Neuromuscular Junction Disorders and Myopathies
Anthony A. Amato
Mohammad Kian Salajegheh
MYASTHENIA GRAVIS
Background
1. Myasthenia gravis is an autoimmune disease caused by an immunologic attack directed against the postsynaptic neuromuscular junction (NMJ).
2. The incidence of myasthenia gravis ranges between 1 and 9 per million, whereas the prevalence ranges between 25 and 142 per million. The incidence of myasthenia gravis is slightly greater in women than in men. The age of onset is bimodal for both men and women. Women demonstrate annual peak incidences at ages 20 to 24 years and 70 to 75 years, whereas men have peak rates between 30 and 34 years and 70 and 74 years.
3. Patients with myasthenia gravis can be classified according to the Osserman criteria:
a. Group 1: ocular, 15% to 20%
b. Group 2A: mild generalized, 30%
c. Group 2B: moderately severe generalized, 20%
d. Group 3: acute fulminating, 11%
e. Group 4: late severe, 9%
4. As many as 70% of patients with myasthenia gravis have thymic hyperplasia, and approximately 10% have a thymoma. Thymomas are much more common in patients between the ages of 50 and 70 years. Importantly, the thymomas can be malignant and invasive. The role of the thymus in myasthenia gravis is unclear.
Pathophysiology
Myasthenia gravis is an acquired autoimmune disorder of neuromuscular transmission resulting from antibodies directed against the acetylcholine receptor (AChR), to a lesser extent, muscle-specific tyrosine kinase (MuSK), and, rarely, lipoprotein-related protein 4 (LRP4).
Prognosis
1. At least 50% of patients initially presenting with purely ocular symptoms eventually develop a more generalized form of the disease.
2. Most patients evolve to their weakest state within the first 3 years.
3. Patients may develop severe generalized weakness with respiratory failure or inability to swallow. Severe respiratory and bulbar weakness can develop in the absence of ocular or extremity weakness.
4. Patients with only mild weakness may respond to anticholinesterase medications. However, patients with moderate or severe weakness require immunosuppressive agents and immunomodulating therapies.
Diagnosis
Clinical Features
1. The clinical hallmark of myasthenia gravis is fluctuating weakness characterized by abnormal fatigability that improves with rest.
2. Patients often complain of drooping eyelids, blurred vision, or frank diplopia, particularly after prolonged reading or at the end of the day. Ptosis is the presenting symptom in 50% to 90% of patients, whereas 15% have blurred vision or frank diplopia. At some point, about 90% to 95% of patients complain of diplopia.
3. Dysphagia and dysarthria occur in as many as one-third of patients.
4. Proximal limb and neck weakness is a presenting symptom in approximately 20% to 30% of individuals. Importantly, approximately 3% of patients manifest with predominantly distal weakness. Head drop secondary to neck extensor weakness is common and can be the presenting feature. There may be fatigue after repetitive activities.
5. Occasionally, patients present with respiratory failure because of weakness of the diaphragm and accessory muscles of respiration.
6. Patients with MuSK antibodies often manifest with bulbar or proximal weakness without ocular involvement.
Pharmacologic Testing
1. The edrophonium (ie, Tensilon) test can be helpful in diagnosing myasthenia gravis. Edrophonium is an anticholinesterase and its ingestion results in a transient increase in AChR in the NMJ.
a. Anticholinergic side effects of edrophonium include fasciculations, bradycardia, nausea, vomiting, increased tearing, and lacrimation.
b. Monitor the pulse and blood pressure of patients and be prepared to administer atropine to counteract the anticholinergic effects of edrophonium.
c. Place a butterfly needle in the antecubital vein and give a 2-mg test dose of edrophonium. If there is no response after 30 seconds, the other 8 mg is administered in increments (2 mg every 15 seconds).
d. It is most important to assess for objective sign of weakness, not the patient’s subjective response. In this regard, evaluating improvement of measured ptosis or ophthalmoparesis is most useful.
e. A test is not considered positive solely if the patient states that he or she feels stronger.
Ice Pack Test
1. The ice pack test can be useful in patients with ptosis. A bag of ice is placed over the eye of a ptotic eyelid for approximately 30 seconds. The cold temperature improves the ptosis in patients with myasthenia.
2. In much the same way that cold temperature reduces decrement on repetitive nerve stimulation, cold may reduce the activity of acetylcholinesterase. This increases the safety factor of neuromuscular transmission by allowing more acetylcholine to be available after release into the NMJ.
Laboratory Features
1. AChR antibodies are detected in about 80% to 90% of patients with generalized myasthenia gravis, with a slightly lower occurrence (70% of patients) in the ocular form.
2. Antibodies directed against MuSK are seen in approximately one-third of patients without AChR antibodies.
3. LRP4 antibodies are about half as common as MuSK antibodies.
Electrophysiologic Findings
1. Repetitive stimulation is typically performed on an intrinsic hand muscle such as the abductor digiti minimi first; however, in patients with only proximal weakness, the trapezius can be assessed. In patients with only ocular or bulbar weakness, a facial muscle (orbicularis oculi, nasalis, or orbicularis oris) should be studied.
a. First, perform a 2- to 3-Hz repetitive stimulation with the patient at rest. Normally, there should be less than a 10% decrement in muscle action potential amplitude.
b. If an abnormal decrement is demonstrated, the patient is instructed to exercise the muscle for 10 seconds to assess for postexercise facilitation and the resulting improvement in the decrement on 2- to 3-Hz stimulation immediately postexercise.
c. If no decrement is seen at rest, the muscle is exercised for 1 minute to see whether postexercise exhaustion brings out an abnormal decrement. Repetitive stimulation at 2 to 3 Hz is performed immediately postexercise and once per minute for the next 5 to 6 minutes.
2. If repetitive nerve stimulation is normal, a single-fiber electromyogram (EMG) can be performed. Single-fiber EMG documents increased jitter in 77% to 100% of patients depending on disease severity and the muscle studied.
Treatment
1. There are various treatment strategies commonly used for myasthenia gravis.
a. Acetylcholinesterase inhibitors (anticholinesterase drugs) (Table 13-1)
b. Immunosuppressive/immunomodulating agents
c. Plasma exchange
d. Thymectomy
2. The regimen used in patients with myasthenia gravis is individualized and dependent on the severity of the myasthenia, age of the patient, the presence or absence of an enlarged thymus, and concurrent medical problems.
3. We try to treat patients with ocular myasthenia only with pyridostigmine bromide (Mestinon). If patients are still symptomatic on pyridostigmine bromide (Mestinon), we initiate prednisone in a slowly incrementing fashion (see the “start-low and go-slow approach” to prednisone treatment under “Specific Therapies” section).
4. Patients in myasthenic crisis (severe respiratory distress or bulbar weakness) represent the opposite end of the spectrum.
a. These patients should be admitted to an intensive care unit and followed closely, particularly for pulmonary function.
b. When the forced vital capacity (FVC) declines to less than 15 mL/kg or the negative inspiratory pressure is less than 30 cm H2O, consider elective intubation of the patient to protect the airway, and begin mechanical ventilation. Alternatively, bilevel positive airway pressure (BiPAP) may be initiated and may alleviate the need for intubation in patients who are not hypercapnic (ie, PaCO2 above 50 mm Hg).
c. Initiate PE and continue until the patient has had significant return of strength and can be weaned off the ventilator. Intravenous immunoglobulin (IVIG) may be an alternative treatment.
d. In addition to starting PE or IVIG, we usually begin high-dose corticosteroids at or around the same time.
