1. DR. ANITA AGGARWAL SENIOR CONSULTANT OB/GYN

2. History 31 yrs old lady first reported in feb 2012 with history of amenorrhea for 2mths and myasthenia gravis for 9 yrs. Personal History: Resident of Assam. Second in birth order. Has 2 sisters 1 brother. Working as CA. Married for 11mths. Family History: Mother Hypertensive, father died of liver cirrohsis. H/o Downs Syndrome both sides. Menstrual history: cycle 3-5days/28-30days. LMP-16.12.2011 3. Past History In 2003- Pt. suddenly developed ptosis and diplopia she was shown to opthalmologist and given conservative treatment. 2007- she started having muscle weakness, knee instability ,inability to climb stairs. Then Neurologist suggested - Neostigmine test,Ach R antibodies. Both were positive. CT Thorax ruled out Thymoma.Put on Distinone 60mg 4hrly. Improved and started working normally. 4. Contd-- In 2008- she was shown in Holy Family Hospital and advised Thymectomy. Surgery was done and she improved a lot.her dose of Distinone was reduced to 120mg daily. H/P-Thymic Follicular Hyperplasia In-2011-Ptosis in left eye increased so Distinone increased to 60 mg 8 hrly.She continued this dose till date. 5. Ante Natal Period. She got married in 2011. Conceived after 6 months spontaneously.She continued on Distinone through out pregnancy. First trimester-has excessive nausea and vomitting and weakness. She stopped going to office and continued resting at home. Second trimester- uneventful.wt. gain, BP was optimum 6. Contd- In late sec. trimester -she started having oedema lowerlimb Third trimester-IUGR noted. Put on amino acids, antioxidants dietary changes and adv. rest.Serial USG with doppler studies done to monitor growth. Investigations-Hb12gm%.Normal TFT,blood sugar, urine,LFT(low A:G ratio).Bl.group-O neg ICT neg.Viral markers NR GPE & Systemic exam- unremarkable. 7. Delivery Details In lieu of IUGR, decreased foetal movements IOL planned at 37.4wks. Induction started with Cerviprime and augmented with Syntocinon but she had uterine inertia and MSL so LSCS was done under spinal anesthesia.She delivered a female baby weighing 2.2 kg. PO period was uneventful.Mother and baby were discharged on 4th PO day. Lactation was not well established. Mother & Baby are doing fine till date. 8. Myasthenia Gravis . Myasthenia gravis is an autoimmune neuromuscular disease characterized by weakness and fatigue of the skeletal muscles of the face and extremities. It affects people of both sexes and all ages. Female patients are affected twice more commonly than male patients. Myasthenia gravis usually strikes in women in their third decade of life. First clinical discription by- Thomas Willis in 1672 9. Epidemiology 20 cases of generalized myasthenia gravis per 100,000 persons in the United States. Worldwide incidence is recorded as ranging from 20-100 per million, with the higher prevalence observed in those nations with greater access to modernized diagnostic resources and treatments, which correlates with increasing longevity as well. The prevalence of myasthenia gravis in pregnancy is estimated at 1 in 20,000. Transient neonatal myasthenia gravis occurs in approximately 10-15% of births by mothers with myasthenia gravis. 10. Etiology Genetic studies have revealed a correlation between early-onset myasthenia gravis, which affects women of childbearing age, and the HLA-DR3 and B8 alleles. The underlying pathology is the autoimmune production of immunoglobulin G (IgG) antibodies directed toward receptors on the postsynaptic membrane at neuromuscular junctions (NMJs). 11. Neuromuscular junction 12. Pathophysiology Normally, a chemical impulse precipitates the release of acetylcholine from vesicles on the nerve terminal at the myoneural junction. The acetylcholine continuously bind to the receptor sites on the motor end plate, for muscle contraction to sustain. 13. PATHOPHYSIOLOGY In NMJ Ach is stored in vesicles---released on Action potential. Combines with AchRs at peak of POST SYNAPTIC FOLDS.---binds with subunit of Ach R ---Rapid influx of cations Na. Depolarization at the end plate region of muscle fiber---if sufficiently large MUSCLE CONTRACTION. Ach is rapidly hydrolized by AchE present in synaptic folds,diffuse away from receptors 14. In myasthenia gravis, autoantibodies, produced in the thymus gland, directed at the acetylcholine receptor sites impair transmission of impulses across the myoneural junction. Therefore, fewer receptors are available for stimulation, resulting in voluntary muscle weakness that escalates with continued activity. These antibodies are found in 80% to 90% of the cases. In patients who are antibody negative, it is believed that the offending antibody is directed at a portion of the receptor site rather than the whole complex. 