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16ournal
of
Neurology,
Neurosurgery,
and
Psychiatry
1997;62:156-162
Ocular
myasthenia
gravis:
response
to
long
term
immunosuppressive
treatment
Norbert
Sommer,
Barbara
Sigg,
Arthur
Melms,
Michael
Weller,
Karsten
Schepelmann,
Volker
Herzau,
Johannes
Dichgans
Department
of
Neurology
N
Sommer
B
Sigg
A
Melms
M
Weller
K
Schepelmann
J
Dichgans
Department
of
Ophthalmology,
Eberhard-Karls-
University
Tubingen,
72076
Tubingen,
Germany
V
Herzau
Correspondence
to:
Dr
N
Sommer,
Department
of
Neurology,
Hoppe-Seyler-
Str
3,
D-72076
Tubingen,
Germany.
Received
6
March
1996
and
in
revised
form
17
September
1996
Accepted
17
September
1996
Abstract
Objective-Ocular
myasthenia
gravis
is
a
subtype
of
myasthenia
gravis
that
causes
relatively
mild
disability,
but
may
convert
into
severe
generalised
muscle
weakness.
A
universal
management
plan
for
ocular
myasthenia
gravis
has
not
been
estab-
lished.
This
study
was
performed
to
determine
the
outcome
of
ocular
myas-
thenia
gravis
with
the
currently
available
therapeutic
options.
Methods-Retrospective
analysis
of
78
patients
with
ocular
myasthenia
gravis
with
a
mean
disease
duration
of
8-3
(range
0
5-58-3)
years.
Results-In
54
patients
(69%)
symptoms
and
signs
remained
confined
to
the
extraocular
muscles
during
the
observa-
tion
period.
The
remaining
24
patients
(31%)
developed
symptoms
of
generalised
myasthenia
gravis;
50%
of
them
within
two
years,
75%
within
four
years
after
onset.
A
somewhat
reduced
risk
of
gener-
alisation
was
found
in
those
with
mild
symptoms,
normal
repetitive
nerve
stim-
ulation
test,
and
low
or
absent
antiacetyl-
choline
receptor
(AChR)
antibodies
at
the
time
of
diagnosis.
Patients
receiving
immunosuppressive
treatment
(corticos-
teroids
and/or
azathioprine)
rarely
devel-
oped
generalised
myasthenia
gravis
(six
of
50,
12%).
Those
without
such
treat-
ment,
usually
due
to
uncertain
diagnosis
and
late
referral,
converted
into
gener-
alised
myasthenia
gravis
significantly
more
often
(18
of
28,
64%).
Conclusions-The
prognosis
of
ocular
myasthenia
gravis
is
good.
A
conventional
scheme
with
short
term
corticosteroids
and
long
term
azathioprine
seems
ade-
quate
to
achieve
remission
in
most
patients.
The
proportion
of
patients
developing
generalised
myasthenia
gravis
was
smaller
in
this
population
compared
with
previously
published
groups
(usually
500/or70%).
Early
immunosuppressive
treatment
is
at
least
partially
responsible
for
this
finding.
Thymectomy
(performed
here
in
12
patients
with
an
abnormal
chest
CT)
also
correlated
with
a
good
out-
come,
but
had
no
apparent
advantage
over
medical
treatment
alone.
(7
Neurol
Neurosurg
Psychiatry
1997;62:156-162)
Keywords:
myasthenia
gravis,
extraocular
muscle
weakness,
immunosuppressive
treatment
Myasthenia
gravis
is
caused
by
autoantibodies
against
the
acetylcholine
receptor
(AChR)
at
the
neuromuscular
junction
leading
to
exer-
tional
weakness
of
striated
muscle.
1
2
3
Its
prevalence
rate
has
been
estimated
to
be
up
to
10
per
100
000
in
recent
epidemiological
sur-
veys,
and
people
of
any
race
at
any
age
may
be
affected.45
Due
to
the
currently
available
treat-
ment
options
the
prognosis
of
myasthenia
gravis
has
greatly
improved
during
the
past
20
years.
Anticholinesterase
drugs
have
been
used
since
the
1930s
and
in
the
1960s
corticos-
teroids
and
other
immunosuppressive
drugs
started
to
be
used.3
67
Furthermore,
the
intro-
duction
of
plasmapheresis,
early
thymectomy,
and
improved
intensive
care
facilities
has
reduced
the
mortality
of
myasthenia
gravis
essentially
close
to
zero
since
the
mid-1970s."'
