Journal of Clinical Neuroscience 20 (2013) 707709

Contents lists available at SciVerse ScienceDirect

Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Clinical Study

Prevalence, clinical features and treatment outcomes of patients with

myasthenia gravis positive for antibodies to muscle-specic kinase in Thailand
Rawiphan Witoonpanich a,, Charungthai Dejthevaporn a, Teeratorn Pulkes a, Supoch Tunlayadechanont a,
Pairoj Boonkongchuen a, Sunsanee Pongpakdee b, Angela Vincent c
a
b
c

Division of Neurology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama 6 Road, Bangkok, Thailand
Division of Neurology, Department of Medicine, Bhumibol Adulyadej Hospital, Bangkok, Thailand
Nufeld Department of Clinical Neurosciences, University of Oxford, Oxford, UK

a r t i c l e

i n f o

Article history:
Received 9 November 2011
Accepted 28 March 2012

Keywords:
Antibody
Clinical feature
Muscle-specic kinase
Myasthenia gravis
Outcome
Prevalence
Thailand

a b s t r a c t
A small but variable subgroup of patients with myasthenia gravis (MG) who have antibodies to musclespecic kinase (MuSKAb-MG) can present with distinct phenotypes and are often treatment-resistant.
The prevalence, clinical phenotypes and outcomes of treatment of patients with MuSKAb-MG in Thailand
were determined. Eight (16.3%) of the 49 patients with generalized MG who were negative for acetylcholine receptor antibodies (AChRAb) were positive for muscle-specic kinase antibodies. Most patients had
predominant oculobulbar features and respiratory failure occurred in three. At follow up, three out of the
seven patients who underwent thymectomy were in complete stable remission and four had improved
and were on reduced immunosuppression medication, suggesting a possible benet of thymectomy.
2012 Elsevier Ltd. All rights reserved.

1. Introduction
The prevalence of acetylcholine receptor antibody (AChRAb)
seronegative patients with generalized myasthenia gravis (MG)
who have antibodies to muscle-specic kinase (MuSKAb) varies
widely among countries and ethnic groups, ranging from 0% in
Norway1 to 48% in Italy2 among Caucasians, and between 2.5%
and 33% in different Asian countries.38 Patients with MuSKAb-positive MG (MuSKAb-MG) form a subgroup of MG patients with distinct phenotypes and they are reportedly often relatively resistant
to treatment. The value of thymectomy is difcult to quantify as
studies are largely retrospective or confounded by the concomitant
administration of immunosuppressive drugs.912 We report here
the rst study of the prevalence, clinical features and treatment
outcomes of patients with MuSKAb-MG in Thailand.
2. Methods
This study was approved by the ethics committee of the Faculty
of Medicine, Ramathibodi Hospital. We studied patients with MG
Corresponding author. Tel.: +66 2 2011386; fax: +66 2 3547233.
E-mail addresses:
(R. Witoonpanich).

rarwt@mahidol.ac.th,

rawiphan.wit@mahidol.ac.th

0967-5868/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jocn.2012.03.047

who attended Ramathibodi Hospital between May 2005 and

January 2009. The diagnosis of MG was based on the common clinical features of this condition, including drooping of eyelids, double
vision and difculty in swallowing, and proximal limb weakness,
with episodes of respiratory failure in some. The clinical diagnosis
of MG was further supported by the results of electrophysiological
tests including repetitive nerve stimulation (RNS) and/or single-ber electromyography (SFEMG). RNS at 3 Hz was performed on the
limb and facial muscles as described elsewhere.13 SFEMG was performed on either the extensor digitorum communis (EDC) or orbicularis oculi as previously described.13 Single stimulation on a nerve
pre- and post-10-s exercises to look for an incremental response
(increased amplitude of the compound muscle action potential
[CMAP]) of the supplied muscle was routinely performed to exclude presynaptic neuromuscular junction disorders. No patient
had clinical features or repetitive CMAP to suggest congenital
myasthenic syndrome. We were able to exclude slow-channel congenital myasthenic syndrome for all our patients in view of the absence of repetitive CMAP. DNA analysis for oculopharyngeal
muscular dystrophy was performed in ocular cases whose diagnosis was considered uncertain. All patients had a blood sample taken
for the IBL AChRAb assay (the radioreceptor assay; Immuno Biological Laboratories [IBL] Minneapolis, MN, USA). Antibody titers of
>0.40 nmol/L were considered positive and those of 60.40 nmol/L

708

R. Witoonpanich et al. / Journal of Clinical Neuroscience 20 (2013) 707709

3. Results

these two abnormalities. The two patients with negative results

had denite clinical diagnoses of generalized MG. The ve patients
who did not have these tests performed also had denite generalized MG on clinical grounds and two of them were in myasthenic
crisis on at least one occasion each.

