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Myasthenia Gravis Association
INFORMATION PACK
Volume 5
Medical Information
(Medical Professionals)
2nd Edition
Revised September 2011
Acknowledgements
The MGA is grateful to the authors, who write impartially, give their
services totally free and have no conflicts of interest.
We are also grateful to all the MGA members and friends who
volunteered to proof-read this Volume.
Contributors
This volume has been compiled from articles and illustrations originally
contributed by the following people and organisations
Dr D Hilton-Jones FRCP
*Prof John Newsom-Davis FRCP, FRS
Dr David Shlugman FFA
Mr John Elston FRCS, FRCOphth
Ms Claire Castling RCSLT
Ms Rebecca Leeson RCSLT
Dr Ian Spreadbury PhD
MG Foundation of America
Advisors
Prof Richard Moxon FRCP
Dr Maria Farrugia MRCP
Compiled by
Prof N Willcox
Series Editors
Mrs H Bedford and RF Haverson BSc Hons MISTC
The Association does its best to ensure that the information contained in
its series of publications is complete and up to date at the time of
publication, but cannot accept any legal liability whether for any
inaccuracy or otherwise.
* Died in 2007
ii
THE INFORMATION PACK
The Board of Trustees of the Myasthenia Gravis Association has
approved the following publications for supply, free of charge, to
anyone with one of the Myasthenias or their families, and to the
medical practitioners and professionals who look after them.
Copies may be obtained from the MGA Headquarters at the
address on the back cover. The pack comprises six volumes:
Volume 1 - A Medical Guide for Patients with MG
Medical Information on Myasthenia Gravis for patients and
families.
Volume 2 - A Medical Guide for Patients with LEMS
Medical Information on LEMS for patients and families.
Volume 3 - Myasthenia for Complete Beginners
A simple guide to the Myasthenias and their treatment.
Volume 4 - General Information for Myasthenic Patients
Information of general assistance to people with
Myasthenia, including Driving and the DVLA, the DSS,
prescription charges, insurance and other helpful
organizations and charities.
Volume 5 - Medical Information (Medical Professionals)
Information for people working in the medical and allied
professions. Details of Myasthenia Gravis, LEMS and
Congenital Myasthenias, with a greater emphasis on the
neurological effects and drug information (in lay language).
The Congenital Myasthenic Syndromes
Information for children and adults diagnosed with
Congenital Myasthenic Syndromes (CMS).
Medical Articles
Medical articles published in MGA News can be viewed
directly on the MGA website: www.mga-charity.org
iii
INFORMATION ABOUT MYASTHENIA GRAVIS
AND RELATED DISORDERS
Foreword to first edition
“The Myasthenia Gravis Association (MGA) has updated the leaflets
providing information about the different types of Myasthenia:
Myasthenia Gravis, the Lambert-Eaton Myasthenic Syndrome and the
Inherited (congenital) Myasthenias. The present Volume (5) is intended
primarily for medical and para-medical professionals at all levels; also
for any patients who want fuller information about their disorder,
perhaps to help them understand better what the doctor is trying to do
or to explain it to their families.
Although information about the Myasthenias is available on the
Internet, it is not always easy to take on board. Several of us have
contributed to this new edition, which has been compiled by Prof Nick
Willcox; we have tried to make it readable and understandable to nondoctors. But we are sure there will be room for improvement, so please
provide feedback that we can apply when we update the next edition.
For those of you who have not heard about MGA, you might like to
know that the Association was formed in 1968, became independent in
1976, and was incorporated as a company in 1995. Its aims are to
provide a care and support network for Myasthenia patients and their
families, and to promote research aimed at understanding what causes
these disorders and at developing better treatments.
The Association wants to foster close links within the patient/member
community, and also with the caring professions and the researchers.
We do that through our local Branches, through Branch and Regional
and National meetings (often with an expert speaker), through MGA
News and through our information leaflets. Our membership is now
nearly 1,500.
We hope you find the information helpful – please let MGA have your
views.”
John Newsom-Davis CBE MD FRCP FRS (1932-2007)
Late President
iv
CONTENTS
Due to the nature of this publication, many items and references are
repeated throughout. Therefore the subjects listed below give only a
general indication of where the topic may be found.
About this Volume ................................................................................. 1
1. The Myasthenias ........................................................................... 2
1.1 Introduction and revision on nerve→muscle junctions ..………..2
1.2 References ................................................................................. 2
1.3 Symptoms, patient subgroups and diagnostic tests ................... 4
1.4 Introduction to Treatment .......................................................... 5
2. What goes wrong and how is MG is treated? .............................. 6
Landmarks in research ..................................................................... 6
References ...................................................................................... 8
3. The immune system and how it goes wrong ............................. 10
Why do some people get autoimmune disorders? ......................... 12
The future ....................................................................................... 13
References ..................................................................................... 13
4. Treatment policy .......................................................................... 13
Finding the right treatment options ................................................. 15
Long term immuno-suppression .................................................... 15
a. Steroids .................................................................................. 15
b. Azathioprine (Imuran®) ........................................................... 17
References ..................................................................................... 18
5. Eye muscle weakness (Ocular Myasthenia) ............................... 18
Diagnosis ........................................................................................ 20
Drug Treatments ............................................................................. 20
Other measures .............................................................................. 20
References ..................................................................................... 21
6. Women’s issues ............................................................................ 22
Pregnancy....................................................................................... 22
Drug treatments during pregnancy ................................................. 22
The delivery .................................................................................... 23
After the birth .................................................................................. 23
The menopause .............................................................................. 24
v
7. Dentistry and myasthenia ........................................................... 25
8. Anaesthetics and the myasthenias ............................................ 26
9. The other myasthenias ................................................................ 28
The Lambert Eaton Myasthenic Syndrome (LEMS) ...................... 28
History ............................................................................................ 29
More about treatment, incl DAP .................................................... 30
References ..................................................................................... 30
The Congenital (Hereditary) Myasthenias .................................... 31
History ........................................................................................... 32
The known faults ............................................................................ 32
Assessment ................................................................................... 33
References ..................................................................................... 34
10. Children with Myasthenias ......................................................... 34
Treatment ....................................................................................... 34
General Measures and advice ....................................................... 35
Vaccinations ................................................................................... 35
Dental Hygiene .............................................................................. 36
General .......................................................................................... 36
11. Speech & Language Therapy and the Myasthenias ................ 36
Swallowing ..................................................................................... 37
Speech ........................................................................................... 38
Special Aids ................................................................................... 39
References ..................................................................................... 39
12. Vaccinations in MG and LEMS .................................................. 40
Whether various vaccines are safe................................................ 41
Are there any vaccines that MG patients should have? ................ 41
Can vaccination trigger or worsen MG? ........................................ 42
13. The drugs used to treat myasthenias and side-effects. .......... 43
Pyridostigmine (Mestinon®)............................................................ 43
Steroids .......................................................................................... 45
Other immunosuppressant drugs .................................................. 47
References ..................................................................................... 49
14. Drugs that can make myasthenia worse .................................. 50
Antibiotics and anti-malarials ......................................................... 51
Drugs for the heart ......................................................................... 51
Drugs used in neurology and psychiatry ....................................... 53
Muscle relaxants ............................................................................ 53
vi
Volume 5
Medical Information
For Medical Professionals
ABOUT THIS VOLUME
Each person’s experience of the Myasthenias is unique, so this
Volume is one view of a complicated subject that we don’t fully
understand. It is one team’s most up-to-date view as of Sept 2011
but is not the only view possible.
It is intended as a compendium for people at all levels (from student
to retired) in the medical and para-medical professions, and also for
interested patients. To enhance its accessibility, we have
deliberately tried to strike a balance between clinical and lay
language; that is not meant to be patronising, only to ensure ease of
understanding to such a wide target readership.
We are grateful to the wide panel of experts who have freely given
of their time to write, check and proof-read each of the sections.
We hope that the list of Contents will help readers quickly to choose
between the introductory / revision sections 1 - 3 and the more
specialised coverage of drugs, their side-effects and interactions,
anaesthetics, vaccines that follow.
In the main text we have used bold italics to emphasise points and
bold to introduce new terms.
As always we are very grateful for constructive comments – which
we will take into account when revising these Volumes.
1
1
THE MYASTHENIAS
1.1 Introduction and revision
The defining feature of all the myasthenias is painless muscle weakness.
They come in three separate types – Myasthenia Gravis (MG; our main
topic), and the rare congenital myasthenias (see Section 9, page 31) and
Lambert Eaton Myasthenic Syndrome (LEMS; see Section 9, page 28).
They all result from defects in the ‘ignition system’ of voluntary muscle.
When an electrical impulse arrives from the brain (or spinal cord), the
nerve endings release packages of a chemical transmitter – acetyl-choline
(ACh) – the ‘ignition keys’ (see Fig 1, opposite). These travel across a
narrow gap and latch into tailor-made ‘locks’ on the muscle surface – the
ACh receptors (AChRs). This opens a central channel in the AChR and
allows charged salts (mainly sodium) to flow in. The resulting electrical
current triggers the muscle to contract (via complicated mechanisms). The
surplus ACh is destroyed by a special protein – AChE (ACh Esterase,
see Fig 1) – allowing the muscle to relax again. Pyridostigmine
(Mestinon®) is used to block the AChE, so that the ACh lasts longer and
has a better chance of triggering.
In the congenital myasthenias, the problem is some inherited fault that
happens to be in the AChR or another nearby partner. In the LEMS, an
immune attack (by antibodies†) damages the nerve endings, and less
ACh is released than normal, so that triggering is inefficient. In most cases
of ‘autoimmune’ MG, different antibodies destroy many AChRs, again
cutting down the chances of a successful contraction. However, in 5 10% of patients with typical generalised MG, other antibodies instead
attack a different nearby target called ‘MuSK’, and again handicap
ignition.
1.2 References
Myasthenia Gravis and Related Disorders; 2nd ed; edited by HJ
Kaminski. 2009. Humana Press, New York and Berlin. ISBN: 978-158829-852-2.
Continued on Page 4
†
Antibodies are immune weapons that help to destroy bacteria, neutralise viruses
or block toxins; they are proteins that circulate around in the blood and tissues
(Section 3, page 11). Alas, if a few of them attack our own tissues, they may
cause ‘autoimmune’ disorders.
2
Figure 1
Diagram of nerve → muscle junctions
Key:
ACh = acetylcholine
AChR = ACh Receptor
AChE = ACh Esterase (which destroys spare ACh)
When an electrical impulse arrives from the brain, it causes
release of packages of ACh – the ‘ignition keys’. These cross
the short gap and latch into the special ‘ignition locks’ – the
ACh receptors (AChR) which they then trigger. The spare ACh
is broken down by AChE and the resulting fragments are recycled (by an enzyme, ChAT) to produce new ACh in the
nerve terminals.
The AChRs are completely different in the voluntary and
‘automatic’ muscles (so we've given them V and U shapes).
However, the nerve endings (and ACh) are similar. Their
Calcium channels – which are attacked by the auto-antibodies
in LEMS patients – are located right at the point of ACh
release on the nerve endings.
Only the (V-shaped ‘nicotinic’) AChRs in voluntary muscle are
affected in the autoimmune and congenital myasthenias: only
the (U-shaped ‘muscarinic’) AChRs in automatic muscle are
blocked by Propantheline (see Section 13, page 44).
3
Grob D, Brunner N, Namba T, Pagala M. 2008. Lifetime course of
myasthenia gravis. Muscle & Nerve. 37: 141-9.
Vincent A, Palace J and Hilton-Jones D. 2001 Myasthenia gravis. Lancet
357: 2122-8.
Newsom-Davis J and Beeson D. 2001. Myasthenia gravis and myasthenic
syndromes; in Disorders of Voluntary Muscle, eds Karpati G, Hilton-Jones
D and Griggs R. pp 650-675. Cambridge University Press.
1.3 Symptoms, patient subgroups and diagnostic tests
In MG, the muscles fatigue – the harder the patients try, the weaker they
get. Both the severity and pattern of progression vary greatly from case to
case. In the early stages, the weakness often comes and goes. Often the
first sign is drooping of the eyelids (ptosis) or double vision (diplopia);
these are the only signs in about 15% of patients – ‘ocular
myasthenia’ (see Section 5, page 18). In the others, the weakness is
more generalised. It can affect face movements, chewing, swallowing and
speech (‘bulbar’ weakness); also the neck or limbs. Trouble with
swallowing or coughing can cause choking and even pneumonia if drink
or bits of food get inhaled. Still more dangerously, breathing muscles can
be affected. In general, the limbs are involved less or later, so that MG
shows a ‘top↓downwards’ bias. Chronic fatigue without weakness is not a
feature of myasthenia.
In about a fifth of patients, the MG starts between ages 10 and 40; these
‘early-onset’ cases show typical lymph node-like changes in the thymus
gland in the chest, which is where many of our immune white blood ‘T
cells’ first develop. Another 10 per cent of patients have a tumour of the
thymus (a thymoma) that is usually benign (see Section 3, page 12). ‘Late
-onset’ MG (nearly half of the total) starts after age 45, and has become
commoner since ~1990, but there are very few other clues as to what
provokes it.
