Palatal prolapse during nasal expiration in patients with myasthenia gravis.

INTRODUCTION/AIMS: We have encountered patients with myasthenia gravis (MG) who exhibited palatal prolapse (PP) during nasal expiration in the supine position while awake. This may be an overlooked cause of dyspnea in MG patients. This study aimed to examine and describe the characteristics of MG patients with PP. METHODS: We reviewed the medical records of 183 consecutive patients who were diagnosed with MG in our hospital from 2012 to 2021. Thirty-two patients underwent laryngoscopy because of bulbar symptoms. Eight of these patients (25%) exhibited PP on laryngoscopy. Clinical features of these eight patients were retrospectively characterized. RESULTS: Median age of the eight patients with PP was 70 years. Six were men. Median body mass index was 21.6 kg/m2 . All patients exhibited PP in the supine position but not the sitting position. Although no patient had abnormal findings on spirometry nor chest computed tomography, six reported dyspnea or difficulty with nasal expiration only in the supine position. PP improved in all four patients who underwent edrophonium testing. All eight patients eventually improved after immunotherapy. DISCUSSION: PP during nasal expiration may be a cause of dyspnea in MG patients, along with respiratory muscle impairment, lung disease, and vocal cord paralysis. Laryngoscopy in the supine position is required to confirm.

LRP4 third ß-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner.

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Using Sanger and exome sequencing in a CMS patient, we identified two heteroallelic mutations, p.Glu1233Lys and p.Arg1277His, in LRP4 coding for the postsynaptic low-density lipoprotein receptor-related protein 4. LRP4, expressed on the surface of the postsynaptic membrane of the neuromuscular junction, is a receptor for neurally secreted agrin, and LRP4 bound by agrin activates MuSK. Activated MuSK in concert with Dok-7 stimulates rapsyn to concentrate and anchor AChR on the postsynaptic membrane and interacts with other proteins implicated in the assembly and maintenance of the neuromuscular junction. LRP4 also functions as an inhibitor of Wnt/beta-catenin signaling. The identified mutations in LRP4 are located at the edge of its 3rd beta-propeller domain and decrease binding affinity of LRP4 for both MuSK and agrin. Mutations in the LRP4 3rd beta-propeller domain were previously reported to impair Wnt signaling and cause bone diseases including Cenani-Lenz syndactyly syndrome and sclerosteosis-2. By analyzing naturally occurring and artificially introduced mutations in the LRP4 3rd beta-propeller domain, we show that the edge of the domain regulates the MuSK signaling whereas its central cavity governs Wnt signaling. We conclude that LRP4 is a new CMS disease gene and that the 3rd beta propeller domain of LRP4 mediates the two signaling pathways in a position-specific manner.

Discordant thymectomy in identical twins concordant for myasthenia gravis.

BACKGROUND: Thymectomy is standard therapy fornonthymomatousmyasthenia gravis despite the absence of randomized clinical trials (1). Myasthenia gravis is uncommonly reported in monozygous twins; disease concordance occurs in approximately one third of such identical twin pairs; and treatment for myasthenia gravis, when described,is usually concordant in identical twin pairs (2). OBJECTIVE: To report an 11-year clinical course of a pair of identical twins concordant for generalized acetylcholine receptor antibody­positive nonthymomatous myasthenia gravis in whom only 1 was treated with extended transsternal thymectomy. CASE REPORT: Twin A was a 19-year-old white woman who presented with an 8-week history of intermittent leg weakness, causing her to fall during activities, such as climbing stairs. On examination,she had moderately severe fatigable proximal muscle weakness and ptosis. Her weakness improved with intravenous edrophonium administration.Initial binding acetylcholine receptor antibody titer was 1.22 nmol/L (normal value, 0.03 nmol/L). Repetitive 2-Hz nerve(median, ulnar, and facial) stimulation studies demonstrated up to a 16% decremental response. Chest computed tomography showed residual thymic tissue without thymoma. An extended transsternal thymectomy was performed 11 weeks after the onset of symptoms.

Two-step nationwide epidemiological survey of myasthenia gravis in Japan 2018.

