Bulbar Myasthenia after 7 yrs of Thymectomy

Dr.Panneer.A Unit

Presenter: Dr.M.Ramesh Babu

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 .

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.

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

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

Investigations

Bed side Test- Neostigmine test- positive

RNS - Showed decremental positivity

Anti Ach R - Strongly positive (87nmol/l)

HRCT- Normal

Thyroid profile- WNL

Audios

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.

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

Pathophysiology

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.

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.

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]

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] .

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

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.

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.

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

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.

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.

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.

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.

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.

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.

Thank You