Myasthenia
gravis
is
one
of
the
best
studied
autoimmune
diseases
and
the
remarkable
progress
in
understanding
the
underlying
aeti-
ology
and
pathogenetic
heterogeneity
has
helped
to
improve
patient
management.
According
to
age
of
onset,
thymic
abnormali-
ties,
and
other
immune
variables
patients
with
generalised
myasthenia
gravis
can
be
divided
into
three
main
groups:
(a)
"young
onset"
patients
(<
45
years,
mainly
female),
who
reg-
ularly
have
thymic
hyperplasia;
(b)
"old
onset"
patients
(>
45
years,
slightly
more
men),
who
normally
have
thymic
atrophy;
and
(c)
the
group
of
thymoma
patients
who
have
no
clear
age
and
sex
bias.'
9
As
not
all
patients
with
ocular
muscle
weakness
fit
into
one
of
these
categories,
there
is
often
uncertainty
about
the
treatment
options
which
are
best
in
ocular
myasthenia
gravis.
Particularly,
there
is
no
clearcut
guideline
as
to
the
need
for
thymec-
tomy,
mostly
performed
in
groups
(a)
and
(c),
or
long
term
immunosuppression,
which
may
be
beneficial
for
all
three
patient
groups
with
generalised
disease.
Apart
from
symptomatic
treatment
with
anticholinesterase
drugs,
corticosteroids
are
regularly
considered
in
all
forms
of
myasthenia
gravis,
with
good
results
in
most
patients.
10'2
The
indications
for
immunosuppressive
drugs,
such
as
azathioprine,
cyclophosphamide,
or
cyclosporine
are
less
clear.
Although
these
drugs
have
clearly
been
shown
to
be
beneficial
in
generalised
myasthenia
gravis,613'415
some
neurologists
prefer
to
limit
their
application
to
the
more
severely
affected
patients.'6
Also,
scepticism
about
the
drug
treatment
is
fos-
tered
by
the
fact
that
very
few
prospective
dou-
ble
blind
trials
have
been
performed
for
any
compound.
1'-15
Thymectomy
is
the
generally
accepted
treatment
for
patients
with
thymoma
156
group.bmj.com on July 16, 2011 - Published by jnnp.bmj.comDownloaded from
Ocular
myasthenia
gravis:
response
to
long
term
immunosuppressive
treatment
and
in
young
onset
patients.
This
is
based
on
immunological
evidence
that
thymic
changes
play
a
central
part
in
the
pathogenesis
of
myas-
thenia
gravis,
at
least
in
these
two
patient
groups.'7-19
Uncertainty,
however,
exists
as
to
the
value
of
thymectomy
in
older
patients
with
thymic
atrophy,
patients
with
generalised
myasthenia
gravis
that
are
negative
for
serum
AchR
antibodies,
and
also
in
purely
ocular
2
20
21
myasthenia
gravis.
In
this
study,
we
have
reviewed
patients
with
purely
ocular
muscle
weakness.
Patients
and
methods
All
patients
included
in
this
study
were
exam-
ined
in
our
myasthenia
clinic
between
January
1989
and
April
1993
at
least
twice
a
year
by
one
of
us
(NS
or
AM).
In
patients
with
a
longer
history
previous
hospital
charts
were
reviewed.
In
a
few
patients
additional
follow
up
data
were
collected
from
referring
neurolo-
gists.
The
diagnosis
of
ocular
myasthenia
gravis
was
based
on
conventional
clinical
and
labora-
tory
criteria.
1
2
7
If
AChR
antibodies
and
repet-
itive
nerve
stimulation
were
both
negative,
then
clinical
signs,
edrophonium
chloride
(Tensilon)
testing,
and
treatment
response,
as
well
as
other
diagnostic
measures
(normal
CT
or
MRI
and
CSF
investigation)
were
re-evalu-
ated
carefully
to
exclude
other
causes
of
eye
muscle
weakness
(see
also
comment
on
differ-
ential
diagnosis
below).
Because
of
its
low
specificity,
a
positive
edrophonium
chloride
test
was
never
used
as
a
single
diagnostic
crite-
rion.22-25
Patients
were
only
included
if
symptoms
and
signs
were
restricted
to
the
extraocular
muscles
for
at
least
three
months
after
onset.
This
arbitrary
limit
seemed
reasonable,
because
early
disease
stages
(often
before
referral)
were
usually
not
well
documented.
Also,
we
thought
that
the
development
of
gen-
eralised
myasthenia
gravis
after
a
few
days
or
weeks
of
exclusive
weakness
of
extraocular
muscles
would
not
qualify
for
a
diagnosis
of
ocular
myasthenia
gravis
as
a
separate
entity.