The outlook
Most patients with MG show a fluctuating course, often with one particular
muscle group bearing the brunt (e.g. ocular, speech, swallowing, limbs).
Fortunately, MG only rarely goes rapidly or severely downhill; on the other
hand, neither the age, sex nor pattern of onset predicts the outcome.
Remissions can occur out of the blue in any patient (and sometimes
persist for years) – but only in around one in twenty patients per year,
alas, so it is wise for patients to get treated soon rather than trust to luck.
4
Diagnosis
In most patients with MG and the LEMS, there are very good blood tests
to detect the causative antibodies; however, a few typical patients test
negative for all of them. Electro-myography (EMG) is a very sensitive
method to assess nerve → muscle ignition electrically. In the ‘Tensilon
test’, injecting edrophonium (a short-acting form of pyridostigmine)
usually produces a swift but brief improvement in muscle strength that is
measured before and afterwards in 2 - 3 muscle groups (e.g. eyes and
breathing). The test carries some risks and should only be done by a
specialist in hospital. Many patients need a chest CT scan to assess the
size and shape of the thymus gland (see Section 3, page 12).
1.4 Introduction to Treatment
(For more detail see Section 4, page 13 and Section 13, page 43)
Pyridostigmine (Mestinon®) is the first-line drug, and is used to soup up
the ignition (like the choke in a car, Fig 1, page 3).
While some patients can manage on pyridostigmine alone, it doesn’t
clean the plugs, and many patients need more fundamental treatments
to reduce the immune attack. When rapid improvement is needed, e.g. for
severe weakness causing breathing or swallowing problems, patients can
come into hospital for plasma exchange, which washes the antibodies
out of the bloodstream.
Another option is an intravenous infusion of immunoglobulin – IvIg –
which is the antibody fraction pooled from thousands of healthy donors.
The benefits of these short-term treatments last only for about six weeks
(see Section 4, page 14).
Surgical removal of the thymus gland (Thymectomy) is essential in
patients with a thymoma to prevent spread (Section 4, page 15 and
Section 8, page 27). Alas, this rarely improves the myasthenia – but it
often does seem to do that in ‘early-onset’ patients without thymomas.
Drugs such as Prednisolone (a steroid) and Azathioprine are often used
to suppress the immune system, especially when thymectomy hasn’t been
done or hasn’t helped enough.
5
2
WHAT GOES WRONG AND HOW IS MG TREATED?
2.1 Landmarks in research
"If I have seen further, it is by standing on the shoulders of giants," Isaac
Newton.
One of the delights of working on MG and its cousins is to see basic
science being applied to help understand, diagnose and treat these
diseases. An early heroine in our story was Dr Mary Walker. In 1935, as a
physician (St Alfege’s Hospital, Greenwich), she was worried about a new
MG patient under her care; in those days, MG was often fatal (hence the
‘gravis’). Discussing the case with the distinguished Neurologist, Dr Denny
-Brown, she felt that the patient’s weakness echoed the effects of the
American Indian arrow poison, curare. So she boldly tried the known
antidote, neostigmine – which is, in fact, a short-acting form of pyridostigmine. This early ‘Tensilon® test’ produced a dramatic improvement;
this and subsequent work led to the longer-acting variants used today.
The plot thickened greatly with early work on how nerve → muscle
triggering normally works. Again in 1935, acetylcholine (ACh) was finally
identified as the crucial ignition key (chemical transmitter). Later on,
various researchers interested in nerve → nerve and nerve → muscle
signalling realised that some snake toxins must affect the AChRs. For
example, among the complicated mix of toxins in their venoms, Cobras
and other snakes have ‘alpha (α) neurotoxins’ which target the AChR
almost irreversibly; by blocking it from binding ACh, they cause paralysis.
In 1963, Drs Chang and Lee (in Taiwan), found that, in their local Banded
Krait snake (Bungarus multicinctus), this toxin (called ‘α-BuTx’) was so
potent and selective that it could be tagged with colours or radioactivity
and used to ‘label’ the AChRs in microscope sections and so measure
their numbers.
This key progress enabled Dr Doug Fambrough and his colleagues in
1973 (in the USA) to show that MG patients had fewer ACh receptors
than normal people. This applies to both the ‘autoimmune’ and most
inherited myasthenias. Their AChR loss entirely accounts for their
defective nerve → muscle ignition; humans have only modest reserves of
AChRs, so losing just over half of them is enough to make us weak.
6
Around that time, other biochemists were trying to understand how
receptors work. They realised that the electric organs of electric eels,
skates and rays are like muscles working backwards, converting chemical
into electrical energy. These organs are packed with AChRs (and are a
much richer source than muscle). These AChRs can be dissolved with
detergents, and then purified using α-BuTx. In 1973, Drs Jon Lindstrom
and Jim Patrick (in California) wanted to make antibodies (to help in their
research), and immunised some rabbits with this pure AChR. To their
surprise, the rabbits soon became floppy (myasthenic). Moreover, when
treated with pyridostigmine, they recovered dramatically – so they must
have had MG; many patients will know how they felt.
That was a crucial breakthrough, partly because it proved that
myasthenia could indeed be caused by ‘autoantibodies’, just as our late
Vice-President, Professor Iain Simpson, had predicted in 1960. It also led
to a very useful blood test for these antibodies, which is now a vital
standard diagnostic tool. It uses radioactive α-BuTx to tag AChR (from
human muscle tumour cells grown in the lab), and quickly detects these
antibodies in about 85% of patients with generalised MG and in about
60% of those with MG restricted to eye muscles.
Early doubts about whether the anti-AChR antibodies in MG are
destructive or protective were soon dispelled by showing that the antibody
-containing fraction of MG blood, when injected into mice, transferred the
electrical defects of MG and also led to loss of AChRs from their muscles.
In fact, Nature had already done that experiment: babies born to around
one in eight myasthenic mothers have a brief (2- 4 week) myasthenic
weakness – neonatal MG – and fully recover afterwards. Like the other
antibodies that protect against infections, those that attack the AChRs are
also transferred across the placenta and in the milk, and cause a shortterm loss of the baby’s muscle receptors (see Section 6, page 24).
The antibodies destroy AChRs by activating the same biochemical
processes (complement and phagocytosis) that normally kill bacteria; also
by increasing the natural rate of AChR breakdown and occasionally by
blocking it from binding ACh. In many MG patients, the antibodies prefer
the slightly different (fetal) form of the AChR that is found in the unborn
baby’s muscles. Very rarely, they can cause paralysis and even
malformations in the baby during late pregnancy (see footnote, page 24).
Plasma exchange provided further proof that antibodies were causing the
7
trouble. The patient’s plasma (which contains the antibodies) is washed
away from the bloodstream and is replaced with a substitute (together
with the patient’s own red cells; see Section 4, page 14)).
It was first used in MG in 1976 when a brave pioneering myasthenic
‘guinea pig’ (in London) was rewarded by getting strikingly better for some
weeks.
Interestingly, about 15% of patients with typical generalised MG are
negative for anti-AChR antibodies (‘seronegative’) in the standard test;
they must have some antibodies, because their MG clearly improves on
plasma exchange. Prof Angela Vincent’s team (Oxford) found that some
of these seronegatives do have antibodies that recognise the AChR, but
only when it is clustered naturally on cell surfaces (Leite et al, 2008).
In 2000, they showed that others instead recognise ‘MuSK’; it is a nearby
partner that helps to cluster the AChRs in the right place and then to keep
them there. In their new test, ~5% of the 15% of seronegatives now test
positive against MuSK in the UK, and ~10% in S.E. Europe. These and
the AChR antibodies are not found in the same patient. ‘MuSK’ patients
seem not to have pure ocular MG, but often to have more ‘bulbar’ weakness – i.e. affecting the face, throat and breathing – with more muscle
wasting, that may respond less well to immuno-suppressive drugs.
Unlike many such tests, those for anti-AChR and anti-MuSK very rarely
give ‘false positive’ results. Partly because such hard-and-fast diagnostic
tests are so valuable, Prof Vincent is still working on the final ‘hard
core’ (~5%) who have neither anti-AChR nor anti-MuSK antibodies.
2.1 References
Walker MB. 1934. Treatment of myasthenia gravis with physostigmine.
Lancet i:1200.
Chang CC and Lee CY. 1963. Isolation of neurotoxins from Bungarus
multicinctus, and their modes of neuromuscular blocking action. Arch Int
Pharmacodyn Ther. 144: 241-257.
Simpson JA 1960. Myasthenia gravis; a new hypothesis. Scott Med J. 5:
419-439.
Fambrough DM, Drachman DB and Satyamurti S. 1973. Neuromuscular
junction in myasthenia gravis; decreased acetylcholine receptors. Science
8
182: 293-5.
Patrick J and Lindstrom JM. 1973. Autoimmune response to acetylcholine
receptor. Science. 180: 871-2.
Pinching AJ, Peters DK and Newsom-Davis J. 1976. Remission of
myasthenia gravis following plasma exchange. Lancet ii: 1373-6.
Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A and Vincent
A. 2001. Auto-antibodies to the receptor tyrosine kinase MuSK in patients
with myasthenia gravis without anti-AChR antibodies. Nature Medicine. 7:
365-8.
Vincent A, Bowen J, Newsom-Davis J and McConville J. 2003.
Seronegative generalised MG: clinical features, antibodies and their
targets. Lancet Neurology. 2: 99-106.
Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, Beeson D,
Willcox N and Vincent A. 2008. IgG1 antibodies to acetylcholine receptor
in ‘seronegative’ myasthenia gravis. Brain. 131:1940-52.
9
Figure 2
The start of an Antibody response against AChR
10
3
THE IMMUNE SYSTEM AND HOW IT GOES WRONG
3.1 The immune system
In general, antibodies are made by ‘B cells’ (which come from the bone
marrow) and each is tailor-made (‘specific’) for its particular target. New B
cells are produced throughout life. Since each one’s particular antibody
‘specificity’ develops randomly, some are inevitably generated that can
attack our own tissues. Luckily, for screening out any immune cells that
might damage self tissues, there are several fail-safe ‘checkpoints’:1. when new B cells first develop, though a few rogues may escape.
2. B cells only actually start making their antibody if switched on by
‘helper T cells’ – the ‘control freaks’ of the immune system (generated
in the thymus; see below*). These T cells again recognise their
particular target specifically. While they develop in the thymus, most of
those that can attack our own tissues are also wiped out by special
quality control screening.
3. in turn, the T cells only get fired up if their target molecule is broken
down by specialised ‘presenting cells’, and these ‘butlers’ serve up
fragments of the target on special ‘silver salvers’† (see Fig 2,
opposite). For unknown reasons, T cells don’t recognise free-floating
targets (like antibodies do), but only fragments (e.g. from AChR) on
butlers’ silver salvers. Luckily, the butlers only fire up the T cells
where there is inflammation. That is unusual in muscle; it normally
contains very few T, B or presenting cells – or silver salvers – and so
is less liable to attack than other tissues.
4.
as a further back-up, there are also some ‘regulator T cells’ whose
* The thymus lives behind the breast-bone. It is where T cells are produced
(starting from stem cells from the bone marrow). As they develop in the thymus,
any T cells that can recognise our own particular silver salvers multiply, while others that can’t do so die of neglect. After they mature, the T cells are exported to
the rest of the body via the blood. Some of them help either presenting cells to kill
germs or B cells to make antibodies, while others directly kill virus-infected cells.
As with the damaging MG antibodies, the T cells that recognise AChR are only a
tiny minority.
†
These silver salvers are actually the tissue-type ‘HLA’ molecules that are
matched for kidney or other transplants because they vary so much from person
to person.
11
job is to stop any one immune response taking over the whole
immune system (like a B cell cancer might do). Some of these
regulators seem normally to prevent autoimmunity.
3.2 Why do some people get autoimmune disorders?
Currently (2012), there are more questions than answers. In general,
getting MG is pure bad luck and nobody’s fault. It very rarely strikes
twice in the same family. However, other autoimmune disorders like
young-onset diabetes and thyroid disease are commoner than in the
national average. Luckily, they can’t be caught from other patients. Even
in families with inherited risk factors, the chances of actually getting any of
these diseases are only around one in twenty at worst – so it is important
that parents do not blame themselves.
In theory, there could be over-enthusiasm or slip-ups at any of the
checkpoints 1 - 4 above. There could also be slightly similar AChR-like
targets in some microbes that provoke a chain-reaction against the AChR;
however, many of us have spent years searching, but found no convincing
support for that. Instead, we are unusually lucky in having other valuable
clues in MG, in particular:(a) in the thymomas, which are tumours that look like a normal thymus
gone crazy. Around one third of all thymoma patients get MG, and we
suspect that some thymic AChR or AChR fragments there – perhaps in
over-active presenting cells – may first trigger specific T cells into activity.
The B cells may only be turned on elsewhere, and also much later,
perhaps explaining why MG sometimes first appears months after a
thymoma has been removed.
(b) in the early-onset MG patients’ thymus, T cells may be primed as in
(a) above. We also know that there are rare muscle-like cells there, with
the complete AChR – even in the normal thymus. Alas, they seem not to
screen out AChR-attacking T cells efficiently; in MG, they may instead
help to fire up the B cells that recognise AChR. They may explain why
early-onset MG patients so often have lymph gland-like invasions in their
thymus – busily making anti-AChR antibodies – and possibly why they
seem to get better after removing the thymus (thymectomy).