5. Specific therapies
a. Acetylcholinesterase inhibitors
1) The acetylcholinesterase inhibitor pyridostigmine bromide (Mestinon) usually improves weakness in patients with myasthenia gravis.
2) Start pyridostigmine in adults at a dose of 30 to 60 mg every 6 hours. In children, start pyridostigmine at a dose of 1 mg/kg. The dosage is gradually titrated as necessary to control myasthenic symptoms and reduce side effects. Most adults require between 60 and 120 mg of pyridostigmine every 4 to 6 hours.
3) There is a timed-released form of pyridostigmine (Mestinon Timespan, 180 mg). A Mestinon Timespan tablet can be given at night to patients who have severe generalized weakness on awakening. Alternately, in patients with only mild or moderate weakness, it is equally efficacious to have the patient set his or her alarm 30 minutes before he or she needs to arise from bed and take a regular pyridostigmine dose at that time.
4) Patients can develop cholinergic side effects secondary to the buildup of AChR at muscarinic and nicotinic receptors. Muscarinic side effects include nausea, vomiting, abdominal cramping, diarrhea, increased oral and bronchial secretions, bradycardia, and, rarely, confusion or psychosis. In patients with significant side effects, we pretreat with anticholinergic medications (eg, hyoscyamine sulfate [Anaspaz] one tablet four times a day [qid]) 30 minutes prior to the pyridostigmine dose.
b. Corticosteroids
1) Most of our patients with moderate to severe generalized myasthenia gravis receive prednisone. There are two treatment strategies generally used when using prednisone in patients with myasthenia gravis.
a) Aggressive high-dose daily steroids at the onset of treatment.
b) “A start-low and go-slow approach.”
c) The high-dose daily regimen leads to a much quicker improvement of strength, but there is about a 10% to 15% chance of early worsening. This transient worsening is typically not seen in the “start-low and go-slow” approach, but it generally takes longer for patients to improve.
2) In patients with moderate to severe generalized myasthenia, we generally initiate treatment with prednisone 0.75 to 1.5 mg/kg/d (up to 50 mg). We maintain the patients on this high dose of prednisone until their strength has normalized or there is a clear plateau in improvement. Subsequently, we slowly taper prednisone by 5 mg every 2 to 4 weeks, down to 20 mg daily. At this point, we taper even more slowly, by 2.5 to 5 mg every 4 weeks. At 10 mg daily, we taper no faster than 2.5 mg a month. It is usually at these low doses that patients may have a relapse.
3) Most patients require some additional form of therapy, but we try to find the lowest doses necessary to maintain their strength.
4) The addition of other immunosuppressive agents (eg, azathioprine) may have a prednisone-sparing effect. Many authorities initiate treatment with one of these agents at the same time that prednisone is started in the hope that it may be tapered quickly and to a lower dose than could be achieved by prednisone monotherapy. We usually initiate treatment with a second-line agent along with prednisone in postmenopausal women, patients with known osteoporosis, or those with increased risk of adverse reaction to corticosteroids (eg, patients with diabetes mellitus).
5) About 5% to 15% of patients experience a varying degree of initial worsening after they are started on high doses of steroids. If patients have moderate weakness, it is reasonable to hospitalize them for the first week after initiating treatment with high-dose corticosteroids.
6) Because of the risk of exacerbation with high-dose corticosteroids, some have advocated the start-low and go-slow approach. Patients are started at a dose of 10 to 20 mg/d, and the dose is slowly increased by 5 mg every 5 to 7 days or so until definite improvement is noted. Unfortunately, improvement takes much longer with this approach and is thus not very useful in patients with severe weakness. We reserve this approach for patients with mild to moderate generalized disease not controlled with pyridostigmine bromide (Mestinon) or for patients with ocular myasthenia.
7) There is a multitude of potentially serious side effects to the chronic administration of corticosteroids (eg, risk of infection, diabetes mellitus, hypertension, glaucoma, osteoporosis, and aseptic necrosis of the joints).
8) We obtain a chest radiograph and a purified protein derivative (PPD) skin test in at-risk populations prior to initiating immunosuppressive medications. A QuantiFERON-TB Gold Plus (QFT-Plus) and T-SPOT.TB test (T-Spot) are more sensitive and specific in patients who are already immunosuppressed or previously received. Vaccination with BCG vaccination. Patients with latent tuberculosis may need to be treated prophylactically with isoniazid.
9) Measure bone density with dual-energy x-ray absorptiometry (DEXA) at baseline and every 12 months while patients are receiving corticosteroids.
10) Calcium supplementation (1 g/d) and vitamin D supplementation (400-800 IU/d) are started for prophylaxis against steroid-induced osteoporosis. We usually recommend calcium carbonate (Tums) for calcium supplementation, because it can also help with the dyspepsia associated with steroid use.
11) Bisphosphonates are effective in the prevention and treatment of osteoporosis. If DEXA scans demonstrate osteoporosis at baseline or during follow-up studies, we initiate alendronate 70 mg/wk. In postmenopausal women, we start prophylactic treatment with alendronate 35 mg orally once a week if DEXA scans show bone loss at baseline (not enough to diagnose osteoporosis at that stage) or if there is significant loss on follow-up bone density scans. Alendronate can cause severe esophagitis, and absorption is impaired if it is taken with meals. Therefore, patients must be instructed to remain upright and not eat for at least 30 minutes after taking a dose of alendronate.
12) We do not prophylactically treat with histamine H2 receptor blockers unless the patient develops gastrointestinal discomfort or has a history of peptic ulcer disease. Calcium carbonate (Tums) can help prevent any discomfort and also serve as a source of calcium.
13) Patients are instructed to start a low-sodium, low-carbohydrate, high-protein diet to prevent excessive weight gain.
14) Patients are also given physical therapy and encouraged to slowly begin an aerobic exercise program.
15) Blood pressure is measured with each visit along with periodic eye examinations for cataracts and glaucoma. Fasting blood glucose and serum potassium levels are periodically checked. Potassium supplementation may be required if the patient becomes hypokalemic.
16) Steroid myopathy versus relapse of myasthenia gravis: High-dose, long-term steroids and lack of physical activity can cause type 2 muscle fiber atrophy with proximal muscle weakness. This needs to be distinguished from weakness caused by relapse of the myasthenia. Patients who become weaker during prednisone tapering and have worsening of their decrement repetitive stimulation or increasing jitter and blocking on single-fiber EMG are more likely experiencing a flare of the myasthenia. In contrast, patients with continued high doses of corticosteroids, normal repetitive stimulation and single-fiber EMG results, and other evidence of steroid toxicity (ie, cushingoid appearance) may have type 2 muscle fiber atrophy and could benefit from physical therapy and reducing the dose of steroids.
c. Azathioprine
1) We prescribe azathioprine for patients with moderate to severe generalized myasthenia gravis whose disease is not well controlled by prednisone and pyridostigmine bromide (Mestinon). As noted previously, we will start azathioprine in patients most at risk of steroid complications at the initiation of treatment along with prednisone.
2) Prior to beginning azathioprine, patients can be screened for thiopurine methyltransferase (TPMT) deficiency. Patients who are heterozygous for mutation in TPMT may be able to tolerate azathioprine at lower dosages, but those who are homozygous should not receive the drug as they cannot metabolize it and may develop severe bone marrow toxicity.
3) We start azathioprine at a dose of 50 mg/d in adults and gradually increase by 50 mg/wk to every 2 to 4 weeks as tolerated up to a total dose of 2 to 3 mg/kg/d.
