A
LIMITED EPIDEMIOLOGICAL STUDY OF SEROPOSITIVE MYASTHENIA GRAVIS IN TAYSIDE
SMJ 2002: 47(6) 132-135
Dr
Maria Elena FARRUGIA
Department
of Neurology
Ward
23A,
Ninewells
Hospital & Medical School,
Dundee
DD1 9SY.
Current
Position: Neuromuscular Research Fellow
Neurosciences
Group
Weatherall
Institute of Molecular Medicine
John
Radcliffe Hospital,
Oxford
OX3 9DS
Telephone
no: 01865 222326
Email:
maria.farrugia@imm.ox.ac.uk
Abstract:
Myasthenia
gravis is an acquired disorder of the neuromuscular junction characterised by
fatiguable weakness of the limbs, bulbar and facial muscles and may be
complicated by respiratory muscle weakness and failure.
One often confirms the diagnosis by a simple serological test looking for
the presence of the nicotinic acetylcholine receptor antibody. However,
seronegative myasthenia constitutes about 20% of cases and in the case of ocular
myasthenia, only 50% will have the antibody.
Therefore, the diagnosis can be less than straightforward especially if
the patient presents with vague symptoms such as “fatigue” or presents to
specialities other than neurology or ophthalmology. The fact that the diagnosis
may prove to be challenging, compounded by the fact that the condition is
relatively rare and that the antibody to the acetylcholine receptor is not
always present , epidemiological data is often less than precise and indeed
difficult to acquire. We
felt it was necessary to try to establish the epidemiological data on
seropositive myasthenia gravis in Tayside, (this has never been carried out)
bearing in mind the above pitfalls, and see how the incidence compares with
similar and previous studies.
Keywords:
epidemiology; seropositive myasthenia gravis; acetylcholine receptor;
seronegative myasthenia gravis; MuSK; Tensilon test; repetitive nerve
stimulation; single fibre EMG.
Introduction
The
diagnosis of Myasthenia Gravis (MG) can often be rather difficult especially
since it is a relatively uncommon disorder and also because patients may be
referred to specialities other than Neurology or Ophthalmology (in the case of
ocular myasthenia), such as gastroenterology (because of swallowing
difficulties), ENT or even psychiatry, the latter because patients are thought
to be suffering from depression, neurosis or chronic fatigue. Because it is
rare, general physicians and GPs may not see many cases throughout the course of
their career and therefore may fail to recognise the condition when faced with
such a case1.
Myasthenia
gravis is characterised by muscle weakness and fatiguability particularly of the
limb and facial muscles.
Patients may present with bulbar involvement and/or respiratory muscle
weakness, the latter may be complicated by respiratory failure requiring support
and ventilation in ITU settings.
It
is caused in most cases by antibodies to the nicotinic acetylcholine receptor, a
sodium-gated channel, sitting at the
postsynaptic membrane of the neuromuscular junction.
The condition is both B cell and T cell mediated and we continue to learn more about the role of the latter2. The association between MG and thymic pathology, namely hyperplasia and thymoma is well known. Thymectomy helps to achieve remission and in the case of thymomas, prevents spread of the tumour. The role of thymectomy in ocular myasthenia is controversial3 while there is no strong evidence to support the role of thymectomy in seronegative myasthenia. There appears to be a correlation between thymic pathology and HLA linkage particularly HLA-A3, HLA-A24 and HLA-B8; this suggests the involvement of MHC class I restricted T cells in myasthenia4.
General
epidemiology
The
annual incidence of MG is thought to be between 0.25 to 2 per 100, 000
population. It appears to have a bimodal frequency with patients being
predominantly female below the age of 40 and predominantly male above the age of
60.
50%
of patients may present with pure ocular involvement and ocular MG can be
difficult to diagnose. 50-70% may develop generalised myasthenia although
treatment with steroids or azathioprine may reduce this risk by 75%.
The predilection of myasthenia for ocular muscles may be related to
differences between limb and extraocular muscles in either physiological
function or antigenicity. The role of thymoma in ocular MG is less clear.
Further investigation with neurophysiology may not be revealing although options
other than repetitive nerve stimulation (RNS) of the ulnar or accessory nerves
ought to be considered.
Instead, one may perform RNS on the masseteric nerve or single-fibre EMG
on frontalis or orbicularis oculi
muscles5,6.
About
20% of patients will be seronegative.