(c) one silver salver [a tissue-type called HLA-DR3] is particularly
common (>70%) in the early-onset MG patients (who are often female)
compared with only about 30% of healthy subjects.
It may happen to present AChR fragments especially well to helper
12
T cells. Intriguingly, however, it is also common in young autoimmune
diabetics and in thyroid disease, so it may just travel with another nearby
gene that generally stimulates antibody reactions.
(d) very occasional patients who are treated for rheumatoid arthritis with a
drug called penicillamine (a fragment of penicillin) develop typical MG
with antibodies to the AChR. Both usually go away a few weeks after the
drug is stopped. We suspect the drug attaches to some part of another
silver salver (DR1) – which somehow makes it seem to some T cells like
an AChR fragment. That drug is rarely used nowadays.
3.3 The Future
The exciting developments in diagnosis, in understanding mechanisms in
the inherited and autoimmune forms, and in treatment, have certainly
improved the outlook for MG patients. We see no reason why that should
stop. We hope that, one day, we will be able to answer the question asked
so often by patients, "Why me"? Some of us are striving for new genetic
treatments for the inherited myasthenias, and others for smart weapons –
for the immune forms – to switch off the damaging immune attack on
muscle while leaving the other protective responses intact. Neither will be
easy, but any successes should be applicable not only in other
autoimmune diseases but also in allergies.
3.4 References
Vincent A, Palace J and Hilton-Jones D. 2001.Myasthenia gravis. Lancet
357: 2122-8.
Meriggioli MN, and Sanders DB. Autoimmune MG; emerging clinical and
biological heterogeneity. Lancet Neurology 2009; 8: 475-490.
4
TREATMENT POLICY
Here we broadly outline the main options and their pros and cons; sideeffects are detailed more in Section 13, page 43.
Broadly, MG (and LEMS) can be treated (i) by souping-up nerve→muscle
triggering and/or (ii) by reducing the damaging antibodies or the cells
producing them.
(i) Anti-cholinesterases such as pyridostigmine and neostigmine have
been wonder-drugs for many MG patients. They are still the first line
drugs, particularly in milder cases.
13
Other drugs such as 3,4-diamino-pyridine (DAP) soup up ACh release
from the nerve endings and are very useful in the LEMS and some
congenital myasthenias (see Section 9, pages 30 onwards).
(ii) Immunological treatments, on the other hand, aim to reduce or
remove altogether the damaging antibodies in MG and the LEMS. As we
saw at the end of Section 1, plasma exchange is both the simplest and
cheaper; antibodies are washed away and replaced with a plasma
substitute. The excellent short-term improvements can be vital in crises
and for ‘tuning-up’, e.g. before an operation. The effects are rather similar
with intravenous immunoglobulin – IvIg – although it is not clear exactly
how it works. Neither is curative, however, since the rogue B cells
obstinately go on making their antibodies, and muscle strength inevitably
declines as their levels rise again. Extra immuno-suppressive treatment is
very often needed (see later).
IvIg is the easier to use and works well in many MG and LEMS patients. It
means infusing the total antibodies (Ig), pooled from huge numbers of
healthy blood donors, into a vein (Iv). It clearly does help, though only for
about 8 weeks, alas. There are more theories than hard facts about how
it works; it may simply water-down the damaging antibodies or side-track
the bystander amplifying mechanisms they recruit (e.g. complement).
IvIg costs slightly more than plasma exchange, but it also means being in
a special hospital ward for 5 days running; the Ig has to be given very
slowly into a small arm vein for about 5 hours each day. Patients often get
a headache and sometimes a rash or rise in blood pressure; blood tests
are used to monitor for possible effects on the kidneys. By their nature,
supplies of human blood products are limited; they also carry low-level
risks. Though the Ig is very carefully screened for known viruses (hepatitis
and HIV), there is obviously a remote possibility of new unsuspected
agents.
Plasma exchange can also be helpful as an alternative, but needs more
complicated machinery. During a thorough ‘plasmapheresis’, several litres
of blood are removed one by one, spun in a separator or filtered, and the
red blood cells are returned in an artificial substitute (albumin and saline
solution) without the antibodies. This means being in a special hospital
ward for 5 days connected by an intravenous line (usually in the groin) to
and fro the separator for around 4 hours per day. After around 1 - 2
weeks, that reliably improves strength for another 6 weeks or so, but then
the benefits wear off as the antibodies are gradually replaced. It is safe, if
slightly uncomfortable.
14
4.1 Finding the right treatment options
Different Neurologists have their own approaches for treating MG, but
here is one view:(i) For the new patient, pyridostigmine is nearly always tried first.
(ii) Subsequent options depend on the patient:- those for pure Ocular MG are given in Section 5, page 20.
● In patients with early-onset (generalised) MG who want to avoid
immuno-suppressive drugs, thymectomy (see Section 8, page 28)
should be considered carefully, although its benefits cannot be
predicted (alas) and have not been rigorously proved. Anywhere from
2 weeks to 3 years after the operation (or even more), around one
quarter of such patients go into remission, and a half are improved so
much that they now need lower doses of steroids; the final quarter
show no effect at all, and may well need more immuno-suppressive
drugs (see below). [Thymectomy was the first immuno-suppressive
approach, though not recognised as such when first tried over 60 years
ago; we still don’t understand exactly how it works, if it really does.]
● Thymomas should be removed (usually at open surgery) unless the
patient is very frail or the tumour has spread too far. Alas, the MG
seldom improves with thymectomy alone. NB thymomas can re-grow
even while the MG is in remission.
● Most other cases have late-onset MG, and generally respond well to
immuno-suppressive drugs.
● One other point to remember when choosing between these treatments
is the possibility of pregnancies in the future (see Section 6, page 22).
4.2 Long-term immuno-suppression
a. Steroids
The first choice drug is usually the synthetic steroid ‘prednisolone’,
which is taken by mouth. It reliably reduces the levels of the damaging
antibodies within 3 - 6 months. (It must have other benefits too, which are
felt usually after 2 - 6 weeks, but which we don’t fully understand). In over
90% of MG and LEMS patients, it gives full remissions or such good
improvements that they can get back to almost normal strength and daily
life. However, they nearly always need long-term treatment – often at
modest doses – to keep their strength up. While about a quarter get sideeffects (see below), the benefits usually far outweigh the snags. Alas,
15
patients vary unpredictably in how well their MG improves, in their ideal
steroid dose and in its side-effects.
Finding the right dose: in the short-term, high doses of prednisolone can
make the muscles weaker, so the dose is usually built up slowly in steps
towards the recommended 80 - 100 milligrams on alternate days (or about
50 milligrams daily) and held there for several months. [Most Neurologists prefer alternate day regimes to reduce side-effects (see ii below),
even though the total dose is the same]. When the improvements seem to
be maximal (after 3 to 12 months), the dose is very slowly tapered down
over many months to the minimum that keeps the MG under control
(ideally, 5 to 10 milligrams). This ‘cruising dose’ varies unpredictably, and
some patients have mini-relapses (through cutting down too far) while
they are fine-tuning it. Not many can give it up altogether; some may need
to boost the dose to cover the stress of anaesthetics/surgery; also during
infections, in careful combination with the right antibiotic (sometimes in
hospital; see Section 14, page 51). Patients also vary unpredictably in the
side-effects they get.
The side-effects fall into three main groups:(i) Being immuno-suppressants, steroids inevitably raise the risk of
infections. Taking reasonable care (e.g. avoiding tightly crowded places or
people with infections) is an acceptable compromise; in fact, serious
trouble from infections is surprisingly rare.
(ii) Adrenal suppression:- even at its best, prednisolone must be used
with care. It mimics the natural corticosteroid or ‘steroid’ hormones
produced by the adrenal glands. We all depend on these hormones to
tune us up just before the evenings and mornings (especially after a rough
night), and particularly to tide us over crises such as infections or
surgery. When prednisolone is taken in doses over 20 milligrams daily for
longer than a week, the adrenal glands naturally start producing less
steroids, ‘assuming they are redundant’. Once this ‘adrenal suppression’
starts, the natural response to any crises may be lost, so there is a risk of
a sudden collapse. To prevent this, many neurologists give steroids on
alternate days – to ‘keep the adrenals on their toes’; this can cause the
MG to fluctuate too, though most patients can handle that. Moreover,
steroids must not be stopped all at once but must be slowly tapered down
over several months to give the adrenals time to get fully back into normal
working order again.
(iii) Steroids lower activity in many cells, so they can cause many other
side-effects. Soon after starting prednisolone, when the dose is likely to
16
be at its highest, the obvious ones include weight gain (particularly around
the face), mood change (either irritability or euphoria), and trouble with
sleep. But it is the long-term side-effects that can be more serious.
Because the effects of prednisolone build up, side-effects can occur even
with fairly modest daily doses. So it is the duration of treatment that
counts, especially in patients taking it in the long-term. These ‘cumulative’
side-effects include thinning of the bones (osteoporosis) leading to the risk
of fractures after minor injury, high blood pressure, diabetes, cataracts,
stomach ulcers, excess hair growth or thinning of the skin with easy
bruising. Additional drugs can help to prevent osteoporosis and stomach
ulcers. High blood pressure and diabetes can be treated with drugs if they
develop, and cataracts can be treated by surgery. More details are given
in Section 13, p 45.
b. Azathioprine (‘Imuran®’) (see also Section 13, page 47)
This drug also reduces antibody levels, but that takes at least a year to
‘kick in’. It is sometimes used by itself in cases who can’t quite manage on
pyridostigmine alone, or who can’t tolerate steroids. More often, it is used
to enhance the benefits of steroids: indeed, patients who also take
azathioprine can clearly get away with less prednisolone – or none at all –
thus reducing the risk of side-effects (Palace et al, 1998). As with steroids,
the dose of azathioprine itself is tapered down when benefits seem to
have reached their maximum.
Some patients are allergic to azathioprine and may react to it in the first
few weeks, with fever, nausea, vomiting, loss of appetite or abdominal
pain, and the drug must then be stopped. Its side-effects include liver
damage and bone marrow suppression, for which regular blood tests are
needed every 1- 2 weeks at the start and every 3 months for ever more
(done by the GP). In the long-term, in any patient, there is also an
increased risk of skin cancers. As always, this potential risk has to be
balanced against the proven benefits of the drug (i.e. keeping the
myasthenia under good control and reducing the cruising dose of
prednisolone).
Other immunosuppressants
Other immunosuppressants, such as ciclosporin A, mycophenolate mofetil
(Cellcept®), methotrexate and cyclophosphamide (see Section 13, page
47) are usually kept in reserve for people who either can’t take the above
front-line drugs or need something more. These others are less well triedand-tested in MG, and have their own side-effects too, partly because
they are more powerful immuno-suppressants.
17
Instead of suppressing all immune responses, what we really need are
smart weapons to reduce only the damaging myasthenic antibodies.
Important
In Conclusion, Steroid treatment is a long-term commitment lasting
several years at least. To help themselves, patients on prednisolone
should watch their weight, keep as physically active as possible (to
prevent osteoporosis), and eat a balanced diet (high in protein,
calcium and potassium (i.e. fruit/ juices) but low in salt, sugar and
fat). While it is wise to avoid other people with infections, normal
social life should otherwise be encouraged. Their blood pressure
and sugar should be checked regularly. Finally, they should carry
a card or bracelet saying they are taking steroids.
4.3 References
Skeie GO, Apostolski S, Evoli A, Gilhus NE, Hart IK, Harms L, HiltonJones D, Melms A, Verschuuren J, Horge HW. 2006. Guidelines for the
treatment of autoimmune neuromuscular transmission disorders. Eur J
Neurol. 13: 691-9.
Newsom-Davis J. 2003. Therapy in myasthenia gravis and Lambert-Eaton
myasthenic syndrome. Seminars in Neurology 23: 191-8.
Palace J, Vincent A and Beeson D. 2001. Myasthenia gravis: diagnostic
and management dilemmas. Curr. Opin Neurol. 14: 583-9.
Palace J, Newsom-Davis and Lecky B. 1998. A randomized double-blind
trial of prednisolone alone or in combination with azathioprine in
Myasthenia Gravis. Neurology 50: 1778-1783.
5
EYE WEAKNESS IN MG (OCULAR MYASTHENIA)
Very typically, MG can affect one muscle group much more than others,
for example just one small muscle that moves one eye in one direction, or
lifts one of the eyelids; or just one of the larger muscles involved in face,
limb or breathing movements, sometimes only on one side. Weakness of
eye movements is particularly common in MG: indeed, it may be the only
problem in some patients, whereas it is often an early sign of a more
general picture in others. So Optometrists are important allies for the MG
community for two reasons. They are often the first to suspect MG.
Secondly, in both community and private practice, they are increasingly
involved in the shared care of MG patients and can sometimes offer them
practical help.
18
Here we summarise advances in treatments for the eye muscle
weakness, stressing the most effective and practical ways to manage
double vision (‘diplopia’) and droopiness of one or both eyelids (‘ptosis’).