In
this
respect
we
follow
the
criteria
of
Oosterhuis.'6
Also,
subtle
signs
of
generalised
weakness,
particularly
facial
weakness,
were
sought
for
and,
if
present,
those
patients
were
not
included.
Grading
of
severity
of
disease
was
semiquantive.
"Mild",
"moderate",
or
"severe"
ocular
myasthenia
gravis
stands
for
mild,
moderate,
or
severe
disability
in
every-
day
life,
with
particular
respect
to
impairment
at
work
and
car
driving.
This
seemed
more
appropriate
as
the
clinically
more
relevant
sub-
jective
impairment
does
not
necessarily
corre-
late
with
the
actual
degree
of
extraocular
muscle
weakness.
Improvement
was
docu-
mented
when
ocular
myasthenia
gravis
was
ameliorated
by
at
least
one
such
grade.
Remission
was
stated
when
there
was
no
remaining
disability
with
or
without
drug
treatment.
Repetitive
nerve
stimulation
was
performed
according
to
Schumm
and
St6hr27
with
minor
modifications.The
accessory
nerve
was
stimu-
lated
behind
the
sternocleidomastoid
muscle
with
supramaximal
intensity
at
3
Hz
with
a
bipolar
surface
electrode
and
recorded
from
the
trapezius
muscle.
A
decrement
of
greater
than
10%
between
the
first
and
fifth
potential
was
considered
pathological.
Antibodies
to
AChRs
were
measured
by
radioimmunoassay
according
to
Vincent
and
Newsom-Davis.'8
Human
amputated
leg
mus-
cle
was
used
as
a
source
of
antigen,
incubated
with
12'I-a-bungarotoxin
(Amersham-Buchler,
Brunswick,
Germany)
and
subsequently
with
different
dilutions
of
the
patients'
serum.
After
thorough
washing
the
bound
radioactivity
was
measured
on
a
1counter.
Known
negative,
positive,
and
equivocal
serum
samples
were
run
in
each
assay.
Values
greater
than
05
nmol
a-bungarotoxin
binding
sites/l
were
considered
positive,
between
0-2
and
0
5
nmol/l
equivocal,
and
less
than
0-2
nmol/l
negative.
To
avoid
variations
between
assays,
follow
up
investigations
always
included
retesting
of
the
previous
one
or
two
serum
samples
of
a
patient
together
with
the
new
serum.
Results
PATIENTS
We
had
clinical
data
from
178
patients
with
myasthenia
gravis;
78
of
them
(44%;
40
female,
38
male)
were
diagnosed
to
have
ocular
myasthenia
gravis
according
to
the
criteria
outlined
above.
Mean
duration
of
disease
was
8
years
4
months
(SD
9
years,
range
6
months-58
years
2
months).
Twenty
four
of
the
78
patients
with
ocular
myasthenia
gravis
(31%,
13
female,
11
male)
developed
symptoms
of
generalised
muscle
weakness
later
during
the
course
(see
below).
Age
and
sex
distribution
of
ocular,
primary,
or
secondary
generalised
patients
were
not
significantly
different
(age
at
onset
for
all
78
patients
with
ocular
myasthe-
nia
gravis:
mean
50-6
(SD
19-5)
years,
range
10-84
years;
data
not
shown).
Remarkably,
the
diagnosis
of
myasthenia
gravis
in
the
78
ocular
patients
was
made
only
39-8
(SD
93-5)
months
after
the
onset
of
symptoms.
Concomitant
autoimmune
diseases
were
diagnosed
in
39
(22%)
of
all
178
patients
with
myasthenia
gravis
reviewed
in
this
study.
Thyroid
disease
was
by
far
the
most
common
condition
(33
patients,
19%;
female:male
ratio
3-1:1).
These
proportions
were
not
signifi-
cantly
different
among
the
ocular
patients
(for
example,
total
incidence
of
thyroid
disease
19
of
78,
24%).
Family
history
disclosed
that
six
of
the
178
patients
(3%)
had
a
first
or
second
degree
rela-
tive
with
myasthenia
gravis.
Two
pairs
of
siblings
(including
one
pair
of
monozygotic
twins)
had
generalised
myasthenia
gravis;
another
two
in
the
ocular
group
had
relatives
with
generalised
myasthenia
gravis
who
were
not
part
of
our
sample.