15. Contd- Acetylcholine receptor (AChR) antibodies are detected in approximately 85% of patients with generalized myasthenia gravis, who are categorized as seropositive. Anti-AChR antibodies reduce the number of available AChR sites with which acetylcholine can interact to induce local depolarization and subsequent muscle fiber contraction. Muscular weakness, the primary symptom in patients with generalized myasthenia gravis, results. 16. Contd- Anti-AChR antibodies are not detected in patients with seronegative myasthenia gravis The membrane protein muscle-specific tyrosine kinase (MuSK) has been identified as the target of antibody attack in approximately 40% of patients with seronegative myasthenia gravis.[2] The MuSK protein functions at the cytoskeletal level of the endplate by anchoring clusters of AChRs to the postsynaptic neuromuscular junction membrane; therefore, autoimmune attack by anti-MuSK antibodies is another mechanism through which interaction with acetylcholine on the postsynaptic surface is reduced.[5] 17. Role of Thymus The autoimmune responses that inhibit acetylcholine interaction on the postsynaptic membrane at neuromuscular junctions (NMJs), resulting in the inability of muscle fibers to contract, are often initiated and maintained by the thymus . Abnormalities of the thymus are observed in nearly 85% of patients with myasthenia gravis However, thymectomies lead to a reduction of symptoms in nearly 85% of patients with myasthenia gravis without identifiable thymus abnormalities.[6] Thus, evidence supports a correlation between thymus activity and the incidence of myasthenia gravis. 18. History Patients with myasthenia gravis present with symptoms such as ptosis, diplopia, breathing and swallowing difficulties, and weak limbs. Intermittent ptosis and diplopia are usually the initial reported symptoms, presenting in about 85% of patients with myasthenia gravis. Symptoms fluctuate in severity; they worsen with exertion and are relieved with rest. Fatigue upon exertion is essential to making the diagnosis. 19. Ptosis 20. Physical Examination Muscle strength should be assessed by having the patient squeeze the examiner's hand repeatedly or having the patient flex her arm against resistance. Facial weakness can be evaluated by asking the patient to smile. A snarling expression may be evident when the patient attempts to smile. Diplopia and ptosis to be adressed. Deep tendon reflexes are preserved. 21. Investigations Blood test- To detect antibodies Electromyogram Muscle Biopsy Nerve Stimulation test Edrophonium (Tensilon test ) Genetic tests Imaging Scan CT or MRI (thymus) 22. Differential diagnosis Lambert-Eaton myasthenic syndrome Botulism Hyperthyroidism Neurasthenia Intracranial mass lesion Progressive external ophthalmoplegia Drug-induced myasthenia gravis 23. Pregnancy and MG Course of disease is variable Pregnant patients face risks of exacerbation, respiratory failure, adverse drug response, crisis, and death. Because the severity of symptoms, as well as maternal mortality, is highest in the first 2 years following onset of myasthenia gravis. It is advisable for women to delay pregnancy for at least 2 years following diagnosis. Severity of symptoms and risk of maternal mortality is lowest 7 years after onset of the disease. 24. Contd- Pregnant patients may have disease exerbation in 40%, remission in 30% or no change in 30%. Emotional distress,systemic illness and hot temprature worsen the disease course. 25. Contd- , Plauche found that exacerbations occurred in approximately 41% of patients during pregnancy 29.8% of patients postpartum. Approximately 4% of patients died because of worsening of the disease or because of treatment complications 26. Contd- A study by Batocchi et al reported that the disease worsened in 19% of patients. Approximately 60% of exacerbations occurred during the first trimester, and approximately 28% post partum. Premature delivery occurred in 7.4% of patients. Cesarean delivery was performed in 30%. .The study concluded that no correlation exists between myasthenia gravis severity before and during pregnancy.[8] 27. Associated Disorders Systemic lupus erythematosus Pemphigus Hashimoto thyroiditis Scleroderma Dermatitis herpetiformis Autoimmune hemolytic anemia Polymyositis Sarcoidosis Thymic abnormalities are also associated with myasthenia gravis. As many as 50-60% of patients have lymphofollicular hyperplasia, and 10-20% have a thymoma 28. Complications Some of the rare complications can occur. Bone marrow suppression- suppression could be due to megakaryocyte colony-forming unit suppressive factor produced by autoimmune mechanisms. Excerbation can be linked to the anxiety and physiologic stress of pregnancy or due to medication. Respiratory crises- This is one of most severe complications. ~ 20% of patients experience that require mechanical ventilation 29. Contd- Infections- due to decreased immunity play a very important role in the exacerbation of myasthenia gravis during pregnancy. Operative deliveries are common. Preeclampsia- due to altered immune response.mag sulf contraindicated (phenytoin) 30. Treatment MG is a life long incurable disease. Early detection is key to successful treatment. Only symptoms can be reduced. Aim of treatment is to prevent respiratory problems. 