Pediatric Myasthenia Gravis

doi:10.1016/j.spen.2017.04.003

Seminars in Pediatric Neurology

Volume 24, Issue 2, May 2017, Pages 116-121

https://doi.org/10.1016/j.spen.2017.04.003 Get rights and content

Myasthenia gravis is a disorder of neuromuscular transmission that leads to fatigue of skeletal muscles and fluctuating weakness. Myasthenia that affects children can be classified into the following 3 forms: transient neonatal myasthenia, congenital myasthenic syndromes, and juvenile myasthenia gravis (JMG). JMG is an autoimmune disorder that has a tendency to affect the extraocular muscles, but can also affect all skeletal muscles leading to generalized weakness and fatigability. Respiratory muscles may be involved leading to respiratory failure requiring ventilator support. Diagnosis should be suspected clinically, and confirmatory diagnostic testing be performed, including serum acetylcholine receptor antibodies, repetitive nerve stimulation, and electromyography. Treatment for JMG includes acetylcholinesterase inhibitors, immunosuppressive medications, plasma exchange, intravenous immunoglobulins, and thymectomy. Children with myasthenia gravis require monitoring by a pediatric ophthalmologist for the development of amblyopia from ptosis or strabismus.

Introduction

The myasthenic syndromes are due to defects of transmission at the neuromuscular junction. Myasthenic syndromes in children have 3 distinct forms with pathophysiologically different mechanisms. The congenital myasthenic syndromes (CMS) are a group of genetic disorders that lead to muscle weakness through structural or functional abnormalities of the proteins involved in neuromuscular transmission itself. Transplacental transfer of maternal antibodies of a myasthenic mother causes transient neonatal myasthenia (TNM) in infants. Juvenile myasthenia gravis (JMG) is an autoimmune disorder that leads to dysfunction of acetylcholine receptors (AChR). All forms of myasthenia lead to muscle fatigue and weakness of varying degrees. Fluctuations in weakness are a hallmark of this disease. If weakness involves the musculature involved in respiration, these diseases can be life threatening.1, 2 This review will focus primarily on the JMG form.

Section snippets

Pathophysiology

In normal synaptic transmission in the neuromuscular junction, the axon is depolarized and this depolarization travels to the axon terminal. Voltage-gated calcium channels open, leading to acetylcholine containing vesicles to fuse to the cell membrane. Acetylcholine is then released from synaptic vesicles into the synaptic cleft from the axon terminal. The acetylcholine travels across the synaptic cleft to the AChR sites where binding causes sodium channels to open, depolarizing the motor end

Demographics

There have been varying estimates of the incidence of myasthenia gravis occurring in the general population in the literature ranging from 1.7-30.0 cases per million person years, with a prevalence of 77.7 cases per million persons.17, 18 Many studies estimating the incidence and prevalence of JMG have also been published. A meta-analysis of the literature on this subject concluded that the incidence of JMG is approximately between 1.0 and 5.0 cases per million person years.¹⁷ Pediatric

Clinical Presentation

Fatigable skeletal muscle weakness that fluctuates is the characteristic sign of myasthenia gravis. Myasthenia gravis is known to preferentially target the extraocular muscles. Cases in which only the extraocular muscles are affected are termed ocular myasthenia gravis (OMG). If any other skeletal muscles are involved, the patient is diagnosed with generalized myasthenia gravis. The vast majority of patients who have myasthenia gravis will have involvement of the extraocular muscles at some

Diagnosis

Making the diagnosis of myasthenia gravis begins when a patient demonstrates some form of fatigable weakness. A thorough targeted clinical examination should include some evaluation of fatigability to address suspicion of myasthenia gravis. Ancillary testing for its diagnosis includes serologic, pharmacologic, and electrophysiologic testing.

Acetylcholinesterase Inhibitors

Pyridostigmine is the main pharmacologic agent used in the treatment of myasthenia gravis, whether in children or adults. Edrophonium has too short a half-life to be of use in long-term treatment of myasthenia gravis. Even with the appropriate usage and dosing of pyridostigmine, symptoms and signs of myasthenia gravis may continue.¹ Pyridostigmine may be combined with other agents such as immunosuppressives. Side effects of pyridostigmine are similar to those of edrophonium described earlier.