DIFFERENTIAL
DIAGNOSIS
OF
SERONEGATIVE
OCULAR
MYASTHENIA
GRAVIS
In
three
female
patients
(ages
45,
57,
and
74
years)
referred
to
us
with
suspected
seronega-
157
group.bmj.com on July 16, 2011 - Published by jnnp.bmj.comDownloaded from
Sommer,
Sigg,
Melms,
Weller,
Schepelmann,
Herzau,
Dichgans
tive
ocular
myasthenia
gravis,
this
diagnosis
had
to
be
revised
during
the
course.
All
three
had
double
vision
and
unilateral
ptosis
with
mild
daily
fluctuations
and
the
diagnosis
had
mainly
been
based
on
a
positive
edrophonium
chloride
test.
AChR-antibodies
and
electro-
physiology
were
normal.
One
of
the
patients
had
been
thymectomised
and
thymic
rem-
nants
without
germinal
centres
were
found.
When
re-evaluating
the
diagnosis,
we
found
unilateral
contrast
enhancing
lesions
on
CT
and
MRI
in
the
region
of
the
cavernous
sinus
in
all
three.
These
patients
are
not
included
in
the
present
evaluation,
but
deserve
mention,
because
their
history
reflects
well
the
diagnostic
problems
encountered
in
ocular
myasthenia
gravis.
The
MRI
of
one
of
the
patients
has
been
published
previously.7
PROGNOSTIC
FACTORS
Using
secondary
generalisation
as
an
end
point,
no
significant
prognostic
factor
could
be
determined.
Nevertheless,
mild
symptoms
at
onset,
normal
results
at
repetitive
nerve
stimu-
lation,
and
negative
serum
AchR
antibody
testing
were
found
more
often
in
patients
whose
myasthenia
remained
limited
to
extraocular
muscles
(fig
lA-C).
Patients
with
mild
ocular
symptoms
developed
generalised
myasthenia
gravis
in
14%
(three
of
22).
In
moderate
and
severe
ocular
myasthenia
gravis
Figure
1
Evaluation
of
prognostic
factors
in
ocular
myasthenia
gravis.
Patients
with
mild
symptoms
(A)
or
normal
repetitive
accessory
nerve
stimulation
(B)
have
a
somewhat
lower
risk
of
developing
generalised
myasthenia
(NS).
Detectable
AchR
antibodies
were
significantly
more
frequent
in
the
group
with
secondary
generalisation.
The
numbers
included
in
the
bars
indicate
the
proportion
of
patients
with
immunosuppressive
drug
treatment
(for
example,
15119:
among
19
patients
in
this
group,
15
received
corticosteroids
andlor
azathioprine).
Note
that
in
B
and
C
the
total
n
=
66,
because
data
were
not
available
in
12
patients
before
generalisation.
m
Remaining
ocular
E
Generalised
U)
a)
0
0
z
40
30
20
10
0
50
X)
40
a)
*;
30
0.
'o
20
0
Z
l
A:
Clinical
severity
these
proportions
were
36%
(15
of
42)
and
43%
(six
of
14)
respectively
(X2
=
4.47,
NS;
fig
1A).
Patients
with
a
pathological
decrement
in
repetitive
accessory
nerve
stimulation
con-
verted
to
generalised
myasthenia
gravis
in
32%
(six
of
19),
but
only
15%
(seven
of
47) did
so
with
an
initially
normal
electrophysiological
result
(x2
=
2-38,
NS;
fig
iB).
Among
the
seronegative
patients
one
of
23
(4%)
developed
generalised
myasthenia
gravis.
This
proportion
was
significantly
higher
in
the
seropositive
group
(11
of
43,
26%;
X2
=
4
54,
P
<
005;
fig
1C).
Also,
in
patients
with
sec-
ondary
generalisation
the
mean
antibody
titre
was
significantly
higher
at
the
first
diagnostic
testing
(mean
11
9
(SD
14-4),
range
0-
47-5
nmol/l)
than
in
the
permanently
ocular
patients
(mean
4
1
(SD
6-0),
range
0-
25
9
nmol/l;
t
=
3-02,
P
<
0-01;
not
shown).
As
expected,
the
maximum
levels
during
the
whole
observation
period
were
tenfold
higher
in
the
patients
with
generalisation
(61-6
(SD
116-7)
nmol/l)
compared
with
those
who
remained
ocular
(6-3
(SD
13-7)
nmol/l).
Tensilon
testing
was
positive
in
97%
of
the
patients
with
ocular
myasthenia
gravis,
but
was
never
used
as
a
single
diagnostic
criterion
(see
above).
Data
on
HIA
were
available
in
21
out
of
the
78
of
the
ocular
patients
and
there
was
detectable
trend
towards
a
specific
association;
further
investigation
was
not
performed.
