A Practical Approach To Managing Patients With Myasthenia Gravis

REVIEW
published: 07 July 2020

doi: 10.3389/fneur.2020.00604
A Practical Approach to Managing

Patients With Myasthenia
Gravis—Opinions and a Review of
the Literature
Maria Elena Farrugia 1* and John A. Goodfellow 1,2
1
Neurology Department, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom,
2
Neuroimmunology Laboratory, Laboratory Medicine and Facilities Building, Queen Elizabeth University Hospital, Glasgow,
United Kingdom
When the diagnosis of myasthenia gravis (MG) has been secured, the aim of
management should be prompt symptom control and the induction of remission or
minimal manifestations. Symptom control, with acetylcholinesterase inhibitors such
as pyridostigmine, is commonly employed. This may be sufficient in mild disease.
There is no single universally accepted treatment regimen. Corticosteroids are the
Edited by:
mainstay of immunosuppressive treatment in patients with more than mild MG to
Nils Erik Gilhus, induce remission. Immunosuppressive therapies, such as azathioprine are prescribed
University of Bergen, Norway in addition to but sometimes instead of corticosteroids when background comorbidities
Reviewed by: preclude or restrict the use of steroids. Rituximab has a role in refractory MG, while
Jeannine Mariette Heckmann,
University of Cape Town, South Africa plasmapheresis and immunoglobulin therapy are commonly prescribed to treat MG crisis
Carlo Antozzi, and in some cases of refractory MG. Data from the MGTX trial showed clear evidence that
Carlo Besta Neurological Institute
(IRCCS), Italy
thymectomy is beneficial in patients with acetylcholine receptor (AChR) antibody positive
*Correspondence:
generalized MG, up to the age of 65 years. Minimally invasive thymectomy surgery
Maria Elena Farrugia including robotic-assisted thymectomy surgery has further revolutionized thymectomy
[email protected] and the management of MG. Ocular MG is not life-threatening but can be significantly
disabling when diplopia is persistent. There is evidence to support early treatment with
Specialty section:
This article was submitted to corticosteroids when ocular motility is abnormal and fails to respond to symptomatic
Neuromuscular Diseases, treatment. Treatment needs to be individualized in the older age-group depending on
a section of the journal
Frontiers in Neurology specific comorbidities. In the younger age-groups, particularly in women, consideration
Received: 16 April 2020
must be given to the potential teratogenicity of certain therapies. Novel therapies
Accepted: 25 May 2020 are being developed and trialed, including ones that inhibit complement-induced
Published: 07 July 2020
immunological pathways or interfere with antibody-recycling pathways. Fatigue is
Citation:
common in MG and should be duly identified from fatigable weakness and managed with
Farrugia ME and Goodfellow JA
(2020) A Practical Approach to a combination of physical therapy with or without psychological support. MG patients
Managing Patients With Myasthenia may also develop dysfunctional breathing and the necessary respiratory physiotherapy
Gravis—Opinions and a Review of the
Literature. Front. Neurol. 11:604.
techniques need to be implemented to alleviate the patient’s symptoms of dyspnoea. In
doi: 10.3389/fneur.2020.00604 this review, we discuss various facets of myasthenia management in adults with ocular
Frontiers in Neurology | www.frontiersin.org 1 July 2020 | Volume 11 | Article 604

Farrugia and Goodfellow Practical Approaches to Myasthenia Management
and generalized disease, including some practical approaches and our personal opinions
based on our experience.
Keywords: ocular myasthenia, generalized myasthenia, refractory myasthenia, thymectomy, myasthenic crisis,
fatigue, dysfunctional breathing
INTRODUCTION the aim of dampening the underlying immunopathology causing

the disease. The aim of treatment is to induce remission
Myasthenia gravis (MG) is a rare acquired autoimmune disorder (pharmacological in the majority or complete stable remission
of the neuromuscular junction (NMJ), caused by antibodies which is rarely achieved) or minimal manifestations (MM).
that target the post-synaptic membrane (1). These antibodies The Myasthenia gravis Foundation of America (MGFA) post-
commonly are to the nicotinic acetylcholine receptor (AChR) intervention status (PIS) (4) defines MM in a patient who
but in a smaller proportion of cases, antibodies to muscle has no symptoms or functional limitations from MG but has
specific tyrosine kinase (MuSK) or to lipoprotein receptor- some weakness on examination of some muscles. There are four
related protein 4 (Lrp-4) can be present instead (1–3). In an different categories of MM depending on whether the patient
even smaller cohort of MG patients, no antibodies are detected is receiving treatment and if this includes immunosuppression
on conventional antibody assay testing and we refer to these and/or symptomatic treatment (for example pyridostigmine as
patients as “seronegative.” Patients with MG typically present will be discussed below). This contrasts to complete stable
with fatigable muscle weakness. They commonly present first remission (CSR) where the patient has no symptoms of MG and
with ocular manifestations such as asymmetrical fatigable ptosis no weakness (excluding residual weakness of eye closure) and
with or without blurred or double vision. The majority, however, has received no therapy for a minimum period of 1 year, and
evolve further into generalized muscle weakness involving the pharmacological remission (PR) which is the same as CSR but
facial and bulbar muscles, the neck and axial muscles and the the patient would have received some therapy for MG excluding
limbs, with the upper limbs often being more severely affected symptomatic treatment.
than the lower limbs. In myasthenic crisis, the severe end of
the disease spectrum, there is neuromuscular dysphagia rapidly
evolving into complete loss of swallow function, and often SYMPTOMATIC THERAPIES
in association with respiratory muscle weakness and type 2
Pyridostigmine is by far the most commonly used symptomatic
respiratory failure. This is a clinical emergency that requires
therapy. This is an acetylcholinesterase inhibitor which blocks the
management in an intensive care setting. Therapies in the field
degradation of acetylcholine at peripheral cholinergic synapses,
of MG have significantly advanced over the years. Now, more
including the neuromuscular junction (NMJ). Originally,
than ever, the treating physician must carefully contemplate
physostigmine and prostigmine (neostigmine) were identified
which treatments are best suited for an individual MG patient
by Mary Broadfoot Walker, a physician in Scotland in the late
since the “one size fits all” approach may not be as relevant.
1880s, as drugs that temporarily improved muscle strength in
There are specific clinical scenarios where one must be extra
patients with MG (5). These drugs work by prolonging the
cautious, for instance the newly diagnosed young female patient,
action of any acetylcholine released into the synaptic cleft and
who may be imminently planning a pregnancy, in contrast to
compensates for the structural and functional deficits in NMJ
a newly diagnosed elderly patient with multiple comorbidities.
transmission that characterizes MG. In early or mild disease
This review discusses the literature with some emphasis on our
pyridostigmine allows significant and rapid improvement
practice based over a time-span of over a decade where we have
in muscle strength (6, 7). However, with longstanding or
treated an excess of 900 MG patients.
severe disease this pharmacological compensation may be
insufficient and there may be minimal clinical effect. Peak
PHARMACOLOGICAL THERAPIES IN blood levels of pyridostigmine occur 1.5–3 h after oral intake
but significant clinical effect occurs within 30 min. Dosing 4–5
GENERALIZED MG times per day leads to very stable blood levels. Renal impairment
Medical therapies are used in MG patients for either direct leads to reduced clearance of pyridostigmine and doses must
alleviation of symptoms, or as immunomodulatory drugs with be adjusted.
Patients are usually prescribed doses of 180–240 mg daily but
patients may require up to 480 mg daily. Although generally
Abbreviations: AChR, Acetylcholine receptor; C5, Complement component 5;
CSR, complete stable remission; DM1, myotonic dystrophy type 1; EFT, early
well-tolerated, side effects from pyridostigmine are very
fast-acting treatment; FSHD, Facioscapulohumeral muscular dystrophy; IvIG, common, are usually dose dependent, and can be debilitating
intravenous immunoglobulin; MG, Myasthenia gravis; MGFA, Myasthenia Gravis necessitating reduction of dose or slower titration. Most side
Foundation of America; MGTX, thymectomy trial in non-thymomatous MG effects arise from the action of pyridostigmine at non-NMJ
patients; MM, minimal manifestations; MMF, mycophenolate mofetil; MuSK, muscarinic peripheral synapses and include, gastrointestinal
Muscle specific tyrosine kinase; NIV, non-invasive ventilation; PE, plasma
exchange/plasmapheresis; PIS, post-intervention status; PR, pharmacological
disturbance (abdominal cramps, bloating, diarrhea, frequency,
remission; RATS, robotic assisted thymectomy surgery; VATS, Video-assisted nausea), urinary frequency, hypotension, bradycardia, sweating,
thoracoscopic surgery. salivation, lacrimation, increased bronchial secretions, and

