Written By: Ellen M. Martin
Autoimmune disease is an “invisible epidemic.” Despite affecting at least 16% of Americans, more than cancer and heart disease, immune-mediated conditions remain under-recognized, under-researched, under-diagnosed and under-treated. To increase awareness and connect patients, families and caregivers with useful resources, we at Your Autoimmunity Connection publish a series of “Spotlights” on autoimmune diseases and other conditions linked to immune dysfunction.
The trigger for this post on Myasthenia Gravis (MG) was one of us hearing from a cherished friend after many years, to hear (quite literally, the vocal effects of the disease are striking, even in a short voicemail) that he has been suffering from late-onset MG for years and is recovering from a myasthenic crisis that required weeks in an induced coma. So, Paul, this one is for you.
A Note to Caregivers
Given that the primary symptoms are muscle weakness, sometimes crippling, many MG patients must rely on caregivers to get them through flares. Educating and supporting caregivers, who are usually spouses, relatives or friends without medical experience, is a particular challenge in MG. This post, the links and further reading is intended to help caregivers, too.
What is Myasthenia Gravis (MG)?
MG is a group of rare (prevalence 14-20:100,000 in US, although probably higher[i]) acquired autoimmune diseases. There are even rarer, non-autoimmune, congenital myasthenic syndromes (CMS) that we will not discuss but see this link to information about them in the endnotes.[ii]
The name was bestowed on the disease in the late 19th C., although the first description of the disease was in 1672 and there are historical accounts of the illness of Chief Opechankanough, who died in 1644, that strongly suggest he suffered from late-onset MG.[iii]
Myasthenia Gravis is one of those Greek-Latin mashups so common in medical lingo. It means “grave muscle weakness” and that sure sounds awful. The good news is that while MG can be life-threatening (see myasthenic crisis below), medical treatment is now available that can give most patients normal life expectancy and good quality of life.
Symptoms and Pathology
Characteristic symptoms include waxing and waning muscle weakness, especially fatigability, where muscles lose strength with use and recover somewhat with rest. Ocular MG, characterized by eye muscle weakness, such as ptosis (droopy eyelid), is the most frequent form of the disease.
Bulbar muscle weakness affects the face, jaws, throat and neck (bulbar = cranial nerves IX-XII that control speech, swallowing, breathing and neck muscles (see illustration). Less frequently, peripheral muscles may be affected, generally more upper body, and more proximal (shoulders) than distal (hands).
However, some of these symptoms also occur in other neurological diseases (ALS, Botulism, MS, Guillain-Barré syndrome), so MG is frequently misdiagnosed, especially in older men.
Figure 1. The cranial nerves as seen from underneath the brain. The ocular motor nerves are III, IV, VI, shown in mid-upper left. The bulbar nerves are IX–XII, described on the lower right.[iv]
What all acquired autoimmune MG cases have in common (we’ll discuss differences too) is a misdirected T- and B-cell attack on the neuromuscular junction (NMJ) receptors of skeletal muscle, most frequently the nicotinic acetylcholine receptors (nAChR) (see illustration). Since acetylcholine receptors transmit motor nerve signals to muscles, damaging them produces painless weakness in the affected muscles. This variety is called seropositive MG because patients have detectable antibodies to nAChR in their blood. In a subset of seronegative (no detected nAChR antibodies) patients, Muscle-Specific Kinase (MuSK) receptors, which also mediate ACh signaling, are the targets. A third receptor target is titin, a striated muscle antigen, generally not found in early-onset MG, but seen in 50% of late-onset patients.[v]
Figure 2. Schematic of striated muscle nerve junction (NMJ), showing ACh neurotransmitter released by nerve and binding to AChR sites on muscle cells. Also shown is the MuSK receptor and deeper in the muscle, the titin receptors. All are potential targets of damage in MG.[vi]
The thymus, a small gland located beneath the breastbone, between the lungs and ventral to the heart (see illustration), is where immune system T-cells mature and learn to differentiate self from foreign antigens. The thymus is abnormal in ~75% of MG patients. Thymic hyperplasia (enlargement), similar to the thyroid hyperplasia in Hashimoto thyroiditis, is common. In about 10% of patients, thymomas, tumors in the thymus gland, trigger MG. These patients especially, but also some patients without thymomas, benefit from thymectomy, surgery to remove the thymus.
