Myasthenia Gravis Learning Zone
Transcript: Myasthenia gravis postpartum case study
Dr Jennifer Spillane
Interview recorded October 2024. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
[Jennifer] Hello. Welcome to this case presentation on Medthority.com. My name is Dr. Jennifer Spillane. I'm a consultant neurologist working at University College London Hospital and Guy's and St Thomas' Hospital in London, and I'm gonna talk to you today about a case of myasthenia gravis that presented in the postpartum phase. So our case is of a lady who was 38. She had just finished her second pregnancy, and had given birth to a healthy baby. She didn't have any past medical history of note, though she had noted she felt tired during the latter stages of this pregnancy. However, she commented herself going through a second pregnancy with a toddler at home, it wasn't necessarily unusual to feel tired, so she hadn't commented on that much during the pregnancy. However, four weeks after she delivered her baby, she developed some neck pain. She put it down to musculoskeletal pain from holding her baby for a long time during feeding. Saw her GP, nothing abnormal was found. She took some simple analgesia and thought no more of it until a couple of days later she noticed she'd additional symptoms, and at that point, she'd difficulty with speech, with her speech sounding slurred, and she developed shortness of breath. Thinking that something wasn't quite right, she went to her local hospital and was seen in A&E there. It became quite apparent early on that something wasn't right. As well as having dysarthria, so difficulty with speech, she had dysphagia. She had difficulty with swallowing and was choking while trying to drink liquids.
She had definite head weakness and had difficulty keeping her head up when she was examined and had breathlessness when lying flat. When she was examined in A&E, it was apparent that she had type 2 respiratory failure with falling forced vital capacity and difficulty breathing when lying down. She was taken to the high-dependency unit, but soon after that was admitted to the intensive care unit and was intubated for type 2 respiratory failure, so at that point, there was no actual clear diagnosis, but when her sedation was lightened and she was examined, it became apparent that she had ptosis, diplopia, and fatigable limb weakness, and that led to the team who were looking after her to consider a neuromuscular cause for her respiratory failure and the other symptoms and signs that they could see. Different diagnoses were considered, such as Guillain-Barre syndrome, but she had maintained her reflex and the temple of the weakness didn't quite fit with that. Furthermore, she had no sensory signs. Myositis was considered, but she had a normal CK. The diagnosis was clinched, both by the physical signs of ptosis and diplopia, but subsequently, by the neurophysiology, so EMG showed features consistent with a post-synaptic disorder of the neuromuscular junction with decrement on repetitive nerve stimulation of weak limbs and both jitter and block seen on single-fiber EMG. It took a couple of weeks for the antibodies to come back, but she was found to be positive for acetylcholine receptor antibodies confirming a diagnosis of AChR antibody-positive generalised myasthenia. Once again, it took a week or so for the mediastinal imaging to be done, but that showed a bulky thymus gland that on initial review by radiology was suspicious for a thymoma, so in terms of management, this lady with type 2 respiratory failure who was intubated and ventilated in the intensive care unit was initially given intravenous immunoglobulin, two grammes per kilogramme.
Prednisolone was commenced, and the dose was relatively quickly, over the course of a week or so, increased initially from 20 milligrammes to 40 milligrammes, and subsequently to 60 milligrammes. After about a week or so, things seemed to improve, and she was extubated, but, as is often in the case in myasthenia, actually, she was weaker than first suspected. She began to tyre quite quickly, and even though she was able to manage her airway and breathe quite well early in the day, by later in the day, she became fatigued, and after a couple of days of this pattern, it became apparent that she had deteriorating respiratory function. She developed a chest infection for which she required antibiotics, and she needed to be reintubated and ventilated in the intensive care unit. At that point, she had a second cycle of IVIG, and despite this, she had ongoing respiratory failure. She continued to need ventilation, and after about two weeks, she underwent plasma exchange treatment. Eventually, after this, she was extubated, but she was extremely weak. She had an NG tube. Her speech was so dysarthric that it was difficult to understand her at times. She was unable to walk or even sit unaided at times and really was quite unwell, so at this point, the diagnosis was clinched. She had seropositive myasthenia gravis. She had received IVIG, two cycles. She had plasma exchange and actually ended up having a second cycle, and her prednisolone dose, at this point, had been increased to 70 milligrammes, and that led the team looking after her at the time to think, "What can we next for this lady?" So there are a number of issues to consider when thinking about this lady, and we'll go through them in turn.