other symptoms of cholinergic excess. Some elderly patients calcium and improves muscle strength in MG (15). This remains
can be extremely sensitive to the cardiac side effects and have an experimental drug.
experienced syncope even with low doses of pyridostigmine.
Some asthmatic patients may show increased sensitivity and
experience increased bronchospasm with pyridostigmine. At IMMUNOMODULATORY THERAPIES FOR
high doses side effects can be severe, and lead to the entity of GENERALIZED MG
“cholinergic crisis,” where neuromuscular weakness worsens
along with the above symptoms leading to bulbar or respiratory Corticosteroids
crisis from drug excess rather than worsening MG (8). Such Prednisolone or prednisone constitute the main
extreme manifestations are uncommon but it is very frequent immunomodulatory therapy in the long-term management
for patients to have gastrointestinal symptoms on starting of patients with MG (16, 17). The majority will require long-
or increasing doses. These tend to lessen within a few days term oral corticosteroid therapy and it is crucial to have
but can persist in some. Propantheline is an antimuscarinic the appropriate discussion with newly diagnosed patients,
agent that counteracts many of the cholinergic side effects of indicating that this will not be a short course of treatment.
pyridostigmine without reducing its action at the NMJ. It can It is equally important to discuss with patients the long list
be very effective at reducing the side effects of pyridostigmine of potential side effects from steroids, necessitating bone and
if given ∼15 min beforehand. Loperamide can alternatively be gastric protection. Patients should also be adequately monitored
prescribed but is not as effective at reducing the other muscarinic for the development of diabetes mellitus, hypertension, with
side effects. When patients fail to respond to pyridostigmine, careful counseling on potential excessive weight gain and
the physician should be cautious about increasing the dose the necessary dietary changes that they may need to pre-
particularly in dysphagic patients, since pyridostimgine emptively and pro-actively address. Other side effects include
will increase salivary secretions and exacerbate their the formation of cataracts, raised intraocular pressures, mood
swallowing difficulties. and sleep disturbances, peripheral oedema and susceptibility
Neostigmine is an alternative acetylcholine esterase inhibitor to frequent infections or even sepsis. The latter may result
that can be used in MG (9, 10). This should only be given in failure of response to conventional MG therapies or even
via the subcutaneous route in MG and not intravenously. It a chronic refractory state and decline in status with multiple
is useful in patients with MG who cannot absorb via the oral hospital admissions.
route (e.g., a MG patient with acute bowel obstruction) but There can be a paradoxical worsening of MG symptoms
should not be first line if the patient has impaired swallow. on commencing corticosteroids at high doses (18). Therefore,
Swallowing difficulties are very common in patients with MG our practice is to start at a low dose and escalate the dose
and if there are concerns about aspiration with oral intake, gradually (16). Our initial practice was to use an alternate day
including medications, the first strategy should always be to place regimen of steroids, where side effects are probably reduced
a nasogastric tube and administer pyridostigmine via this. Only when compared to the daily dosing schedule. However, we have
if this cannot be undertaken should subcutaneous neostigmine encountered many difficulties with the alternate day regimen
be used. It has the same side effect profile as pyridostigmine including patients and physicians in primary and secondary care
albeit with more marked cardioinhibitory effects and a shorter becoming easily confused, and we have therefore resorted, in
half-life leading to more frequent dosing. However, neostigmine the last 3 years or so, to applying the daily steroid regimen.
should always be used with caution since it may cause excessive We initiate prednisolone at 5 mg daily and increase every third
salivary secretions and as a result may further negatively impact dose (day) by 5 mg until we achieve stability in MG symptoms
and exacerbate swallowing difficulties. and significant improvement, with our ceiling dose usually being
Experimental models of AChR deficiency show how oral 50 mg daily but higher doses have been prescribed in a few
ß-2 adrenergic receptor agonists such as salbutamol enhance select cases.
function of the NMJ (11). Oral salbutamol can rarely be of We treat the majority of patients in the outpatient setting,
clinical utility in mild autoimmune MG disease too especially giving clear instructions to the primary care physician and to
where the patient has not tolerated pyridostigmine. We have the patient, with contact details of the myasthenia team. The
used successfully in a couple of patients. Side effects commonly nurse specialist phones in on the patient regularly to ensure
include tachycardia, tremor and a sense of anxiety and these that the treatment plan is being ensued and to monitor patients’
can be limiting factors. MG patients with MuSK antibodies symptoms over the phone. In patients demonstrating significant
tolerate albuterol and 3,4-diaminopyridine (12) more than bulbar weakness, our preference is to admit them immediately
pyridostigmine which, in MuSK-MG, is commonly associated to the neurology ward and to initiate treatment accordingly
with enhanced side effects especially of cramp and muscle including symptomatic treatment with pyridostigmine and
fasciculations. A small clinical trial (phase IIB) studying where necessary intravenous immunoglobulin (ivIG).
amifampridine phosphate in MuSK-MG demonstrated this drug With the slow steroid dose escalation that we apply, patients
to be safe and effective (13). Ephedrine, a sympathomimetic improve after 2–4 months of initiation, but some do take much
agent, can also be used as an add-on treatment and improves longer to improve significantly. This can be problematic in some,
symptoms and weakness (14). Tirasemtiv has been explored in and occurs in circa 20% of patients that we manage. In patients
a clinical trial and found to increase the muscle response to with moderate bulbar muscle involvement or disabling fatigable