NB By itself, MG does not affect focussing by the eyes.
Strictly, we label myasthenia as ‘Ocular MG’ only if the weakness is
still restricted to eye movements at least two years after the very
first symptom. We do that because generalised MG begins with ocular
weakness in around three quarters of all myasthenics (and affects about
9 in 10 eventually); it may start to affect other muscles only after 6 months
(in about a quarter of them), or even longer (in about an eighth). So, if the
MG remains purely ocular for two years, there is only about a 1 in 20
chance that it will ‘generalise’ after that.
Just as with any muscles in MG, those that move the eyes may be quite
strong in well-rested patients. However, they can tire easily on endurance
testing or emotional strain. For example, after prolonged gazing upwards
or sideways, the eyelids may gradually start drooping or the patient may
see double as one of the muscles weakens. If they see well in all
directions except upwards, this tells us that one of the elevator muscles is
weak. The eyes may even refuse to move altogether. These signs can
easily be mistaken for other medical conditions with similar effects, e.g.
strokes, tumours, thyroid eye disease, infections or multiple sclerosis. So
MG is often first suspected by opticians or eye specialists.
Why are the eye muscles so commonly involved in MG? As you know
from watching people nodding off, the eye muscles are especially
vulnerable to tiredness, probably for several reasons:(a) they need to be much more precise than most other muscles;
(b) they are very small and have less reserve capacity;
(c) there are subtle differences (from other muscles) in their nerve
endings and possibly their AChRs;
(d) they get less rest, even during sleep.
What makes eye weakness worse? Bright sunlight, emotional stress, viral
illness, surgery, menstruation, pregnancy, immunisations and other
factors may all provoke changes in the ocular weakness, although not in
predictable directions.
5.1 Diagnosis
The diagnosis depends on the patient’s story and physical findings, and
19
on a blood test for the anti-AChR antibodies (positive in about 60% of
patients with pure Ocular MG*). If it is negative, a very sensitive electrical
test (single fibre EMG) can be done on the facial muscles around the
eyes; interestingly, patients with apparently pure ocular MG often have
electrical faults in other muscles too, even without obvious weakness
there. In a few cases, we need to test the response to an injection of
Tensilon (edrophonium; Section 1, page 5).
5.2 Drug Treatments
Pyridostigmine (Mestinon®) is usually the first-line treatment. With
careful use, it often helps, but may not eliminate all ocular weakness –
possibly because:(i) the double vision may be resistant (perhaps it is hard to restore a perfect
balance) and may even be unmasked by strengthening the eyelids:
(ii) the dosage schedule may need fine-tuning:
(iii) the side-effects may be intolerable.
If pyridostigmine is not enough, then immuno-suppressive drugs usually
succeed. As with any treatment, it is important to weigh their likely
benefits against their side-effects (see Section 4, page 16 and Section 13,
page 45). Most patients respond well to lower doses of prednisolone than
are used for generalised myasthenia, and azathioprine or other secondline drugs are seldom needed. (Although thymectomy sometimes seems
to help, most specialists feel that it is ‘over the top’ for such relatively mild
symptoms that are likely to respond to other treatments).
5.3 Other Measures
For double vision, patients can tilt their heads or turn their faces to bring
their relatively stronger eye muscles into play. If looking upwards is the
main problem, he/ she would tilt the head back, thus bringing the gaze
downwards out of the ‘territory’ of the weakened elevator muscle.
If drugs work poorly or cause side-effects, other methods may relieve the
patient’s double vision. Fresnel (stick-on) prisms, for instance, can be
attached to a patient’s eyeglasses to relieve double vision; if helpful, they
can then be incorporated into the lenses. By optically ‘bending light’, they
*In the other 40%, the anti-AChR antibodies may be too dilute to detect,
or there may be others attacking some different nearby target – but they
rarely (if ever) recognise MuSK (see end of Section 2, page 8).
20
enable the patients comfortably to look straight ahead or downwards and
read with both eyes open. Sometimes, a pirate’s eye patch, a frosted lens,
or simply sticking a piece of tissue paper over one lens in the spectacles
is an easy short-term way of stopping double vision to allow more
comfortable reading or TV-watching. Very rarely, surgical correction can
be useful for long-term deviations that don’t vary.
For droopy eyelids (ptosis), surgical correction may rarely be
considered if the ptosis is stable and other measures are not working. NB
before recommending either surgery or props, it is particularly important
to ensure a good capacity for eye closure, which is often weak in MG.
Otherwise, defects in the normal protective reflexes may confer a risk of
damage to the cornea.
If drug treatments are not successful, some patients use sticky tape to
hold the eyelids up, or else Ptosis props, which come in two forms:Lundie Loops act as a spring-based support for the upper lid and are
fitted to the spectacle frame, which needs to be thick enough along its top
rim to support them. They are supplied exclusively by Mr J B Lundie, 76
Parc Gilbertson, Gelligron, Pontardawe, Swansea. SA8 4PU
<[email protected]>.
Traditional bar ptosis props can be fitted by most glazing houses; their
projection, length and size are specified by the optometrist. Rubber tubing
can be used to cushion the bar. A few patients find them a tolerable longterm solution.
5.4 References
Luchanok U, Kaminski HJ. 2008. Ocular myasthenia: diagnostic and
treatment recommendations and the evidence base. Curr Opin Neurol. 21:
8-15.
Benatar M, Kaminski HJ; Quality Standards Subcommittee of the
American Academy of Neurology Evidence report: the medical treatment
of ocular myasthenia (an evidence-based review): report of the Quality
Standards Subcommittee of the American Academy of Neurology.
Neurology. 2007; 68: 2144-9.
6
21
WOMEN’S ISSUES IN MG
By and large, women experience the same problems as men with MG,
but may have extra ones at the time of monthly periods, pregnancy and
the change of life (menopause).
In around 2/ 3of women, the MG symptoms can get worse before and
during their periods, sometimes lasting into the third day, regardless of
any discomfort/pain. They may need to increase the dose of their
pyridostigmine. Using the oral Contraceptive Pill doesn’t affect MG.
6.1 Pregnancy
If the MG is well controlled, pregnancy should not pose many problems,
but women with MG may get more tired simply because of the extra
weight and changing centre of gravity, and extra strains on some
muscles. In general, the long-term outcome doesn’t change, but the
effects on the MG are very unpredictable, and can vary from one
pregnancy to the next. The MG improves in around a third of mums
during pregnancy, gets worse in a third and remains steady in the rest.
They seem most vulnerable in the first three months and just after the
birth – when they may need higher doses of their drugs.
It is wise to make sure that the MG is as well controlled as possible
before planning a pregnancy, and to plan it in consultation with the
Neurologist; conversely, to think ahead about possible future
pregnancies when deciding between treatment options.
6.2 Drug treatments during pregnancy
Obviously, to prevent any risk to the baby, mothers should try to keep
drugs to the minimum – but they also need to keep strong for both their
sakes. NB pyridostigmine is quite safe as it doesn’t cross the placenta.
But it may not be absorbed well if there is much vomiting; drug doses
may also need fine tuning because of the usual fluid retention in
pregnancy.
Obviously too, good control of the myasthenia is in the best
interests of both the mum and the developing child. So, if immunosuppressive drugs are really needed, there are acceptable options
available:From a lot of evidence gathered over many years from a wide range of
conditions, prednisolone appears to be safe; most of it is destroyed by
the placenta. Similarly, the use of azathioprine in pregnancy is
accepted generally in the different specialities in the UK. After much
experience worldwide in many diseases (including some MG cases),
22
there is no evidence that azathioprine damages the developing baby. The
British National Formulary states “there is no evidence that azathioprine is
teratogenic. However, there have been reports of premature birth and low
birth-weight following exposure to azathioprine, particularly in combination
with corticosteroids. Spontaneous abortion has been reported following
maternal or paternal exposure.”
In each patient, therefore, the proven benefits of these treatments
have to be balanced against these very small and unsubstantiated
risks; in most cases, good control of the mother’s MG takes priority.
Several other immuno-suppressants clearly can cause problems for the
baby – for example, if methotrexate is taken by the mother during
pregnancy or by the father beforehand*. The manufacturers of ciclosporin, cyclophosphamide* and mycophenolate mofetil also
specifically caution against using them in pregnancy. Rarely, there may be
a serious need for one of these drugs to control the MG, and the parents
may decide to accept the risk. Do remember that the main danger period
for the baby is up till around 12 weeks of pregnancy, by when nearly all of
the vital stages of development are complete.
Because of these risks to the baby, contraception is strongly recommended while women are taking these other immuno-suppressants – and
for at least three months afterwards. Some can also affect sperm as
well as eggs (see Section 13, page 48).
6.3 The delivery
In MG, there are almost no increased risks of miscarriages or premature
delivery** (see next page), or of needing Caesarean section. The
pregnancy can be booked and managed with the standard prenatal care.
The labour should be managed normally, but the MG may get worse if it
is difficult or prolonged. The pushing needs the voluntary muscles that are
affected by the myasthenia, whereas the uterine contractions are
‘automatic’ and are not weakened by the MG. To prevent a very long
labour, forceps or ventouse may be needed. It is safe to use normal
painkillers or epidural anaesthesia, but general anaesthetics are best
avoided if possible.
6.4 After the birth
Some mothers find their MG gets worse again for a few weeks or even
months. It is important to avoid infections. Breast-feeding is good even in
*Men are recommended to stop these two drugs at least a year before giving
sperm, or even to get sperm banked before starting on them.
23
mothers taking medium doses of steroids and/or azathioprine (which are
safe), but should be avoided if:(a) doses exceed 40mg prednisolone daily (or 80mg on alternate days);
(b) any other immunosuppressant is needed (e.g. methotrexate);
(c) the baby has serious neonatal MG, even after pyridostigmine (as it will
absorb yet more of the harmful antibodies from the milk).
With around 1 in 8 myasthenic mothers, the babies have ‘neonatal MG’ –
short-term myasthenic weakness**, which is usually similar in the same
mother's subsequent babies. With improved treatments that lower the
mother’s antibody levels, it seems to be getting less common. It is caused
by the transfer of the mother’s damaging antibodies to the baby across
the placenta; luckily, the baby does not make any of these itself, so its MG
only lasts for 2 - 4 weeks while those it gets from mum slowly wane. In the
first few days, the baby may seem floppy, and cry or suck weakly or even
have breathing difficulties. It usually helps to give pyridostigmine just
before a feed. Very rarely, tube-feeding, suction of mouth / throat fluids, or
even artificial respiration and treatment with IvIg or plasma exchange,
may be needed. In occasional cases, the mother's MG has not yet been
recognised; in that case, antibody tests on her and baby can be very
useful in distinguishing neonatal MG from congenital myasthenia.
6.5 The menopause
Around the menopause, the MG can flare up, and may demand higher
doses of pyridostigmine or immuno-suppressants. Hormone replacement
therapy (HRT) is perfectly acceptable. Calcium supplements may be
important; bone thinning (osteoporosis) is likelier from now on – even
more so if mobility is restricted by the MG, or if the patient is taking
steroids – but it can then be prevented by a variety of drugs.
Finally, sexual drive is not directly affected by MG, unlike in the LEMS.
** Very rarely, the antibodies are particularly damaging to the baby during the
later months of pregnancy. They may stop the limbs moving normally in the
womb†, so that some of the joints can’t straighten properly at birth (arthrogryposis); usually, however, these then gradually grow back towards normal during
infancy. In extreme cases, the paralysis even prevents the lungs from developing
perfectly, and, sadly, the baby may be stillborn or die during the first few days.
Thorough treatment of the mother with immuno-suppression and/or plasma exchange can lower the antibodies so much that her later babies are almost normal.
†
All that normal moving around is not just a bore for the mother – it is actually
needed to prevent these defects.
24
However, general fatigue, anxiety about physical limitations from the MG,
and drug side-effects, can have indirect effects.
6.6 Reference
Batocchi AP, Majolini L, Evoli A, Lino MM, Minisci C, Tonali P. Course and
treatment of MG during pregnancy. Neurology. 1999; 52: 447-52.
7
DENTISTRY AND MYASTHENIA
If the myasthenia is under good control, there is no reason why patients
can’t have normal dental care. Good communication between patient and
dentist is vital. The patient must know exactly what the dentist is going to
do. The dentist needs to know the patient’s limitations, and to be prepared
for them. This should help the patient to relax and co-operate more fully. It
is vital that the dentist consults with the Neurologist at the planning stage
if surgery is necessary, and it may also help even for normal care.
It helps to book appointments for the morning or whenever strength is
greatest, and to keep them short. If there are difficulties in opening and
closing the mouth, in holding the head up, or in swallowing, the dentist
needs to know so as to prevent problems. A mouth prop may help for
keeping the mouth open; thorough suction (e.g, controlled by the patients
themselves) helps to avoid drooling or choking problems.
Even root canal work need not be traumatic. A rubber dam may be
needed to prevent worries about choking. Patients who can’t close off
their throats, or who tend to regurgitate fluids into the nose, may prefer to
sit more upright in the dental chair.
Local anaesthetics are preferable to general in MG.