There was management of the myasthenic crisis. They've got a patient who's intubated and ventilated because of myasthenia in the intensive care unit. We know that she has seropositive myasthenia gravis. We also know that she has a bulky thymus gland that is suspicious for a thymoma, so the question is whether thymectomy is appropriate. There's the question about what ongoing treatment she needs, and also, let's not forget she's got a small baby at home. She's in the first few weeks in her postpartum stage after her pregnancy, and that her condition needs to be considered in that context as well, so first of all, let's think about the myasthenic crisis, so a myasthenic crisis, as you know, is a severe myasthenic weakness that requires ventilatory support, and the literature tells us that 10 to 15% of people with generalised myasthenia will develop a crisis, and it typically is within the first two years of disease, and actually, as with this lady, it can be the first presentation of myasthenia gravis in up to 26% of cases. Looking at the annual incidence, it can be as high as 2.5% of all myasthenic patients. With ITU supportive care being the most important part of the management and the developments and improvements in ITU care have been what has led to improvements in the survival from myasthenic crisis.
The most important aspect of the treatment is appropriate ventilatory support, and this can be prolonged so patients can require ventilatory support for many days, if not weeks, and it's not unusual for those with a myasthenic crisis to require tracheostomy, such is the degree of their ongoing respiratory weakness. As we saw in our patients, there can be a temptation occasionally, particularly in younger patients, to extubate them quite early before their weakness has resolved, only for the fatigability of their respiratory muscles to catch up with them and for them to require reintubation or ongoing ventilatory support. The other aspects of myasthenic crisis care that are important are supportive care, so as with our patient, she developed a respiratory tract infection, and that required antibiotic treatment, and also appropriate feeding, so even if ventilatory support is not required, NG supplemental feeding is often required when there is severe bulbar respiratory failure. Now, that's the ITU-level care. What about the management of the myasthenic crisis from a neuroimmunology point of view? So when somebody has a myasthenic crisis, you want a fast-acting rescue treatment, and there is evidence for both IVIG and plasma exchange in these scenarios. There is a randomised controlled trial that looked at rapidly deteriorating myasthenia and concluded that IVIG and plasma exchange were roughly equivalent. However, not everybody will respond to IVIG, and some patients will respond to plasma exchange when IVIG was not effective.
It's my preference, if possible, to use plasma exchange first, followed by IVIG, but that's not always possible. The effect of these treatments can be short-lived, up to weeks at a time, and multiple courses of IVIG or plasma exchange may be required, as was the case in our patient. Now, the next question that came from this case was is thymectomy appropriate in this emergency setting? It's the general teaching that thymectomy is only appropriate when the patient's myasthenia is stable, as putting a patient through a surgery does occasionally run the risk of exacerbating their myasthenic weakness and putting them at risk of a postoperative myasthenic crisis. In our patient, there was a concern about a thymoma which could have been driving the underlying process, and that led us to worry about starting an referring her for an early thymectomy, but just stepping back a bit and thinking about thymectomy in general, when is it appropriate for your patients with myasthenia? From the MGTX trial, we know that there is randomised evidence to support its use in those with younger onset, so under the age of 50, even though the trial did go up to 65, patients with generalised myasthenia with acetylcholine receptor antibodies. There are less data surrounding the use of thymectomy in ocular myasthenia, though it's increasingly been used.
Of course, if a patient has a thymoma, thymectomy is indicated to reduce the risk of invasive spread of the thymoma. In terms of what type of thymectomy is appropriate, in the last number of years, there has been an absolute explosion in the use of minimally invasive often robotically assisted approaches, and those approaches do seem to be as effective as the traditional open sternotomy and are certainly better tolerated, so it's general practise to refer patients for minimally invasive thymectomy to an experienced surgeon when that is available. The next thing we have to consider in this patient is the treatment algorithm for myasthenia. Now, depending on the region in which you are practising , the neurology associations or local guidelines may have different approaches to the management of generalised myasthenia. Traditionally, there has been a rather stepwise approach to the initiation and addition of different immunosuppressive and immunomodulatory agents for myasthenia, so traditionally, we would consider using pyridostigmine first, which has symptomatic effect on the symptoms of myasthenia by inhibiting acetylcholinesterase, then moving on to corticosteroids, which help manage the immune process associated with myasthenia and can generally bring about a rapid improvement in symptoms with the addition of other agents that we think of as steroid-sparing agents, such as azathioprine, mycophenolate, methotrexate, et cetera. If ongoing steroids are required, as we know, there are a plethora of side effects associated with steroids, and we need another agent to try and allow us to use a lower steroid dose and help mitigate these side effects. Other agents, such as rituximab and other B-cell therapies, have traditionally been reserved for patients who have failed to respond to the typical more standard immunosuppressant agents we use, and then, IVIG and plasma exchange have been used as rescue treatments.