4) A systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurs in 12% of patients, requiring discontinuation of the drug. This reaction generally occurs within the first few weeks of therapy and resolves within a few days of discontinuing the azathioprine.
5) A major drawback of azathioprine is that it takes a long time to see an effect. A double-blind, placebo-controlled trial of azathioprine did not show a statistically significant benefit in terms of cumulative corticosteroid dose reduction until 18 months of treatment.
6) Monitor complete blood counts (CBCs) and liver function tests (LFTs)—aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubins every 2 to 4 weeks until the patient is on a stable dose of azathioprine and then every 3 to 6 months.
7) If the WBC count falls less than 3,000/mm3, we decrease the dose. Azathioprine is held if the WBC count declines to 2,500/mm3 or the absolute neutrophil count falls to 1,000/mm3. Leukopenia can develop as early as 1 week or as late as 2 years after initiating azathioprine. The leukopenia usually reverses within 1 month, and it is possible to then rechallenge the patient with azathioprine without recurrence of the severe leukopenia.
8) Discontinue azathioprine if the LFTs increase to more than twice the baseline values. Liver toxicity generally develops within the first several months of treatment and can take several months to resolve. Patients can occasionally be successfully rechallenged with azathioprine after LFTs return to baseline without recurrence of hepatic dysfunction.
9) Allopurinol should be avoided because its combination with azathioprine increases the risk of bone marrow and liver toxicity.
d. Mycophenolate mofetil
1) Mycophenolate mofetil inhibits the proliferation of T and B lymphocytes by blocking purine synthesis in only lymphocytes.
2) The starting dose is 1 g twice daily and can be increased by 500 mg a month up to 1.5 g twice a day (bid).
3) Mycophenolate is renally excreted; therefore, the dose should be no more than 1 g/d (ie, 500 mg bid) in patients with renal insufficiency.
4) A benefit of mycophenolate compared to other immunosuppressive agents is the lack of renal or liver toxicity with the drug.
5) The major side effect is diarrhea. Less common side effects include abdominal discomfort, nausea, peripheral edema, fever, and leukopenia.
6) Use of mycophenolate has been tempered by the results of two controversial double-blind, placebo-controlled trials that failed to demonstrate any benefit. Nevertheless, some authorities are still strong advocates and believe that it is beneficial in some patients. Given its high cost and lack of proven efficacy in two large trials, we no longer routinely prescribe it. However, we keep patients who are currently doing well with it on mycophenolate.
e. Cyclosporine
1) Cyclosporine inhibits primarily T cell-dependent immune responses. We reserve cyclosporine to patients who are refractory to prednisone and azathioprine.
2) Most patients notice improvement within 2 to 3 months of initiating treatment; thus, it works much faster than azathioprine.
3) We start cyclosporine at a dose of 3 to 4 mg/kg/d in two divided doses and gradually increase to 6 mg/kg/d as necessary.
4) The cyclosporine dose should initially be titrated to maintain trough serum cyclosporine levels of 50 to 150 ng/mL. Adjust the dose to keep the trough less than 150 ng/mL and the creatinine level less than 150% of baseline.
5) Blood pressure, electrolytes, renal function, and trough cyclosporine levels need to be monitored.
f. Tacrolimus
1) Tacrolimus is similar to cyclosporine but may be associated with fewer side effects. Therefore, many authorities prefer tacrolimus over cyclosporine.
2) The starting dose is 0.1 mg/kg and can be gradually increased up to 0.2 mg/kg (in two divided doses) as needed.
3) The dose is titrated to maintain a trough level of 5 to 15 mg/mL.
4) As with cyclosporine, it is important to monitor blood pressure, electrolytes, and renal function.
g. IVIG
1) Some studies have found that IVIG is equivalent to PE in the treatment of myasthenic crisis, whereas other studies have suggested that PE is more efficacious. We have successfully used IVIG in patients in myasthenic crisis and believe it is an equal alternative to PE until proven otherwise.
2) IVIG has not been found to be beneficial as maintenance therapy.
3) We initiate IVIG (2 g/kg) slowly over 2 to 5 days and repeat infusions at monthly intervals for at least 3 months. Thereafter, treatment is individualized. Some patient may need treatment (0.4-2 g/kg) every week, whereas others may go several months between IVIG courses.
4) Flulike symptoms—headaches, myalgias, fever, chills, nausea, and vomiting—are common and occur in as many as half the patients receiving IVIG. These symptoms can be reduced by premedication with a corticosteroid and lowering the rate of infusion.
5) Rash, aseptic meningitis, myocardial infarction, and stroke may also complicate IVIG infusions. IVIG should be avoided in patients with hypercoagulable states and significant atherosclerotic cardiovascular disease.
h. PE
1) PE is used in patients with myasthenic crisis or those with moderate weakness prior to thymectomy to maximize their preoperative strength.
2) The typical course involves exchange of 2 to 3 L of plasma three times a week until strength is significantly improved (usually five to six total exchanges). Improvement is noticeable after two to four exchanges.
3) PE lowers the serum concentration of anti-AChR antibodies, but it must be repeated at relatively regular intervals because of its limited duration of effect.
4) Within a week of PE, the autoantibodies begin to rebound. Therefore, patients will also need to be started on an immunosuppressive agent.
5) Some patients who are refractory or intolerant of prednisone, immunosuppressive agents, and IVIG may need to be managed with intermitting PE (eg, weekly PE).
i. Thymectomy
1) Thymectomy is clearly indicated in patients with a thymoma.
2) A recently single blind study of thymectomy (extensive transsternal approach) plus standard medical treatment (prednisone and pyridostigmine bromide [Mestinon]) versus standard medical treatment alone in nonthymomatous AChR antibody positive patients with generalized myasthenia gravis (age 18-65 years and myasthenia gravis <5 years) demonstrated that thymectomy improved myasthenia gravis scores, lowered cumulative prednisone dosage, and reduced need for second-line immunosuppressive agents.
3) It is not clear if thymectomy works in patients who are not AChR antibody positive, have only ocular myasthenia gravis, have had disease duration greater than 5 years, or are less than 18 years of age.
j. Rituximab
1) Rituximab is a monoclonal antibody directed against CD20 cell marker and depletes B cells for 6 months to a year or more. As B cells are precursors to plasma cells, antibody production drops over time as well.
2) Several small reports have suggested that rituximab may be effective in patients with refractory myasthenia gravis, in particular those with MuSK antibodies who can be difficult to treat. A large National Institutes of Health-sponsored double-blind, placebo-controlled trial failed to demonstrate efficacy in patients with AChR antibody positive generalized MG. However, a subsequent trial of low-dose Rituximab (0.5 mg/m2 × 1) in newly diagnosed patients with generalized AChR antibody positive MG was found to be beneficial.
3) The treatment of choice in patients with anti-MuSK generalized MG is rituximab 750 mg/m2 (up to 1 g) IV. The dose is repeated in 2 weeks. This sometimes works for 2 to 3 years before patients need another course.
4) In anti-AChR MG a low dose of rituximab at 0.5 mg/m2 once can be given in patients with early disease.
