1. MYASTHENIA GRAVIS Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin

2. MYASTHENIA GRAVIS OVERVIEW  Historical Background  NMJ Physiology  Pathogenesis  Clinical Manifestations  Diagnosis  Treatment  Associated Conditions  Related Disorders

3. 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” This has been interpreted as being the first written description of myasthenia gravis. History of MG Thomas Willis (1621–1675)

4. Chief Opechancanough "The excessive fatigues he encountered wrecked his constitution.………………his eyelids were too heavy that he could not see unless they were lifted up by his attendants.“ While in Jamestown, Chief Opechancanough was able to rest and he then could raise himself up to a standing position. History of MG Opchanacanough was a tribal chief of the Powhatan Confederacy of what is now Virginia in the United States, and its leader from sometime after 1618 until his death in 1646.

5.  Most common disorder of NMJ transmission  Annual incidence of 10- 20 new cases per million  Prevalence: 14.2:100000 (US) but on rise due to ↓ mortality, longer survival  The M:F ratio of MG in children and adults is 2:3.  Onset of MG at a young age is slightly more common in Asians than in other races  Age of onset has a bimodal distribution  Second and third decades (female predominance)  Sixth to eighth decade (male predominance) Epidemiology: Myasthenia Gravis

6. n=868 Generalized Myasthenia (Grob et al. ‘81)

7. n=168 Ocular Myasthenia (Grob et al. ‘81)

8. M-Muscle cell. T-synaptic terminal Axon

9. Pathophysiology  To understand MG, familiarity with normal anatomy and functioning of NMJ is necessary.  The nerve terminal of the motor nerve enlarges at its end, which is called the bouton terminale (terminal bulb). It lies within a groove or indentation along the muscle fiber.  The presynaptic membrane (nerve membrane), postsynaptic membrane (muscle membrane), and synaptic cleft (space between the 2 membranes) constitute the NMJ.  Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.

10. Chemical synapses  Illustration of the major elements in chemical synaptic transmission.  An electrochemical wave called an action potential travels along the axon of a neuron.  When the wave reaches a synapse, it provokes release of neurotransmitter molecules, which bind to chemical receptor molecules located in the membrane of another neuron, on the opposite side of the synapse. NMJ Transmission

11.  MG autoimmune channelopathy: antibodies directed against the body's own proteins  Autoantibodies [IgG] develop against ACh nicotinic postsynaptic receptors.  Slight genetic predisposition: HLA types B8 & DR3 predispose for MG. DR1 more specific for ocular myasthenia.  The antibodies are produced by plasma cells, derived from B- cells converted into plasma cells by T-helper cell stimulation.  Cholinergic nerve conduction to striated muscle is impaired and postsynaptic receptor are destroyed.  The cholinergic receptors of smooth and cardiac muscle are not affected by the disease.  Patients become symptomatic once the number of ACh receptors is reduced to about 30% of normal.  Serum IgG from MG patients increases degradation of AChR. Pathophysiology

12. NORMAL NMJ ABNORMAL NMJ

13. ROLE OF THYMUS IN MG  Thymomas were first noticed in MG patients in 1899 C. Weigert Frankfurt.  Drs Jacques Miller (London) and Bob Good (USA) in 1960s showed that the thymus was a key ‘immune organ’. It generates ‘T cells’, the control freaks that help to switch on other immune cells to make antibodies and/or destroy germs.  1973 physiologists realized that the ACh, the ignition keys, must somehow latch into specialized Ach receptors (AChRs) – the ignition locks.  Basic scientists were using snake venoms to purify AChR (from electric fish)  It was soon shown that most MG patients had similar antibodies – so giving us a valuable diagnostic test, which is now in routine use around the world C. Weigert Jacques Miller

14. Presenting symptomsOther disorders to consider Ocular (50 percent) Brainstem and cranial nerve lesions (including Horner's syndrome), thyroid ophthalmopathy, oculopharyngeal muscular dystrophy, chronic external ophthalmoplegia (mitochondrial disease) Bulbar (15 percent) Brainstem and multiple cranial nerve lesions, motor neuron disease, obstructive or malignant lesion of the nasal and oropharynx Limb weakness (<5 percent) Motor neuron disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and other motor neuropathies, multiple radiculopathies, Lambert-Eaton myasthenic syndrome, myopathies Isolated neck (uncommon) Motor neuron disease, inflammatory myopathy, paraspinous myopathy Isolated respiratory (rare) Motor neuron disease, acid maltase deficiency, polymyositis Distal limb (rare) Motor neuron disease, CIDP and other motor neuropathies, distal myopathies