COURSE
AND
TREATMENT
OF
OCULAR
MYASTHENIA
GRAVIS
Outcome
Twenty
four
of
the
78
patients
with
ocular
myasthenia
gravis
(31%)
developed
secondarily
generalised
muscle
weakness.
The
median
onset
of
generalisation
was
24-5
months
(range
3-132)
after
the
first
ocular
symptoms
(fig
2).
Among
the
54
permanently
ocular
patients
29
(54%)
had
reached
remission
by
18j
15
12
U)
9
a)
6
0._
4-
3
0
0
z
c
A
I1
6
4
2-
Seronegative
Seropositive
B
D
12
24
36
48
60
72
84
96
108 120
132
Time
(months)
Figure
2
Cumulative
incidence
of
generalised
symptoms
in
patients
with
initially
purely
ocular
myasthenia
gravis.
A
shows
the
patients
without,
B
with
immunosuppressive
drug
treatment.
The
median
time
to
generalisation
was
16
months
in
A
and
33
months
in
B.
The
risk
of
converting
to
generalised
symptoms
is
greatest
during
the
first
years,
but
is
still
present
after
many
years.
U1)
4)
CL
0.,
0
0
z
158
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Ocular
myasthenia
gravis:
response
to
long
term
immunosuppressive
treatment
the
end
of
the
observation
period.
All
others
improved
(n
=
18)
or
remained
the
same
(n=
7);
none
of
the
permanently
ocular
patients
worsened.
Although
patients
after
generalisation
were
not
analysed
in
detail
in
this
study,
it
is
worthwhile
mentioning
that
11
of
the
24
(46%)
had
also
reached
remission
by
the
end
of
the
observation
time.
Symptomatic
treatment
Sixty
of
the
78
patients
received
pyridostig-
mine
at
some
time
during
their
follow
up.
The
maximum
individual
daily
dose
was
149-8
(SD
74
2)
mg.
The
duration
of
pyridostigmine
treatment
was
on
average
45-6
(SD
39
9)
months.
Fourteen
patients
were
treated
with
pyridostigmine
alone
for
some
time.
Of
those,
seven
(50%)
reported
considerable
improve-
ment,
six
(43%)
mild
improvement,
and
in
one
patient
no
effect
was
reported.
Immunosuppressive
drug
treatment
Forty
five
patients
received
prednisolone
and
27
azathioprine.
Figure
3
gives
an
overview
of
the various
combinations
of
immunosuppres-
sion
and
thymectomy.
Prednisolone
was
given
for
an
average
of
32-3
(SD
32.3)
months,
with
a
maximum
individual
daily
dose
of
51-9
(SD
26-1)
mg.
(In
those
patients
who
always
received
alternate
day
regimens
50%
of
their
maximum
dose
was
used
for
the
calculation.)
The
mean
duration
of
treatment
with
azathio-
prine
was
43-7
(SD
35.2)
months
with
a
mean
maximum
dose
of
145-3
(SD
25-0)
mg.
Among
the
patients
who
were
treated
with
prednisolone
but
without
azathioprine,
a
clear
positive
effect
was
found
in
19
of
22
(86%).
Among
the
four
patients
treated
with
azathio-
prine
alone,
we
found
an
unequivocally
posi-
tive
effect
in
three
of
them.
A
combination
of
both
drugs
was
used
in
23
and
was
beneficial
in
21
(91%).
Figure
3
Frequency
of
the
different
immunosuppressive
therapies.
Total
number
of
patients
=
78.
The
numbers
in
parentheses
(total
=
24)
give
the
numbers
of
those
who
developed
generalised
myasthenia
gravis.
Note
the
low
proportion
of
patients
with
secondary
generalisation
with
any
immunosuppressive
treatment.
Thymectomy
Thymectomy
was
performed
in
12
patients
with
purely
ocular
symptoms,
because
of
an
abnormal
chest
CT
(fig
3).
Probably
due
to
the
late
diagnosis
(see
above)
the
procedure
was
performed
on
average
50
(range
2-253)
months
after
onset
of
symptoms.
Histology
was
available
in
11
and
disclosed
thymoma
in
four
(three
non-invasive,
one
invasive),
lym-
phofollicular
hyperplasia
in
two,
thymic
rem-
nants
in
two,
and
thymic
involution
in
three
patients.
Thymectomised
patients
were
fol-
lowed
up
for
an
average
of
81
(range
18-190)
months
after
the
operation,
and
all
but
one
were
treated
with
additional
immunosuppres-
sants
(fig
3).
Six
patients
reached
remission
during
follow
up;
in
another
four
ocular
weak-
ness
improved.