Immunosuppressive Agents

Ophthalmic Outcomes

Patients with JMG should be monitored for the development of amblyopia and strabismus.⁷⁶ Amblyopia should be treated to prevent permanent vision loss. Up to 96% of patients with the ocular form of JMG will have ptosis, and up to 88% will present with strabismus.²⁸ Amblyopia has been found in 21%-50% of children with ocular JMG, but following properly diagnosis and treatment, that proportion of patients with amblyopia has been found to decrease as low as 3%.24, 25, 28 Strabismus is more

Conclusions

Pediatric myasthenia gravis can present as neonatal myasthenia gravis (CMS, TNM) or during adolescence (JMG). The latter is an autoimmune disease that can have a variable presentation, ranging from mild ophthalmic symptoms, such as isolated fatigable ptosis, to myasthenic crises involving the respiratory muscles, requiring ventilator support. Making a formal diagnosis of the disease can be difficult, but when suspicion is raised for a fatigable deficit, appropriate diagnostic testing can be

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Cited by (44)

Measuring the Efficacy of Thymectomy for Pediatric Myasthenia Gravis Across Tertiary Children's Hospitals
2023, Pediatric Neurology
Thymectomy is a treatment for pediatric myasthenia gravis, but the efficacy over time is unknown. Multi-institutional data are also lacking. Therefore, the objective of this study was to determine the efficacy of thymectomy for pediatric myasthenia gravis using medication burden and health care utilization as proxies for disease severity.
This was a cross-sectional study of the Pediatric Health Information System database among children who underwent thymectomy at one of 49 children's hospitals from 2004 to 2022. Differences in annual median number of doses of myasthenia-related medications, admissions, and health care costs in the year before thymectomy to three years after were compared. A comparison cohort that did not undergo thymectomy was utilized. Medians were compared using the Wilcoxon signed-rank test. Generalized linear regression estimated the effect of surgical approach on outcomes.
A total of451 patients (238 patients who underwent thymectomy and 213 nonthymectomy patients) were identified. Following thymectomy, the decrease in annual median total number of myasthenia-related doses was 12.0 (interquartile range: 6 to 31) (P < 0.001). The decrease in number of annual admissions was 2.0 (1 to 4) (P < 0.001), which represented a cost difference of $5292 ($3533 to $8681) (P < 0.001). No differences were observed in the control cohort. In a generalized linear regression model, surgical approach was not associated with the efficacy of thymectomy (P = 0.55).
Thymectomy is an effective treatment for pediatric myasthenia gravis, evidenced by the decreased medication burden and health care utilization after surgery. Surgical approach did not influence the success of surgery. Thymectomy should be considered earlier in the treatment algorithm.
New-Onset Ocular Myasthenia after Multisystem Inflammatory Syndrome in Children
2022, Journal of Pediatrics
Vaccination in pediatric acquired inflammatory immune-mediated neuromuscular disorders
2022, European Journal of Paediatric Neurology
To analyse literature data on vaccine related induction, worsening of the disease and disease reccurrences as well as vaccine safety and efficacy among pediatric patients with acquired inflammatory immune-mediated neuromuscular disorders (NMD).
Medline, Pub Med and Scopus database search from 1975 to 2020 focused on pediatric age was conducted including peer reviews, meta analyses and epidemiological studies on vaccination and Guillain-Barré syndrome (GBS), Bell's palsy, optic neuritis (ON), myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP) and immune-mediated inflammatory myopathy (IM).
s: There are no strong evidence supporting relationship between vaccination with different pediatric vaccines and development of first episodes or reccurrences of GBS, Bell's palsy, optic neuritis (ON), juvenile MG, CIDP, and IM. The vaccination and revaccination with inactivated vaccines is considered safe in children with medical history of GBS, Bell's palsy, ON, MG and IM. Caution when immunization against influenza, quadrivalent conjugated meningococcal vaccine (MCV4) and pneumococcal disease and avoiding tetanus toxoid immunization in CIDP patients is suggested. Patients with immune mediated acquired NMD should be vaccinated with live vaccines before the initiation of immunosupressive treatment. Immunosuppressed patients with low protective antibody titers should be considered for revaccination.
Outcomes of Juvenile Myasthenia Gravis: A Comparison of Robotic Thymectomy With Medication Treatment
2022, Annals of Thoracic Surgery
The study aimed to compare the clinical outcomes of patients with juvenile myasthenia gravis (MG) who underwent robotic thymectomy with that of those who only received medication therapy.
We retrospectively reviewed patients who visited our institution for the diagnosis or treatment of MG with an age at onset younger than 18 years. Patients who underwent thymectomy comprised the surgical group and those who received only medication therapy comprised the nonsurgical group. The clinical outcomes were assessed according to the Myasthenia Gravis Foundation of America Post-Intervention Status.