Prevention is vital to avoid dental emergencies; they are most
stressful and can aggravate the myasthenia. Excellent home care habits
are crucial, however difficult they may be. They include regular brushing,
daily flossing, cleaning between teeth, and oral cleanliness; also regular
dental visits and cleaning, to keep the teeth free of plaque.
The gums are liable to infections – and the patient may not even be aware
of them; if severe, they can have knock-on effects on the MG and/or lower
resistance. So proper care is vital.
In patients taking immuno-suppressants, infections are more likely, and
healing may take longer than expected. Finally, weakness of jaw muscles
can affect the closing of the teeth. That, in turn, can create extra stresses
25
or even pain.
Reference
Yarom N, Barnea E, Nissan J, Gorsky M. 2005. Dental management of
patients with myasthenia gravis: a literature review. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod. 2005; 100: 158-63.
8
ANAESTHETICS AND THE MYASTHENIAS
Nowadays, the myasthenias should not cause problems for the
anaesthetist – thanks to better awareness, understanding and treatment;
also, patients are usually much better prepared in advance for their
operations. The one exception, of course, is when the myasthenia is not
suspected (see (a) below). However, MG is such a well-known pitfall for
anaesthetists that it is a very common question in their final exams.
It helps both sides if patients can discuss all the options in advance with
the anaesthetist – who can then also assess the severity of the MG and
the overall fitness for anaesthesia and surgery, and arrange for an
intensive care bed if needed for recovery afterwards. Importantly, it gives
patients confidence and courage, and that helps everyone.
Very often, so as not to depress breathing, doctors prefer local or
regional to general anaesthetics (e.g. with lignocaine, bupivicaine; also
mepivacaine which is shorter-acting and has fewer side-effects). They are
injected around nerves and block their electrical conduction completely for
several hours. They work identically whether they are injected near the
nerve endings (e.g. into the jaw nerve by the dentist) or around the nerve
roots (as for spinal and epidural anaesthetics). They are often chosen to
avoid the depression of breathing that is caused by some general
anaesthetics, and to allow other treatments to continue normally. Local
anaesthesia combined with light sedation is suitable for most operations
below the waist, e.g. hip/knee surgery, varicose veins, hernias, and some
gynaecological operations.
Before any general anaesthetic, the myasthenia should be under the
best possible control, which may mean ‘tuning up’ with plasma exchange
or IvIg about 2 weeks beforehand. Then, it should be just as safe in
myasthenic patients as in anyone else, as long as care is taken over:(a) muscle relaxants*; competitive blockers** of nerve → muscle
triggering (like curare), which now include atracurium, rocuronium and
vecuronium. They are given nowadays for easier access for ‘deep’
26
operations, to relax all the voluntary muscles. Because these drugs also
paralyse the breathing muscles, mechanical ventilation is obviously also
essential.
NB many operations need neither muscle relaxants nor ventilation.
(When they did, in the old days, we used deeper anaesthesia instead,
which meant more depression of blood pressure and breathing and longer
recovery times, often with much nausea and vomiting.)
With their lower reserve of muscle-triggering power, myasthenic patients
are much more sensitive to muscle relaxants, so the dose has to be
reduced by 5 or even 10 times. The degree of muscle paralysis can be
monitored throughout the operation by a ‘peripheral nerve stimulator’.
These cheap and simple instruments are in routine use in all operating
theatres. Neostigmine, a short-acting pyridostigmine cousin, is routinely
used to stop the effects of muscle relaxants at the end of operations.
It still occasionally happens that patients with unsuspected myasthenia
(including LEMS) are given standard doses of relaxants and then need
more neostigmine than expected to perk them up after the operation –
one roundabout way in which MG can be diagnosed, even today.
(b) should pyridostigmine be stopped beforehand? No, not for either
local or general anaesthetics. But, because it counter-acts the muscle
relaxants, they may need to be given at slightly higher doses if
pyridostigmine has just been taken (adjusted according to the nerve
stimulation results). This should not be a problem, and may even help,
because so many MG patients find it reassuring to take it regularly. After
the operation, it is often given into a stomach tube if the patient has
trouble with swallowing.
(c) should steroid doses change? Yes, because the natural steroid
response to stress that tides us over operations is shut off by prior steroid
treatment. So we usually supplement with extra steroids by injection
before, during and after the operation.
Thymectomy
The rules are exactly the same as above, though a general anaesthetic is
essential. The breast-bone (sternum) can be split open to allow direct
removal of the thymus. That usually takes only around 1½ hours, and is
** another group of ‘depolarising’ drugs (like suxamethonium) paralyses
muscles after first stimulating them; myasthenic patients are ~2-fold less
sensitive to them, because they have fewer receptors.
27
still the usual approach for thymomas. Surprisingly, it’s not very painful,
and most patients don’t need any blood transfusion. They may spend 1 - 3
days recovering in intensive care, but are often home within a week. Since
about 1995, keyhole surgery (video-assisted thoracoscopic surgery,
VATS) has become popular, because of the much smaller scars and faster
recovery afterwards. It requires careful scanning in advance to locate the
veins, and either a trans-cervical approach and/ or 2 - 3 port-holes in the
anterior axillary line on each side, to ensure access to all thymic tissue,
even in the neck. As all that is more fiddly, it can take 2 hours or more.
The results are reportedly as good as with the traditional method.
References
Hirsch NP. Neuromuscular junction in health and disease. 2007. Br J
Anaesth. 99: 132-8.
Shigemura N, Shiono H, Inoue M, Minami N, Ohta M, Okumura M and
Matsuda H. 2006. Inclusion of the trans-cervical approach in videoassisted thoracoscopic extended thymectomy (VATET) for myasthenia
gravis; a prospective trial. Surg Endosc. 20: 1614-8.
9
THE OTHER MYASTHENIAS
As we saw in the Introduction, there are two much rarer myasthenic
syndromes which are subtly different from MG. Whereas the congenital
myasthenias are caused by inherited faults in the ignition system, the
Lambert-Eaton Myasthenic Syndrome (LEMS) is autoimmune in origin,
like MG, but the target is on the nerve endings rather than the muscle.
Each also has a Volume to itself (see p iii).
9.1 The Lambert-Eaton Myasthenic Syndrome (LEMS)
The LEMS is at least ten times less common than MG, and seldom starts
before the age of 30. It shows other differences from MG:- (a) although
muscle weakness is again the main problem, it fluctuates much less than
in MG, though heat often makes it worse; (b) the LEMS shows a
‘bottom ↑ upwards’ pattern (almost reversing that in MG), with difficulty in
walking and ‘heavy legs’, almost like walking through treacle. It can affect
the arms, but less commonly the muscles of speech, swallowing,
breathing or eyes; (c) since our ‘automatic’ functions rely on similar nerve
endings to those in muscle, they get attacked too (Fig 1, page 3). Hence,
many LEMS patients also notice a dry mouth, constipation or even
impotence (in men).
28
There are two subgroups of LEMS patients. About half of them have a
‘small cell’ lung cancer; it is found only in smokers, and their LEMS is
an unusual reaction against it and usually starts after age 40 years. In the
others, there is no tumour; their LEMS can even start as young as 9 years
old, but more often after 30 – and the reasons are completely unknown.
Obviously, checking LEMS patients (especially smokers) for tumours, and
treating them, must take priority (see below).
9.2 History
The differences between the LEMS and MG were only clearly recognised
in the 1950s, when the American physiologist Dr Ed Lambert (at the
Mayo Clinic) noticed that too little ACh is released from the nerve
endings – so the ‘quantal content’ is about half-normal. However, it can
build up with repeated stimulation; as many patients notice, the harder
they try, the better their muscles work (for a short time) – the exact
opposite of MG (‘post-tetanic potentiation’).
Noting that LEMS patients often have other autoimmune disorders too,
Prof John Newsom-Davis and Dr B Lang tried plasma exchange in 1981;
to general delight, their LEMS improved. Moreover, the plasma caused
similar electrical and structural defects in the muscle ignition system when
transferred to mice; evidently, the LEMS is also caused by antibodies.
Interestingly, the benefits of removing them in the patients (and the
defects in the mice) take longer to kick-in than in MG (around 3 weeks
versus 2-3 days).
The diagnostic blood test for the LEMS was greatly improved when Dr
Lang identified targets in the nerve endings – special calcium channels
involved in ACh release. When tagged with radioactive toxins (from
predatory snails), these detect the antibodies in the LEMS very sensitively
and specifically, with positive results in about 90% of patients. They are
now a standard part of the diagnosis; so is EMG testing for decreased
quantal content and post-tetanic potentiation.
More recently, IvIg has also proved to be good treatment for the LEMS; as
with plasma exchange, the benefits tail off after 6 - 8 weeks. For treating
the autoimmune response, steroids and azathioprine are as beneficial
as in MG. In patients with tumours, steroids are often used alone, but the
treatment for the tumour often helps too.
9.3 More about treatment
Pyridostigmine is often less helpful than in MG, but another drug –
29
‘3,4-diamino-pyridine’ (DAP) – works better in LEMS patients; it acts by
boosting the feeble ACh release – the key defect in the LEMS (DAP
makes the electrical messages in the nerves last longer). DAP has to be
used carefully; it is sometimes combined with pyridostigmine. At normal
doses, DAP can cause short-term tingling around the mouth or in the
fingers and toes. At high doses, it can also affect the brain, causing
anxiety, over-excitement and even epileptic fits, but this is very rare below
100 mg per day.
Drug interactions: The damaging antibodies in the LEMS attack calcium
channels in the nerve endings; since drugs like Verapamil and Diltiazem
block these channels, they can make the LEMS worse. They are often
used to treat high blood pressure, and occasionally by anaesthetists, but
should be avoided in the LEMS.
Finally, what causes these antibodies to develop? The thymus seems
not to be involved, and thymectomy is not used. In around half of the
patients, the cause is a mystery, though they often have the ‘DR3--B8’
tissue type common in young myasthenics. The lung tumours in the other
half are an even more striking clue. The tumour cells have very similar
calcium channels that somehow immunise the patients and trigger
production of the autoantibodies that then attack their nerve endings. If
the tumour can be removed or destroyed (with surgery or chemo-therapy),
the antibodies decline and the muscles get stronger. Very interestingly,
having the LEMS is not only a valuable early warning of a lung tumour
(like the MG in thymoma patients): the immune attack seems to slow its
growth so that some patients survive surprisingly better than those without
the LEMS.
9.4 References
Lambert EH, Eaton LM and Rooke ED. 1956. Defect of neuro-muscular
conduction associated with malignant neoplasia. Am J Physiol. 187:
612-3.
Lang B, Newsom-Davis J, Wray D, Vincent A and Murray N. 1981.
Autoimmune aetiology for the myasthenic (Eaton-Lambert) syndrome.
Lancet ii: 224-6.
Bain PG, Motomura M, Newsom-Davis J, Misbah SA, Chapel HM, Lee
ML, Vincent A and Lang B. 1996. Effects of IvIg on muscle weakness and
calcium channel antibodies in the Lambert-Eaton myasthenic syndrome.
Neurology 47: 678-683.
30
Motomura M, Johnston I, Lang B, Vincent A, Newsom-Davis J. 1995. An
improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J
Neurol Neurosurg Psychiatry 58: 85-7.
Maddison P, Newsom-Davis J, Mills KR and Souhami, RL. 1999.
Favourable prognosis in the Lambert-Eaton myasthenic syndrome and
small cell lung carcinoma. Lancet 353: 117-8.
Newsom-Davis J. 2003. Therapy in myasthenia gravis and Lambert-Eaton
myasthenic syndrome. Seminars in Neurology 23: 191-8.
9.5 The Congenital (hereditary) Myasthenias
(see also the MGA’s separate booklet [p iii])
These Myasthenias are quite different from MG and LEMS, and rarer than
either of them (fewer than 1 myasthenic in 30). The weakness in each
patient is generally less variable than in MG, but some children have
bouts when it gets worse and needs special care (see below).
These myasthenias don’t involve the immune system at all, so immune
suppression and thymectomy are not suitable in any way. They are
inherited genetic faults (‘mutations’); in general, since mutations arise
randomly, they can occur anywhere in any gene. So the congenital
myasthenias are a mixed bunch, ranging from mild cases, mainly with
droopy eyelids, to wheelchair users. As ‘congenital’ implies, their
myasthenia is typically noticeable from birth. However, in some, it
becomes obvious only in the teens – by when others may even have
improved – although the inherited fault hasn’t changed (see below).
Typically, patients have obvious weakness in movements of the eyes/
eyelids, face, throat and/or chest. It is often made worse by crying in
babies, and by effort at any age, because of limited staying power. In
infancy, they are often slow in reaching the normal milestones for
movement (walking etc). They may have bouts – often brought on by
infections – when their breathing becomes very shallow or even stops
altogether (apnoea) for short periods (see Known Faults (b), below).
Almost all our genes come in pairs; we get one copy of each from our
mother and one from our father. In most of the congenital myasthenias,
the patient has two faulty copies of one of the key genes, so muscle
triggering is inefficient. Usually, the parents seem healthy because they
each have only one faulty gene (which is ‘recessive’). In such families,
there is a 1 in 4 chance of each subsequent child getting a faulty gene
from each parent and so having myasthenia. The same fault is much
31
more likely to be shared – and therefore to show-up – if the parents are
related, as in cousin marriages. Many of the known inherited faults are in
the AChR: others are now being identified in other nearby genes that
vitally help to cluster the AChRs together.
