Bulbar mg ppt

A rare case of BULBAR MYASTHENIA after 7 yrs of THYMECTOMY

1. Bulbar Myasthenia after 7 yrs of Thymectomy Dr.Panneer.A Unit Presenter: Dr.M.Ramesh Babu

2. History A49 yrs female presented with complaints of change in voice since 1 month - her voice felt "horrible and nasty" and that she could not speak loudly and had difficulty being understood by others. The main vocal aspects indicated by the patient were vocal fatigue, hoarseness, voice failure, vocal tremor, and the need to make an effort to speak. Symptoms are more at the end of the day and feels better in early morning .

3. No H/O difficulty in chewing, swallowing, no respiratory difficulty No H/O difficulty or heaviness in opening her eyes, diplopia, weakness in neck muscles. No H/O fatiguability in walking or in daily activities.

4. Past History: H/O Total thymectomy done in 2010, where identified by routine health screening. Post Thymectomy - No complaints HPE Report - Nodular sheets and proliferation of monomorphic lymphoid cells separated by wide bands of fibrocollagenous tissue. The lymphoid cells appear hyper chromatic nuclei . Mitosis is low. F/S/O - Low grade Thymoma. H/O Hypothyroidism - since 6yrs on treatment

5. General Physical Examination Patient moderately built and nourished Vitals : H.R- 88/min, B.P- 130/80 mmhg Voice fatiguabity + Nasal Twang + Single breath count- 56 CNS Examination- Normal Other Systemic examination - Normal

6. Investigations Bed side Test- Neostigmine test- positive RNS - Showed decremental positivity Anti Ach R - Strongly positive (87nmol/l) HRCT- Normal Thyroid profile- WNL

7. Audios

8. Myasthenia Gravis Myasthenia Gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. Key Concept :- It is due to the decrease in the number of available acetylcholine receptors (AchRs) at neuromuscular junctions due to antibody mediated autoimmune attack.

9. Pathophysiology Autoimmune channelopathy Genetic predisposition: HLA B8 & DR3 DR1 specific for ocular myasthenia 75% patients have abnormality of thymus 10% have Thymoma Autoantibodies against nicotinic acetylcholinrereceptors (nAchRs) These antibodies prevent binding of Ach to its receptors Other action: Destruction of receptors By complement activation Elimination by endocytosis

10. Pathophysiology

11. Anti–acetylcholine receptor antibody The anti AChR antibody test is reliable for diagnosing autoimmune MG. It is highly specific (as high as 100%, according to Padua et al). [ 4 ] Results are positive in as many as 90% of patients who have generalized MG but in only 50-70% of those who have only ocular MG; thus false negatives are common in cases of purely ocular MG. False-positive anti-AChR Ab test results have been reported in cases of thymoma without MG and in patients with Lambert-Eaton myasthenic syndrome , small cell lung cancer, or rheumatoid arthritis treated with penicillamine, as well as in 1-3% of the population older than 70 years.

12. Tindall reported AChR Ab results and mean Ab titers in a group of patients with MG Data suggest a trend toward higher Ab titers in more severe disease, though the titer does not predict severity in an individual patient. Changes in the anti-AChR titer correlate with long-term improvement induced by prednisone or azathioprine; the same changes are not observed consistently in patients who undergo thymectomy. However, this finding is not consistent, and serial Ab titers alone are not reliable.

13. Anti-MuSK antibody About half of the patients with negative results for anti-AChR Ab (seronegative MG) may have positive test results for antibody to muscle-specific kinase (MuSK), a receptor tyrosine kinase that is essential for neuromuscular junction development. [ 26 ] These patients may represent a distinct group of autoimmune MG, in that they show some collective characteristics that are different from those of anti-AChR–positive patients. [ 27 ] Anti-MuSK–positive individuals tend to have more pronounced bulbar weakness and may have tongue and facial atrophy. They may have neck, shoulder and respiratory involvement without ocular weakness. They are also less likely to respond to acetylcholine esterase (AChE) inhibitors, and their symptoms may actually worsen with these medications. [ 28 , 29 ]

14. Anti-lipoprotein-related protein 4 (LRP4) antibody Lipoprotein-related protein 4 is present on the postsynaptic membrane and is a receptor for agrin and is essential for neuromuscular junction formation. Antibody to this protein is present in 2-27% of double seronegative myasthenics (absence of AChR and Anti-MuSK antobodies) [ 30 ] .

15. Antistriational antibody Serum from some patients with MG possesses antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections. These antibodies react with epitopes on the muscle protein titin and ryanodine receptors (RyR). Almost all patients with thymoma and MG, as well as half of the late-onset MG patients (onset at 50 years or later), manifest a broad striational antibody response. Striational antibodies are rarely found in anti-AChR–negative patients. They can be used as prognostic determinants in MG; as in all subgroups of MG, higher antibody titers are associated with more severe disease. [ 31 ] Because of a frequent association with thymoma, the presence of titin/RyR antibodies should arouse a strong suspicion of thymoma in a young patient with MG.

16. Anti–striated muscle antibody Anti-SM Ab is present in about 84% of patients with thymoma who are younger than 40 years and less often in those without thymoma. Positive test result should prompt a search for thymoma in patients younger than 40 years. In individuals older than 40 years, anti-SM Ab can be present without thymoma.