limb weakness, we prefer to admit to the acute neurology ward or of treatment. Furthermore, in some patients, corticosteroid
to the day-case ward (if they are generally stable) to treat them treatment is absolutely or relatively contraindicated because of
with a course of ivIG during the steroid escalation process in background comorbidities and in this scenario we immediately
order to help expedite the process of their recovery. Occasionally, prescribe a steroid-sparing immunosuppressant agent without
patients require more than a single course of ivIG to help stabilize the addition of steroids. Stabilization can be prolonged with this
their symptoms or to significantly improve their symptoms while strategy, and we prescribe ivIG in the interim with or without
increasing their corticosteroid dose. Some patients may not low-dose corticosteroids depending on the clinical picture. Some
respond to ivIG. In this case, we employ plasma exchange (PE) patients refuse to be started on steroids because of concerns
if we feel their symptoms are sufficiently disabling. If patients of side effects and in these circumstances adding a steroid-
are stable (but symptomatic) then PE can be administered in a sparing immunosuppressant at diagnosis is a viable option. A
day-case unit in an outpatient setting and PE carried out through retrospective study by Abuzinadah et al. (23), showed that a
peripheral venous access. satisfactory response (which included CSR, PR, and MM) was
The slow steroid escalation regimen of treatment that we achieved in about 50% of MG patients with generalized disease
employ is in contrast to the early fast-acting treatment (EFT) when they were maintained on low dose prednisolone, without
strategies applied by the Japanese group (19, 20). This strategy a steroid-sparing immunosuppressant with follow-up extending
always involves patients being admitted to hospital for treatment up to 6 years.
where they would receive 1–2 plasmapheresis sessions followed We advocate checking thiopurine S-methyltransferase
immediately by high-dose intravenous methylprednisolone (0.5– (TPMT) levels (24) prior to initiating azathioprine treatment.
1 g), with or without intravenous immunoglobulin therapy. If levels are in the normal range, we initiate azathioprine at
Treatment would be repeated if significant improvement did not 25 mg daily and increase weekly by 25 mg until target dose is
take place. Patients were then discharged from hospital on the reached, with blood monitoring carried out in primary practice.
lowest dose possible of oral steroids. In some patients, who did Generally, the drug is well-tolerated and we rarely encounter
not have severe MG symptoms, high dose methylprednisolone idiosyncratic reactions in our population. The drug however
was not required. Achievement of MM was more frequent and takes 8–12 months to become effective and we counsel patients
occurred earlier in the EFT therapy cohort were compared about this. In our opinion the drug is not entirely benign and
to those in the non-EFT one (19, 20). While this regimen we have observed many patients develop multiple skin lesions
of treatment is highly attractive, it does require easy access namely actinic keratosis, as a result of long-term azathioprine
to neurology inpatient beds and the necessary manpower (for use and also skin malignancies such as squamous cell carcinoma.
instance accessibility to the plasmapheresis team) and would If the TPMT levels are deficient but not absent, then we consider
not be practical in our regional neurology center (which has 21 using lower doses of azathioprine, monitoring the level of the
neurology beds serving a population of 2 million). active metabolite, 6-thioguanine nucleotides (6-TGN), in the
blood and titrating the dose accordingly.
Our second steroid-sparing agent of choice is mycophenolate
Steroid Sparing Immunosuppressive mofetil (MMF) at a dose of 1 g twice daily. In general, we have
Agents found it practical to use this drug and it is well-tolerated and
Until recently our practice has been to initiate a steroid (as previously reported in the literature) (25, 26) except for
sparing agent such as azathioprine, almost simultaneously as a small number of patients who complain of associated side
initiating corticosteroids and using a dose of 2.5 mg/kg/day effects including disabling dizziness and insomnia, and have
(17). This was based on the study by Palace et al. (21) which discontinued this as a result. In patients with very high body mass
showed that azathioprine was an effective adjunct treatment indices, we have used doses of up to 2.5 g daily. Infrequently we
to prednisolone and was effective in reducing the long- have prescribed mycophenolic acid which can be better tolerated
term maintenance prednisolone dose, in reducing relapses, than MMF, in those with side effects from MMF. We find that
and in achieving remission in the long-term. However, our the efficacy of MMF is noted after circa 6 months of treatment as
practice changed a few years ago (16, 22), when we began to was also observed in previous studies (27). Based on our clinical
treat newly-diagnosed MG patients with steroids alone first. observations, and in contrast to the findings from a previous
A steroid-sparing immunosuppressive agent would be later randomized controlled trial (28) oral weekly methotrexate is as
added if the patient relapsed while reducing their steroid effective as MMF and its efficacy becomes apparent at around the
dose indicating that they will require more than 10 mg same time-point as MMF. It is about 20 times cheaper than MMF.
daily of prednisolone to maintain MM and thus justifying Nausea and vomiting can be limiting side effects experienced
the addition of such an agent. We also consider adding by some. In general, folic acid 5 mg daily is prescribed day 4
in immunosuppression early if the patient has pre-existing after methotrexate but when nausea is prominent, daily folic acid
comorbidities such as diabetes, significant depression (with (except for the day of methotrexate dosing) can help alleviate this.
steroids potentially exacerbating their mood), osteoporosis, Ciclosporin (used at a dose of 3.5 mg/kg/day) is probably the
leg ulcerations, that would be compounded by several-month most potent immunosuppressive agent with the added advantage
treatment with corticosteroids. Also, in patients who are that it is not teratogenic (29). From our clinical observations, we
demonstrating a slow response with corticosteroid treatment have deduced that ciclosporin is, at minimum, effective within
then we would an immunosuppressant early in the course 3 months of initiation. However, we have observed that the