OBJECTIVE: To study the updated prevalence and clinical features of myasthenia gravis (MG) in Japan during 2017. METHODS: We sent survey sheets to the randomly selected medical departments (number = 7,545). First, we asked the number of MG patients who visited medical departments from January 1, 2017, to December 31, 2017. Then, we sent the second survey sheet to the medical departments that answered the first survey to obtain the clinical information of patients who received MG diagnosis between January 1, 2015, and December 31, 2017. RESULTS: The received answer to the first survey were 2,708 (recovery rate: 35.9%). After all, the prevalence of the 100,000 population was estimated as 23.1 (95%CI: 20.5-25.6). As a result of the second survey, we obtained 1,464 case records. After checking the duplications and lacking data, we utilized 1,195 data for further analysis. The median [interquartile range (IQR)] from the onset age of total patients was 59 (43-70) years old. The male-female ratio was 1: 1.15. The onset age [median (IQR)] for female patients was 58 (40-72) years old, and that for male patients was 60 (49-69) years old (Wilcoxon-Mann-Whitney test, p = 0.0299). We divided patients into four categories: 1) anti-acetylcholine receptor antibody (AChRAb) (+) thymoma (Tm) (-), 2) AChRAb(+)Tm(+), 3) anti-muscle-specific kinase antibody (MuSKAb) (+), and AChRAb(-)MuSKAb(-) (double negative; DN). The onset age [median (IQR)] of AChRAb(+)Tm(-) was 64 (48-73) years old, and AChRb(+)Tm(+) was 55 (45-66), MuSKAb(+) was 49 (36-64), DN was 47 (35-60) year old. The multivariate logistic regression analysis using sex, initial symptoms, repetitive nerve stimulation test (RNST), and edrophonium test revealed that sex, ocular symptoms, bulbar symptoms, and RNST were factors to distinguish each category. The myasthenia gravis activities of daily living profile at the severest state were significantly higher in MuSKAb(+). MuSKAb(+) frequently received prednisolone, tacrolimus plasmapheresis, and intravenous immunoglobulin; however, they received less acetylcholine esterase inhibitor. 99.2% of AChRAb(+)Tm(+) and 15.4% of AChRAb(+)Tm(-) received thymectomy. MuSKAb(+) did not receive thymectomy, and only 5.7% of DN received thymectomy. The prognosis was favorable in all categories. CONCLUSION: Our result revealed that the prevalence of Japanese MG doubled from the previous study using the same survey method in 2006. We also found that the onset age shifted to the elderly, and the male-female ratio reached almost even. Classification in four categories; AChRAb(+)Tm(-), AChRAb(+)Tm(+), MuSKAb(+), and DN, well describe the specific clinical features of each category and differences in therapeutic approaches.

The history of acetylcholinesterase inhibitors in the treatment of myasthenia gravis.

The beneficial effects of acetylcholinesterase inhibitors for the treatment of myasthenia gravis (MG) was a major discovery that came about through one young physician putting together a string of previous observations. To understand how this discovery came to light, we must first go back to earlier times when men hunted by bow-and-arrow to capture their prey. The substance used to poison the prey was eventually was identified as curare. Centuries later, a connection was made between the physiological effects of curare and a disease entity with no known pathological mechanism or treatment, myasthenia gravis. In 1935, house officer Dr. Mary Walker was the first physician to try physostigmine in the treatment of MG, which had previously been used to treat curare poisoning. What she saw was a dramatic improvement in the symptoms experienced in patients with MG, and thus became the first documented case of use of physostigmine, an acetylcholinesterase inhibitor, in the treatment of MG. This article is a summary of the history of the use of acetylcholinesterase inhibitors in the treatment of myasthenia gravis. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Autoimmune response to acetylcholine receptor.

Injection of rabbits with acetylcholine receptor highly purified from the electric organ of Electrophorus electricus emulsified in complete Freund's adjuvant resulted in the production of precipitating antibody to acetylcholine receptor. After the second injection of antigen, the animals developed the flaccid paralysis and abnormal electromyographs characteristic of neuromuscular blockade. Treatment with the anticholinesterases edrophonium or neostigmine dramatically alleviated the paralysis and the fatigue seen in electromyography.

