with only ocular symptoms • Benefits: reduce need for immunosuppressant minimal clinical manifestation may be associated with remission

19. ANAESTHETIC MANAGEMENT PRE-OP ASSESMENT 1.HISTORY • Muscles involved • duration and severity of disease • total daily requirement of pyridostigmine and other drugs 2.LAB INVESTIGATIONS • CBC : specially if patient is on cyclosporine (Neutropenia) • TFT • Serum electrolytes : hypokalemia increase muscle weakness • Blood glucose levels : as patients are on long term corticosteroid therapy • LFT & RFT : Specially if cyclosporine has been used • ECG : As pyridostigmine causes bradycardia

20. 2.LAB INVESTIGATIONS • X ray chest : to look for aspiration pneumonitis • Pre-op PFT & ABG : Use as baseline respiratory reserve • CT/MRI of thymus • Serological tests for : • Lupus erythematosus • ANA • Rheumatoid factor • Bone densitometry in older patients

21. Predictors of post op myasthenic crisis :- • Duration of disease more than 6 years • history of concomitant COPD • history of myasthenic crisis • preoperative bulbar symptoms • Dose of pyridostigmine more than 750 milligram per day • Vital capacity < 2-2.9 Litres • Serum ACHR antibody titres more than 100 millimole per ml • Intra-op blood loss more than 1 lt The Levinthal scoring system   -Involves a set of risk factors that predict the increased likelihood for postoperative mechanical ventilation for patients with MG . Leventhal, et al. identified four risk factors felt to have predictive value, namely : ( 1)  duration of myasthenia gravis greater than or equal to 6 years , (2 ) chronic respiratory disease, ( 3) dose of pyridostigmine greater than or equal to 750 mg per day, and ( 4) vital capacity less than or equal to 2.9 litres .

22. Pre-op preparation and pre-medication • Admit 24 hours before surgery while in remission • consider Pre op physiotherapy and incentive spirometry • discuss need for post op ventilation and obtain the consent • schedule first case of day in OT • ACHE is controversial as it may alter the effect of NMBA, inspite of this continue ACHE till the morning of surgery • Steroids : Continue morning dose • Anti-aspiration prophylaxis if the bulbar muscles are involved to reduce the secretions of ACHE therapy • Premedication : small less effective dose of benzodiazepines (incremental 0.5 milligram dose of midazolam with continuous monitoring of bulbar weakness) • Avoid opioids in patients with less respiratory reserve as it may causes respiratory depression • Pre-op plasmapheresis in poorly controlled patients

23. Plasmapheresis reduces the antiAch receptor antibody titer in myasthenia gravis and alleviates symptoms. However its effects are short lasting as it cannot prevent resynthesis , and there are several adverse effects of plasmapheresis including hypotension coagulopathy , catheter-related complications,(infection) high cost Hypomagnesimia Hypocalcemia Cholinesterase depletion due to plasmapheresis or inhibition caused by pyridostigmine given preoperatively may affect the metabolism of succinylcholine (40) and mivacurium (32), resulting in prolonged blockade. that has brought plasmapheresis into question as to whether it should be routinely used or only in selected cases. DISADVANTAGES OF PRE OP PLASMAPHERESIS TREATMENT

24. ANAESTHETIC CONSIDERATION • Use regional or local anaesthesia wherever possible • Mid thoracic or higher levels can paralyse the accessory muscles of breathing so high neuraxial block is avoided • Careful while giving supraclavicular and interscalene block as inadvertent block of phrenic nerve result into ipsilateral diaphragmatic palsy precipitating myasthenic crisis in poorly controlled patients • Reduce the dose of Ester local anaesthetic which inhibits plasma cholinesterase activity example Benzocaine chloropropane tetracaine • Use short acting anaesthetic agents to minimise respiratory depression on emergence • Consider reversal with sugammadex rather than neostigmine • avoid opioids in patients with poor respiratory reserve • post op ventilation may be required • initial dose of NDMR reduced to 10 to 20% of normal dose • Dose titrated with train of 4 response with nerve stimulator • corticosteroids may block the effect of steroidal relaxant like vecuronium

25. MONITORING • Pulse oximetry • temperature • ETCO2 • CVP if significant fluid shift is present • NIBP / IBP in case of CVS instability • baseline ABG • urine output • Frequent blood sugars • N euromuscular monitoring : • Mechanomyogram • Twitch monitor • Integrated electromyographic monitor • Accelerograph monitor • Response of orbicularis oculi is reduced more than adductor policies due to ocular involvement

26. CONSIDERATION FOR NM BLOCKADE SUCCINYLCHOLINE • Variable response to succinylcholine in patients due to reduced acetylcholine receptors • patients not receiving anticholine esterase therapy : -Succinylcholine resistance occurs -Due to reduced number of functional ACHR at NMJ -ED95 increases up to 2.6 times so dose can be increased to 2 MG/KG • Patients receiving anticholine esterase therapy has plasma cholinesterase activity got inhibiting leading to inhibition of succinylcholine metabolism resulting into increase duration of action of succinylcholine