5) The main side effects are infusion reactions. Because rituximab depletes B cells, there is increased risk of infection. There have been a few reports of progressive multifocal leukoencephalopathy treated with rituximab, but none to our knowledge had myasthenia gravis.
k. Complement-inhibitors (two currently FDA-approved: Eculizumab and Ravulizumab)
1) Meningitis prophylaxis is essential for patients treated with complement inhibitors as life-threatening and fatal meningococcal infections have occurred in treated patients and may become rapidly life-threatening or fatal if not recognized and treated early
a) Comply with the most current Advisory Committee on Immunization Practices recommendations for meningococcal vaccination in patients with complement deficiencies (5.1) (see: www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/mening.html).
b) Three quadrivalent meningococcal conjugate (MenACWY) vaccines are currently licensed and available in the United States: (I) meningococcal groups A, C, W, and Y polysaccharide Recommendations and Reports US Department of Health and Human Services/Centers for Disease Control and Prevention MMWR/September 25,
2020/Vol. 69/No. 9 7 diphtheria toxoid conjugate vaccine (MenACWY-D) (Menactra); (II) meningococcal groups A, C, W, and Y oligosaccharide diphtheria CRM197 conjugate vaccine (MenACWY-CRM) (Menveo); and (III) meningococcal groups A, C, W, and Y polysaccharide tetanus toxoid conjugate vaccine (MenACWY-TT) (MenQuadfi).
c) Patients treated with complement inhibitors need to be warned about symptoms and signs of meningitis including:
moderate to severe headache with nausea or vomiting
moderate to severe headache and a fever
moderate to severe headache with a stiff neck or stiff back
fever of 103 °F (39.4 °C) or higher 285
fever and a rash 286
confusion 287
severe muscle aches with flu-like symptoms, and eyes sensitive to light
d) Other common side effects include increased risk of viral infections, infusion reactions
2) Eculizumab (intravenous administration)
For adult patients with generalized myasthenia, eculizumab (Solaris) therapy consists of:
a) 900 mg weekly for the first 4 weeks, followed by
b) 1,200 mg for the fifth dose 1 week later, then
c) 1,200 mg every 2 weeks thereafter.
3) Ravulizumab (intravenous administration)
a) The recommended weight-based dosing regimen consists of a loading dose followed 2 weeks later by the start of maintenance dosing every 8 weeks:
Body weight of 40 kg to less than 60 kg: loading dose is 2,400 mg and maintenance dose is 3,000 mg. Minimum infusion time is 58 to 54 minutes.
Body weight of 50 kg to less than 100 kg: loading dose is 2,700 mg and maintenance dose is 3,300 mg. Minimum infusion time is 36 to 42 minutes.
Body weight of 100 kg or more: loading dose is 3,000 mg and maintenance dose is 3,600 mg. Minimum infusion time is 24 to 30 minutes.
4) Neonatal fragment crystallizable (Fc) receptor (FcRn) inhibitors
a) The FcRn receptor functions as a recycling mechanism to prevent degradation and extend the half-life of IgG. Blocking of the receptors leads to increased degradation if antibodies cause MG.
5) Efgartimod (vyvgart) intravenous administration
a) The recommended dosage is 10 mg/kg administered as an intravenous infusion over 1 hour once weekly for 4 weeks. In patients weighing 120 kg or more, the recommended dose is 1,200 mg per infusion.
b) Administer subsequent treatment cycles based on clinical evaluation; the safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.
6) Efgartigimod plus hyalurondase (vyvgart hytrulo subcutaneous administration
a) The recommended dose is 1,008 mg/11,200 units (1,008 mg efgartigimod alfa and 11,200 units hyaluronidase) administered subcutaneously over approximately 30 to 90 seconds in cycles of once weekly injections for 4 weeks.
b) Administer subsequent treatment cycles based on clinical evaluation; the safety of initiating subsequent cycles sooner than 50 days from the start of the previous treatment cycle has not been established.
c) Most common adverse reactions (≥10%) in patients treated with efgartigimod are respiratory tract infections, headache, and urinary tract infection. Hypersensitivity reactions (eg, angioedema, dyspnea, and rash) may occur.
7) Rystiggo (rozanolixizumab-noli) for the treatment of generalized myasthenia gravis in adult patients who are anti-AChR or anti-MuSK antibody positive.
a) There are three recommended doses of rozanolixizumab-noli, based on body weight. Preparation and infusion time may vary by patient, dosage, infusion provider, and/or provider location.
Less than 50 kg body weight: infuse 420 mg (3 mL)
50 kg to less than 100 kg body weight: infuse 560 mg (4 mL)
100 kg and above: infuse 580 mg (6 mL)
b) Administer the recommended dosage as a subcutaneous infusion using an infusion pump at a rate of up to 20 mL/h once weekly for 6 weeks.
c) The most common side effects of rozanolixizumab-noli include headache, infections, diarrhea, fever, hypersensitivity reactions, and nausea. It can also cause aseptic meningitis.
Table 13-1 Anticholinesterase Drugs Commonly Used for Myasthenia Gravis | ||||||||||||||||||||||||||||||||||||
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TRANSIENT NEONATAL AUTOIMMUNE MYASTHENIA GRAVIS
Background
Transient neonatal autoimmune myasthenia gravis develops in approximately 10% of infants born to mothers with AChR-positive myasthenia gravis but has also been reported in anti-MuSK myasthenia gravis.
Pathophysiology
Weakness results from the passive transfer through the placenta of the mother’s autoantibodies.
Prognosis
1. Onset is usually within the first 3 days of life and manifests with a weak cry, difficulty feeding because of a poor suck, generalized weakness and decreased tone, respiratory difficulty, ptosis, and diminished facial expression (facial muscle weakness).
2. Weakness is usually temporary, with a mean duration of about 18 to 20 days.
3. Rare affected infants are born with arthrogryposis and have some degree of persistent weakness, perhaps related to damage to the NMJ by autoantibodies directed against components.
Diagnosis
1. The diagnosis should be suspected in any infant born to a mother with myasthenia gravis.
2. Mothers of floppy infants should be examined for signs of myasthenia gravis because not all mothers are symptomatic.
3. Diagnosis can be confirmed by demonstrating autoantibodies in the infant’s serum or decremental response to repetitive nerve stimulation in child or mother.
Treatment
1. Infants with neonatal myasthenia and weakness may be treated with anticholinesterase medications for 3 to 6 weeks until antibody levels have diminished to the point where sufficient safety factors are reestablished at a significant number of NMJs.
2. Infants with severe weakness may require mechanical ventilation and treatment with PE.
LAMBERT-EATON MYASTHENIC SYNDROME
Background
1. Lambert-Eaton myasthenic syndrome (LEMS) is the second most common NMJ disorder following myasthenia gravis.
2. LEMS is an immunologic disorder caused by antibodies directed against voltage-gated calcium channels (VGCCs).
3. Approximately 85% of patients with LEMS are older than 40 years, with mean age at presentation in the mid-50s.
4. In approximately two-thirds of cases, LEMS arises as a paraneoplastic disorder, usually secondary to small cell carcinoma of the lung. Small cell carcinoma of the lung is the culprit for approximately 90% of the paraneoplastic cases of LEMS. Other malignancies associated with LEMS include lymphoproliferative disorders, pancreatic cancer, and breast and ovarian carcinoma. The LEMS symptoms usually precede tumor diagnosis by an average of 10 months (can range from 5 months to 4 years).
5. In the other one-third of patients, LEMS occurs as an autoimmune disorder without an underlying cancer. Such cases are more common in females and younger patients and are associated with other autoimmune disorders.
6. The paraneoplastic and nonparaneoplastic forms of LEMS are otherwise clinically and electrophysiologically indistinguishable.