31. Drugs Cholinestrase inhibitors- Pyrido- & Neostigmine to improve Ms. strength Corticosteroids- To reduce Ab production. Immunosupressants- Azathiopurine,cyclosporins etc. Plasmapheresis-To remove Ab.Effect last only for 2-3 wks.* IVIG-0.4- 1mg/kg.Effect may last upto 3 mth 32. Anticholinesterase medications At least partial improvement PYRIDOSTIGMINE :most widely used drug MOA within 15-30 min Lasts for 3-4 hrs 30-60 mg tid Long acitng at night time Max dose 120 mg 3-6 hrs daytime Muscarnic side effects diarrhea,abdominal cramps .salivation atropine,lopermaide . 33. immunosuppression Immediate improvement IV Ig, plasmapheresis Intermediate glucocorticoids,cyclosporine,tacrolimus Late mycophenolate mofetil,tacrolimus Refractory cases -High dose cyclophosphamide reboots the immune system eliminates mature lymphocytes,but stem cells are spared for the presence of aldehyde dehydrogenase . 34. Glucocorticoids Single dose only 15-25mg/d High doses weakening Increase by 5 mg/d at 2-3 day interval 50-60 mg/d for 1-3 months Alt day 1-3 months Zero dose when off symptoms 35. Mycophenolate mofetil 1-1.5 g bid Inhibition of purine synthesis by denovo pathway Inhibits proliferation of lymphocytes Lack of adverse side effects Skin rashes,leucopenia. 36. Azathioprine 50mg/d should be used 2-3 mg/kg in children 10 % develop idiosyncratic reactions Not to give allopurinol. Cyclosporine ,tacrolimus as adjunctives 37. Cholinergic crises Muscular weakness resulting from depolarization due to overdosage of anticholinesterase agents used for MG Excess dose of anti Ach ase inhibitors Symptoms of OP poisoning Worsened by edrophonium test treatment -atropine 38. Surgery Thymectomy-Thymectomy is recommended for most young patients. It improves the disease course and can improve remission. Thymectomy is thought to remove an antigen source and reduce an anti-AChR antibody source. Thymectomy is performed when the disease is in control. 39. Other Treatment considerations Monitoring patients for infection especially those on steroids. Serial ultrasonography, nonstress tests, and biophysical profiles should be used for pregnancies at risk as per the usual obstetrical management protocol. Many patients develop depression or comorbid depressive episodes. Bupropion (Wellbutrin XL) can be added Potassium rich diet and adequate rest. 40. Precautions during LSCS Surgery is very stressful. Cesarean delivery is reserved only for necessary cases. Regional anesthesia is good for abdominal delivery. Epidural anesthesia could be used to decrease the requirements of systemic medications and provide anesthesia for outlet forceps. Amide-type local anesthetics are thought to be safe when large doses of drugs are needed. The group recommended general endotracheal anesthesia for cesarean delivery in patients with respiratory problems. Depolarizing anesthetics must always be avoided. 41. Neonatal Effects Not only is the mother at risk, her baby also faces significant risks, Neonatal myasthenia gravis- are as high as 10-20%. Show espiratory distress and inadequate suck.Most of the time it is transient and last for app. 3wks. Due to transplacental transfer of antibodies. Prematurity- approximately 36.5% Severe malformation,- are pulmonary hypoplasia and arthrogryposis Death- Breastfeeding by the mother with myasthenia gravis is safe if she is following a treatment course that utilizes pyridostigmine or corticosteroids Mothers with myasthenia gravis being treated with azathioprine, methotrexate, mycophenolate mofetil, or cyclophosphamide should avoid breast feeding. 42. Pharmacologic precautions the following drugs should be avoided: Narcotics Tranquilizers Barbiturates Inhalation anesthetics (ie, halothane, trichloroethylene, ether) Magnesium and lithium salts Penicillamine Beta-adrenergic agents Aminoglycoside antibiotics Colistin Neomycin Tetracycline drugs Lincomycin Polymyxin Quinacrine Chloroquine. Quinolones. 43. Drugs to be avoided in MG Not all patients have adverse effects Myasthenic Weakness exaggerated Erythromycin Azithromycin Local anaesthetic xylocaine Streptomycin Ciprofloxacin Levofloxacin Ofloxacin Gatifloxacin Non depolarizing muscle relaxants DTC,pancuronium Propanol Atenolol Quininine Magnesium penicilliamine 44. Summary Pregnancy- Counselling about the risks Review therapy consider thymectomy Prenatal- Joint obs and Physician care Drugs Plasmapheresis in resistant cases Foetal survellance Avoid stress. 45. Summary contd. Labour &Delivery- Minimize stress, Continue drugs, Steroid if reqd.regional analgesia, Assist ll-stage Avoid mgso4 Postnatal- Review drug neonatal monitoring, shorterm AchE to neonate. 46. CONFUCIUS-- OUR GREATEST GLORY IS NOT IN NEVER FALLING BUT IN RISING EVERY TIME WE FALL.