Earlier this year, the combined Neuroimmunology group in Oxford and the
Max Planck Institute in Germany described that in 70% of seronegative patients,
the antibody to MuSK (Muscle specific receptor tyrosine kinase) is present
instead7. This is another protein at the neuromuscular junction,
which has close links with the nicotinic acetylcholine receptor.
It is a dynamic and versatile protein which we need to learn more about
especially since it appears to have a crucial role in the maintenance of the
architecture of the neuromuscular junction. The discovery that a number of so
called seronegative myasthenia patients may have this antibody will obviously
alter our epidemiological data in the future.
Diagnosis
of Myasthenia
The
diagnosis of myasthenia gravis is based on
(a)
the clinical presentation and findings of fatiguability in characteristic
muscle groups;
(b)
immunological confirmation of the presence of significant nicotinic
acetylcholine receptor antibody titres;
(c)
neurophysiological evidence with a decremental response on repetitive
nerve stimulation or the presence of jitter and blocking on single–fibre EMG;
(d)
Tensilon test, where the short acting acetylcholinesterase inhibitor
preparation, edrophonium bromide, is administered intravenously with objective
and subjective reversibility of fatiguability and weakness.
There
are some pitfalls, however, in relation to the above, not least due to the fact
that a percentage of myasthenia gravis patients, about 20% will be seronegative
ie will not have the antibody to the acetylcholine receptor.
Patients with ocular myasthenia may have normal neurophysiological
findings (unless one performs single-fibre EMG on the orbicularis oculi muscle);
not every neurophysiology department may perform single- fibre EMG and the
Tensilon test may be difficult to interpret objectively.
Epidemiology
in Tayside
We
recently carried out a small epidemiological study of the seropositive
myasthenia gravis (SPMG) patients in Tayside, in an attempt to establish the
incidence of SPMG in the area and to be able to see how our data compares with
other similar studies. This was a
retrospective analysis based on the Neuroimmunology database in Ninewells
Hospital, Dundee, looking specifically at the positive titres for acetylcholine
receptor antibodies, of newly diagnosed patients referred from June 1994 to May
2001 ie a period of six years.
This
obviously excludes the patients with seronegative
myasthenia because the aim of the study was to ascertain the incidence of
seropositive myasthenia. Establishing a diagnosis of seronegative myasthenia
gravis may be difficult, indeed nebulous at times. Interspersed among the
“seronegative patients” may be rare forms of congenital myasthenia, who
would not have responded to immunosuppressive treatment and whose symptoms may
not have been severe enough to warrant referral to a myasthenia specialist
centre. Extracting data purely from neurophysiological data is also erroneous.
The findings of jitter and blocking on single-fibre EMG are not specific for
myasthenia gravis and may also be found in other muscle disorders, for example
mitochondrial diseases.
From
a total of 587 patients who had the acetylcholine receptor antibody assay
requested, only 50 patients, (8.5%), were identified as having a positive titre.
Two of these 50 patients had false positive low titres for acetylcholine
receptor antibodies but did not have a clinical diagnosis consistent with MG.
4 other patients had actually been diagnosed earlier and therefore did
not form part of the incident group, which we were interested in. Their titres
had been rechecked because they had relapsed while on treatment.
Unfortunately, 2 patients (incident data) are deceased and the medical
records of one of these patients were inaccessible while we could extrapolate
some date regarding the other patient from computer-based data.
Therefore we had 44 new patients diagnosed in a six-year period. Figure 1
shows the number of new patients diagnosed per year, bearing in mind that our
data commenced from June 1994 extending up to May 2001.
Referrals
of MG patients:
The
GPs referred their myasthenia patients to the following departments, all were
subsequently referred on to the Neurologists:
19
to Ophthalmology,
23
directly to Neurology ( 4 diagnosed earlier than June 1994),
2
to Rheumatology,
1
to ENT,
1
to Endocrinology,
1
to Medicine.
Male/
Female distribution:
Out
of our incident group, 26 were male and 18 were female, with a male to female
ratio of 1.4:1. The age distribution of the male patients varied between 34
and 86y with the mean age of presentation being 62.5y. While, in the female
group, the age ranges varied between 25 and 87y and the mean age of presentation
was slightly younger than that of the males, at 58.8y. It was interesting to
study the cumulative data of male/ female patients and their age distribution
(see Figure 2). Below the age of
40, there were 4 female patients and 3 male patients.
Above the age of 60, there were 15 males and 9 females. Albeit the small
size of this study, the bimodal distribution was still shown beautifully in this
study.