Pathophysiology
1. LEMS is caused by antibodies directed against VGCCs on presynaptic motor nerve terminals.
2. The antibodies bind to the VGCCs and subsequently inhibit the entry of calcium into the nerve terminal, which is required for the release of AChR. In addition, the antibodies may cross-link neighboring calcium channels, thus precipitating the process of internalization and degradation of the calcium channels.
Prognosis
1. Patients generally improve with treatment.
2. Patients with primary autoimmune LEMS without underlying malignancy tend to do well. However, the prognosis in patients with an underlying cancer is more related to that of the malignancy, which generally is poor.
Diagnosis
Clinical Features
1. Patients with LEMS usually complain of proximal weakness and easy fatigability.
2. Ptosis and diplopia are often transient and mild. Some patients develop dysarthria or dysphagia, but these are more commonly secondary to dryness of the mouth.
3. Autonomic dysfunction as reduced saliva, dry eyes, blurred vision, constipation, decreased sweating, and impotence are commonly seen in patients with LEMS.
4. Although most patients do not have respiratory problems related to the NMJ defect (they may have dyspnea related to their lung cancer), rare cases of LEMS presenting with respiratory failure have been described.
5. Neurologic examination demonstrates symmetric, proximal greater than distal, weakness affecting the legs more than the arms. Mild ptosis, ophthalmoparesis, and bulbar weakness may be apparent, but these are not as common or as severe as in myasthenia gravis. Deep tendon reflexes may be diminished or absent but then become significantly easier to obtain once a slight contraction of the muscle has been performed.
Laboratory Features
1. Antibodies directed against the P/Q-type VGCCs of motor nerve terminals are detected in the serum in more than 90% of patients with LEMS (both paraneoplastic and non-cancer-related cases).
2. Antibodies directed against the N-type calcium channels, which are located on autonomic and peripheral nerves as well as cerebellar, cortical, and spinal neurons, are present in 74% of patients with LEMS and lung cancer and 40% of patients without cancer.
3. Some patients with paraneoplastic LEMS also have anti-Hu antibodies and the associated sensory ganglionopathy, cerebellar degeneration, and encephalopathy.
4. As many as 13% of patients with LEMS also have AChR-binding antibodies. The anti-AChR antibodies are not necessarily pathogenic in patients with LEMS and may just represent an epiphenomenon.
Electrophysiologic Findings
1. Motor nerve conduction studies (NCS) reveal a marked reduction in the compound muscle action potential (CMAP) amplitude.
2. With 10 seconds of exercise, repeated stimulation of the nerve elicits an increment in the CMAP amplitude because of postexercise facilitation.
3. If patients are unable to cooperate, high rates of repetitive stimulation at 20 to 50 Hz for up to 10 seconds produces an incrementing response. We do not routinely use high rates of repetitive stimulation, unless necessary, as it can be quite painful.
4. Repetitive stimulation at 2 to 3 Hz demonstrates an abnormal decrement.
5. Single-fiber EMG demonstrates increased jitter.
Treatment
1. Patients with LEMS should undergo a thorough investigation for underlying carcinoma, particularly carcinoma involving the thoracic cavity (ie, small cell lung cancer). Many other neoplasms have been responsible for the syndrome. In patients with paraneoplastic LEMS, muscle strength may improve with surgical removal of the tumor, radiation therapy, and chemotherapy.
2. In patients with and without tumor, a number of therapeutic medications can be given to assist with the symptoms of weakness and fatigue.
a. Acetylcholinesterase inhibitors
1) We generally treat patients with pyridostigmine bromide (Mestinon) 60 mg four to five times a day, as in patients with myasthenia gravis.
2) The response is variable and often modest in comparison to that seen in myasthenia gravis.
b. 3,4-Diaminopyridine (3,4-DAP)
1) The aminopyridines block voltage-dependent potassium conductance, thereby prolonging nerve terminal depolarization and facilitating AChR release.
2) Firdapse (amifampridine phosphate, 3,4-DAP phosphate) by Catalyst Pharmaceuticals, Inc (Coral Gables, FL) is FDA approved for LEMS. This is a 50-mg tablet, containing the equivalent of 10 mg 3,4-DAP. The starting dose is one tablet three times daily and increased as needed up to two tablets four or five times a day as needed and tolerated. Amifampridine phosphate should be taken with food.
3) 3,4-DAP appears to be well tolerated, with few patients experiencing perioral and acral paresthesias. It is recommended that the dosage not exceed 100 mg/d as higher doses may result in seizures.
c. Immunosuppressive agents and immunomodulating therapies (see Table 12-1)
1) Corticosteroids and other immunotherapies are helpful.
2) Dosing is similar to that described in the section on Myasthenia Gravis.
3) Unlike myasthenia gravis, there is no role for thymectomy in the treatment of LEMS.
4) Plasmapheresis may be beneficial in patients with LEMS, but the effect wears off after a few weeks, and it must be repeated.
5) IVIG has been noted to be beneficial in small, uncontrolled series of patients with LEMS. Dosing is similar to that outlined for myasthenia gravis.
6) It is unclear if rituximab may be of benefit, but it is worth considering in refractory patients.
BOTULISM
Background
1. Botulism is a serious and potentially fatal disease caused by one of several protein neuroexotoxins produced by the bacterium Clostridium botulinum.
2. There are eight immunologically distinct types of botulinum neurotoxins (BTXs) designated alphabetically in their order of discovery: A, B, C1, C2, D, E, F, and G.
3. Types A, B, and E account for most reported food poisoning cases; however, D, F, and G have been responsible for a few deaths. Toxin type C affects animals and not humans.
4. Five clinical forms of botulism have been described: (a) classic or food-borne botulism, (b) infant botulism, (c) hidden botulism, (d) wound botulism, and (e) inadvertent botulism.
a. Classic or food-borne botulism
1) The method of transmitting the botulinum toxin is usually through poorly prepared home-canned vegetables.
2) The number of fatalities resulting from food-borne botulism has declined from about 50% prior to 1950 to approximately 7.5% from 1976 to 1984.
3) Persons over 60 years of age are particularly prone to more serious complications, possibly less complete recovery, and certainly a higher mortality rate.
b. Infant botulism
1) This is the most common form of botulism in the United States, with an incidence of 1 per 100,000 live births.
2) The mortality rate among recognized infants infected with botulinum spores is less than 4%.
3) Spores of C. botulinum inadvertently enter the infant’s intestinal tract, germinate, and colonize this region, and then produce the toxin that is absorbed through the intestinal tract’s lumen.
4) Epidemiologic studies reveal risk for botulism in infants consuming honey. As many as 25% of tested honey products contain clostridial spores. Because of this, honey should be avoided in infants.
c. Hidden botulism
1) Hidden botulism is believed to be a form of infantile botulism occurring in individuals older than 1 year.
2) Patients have a typical clinical presentation suggestive of botulinum intoxication with supportive laboratory findings but no obvious food or wound source for the disease.
3) The disorder manifests in individuals who have intestinal abnormalities (eg, Crohn disease or following gastrointestinal surgery) that allow colonization by C. botulinum, leading to the in vivo production of the toxin.
d. Wound botulism
1) A wound is infected by C. botulinum with the subsequent production of toxin in vivo. The typical insult is some type of focal trauma to a limb with or without a compound fracture.
2) There have been increasing reports of wound botulism occurring in intravenous (IV) drug abusers. BTX type A is more often the offending agent; however, type B has also been implicated.
e. Inadvertent botulism
1) This is the most recent form of botulism and refers to iatrogenic cases. BTX is now commonly used to treat focal dystonias and other movement disorders.
