Myasthenia Gravis - Rivin

Myasthenia gravis (MG) is a long-term neuromuscular disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing.

1. Myasthenia Gravis W. P. Rivindu H. Wickramanayake Group no. 04a 3 rd Year 1 st Semester – 2017 May Tbilisi State Medical University, Georgia.

2. History of Myasthenia Gravis Myasthenia (Greek – muscle illness) Gravis (Latin – “grave or serious”) First description in the 17 th century Sir Thomas Willis - “a woman who spoke freely and readily enough for a while, but after a long period of speech was not able to speak a word for one or two hours” - ‘On the palsy’, persons who (translated) in the morning are able to walk firmly, to fling about their Arms hither and thither, or to take up any heavy thing, before noon the stock of Spirits being spent, which had flowed into the Muscles, they are scarce able to move Hand or Foot.

3. Introduction It is an acquired Autoimmune D isorder mediated by Antibodies against the Acetylcholine-Receptor ( AChR ) at the Neuromuscular Junction(NMJ) . It can be characterized by varying degrees of Weakness of the Voluntary Muscles . Simply, “ A defect in the transmission of impulses from nerve endings in the muscle fibers result in the development of skeletal muscle weakness .”

4. Scientists have not yet been able to determine the exact cause of the development of autoimmune diseases, in which the immune system of the human body begins to produce antibodies against its own healthy cells. Researchers believe the thymus could be one of the factors responsible for the condition by producing antibodies to block acetylcholine (a neurotransmitter ) Furthermore, antibodies may block a receptor protein called tyrosine kinase. Myasthenia gravis can exacerbate by i ) viral infection , ii) severe stress and c iii) certain types of medication . Autoimmune form is not contagious and is not inherited . The disease is most common in young women (under 40 years of age), but can develop at any age, in addition, it affects men over 60 years of age.

5. Types of Myasthenia Gravis Congenital myasthenia – not autoimmune disease but a defect in the genes which result in abnormal proteins, inherited as an autosomal recessive disease Transient neonatal myasthenia gravis - relatively rare form of myasthenia gravis may develop in a child immediately after birth . The reason for this are the mother's antibodies , suffering from a disease transmitted through the placenta. It is necessary to distinguish the neonatal form of another type of myasthenia gravis associated with a genetic mutation COLQ, and inherited Juvenile myasthenia gravis - Develops in childhood and adolescence , usually girls, occurs in approximately 10% of Myasthenia gravis cases Generalized myasthenia gravis - the most common form of the disease. The most characteristic occurrence of the disease in women aged 20-30 and men aged 50-60 years Ocular myasthenia gravis – around 10-15% of people only experience problems with the muscles that control eye  

6. Myasthenia Gravis Symptoms Visual problems - ptosis (drooping of the upper eyelid), diplopia (double vision) Weakness of the muscles of the upper and lower extremities . - Patients often describe the following symptoms of myasthenia gravis: Difficulties in the transition from a sitting to a standing position, as well as climbing the stairs, the inability to raise his hands above his head, reduced tolerance to previously routine physical activity Violations of speech ( Dyrathria ) and swallowing ( Dysphagia ) Extreme weakness of the neck muscles Facial expressions ( mask-like face ), altered speech ( nasal-sounding ), difficulty chewing and swallowing The symptoms of myasthenia gravis usually worsen when muscles are overly used during the day, while at rest symptoms improve. However over time, progressive autoimmune disease gradually leads to significant functional impairment (including secondary muscle atrophy), and can cause severe disability . Myasthenic crisis , for example, occurs in severe, progressive forms of Myasthenia gravis, where the muscles that control breathing are affected – this is a life-threatening situation and requires immediate attention.

7. Myasthenia Gravis W eakness

8. Why does Myasthenia Gravis causes Muscle Weakness.

9. The Immune System’s Job: - The body’s homeland defense . - Must correctly recognize potential threats and distinguish “good” from “ bad” The Neuromuscular Junction: - Target of the immune system in Myasthenia Gravis The Immune System and Myasthen ia Gravis

10. Myasthenia Gravis is an Autoimmune Disease!

11. The Problem Normal Immune system : Protects against foreign invaders Autoimmune Disease: Occurs when the immune system loses tolerance to self tissues

12. Why do people get Autoimmune Diseases like Myasthenia Gravis? Nature Immunology (9): 759-761 (2001) 1) Probably these reasons 2) We don’t really know 3) Thymus gland Thymic hyperplasia AChR Tumor cell AChR T Thymoma

13. The Thymus Gland and the Origin of Myasthenia Gravis The thymus gland is abnormal in many MG patients Thymectomy makes Myasthenia gravis better (we think) Muscle-like cells express AChR BUT- What triggers immune attack? - Abnormal AChR ? - Viral infection?