9.6 History
Families with inherited myasthenias began to be noticed in the 1930s;
they were studied in more detail in the 1970s – after the AChR was shown
to be the target in MG. The next key breakthrough came with the
identification of the AChR genes, first in animals and then (mostly by Prof
David Beeson) in humans (in the 1980s). At first, finding the faults was
very difficult and took several years, both in David’s lab and by Dr Andrew
Engel’s team in the Mayo Clinic (USA). Luckily, the methods improved
dramatically in the early 1990s. Faults in other vital nearby proteins were
first defined only in the late 1990s.
The known faults can lead to either:(a) too few AChRs, the end-result of most recessive faults, whether in
the AChR itself, or in its near neighbour, Rapsyn, that helps to cluster it
correctly. These patients are often helped by pyridostigmine, which gives
the ACh a better chance of triggering, or 3,4-diaminopyridine (DAP),
which boosts the release of ACh (see Fig 1, page 3), or both. There is
more about DAP on p 30, and about pyridostigmine on p 43.
(b) endplate instability specially affecting the limb girdle muscles. That is
caused by faults in ‘Dok-7’, which normally activates Rapsyn to cluster the
AChRs. Ephedrine and salbutamol help to restabilise the endplates, and
muscle strength builds up over several months, whereas pyridostigmine
worsens this particular condition – hence the importance of expert
advice.
(c) too little ACh is released, e.g., because of faults in the production of
ACh in the nerve endings (i.e. in a protein called ChAT). Occasionally, as
young children, these patients have bouts when their chest muscles are
affected and breathing becomes very shallow or even stops altogether
(apnoea) for short periods. Parents and other carers can be trained to
cope with them (see also Section 9.7, page 33): obviously, it is vital that
the risk is recognised so that everyone is suitably forewarned. These
episodes are rare after the age of about 6 years, and the other disabilities
often get milder in the teens.
(d) ‘Over-choking the ignition’. Other cases inherit a single faulty
AChR gene (‘dominant’) from just one of the parents – who is usually
32
affected too – with the ‘slow channel syndrome’. If so, there is a 1 in 2
chance of myasthenia in each subsequent child. These faults are actively
harmful; the abnormal AChR channel allows too much salt (including
calcium) to get into the muscle because it stays open for too long during
triggering. Gradually, this damages the muscle endplates, eventually
causing weakness in childhood or the teens. It often particularly affects
neck movements and finger straightening. Pyridostigmine may actually be
harmful (it leads to even more calcium damage). By contrast, quinidine or
fluoxetine may be helpful; by encouraging the faulty AChRs to close, they
cut down the long-term muscle damage. NB careful monitoring is
essential for cardiac side-effects or mood changes, respectively.
(e) Too much ACh. As we saw in the Diagram (Fig 1, page 3), any spare
ACh is normally broken down by the enzyme AChE. That helps the AChR
– and thus the muscle – to relax and also prevents the endplate damage
mentioned in (d). Defects in the AChE are recessive. Again, ephedrine
and salbutamol may help these myasthenias – whereas pyridostigmine
makes them worse.
9.7 Assessment
Patients with any of these very unusual myasthenias need to go to a
specialist centre for:EMG: Electrical testing of nerve → muscle ignition (EMG), which is often
particularly useful for sorting them out there and then. Finding the faulty
gene is the definitive test (see below). Exact diagnosis helps for advising
the parents about the chances of similar trouble in later children, and
about their care and treatment – which needs to be tailored according to
the particular fault, as we saw in (b, d, e) above. In congenital
myasthenias, night-time breathing difficulties may demand particular
attention; some children may need non-invasive ventilation in bed,
especially when they are unwell.
Since the immune system is not affected, vaccinations can proceed as in
any normal subject, and may be especially important (e.g. against ‘flu or
pneumonia), especially in children at risk of breathing problems.
Genetic diagnosis: For these very rare patients, there are Specialist
Centres at The Hospital for Sick Children, London, at Newcastle-uponTyne – and at Oxford, where Prof Beeson and colleagues also run a
*diagnostic service for identifying the faults (in DNA from blood samples).
Obviously, with so many genes at risk, that can take time. There are
33
surely still more to be found. *(Email: [email protected])
The future. David is also researching possible new treatments to try
selectively to turn off the damaging genes in the dominant forms. The
AChR is built up from five different chains, and one of these (gamma) is
used only by the unborn baby. During the last two months before birth, it
is normally replaced by the ‘adult’ (epsilon) chain – and that is very often
the one at fault in the AChR-deficient cases. So David is also hoping to reactivate the gamma to compensate.
9.8 References
Spillane J, Beeson DJ, Kullmann DM. 2010. Myasthenia and related
disorders of the neuromuscular junction. J Neurol Neurosurg Psychiatry.
81: 850-7.
Websites: On www.genetests.org there is a link via 'gene reviews' to an
excellent overview by Lochmuller.
There is another at www.neuro.wustl.edu/neuromuscular/synmg.html
10
CHILDREN WITH MYASTHENIAS
Before adolescence, autoimmune myasthenia gravis with the typical antiAChR antibodies (anti-AChR+ MG) is rare in Europeans, but a little
commoner in Afro-Caribbeans*. Before adulthood, inherited faults cause a
higher proportion of myasthenias – which are so rare overall that any
patient should be referred to a Paediatric Neurologist with particular
expertise in them. Breathing difficulties are no more troublesome in children with MG than in adults. However, they need careful consideration/
assessment in every child with an inherited myasthenia.
10.1 Treatment
The treatment of autoimmune MG in childhood is similar to that in adults.
However, Neurologists try to avoid high doses of steroids if possible,
because of their potential side-effects, particularly interference with
growth. If they must be used, they can be combined with other immunosuppressants that have ‘steroid-sparing’ effects (e.g. azathioprine).
Thymectomy may well be advised in children with anti-AChR+ MG; after
* Curiously, autoimmune ocular MG is much commoner in young children in
China and Japan.
34
about age 5, the thymus has largely done its duty and its removal causes
no documented immunological problems.
10.2 General measures and advice for any myasthenic child
These are important to help both the parents and the schools to support
children with myasthenia optimally. They include warning them:● of the typical signs, including droopy eyelids, snarling smile and nasal
voice, which may provoke teasing by classmates;
● that the MG may vary during the day and from one day to the next;
● that the myasthenia does not affect the child’s intelligence.
However, it may make reading (from the blackboard) and writing
harder, reduce stamina, or demand a chair of the right height or more
rests than normal. For tests/ exams, extra time, or even a scribe or a
laptop, might help**;
● a Consultant’s support to gain a Statement of Special Educational
Needs may help, e.g. to obtain transport to and from school and / or a
one-to-one helper;
● to take care over swallowing – e.g. not to expect children to take foods
that are difficult to swallow at times when they are weaker than usual;
● they may also have limited strength for games, queuing or putting their
hands up in class;
● that infections often worsen any myasthenias, whether inherited or
autoimmune. Chest infections can be particularly troublesome and
require early assessment and treatment. Diarrhoea and vomiting impair
absorption of drugs, so early advice should be sought.
10.3 Vaccinations
Vaccinations are recommended to prevent certain infections (e.g. ‘flu and
pneumococcal pneumonia).
10.4 Dental Hygiene
Good dental hygiene can reduce the risk of mouth infections; if they do
**The MGA has compiled a helpful check-list of information that schools may
need to be aware of.
35
begin, early assessment and treatment with antibiotics should help.
10.5 In General
For all of these reasons, both parents and schools may need to be extraflexible and keep on the alert.
Although myasthenia in childhood can be draining and limit activities, the
main aim should be to help the child lead as normal a life as possible.
Unreasonable restrictions (‘wrapping the child in cotton wool’) should be
avoided, but sensible precautions and interventions, as noted above,
should be encouraged. One of the most important is to make certain that
the child, the parents and the school are fully and correctly informed about
the particular condition concerned (remember the MGA has a checklist).
10.6 References
Parr JR, Jayawant S. 2007. Childhood myasthenia: clinical subtypes and
practical management. Dev Med Child Neurol. 49: 629-35.
Ashraf VV, Taly AB, Veerendrakumar M, Rao S. 2006. Myasthenia gravis
in children: a longitudinal study. Acta Neurol Scand. 114: 119-23.
11
SPEECH & LANGUAGE THERAPY AND THE MYASTHENIAS
Speech & Language Therapists (‘Therapists’ for short) are often needed
in the assessment and management of difficulties in eating/swallowing
(dysphagia), in articulating words (dysarthria) or in making them heard
(dysphonia), in patients with MG or congenital myasthenias. In the
LEMS, such problems with swallowing and speech are rare: in MG they
can be very serious, leading to choking or inhalation of food – which can
even cause ‘aspiration pneumonia’. Patients may be unaware of
these problems. Obviously, dysphagia can also affect the ability to take
oral medications as well as a balanced diet; it is the presenting symptom
in 5 - 25% of MG patients1. Because it is easily under-estimated,
especially in the elderly2, it should be checked carefully at the patient’s
first visit to a Neurologist, and monitored during follow-up, since MG can
vary so much.
Assessment
Dysphagia, dysarthria and dysphonia are usually first assessed
subjectively at the bedside by the Therapists.
36
To monitor swallowing, they evaluate the movement and strength of the
oral muscles, and feel the laryngeal movements as the patient eats and
drinks. They can thus assess the manipulation of food and fluids in the
mouth, the promptness of swallowing and the guarding of the airway. The
Therapists will also check for any build-up of food or fluid in the pharynx,
and note how many swallows are needed to clear any residue. Patients
with MG swallow more slowly, and require more swallows for the same
quantity of water, than healthy controls3. In specialist centres, swallowing
can be assessed objectively by:- radiological methods1 (e.g. Videofluoroscopy – VDF), endoscopic4 (e.g. Fiberoptic Endoscopic Evaluation of
Swallowing – FEES), manometric4 and electrophysiological studies5,6.
Though often not routinely available, these may help to detect
unsuspected aspiration.
Therapists assess speech both subjectively and objectively, checking
respiratory and phonatory mechanisms. They assess:● the facility of movement of the speech muscles, articulation and
intelligibility;
● the key essentials in the patient’s respiration, phonation and
articulation in speech – especially their strength, speed and range of
movement, accuracy, steadiness and tone;
● the flow, intonation, stress, rhythm and rate of spoken sentences
(‘prosodic features’);
● the overall speech intelligibility, as judged in connected speech tasks.
Formal dysarthria assessments include the Frenchay Dysarthria
Assessment7, The Dysarthria Profile8 and the Assessment of
Intelligibility of Dysarthric Speech9.
11.1 Dysphagia—Swallowing
Swallowing problems can result from weakness and fatigue in the oral,
pharyngeal and/or laryngeal muscles.
In oral-stage dysphagia, weakness and fatiguability of the lips, jaw and
tongue can impair the ability:● to form a suitable gobbet (bolus)1;
● to hold matter in the right part of the mouth without spilling it, whether
out through the lips or back into the throat;
● to chew it effectively; jaw opening and closure are often weak in MG4;
37
● to transfer it to the back of the mouth (ready to swallow);
● to close off the palate and prevent nasal regurgitation.
Pharyngeal-stage dysphagia can be more serious, and is relatively
common in MG. Importantly, it raises the risks not only of under-nutrition
but also of aspiration. In general, residue may spill over into the
unprotected airway or actually obstruct it, e.g. if the pharynx is not
adequately cleared in time or laryngeal elevation is weak and/or delayed1.
Risks of aspiration increase if there is weakness:● in closing the palate against the back of the tongue, because the bolus
may enter the pharynx before the swallow is triggered; if so, it can
easily be aspirated as the airway is still open at this stage1;
● in retracting the base of the tongue, because food can pool in the fold
between the tongue and the epiglottis, and so spill over into the
unprotected airway1;
● in pharyngeal movements, because food may pool in the pyriform
fossae beside the epiglottis1;
● in elevating the larynx (weak or delayed), because this can impair
relaxation of the lower pharynx and closure of the vocal cords, so
increasing the risks of aspiration – both before and during a swallow1.
11.2 Dysarthria—Speech
Weakness or incoordination of key muscles often causes speech
disorders. Clear elocution depends on several subsystems working well
together: weakness in any one of them can result in dysarthria. In MG, the
voice is often flaccid and fades rapidly with continued effort. Respiratory
or laryngeal weakness can cause dysphonia. Characteristic features of
‘myasthenic speech’ are weakness:● in the breathing needed to support speech, resulting in a quiet voice;
● in the laryngeal system, resulting in breathy, quiet and slow speech;
● in closure of the palate, causing ‘nasal’ speech;
● in articulation by the lip, tongue and jaw muscles, with consequently
slurred and laboured speech;
● in facial expression, smiling and pouting the lips3.