majority of patients prescribed this drug run into problems immunosuppressant dose (17). The difficulties are 2-fold: firstly
with significant side effects including hypertension, alteration in there is little data on the actual risk of relapse on withdrawal
their glomerular filtration rates, nephrotoxicity, tremor and in of immunosuppression and secondly there is no consensus or
female patients also problems with hirsutism. We have prescribed guideline on how rapidly the dose should be reduced. With
ciclosporin in around 25 MG patients, where they have proven regards to the first point, the limited studies on this indicate
refractory to other steroid-sparing immunosuppressants, and that the risk of relapse on withdrawal of immunosuppression
usually belonging to a younger age-group. We avoid prescribing may be rather high. In two respective studies, more than 50% of
in older patients because of the potential complications and side patients who were in CSR and who were prescribed azathioprine
effects and aim to reserve for younger patient groups. Tacrolimus (32) and nearly all patients who had significantly reduced the
is of similar efficacy (30) but with a similar side effect profile dose or withdrawn MMF, experienced a relapse in their MG
as ciclosporin. We have not prescribed cyclophosphamide in (33) necessitating the reintroduction of immunosuppression.
MG but there is a role for prescribing this drug as a monthly With regards to the second difficulty: we usually take an
intravenous pulsed treatment in patients with refractory disease ultra-conservative approach when reducing the dose of any
and who are unable to reduce their maintenance steroid doses immunsuppressant. In the case of azathioprine we reduce the
(31), and this is generally tolerated without significant side effects. dose by 25 mg every 6 months (infrequently weaning altogether)
while with MMF we reduce no faster by 500 mg per year, as
Withdrawing Symptomatic Therapies and previously reported (34). We always advocate close monitoring
Achieving Maintenance Therapy of patients’ MG status and symptoms during the reduction
When the MG status starts to stabilize, MG patients no process. The rate of CSR is low and we often opt, after discussion
longer experience the significant fluctuation and variability in with patients and balancing the decision against their age and
symptoms, become less fatigable and their strength starts to comorbidities, to maintain them on the lowest dose possible of
normalize. We educate patients about this time-point being immunosuppressant in the long-term unless there is a pressing
reached and trying to recognize when they no longer need to requirement that this is discontinued altogether.
reach out for their next pyridostigmine dose which is a good
prognostic sign for stabilization. At that stage, while maintaining Thymectomy
the same dose of corticosteroids, we advise patients to reduce Thymectomy in generalized AChR antibody positive MG should
their pyridostigmine dose by 30 mg per week (or sometimes be considered as early as possible in the management plan and
faster), with the aim to wean this altogether but in some cases thymectomy should be performed where relevant when the MG
patients prefer or require to remain on low doses of up to 120 mg status has been stabilized (17). Imaging of the thymus gland,
daily. Reduction of their steroid dose then ensues following using CT or MR modalities, should be performed in all AChR
a similar regimen previously described (16) −5 mg reduction antibody positive MG patients, also to rule out thymoma and
per month down to 20 mg daily, then 2.5 mg reductions per in the younger patients to look for evidence thymic hyperplasia.
month down to 10 mg daily, then 1 mg reduction per month The role of the thymus gland in driving MG has been known
or slower, aiming to reach 5 mg daily. In some cases, it is for almost a century (35, 36). The results from the international
possible to wean steroids altogether especially if a steroid sparing thymectomy trial (MGTX) have been crucial in underscoring
immunosuppressive agent has already been added. However, if the role of thymectomy in the management of MG (37). In
this is not the case then careful consideration needs to be taken, this trial, non-thymoma MG patients up to the age of 65,
with detailed discussion with the patient, about withdrawing with generalized disease and with positive AChR antibodies,
steroids altogether and a potential risk of future relapse. There were recruited. Patients whose MG onset was up to 5 years
is an argument for maintaining on low-dose prednisolone such prior were recruited. The goal of the surgical procedure, in
as 5 mg daily for life where the cumulative life-time risk is those who received thymectomy, was to remove all thymic
likely to be small vs. further reduction or absolute withdrawal tissue including ectopic tissue and surrounding fat. The results
of prednisolone that might trigger a significant relapse of MG. showed that patients who had thymectomy (which involved
In our experience, most patients favor the former option. an extended trans-sternal procedure) required lesser doses of
Also, we are of the opinion that the long-term risk of such corticosteroids both in the short and in the long-term (38), had
low-dose prednisolone (development of diabetes, hypertension, better functional outcomes, were less likely to be hospitalized
osteoporosis, glaucoma etc.) is significantly less than for example due to their MG and were less likely to require additional
being maintained on 100 mg of azathioprine for life—although immunosuppression with azathioprine for instance. The benefit
there are no long-term studies that quantitate this risk. was seen across all age-groups and was sustained on follow-up.
This trial has been pivotal in the way we neurologists are now
approaching MG management. Thymectomy now is more widely
REDUCING THE DOSE OF SECOND-LINE offered to patients with generalized disease associated with AChR
AGENTS antibodies, including patients with late-onset MG and up to the
age of 65, as part of the overall treatment of their MG.
When patients have achieved pharmacological remission and Minimally-invasive thymectomy surgery has been further
have successfully withdrawn corticosteroids, then it would be revolutionary in the field. Reports of video-assisted thorascopic
sensible to consider a gentle reduction in their steroid sparing surgery (VATS) thymectomy began to emerge in 1993 and 1994,

with a number of centers using alone or in combination with a are present (50). The jury is out as to whether thymectomy
trans-cervical approach (39–41). Reports of robotic surgery in would benefit MG patients without AChR or MuSK antibodies
the field of thoracic surgery began to emerge in the early 2000s (traditionally referred to as double seronegative) and if there is
(42) with the use of the da Vinci robotic system applied in a 28- a role for thymectomy in MG with LRP-4 antibodies (51). Leite
year old patient with MG. With both types of minimally invasive et al. (52) had shown that the thymic abnormalities in double
procedures, patients are reported to experience less blood loss seronegative patients had more thymic abnormalities than the
intra-operatively, complain of less pain post-operatively and have MuSK-MG thymus, but less than seen in the AChR-MG cohort
a shorter post-operative hospital stay when compared to open (52). Thus, these patients may benefit from thymectomy too but
thymectomy. In a systemic review comparing robotic assisted this is an area that requires further research.
thymectomy surgery (RATS) with VATS and open surgery (43), Thymoma, in contrast, is a rare epithelial tumor of the anterior
there are clear advantages of RATS or VATS over open surgery, mediastinum and 50% of cases occur in association with MG.
but no significant advantage of RATS over VATS at least to date. Thymoma occurring in association with MG, should always be
Clinical outcomes have been compared in a retrospective study surgically removed (17). Minimally invasive surgical approaches
in MG and found to be comparable between thoracoscopic vs. are feasible in most but may not be possible in the larger tumors.
trans-sternal thymecetomy (44). Data analyses, after propensity Complete surgical resection is aimed for but radiotherapy may be
score matching, also confirmed that robotic thymectomy in required for invasive thymomas. Where resection is incomplete
early stage thymoma was safe and feasible with oncological and/or surgical margins are positive for thymoma, radiotherapy
outcomes that were comparable to trans-sternal thymectomy (45) improves the prognosis by 50–60% (53, 54). Thymomas are also
and in thymoma exceeding 5 cm (46, 47). In relation to MG chemosensitive. Platinum-based agents show consistent efficacy
outcomes, it would be very challenging to design a further trial (55) and can improve the outcome of Masaoka stage III and
that would compare clinical MG status and outcomes after open IV thymomas or recurrent thymomas. Non-platinum based
thymectomy vs. minimally invasive surgery. regimens are also prescribed in some tumors and the role of
In our experience, patients with non-thymoma MG are now immunotherapy still remains to be further investigated.
more encouraged to pursue thymectomy, during the course of
their MG management, when provided with the results from the Ocular MG
MGTX trial. We have also observed that patients are also more Isolated ocular myasthenia is rare. While ptosis and diplopia
comfortable in pursuing minimally invasive thymectomy surgery are common presenting symptoms including in patients who
in contrast to open surgical approaches. For the past 3 years, will eventually evolve into generalized myasthenia, only 20%
our thoracic surgeons have been employing RATS, which we of patients will turn out to have pure ocular MG—signifying
perceive as further advantageous specifically from the perspective that these patients will never develop generalized disease) (56,
of post-operative morbidity. For those who are in employment, 57). The diagnostic difficulty with this entity is that only 50%
who drive, who are parents looking after young children, and also have detectable antibodies to the AChR (57). Single fiber EMG
for those younger adults who may be pursuing studies at school studies support the diagnosis of neuromuscular transmission
or university, RATS evokes less anxiety about the post-operative failure in patients without detectable antibodies, including
period impacting on their work, studies, social, or family life. ocular myasthenia (58). The main differential diagnoses include
Minimally invasive thymectomy procedures also overcome the thyroid eye disease, and a progressive external ophthalmoplegia
aesthetic problems that patients faced with open thymectomy associated with a mitochondrial disorder. The latter group of
mediastinal scars. We, as a center, have also gained confidence in patients may also have some minor abnormalities on single fiber
referring older MG patients for thymectomy, acknowledging that EMG studies with borderline increased jitter values making the
there is data to support its benefit also in this age-group (48, 49), diagnosis even more challenging (58). Other diagnostic cues
and since the MGTX trial, we have been consistently referring are therefore crucial, and ultimately a muscle biopsy may be
patients up to the age of 65. necessary to clinch the diagnosis.
Although it is perceived that that there is a 2-year window
of opportunity for thymectomy from disease onset, there is no First-Line Pharmacological Therapy in
evidence to suggest that the MG status is negatively impacted Ocular MG
when thymectomy is performed beyond this time-frame. In the While ocular MG is not life-threatening, diplopia is a very
MGTX trial there was no evidence to support that patients disabling symptom. It significantly impacts an individual’s quality
who had thymectomy within 2 years did better than those of life—it impacts patients’ driving ability, it may impact their
who had thymectomy within 5 years of disease onset. This is employment, their social life, and their hobbies including sports,
particularly relevant to patients, who have proven refractory to reading etc. When a patient presents with ocular myasthenia,
all conventional immunosuppression, and where thymectomy the first treatment that should be initiated is pyridostigmine in
at a later time-point in their disease could potentially offer order to achieve symptom control and to determine reversibility.
additional benefit; we have been exploring this as an option in a This may be sufficient in patients with mild symptoms and signs,
small category of patients. In contrast, there are various reports but is unlikely to be adequate in patients with significant ocular
indicating that thymectomy is contraindicated in MuSK-MG, motility disturbance. If patients remain symptomatic despite
with patients’ MG status often worsening after the procedure and, maximal doses of pyridostigmine, then the next step should be
therefore, thymectomy should not be pursued if MuSK antibodies prompt treatment with corticosteroids (59–63). Early treatment