3.1. Patients

3.2. Treatment

Eight of the 49 patients with AChRAb seronegative generalized

MG (16.3%) were positive for MuSKAb, consisting of six women
and two men with the age at presentation ranging from 27 years
to 51 years. The ethnicity of these eight patients included Thai, Chinese and mixed Thai Chinese. These eight patients are designated
here as P.1 to P.8.
The most common features were related to facial and bulbar
muscles, with marked difculty in swallowing in seven of eight patients (Table 1). The difculty in swallowing was often preceded by
either drooping of the eyelids or double vision or both. Hoarseness
of voice was a complaint in two patients. Tongue atrophy was not
present. Respiratory failure occurred in three patients (P.5, P.7 and
P.8), one of whom (P.8) suffered from recurrent respiratory insufciency with only mild weakness of the limbs. Among the eight patients with MuSKAb-MG, ve (62%) had positive RNS, seven (87%)
had positive SFEMG and seven (87%) had at least one of these two
abnormalities.
Electrophysiological studies were performed in 36 out of 41
patients with AChRAb-negative, MuSKAb-negative generalized
MG. Among these 36 patients, 14 (39%) had a positive RNS test,
34 (94%) had a positive SFEMG and 34 (94%) had at least one of

Two patients (P.2 and P.4) did not respond to pyridostigmine.

Every patient received prednisolone with reasonably good responses, but azathioprine was also given to three patients (P.5,
P.6 and P.8). Seven of eight patients underwent transsternal thymectomy. Pathologically, the thymus glands of all seven patients
showed some lymphoid inltration but no lymphoid follicles with
germinal centers in ve patients and involution in two patients
(P.5 and P.6).

were considered negative. Sera of 49 patients with generalized MG

seronegative for AChRAb were sent to Oxford for MuSKAb assay by
radioimmunoprecipitation as described elsewhere.7,8

Table 1
Clinical features, treatment and outcomes of eight patients with myasthenia gravis
positive for antibodies to musclespecic kinase in Thailand
Patient number

Total

P.1 P.2 P.3 P.4 P.5 P.6 P.7 P.8

Age (years)
Sex
Age at onset (years)
Symptoms
Drooping of eyelids
Double vision
Difculty in swallowing
Difculty in chewing
Choking
Difculty in speaking
Unclear speech
Hoarseness of voice
Weakness of arms and legs
Shortness of breath at times
Signs
Nasal voice
Ptosis
Ophthalmoparesis
Weakness of orbicularis oculi
Weakness of orbicularis oris
Tongue atrophy
Weakness of neck exor
Weakness of proximal muscles
Respiratory failure
Treatment
Acetylcholinesterase inhibitor
Immunosuppressive drugs
Intravenous immunoglobulin
TX
Outcome
Time from TX, months
Complete stable remission
Pharmacological remission
Improved

28
F
26

+
+
+
+

28
M
27

41
F
39

+
+
+

42
F
40

45
F
44

45
F
44

+
+

+
+
+

+
+
+
+

+
+
+

+
+
+

+
+
+
+

+
+

+
+

+
+

+
+

+
+

NR +
+
+

NR +
+
+
+
+

47

65
+

88
+

NA 58
+
+

52
M
50

+
+

+
+
+

52
F
51

+
+

+
++
+

+
+

2
4
3
6
4
0
5
6
3

+
+
+

+
+
+
+

+
+
+
+

6
8
3
7

68

40

44

+
+
+
+

+
+

+
+

4
5
7
2
4
1
3
2
5
2

+
+

4
0
4

= No, + = yes or mild degree as applicable, ++ = moderate degree, F = female,

M = male, NA = not applicable, NR = not responsive, TX = thymectomy.

3.3. Outcomes
Three patients (P.2, P.3 and P.5) who were thymectomized
achieved complete stable remission (CSR). One of these (P.2) took
6 months to taper off prednisolone after thymectomy. Another patient (P.5) was well 2.5 years after thymectomy, and prednisolone
and azathioprine were discontinued 6 months later. For the third
patient (P.3), pharmacological remission (PR) began 3 years after
thymectomy and the patient was in complete remission 4 years later. The only patient who was not thymectomized (P.4) achieved
CSR 2.5 years after starting treatment. All the four other thymectomized patients (P.1, P.6, P.7 and P.8) improved and were on
1025 mg of prednisolone on alternate days at 4068 months after
thymectomy. Two patients with respiratory failure (P.7 and P.8) no
longer suffered from respiratory insufciency after the operation.