Generalized and neurotransmitter-selective noradrenergic denervation in Parkinson's disease with orthostatic hypotension.

Patients with Parkinson's disease (PD) often have manifestations of autonomic failure. About 40% have neurogenic orthostatic hypotension (NOH), and among PD+NOH patients virtually all have evidence of cardiac sympathetic denervation; however, whether PD+NOH entails extra-cardiac noradrenergic denervation has been less clear. Microdialysate concentrations of the main neuronal metabolite of norepinephrine (NE) and dihydroxyphenylglycol (DHPG) were measured in skeletal muscle, and plasma concentrations of NE and DHPG were measured in response to i.v. tyramine, yohimbine, and isoproterenol, in patients with PD+NOH, patients with pure autonomic failure (PAF), which is characterized by generalized catecholaminergic denervation, and control subjects. Microdialysate DHPG concentrations were similarly low in PD+NOH and PAF compared to control subjects (163 +/- 25, 153 +/- 27, and 304 +/- 27 pg/mL, P < 0.01 each vs. control). The two groups also had similarly small plasma DHPG responses to tyramine (71 +/- 58 and 82 +/- 105 vs. 313 +/- 94 pg/mL; P < 0.01 each vs. control) and NE responses to yohimbine (223 +/- 37 and 61 +/- 15 vs. 672 +/- 130 pg/mL, P < 0.01 each vs. control), and virtually absent NE responses to isoproterenol (20 +/- 34 and 14 +/- 15 vs. 336 +/- 78 pg/mL, P < 0.01 each vs. control). Patients with PD+NOH had normal bradycardia responses to edrophonium and normal epinephrine responses to glucagon. The results support the concept of generalized noradrenergic denervation in PD+NOH, with similar severity to that seen in PAF. In contrast, the parasympathetic cholinergic and adrenomedullary hormonal components of the autonomic nervous system seem intact in PD+NOH.

A case report of myasthenia gravis localized to the larynx.

This report describes a very rare case of myasthenia gravis (MG) localized to the larynx, with the onset of dyspnea requiring tracheotomy. The vocal cords of this patient were fixed in the paramedian position. Under fiberscopic observation, improvement of laryngeal function was demonstrated after intravenous injection of edrophonium. However, no voice change occurred. The posterior crico-arytenoid muscle has the sole responsibility of abducting the vocal cord; thus, it is concluded that the dyspnea was caused by the selective paralysis of this muscle. We suggest that MG should be considered in cases of vocal cord paralysis of unknown etiology.

Detectable voice change with the edrophonium test in laryngeal myasthenia gravis.

A case of laryngeal myasthenia gravis in a 65-year-old woman presenting with hoarseness as the sole symptom is reported. Voice spectrography was performed before and after injection of intravenous edrophonium. There was a marked improvement in the patient's voice after the administration of edrophonium, which was confirmed by the changes seen on the sound spectrogram. This was the only objective indication of a diagnosis of myasthenia gravis. No thymoma was seen on chest X-ray and the patient was negative for anti-acetylcholine receptor antibodies. Treatment for laryngeal myasthenia gravis was initiated and the patient's vocal problems resolved. This case emphasizes the need to consider systemic diseases in the differential diagnosis of hoarseness and demonstrates the need for careful follow-up in such patients.

Reversing neuromuscular blockade: inhibitors of the acetylcholinesterase versus the encapsulating agents sugammadex and calabadion.