15. The usual initial complaint is a specific muscle weakness rather than generalized weakness Extraocular muscle weakness or ptosis is present initially in 50% of patients The disease remains exclusively ocular in only 16% of patients Rarely, patients have generalized weakness without ocular muscle weakness Bulbar muscle weakness is also common, along with weakness of head extension and flexion Limb weakness may be more severe proximally than distally Isolated limb muscle weakness is the present in fewer than 10% of patients Weakness is least severe in the morning and worsens as the day progresses Weakness is increased by exertion and alleviated by rest Weakness progresses from mild to more severe over weeks or months, with exacerbations and remissions Weakness tends to spread from the ocular to facial to bulbar muscles and then to truncal and limb muscles About 87% of patients have generalized disease within 13 months after onset Less often, symptoms may remain limited to the extraocular and eyelid muscles for years Signs and Symptoms

16. Muscle fatigability can be tested for many muscles. A thorough investigation includes:  looking upward and sideward for 30 seconds: ptosis and diplopia  looking at the feet while lying on the back for 60 seconds  keeping the arms stretched forward for 60 seconds  Ten deep knee bends  Walking 30 steps on both the toes and the heels  Five sit-ups, lying down and sitting up completely  "Peek sign": after complete initial apposition of the lid margins, they quickly (within 30 seconds) start to separate and the sclera starts to show PYSICAL EXAMINATION FOR MG

17. Ice pack test  MG who has ptosis, placing ice over an eyelid will lead to cooling of the lid, which leads to improvement of the ptosis.  Lightly placing ice that is in a surgical glove or that is wrapped in a towel over the eyelid will cool it within 2 minutes.  Positive test is clear resolution of the ptosis.  This test has a pooled sensitivity and specificity of 82% and 96%, respectively.  Patients with respiratory distress should have an evaluation of pulmonary function.  This evaluation includes pulse oximetry, a measure of pulmonary function ( PEFR, [FEV1]), and ABG sampling to determine PCO 2 level.  Evidence of hypoxemia, poor respiratory effort, or CO 2 retention is an indication for intubation and mechanical ventilation. Additional Tests for MG Diagnosis

18. Tensilon Test  Edrophonium is an AChE inhibitor.  Rapid onset (30s) and short duration of action (about 5 minutes).  Focus on a weak muscle group and evaluate for change.  Initial dose of 2mg given IV. If no change give additional 8mg IV.  Beware cholinergic effects (nausea, diarrhea, salivation, fasciculations, bradycardia).  Have atropine at bedside.

19. Anti–acetylcholine receptor antibody  (AChR) antibody (Ab) test is reliable for autoimmune (MG).  Highly specific (100%).  Positive in 90% generalized MG.  50-70% ocular MG False-positive anti-AChR Ab test results occur in :  Thymoma without MG  L-Eaton myasthenic syndrome  R A treated with penicillamine Anti-MuSK– antibodies  About 1/2 Seronegative MG may have positive (Anti-MuSK antib)  Anti-MuSK (Muscle specific tyrosine kinase) positive individuals may have more pronounced  Bulbar weakness  Tongue and facial atrophy.  Neck, shoulder and respiratory involvement without ocular weakness. Additional Tests for MG Diagnosis

20. Generalized myasthenia percent positive Ocular myasthenia percent positive AChR antibodies 80 to 9040 to 55 MuSK antibodies (in AChR Ab negative patients) 40 to 50<10 Repetitive nerve stimulation 75<50 Single fiber electromyography 92 to 9980 to 95 MG: myasthenia gravis; AChR: acetylcholine receptor; MuSK: muscle- specific kinase. Approximate sensitivity of the confirmatory tests for myasthenia gravis

21. Plain chest radiographs may identify a thymoma as an anterior mediastinal mass Chest computed tomography is important to identify or rule out thymoma or thymic enlargement in all cases of MG In strictly ocular MG, magnetic resonance imaging of the brain and orbit is helpful to evaluate for mass lesions compressing the cranial nerves or a brainstem lesion that may masquerade as ocular MG Other studies (Imaging) Thymoma

22. Stage IVa thymoma in a 50- year-old man. Contrast- enhanced chest CT scan shows a primary mass (M) and a pleural drop metastasis (arrow) THYMOMA ASSOCIATED WITH MG CT showing Thymoma marked with blue arrow

23.  ALS  Basilar artery thrombosis  Brain stem gliomas  Cavernous sinus thrombosis  Dermatositis/Polymyositis  LEMS  Multiple sclerosis  Sarcoidosis & neuropathy  Thyroid disease  Tolosa-Hunt Syndrome  Myasthenic syndromes  Mitochondrial cytopathies  Mitochondrial myopathies ± external ophthalmoplegia  Neurasthenia  Oculopharyngeal muscular dystrophy  Botulism  Brainstem syndromes  Compressive lesions of cranial nerves  Congenital myasthenic syndromes MG: DIFFFERENTIAL DIAGNOSIS

24. Repititve nerve stimulation  Anti-AChE inhibitors stopped 6-24 hrs prior to testing.  2-3 electric shocks/second delivered, action potentials recorded.  In normal individual, amplitude of evoked muscle action potential dose not change.  In MG, rapid reduction in the amplitude of the evoked response of more than 10-15%

25. Single Fiber EMG The most sensitive test for MG  Electrode measures action potentials of two muscle fibers innervated by the same motor axon.  Variability in time of the 2 nd action potential relative to the 1 st is called “jitter”.  MG causes increased “jitter”.