4. Discussion
The clinical features of MuSKAb-MG are often severe with predominant facial and bulbar involvement. Treatment can be difcult
and a lack of response to thymectomy has been reported. Here we
describe the rst eight MuSKAb-MG patients identied in Thailand,
from a total of 49 AChRAb-negative generalized MG patients, representing 16.3%. The MuSKAb phenotype was similar to that previously described11,1416 but there was no muscle atrophy and all the
patients responded well to treatments.
Thymectomy appeared to be more benecial in our patients
compared with previous studies.10,17,18 Three out of seven patients
who underwent thymectomy achieved CSR. For the other four patients who improved after thymectomy, it was possible to gradually taper down the doses of immunosuppressive drugs. This
contrasts with the few previous reports of MuSKAb-MG patients
achieving complete remission after thymectomy,1719 and the fact
that unthymectomized patients seldom became symptom free on
immunosuppression alone.10,17,18 It may be argued that our single
patient who did not have a thymectomy also achieved CSR. Therefore, it may be that Thai/Chinese MuSKAb-MG patients have a generally more favorable response to treatment than those in other
published series, whether or not they had thymectomies.
On the other hand, the interval between thymectomy and CSR
did appear to be longer overall in MuSKAb-MG patients than in
those with AChRAb-MG (unpublished observations). Our patients
took 6 months, 2.5 years and 7 years to achieve CSR. All the other
four thymectomized patients improved and have been followed
up for 4068 months.
The thymic pathology in our seven patients showed either involution or some lymphoid inltration but no lymphoid follicles with
germinal centers. However, although the lack of lymphoid

R. Witoonpanich et al. / Journal of Clinical Neuroscience 20 (2013) 707709

hyperplasia may argue against the role of the thymus in antibody

production in MuSKAb-MG, we believe our data indicate the need
for closer investigation of thymic pathology and the role of thymectomy in this condition.
Conict of interests/disclosures
AV and the University of Oxford hold a patent for MuSK antibody detection and receive royalties and payments for antibody
tests.
References
1. Romi F, Aarli JA, Gilhus NE. Seronegative myasthenia gravis: disease severity
and prognosis. Eur J Neurol 2005;12:4138.
2. Padua L, Tonali P, Aprile I, et al. Seronegative myasthenia gravis: comparison of
neurophysiological picture in MuSK+ and MuSK
patients. Eur J Neurol
2006;13:2736.
3. Chang T, Gunaratne P, Gamage R, et al. MuSK-antibody-positive myasthenia
gravis in a South Asian population. J Neurol Sci 2009;284:335.
4. Huang YC, Yeh JH, Chiu HC, et al. Clinical characteristics of MuSK antibodypositive myasthenia gravis in Taiwan. J Formos Med Assoc 2008;107:5725.
5. Lee JY, Sung JJ, Cho JY, et al. MuSK antibody-positive, seronegative myasthenia
gravis in Korea. J Clin Neurosci 2006;13:3535.
6. Ohta K, Shigemoto K, Fujinami A, et al. Clinical and experimental features of
MuSK antibody positive MG in Japan. Eur J Neurol 2007;14:102934.

709

7. Yang L, Maxwell S, Leite MI, et al. Non-radioactive serological diagnosis of

myasthenia gravis and clinical features of patients from Tianjin, China. J Neurol
Sci 2011;301:716.
8. Zhang X, Yang M, Xu J, et al. Clinical and serological study of myasthenia gravis
in HuBei Province, China. J Neurol Neurosurg Psychiatry 2007;78:38690.
9. Deymeer F, Gungor-Tuncer O, Yilmaz V, et al. Clinical comparison of antiMuSK vs anti-AChR-positive and seronegative myasthenia gravis. Neurology
2007;68:60911.
10. Evoli A, Bianchi MR, Riso R, et al. Response to therapy in myasthenia gravis with
anti-MuSK antibodies. Ann N Y Acad Sci 2008;1132:7683.
11. Oh SJ. Muscle-specic receptor tyrosine kinase antibody positive myasthenia
gravis current status. J Clin Neurol 2009;5:5364.
12. Zhou L, McConville J, Chaudhry V, et al. Clinical comparison of muscle-specic
tyrosine kinase (MuSK) antibody-positive and -negative myasthenic patients.
Muscle Nerve 2004;30:5560.
13. Witoonpanich R, Dejthevaporn C, Sriphrapradang A, et al. Electrophysiological
and immunological study in myasthenia gravis: diagnostic sensitivity and
correlation. Clin Neurophysiol 2011;122:18737.
14. Evoli A. Clinical aspects of neuromuscular transmission disorders. Acta Neurol
Scand Suppl 2006;183:811.
15. Sanders DB, El-Salem K, Massey JM, et al. Clinical aspects of MuSK antibody
positive seronegative MG. Neurology 2003;60:197880.
16. Wolfe GI, Oh SJ. Clinical phenotype of muscle-specic tyrosine kinaseantibody-positive myasthenia gravis. Ann N Y Acad Sci 2008;1132:715.
17. Lavrnic D, Losen M, Vujic A, et al. The features of myasthenia gravis with
autoantibodies to MuSK. J Neurol Neurosurg Psychiatry 2005;76:1099102.
18. Pasnoor M, Wolfe GI, Nations S, et al. Clinical ndings in MuSK-antibody
positive myasthenia gravis: a U.S. experience. Muscle Nerve 2010;41:3704.
19. Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical
ndings and response to treatment in two large cohorts. Muscle Nerve
2011;44:3640.