Clinical
Features:
We
looked at the distribution of weakness that was their main symptom during the
course of their illness. 48 % had generalised myasthenia while 32% of the
patients had pure ocular weakness. 13 % had ocular and bulbar involvement while
7% had pure bulbar involvement. 9% of the patients required ventilatory support
at some stage of their condition because of respiratory weakness (see Figure
3).
The Osserman’s classification is rarely utilised by myasthenia specialists
nowadays and the jury is still out as to which is the most appropriate means of
classifying disease. Most centres
use the MGFA classification where I represents ocular disease; IIa, IIIa and IVa
represent mild, moderate and severe limb weakness respectively and IIb, IIIb and
IVb represent mild, moderate and severe bulbar weakness. Grade V represents
severe respiratory weakness necessitating ventilatory support in an ITU setting.
In
our epidemiological study, we did not utilise any of the classifications above.
The reason for this was that patients
were not always assessed by a
neurologist at initial presentation, which would have been the time-point of
interest, and when the patient did subsequently present to a neurologist, bulbar
weakness was not being assessed in a quantitative fashion (eg measuring the time
to drink 400ml of water etc). We would,
therefore, have classified bulbar disease in a “subjective” manner from impressions
obtained from medical notes and this would undoubtedly have been inaccurate.
We
wanted to elicit from our data, what other autoimmune diathesis our patients
had. 7 patients had thyroid
disease, one had severe dysthyroid eye disease which initially complicated
further the recognition of concomitant ocular myasthenia symptoms.
3 patients had diabetes mellitus while one patient had evidence of
impaired glucose tolerance. Two
patients had both thyroid disease and diabetes mellitus, one of these patients
presented with severe diabetic amyotrophy few months after being diagnosed
with diabetes. Two patients had Vitamin B12 deficiency (but no evidence of
pernicious anemia), two patients had SLE and two patients had rheumatoid
arthritis with penicillamine-induced myasthenia gravis. Two patients had only a
family history of pernicious anemia and SLE.
Investigations:
(a)
The Tensilon test is a simple straightforward test that is often useful
in supporting the diagnosis of MG. However,
one must be aware of the cardiac adverse effects that may occur secondary to
administering the short acting acetylcholinesterase inhibitor especially in the
older age group and in patients with a cardiac history. One must also be aware
of the risk of the patient developing significant bronchospasm on administering
the drug. It is therefore good
clinical practice to prepare and keep at hand a resuscitation trolley prior to
performing the test. In
general, however, it is felt that the test is safe to perform 8,9
though it is sometimes difficult to interpret and the results may be
subjectively felt by the patient, though not so clear objectively or may have an
apparent placebo effect which may be overinterpreted unless one is aware of the
transient clinical improvements that one should be witnessing.
In
our group of patients, 18 had the test; 10 had a positive result, two were
equivocal and 6 had a negative response.
11
out of 44 patients received either repetitive nerve stimulation or EMG to
further confirm the diagnosis. 10
had a positive result with evidence of a decremental response on repetitive
nerve stimulation or single fibre EMG showed
unstable units. One patient, whose
diagnosis of MG was clearly unequivocal, had
no evidence of a decremental response on RNS. A recent literature review10
on the usefulness of RNS and SFEMG in the electrodiagnosis of patients with MG
concludes that one should be looking for the following two criteria:
(1)
On RNS, a 10% decrement in amplitude from the first to the fourth or
fifth intravolley waveform while performing the test at low frequency
stimulation at 2 to 5 Hz.
(2)
Looking for abnormal jitter or impulse blocking on single fibre EMG,
bearing in mind that this is more sensitive albeit less specific than RNS and
merely confirms a disturbance of the neuromuscular junction.
Treatment
Treatment
of myasthenia is often commenced with acetylcholinesterase inhibitors. By
inhibiting the degradation of the acetylcholinesterase enzyme at the synaptic
cleft, more acetylcholine will be available to occupy the receptor at the
post-synaptic membrane.
This leads to muscle strengthening but the effect of the drug is
short-term and administration on a qid basis is often necessary.
Acetylcholinesterase inhibitors also will not encourage remission of
disease and therefore implementation of immunosuppression is often essential to
control symptoms. There is now evidence that combination treatment with steroids
and azathioprine is superior to that with steroids alone11.
One therefore commences prednisolone at low doses, increasing gradually
to 1mg/kg
(maximum) on an alternate day regime, the latter discouraging the development of
serious side effects particularly osteoporosis. Rapid increments of the steroid
dose may trigger increased weakness and is to be avoided unless carried out in
the hospital setting.