of ocular myasthenia improves the chances of reversibility or on their prism in the long-term. Using a patch over one eye
significant improvement in the long-term (64). There is some in the short-term is another option for some patients to help
evidence to indicate that early treatment of ocular myasthenia obliterate the false image while others tolerate using an occlusive
delays or prevents the development of generalized disease (64– contact lens.
66). Delaying corticosteroid treatment, in our experience, reduces Residual ptosis can be a significant problem in some patients
the chances of recovery of the extraocular muscles. In some either causing obstruction of one’s vision or from an aesthetic
patients, in spite of prompt and adequate treatment, they do not perspective. In older patients, ptosis may be aggravated further
respond to therapies and are left with a fixed ophthalmoplegia in by senile dehiscence or dermatochalasia. In general, if patients’
the absence of any other signs or symptoms. This may reflect the ptosis does not reverse in spite of maximal treatment received
complex sarcomeric organization (67, 68), gene expression (69), over a 2-year period, then the chances of recovery after that
distinct complement expression (68, 70), and unique metabolic period of time are rather slim. In a select group of patients,
demands and vulnerability of mitochondrial oxidation pathways ptosis repair surgery performed by an oculoplastic surgeon may
within the extraocular muscles (71) that are susceptible to disease be indicated (72, 76). The surgeon needs to ensure that the risk
including autoimmune disorders. In patients who are refractory of corneal exposure is minimal and repeated procedures are best
to treatment, and especially when they have no detectable to be avoided. In contrast using ptosis props is a less invasive
antibodies and/or equivocal SFEMG findings, there is scope for way of dealing with the problem but some patients complain
investigating with an MRI scan of the orbits with gadolinium to that these cause discomfort or corneal dryness since the props
exclude alternative, namely inflammatory, processes for instance limit blinking, and may be simply impractical for some. In some
thyroiditis. Commonly in ocular myasthenia patients with patients, the extraocular motility may remain abnormal in spite
refractory disease and fixed ophthalmoplegia, the MRI shows of adequate treatment with steroids, and may become fixed.
atrophic extraocular muscles with asymmetric involvement and In a highly select group, strabismus surgery may be of benefit
with no enhancement following gadolinium administration. but careful discussion with an ophthalmologist who specializes
The ceiling steroid dose in ocular myasthenia is deemed in squint surgery is required for these cases. Botulinum toxin
to be lower than that used in generalized myasthenia to correct the strabismus should be avoided altogether in MG
(16, 57). One usually aims for a maximal steroid dose because of the toxin’s systemic effects, which may destabilize MG
(prednisolone/prednisone) of around 25 mg daily (or equivalent patients even when their status (other than their ocular features)
of 50 mg alternate days) but in some instances higher doses has been stable for many years (77).
may need to be considered particularly if there is a delay in the Thymectomy in ocular myasthenia remains controversial
correction of the ocular motility disturbance and if diplopia but there are various small studies indicating that this is
remains a persistent symptom. Recovery of the extraocular beneficial particularly when considered early in the disease (78–
muscles in ocular myasthenia may take several months and there 82). The task force for the EFNS/ENS guidelines (62) agreed
may be scope for adding in immunosuppressive agents for the that thymectomy is not recommended for ocular myasthenia
same reasons as in generalized MG (16, 22, 72). The indications as first-line treatment but should be considered if drug therapy
for this includes patients whose ocular motility does not respond was not successful and may prevent MG generalization (good
to corticosteroids alone, or who experience frequent relapses practice point). Given that ocular myasthenia often evolves into
and are unable to reduce the corticosteroid dose below an generalized disease (and there are no markers to predict this)
acceptable level, or the physician feels that additional treatment and given the increased access to minimally invasive thymectomy
is required especially if there has been incomplete response to surgery, early intervention may be of benefit. For these reasons,
corticosteroids and pyridostigmine. Other patients are unable we have increasingly been referring ocular MG patients for
to tolerate corticosteroids or may have comorbidities such as thymectomy in the last 3 years. Furthermore, it is unknown, if
diabetes, osteoporosis, depression, or glaucoma that preclude the early thymectomy may also prevent these patients developing a
long-term use of steroids. fixed ophthalmoplegia in the long-term.
It is important to monitor patient’s response to treatment
carefully and working with an orthoptist can be of immense MG IN SPECIFIC PATIENT GROUPS
assistance. There also needs to be an objective assessment of
ptosis and ocular motility for instance using the Jampolsky The Pregnant Patient
scheme (73, 74), and collaborative work with an orthoptist In practice, the majority of MG patients, who are treated
is often very helpful in monitoring response to treatment adequately before pregnancy, do not experience any
and progress. complications during pregnancy or in the post-partum phase.
However, some report an increased risk of MG relapse during
pregnancy that varies between 17% (83) to 41% (84). Some
Non-pharmacological Therapies in Ocular patients’ MG status improves during pregnancy (85) as one
MG observes with other autoimmune conditions such as multiple
In the short term, patients may be fitted with a Fresnel prism to sclerosis. In the ideal scenario, the pregnancy is planned to
allow some correction of their double vision (75). Reducing the allow optimization of MG status and withdrawal of teratogenic
strength of the prism over time is a clear indication of response medications where relevant. Pyridostigmine, corticosteroids,
and improvement. Some patients, however, will continue to rely and azathioprine are all safe to be used in pregnancy and