Types of Myasthenia Gravis
For such a rare disease, MG comes in a surprising variety of forms. MG is classified by age of onset (note that researchers use several different arbitrary cutoff ages for early- and late-onset MG).
- Transient neonatal MG: mothers with MG may transfer anti-nAChR antibodies to their newborns. With supportive care, most of these babies recover completely within a few months.
- Pediatric or Juvenile onset MG: Less than 10% of cases. Like type 1 diabetes, a childhood autoimmune reaction to unknown triggers.
- Early-onset MG, primarily (3-4:1) females aged 20-30. This used to be the predominate form, but as the population lives longer, more late-onset disease is being detected.
- Late-onset MG: primarily males aged 50-60, sex ratio equal after 70. Until recently, LOMG in men was under-detected, but evidence is increasing that actual incidence has grown, too. [vii]
Across cases at any age there are five classes of severity (Osserman classification)[viii]:
- Ocular weakness
- Mild weakness:
- Moderate weakness (same subtypes)
- Severe weakness (same subtypes)
- Intubation or ventilation needed (myasthenic crisis)
A myasthenic crisis is a severe, life-threatening episode of weakness that affects swallowing or breathing and may require intensive care, intubation, ventilation or even induced coma.
Triggers of MG
Like most autoimmune diseases, symptoms wax and wane, with exacerbations (flares) often set off by specific triggers, such as:
- Infections, especially viral infections
- Vaccinations (although MG patients should be vaccinated against flu and other viral diseases)
- Certain drugs, especially antibiotics and cardiovascular
- Emotional stress
- Temperature extremes
- Bright sunlight may trigger ocular symptoms
A family history of MG is unusual, but family members with other autoimmune diseases (e.g., MS) are more frequent and suggests a genetic predisposition, although the genomic patterns are poorly understood. Moreover, MG patients are more likely to have other autoimmune diseases, especially Hashimoto thyroiditis, rheumatoid arthritis, scleroderma, lupus, and Sjogren’s.
How is Myasthenia Gravis Diagnosed?
As with other autoimmune diseases, diagnosis is often difficult or incorrect, especially for late-onset disease in males, frequently because practitioners do not consider MG in the differential diagnosis. This is particularly true of ocular MG (OMG), where ophthalmologists are often the first physicians consulted, and MG is frequently not high on their index of suspicion.
For OMG there are several alternative diagnoses, from blepharospasm and cranial nerve palsies to stroke. In patients with bulbar or general symptoms, there are also many alternative diagnoses, including: ALS, botulism, brainstem gliomas, Lambert-Eaton Myasthenic Syndrome, Multiple Sclerosis (MS), progressive bulbar palsy, thyroid disease, stroke and others.
Tests for MG
Legacies of old-style doctoring, a few hands-on clinical tests are still used, including resting eyelid and ice-pack tests. Imaging frequently shows an enlarged thymus. Electrophysiologic nerve stimulation testing can detect abnormal neuro-muscular transmission. Pharmacological tests using short-acting acetylcholinesterase inhibitors temporarily increase ACh levels and produce a brief but diagnostic improvement of symptoms. More recently, immunologic testing can detect elevated AChR, MuSK or titin antibodies in blood, but these are costly tests only used when index of suspicion is high. Thyroid testing may also be worthwhile, since 4-5% of MG patients have concurrent autoimmune thyroid disease.[ix]
There is an unmet need for faster and more accurate detection and diagnosis, especially since patients respond best to early treatment. As with other rare diseases, education, awareness, analytics and decision-support technology may help medical practitioners consider MG more frequently, enough to move patients up the care pathway to more determinative diagnostic tests.
How is MG treated?
Once diagnosed, there are four major modalities for MG treatment: surgery, acetylcholinesterase inhibitors, immunosuppressants (corticosteroids, etc.), and for myasthenic crisis, rescue treatments, including plasmapheresis and intravenous immunoglobulin.[x]
Once the role of the thymus was suspected in MG (Carl Weigert in 1901 was the first to describe a myasthenic patient with a thymic mass), surgery became a treatment option. Thymectomy provides robust remission in 80% of patients with thymoma. Some patients with other thymus abnormalities also benefit dramatically from surgery. OMG-only patients are the least likely to benefit from surgery.
Pharmacologic treatments for MG are complex. Most patients require two classes of drug to achieve remission and many then need additional drugs to cope with the side effects of the main regimen.