The
remaining
two
patients
(both
with
thymoma,
one
non-invasive,
the
other
invasive)
developed
generalised
myas-
thenia
after
six
or
125
months
respectively.
SIDE
EFFECTS
No
lasting
sequelae
of
thymectomy
were
reported.
Pyridostigmine
was
associated
with
side
effects
in
two
patients.
In
one
a
systemic
allergic
reaction
(generalised
exanthema
two
days
after
starting
the
drug)
was
reported,
in
another
patient
bradycardia
was
ascribed
to
drug
overdose.
Corticosteroids
led
to
moder-
ate
side
effects
in
12
patients
(cushingoid
in
five,
restlessness
and
sleeplessness
in
five,
severe
acne
vulgaris
in
one,
and
gastric
upset
in
one),
and
severe
side
effects
in
two
patients
(one
each
with
decompensation
of
diabetes
mellitus
or
psychosis).
Moderate
side
effects
of
azathioprine
occurred
in
six
patients
(leucope-
nia
between
2000
and
4000/Ml
in
two
patients,
hair
loss
in
two,
nausea
in
one,
and
skin
and
nail
changes
in
one).
Severe leucopenia
(<
2000/,l)
occurred
in
one
patient.
In
another
two
(not
considered
in
fig
3)
azathio-
prine
had
to
be
stopped
within
the
first
months
due
to
gastrointestinal
upset.
No
severe
infections
were
found
under
immuno-
suppressive
treatment
in
this
patient
group.
Discussion
Ocular
myasthenia
gravis
had
a
good
progno-
sis
in
most
patients
in
this
study.
In
69%
the
disease
remained
confined
to
the
extraocular
muscles.
Of
these,
54%
were
in
remission,
33%
improved,
and
13%
patients
were
unchanged
at
the
end
of
the
study.
The
most
remarkable
difference
from
previous
studies
is
the
relatively
low
fraction
of
patients
convert-
ing
to
generalised
myasthenia
gravis,
which
was
31%
in
our
population,
but
49-69%
in
other
previous
reports.
The
development
of
generalised
symptoms
was
used
as
a
major
end
point
by
us
and
others,
because
it
indicates
major
progression
of
disease
and
management
has
to
be
re-evaluated.
In
the
study
published
in
1983
by
Bever
et
al29
53
of
108
patients
(diagnosed
1957-69
in
New
York
City)-that
is,
49%-later
gener-
alised.
Grob
reported
in
his
large
collective30
that
about
40%,
and
in
a
later
survey3l
34%
of
202,
of
his
patients
with
initial
ocular
myasthe-
159
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Sommer,
Sigg,
Melms,
Weller,
Schepelmnann,
Herzau,
Dichgans
nia
gravis
would
remain
ocular.
The
authors
of
those
studies
do
not
report
details
on
possible
immunosuppressive
treatments
applied
to
patients
with
ocular
myasthenia
gravis.
As
both
series
started
decades
ago
it
might
safely
be
assumed
that
only
a
small
proportion
of
patients
had
corticosteroids
and
even
fewer
had
azathioprine.
Oosterhuis
reviewed
an
even
earlier
series
of
patients
who
were
first
documented
between
1926
and
1965
in
Amsterdam
and
had
to
be
managed
without
steroid
or
other
immuno-
suppressive
treatment.26
In
this
group
24
of
35
(69%)
developed
generalised
myasthenia
gravis,
probably
most
realistically
reflecting
the
natural
course
of
the
disease.
Although
patient
groups
in
the
various
studies
may
not
be
comparable
with
each
other,
it
is
evident
that
there
is
a
gradual
evolution
towards
a
lower
proportion
with
secondary
generalisa-
tion.
Common
to
all
studies,
including
ours,
is
the
finding
that
the
risk
of
generalisation
is
greatest
soon
after
onset,
gradually
declining
with
time.
Of
the
patients
developing
gener-
alised
myasthenia
gravis
50%
did
so
by
two
years
after
onset
in
our
study,
88%
in
Oosterhuis'
group,26
83%
in
the
study
of
Bever
et
al.29
The
proportion
of
64%
seropositive
patients
in
our
group
was
comparable
with
most
of
the
previously
published
results
(45%-71%).28
32
30
Whereas
diagnosis
of
ocular
myasthenia
gravis
is
straightforward
in
a
patient
with
a
compatible
history
and
detectable
serum
AchR
antibodies,
diagnostic
problems
arise
in
the
seronegative
patients.
Suspicion
should
be
aroused
espe-
cially
if
extraocular
muscle
weakness
is
unilat-
eral
and
follows
a
neurogenic
pattern.