should not be discontinued during pregnancy (85, 86). MMF clinical picture must be promptly recognized and the patient
and Methotrexate are teratogenic and should be avoided (85). requires to be monitored closely in hospital, usually in a high
Ciclosporin and tacrolimus are not teratogenic but their use dependency unit setting, since this clinical picture often evolves
can be associated with the development of hypertension and further with significant respiratory muscle weakness. Arterial
gestational diabetes and, therefore, the patient requires close blood gases should be checked to identify when type 2 respiratory
monitoring (85). IvIG and PE are also safe to be used during failure occurs. At the bedside, assessing the patient’s respiratory
pregnancy (87). There are some reports suggesting that MG rate and forced vital capacity, and observing whether the patient
patients are at risk of preterm rupture of membranes (88, 89). is using their accessory muscles are all helpful measurements,
We have not encountered this in our practice, however. predictors or cues. If parameters allow then the patient could
Therapy for MG should be optimized where possible before be treated with non-invasive ventilation (NIV) first but if
and during pregnancy. The neurologist and obstetrician should parameters fail to improve or the patient continues to tire with
be in regular dialogue particularly in the third trimester of NIV or is intolerant of this, then treatment must be quickly
pregnancy, when plans should be initiated on how the baby escalated and the patient must be intubated and mechanically
should be best delivered. Medications for MG should continue ventilated in an intensive care setting.
uninterrupted before and throughout labor. Patients should The two primary pharmacological therapies to treat MG crisis
undergo spontaneous vaginal delivery in most cases and epidural are ivIG, at a dose of 0.4 g/kg/day for 5 days or PE—usually
labor analgesia should be considered early in patients who are 4–6 exchanges (17). They are equally effective in the treatment
likely to experience fatigue during labor (90). Nitrous oxide is safe of MG crisis or a significant MG relapse (95). We commonly
to use (85). prescribe ivIG first, unless there are contraindications, and resort
Surgical delivery should be considered in those who MG status to PE as second-line therapy if the patient fails to respond to
is poorly controlled and in those patients where muscle weakness ivIG. However, if PE is readily available we would recommend
is significant or their MG is considered brittle. Ideally this using as first-line in the context of MG crisis since it is more
should be planned adequately in advance with multidisciplinary rapid in its effect than ivIG. This has been our experience and
team discussions throughout but especially in the latter part of also previously shown by Qureshi et al. (96). PE is not without
the pregnancy. MG patients are usually extremely sensitive to risk however. It is more invasive, more labor-intensive and more
depolarizing muscle relaxants, and should be administered the expensive than ivIG (97). PE should be performed via peripheral
least possible dose (85). Magnesium sulfate for the treatment of venous access, where feasible, but central catheters may be
eclampsia should be avoided in MG since this will exacerbate necessary in some which pose additional risks of an infection
myasthenic weakness (85). Opiates for pain relief especially in source if mishandled or if left in situ for too long (98). The
the post-partum phase should be used with caution since they too same dose of ivIG could be administered over a shorter period
may exacerbate weakness. Breast feeding of the newborn should for example 2–3 days if tolerated by the patient. We prefer to
be encouraged. Neonatal myasthenia, with temporary and usually administer over 5 days, especially in patients who are ivIG naïve
mild myasthenic weakness, occurs in 10% of neonates due to at least initially, and we consider administering over 2–3 days in
transplacental transfer of antibodies (86, 91). It usually resolves subsequent treatments.
spontaneously within 3 weeks of the birth of the infant. Rarely Corticosteroids are added or increased simultaneously with
the presentation of the neonate can be more complex, especially ivIG or PE therapy (16). In our practice, we still initiate
if the mother’s MG was undertreated during pregnancy, and may corticosteroids at low doses but then we escalate the dose more
require the neonate to be managed in an intensive care setting rapidly over 5–7 days, since the steroid dip is likely to be
for a short period. Very rarely, infants of MG mothers are born counteracted by the simultaneous use of ivIG or PE. The role of
with mild myopathy and—at the severe end of the spectrum— acetylcholinesterase inhibitors is limited in MG crisis. They may
arthrogryposis multiplex congenita (92). The mothers may in fact exacerbate bronchial secretions and so one should be mindful
be asymptomatic or minimally symptomatic with elevated AChR of identifying the clinical situation when they are likely to be
antibodies and some may be asymptomatic with antibodies of benefit even to the MG patient in crisis. Some patients may
specific to the fetal AChR γ subunit (92). require further courses of PE or ivIG 4–5 weeks after their
initial therapy and may relapse even after their initial significant
The MG Patient in Crisis improvement. This is because the effect of corticosteroids may be
MG crisis occurs in circa 20% of MG patients who are apparent after 6–8 weeks while the effect of ivIG or PE usually
newly presenting with MG (93, 94). It occurs more frequently lasts circa 4 weeks.
in MG patients who are undertreated, or who have newly Weaning from the ventilator should be considered when
presented and whose treatment is being slowly escalated but the patient demonstrates an improvement in vital capacity
whose presentation has evolved more rapidly than therapy and is strong enough to transition to spontaneous mode
has originally been scheduled for stabilization. Patients develop ventilation, which allows the patient to initiate breathing
severe muscle weakness including weakness of the respiratory (99). The patient should be observed for fatigability with
muscles, commonly preceded by severe bulbar weakness with switch-over to assisted-ventilation when they fatigue. There is
dysphagia, with or without palatal weakness and nasal escape. In concomitant improvement in bulbar and neck muscle strength
this situation, patients require a nasogastric tube to be inserted when respiratory muscle improvement is observed. If their cough
to allow medications to be administered and for feeding. This remains weak and the patient is struggling to clear their airways