38
Management of Dysphagia, Dysarthria and Dysphonia in MG
Simple measures
Obviously, it is wise for patients to eat when they are strongest – e.g.
soon after a dose of pyridostigmine – and maybe to eat little and often;
likewise, to speak in short bursts and then rest. It also helps to sit upright,
and to get the food to the right consistency (e.g. puréed or mashed with
plenty of gravy or custard); Therapists can advise about this and also
about compensatory swallowing techniques. Alas, standard exercises
designed to overcome dysarthria/ dysphonia/ dysphagia are not
recommended because MG patients’ weakness fatigues.
11.3 Special aids
Therapists can also advise about available alternative or augmentative
systems, e.g. voice amplifiers, picture symbol boards, alphabet charts or
communication books.
If these measures are needed, then the patient’s MG probably needs
better control, e.g. with immuno-suppressant drugs.
Finally, some of the drugs used for MG may also impair speech and
swallowing, for example overdosing with pyridostigmine (see Section 13,
page 44). As with other movements, those of eating and speech may get
weaker for 1- 2 weeks when steroids are started (see Section 4, page 16),
and need careful monitoring.
11.4 References
1. Colton-Hudson,A, Koopman WJ, Moosa T, Smith D, Bach D and
Nicolle M. A Prospective assessment of the characteristics of dysphagia
in Myasthenia Gravis. Dysphagia 2002. 17: 147-151.
2. Kluin KJ, Bromberg MB, Feldman EL and Simmons Z. Dysphagia in
elderly men with myasthenia gravis. J Neurol Sci. 1996; 138: 49-52.
3. Weijnen, FG, Van Der Bilt, A, Wokke, JH, Wassenberg MW and
Oudenaarde I. Oral functions of patients with Myasthenia Gravis. Annals
of the New York Academy of Sciences 1998. 841: 773-776..
4. Oda AL, Chiappetta AL, Annes M, Marchesan IQ and Oliveira AS.
Clinical, endoscopical and manometric evaluation of swallow in patients
with acquired autoimmune myasthenia gravis. Arq Neuropsiquiatr. 2002
60: 986-95.
5. Van der Bilt A, Weijnen FG, Bosman F, Van der Glas HW and Kuks JB.
Controlled study of EMG activity of the jaw closers and openers during
39
mastication in patients with myasthenia gravis. Eur J Oral Sci. 2001. 109:
160-4.
6. Ertekin C, Yuceyar N and Aydogdu I. Clinical and electrophysiological
evaluation of dysphagia in Myasthenia Gravis. J. Neurol Neurosurg
Psychiatry 1998. 65: 848-856.
7. Enderby PM. Frenchay Dysarthria Assessment; College Hill Press,
1983.
8. Robertson SJ. The Dysarthria Profile. Working with Dysarthric Clients.
Communication Skill Builders, Inc., Tuscon 1987.
9. Yorkston KM, Beukelman DR, Traynor C. Assessment of Intelligibility of
Dysarthric Speech; Pro-Ed Inc., 1984.
12
VACCINATIONS IN THE MYASTHENIAS
The most commonly raised issues are:(1) whether various vaccines are safe, especially those required for
some foreign countries;
(2) whether MG or LEMS patients need to have any particular vaccines;
and
(3) whether vaccination can trigger or worsen MG or LEMS.
Vaccination is a way of preventing infections. Vaccines contain germs, or
their products, made harmless. Still recognisable by T and B cells, they
can be given in advance, thus stimulating these cells to multiply and
forearm us before the real menace comes along.
Everything said below applies equally to ALL the ‘autoimmune’
groups – MG (anti-AChR or anti-MuSK) or LEMS.
According to the method that made the germ harmless, vaccines are
divided into three types (see Table 1, page 42):Type 1. Live Attenuated Vaccines: i.e. the live germ has been altered to
ensure that it will not cause full-blown disease when given to healthy
subjects;
Type 2. Inactivated vaccines: here the germ has been killed;
Type 3. Inactivated toxins: here the dangerous toxin (e.g. of Diphtheria) is
first purified and inactivated before injection.
Vaccines of types 2 and 3 can be given to all patients with MG, so it
is only the live attenuated vaccines where care needs to be taken.
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12.1 Whether various vaccines are safe
Since MG itself does not affect handling of vaccines, patients who are
only on pyridostigmine or DAP, and/or have simply been thymectomised,
can have all vaccines – even those of Type 1. In patients taking
prednisolone, azathioprine, or any of the other immuno-suppressive
drugs, the only concerns are that their immune systems might be so
weakened that:(a) they can’t control even the modified form of the germ in a live
vaccine;
(b) they simply fail to respond to the live vaccine, even if it doesn’t get
out of hand.
The current advice from the Department of Health is that patients on
immuno-suppressive treatments – such as steroids, azathioprine,
ciclosporin, methotrexate, mycophenolate mofetil or cyclophosphamide –
should not receive vaccines of type 1 for the first time if they have
significant immuno-suppression. In this country, that arises very rarely,
because most of these vaccines are given in early life, long before the
onset of MG, and should then confer life-long protection, e.g. against
measles, German measles, mumps, tuberculosis (BCG) and polio. If
needed, booster doses can be given despite immuno-suppression,
because most established immune ‘memory’ is so robust that it survives
steroid treatment. Conversely, for young females, it may be wise to
consider getting immunised against cervical cancer (both vaccines are
killed) before starting immuno-suppressive treatments, so as to get better
responses.
Before travelling to certain high-risk areas, people are sometimes advised
to have a polio booster. In general, it is safest to stick to the killed vaccine.
The rest of the Type 1 vaccines are usually only needed before foreign
travel, as diseases such as yellow fever cannot be caught in the UK. The
safest advice is for immuno-suppressed patients not to travel to countries
where they are at risk of catching these diseases as there is no
completely safe way of protecting them by vaccination.
12.2 Are there any vaccines that MG patients should have?
This mainly applies to patients on immuno-suppressive treatment, who
have a slightly higher risk of infections. Yes, it may be wise for some of
them to have additional vaccines to protect against pneumonia and ‘flu
(influenza); indeed, these are given routinely to most patients on longterm immuno-suppressants nowadays, particularly the old and infirm who
are most at risk. If so, then the GP can give a ‘flu vaccination in the
41
autumn of each year which should provide 70% protection for that winter,
and perhaps a pneumococcus jab (every ten years) too.
12.3 Can vaccination trigger or worsen MG?
There is no convincing evidence that any vaccination affects MG or LEMS
symptoms in any way. Conversely, it is well known that episodes of
infection can bring on myasthenic crises: since vaccines help to prevent
some of these infections, it seems sensible for MG patients to have them
where appropriate.
In summary, MG by itself does not affect vaccination, so these warnings
only concern people on immuno-suppressive treatments – which they
should remember always to mention before they are given vaccines; a
good rule of thumb is that live attenuated vaccines should be avoided,
while the others are safe.
For additional information please consult the ‘NHS Immunisation Against
Infectious Disease’ book. Every doctor should have a copy.
Table1 Vaccines commonly used against the Germs listed
*The ‘Meningococcus’ is now called Neisseria meningitidis and can also
cause sepsis; the Pneumococcus, now called Streptococcus pneumoniae,
can also cause sepsis and meningitis.
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13
DRUGS USED TO TREAT MG, AND THEIR SIDE-EFFECTS
[NB for plasma exchange and IvIg see Section 4, page 14]
The ideal drug would be 100% effective and have no side-effects. As
yet, no such drug is known to man – even humble aspirin can kill: but it
can also do a lot of good. So we always have to balance the benefits
against the side-effects. All of the drugs that we use to treat MG can
cause problems, some of them serious and potentially fatal. With careful
instruction and close monitoring (e.g. regular blood tests), most patients
find a combination that substantially helps their MG without undue sideeffects. This section lists all of the drugs that we use to treat MG and
their most important drawbacks.
13.1 Pyridostigmine (Mestinon® )
Virtually everybody with MG is given pyridostigmine at the time of
diagnosis, often with a dramatic improvement in symptoms. Some may
be able to stop it later when thymectomy or immuno-suppressant drugs
have taken effect, but others need it indefinitely. Since its effects last
only a few hours, it is more important to take it frequently than to worry
about the exact dose, which may vary a lot, even in the same patient. A
few patients prefer the related drugs neostigmine and distigmine – but
their mode of action and side-effects are all the same.
Pyridostigmine blocks the enzyme acetylcholinesterase (AChE in Fig 1,
page 3) which breaks down the chemical transmitter ACh at the nerve →
muscle junction, resetting everything for the next command to move the
muscle. When its breakdown is blocked, the ACh survives longer and
has a better chance of triggering.
‘Automatic’ organs like the bowels and the bladder use different ‘smooth’
muscle cells, but they are also activated by ACh. So pyrido-stigmine
stimulates them too, quite often causing tummy cramps, excessive wind,
and diarrhoea; that can be reduced by taking it with bland food such as
crackers or milk. It can make a few patients want to pass water more
often or even cause incontinence. Less commonly still, the heart may
slow down, which can lead to light-headedness, and there may be
drooling at the mouth. The focussing and pupil muscles in the eyes may
be affected too, causing blurred vision.
All of these problems can be prevented by drugs that block only these
unwanted effects on smooth muscles and glands. The commonest
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include propantheline and atropine, but there are others. They are
taken about half an hour before the pyridostigmine.
Too much pyridostigmine, and thus too much ACh, over-stimulates
voluntary muscles and (curiously) increases MG weakness, as well as
causing obvious ‘automatic’ side-effects (as above). That sometimes
used to develop into a cholinergic crisis – and the cure was to cut
down the pyridostigmine. Though the ‘automatic’ side-effects can be
a valuable clue, it is sometimes a little difficult to distinguish that from
a myasthenic crisis, where more treatment is needed. Cholinergic
crisis is extremely unlikely if the total daily dose of pyridostigmine is
kept below seven tablets (60mg) a day. Indeed, if somebody needs
more than six tablets a day, their MG clearly needs better control with
additional treatments.
Mestinon® ‘prolonged release’ tablets 180 mg
On a ‘named patient’ basis, these tablets are currently being
imported:- either ‘Mestinon Retard®’ (from Europe by Meda Pharmaceuticals), or ‘Mestinon Timespan®’ (from the USA via IDIS); both are
quite expensive.
According to Meda (formerly Valeant or ICN):1. Although not true ‘slow-release’ preparations, they do have a
prolonged duration of action, because the pyridostigmine is
incorporated into a matrix that releases it more slowly as it passes
through the stomach and intestine. Obviously, the aim is for more
sustained blood levels and a steadier course of action over a longer
period than with pyridostigmine.
2. Since both formulations contain *three times the standard (60mg)
dose of the drug, they may give higher peak plasma concentrations
about 1 hour after administration. Thus one might expect more sideeffects on the bowels etc. However, the plasma level should also take
longer to fall below the therapeutic level, giving cover for 6 - 8 hours.
3. Therefore, the 180mg tablets may be most suitable for overnight
cover, when side-effects can be borne better. It might also save
patients from waking up at about 3am to take another tablet to give
them strength in the early morning. So they might be most useful
in patients with the rare congenital myasthenias, where few other
treatments are available. For those with the commoner autoimmune myasthenias, other options, e.g. immunosuppressants,
* It might seem a good idea to take only half a tablet at a time, e.g. in children,
but breaking the tablet affects the ‘prolonged release’ action.
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might be the next step if their symptoms are so troublesome.
NB There are no published studies of the advantages or drawbacks of
either Mestinon ‘Retard®’ or ‘Timespan®’, and very little experience of their
use in the UK. Therefore, they should be taken only on the advice of each
patient’s Consultant.
13.2 3,4-diamino-pyridine ‘DAP’
This is used most for the LEMS and some congenital myasthenias (see
Section 9, page 30).
13.3 Steroids
(see Section 4, page 16, for more about their natural counterparts)
Although other drug preparations can be used, the vast majority of
patients are treated with prednisolone, one of the corticosteroid group of
drugs (steroids for short) that are used to treat many diseases like MG.
(They are quite different from the anabolic steroids abused by athletes
and body builders). They help MG by suppressing the immune system
that is producing the damaging autoantibodies. So do many other
immunosuppressant drugs (see below), though they work rather
differently and have only a few side-effects in common.
The list of potential side-effects from corticosteroids sounds horrendous.
Most patients will notice some problems, particularly early on in their
treatment when doses tend to be higher. Usually, in the end, they find a
reasonable balance between benefits and drawbacks, but occasional
patients just can’t tolerate them.
Taking prednisolone every other day rather than every day reduces the
risk of problems, even though the total dose is the same. Obviously,
keeping the dose as low as possible helps, but, if it goes too low, the MG
may relapse. The ‘cruising dose’ varies a lot between patients.
Some of the side-effects are just annoying and upsetting, and others are
potentially very serious, though patients don’t always agree which belong
to which group (e.g. weight gain).
Annoying problems
Weight: Steroids are well known to cause weight gain, which can become
a major health issue. It results from increased appetite, fluid retention,
and an altered distribution of fat – with the typical moon-shaped face of
people who have been on steroids for a long time. Careful attention to diet
45
helps – easier said than done, alas.
Bad sleeping can be a real nuisance, particularly at higher doses.
