MYASTHENIA GRAVIS

MODERATOR: DR ANITHA PG: DR VIJETHA

 MG is chronic autoimmune disorder. Derived from greek word myasthenia muscle weakness and from latin word gravis serious Caused by decrease in functional acetylcholine receptors at NMJ due to their destruction or inactivation by circulating antibodies. Prevalence 1 in 7500 Women- 20 to 30yrs Men 60 yrs

ASSOCIATED CONDITIONS
70 % of pts with MG -thymic hyperplasia 10-15% - thymomas Hyperthyroidism is present in approx-10% Rheumatoid arthritis SLE Pernicious anaemia Ulcerative colitis Vitiligo Pemphigus polymyositis

CLASSIFICATION (OSSERMAN)
grade I only eyes affected, grade IIa mild generalized MG responding

well to therapy, grade IIb moderate generalized MG responding less well, grade III severe generalized disease, grade IV myasthenic crisis requiring mechanical ventilation

PHYSIOLOGY

PATHOPHYSIOLOGY
Auto antibodies develop

against Ach nicotinic post synaptic receptors Cholinergic nerve conduction to striated muscle is impaired by a mechanical blockage of the binding site by antibodies ultimately destruction of post synaptic receptors Pts become symptomatic once the number of Ach receptors are reduced to 30% of normal

PATHOPHYSIOLOGY
Antibodies to the Ach receptors reduce the number of functional receptors by

blocking the attachment of Ach molecule increasing the rate of degradation of receptors Complement induced damage to the NMJ The cholinergic receptors of smooth and cardiac muscle have a different antigenicity so not affected by the disease.

SIGNS AND SYMPTOMS

Ptosis & diplopia - resulting from extraocular muscle weakness are the most common & initial complaints. dysphagia , dysarthria and difficulty handling saliva -result from weakness of pharyngeal & laryngeal muscle

SIGNS AND SYMPTOMS

The clinical course of MG is marked by

periods of exacerbation & remission Muscle strength may be normal in well rested pts, but weakness occurs promptly with exercise. High risk of pulmonary aspiration of gastric contents. Muscle atrophy does not occur. Myocarditis can result in AF , heart block , or cardiomyopathy.

SEVERE EXACERBATIONS OF MG
Severe episodes may be caused by insufficient medication (myasthenic crisis) or excessive medication (cholinergic crisis) Facial muscles may be slack , and the face may be expressionless

Inability to support the head , which will fall onto the chest while the pt is seated Jaw is slack , voice has a nasal quality , body is limp Gag reflex is often absent and such pts are at risk for aspiration of oral secretions The pts ability to generate adequate ventilation and to clear secretions are of utmost concern

CHOLINERGIC CRISIS
Cholinergic crisis results from an excess of

acetylcholine at the nicotinic and muscarinic receptors. Nicotinic overstimulation results in involuntary twitching , fasciculations , and flaccid muscle paralysis that is clinically indistinguishable from weakness due to MG The weakness results from an inability to coordinate muscle contraction and relaxation

Myasthenic crisis or cholinergic crisis may cause Bronchospasm Bronchorrhorea Diaphoresis Cyanosis Respiratory failure Miosis and SLUDGE syndrome (salivation , lacrimation , urinary incontinence , diarrhoea , GI upset and hypermotility , emesis) Despite muscle weakness tendon reflexes are preserved To distinguish cholinergic crisis from myasthenic crisis tensilon test is used

TENSILON CHALLENGE TEST

Once the pts airway and ventilation are secured an initial test

dose of (1 mg) edrophonium is given If no adverse reactions occur following test dose , another dose(3 mg) of edrophonium produces noticeable improvement in muscle strength with in one minute If no improvement occurs an additional dose of 5 mg can be administered to total no more than 10 mg Pt who respond generally show dramatic improvement in muscle strength , regaining facial expression , posture and respiratory function with in one minute

 During this procedure pt must be monitored carefully

because edrophonium can cause significant bradycardia , heart block , and asystole The return of muscle weakness after edrophonium wears off combined with residual increased oral secretions can exacerbate respiratory distress and the risk of aspiration Pts with a cholinergic crisis may respond by increasing salivation and bronchopulmonary secretions (SLUDGE SYNDROME) this changes should be managed expectantly If muscle strength fails to improve following a max dose , the pt is having CHOLINERGIC CRISIS