2) Rarely, patients may develop distant or generalized weakness after focal injections of BTX. The mechanism is likely hematogenous spread of the toxin.
Pathophysiology
The net effect of BTX intoxication is the inhibition of release of AChR vesicles.
Prognosis
1. In the adult, the clinical presentation of botulinum intoxication is similar regardless of whether the disease is acquired through the food-borne, wound, or hidden (ie, suspected gastrointestinal) route.
a. Patients develop dysphagia, dry mouth, diplopia, and dysarthria beginning rather acutely and progressing over the course of 12 to 36 hours. The time course is dependent in part on the amount of toxin consumed.
b. Gastrointestinal symptoms of nausea, occasional vomiting, and initial diarrhea followed by constipation may occur just before or coincident with the earlier noted neurologic symptoms. Associated complaints of abdominal cramps, undue fatigue, and dizziness may also be described during the disease’s evolution.
c. Then patients develop progressive weakness, affecting first the upper and then the lower extremities. The patient may begin to notice shortness of breath prior to extremity involvement.
2. In wound botulism, gastrointestinal complaints of nausea, vomiting, and usually abdominal cramps are less common than in food-borne botulism. The period of symptom development is longer in wound botulism as 4 to 14 days are required for the incubation period compared to hours for toxin or spore ingestion.
3. In infants, botulinum intoxication can manifest with an entire spectrum of disease, from mild symptoms to sudden death.
a. A relatively early sign is constipation.
b. The infant may later appear listless, with a diminution in spontaneous movements. Parents may note that the child has a poor ability to take in nutrition secondary to a diminished suck.
c. Respiratory function should be closely monitored as approximately 50% of infants require assisted mechanical ventilation. This necessity of respiratory assistance may be because of not only respiratory muscle weakness but also airway obstruction secondary to pharyngeal muscle weakness and loss of tonus.
d. Several weeks may be required before the patient shows any signs of recovery. The duration of required mechanical ventilation is dependent on the severity of the illness and the serotype of the infecting organism, with a mean of 58 days for type A and 26 days for type B botulism.
e. Recovery is usually satisfactory in all patients provided they are cared for in a hospital setting from the first manifestations of the disease. In the elderly, associated complications can lead to unavoidable death. There are long-term sequelae of fatigue and mild reduction in respiratory capacity in selected patients.
Diagnosis
Clinical Features
1. Cranial nerve evaluation reveals ptosis, diminished gag reflex, dysphagia, dysarthria, and weakness of the face, jaw opening and closing, and tongue.
2. Depending on the length of time between presentation and examination, the upper and lower limbs may be involved to varying degrees. The upper limbs are typically more affected than the lower limbs, with an occasional asymmetry noted.
3. Deep tendon reflexes may be normal or diminished initially, with progression to complete loss in severely affected individuals.
4. Careful patient examination can reveal disturbances of autonomic function affecting both the sympathetic and parasympathetic systems. Pupils are often poorly reactive to light. In addition, there can be loss of vagal cardiac control, ileus, hypothermia, and urinary retention possibly requiring catheterization. In addition, hypotension without tachycardia may be present and a lack of vasomotor responses to postural change may be observed.
5. In cases of suspected wound botulism, the integument should be carefully searched for not only gross disruption and wound contamination but also for apparently minor bruises with or without signs of infection.
Laboratory Features
1. Stool and serum samples can be sent for toxin identification; however, this is a time-consuming process.
2. Less commonly, the organism can be cultured from the stool or a wound site.
Electrophysiologic Findings
1. CMAP amplitudes become reduced; however, it is common for patients examined relatively early after symptom onset to demonstrate normal amplitudes.
2. At low rates of repetitive stimulation (2-3 Hz), more than 50% of patients demonstrate a decremental response. Approximately 25% do not reveal a decrement at low stimulation rates, whereas 20% have an increment.
3. About 90% of infants with botulism demonstrate an increment on 20- to 50-Hz repetitive stimulation.
4. The needle EMG examination can be somewhat variable depending on the time of examination.
a. Early in the course of the disease, there is usually normal needle insertion activity and a lack of abnormal spontaneous activity.
b. Fibrillation potentials and positive sharp waves may be found in severely affected muscles.
c. The motor unit action potentials (MUAPs) have a myopathic appearance.
d. Abnormal increases in jitter can be observed very early in the disease in 40% to 50% of single-fiber EMG studies.
Treatment
1. Antitoxin should be administered within 24 hours of symptom onset, before toxin binding and entry into the nerve terminals. Once nerve terminal entry has been accomplished, the antitoxin is no longer capable of neutralizing the toxin.
2. The mainstay of care is supportive from the perspective of maintaining adequate ventilation and being prepared for prompt mechanical ventilation intervention.
3. Secretions must be handled and adequate nutrition provided.
4. Constipation must be kept under control.
TICK PARALYSIS
Background
1. There are three major families of ticks: Ixodidae (hard body ticks), Argasidae (soft body ticks), and Nuttalliellidae. Ticks belonging to the first two families are responsible for causing human paralysis. These creatures are found worldwide, primarily inhabiting rural and wilderness areas.
2. In North America, the tick Dermacentor andersoni (common wood tick) usually causes the disease, but Dermacentor variabilis (dog tick) can also cause the disorder. Occasionally, ticks such as Amblyomma americanum and Amblyomma maculatum, as well as others, have been implicated in human paralysis.
3. In Australia, Ixodes holocyclus (Australian marsupial tick) causes especially severe disease in humans.
4. Peak occurrence of paralysis caused by ticks is in the spring and summer months. Children are three times as likely to be involved as adults.
Pathophysiology
1. Gravid female ticks are more commonly implicated because they feed for considerably longer times (days) and inject more toxin into their hosts compared to nongravid females and males.
2. In North American cases of tick paralysis, the toxin may block the sodium channel at the nodes of Ranvier and the distal motor nerve terminals.
3. Ixovotoxin released by the Australian I. holocyclus tick most likely interferes with the release of acetylcholine at the NMJ, perhaps similar to the effect of botulinum toxin.
Prognosis
1. Patients develop acute or subacute progressive weakness that may require ventilatory support.
2. Removal of the tick results in prompt improvement in strength, except for the Australian variety in which weakness may continue to progress to respiratory failure even after the tick is removed.
Diagnosis
Clinical Features
1. Patients typically present with ascending weakness, developing over the course of a few hours or days to flaccid paralysis that can mimic Guillain-Barré syndrome, myasthenia gravis, and botulism.
2. Early cranial nerve involvement including internal and external ophthalmoplegia, facial weakness, dysarthria, dysphagia, and respiratory muscle weakness is a salient feature.
3. Patients may complain of pain, itching, burning, or numbness in the extremities.
4. Deep tendon reflexes are diminished or absent.
5. If there is a recent history of camping or other types of leisure activity involving wooded or high grassy areas, the suspicion of tick paralysis should be raised.
Laboratory Features
1. Cerebrospinal fluid (CSF) protein concentration is usually normal in tick paralysis.
2. AChR antibodies are absent.
Electrophysiologic Findings
1. The sensory NCS usually reveal normal amplitudes, latencies, and velocities.
2. Motor conduction velocity is usually slow or borderline in weak extremities. The CMAP amplitudes are borderline or decreased in size.
3. Removal of the tick within several days of clinical presentation results in the prompt resolution of amplitude and conduction velocity abnormalities.
4. Repetitive nerve stimulation at low and high rates usually fails to reveal either a significant decrement or increment.