27. 2. NDMR • As a rule NDMR are avoided • Patients are extremely sensitive to NDMR as ACH receptors are reduced by 70% • Some safe NDMR : atracurium , Cisatracurium , vecuronium , rocuronium • when used these agents are reversed with sugammadex • Cisatracurium is preferable as : • Short half life • small volume of distribution • lack of cumulative effect • high clearance • spontaneous reversal

28. INDUCTION • Neuromuscular blockade avoided as much as possible • Propofol 2 mg/kg + remifentanyl 4-5 mcg/kg + O2 + N2O may be use for induction • avoid remifentanil in patients with low respiratory reserve • This combination provide optimum condition for intubation within 2.5 minutes • volatile anaesthetics sevoflurane or isoflurane provide muscle relaxation for intubation • NDMR is reduced to dose of 10 to 20% and are used if cardiovascular depressant effect of volatile anaesthetic agent is pronounced • Local anaesthetic is spread on vocal cords reduce intubation response for example : lidocaine 4 % • In case of RSI, 2 milligram per kg succinylcholine can be use safely • Insert orogastric tube if early return to oral intake is not predicted

29. Transoperative management. 

30. MAINTAINANCE • O2 + N20 + ISOFLURANE + REMIFENTANYL • Role of NM blocking agents: • Cisatracurium is preferred in reduced doses • 10 to 25% ED95 of intermediate acting muscle relaxants are sufficient for most cases • If succinylcholine is used other muscle relaxants are avoided till muscle function has returned • Controlled ventilation to ensure adequate gas exchange • TIVA WITH PROPOFOL & REMIFENTANYL CAN BE A SAFE ALTERNATIVE • Dexmedetomidine is associated with asystole and accentuates the PYRIDOSTIGMINE associated vegal activity

31. EXTUBATION • Use sugammadex rather than neostigmine • Extubation is done in fully awake plane • Extubation criteria : • train of 4 ratio > 0.9 • ability to generate negative inspiratory pressure of > -20 cm of water • Airway occlusion pressure more than 30 cm water • FVC > 15ml/kg With sustained head lift > 5 seconds • mechanical ventilation continued till recovery of NM function occurs • Total pulmonary toilet is essential prior to extubation ( procedures that clear airway of mucus and other secretions ) • use sugamadex 2-4 mg/kg can Reverse the deep NDMR within 4-5 minutes; not affected by ACHE activity • Anticholinesterase reversal agents such as neostigmine are avoided as it may results in cholinergic crisis but if using then drugs should be titrated in incremental dosing.

32. Criteria for extubation . 

33. MANAGEMENT • Physiotherapy and incentive spirometry • Pyridostigmine therapy is resumed as soon as possible post surgery • Dose of neostigmine should be titrated with neuromuscular monitoring • Dose titration : 2.5 mg-5 mg iv bolus given Initially then 1 mg boluses given every 2 to 3 minutes • Dose can be increased up to Maximum equivalent dose of pyridostigmine ( 1 mg neostigmine is equivalent to 30 mg pyridostigmine ) • Repeated PEFR( peak expiratory flow rate) and FVC(functional vital capacity) measurement to monitor impending respiratory failure as ABG changes occur very late • Oral anticholinesterase therapy is resumed as soon as possible post operatively

34. COMPLICATIONS CHOLINERGIC CRISIS • Overdosage of ACHE reversal agent • Associated with paradoxical weakness • Signs of cholinergic excess are present : salivation, lacrimation, bradycardia, respiratory secretions, Bronchospasm • Miosis • No improvement or worsening of symptoms on 10 mg Tensilon ( endrophonium ) • Treatment :- IV Atropine 0.4- 2 mg IV, Glycopyrrolate 0.2-1 mg -Electrical pacing in case of profound and refractory bradycardia not responding to IV Atropine

35. DELAYED EXTUBATION • Extubation performed after more than 24 hours of the surgery • Occurs in postoperative period due to underdosage of ACHE reversal agent • Residual anesthetic action • Stress of surgery • Stress associated with infections • Administration of drugs known to exacerbate NM weakness • Usually causes respiratory and bulbar muscle weakness resulting into : dysphagia, change in phonation, weak cough, difficulty in handling secretions, tachypnea with shallow tidal volume breaths, use of accessory muscles of respiration

36. • ABG : Hypocapnea in initial stages due to hyperventilation Followed by hypercarbia in later stages i /v/o impending respiratory failure. hypercarbia also causes pupillary dilatation • Tensilon test can differentiate residual paralysis from myasthenia crisis as symptoms improves rapidly in the former after 10 mg Tensilon • Plasma exchange • IVIG • Electrical pacing in profound bradycardia