However, in this era of more targeted specific therapies for myasthenia and with data from different trials showing that certain therapies such as B-cell therapies may be used earlier, there has begun to be a rethinking of whether we should think of highly active refractory disease as different to patients who are more likely to respond to more standard treatments, and what you see on this slide here is an example from the German guidelines where they do divide up both AChR and MuSK antibody-positive myasthenia into fairly stable disease and highly active disease, and give recommendations on what types of agent, from an immunosuppressive point of view, that could be used in different scenarios. With regard to surgery, thymectomy, of course, is indicated in acetylcholine receptor myasthenia, as I mentioned earlier, but it is not indicated in MuSK myasthenia. The data here look at the use of rituximab in early onset myasthenia, so this comes from the RINOMAX trial, which was published almost three years ago now, and in contrast to using rituximab as we traditionally used it in myasthenia and quite refractory long-lasting myasthenia, in this study, they used a single dose of 500 milligrammes rituximab in patients who were naive to other immunosuppressant agents other than steroids, and they looked at the proportion of patients who went into minimal disease manifestations at different stages of the study, and they also looked at the use of rescue therapies such as IVIG and plasma exchange, and the finding from this study was that rituximab-treated patients were more likely to enter a minimal disease manifestations phase and were less likely to require rescue treatments, and that suggested that early use of rituximab may be effective for patients with generalised AChR-positive myasthenia gravis, and the other thing that we had to think about in this patient's case was the fact that she had just had a baby, and this brought up questions such as what's the impact of pregnancy on myasthenia? And could there be any possible impact on her baby? So as with a lot of autoimmune diseases, myasthenia gravis can actually become fairly quiescent during pregnancy, though some patients can have exacerbations. However, once again, in common with other autoimmune diseases, there can be a resurgence of disease symptoms in the postpartum period, and up to 28% of patients with myasthenia are known to have a postpartum dip. Up to 8.2% of patients have been described as being at risk of developing crisis in the postpartum period.
The postpartum period and the peripartum period can put patients at risk. For example, if they require antibiotics, there is a risk that the antibiotics that are chosen may exacerbate myasthenia. That is possible, particularly when the myasthenia gravis is not known about, as was the case in our patients. If IV magnesium is required for preeclampsia, magnesium is known to affect neuromuscular junction transmission, and that can also exacerbate myasthenic symptoms. With regard to the baby, babies of myasthenic mothers are at risk of transient neonatal myasthenia caused by placental transfer of maternal antibodies, and that has been described in up to 10 to 15% of babies born from myasthenic mothers. Of course, in the postpartum period, the patient may be breastfeeding, and one needs to consider the safety of drugs in that scenario, and also, this woman is of childbearing age. She may want another pregnancy, and any drugs that are initiated must be considered with that in mind. Of course, a lot of that was unknown in our patient because her presentation was in the postpartum period. Though, in retrospect, the fatigue that she developed in the last trimester was probably the beginning of her myasthenic symptoms, so going back to our patient, having considered the various aspects associated with myasthenic crisis, having considered about thymectomy, having thought about the impact of her recent pregnancy on her symptoms, and having correctly diagnosed her as having highly active disease, and thinking about what type of treatments will be most appropriate, this is what happened to her, so she was extubated, but was still very weak, still requiring an NG tube, still requiring help with mobilisation, and required a wheelchair. She did undergo a thymectomy. This was a robotically assisted thymectomy, and, in fact, she did not have a thymoma, but rather, had a bulky hyperplastic very inflammatory-looking thymus, and the learning I took from this is that it's not always apparent on the radiological report whether something is a thymoma or a very bulky hyperplastic gland.
She had postoperative IVIG to reduce her risk of postoperative myasthenic crisis, and actually, she did quite well. She was still on a high dose of steroids at this point, 70 milligrammes. We reduced it slightly, and then she went on to have rituximab. We gave her the full induction dose of one gramme for two doses. She required a lot of rehabilitation, and this brings up another important point, that the management of severe myasthenia, particularly myasthenic crisis, requires more than just the neurologist. She needed a lot of respiratory and physical rehabilitation to enable her to be discharged. The speech and language team were heavily involved in rehabilitating her swallow, and eventually, about two weeks after her thymectomy, the NG tube was removed. At that point, she was able to go home, and her myasthenia gravis ADL score was five on discharge, having been a maximum of 24 during the most severe phase of her illness.
This was really a great improvement. She returned to see us at 12 weeks, and at that point, she was in minimal manifestations with an MG ADL score of zero. Over the next few months, we gradually weened her prednisolone, and she's currently taking 10 milligrammes per day. That is the case of our patient with postpartum myasthenia gravis. To reiterate the important points, the management of myasthenic crisis is most dependent on good ITU care with good supportive management. Beware of extubating the patient too early, as they can often fatigue, and multiple courses of rescue treatment may be required. Early thymectomy can be done even if a patient is recovering from myasthenic crisis, but only in a specialised centre and with appropriate rescue therapy. Early rituximab was helpful for this patient, and there are data that suggests that early rituximab can be helpful in acetylcholine receptor antibody myasthenia, particularly when it's highly active, and myasthenic crisis can be the presenting feature of myasthenia gravis, and this can occur just post-pregnancy, as it did in our patient, and it's important to be aware of myasthenia gravis as a differential diagnosis in this scenario. I hope you found this podcast helpful and this case discussion useful and that it will add to your knowledge about the management of generalised myasthenia gravis. Thank you very much.
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