Azathioprine
can be commenced simultaneously at a regime of 2.5 mg/kg/day.
The effect of azathioprine takes 8 to 12 months to become apparent, which
is why the role of steroids is crucial at this stage. When azathioprine starts
to take effect, sometimes even earlier, one can initiate a slow tapering of the
steroid dose often maintaining the patient at the lowest maintenance dose
possible which controls his/her myasthenia symptoms.
Other immunosuppressive treatments may need to be considered either
because azathioprine is not well tolerated or because of side effects or simply
due to lack of effect.
Methotrexate, cyclosporin, cyclophosphamide or mycophenolate may be added
to the regime. Sometimes, supplementary treatment with plasmapheresis or
intravenous immunoglobulins is necessary.
However the former is an invasive form of treatment while the latter can
be associated with side effects particularly renal adverse events may be a
complication.
Thymectomy
is known to be effective in seropositive patients.
The perioperative complications are minimized if the procedure is
performed in a centre where referrals for thymectomy are made regularly. About
25% of thymectomised patients will go into remission post-thymectomy,
25% show moderate improvement, 25% show mild improvement and the rest may
simply show no sign of change in their clinical status post-operatively.
Treatment
in our cohort:
Figure
4 shows the percentage of patients on various treatments and includes the group
of patients being treated conservatively.
From our cohort of 42 patients, five of our patients had had a thymectomy
in the past: four females (aged 25, 28, 33 and
52) and one male patient aged 57. They all had evidence of thymic
hyperplasia on
pathological examination. Unfortunately, none of these patients went into
remission and as is evident below, all
continued to require other treatments.
Six
patients were on no treatment whatsoever. 12 were being treated with
pyridostigmine only (two of whom had received a thymectomy previously). Seven
patients were being treated with a combination of pyridostigmine and steroids
(one of whom had required plasmapheresis previously). Five patients were being
treated with pyridostigmine and azathioprine ( one patient having been
plasmapheresed in the past and one had penicillamine-induced myasthenia, the
responsible drug had been discontinued). One patient required pyridostigmine,
azathioprine and cyclophosphamide. 11 patients were being treated with
pyridostigmine, azathioprine and steroids. Of this last group, it was evident
that a number required other supplementary treatment and this was as follows:
3
had received a thymectomy in the past;
2
had previous plasma exchange;
2
had received intravenous immunoglobulins;
another
patient had a thymectomy in the past but remained weak despite immunosuppression
and required intravenous immunoglobulins to control her relapses;
the
last patient was initially treated with plasma exchange, later received a
thymectomy but remained weak again despite immunosuppression.
Comparing
the incidence of seropositive myasthenia in Tayside with other
epidemiological data.
We wanted to know how our incident data compared to epidemiological
studies elsewhere.
The population in Tayside is that of 600,000.
With 44 new cases diagnosed in a six year period, we established an
incidence for seropositive myasthenia gravis of 10.5 per million population.
This is comparable with the incidence obtained in a population-based
epidemiological study in Cambridgeshire
where the incidence was that of 11per million population12.
Figure 5 shows
how the incidences of myasthenia gravis compare in other countries with an
incidence of 5per million population in western Denmark13 (studying
data from 1975 to 1989), 7.1 per million population in Belgrade, Yugoslavia14
(data obtained over a survey period between 1983 to 1992) and 7.8 per million in
Reggio Emilia, Italy15 where they obtained data on patients between
1980 through to 1994.
Conclusion
We
wanted to know whether the data we obtained from our epidemiological study of
myasthenia gravis in Tayside was comparable to studies performed elsewhere in
the UK and globally. It is
certainly difficult to obtain data on the so called seronegative patients at
this stage but by developing an effective assay for MuSK antibody we will be in
a position to detect about 50-70% of the seronegative group. Further research
may lead towards not only understanding the role of MuSK at the neuromuscular
junction but also towards improving
our epidemiological data.
References:
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Maher J, Grand’Maison F, Nicolle MW, Strong MJ, Bolton CF. Diagnostic
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Newsom-Davis J, Vincent A, Willcox N. Mature, long-lived CD4+ and CD8+ T cells
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(3)
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ACKNOWLEDGEMENTS:
Dr
Elizabeth Spiers in Immunology Department in Ninewells Hospital & Medical
School who kindly provided the database for the acetylcholine receptor antibody
results for the period under study.