DIFFERENTIAL DIAGNOSIS
Congenital myasthenic syndromes Eaton-Lambert syndrome Hyperthyroidism Graves disease Botulism Progressive external ophthalmoplegia Intracranial mass compressing

cranial nerves

EATON-LAMBERT SYNDROME
Myasthenic syndrome is an acquired auto immune

disease with immunoglobulin G antibodies to voltage sensitive calcium channels The deficiency of this channels restrict calcium entry when the terminal is depolarized These pts are sensitive to the effects of both succinyl choline and NDMR Antagonism of neuromuscular blockade with anti cholinesterase drugs may be inadequate

MYASTHENIA GRAVIS
Extraocular ,bulbar and

MYASTHENIC SYNDROME
Proximal limb weakness (legs

facial muscle weakness Fatigue with exercise

Reflexes normal, muscle

more than arms) Strength improves with exercise Reflexes absent or decreased , muscle pain common
Almost entirely male

pain uncommon.
Females more often than

males Thymoma Resistant to sch, sensitive to NDMR Good response to anti cholinesterases

Small-cell lung cancer Sensitive to sch and NDMR Poor responce

DIAGNOSIS
None are available in a time frame that is

useful to confirm the emergency diagnosis of MG An arterial blood gas determination-an elevated paco2 suggest progressive respiratory failure Anti Ach R antibodies are detected in 80-85% of pt with MG and are pathognomonic for the disease

 Chest x-ray presence of aspiration or pneumonias A ct scan or MRI of chest is highly accurate in detecting thymoma and should be done in every new presentation. Tensilon challenge test- useful in diagnosing

MG and in distinguishing myasthenic crisis from cholinergic crisis Ice pack test Electromyography-reduced compound muscle action potential to single supramaximal twitch and decrement of >10% on tetanic stimulation

DRUGS INDUCING

MG

Some of the medications reported to cause

exacerbations of MG include the following: Antibiotics macrolides, fluoroquinolones, aminoglycosides, tetracycline, and chloroquine Antidysrhythmic agents beta-blockers, calcium channel blockers, quinidine, lidocaine, procainamide, and trimethaphan Miscellaneous diphenylhydantoin, lithium, chlorpromazine, muscle relaxants, levothyroxine, adrenocorticotropic hormone (ACTH), and, paradoxically, corticosteroids

MG IN PREGNANCY
1/3 rd cases of pregnant suffer from exacerbated myasthenia Usually occur in the first trimester Signs and symptoms in pregnant mother tend to improve during the second & third trimester Some mothers experience complete remission Immunosuppressive therapy should be maintained throughout pregnancy as this reduces the chances of neonatal muscle weakness , as well as controls the mother myasthenia

TRANSIENT NEONATAL MYASTHENIA

Up to 10% -15% neonates born to myasthenic

mothers have transient neonatal myasthenia Which generally produce feeding and respiratory difficulties , presents as poor suckling and generalized hypotonia Other symptoms include weak cry , facial diplegia , paresis and mild respiratory distress A child with TNM typically responds well to acetylcholinestirase inhibitors Very rarely an infant can be born with arthrogryposis multiplex congenita secondary to profound intrauterine weakness due to maternal antibodies that target an infants acetyl choline receptors.

TREATMENT
ANTI CHOLINESTIRASE DRUGS:
First line Rx

Inhibit the enzyme responsible for hydrolysis of ACH increase the amount of NT available at NMJ.
PYRIDOSTIGMINE most widely used drug, onset -30 min,peak after 2hrs,t1/2 200 min Higher doses may actually induce more muscle weakness the so called CHOLINERGIC CRISIS

 MUSCARINIC SIDE EFFECTS:

Abdominal cramping , bradycardia Diarrhea Flushing (transient redness of the face and neck) Increased salivation Miosis (contraction of the pupils) Incontinence Broncho spasm(can exacerbate bronchial asthma)

THYMECTOMY
Pts with generalized MG are candidates for

thymectomy. It is intended to induce remission or atleast allow for dose of immunosuppressive medication to be reduced. More minimal invasive surgery is preferred. Acetylcholine receptor antibody levels usually decrease following thymectomy.

IMMUNOSUPPRESSIVE THERAPY
Corticosteroids, azathioprine , cyclosporine

mycophenolate-indicated when skeletal muscle weakness is not adequately controlled by anticholinesterase drugs. corticosteroids are most consistently effective and most commonly used drug but ass with greatest likelyhood of adverse effcts.