Treatment
1. The treatment of tick paralysis is prompt removal of the tick, with hospitalization for observation of potential impending respiratory failure.
2. Begin supportive and respiratory therapies as outlined in the Guillain-Barré syndrome section in Chapter 10.
3. A meticulous and comprehensive search for a tick is required. Common places for a tick to be present include the inferior hairline in the neck, periauricular area and the ear itself, the hair about the parietal scalp, the axillae, and the inguinal region.
4. Use a pair of tweezers or forceps and firmly grasp the tick as close to the patient’s skin as possible (ie, near the tick’s mouth parts). A firm, steady pull should then be applied. The body of the tick should never be pierced as more toxin may be released.
5. Within 24 to 48 hours of tick removal, most patients are well enough to be discharged from the hospital provided the tick is removed prior to profound functional loss.
6. An exception is the Australian variety of the tick, which produces such a virulent toxin that weakness may continue to progress to respiratory failure even after the tick is removed.
a. An antitoxin in the form of polyclonal dog antiserum is available for the Australian form of the disease.
b. The antiserum treatment is expensive and only effective if given in the early stages of paralysis, and it may be associated with serum sickness.
c. Continued ventilator support is required for several additional hours or until the patient can once again sustain voluntary ventilation.
CONGENITAL MYASTHENIC SYNDROMES
Background
An increasing number of distinct congenital myasthenic syndromes (CMSs) are becoming better characterized. The individual types of CMSs are subdivided according to the previously used scheme of presynaptic, synaptic space, and postsynaptic locations of the presumed site for the abnormality. Unlike autoimmune myasthenia gravis, these disorders may manifest within the first year of life (Table 13-2).
Table 13-2 Congenital Myasthenic Syndromes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pathophysiology
1. Presynaptic disorders
a. Congenital paucity of synaptic vesicles and reduced quantal release (choline acetyl transferase [ChAT])
2. Synaptic disorder
a. Acetylcholinesterase (AChE) deficiency (ColQ)
3. Postsynaptic disorders
a. Slow-channel syndrome
b. Low-affinity, fast-channel syndrome
c. Primary AChR deficiency
d. Congenital myasthenia with mode-switching kinetics
e. Rapsyn deficiency
f. Plectin deficiency
g. MuSK deficiency
h. Downstream of kinase 7 (Dok-7) deficiency
i. Others: limb girdle CMS with tubular aggregates (GFT1, DPAGT1, ALG2, ALG14)
Prognosis
1. Weakness is stable or only slowly progressive.
2. Patients may develop respiratory failure at times of intercurrent illness.
3. Although patients may improve with various forms of treatment (see below), the improvement is not as dramatic as that seen in myasthenia gravis or LEMS.
Diagnosis
Clinical Features
1. Onset may be congenital or in early adulthood.
2. Ptosis and ophthalmoparesis are common.
3. Fatigable weakness of the extremities as well as ocular and bulbar muscles may be present.
4. Response to Tensilon is variable and dependent on the specific subtype of CMS. Patients with acetylcholinesterase deficiency and slow-channel syndrome may actually do worse with Tensilon.
Laboratory Features
1. Serum creatine kinase (CK) levels are normal.
2. AChR antibodies are absent.
3. Genetic testing is only available in a few laboratories.
Electrophysiologic Findings
1. Motor NCS demonstrates repetitive after-discharges in patients with acetylcholinesterase deficiency and slow-channel syndrome.
2. Repetitive NCS at 2 to 3 Hz reveals abnormal decrement.
3. EMG shows small myopathic MUAPs without abnormal insertional or spontaneous activity.
4. Single-fiber EMG demonstrates increased jitter.
5. Sophisticated electrophysiologic studies in intercostal muscles are used to define the different subtypes but are not readily available.
6. Genetic testing for some of the disorders is available at research laboratories (check www.genetest.com for listings).
Treatment
1. CMSs are not autoimmune in etiology, and thus, antibodies to AChR are not present. Therefore, treatments aimed at modulating the immune system (eg, PE, IVIG, thymectomy, corticosteroids, and other immunosuppressive agents) are not effective in the CMS.
2. Pyridostigmine 1 mg/kg given four to six times per day may improve strength in patients with presynaptic defects, primary AChR deficiency, and fast-channel syndrome.
3. In patients with the fast-channel syndrome, 3,4-DAP starting at 1 mg/kg/d in divided dosages is helpful (see section on Lambert-Eaton Myasthenic Syndrome). In some studies, only a few of the patients with primary AChR deficiency responded, whereas the other patients with CMS failed to improve.
4. Pyridostigmine and 3,4-DAP may lead to worsening in patients with the slow-channel syndrome and end-plate acetylcholinesterase deficiency.
5. Albuterol starting at 2 mg bid and going up to 6 mg three times a day (tid) may be beneficial in cases of slow-channel syndrome, AChE deficiency, and those associated with mutations in Dok-7, agrin, MuSK, DPAGT1, and LAMB2.
6. Quinidine may help in slow-channel syndrome by shortening and even normalizing the duration of mutant channel openings. Administration of quinidine with serum levels of 0.7 to 2.5 μg/mL improved the clinical and electrophysiologic features in patients with slow-channel syndrome. However, the FDA has warned against the off-label of quinidine because of the risk of significant side effects (eg, hemolytic uremic syndrome, cardiac arrhythmia).
7. Ephedrine may be beneficial in patients with Dok-7 mutations.
8. Patients with respiratory weakness may benefit from BiPAP treatment.
INFLAMMATORY MYOPATHIES
Background
1. Inflammatory myopathies are a heterogeneous group of disorders characterized by muscle weakness, elevated serum CK levels, and inflammation seen on muscle biopsy.
2. The inflammatory myopathies can be divided into four groups: the more common idiopathic group, in which the etiology is unknown; myositis associated with connective tissue disease (CTD) and autoimmune disorders; myositis associated with cancer; and myositis because of various infections.
3. The major categories of idiopathic inflammatory myopathies include
a. Dermatomyositis (DM)
b. Antisynthetase syndrome
c. Inclusion body myositis (IBM)
d. Autoimmune necrotizing myopathy (NM)
4. Overlap syndromes refer to myositis occurring in association with another autoimmune CTD such as systemic lupus erythematosus, mixed CTD, scleroderma, rheumatoid arthritis, and Sjögren syndrome.
5. Most of what were previously called “polymyositis” is now known to be one of these other forms of myositis.
Pathophysiology
1. DM is associated with a microangiopathy. Previously, many investigators had felt that the myopathy was caused by complement-mediated destruction of capillaries resulting in ischemia/infarction of muscle. Recent studies suggest that overexpression of type 1 interferon-inducible proteins may be directly toxic to small blood vessels, muscle fibers, and skin.
2. The pathogenic mechanism of antisynthetase syndrome and autoimmune NM are not known and is likely multifactorial.
3. IBM has an unclear pathogenesis, but most research now points to an autoimmune basis
Prognosis
1. DM, antisynthetase syndrome, and NM are responsive to immunotherapies.
2. IBM is refractory to immunotherapy.
Diagnosis
Clinical Features
1. DM
a. May present with acute or insidious onset of proximal greater than distal weakness.
b. Characteristic skin rash (eg, heliotrope, scaling rash on forehead and malar regions, chest and neck, extensor surface of extremities/joints, Gottron sign and papules, periungual telangiectasias) usually accompanies or precedes muscle weakness.
c. Other organ systems may be involved: interstitial lung disease (ILD) in 10% to 20%, myocarditis, gastrointestinal bleed secondary to vasculopathy of gut, arthritis.
d. Increased incidence of malignancy.