17. Clinical features Fluctuation weakness increasing trough the day & relieved by rest. Extra ocular muscle weakness Present in 50% of patients initially. Present in 90% of patients during the course of disease. Disease remains ocular in 16% of patients.

18. Pathophysiology Antibodies to AChR protein: 85 % of patients with generalized myasthenia and 60% of those with ocular myasthenia shows AChR Antibodies Anti-MuSK Ab(40% of seronegative cases) An immune response to muscle-specific kinase (MuSK) can also result in myasthenia gravis, possibly by interfering with “AChR clustering” How do these antibodies act? Blocks the binding of ACh to the AChR. INCREASES THE DEGRADATION rate of AChR ANTIBODIES→ CROSS LINKING OF RECEPTORS → CLUSTERING → ENDOCYTOSIS → DEGRADATION A complement-mediated destruction of the postsynaptic folds. The latter two mechanisms would be expected to reduce the number of AChR at the synapse.

19. Pathophysiology The muscle fibers are generally intact In fatal cases with extensive paralysis, “ Segmental necrosis with variable regeneration” Scattered aggregates of lymphocytes, “Lymphorrhages” especially associated with thymomas MOTOR END PLATE: a reduction in the area of the nerve terminal, a simplification of the postsynaptic region (sparse, shallow, abnormally wide or absent secondary synaptic clefts) a widening of the primary synaptic cleft PRESYNAPTIC VESICLES AND NERVE TERMINALS ARE NORMAL

20. Discussion Thymus plays a key role in the immunologic status of an individual, and disease of the thymus can be associated with autoimmune disorders. Thymus is abnormal in ~75% of patients with MG In ~65% the thymus is "hyperplastic," (a nonneoplastic lymphofollicular hyperplasia of the thymic medulla) with the presence of active germinal centers detected histologically 10% of patients have thymic tumors (“ neoplastic”) Thymomas with malignant characteristics may spread locally Upon distant spread, the lungs and liver are usually affected.

21. Pathogenic Mechanism of PTMG Current hypothesis of the pathogenic mechanism of PTMG includes: Thymoma recurrence Surgical exposure to larval MG and Activation of peripheral lymphocytes from thymoma after surgery. Muscle-like cells within the thymus (myoid cells) which bear AChRs on their surface may trigger immune response first appearing many years following the removal of a thymoma reportedly occurs in 1.5-28% of cases. Hoffacker V, Schultz A, Tiesinga JJ, Gold R, Schalke B, Nix W, et al. Thymomas after the T-cell subset composition in the blood: a potential mechanism for thymoma associated autoimmune disease. Blood 2000;96:3872-3879

22. The interval between a thymectomy and the onset of postoperative MG has varied between studies. Two of the studies involving an adequate number of cases and obtaining detailed clinical data found that the mean interval between thymectomy and the onset of postoperative MG was 19 and 18 months. Namba et al. reported that patients with a shorter onset of postoperative MG had a better prognosis, but other study did not find this relationship. 3 , 8 rarity of postoperative MG cases has meant that it remains unclear whether the interval between thymectomy and the onset of postoperative MG influences the prognosis.

23. This discrepancy may be due to different therapies being applied for MG. Most reports demonstrate that postoperative MG responds to anticholinesterase drugs and/or steroids, and that the prognosis is relatively good. 5 , 8 Although a thymectomy does not prevent the onset of postoperative MG, this procedure is associated with a good prognosis.

24. In the study of Kondo and Monden, the anti-AChR antibody at onset varied between 1.8 and 91 nmol/l. 8 The majority of patients show a clinical severity of type I or type IIA on Osserman's classification. However, they found that the titer of anti-AChR antibody did not correlate with clinical severity, as was the case in our patient.

25. The mechanism underlying the onset of postoperative MG is unclear. The various time periods between a thymectomy and the onset of postoperative MG raise doubts as to whether a thymectomy directly triggers MG onset. Two useful studies were recently published. Hoffacker et al. found using T-cell-proliferation assays for a fragment of the AChR that the thymoma released mature auto-antigen-specific T-cells into the periphery. 9 Buckley et al. found that T-cells in a thymoma were exported to the peripheral blood, and that these T-cells could persist in the periphery for many years. 10 These studies suggest that a thymoma actively exports large numbers of mature T-cells into the peripheral blood, with these cells persisting in the periphery, potentially stimulating autoantibody production and subsequent autoimmune disease.

26. The late onset of MG and other autoimmune disorders should be kept in mind as possible complications of surgical treatment for thymoma. Therefore postoperative follow-up care with consideration of postoperative MG is necessary after resecting a thymoma. In postoperative MG cases, recurrent or metastatic thymoma should be ruled out because reoperation can be effective even in the treatment of MG.

27. Can Vaccine trigger or worsen Myasthenia? There is no convincing evidence that any vaccination affects MG symptoms in any way. It is well known that episodes of infection can bring on myasthenia crises. Since vaccination help to prevent some of these infections, it seems for patients with myasthenia to have them appropriate. MG by itself does not affect vaccination , so these warnings only concern people on immunosuppressive treatments. These patients should remember to always mention this before they are given vaccines . A good rule of thumb is that live attenuated should be avoided , while others are safe.