Corticosteroids
Decresed AChR antibodies

80% remission Limited by longterm S/E GI bleed Cortisol suppression, HTN, hyperglycemia Cataracts Osteoporosis Inc susceptibility to infection

Immunosuppressives
Interferes with formation of AChR

antibodies Used in debilitating, widespread disease Side effects Bone marrow suppression Susceptibility to infections Inc malignancy

SHORT-TERM IMMUNOTHERAPY
Plasmapheresis removes

antibodies from the circulation. in pts experiencing myasthenic crisis or are being prepared for thymectomy. The beneficial effects are transient and repeated Rx introduces the risk of infection, hypotension , and pulmonary embolism.

IVIG
The indication for administration of

immunoglobulin are the same as for plasmapheresis. The effect is temporary. This treatment has no effect on circulating concentrations of acetylcholine receptor antibodies.

MANAGEMENT OF ANAESTHESIA

PRE-OPERATIVE EVALUTION
Adequate pre op evaluation ,
Age , sex ,onset & duration of the disease determine the

outcome. Severity of the MG , and the involvement of bulbar (or)respiratory muscle must be evaluated Pt should be admitted 24-48 hrs before surgery to allow detailed assessment respiratory muscle Respiratory muscle strength can be quantified by pulmonary function tests(neg inspiratory pressure and forced vital capacity other autoimmune diseases need to be elicited and appropriate pre op investigations initiated. If the pt is poorly controlled , a course of plasmapheresis may be of benefit in the pre operative period

PRE MEDICATION
If pt is on

anticholinestirases adequate atropinization must be ensured As they have little respiratory reserve depressant drugs for pre medication should be used with caution and avoided in pts with bulbar symptoms

MUSCLE RELAXANTS

DEPOLARIZING AGENTS
Anticholinesterase drugs & corticosteroids used to treat MG can influence the response to muscle relaxants. Pts with MG show resistance to depolarizing agents (ED95 is 2.6 times of control for succinyl choline).
Mechanism for resistance is unknown but the

decreased number of Ach receptors at the post synaptic NMJ may play a role. More likely to develop phase II block , particularly with repeated doses of sch.

NON DEPOLARIZING MUSCLE RELAXANTS

MG patient is typically sensitive to NDNMB in contrast to Sch. Long acting NDNMB (pancuronium, pipecuronium, doxacuronium) :avoided Intermediate and short acting: used with careful monitoring. ED95 for vecuronium : 40%-55% of that in normal

controls Atracurium :58% increased sensitivity to mivacurium reported in a pt receiving pyridostigmine.

INDUCTION OF ANESTHESIA
Induction of anesthesia

with short acting intravenous anesthetic is acceptable Respiratory depressant effect may be accentuated.

 Propofol
Anesthetic management using

propofol without untoward effects have been described. Short duration, no effect on NM transmission.

Opioid
do not appear to depress NM

transmission in MG muscle. Central respiratory depression may be a problem. Use of short-acting opioids : more titratable. Remifentanil (elimination half-life:9.5min) Etomidate, althesin and ketamine : Reports of uneventful anesthesia

MAINTENANCE OF ANESTHESIA
Several technique have been recommended

in myasthenic pt ,although none is superior (1) Avoid muscle relaxants , use inhaled agents both for facilitating intubation and relaxation for surgery Sevoflurane is superior due to its lower incidence of exitatory airway reflexes during inhalation induction

(2) Balanced technique titrate small doses of intermediate acting muscle relaxants (10-25% of ED-95) (3) TIVA hemodynamic instability in older pts makes it problem , young pts usually tolerate well. (4) When possible many prefer regional or local anesthesia

Regional Anesthesia
Potentiation of NM blockade by local anesthetics

has been reported.

Decreased sensitivity of the postjunctional membrane

to Ach.

Ester anesthetics, metabolized by cholinesterase,

may present particular problems in patients taking anticholinesterases. Use reduced doses of amide to avoid high blood levels. Spinal anesthesia has the advantage of reduced drug dosage , where as epidural techniques facilitate easier control of blockade level and may obviate the need for opioids in post op pain management

POST OPERATIVE CARE

Closely monitored in ICU where respiratory support can be immediately reinstitute Criteria that correlate with the need for mechanical ventilation during post op period disease duration more than 6 yrs,

chronic obstructive pulmonary disease unrelated to MG daily dose of pyridostigmine higher than 750 mg, and vital capacity less than 2.9 L following transsternal thymectomy

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