INTRODUCTION: Acetylcholinesterase inhibitors (neostigmine, edrophonium) and encapsulating agents (sugammadex and calabadion) can be used to reverse residual neuromuscular blockade (NMB). AREAS COVERED: This review provides information about efficacy, effectiveness, and side effects of drugs (acetylcholinesterase inhibitors and encapsulating agents) used to reverse neuromuscular blocking agents (NMBAs). EXPERT OPINION: The therapeutic range of acetylcholinesterase-inhibitors is narrow and effectiveness studies demonstrate clinicians don't use these unspecific reversal agents effectively to increase postoperative respiratory safety. The encapsulating drugs sugammadex and calabadion reverse all levels of NMB, and complete recovery of muscle strength can be achieved almost immediately after administration. For this reason encapsulating agents can be used as a solution for "cannot intubate cannot ventilate"- situations. Poor binding selectivity of encapsulating agents carries the risk of displacement of the NMBA by a competitively binding drug, which may lead to recurarization. In order to avoid side-effects, related to unspecific binding of endogenous proteins and drugs administered perioperatively it is prudent to titrate the dose of reversal agents to the minimal effective dose, depending on the depth of neuromuscular transmission block identified by neuromuscular transmission monitoring. Calabadions provide a diversified (increased binding selectivity) and expanded (reversal of benzylisoquinolines) spectrum of possible indications.

Putative role of antireticulin antibody in antiacetylcholine-receptor-antibody-negative myasthenia gravis.

It has recently been demonstrated that pathogenic immunoglobulins circulate in the blood of patients with acetylcholine-receptor-antibody (A-AChR)-negative myasthenia gravis (MG). Evidence has been presented that in this form of MG the neuromuscular transmission is impaired by antibodies that bind to endplate determinants other than the AChR. We describe three patients with clinical manifestations of A-AChR-negative MG in whom antibody directed to reticulin (A-Ret) was detected. Antibody directed to reticulin is usually associated with celiac disease; however, none of the patients had symptoms or signs of celiac disease. To our knowledge, the association of A-Ret with A-AChR-negative MG has not been reported before. We postulate that A-Ret might help to differentiate between A-AChR-negative MG and congenital myasthenia. Further studies are needed to determine whether A-Ret plays a pathogenic role in A-AChR-negative MG or should instead be considered as an epiphenomenon.

Amyotrophic lateral sclerosis. Impairment of neuromuscular transmission.

Neuromuscular transmission was studied in the ulnar-hypothenar group in 55 patients with amyotrophic lateral sclerosis. A decremental response was found in 67.0%. The decrement was larger and present more often in muscles showing atrophy. In addition, muscles with frequent fasciculations showed a larger decrement than the ones with rare fasciculation. A temperature effect similar to that in myasthenia gravis was observed, with a reduction of the decrement following local cooling of the muscles. Administration of edrophonium chloride improved the synaptic defect. Posttetanic exhaustion was observed as well. It is thought that the defect of neuromuscular transmission is due to a decreased trophic function of the neuron followed by morphological changes at the endplate.

Familial infantile myasthenia.

Familial infantile myasthenia is a rare type of myasthenia that usually occurs in connection with respiratory depression. The condition is characterized by (1) absence of myasthenia in the mother, (2) occurrence of a similar disorder among siblings, (3) respiratory depression at birth, (4) episodic weakness and apnea during the first two years of life, and (5) improvement with age. Since the condition responds to anticholinesterase medication, early diagnosis is important. Familial infantile myasthenia is a potential cause of sudden infant death and should be considered in infants with unexplained respiratory distress.

Development of generalized disease at 2 years in patients with ocular myasthenia gravis.