26.  Disorders of the thymus  Thymoma  Hyperplasia of thymus  Autoimmune disorders  Thyroiditis  Autoimmune thyroid disease (3-8%)  RA  SLE  Lymphoid Hyperplasia  Rebound Hyperplasia secondary to  Chemotherapy  Radiotherapy  Corticosteroid Therapy  Thermal Burns  Systemic Stress  MG can be exacerbated by hyper/hypothyroidism, occult infection or drugs. Associated Conditions

27.  Anti-cholinesterase Inhibitor ( AChEI) inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.  Acetylcholinesterase inhibitors :  Occur naturally as venoms and poisons.  Are used as weapons in the form of nerve agents.  Are used medically :  In myasthenia gravis, to prevent enzymatic breakdown of ACh to increase neuromuscular transmission.  In the treatment of Glaucoma.  To treat Alzheimer's disease.  To treat Lewy Body Dementia.  As an antidote to anticholinergic poisoning. Acetylc holine Acetylcholin esterase Anti-cholinesterase Inhibitor

28.  MG is one of the most treatable neurologic disorders.  These agents increase the amount of available ACh at the NMJ by inhibiting the degradation of ACh.  Most patients are able to titrate the dosage of their medication to control the symptoms of the disease, but severe exacerbations can occur in patients with previously well- controlled disease  Pyridostigmine is the most used AChE inhibitor.  Peak serum concentrations reach in 90 to 120 minutes and has a similar half-life.  60 to 120 mg every 3 to 4 hours are most effective.  Patients may modify their dose to their level of activity  It is rare for pyridostigmine alone to improve transmission to a satisfactory level, and therefore most patients require more definitive therapy. Cholinesterase Inhibitors

29. The corticosteroid regimen should be tailored according to the patient’s overall improvement. The lowest effective dose should be used on a long- term basis. Because of the delayed onset of effects, steroids are not recommended for routine use in the emergency department (ED). Other medications that are used to treat more difficult cases include – azathioprine, – mycophenolate mofetil, – cyclosporine, – cyclophosphamide However, the effectiveness of many of these medications is far from proved, and caution should be advised against using any of them lightly Immune modulation: Most patients with generalized MG require additional immunomodulating therapy. Immunomodulation can be achieved by various medications, such as commonly used corticosteroids

30.  Mary Broadfoot Walker (1888—1974) was a British physician who first demonstrated the effectiveness of physostigmine in the treatment of myasthenia gravis.  She had noted that the symptoms and signs of myasthenia were similar to those found in curare poisoning, and physostigmine was used as an antidote to curare poisoning at that time.  The first case of MG successfully treated with physostigmine was published in the Lancet in June 1934. Mary Broadfoot Walker MYASTHENIA GRAVIS TREATMENT

31.  She was the first to recognize (1935) the association between the condition familial periodic paralysis and hypokalaemia.  Described the glucose challenge test used in diagnosing hypokalaemic periodic paralysis and the use of intravenous potassium in its treatment.  In1935 her research on myasthenia was incorporated into her MD thesis which was submitted via the University of Edinburgh and for which she received a Gold Medal.  Although she never became a Fellow of the Royal College of Physicians she was awarded the Jean Hunter Prize in 1962 Mary Broadfoot Walker MYASTHENIA GRAVIS TREATMENT

32. Plasmapheresis  The response occurs over hours to days and is useful to treat or abort myasthenic crisis preoperatively.  Pathogenic antibodies removed at NMJ.  Usually a course of 5 exchanges over a 2 week period is useful for relief of symptoms. IVIG  The recommended total monthly dose is 2 g/kg in five daily doses slowly enough to avert rate related side effects.  Half-life of IVIg is about 4weeks, and monthly doses are reasonable, with the goal of slowly tapering the frequency of treatments based on the clinical status.  Clinical responses occur over 2 to 4 weeks. Plasmapheresis and IVIG

33. THYMECTOMY  Thymus has a central role in pathogenesis - thymectomy is an important part of Rx.  Radiographic/CT evidence of an anterior mediastinal mass warrants thymectomy at any age because 10% of patients with MG will have thymoma.  In the absence of mediastinal mass, it seems appropriate to counsel the patient to undergo thymectomy to increase the probability of sustained remission. “Ernst Ferdinand Sauerbruch”, German surgeon (1875-1951) performed thymectomy for the relief of myasthenia gravis.

34.  Fifty-six board-certified neurologists with interest and expertise in myasthenia completed a survey of indications for thymectomy in myasthenia gravis.  Thymectomy was advocated for virtually all patients with thymoma.  Variable subset of patients with generalized myasthenia without thymoma.  Occasionally for selected patients with disabling ocular myasthenia. EVIDENCE BASED EFFECTIVENESS OF THYMECTOMY IN MG