The
briefly
summarised
history
of
three
patients
with
fluctuating
extraocular
muscle
weakness
and
a
positive
edrophonium
chloride
test
(see
above)
adds
to
other
reports
of
patients
with
a
missed
tumour
of
the
skull
base.
The
largest
such
series,
consisting
of
eight
patients
with
extraocular
muscle
weakness,
positive
response
to
anticholinesterase
treatment,
and
intracranial
mass
lesions
was
reported
by
Moorthy
et
al.2
'3
Thus
seronegative
ocular
myasthenia
gravis
must,
in
our
opinion,
remain
a
mainly
clinical
diagnosis
after
a
careful
diagnostic
work
up
including
skull
imaging.
The
lack
of
specificity
of
the
edro-
phonium
chloride
test
has
been
discussed
repeatedly,7
222425
and
we
cannot
but
repeat
the
warning
not
to
interpret
response
to
anti-
cholinesterase
drugs
as a
certain
diagnostic
sign
for
ocular
myasthenia
gravis.
The
good
outcome
in
patients
with
ocular
myasthenia
gravis
in
this
study
undoubtedly
reflects
the
overall
improvements
in
the
treat-
ment
of
autoimmune
diseases.
However,
the
beneficial
effects
of
the
different
treatments
are
difficult
to
distinguish.
Steroids
and
aza-
thioprine
clearly
improve
symptoms
and
signs
in
all
forms
of
autoimmune
myasthenia
gravis12
and
it
would
therefore
seem
natural
to
give
both
drugs,
steroids
for
short
or
medium
term
treatment
and
azathioprine
for
long
term
immunosuppression.
Nevertheless,
detailed
reports
on
therapeutic
experiences
in
ocular
myasthenia
gravis
as
a
separate
entity
are
rare.
Whereas
steroids
are
probably
widely
applied
in
ocular
myasthenia
gravis,
the
use
of
other
immunosuppressants
has
hardly
been
dis-
cussed.
Evoli
et
al
report
a
series
of
48
patients
with
ocular
myasthenia
gravis.37
They
state
that
corticosteroids
are
effective
in
most
cases,
but
may
cause
problems
when
being
tapered
off.
Azathioprine
was
not
considered
in
those
patients
followed
up
between
1968
and
1986.17
Considering
the
beneficial
effect
of
azathioprine
alone
or
in
combination
with
prednisolone
in
our
patients,
we
would
pro-
pose
that
azathioprine
is
a
valuable
immuno-
suppressant
in
ocular
myasthenia
gravis.
The
steroid
sparing
effect
of
the
drug
is
generally
accepted,2
and
side
effects
are
usually
tolera-
ble.
Haematological
(in
11%)
and
other
side
effects
were
rare
compared
with
other
studies.
Hohlfeld
et
al38
reported
haematological
side
effects
in
18%,
Kissel
et
al39
in
22%,
and
Witte
et
al
10
in
17%
of
their
patients.
However,
all
these
studies
were
performed
in
generalised
myasthenia
gravis,
and
often
side
effects
were
considered
to
be
dose
related
in
patients
requiring
relatively
high
dosage
for
stabilisa-
tion
of
symptoms
(up
to
6
6
mg/kg
in
the
study
of
Hohlfeld
et
al,38
and
up
to
3
4
mg/kg
in
that
of
Witte
et
al
-10).
In
our
clinic
patients
with
generalised
myasthenia
gravis
are
treated
with
2-2-5
mg/kg
azathioprine
with
an
increase
in
dose
(usually
not
above
3
0
mg/kg),
if
the
treatment
result
is
not
satisfactory.
In
patients
with
ocular
myasthenia
gravis,
how-
ever,
we
find
that
in
most
patients
2
0
mg/kg
is
sufficient
to
lead
to
improvement
(results
not
shown
in
detail).
Thymectomy
is
now
a
standard
treatment
for
patients
with
myasthenia
gravis
with
sus-
pected
thymoma
and
in
young
onset
patients
in
whom
thymic
hyperplasia
with
germinal
centres
can
be
expected.1
2
However,
in
most
neurologists'
opinions
thymectomy
is
not
a
standard
treatment
for
ocular
myasthenia."l
In
our
series
thymectomy
was
only
performed
when
chest
CT
indicated
thymoma.
Thymoma
was
found
in
four
of
12
patients,
and
two
of
those
developed
generalised
myas-
thenia
gravis,
whereas
all
patients
without
thy-
moma
remained
ocular.