BACKGROUND: Generalized myasthenia gravis will develop in more than 50% of patients who present with ocular myasthenia gravis, typically within 2 years. The optimal treatment of ocular myasthenia gravis, including the use of corticosteroids, remains controversial. In addition, the prevalence of thymoma and the optimal performance of the edrophonium chloride test for ocular myasthenia remain unknown. OBJECTIVE: To assess the effect of oral corticosteroid therapy on the frequency of development of generalized myasthenia gravis within 2 years, the incidence of thymoma, and the amount of edrophonium needed for a positive test result in patients with ocular myasthenia gravis. METHODS: We reviewed an ocular myasthenia gravis database of 147 patients. Patients underwent measurement of acetylcholine receptor (AChR) antibody levels and chest computed tomography. Unless contraindicated, patients with diplopia were recommended for therapy with prednisone, up to 40 to 60 mg/d, with the dosage tapered for 5 to 6 weeks. Most continued to receive daily or alternate-day doses of 2.5 to 10 mg to prevent diplopia. Patients not given prednisone (untreated group) received pyridostigmine bromide or no medication. After the diagnosis, we documented the signs and symptoms of ocular and generalized myasthenia gravis and performed 2-year follow-up in 94 patients. RESULTS: The mean dose of edrophonium chloride to give a positive response was 3.3 mg (SD, 1.6 mg) for ptosis and 2.6 mg (SD, 1.1 mg) for ocular motor dysfunction. Thymoma occurred in 1 patient (0.7%). Generalized myasthenia gravis developed within 2 years in 4 of 58 treated and 13 of 36 untreated patients. The odds ratio (OR) for development of generalized disease in the treated group was 0.13 (95% confidence interval [CI], 0.04-0.45) compared with the untreated group. The AChR antibody level was not predictive of development of generalized myasthenia gravis at 2 years, but the risk was greater in patients with abnormal AChR antibody levels (OR, 6.33; 95% CI, 1.71-23.42). Logistic regression that included age, abnormal AChR antibody level, and prednisone therapy yielded significance only for abnormal AChR antibody level (OR, 7.03; 95% CI, 1.35-36.64) and treatment (OR, 0.06; 95% CI, 0.01-0.30). CONCLUSIONS: At 2 years, prednisone treatment appears to reduce the incidence of generalized myasthenia gravis to 7% in contrast to 36% of patients who did not receive prednisone. Thymoma, although uncommon, occurs in ocular myasthenia gravis. Only small amounts of edrophonium are needed to diagnose ocular myasthenia gravis.

Myasthenia gravis and Schmidt syndrome.

A patient with myasthenia gravis developed both Addison disease and primary hypothyroidism, with demonstrable anti-adrenal and antithyroid antibodies in her serum. The association of myasthenia gravis with Schmidt syndrome does not seem to be a chance occurrence, considering the autoimmune pathogenesis of each of these disorders.

Myasthenic crisis after intravenous administration of iodinated contrast agent.

Two women with myasthenia gravis became apneic immediately after IV injection of iodinated contrast material for CT. Aggravation of myasthenia continued for days after this initial reaction.

Vagal techniques for termination of paroxysmal supraventricular tachycardia.

Maneuvers that reflexly increase vagal tone were deployed to terminate the tachycardia in 68 consecutive patients with paroxysmal supraventricular tachycardia. The order and success rate of the protocol was as follows: 57 episodes were terminated with carotid sinus pressure alone or after pretreatment with edrophonium, 5 were terminated with the Valsalva maneuvers and 6 were terminated with phenylephrine. Potency testing showed that phenylephrine evoked the greatest increase in vagal tone. All cases demonstrated slowing of tachycardia ranging from 40 to 220 ms +/- standard error of the mean (mean 79.0 +/- 3.8 ms) followed by abrupt termination. Pauses after termination ranged from 900 to 3,300 ms (mean 1,683.8 +/- 66.6) with 54 patients showing pauses of 2,000 ms or less. Termination was highly reproducible showing an overall success of 148 (92 percent) of 160 trials among 22 selected cases. The extent of increased vagal tone needed to terminate paroxysmal supraventricular tachycardia was raised by augmented sympathetic tone (infusion of isoproterenol) and decreased by reduced sympathetic tone (pretreatment with propranolol). Thus, paroxysmal supraventricular tachycardia can be rapidly, safety and consistently terminated by maneuvers that reflexly increase vagal tone.

Alternating myasthenia and myastheniform syndrome in the same subject.

A man of 23 years was affected by myasthenia with amyotrophic patterns. From the neurophysiological viewpoint, there were typical electrophysiological aspects of myasthenia gravis and the Eaton-Lambert syndrome simultaneously. In some instances the various electrophysiological tests were preceeded by the administration of Tensilon, calcium gluconate and sodium benzoate caffeine. It is hypothesized that there are two types of endplates present, or there is a functional variability by which at different moments a block results from a defect in the formation or liberation of acetylcholine.