14. Examination of neuromuscular endplates by immunochemical techniques has demonstrated; - IgG and the complement proteins C3 and C9 - on the postsynaptic folds of the muscle . Pathogenetic role of IgG; - Transient muscle weakness in babies born to mothers with myasthenia gravis - Significant – Because IgG can cross placenta, entering the blood stream of the fetus IgG and Complement are thought to act in two ways; 1) By increasing the rate turnover of the acetylcholine receptors ; and 2) By partial blocking of acetylcholine binding

15. 40-50% of patients with ocular MG MuSK antibodies in 40% of AChR negative, generalized MG “Low-affinity ” antibodies in “double negatives” ?? AChR Antibody Test Positive in 85% of MG patients Antibody level does NOT correlate with disease severity between patients In an individual patient, changes in antibody levels do correlate “Antibody negative” - Myasthenia Gravis

16. How does research in Myasthenia Gravis can be carried out? 1) Experimental MG 2) Patient-related research Torpedo californica Muscle Acetylcholine α ε α β δ AChR

17. 1) Experimental Myasthenia Gravis Rabbits, rats, mice, etc. Immunize with AChR from electric organs of electric eels or fish. Weakness , Antibody responses 2) Myasthenia Gravis – Clinical Trials PHASE I TRIALS: Initial studies to determine the metabolism and pharmacologic actions of drugs in humans , the side effects , early evidence of effectiveness ; may include healthy participants and/or patients. PHASE II TRIALS: Controlled clinical studies conducted to evaluate the effectiveness and safety of the drug in patients. PHASE III TRIALS: Expanded controlled trials provide and adequate basis for FDA labeling

18. What would be the ideal treatment for Myasthenia Gravis? The Ideal Immunotherapy Treatment applied for a short time Long-lived result Target effects to autoreactive cells ( Antigen-specific) No side-effects Immune Tolerance Auto-Reactive Treatment Immune Tolerance

19. Obstacles Treatment of autoimmune disease occurs months or even years after the onset of the disease process Autoimmune response becomes more complex as disease progresses Benefit achieved by interfering with the immune system’s defense mechanisms Before After

20. Myasthenia Gravis upsets the Balance in the Immune S ystem

21. How do we restore the balance? “The art of medicine consists in amusing the patient while nature cures the disease”       - Voltaire (1694 - 1778) Expand regulatory immune cells Use agents (drugs) that promote their mobilization and growth Grow them in culture? - Make them AChR -specific - Stem cells?

22. - Blocking the destruction of ACh causes Improvement for the patient Anticholinesterase drugs – Pyridostagmine , N eostigmine ( Prostigmin ) or Edrophonium ( Tensilon ), a group of drugs that inhibit cholinesterase activity , enhancing smooth muscle of various organs Drugs that suppress the activity of the autoimmune process, including steroids – Prednisolone Plasmapheresis . Intravenous immunoglobulin (IVIG) therapy . Removal of the thymus gland ( Thymectomy ). It is noted that after this procedure, patients’ antibody titer is significantly reduced , which increases the likelihood of prolonged remission. Myasthenia Gravis Treatment

23. Myasthenic Crisis Complications A myasthenic crisis is an exacerbation of the myasthenia gravis process characterised by severe generalised muscle weakness and respiratory and bulbar weakness that may result in respiratory failure . Treatment i ) Neostigmine methylsulfate -IM/IV ii) Plasmapharesis and IVIG iii) Endotracheal intubation and mechanical ventilation Cholinergic Crisis   Anticholinergic overmedication leads to cholinergic crisis . The symptoms are similar to myasthenic crisis. Treatment i ) Withdraw the anticholinergic medication and administer Atropine sulfate (antidote to anticholinesterase drugs) ii) Endotracheal intubation and mechanical ventilation .

24. Thank You!  Rivin..®