Remarkably,
in
two
young
onset
patients
(onset
<
45
years)
with
short
duration
of
disease
there
was
histological
evidence
for
lymphofollicular
hyperplasia,
whereas
in
two
other
young
onset
patients
with
much
longer
duration
of
disease,
similar
to
those
with
onset
over
45
no
hyperplasia
was
found.
This
supports
the
hypothesis
that
at
least
a
proportion
of
ocular
patients
with
myasthenia
gravis
have
thymic
changes
similar
to
generalised
young
onset
patients,
and
thus
a
similar
pathogenesis
may
be
assumed.
How-
ever,
evaluation
of
the
retrospective
data
is
dif-
ficult,
because
all
except
one
patient
required
immunosuppressive
drug
treatment.
In
1985
Schumm
et
al
reported
a
series
of
18
mainly
young
patients
with
ocular
myasthenia
gravis
who
seemed
to
benefit
from
thymectomy
and
13
of
whom
showed
thymic
hyperplasia.2'
Although
immunosuppressants
were
used
in
parallel
and
clear
criteria
for
an
expected
ther-
160
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Ocular
myasthenia
gravis:
response
to
long
term
immunosuppressive
treatment
apeutic
effect
could
not
be
identified,
the
authors
concluded
that
thymectomy
should
be
considered
in
ocular
myasthenia
gravis.
What
general
treatment
plan
should
be
fol-
lowed
in
ocular
myasthenia
gravis?
Ocular
myasthenia
gravis
is
treated
as
an
entity
for
practical
reasons
in
this
study.
However,
there
is
ample
evidence
that
in
most
patients
it
is
probably
simply
a
mild
form
of
myasthenia
gravis,
without
fundamental
pathogenetic
dif-
ference
to
the
three
forms
of
generalised
myas-
thenia
gravis
outlined
above.
All
clinical
findings,
such
as
thymic
changes,
associated
autoimmune
disease,
and
occasional
familial
occurrence
(see
results)
can
also
be
made
in
ocular
myasthenia
gravis
with
roughly
similar
frequency
as
in
generalised
myasthenia
gravis.4243
Therefore,
treatment
of
ocular
myasthenia
gravis
should
follow
the
general
principles
of
myasthenia
gravis
therapy.
The
use
of
pyridostigmine
and
corticos-
teroids
is
generally
accepted
in
ocular
myas-
thenia
gravis.
Practically,
we
start
with
20-
30
mg
pyridostigmine
three
to
four
times
daily,
gradually
increasing
the
dose
until
symptoms
disappear.
Normally,
240
mg
per
day
are
not
exceeded.
Most
patients
will
require
additional
steroids.
For
mild
symp-
toms
we
start
with
20-30
mg
prednisolone
on
alternate
days.
This
will
often
lead
to
consider-
able
improvement
after
four
to
six
weeks.
For
more
severe
ocular
symptoms
up
to
50-60
mg
prednisolone
daily
(or
an
equivalent
steroid)
are
given
for
two
to
three
months
until
improvement
is
detectable.
Dose
reduction
should
not
be
faster
than
5
mg
in
six
to
eight
weeks.
Too
fast
a
reduction
of
steroids
is
the
most
common
mistake
leading
to
a
relapse.
1
44
From
our
experience
in
ocular
myasthenia
gravis,
we
suggest
that
azathioprine
should
be
used
as
the
immunosuppressant
of
choice,
if
ocular
symptoms
do
not
remit
completely
under
steroid
treatment
or
cannot
be
con-
trolled
on
a
very
low
dose
of
steroids.
Long
term
azathioprine
treatment
seems
safe,
pro-
vided
blood
count
and
liver
enzymes
are
checked
regularly.
Thymectomy
might
be
an
additional
treatment
option,
but
cannot
clearly
be
evaluated
on
current
evidence.
A
prospec-
tive
trial
could
settle
this
issue
and
seems
most
rewarding
in
patients
with
onset
before
45
years
of
age.
If
thymectomy
is
considered
in
ocular
myasthenia
gravis,
it
should
in
any
case
be
limited
to
patients
with
detectable
AChR-
antibodies,
because
seronegative
patients
vir-
tually
never
have
thymoma
in
our
experience
and
that
of
others4546
and
do
not
normally
have
lymphofollicular
hyperplasia
like
the
seropositive
young
onset
patients.20
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doi: 10.1136/jnnp.62.2.156
1997 62: 156-162J Neurol Neurosurg Psychiatry
N Sommer, B Sigg, A Melms, et al.
long-term immunosuppressive treatment.
Ocular myasthenia gravis: response to
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