Mood change is common. A few patients feel unduly elated, but more
get depressed; mercifully, that is rarely severe.
A greasy skin, an acne-like rash or excess hair growth may be
distressing. With prolonged and high-dose treatment, the skin becomes
thinner and is easily damaged or bruised, even after minor bumps.
Serious problems
Although some of the serious side-effects are commoner at particularly
high doses of prednisolone, the main risk factor is the duration of
treatment and the total dose that has been taken over that time. In other
words, there is a cumulative build-up of problems.
Infections. Unfortunately, steroids and immuno-suppressant drugs are
not clever enough to knock out only the damaging antibodies. If they are
working, they are bound to suppress the ‘good’ antibodies and immune
cells that protect us against infections – which are thus an inevitable risk.
Surprisingly, in practice, that is not a common problem; occasionally,
however, patients get severe infections, quite often with germs that rarely
cause problems in healthy (untreated) people, but which can be fatal if not
treated aggressively.
Osteoporosis. Our bones get thinner and more fragile as we get older.
Steroids greatly speed up the process and substantial thinning can occur
within months of starting on a high dose. There is still debate about how
best to handle that, and national guidelines are still being discussed.
Some doctors only start treating if bone density scans (Dexa scan) show
thinning, while others prefer to start preventive drugs at the same time as
the steroids. The main ones are ‘bisphosphonates’ and include etidronate,
alendronate and risedronate, although new ones are appearing all the
time. There is some uncertainty about their long-term safety, and they
should not be taken during pregnancy.
Patients can help themselves to avoid osteoporosis by taking:regular exercise (especially weight-bearing); no tobacco; a diet containing
plenty of calcium, or possibly taking a tablet containing calcium and
vitamin D (which helps to absorb the calcium).
Diabetes. The sugar level in the blood increases in most people taking
steroids; in some, it is high enough to be called diabetes. This can have
46
long-term damaging effects on many parts of the body. Careful diet can
help, but tablets may be needed to keep the blood sugar down; insulin is
rarely required for this type of diabetes.
High blood pressure has long-term damaging effects on many parts of
the body and is a major risk factor for stroke and heart attack. It should be
checked regularly; if persistently high, it will need tablet treatment.
Cataracts are another common problem in older age that steroids bring
on earlier. When vision starts to get worse, surgery is required.
Peptic ulcers are a particular problem in patients taking high doses of
steroids. We often recommend starting drugs to protect the stomach when
patients with known indigestion start on steroids.
Myopathy means muscle damage, which of course is what we are trying
to cure! However, high-dose steroids, especially if taken over a long time
and every day, can cause myopathy. It can be confused with worsening of
the MG, but gets better when the steroid dose is reduced. It seems to be
very rare with alternate day treatment.
Failing to react to stress (see also Section 4, page 16). We naturally
produce more steroids to tide us over severe physical stress, e.g. during
infections. Because steroid treatment suppresses that defence, and also
damps downs inflammatory reactions, the body may ‘collapse’ suddenly,
with failure of many organs. As long as the doctors know, they can treat
that by simply increasing the dose of steroids, as they routinely do to
cover operations, for example. So patients on steroids must always
wear a bracelet or carry a card to warn their carers.
Likewise, it is important that steroids are not stopped suddenly, because
the body’s own steroid-producing ‘adrenals’ have been suppressed by the
tablets and can’t immediately switch back on again. Indeed, even when
steroid tablets have been tailed off gradually, the adrenals may still not be
able to react normally to crises for many months afterwards.
13.4 Other immunosuppressant drugs (see also Section 4)
Like steroids, these drugs slow the production of the antibodies that cause
the MG, and likewise increase the risk of infections. Azathioprine is the
most widely used (see below); it is the only one that has been thoroughly
assessed in clinical trials in MG and proved to be beneficial. It especially
helps to keep steroid doses down, though it takes months to ‘kick-in’.
Most of the others are clearly more powerful immunosuppressants and
act sooner (as shown in transplant recipients or rheumatoid arthritis, for
47
example). They also tend to have more side-effects, but have not yet
been proved to bring more benefits / fewer snags in MG. We use them
most when MG is severe, or azathioprine has failed or can’t be tolerated.
They include methotrexate, ciclosporin A, cyclophosphamide and mycophenolate mofetil. Most of the problems with azathioprine, discussed
below, apply to these drugs as well, if not more so, but there are a few
additional specific problems.
Use in pregnancy (see also Section 6 page 23). Azathioprine seems to be
safe, but these other drugs are either known to cause problems for the
developing baby, or haven’t yet been shown to be safe. Methotrexate and
cyclophosphamide can also affect sperm and egg generation. They should
not be taken by men or women trying to have a child. Men are
recommended to get some sperm banked before these drugs are started
(or to stop the drug at least a year before giving sperm).
Methotrexate can also cause a serious lung problem (pneumonitis); cough
and breathlessness are warning signs. Ciclosporin A can cause an
increase in blood pressure and can impair kidney function. Cyclophosphamide can lead to cancer of the bladder. Apart from azathioprine, these
drugs should not be combined with breast-feeding.
Back to azathioprine, the other main problems relate to ‘allergy’, liver
and bone marrow/ blood disorders (as with many drugs): see below about
the risk of cancer. In general, some people (about 1 in 200) are
particularly sensitive to azathioprine because they have an inherited
weakness in breaking it down; thus it builds up quickly and causes
poisoning. In theory, we can do a blood test for that in advance, but it is
not essential or widely available: standard simple early monitoring is
clearly sufficient.
‘Allergic’ reactions include ‘flu-like symptoms, nausea, vomiting and
diarrhoea. They are very troublesome in around 1 in 20 people, and
develop very soon after starting the tablet. If so, the drug has to be
stopped, when the symptoms should resolve rapidly.
Liver The drug can upset liver function (one reason why routine blood
tests are essential). That usually happens early and is very rare once the
patient is well established on it. It settles quickly once the drug is stopped
and causes no long-term damage. Blood tests should be arranged (by the
GP) – weekly at first and, if all is well, gradually less often, ending up with
tests every three months.
Blood Azathioprine can slow the production of new blood cells,
48
particularly the white cells (as you remember, they are involved in
antibody production and the normal immune response). A mild drop in
their numbers is normal; indeed, some doctors use it as a sign that they
are giving enough of the drug. A marked fall in numbers of neutrophils is
dangerous, as it increases the risk of infections. Strangely, the red blood
cells increase in size, another sign of adequate dosage. Regular blood
tests are needed (as for the liver), and the drug must be either stopped or
reduced in dose if they reveal problems.
Cancer In the long term, most of these ‘other’ immunosuppressants can
increase the risk of developing some cancers, particularly skin warts and/
or tumours, so patients should be careful about sun exposure. In transplant recipients, azathioprine carries risks of tumours of the lymph glands
(lymphomas), but that has hasn’t specifically been proven in MG. At worst,
any increase in risks is low. Nevertheless, in this litigious age, it is important for the doctor to at least discuss the issue. As always, one has to
balance such possible risks against the proven benefits of the drug; don’t
forget that it helps to improve the control of the MG with lower doses of
steroids, thus lowering the risks of all their complications. Reassuringly,
most forms of lymphoma respond well to treatment.
13.5 References
Gold R, Schneider-Gold C. 2008. Current and future standards in
treatment of myasthenia gravis. Neurotherapeutics. 5: 535-41.
Sathasivam S. 2008. Steroids and immunosuppressant drugs in
myasthenia gravis. Nat Clin Pract Neurol. 4: 317-27.
Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for
myasthenia gravis. Cochrane Database Syst Rev. 2008 23; CD002277
Hilton-Jones D. 2007. When the patient fails to respond to treatment:
myasthenia gravis. Pract Neurol. 7: 405-11.
Hilton-Jones D, Palace J. 2005. The management of myasthenia gravis.
Pract Neurol 5: 18-27.
Skeie GO, Apostolski S, Evoli A, Gilhus NE, Hart IK, Harms L, HiltonJones D, Melms A, Verschuuren J, Horge HW. Guidelines for the
treatment of autoimmune neuromuscular transmission disorders. Eur J
Neurol. 2006; 13: 691-9.
Keesey JC. Clinical evaluation and management of myasthenia gravis.
Muscle Nerve. 2004; 29: 484-505.
Jani-Acsadi A, Lisak RP. 2007. Myasthenic crisis: guidelines for
prevention and treatment. J Neurol Sci. 261: 127-33.
49
Lacomis D. 2005. Myasthenic crisis. Neurocrit Care. 3: 189-94.
Hetherington KA, Losek JD. 2005. Myasthenia gravis: myasthenic vs
cholinergic crisis. Pediatr Emerg Care. 21: 546-8.
14
DRUGS THAT CAN MAKE MYASTHENIAS WORSE
In theory, more than 30 drugs – used currently for many different
conditions – can interfere with nerve → muscle transmission (all listed in
tables further on). Nature has made the ignition system very secure;
normally there is such a safety factor that, even if a drug interferes by up
to 50%, there is still enough in reserve to prevent any weakness. The
problem in MG is that the reserves are low; only a very slight further dip in
transmission can make things a lot worse.
Below is a list of drugs that can make myasthenia worse; while reading it,
try to remember these very important general guidelines:(a) When the myasthenia is well controlled, the safety factor of
nerve→muscle transmission has been largely restored, which is why the
patient is stronger. If so, the listed drugs are unlikely to cause a major
problem, although mild worsening may be noticed, and one must keep on
the lookout.
(b) Obviously, therefore, patients with poorly controlled MG are most at
risk from such drugs. Infections (e.g. pneumonia) can make myasthenia
worse (myasthenic crisis). If it is a serious infection, then one of the
powerful antibiotics on the list may have to be used, with the risk of
making the myasthenia worse still. So the hospital specialists need to
be fully aware of all of the potential problems and must be ready to
deal with them.
(c) Any reaction to any drug can be very specific to the individual patient –
including worsening of MG. So some drug reactions are rare, and most
people with MG would never get them.
(d) Some drugs have been proved to affect nerve → muscle transmission. Many others are suspects but have never actually been tested:
indeed our only evidence against them may be that one MG patient
became weaker after taking it. As you know, MG weakness can vary a lot
from day-to-day without any obvious cause, so some drugs have probably
been blamed unfairly for a dip that was purely coincidental.
(e) The take-home message is very simply to check the list of suspect
drugs when starting any new one; if it is there, both the MG patient and the
50
prescribing doctor should be aware that it might worsen the MG. They
should also remember that, with any drug, they might be the first to notice
a problem – especially if that drug is an unusual one, or a newcomer. So
its absence from the list is not a cast-iron guarantee of an easy ride.
(f) The Tables give warnings, not a list of banned drugs. While doctors
will always try and use safe alternatives, some of those on the list may be
life-saving (e.g. for a resistant germ); if they really are needed, it may still
be possible to control any effects on the MG.
(g) All drugs have what is known as a proper, or generic, name. These are
sometimes rather long and complicated and drug manufacturers use
shorter names, not least so that they can patent them. A single drug may
be known by literally dozens of brand names. Also, drugs are sometimes
combined and prescribed under a name that doesn’t clearly indicate the
individual components. It is now recommended that doctors only use the
proper (generic) names of drugs – the only ones used here. If popular
trade names were used, there would be a danger of omissions; also, such
names may come and go.
Every drug, whether prescribed by the doctor or bought over the
counter, has to be labelled with the proper name – so check that!
14.1 Antibiotics and anti-malarials (see Table 2 on next page)
These are used to treat infections and are amongst the commonest drugs
prescribed by GPs. Remember that the infection rather than the drug
might be worsening the MG, and it may be hard to know which to blame.
The antibiotics most likely to worsen MG are usually given in hospital, by
injection, for very serious infections. The one exceptional drug that must
be avoided in myasthenias is the ketolide antibiotic Telithromycin
(Ketek®), which has caused deaths.
Drugs for malaria are also sometimes used to treat rheumatic
problems.
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Table 2 Antibiotics and anti-malarials
Table 3 Drugs for the heart
52
14.2 Drugs for the heart (see Table 3 on next page)
Beta-blockers are widely used to treat high blood pressure and angina,
and occasionally also for anxiety. A fairly common side-effect is a feeling
of tiredness, but rarely they may specifically worsen MG. New ones are
being introduced all of the time so this list may not be complete. Most of
their names end in –olol.
14.3 Drugs used in neurology and psychiatry (See Table 4 below)
These drugs are used for a wide range of neurological and psychiatric
disorders. For most of them, the evidence that they cause problems in MG
is limited and none is absolutely banned, but it is sensible to be cautious,
as with all new prescriptions.
Table 4 Drugs used in neurology and psychiatry
14.4 Muscle relaxants
These are discussed under anaesthesia (see Section 8, pages 26-7).
Finally
Typical MG can appear in some rheumatoid arthritis patients who are
treated with the drug penicillamine, which is therefore best avoided.
53
Myasthenia Gravis Association
The College Business Centre,
Uttoxeter New Road, Derby
DE22 3WZ
Tel: 01332 290219
Freephone UK: 0800 919922
Freephone Eire: 1800 409672
Web Site: www.mgauk.org.uk
Email: [email protected]
MGA is a Registered Charity No. 1046443
February 2012
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