secretions, then extubation is likely to be precocious and failure cycle of Rituximab is sustained (110, 111) allowing subsequent
is more likely to occur. reduction in steroid doses and in some inducing remission (112).
Consideration for thymectomy should be considered where Patients with MuSK-MG respond extremely well to Rituximab
relevant and after the patient has been weaned off ventilation and the drug often induces remission without the requirement
and extubated. Also, they should demonstrate stability in their for subsequent infusions (112, 113). Rituximab has a role in
MG status, have been stepped down to a regular ward and are patients presenting aggressively and explosively at onset and who
becoming less dependent for their daily activities of daily living. are refractory to all conventional therapies. Brauner et al. (114)
The prognosis of MG crisis is worse in patients with thymoma. demonstrated that clinical outcomes were better in patients who
In this group of patients, managing their MG crisis can be were treated early rather than later with Rituximab. There is
challenging and response to therapy may be delayed (93). When scope for considering Rituximab in patients who are in crisis
their MG status has been stabilized, however, thymectomy should and who are not responding to high dose corticosteroids or ivIG
follow on promptly when safe to do so. or PE, and when patients demonstrate resistance in weaning off
ventilation during the treatment pathway of MG crisis. Caution
The Older MG Patient must be exerted in this scenario, acknowledging that Rituximab
World-wide epidemiological studies confirm that the incidence will not be effective immediately and may pose an added risk to
of MG is increasing among male and female patients who are the patient for developing infection. Rituximab is contraindicated
older than 65 years (100–102) and the prevalence is also rising during pregnancy (87).
due to patients living longer (103, 104). Multiple comorbidities In our experience, where we have treated a small cohort
often exist in older patients. They are less likely to tolerate the of 17 MG patients with MuSK-MG, AChR-MG, and MG with
more potent immunosuppressive agents that benefit the younger no detectable antibodies, the majority of patients improved
MG patients (105–107). In older patients, careful consideration significantly but remain dependent on immunosuppression
needs to be given of the potential impact of corticosteroid (unpublished data). Our single MuSK-MG patient, within this
treatment on other systems for example the development of small cohort, responded best to Rituximab although this did
diabetes, hypertension, obesity with cardiac strain and heart not induce complete remission of her disease. In contrast, about
failure, significant osteoporosis with vulnerability to various a third of MG patients did not respond to Rituximab and
fractures. They become more vulnerable to infection including their MG status was not altered by this therapy. In general,
recurrent infections and sometimes resulting in life-threatening we have found that the drug is well-tolerated with minimal
sepsis especially when more potent immunosuppressive agents side effects. However, in two patients we have observed delayed
such as MMF or Methotrexate are prescribed. Some older neutropenia developing many months after Rituximab treatment,
patients suffer recurrent infections when managed with maximal including one patient whose presentation was complicated by
immunosuppression for their MG which in turn results in two neutropenic sepsis episodes several months after their
hospitalization, further deconditioning and a significant delay Rituximab treatment. This has been observed in other patient
in recovery from their MG. From our experience, we have groups treated with Rituximab (115–117).
noted that in the older perhaps frailer patients it may be In a large systemic review of 169 MG patients who received
safer in the longer term to slightly undertreat their MG rather Rituximab, remission (PR or CSR) and MM was achieved in
than aim to induce remission, since prescribing conventional 72% of MuSK-MG patients in contrast to 30% of AChR-MG
doses of immunosuppression in this age-group often leads to patients, with post-treatment relapses being markedly reduced
fatal consequences. MG patients are also more vulnerable to in the MuSK-MG cohort (118). It is still unclear why MuSK-
developing osteoporosis (108) and the prescribing neurologist MG patients respond so well to this drug. It would be crucial for
needs to be aware of this and monitor closely patients’ biomarkers to be developed that will allow physicians to predict
bone densities since osteoporotic fractures result in significant a patient’s response to Rituximab. There is also a similar crucial
morbidity, chronic pain and reduced mobility, which may need for robust trial data for this drug, since the efficacy of
already be compromised in an older patient. Rituximab in AChR-MG is still debatable and the studies that are
available may be limited by an element of reporting bias (119).
The Refractory MG Patient and Novel This data will also help physicians counsel patients adequately
Therapies when embarking on this therapy.
About 20% of MG patients are refractory to all conventional MG treatment can also be addressed by switching off
treatments. Monoclonal antibody treatments that bind the B complement pathways and their activation, or by altering the
lymphocyte membrane protein CD20, such as Rituximab have Fc region of the antibody such that less antibodies are available
been increasingly prescribed in this group of patients with for recycling, more are destroyed and thus unavailable for
successful outcomes. The rationale behind preparations such as pathogenic processes. Novel therapies have been developed
Rituximab is that they destroy and deplete pathogenic B cells and to address both. The efficacy and safety of the terminal
decrease AChR antibody production. Rituximab influences the complement inhibitor eculizumab (a humanized monoclonal
whole spectrum of B cell function including antigen presentation, anti-C5 antibody) in MG has been rigorously studied in the
cytokine production, and T cell stimulation and hence has a REGAIN trial (120, 121). Improvements were noted in all
role in T cell mediated autoimmune diseases too (109). Studies objective MG-related scores and in the patients’ quality of life
have demonstrated that clinical improvement even with one scores for all those actively treated with eculizumab, and were

sustained during the 52-week study period. Patients treated in and the impact on reducing in-patient hospital care (reducing
the placebo arm experienced rapid and sustained improvement hospital admissions including to intensive care units, the
in their MG status when switched to open-label eculizumab. requirement for regular ivIG, or frequency of attend clinic
The drug also improved fatigue scores which in turn correlated appointments due to stable disease etc.).
strongly with MG-specific outcome measures (122). However,
the response among patients in the REGAIN trial was variable Fatigue in MG
with some improving substantially, some modestly and some Fatigue is common in all neuromuscular conditions including
patients showing no response whatsoever (123). Eculizumab MG, and around 80% of MG patients will experience significant
is now a registered therapy for myasthenia gravis. It remains fatigue at some stage of their disease (129, 130). It is distinct
an expensive drug with costs for one patient’s treatment per from fatigability and muscle weakness and therefore it is crucial
annum amounting to $500,000. It is unclear whether this drug that the physician recognizes this entity since its management
is cost-effective in MG. A trial of zilucoplan, a subcutaneously does not involve escalation of treatment for MG (131). Fatigue
self-administered inhibitor of complement component 5, has is as disabling to the patient as active muscle weakness, and may
been recently studied (124). The trial confirmed that zilucoplan negatively impact patients’ quality of life, their quality time with
was safe and well-tolerated and patients rapidly showed clinical their family, their employment status, and their social lives. It
improvement with this drug. The extent of clinical response contributes to the disease burden but is more difficult to assess
correlated with the level of complement inhibition such that or objectively measure in the clinic. Fatigue may be problematic
near-complete inhibition was demonstrated to be superior to even when MG symptoms have largely settled or when the patient
submaximal inhibition. has achieved minimal manifestations.
Efgartigimod (also known as ARGX-113) has been trialed in Fatigue is multifactorial. Primary fatigue occurs when muscle
generalized MG in a phase-2 randomized double-blind, placebo- weakness and fatigability are active in MG and has an inherent
controlled study in 15 centers (125). ARGX-113 is the anti- physical component (132) contributing to fatigue. They also
neonatal Fc receptor immunoglobulin IgG1 fragment. It has been complain of cognitive fatigue which patients often allude to
modified to increase its normal affinity for IgGs, thus blocking as “brain fog” (133). It is difficult to dissect out primary
the formation of disease-causing IgG. Efgartigimod was well- from secondary fatigue, with the latter occurring for various
tolerated in this trial. In the 12 patients treated with the active reasons. Patients with MG, often gain weight primarily due to
drug, there was a rapid decline in total Ig levels and in AChR corticosteroid treatment (134), sleep less efficiently (135), move
titers, which in turn correlated with a clinical improvement of less and develop muscle stiffness and discomfort (136). They
their MG, and this was sustained in the majority. are more likely to become anxious and depressed about their
The proteasome inhibitor, Bortezomib, depletes short-lived physical limitations and the variability and unpredictability of
and long-lived B cells and is applied in the treatment of multiple their symptoms (137). They resort to socializing less, they might
myeloma (126) and plasmablastic lymphoma (127). It is likely discontinue their employment, which in turn may have financial
to have a role in the treatment of refractory MG including consequences, and do less chores in the house or even become
MuSK antibody positive MG (128) but the development of a virtually house-bound. O’Connor et al. (138) identified that
sensorimotor polyneuropathy, a recognized side-effect of this MG patients were more likely to become sedentary even when
drug, is likely to be a limiting factor. asymptomatic. It is unclear whether this is learnt behavior or
Questions remain unanswered about the long-term safety, fatigue-driven or simply part of a vicious cycle. Because MG
efficacy, and tolerability of these novel therapies (meaning after patients exercise less they become quickly deconditioned and
several years of continuous treatment). It is unclear whether often develop breathlessness that is not secondary to respiratory
long-term complement inhibition, for instance, would pose muscle weakness. Their breathing becomes shallow with a
increased general infection risks particularly in older age-groups. tendency to hyperventilate which develops as a learned pattern
Determining the category of patients who are likely to benefit and is often misinterpreted as a sign of early MG crisis. Their
from these therapies is crucial. Would these therapies be aimed sleep pattern is less efficient. They may develop obstructive sleep
only for “refractory” and “severe” MG? If so, how do we precisely apnoea due to weight gain. They socialize less and this in turn
define these entities? Would drug holidays be considered and if negatively impacts their mood further.
so for how long? It is also less clear how cost-effective these novel Fatigue is not unique to MG but is also prevalent in
therapies are, how the various global health systems would fund other neuromuscular disorders such as different types of
these drugs and how the different health insurance companies muscular dystrophy and myotonic dystrophy (DM1). Patients
will cover the costs of these drugs. A detailed cost-utility with facioscapulohumeral muscular dystrophy (FSHD) often
analysis is required that will allow the diverse health systems to complain of fatigue and pain, and hypersomnolence is very
better understand the long-term efficacy of these therapies, how common in patients with myotonic dystrophy. Various studies
improvements in objective measurements translate into better have studied the role of exercise in various neuromuscular studies
function for the patient, and how they improve patients’ quality including MG (139, 140). Other studies have explored using
of life. It would be imperative to ascertain and quantify the cognitive behavioral therapy in combination with graded exercise
potential socioeconomic gains when using these therapies (do in MG, DM1, and FSHD including high intensity training and
these therapies allow individuals to return to their employment, aerobic exercise which led to functional benefits in patients
increase independence and reduce dependence on care-givers?) without evidence of damaging muscle (141–144). In a very small