Before the 1930s, there were no pharmacological treatments for MG, and mortality rates were high. In 1934, Mary Broadfoot Walker published her discovery (based on her experience treating curare paralysis) that injections of physostigmine, an acetylcholinesterase inhibitor, relieved MG symptoms, leading to her insight that MG was a disease of the NMJ. Physostigmine has particularly harsh side effects, so it has been largely replaced by pyridostigmine bromide (Mestinon, patented 1945, and generics), prescribed to some 60% of MG patients, as well as neostigmine and others.
Dosing of AChE inhibitors can be tricky, and overdoses unfortunately resemble some of the symptoms of the disease itself, presenting a challenge to patients and practitioners to monitor dose response and keep the effective dose as low as possible.
Nevertheless, oral acetylcholinesterase inhibitors remain first-line treatments for MG, but these drugs do not stop the underlying autoimmune disease progression, rarely relieve all symptoms completely, and many patients become refractory. Therefore, it is usual for patients to be prescribed concomitant immunosuppressants or other immune system modulators.
Corticosteroids were the first immunomodulators to be used in MG. Prednisone, prednisolone and methylprednisolone may be familiar to readers from their widespread use in other autoimmune diseases. They quickly and effectively mute the autoimmune response but have notorious side effects, including weight gain, bloating, GI discomfort, higher risk of infection and the need to reduce doses gradually if drug is discontinued.
Non-steroidal Immunosuppressants used to prevent transplant rejection are also used in MG: These include Azathioprine, Mycophenylate mofetil, cyclosporine, tacrolimus and methotrexate, among others. Side effects are similar to steroids, but differ from patient to patient, so regimens may be adjusted to provide the best primary effect and the most tolerable side-effects.[xi]
Biologicals: Few specialty drugs are specifically approved for MG. Only one monoclonal antibody biologic, Soliris (eculizumab), is approved (since 2017) for generalized MG (gMG).[xii] Off-label use of other MAbs, especially rituximab[xiii] has shown promise in MG and clinical trials are underway. Cladribine, a targeted anti-lymphocyte drug approved for MS, has also shown encouraging results in a small study.[xiv] Several investigational drugs are in various stages of progress.[xv]
Clinical Trials: Quite a few clinical trials are ongoing. See these resources.[xvi] [xvii] [xviii]
Rescue therapies: Immunoglobulin infusions and plasmapheresis
During myasthenic crisis, emergency supportive care (intubation, ventilation, coma) may be needed, obviously in patients with swallowing or breathing difficulties that can become life-threatening within hours. Intensive care may be combined with plasmapheresis or immunoglobulin infusions. The former involves running the patient’s blood through a system similar to that used in kidney dialysis patients, but that removes AChR antibodies. Immunoglobulin infusions bind and neutralize the antibodies, keeping them from further damaging the ACh receptors.
Other treatment considerations
Side effects are a big issue for MG patients.[xix] All drugs used have GI side effects, some of which can be mitigated by careful timing before meals (where the effect of the drugs may also help with swallowing problems). AChE inhibitors are associated with nausea, vomiting and diarrhea, as well as muscle cramps, weight loss, headache, insomnia and abnormal dreams. Corticosteroids are notorious for appetite stimulation, weight gain and bloating, and all immunosuppressants for increasing risk of infection and lymphomas. Complicating things further is dose sensitivity, which varies by patient and over time and must be carefully managed. Most MG patients are on at least two drugs, and many are taking more, presenting additional challenges to patients and their caregivers.
Particularly important for MG patients is a long list of drugs to avoid.[xx] These include common antibiotics, especially the aminoglycosides and quinolones, neuromuscular blocking agents, opioids and other CNS inhibitors, anticonvulsants, and others.
Anesthesia and vaccination present particular challenges to MG patients. Anesthesia generally exacerbates symptoms, and the anesthesiologist has to be especially attentive to these effects. Since viral diseases can exacerbate weakness, it is generally recommended that MG patients receive influenza and other viral vaccines, even though the vaccines themselves may provoke flares. Careful monitoring of MG patients after vaccination is therefore necessary.
Beneficial lifestyle changes include avoiding excessive heat, reducing stress, eating a high-potassium diet, being alert to (and alerting caretakers and practitioners to) potential flares triggered by other drugs.
For further reading (all the links in the notes contain a wealth of further information, too)