2. Antisynthetase syndrome
a. May present with acute or insidious onset of proximal greater than distal weakness
b. Interstitial lung disease, myocarditis, arthritis
c. Raynaud
3. IBM
a. Presents with an insidious onset of proximal and distal weakness.
b. Early involvement of wrist and finger flexors in arms, with relative sparing of the deltoids, and of the quadriceps and ankle dorsiflexors in the legs help distinguish IBM from other myopathies.
c. Weakness is often asymmetric. Severe dysphagia can develop.
d. No increased risk of malignancy.
4. Immune-mediated Necrotizing Myopathy (IMNM)
a. May present with acute or insidious onset of proximal greater than distal weakness. Can mimic a limb-girdle muscular dystrophy
b. No rash.
c. Other organ systems may be involved: myocarditis, arthritis.
d. Often develops in the setting of taking cholesterol-lowering agents (eg, statins). However, patients do not improve and still have marked weakness and elevated serum CK months after stopping the cholesterol-lowering agent.
Laboratory Features
1. DM
a. Serum CK level can be normal in DM, particularly early in the course or with insidious onset but more commonly is moderately elevated up to more than 10 times normal.
b. Serum CK level is not a good indicator of disease activity.
c. ANAs may be detected in patients with overlap syndrome (eg, myositis associated with and underlying CTD).
d. Anti-myositis-specific antibodies can be ordered as they may influence prognosis and treatment. For example, Jo-1 antibodies are associated with ILD, which is more difficult to treat (see below).
2. Antisynthetase Syndrome
a. Serum CK level is elevated.
b. Anti-synthetase antibodies should be present.
3. IBM
a. Serum CK level is normal or only mildly elevated (<10 times normal).
b. Autoantibodies directed against cytosolic 5′-nucleotidase IA are present in one-third to two-thirds of patients with IBM and are very specific for the disorder.
4. IMNM
a. May have acute onset of severe proximal greater than distal weakness or a more insidious course mimicking limb-girdle muscular dystrophies.
b. Serum CK level is elevated, often more than 10 times normal and correlated well with disease activity.
c. Anti-HMG-CoA reductase (HMGCR) antibodies are found in approximately 70% of IMNM. These antibodies may be found in cases triggered by statin use (usually patients over age of 50 years), as well as in cases without statin use (typically younger patients. Anti-signal recognition particle (SRP) antibodies are present in about 10% of IMNM.
Electrodiagnostic Features
1. EMG demonstrates increased insertional and spontaneous activity (fibrillation potentials and positive sharp waves).
2. MUAPs are usually small in amplitude, short in duration, polyphasic, and recruit early.
3. Long-duration units, which are often seen in neurogenic disorders, also may be seen, particularly in IBM. This abnormality reflects chronicity of the myopathic process as opposed to a superimposed neurogenic disorder.
Histologic Features
1. DM
a. The characteristic histopathologic abnormality is perifascicular atrophy, but this is not always evident and is seen for the most part in patients with long-standing weakness.
b. Inflammatory cell infiltrate, when evident, is seen in the perimysium and around blood vessels (perivascular). The predominant infiltrate is plasmacytoid dendritic cells, which are the body’s natural producers of type 1 interferon.
c. Type 1 interferon-inducible proteins (eg, myxovirus resistances protein A or MXA) and major histocompatibility antigen (MHC1) are overexpressed on capillaries and muscle fibers, particularly perifascicular muscle fibers.
d. Unlike IBM, there are no endomysial inflammatory cells surrounding or invading nonnecrotic muscle fibers.
e. Immunoglobulin, complement, and membrane attack complex deposition (MAC) on small blood vessels may be appreciated.
f. Tubuloreticular inclusions in endothelial walls may be found on electron microscopy (EM).
2. Antisynthetase syndrome
a. Muscle biopsy perimysial muscle pathology with atrophic and necrotic fibers that mimic what is muscle fibers. The sarcolemma of perimysial muscle fibers express major histocompatibility antigen type 1 (MHC1) and MAC deposition.
b. Fragmentation of the perimysial connective tissue that stains for alkaline phosphatase.
3. IMNM
a. Muscle biopsy demonstrates many necrotic and regenerating muscle fibers. However, inflammatory cell infiltrate is absent or scant.
b. There is scattered MHC1 and MAC expression on the sarcolemma of nonnecrotic muscle fibers.
c. Some biopsies may show capillaries with thickened basement membranes (so-called “pipe-stem capillaries”) and MAC deposition.
4. IBM
a. Muscle biopsy demonstrates endomysial mononuclear inflammatory cell infiltrate surrounding and invading nonnecrotic muscle fibers expression MHC1, similar to PM.
b. Muscle fibers with one or more rimmed vacuoles are often but not invariably seen.
c. Increased number of ragged red and cytochrome oxidase-negative fibers are seen, indicative of mitochondrial abnormalities.
d. Amyloid deposition in vacuolated muscle fibers may be seen on frozen sections but not paraffin sections. These can be very difficult to appreciate. Much
more common, the inclusions stain positive with p62 and to a lesser extent TDP-43 antibodies.
e. EM may demonstrate 15- to 21-nm tubulofilaments in the cytoplasm of vacuolated muscle fibers and less commonly in myonuclei.
f. Because of sampling error, as many as 20% to 30% of muscle biopsies will not demonstrate all these histologic abnormalities, leading to erroneous diagnosis of PM unless the clinical pattern of weakness that is specific for IBM is not recognized by the clinician.
Treatment
Immunotherapy is recommended for DM, antisynthetase, NM, and overlap myositis (see Table 12-1). We do not recommend such treatment for IBM as this myopathy is refractory to such therapies.
1. Corticosteroids
a. In patients with severe weakness (unable to ambulate) or with severe systemic involvement (myocarditis, dyspnea related to ILD), we usually initiate treatment with Solu-Medrol 1 g IV daily for 3 days and then start oral prednisone.
b. In patients with mild or moderate weakness, we typically begin treatment with single-dose prednisone (0.75-1.5 mg/kg up to 60 mg) by mouth (p.o.) every morning.
c. Patients are initially seen every 2 to 4 weeks, and we maintain the high-dose prednisone until the patients are back to normal strength or until improvement in strength has reached a plateau (usually 3-6 months). Subsequently, the prednisone dose is tapered by 5 to 10 mg every 2 to 4 weeks. Once the dose is reduced to 20 mg daily, prednisone is tapered no faster than 5 mg every 4 weeks. Once on 10 mg daily, prednisone is tapered no faster than 2.5 mg every 4 weeks.
d. If a patient does not significantly improve after 2 to 4 months of prednisone, or if there is an exacerbation during the taper, we add a second-line agent (eg, methotrexate, azathioprine, mycophenolate mofetil, or IVIG) if not started one at the same time as the prednisone.
e. In addition, if the patient relapses during the taper, we generally double the prednisone dose (or at least put the patient back on a dose he or she was stable on in the past). Once a patient has regained his or her strength, we resume the prednisone taper at a slower rate.
f. Although serum CK level is monitored, adjustments of prednisone, and other immunosuppressive agents should be based on the objective clinical examination and not the CK level or the patient’s subjective response.
1) An increasing serum CK level can herald a relapse, but without objective clinical deterioration, we would not increase the dose of the immunosuppressive agent.
2) However, in such cases, we would hold the dose or the slow the taper.Related posts:
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