and select group of patients, where fatigue is compounded by It is therefore imperative that physicians recognize the entity
pain, anxiety and insomnia, and perhaps with an overlay of their of dysfunctional breathing in MG patients and refer them on
myasthenic symptoms (i.e., true MG coexisting with an aspect of for respiratory-based physiotherapy. This is a crucial adjuvant
a functional neurological disorder) we have managed them also treatment in MG patients, who complain of dyspnea, and
with psychology input and cognitive behavioral therapy (145). intervention helps their overall MG symptoms, improves their
It is challenging when prescribing exercise to MG patients exercise capacity and increases their chances of overall recovery
or indeed to any neuromuscular patient. Different types of with improved quality of life.
exercise are suitable for MG patients at different phases of their
MG. Aerobic or high intensity training is not possible when The End-Result—Our Practice and
MG patients are very symptomatic. In this situation, stretching
Comparison With Reported Outcomes
exercises such as Tai chi, slow flow yoga or pilates are probably
When we set up the myasthenia clinic 13 years ago, we primarily
most appropriate with emphasis also on balance maintenance.
aimed this to be a regional service that manages MG patients
When MG symptoms stabilize, physical therapy should focus
residing in the West of Scotland. However, we were subsequently
on balance and muscle strengthening but physicians should
referred MG patients who were refractory to standard therapies
also enquire specifically about other symptoms including pain,
and who came from other parts of Scotland. Our patient
residual fatigue, sleep disturbance and mood problems and
cohort, served over a 13-year period, is heterogeneous including
address these accordingly.
ocular and generalized MG, spanning all age groups (including
patients in their tenth decade), with different antibody status
Dysfunctional Breathing in Myasthenia and thymic pathology. About 10% of our cohort is refractory to
conventional treatments. Our experience, as previously reported
Gravis in the literature (150), has been that most patients’ MG status
It has long been observed that breathing patterns and the central
evolves within the first 2 years of symptom onset. Broadly, CSR
ventilator drive can be altered in patients with mild or moderate
has been achieved in 5–10% of our case-load, PR in 20%, MM in
MG (146). In our practice, we have observed several patients, who
25%, improvement in 35%. About 10% of our cohort’s MG status
we deem stable or in minimal manifestations, complaining of
remains unchanged by our therapeutic interventions. Patients
dyspnoea as a residual prominent symptom in spite of them not
were worsened by therapy in 1–2%, and 1% died from direct
having any objective evidence of respiratory muscle weakness. A
complications of their MG. Our rate of PR is comparable to what
very small proportion, may have had a MG crisis at some stage
has been reported in the literature but it is difficult to make direct
of their disease, which inevitably raises long-term anxiety levels
comparisons since our treatment regime has also evolved over
to the patient and their carer, about the potential severity and
time. Mantegazza et al. (151) reported PR in 24% and CSR in 11%.
sometimes unpredictability of the disease. In some, contributory
Beghi et al. (152) reported a higher chance of CSR in patients
factors are clear and include deconditioning or weight gain.
who were younger and who had a shorter disease duration. These
We have identified, through collaborative work with the local
findings were echoed in a further study by the same group almost
respiratory team, that many of these patients have developed
a decade later (153). Yang et al. (154) reported a CSR rate of 60%
dysfunctional breathing (unpublished observation). Our local
in patients who received thymectomy for thymic hyperplasia with
respiratory physiotherapist has been working with these patients,
younger patients having a higher CSR rate. Given that we have
employing physiotherapy-based breathing pattern modification
put more MG patients forward for thymectomy in the last 3–4
interventions. These include relaxation of intercostal muscles,
years, it is likely that this would further influence our remission
accessory muscles and full utilization of the diaphragm thus
rates. If we were to categorize our patient cohort according to age-
helping them to regulate and improve their breathing pattern
groups, thymus pathology, and thymectomy status this would
with good results (unpublished).
refine our CSR and PR rates, but we have not carried out that
Dysfunctional breathing has been studied extensively in
detailed analysis to date.
poorly controlled asthma (147) because it is common and
is associated with significantly poor asthma control and
lower quality of life. Evidence-based guidelines recommend CONCLUSIONS
breathing retraining interventions as adjuvant treatment in
uncontrolled asthma. A multicenter randomized controlled trial There are various guidelines in the literature on MG
is currently underway in Denmark to investigate the effect of management. Physicians usually adhere to and achieve
breathing retraining on the impact on quality of life in poorly confidence and familiarity with specific treatment plans.
controlled asthmatics (148). In a small study (149), 12 MG However, the “recipe” for treatment can and should be designed
patients underwent long-term respiratory muscle endurance for the individual patient’s comorbidities. The aim in MG
training, which resulted in a change in their breathing pattern treatment is to induce remission or MM and to enable patients
with prolonged expiration. Interestingly patients reported an to resume their normal life-style. Each patient, however, is
improvement in their MG symptoms, in their respiratory unique with respect to their comorbidities and their social or
symptoms and in their physical fitness. This study proves that personal circumstances. As a result, the immunosuppressive
normocapnic hyperpnea training is a useful adjuvant therapy therapy prescribed needs to be “catered” for that particular
in MG. individual bearing all those pertinent variables in mind. Residual

myasthenic symptoms, which physicians may perceive as since this will help their overall well-being in the long-term.
minimal may have a significant impact on a patient’s daily Finally, dysfunctional breathing should be recognized and
life. As physicians, we need to be mindful of the impact of treated accordingly.
patients’ MG on their physical and mental health, the impact
on their family or carers, and the impact of adverse effects from AUTHOR CONTRIBUTIONS
MG-related therapies on their general health. The development
of new therapies for the severe end of the MG spectrum MF and JG contributed equally to conceptualizing this document.
is exciting. We need to learn more about these drugs, gain MF wrote the manuscript with contributions from JG to different
familiarity and identify the patient groups who are more likely sections. All authors contributed to the article and approved the
to benefit from them. Detailed cost-utility analysis is required submitted version.
for individual health-care systems to enable physicians in their
process of justifying the use of these drugs to their respective ACKNOWLEDGMENTS
hospital systems. Addressing fatigue and its management
is paramount to the overall MG management. Encouraging We are indebted to Ms. Caroline Carmichael, myasthenia nurse
patients to exercise should be an integral part of their treatment specialist, who makes our busy service possible and sustainable.
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A Practical Approach to Managing

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INTRODUCTION the aim of dampening the underlying immunopathology causing

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