Forty-seven patients (35 female, 12 male) were included as the surgical group and 20 patients (15 female, 5 male) comprised the nonsurgical group. Significant differences were observed between the surgical and nonsurgical groups in antibody against acetylcholinesterase receptor (91.5% vs 65%; P = .012), disease duration (median 16 [interquartile range, 7-25] months vs 96 [interquartile range, 42-480] months; P < .001), and corticosteroids requirement (53.2% vs 15%; P = .004) at baseline. Kaplan-Meier analysis showed a higher cumulative probability of complete stable remission in the surgical group (P = .002) compared with the nonsurgical group. Moreover, thymectomy (hazard ratio, 3.842; 95% confidence interval, 1.116-13.230; P = .033) and age at onset (hazard ratio, 0.89; 95% confidence interval, 0.80-0.99; P = .037) were still associated with the achievement of complete stable remission in the multivariable analysis. Furthermore, a significant steroid-sparing effect was observed in the surgical group but not in the nonsurgical group.
Robotic thymectomy seems to be more effective than medication therapy on juvenile MG in terms of inducing remission and reducing the use of corticosteroids.
Comparison of anti-acetylcholine receptor profiles between Chinese cases of adult- and juvenile-onset myasthenia gravis using cell-based assays
2020, Journal of Neuroimmunology
Juvenile-onset myasthenia gravis (JOMG) is a unique clinical subtype in China, featured by a higher prevalence of ocular myasthenia gravis (OMG), higher seronegativity of acetylcholine receptor (AChR) antibodies, and better prognosis than that in adult-onset myasthenia gravis (AOMG). We previously identified low-affinity AChR antibodies in Chinese JOMG patients using cell-based assays (CBAs), indicating a predominantly AChR antibody-positive profile. Here, we further screened AChR antibodies in both Chinese AOMG and JOMG patients by CBAs.
We recruited patients with MG who had not received prednisone or immunosuppressive therapies between June 2015 and June 2019, and divided them into AOMG and JOMG subgroups according to their ages at the time of recruitment. Clinical information and blood samples were collected. Serum AChR antibodies were detected by CBAs in HEK293T cells expressing clustered adult and fetal AChRs, as well as by enzyme-linked immunosorbent assays (ELISAs). Differences in AChR antibody profiles between AOMG and JOMG subgroups were determined.
A total of 239 patients with MG were enrolled in the present study, including 121 AOMG and 118 JOMG patients. Based on ELISAs, 74.4% of AOMG (90/121) and 59.3% of JOMG (70/118) patients were anti-AChR positive (p = 0.02). However, CBAs yielded equal anti-AChR positivities (p = 0.64), as indicated by 80.2% of AOMG patients (97/121) and 77.1% of JOMG patients (91/118). Furthermore, among AOMG patients, 67.8% (82/121) were positive for both adult and fetal AChR antibodies, 5.8% (7/121) were positive for only adult AChR antibodies, and 6.6% (8/121) were positive for only fetal AChR antibodies, while these rates were 50.8% (60/118), 21.2% (25/118), and 5.1% (6/118), respectively, in JOMG cohorts (p < 0.01). Twenty-nine AOMG patients and 10 JOMG patients underwent IgG subclassification of AChR antibodies, which were all confirmed to be predominantly IgG1.
The positive rates of AChR antibodies did not differ between Chinese AOMG and JOMG patients, as revealed by CBAs. Furthermore, the screened AChR antibodies were predominantly IgG1 in both AOMG and JOMG patients.
Robotic-assisted thoracoscopy thymectomy for juvenile myasthenia gravis
2020, Journal of Pediatric Surgery Case Reports
Citation Excerpt :
Thymectomy for patients with sieropositive JMG has been evaluated and has been found to be associated with improved remission rates and minimized of medical therapy dosage and duration. Therefore, thymectomy may have a role for children who are unresponsive to medical therapy or who cannot undergo standard immunsuppression, although long-term effects of thymectomy in children are however unclear [10]. The role of thymectomy in prepubertal age, especially in very young children is still controversial because of thymus gland'role in the development of our immune system with possible immunological alterations [11].
Juvenile myasthenia gravis (JMG) is a rare debilitating and potentially fatal autoimmune disease, with unclearify pathogenesis. Surgical immunomodulation with thymectomy has been repeatedly demonstrated to be a safe and effective treatment for JMG in both adult and pediatric patients. In the last few years, minimally invasive approach and above all robotic assisted thoracoscopy, replaced sternotomy which is widely used in adult patients. We report our experience in a case of robot-assisted thoracoscopic thymectomy approach in a 12 years old boy for juvenile myasthenia gravis (JMG).
Procedure was performed with the Da Vinci surgical robot (Xi) using left-sided approach. Left lung was kept out from mechanic ventilation. A 8 mm port for the 3-D camera was introduced on the V intercostal space on the anterior axillary line. Others two 8mm thoracic ports were placed under vision after the induction of a low-pressure pneumothorax, respectively on the midaxillary line on the III intercostal space and on the parasternal space on the V intercostal space. Bulk resection of gland was made using Maryland grasper and Harmonic scalpel, starting at level of the left pericardiophrenic angle and continuing cranially. Thymus was unstick from the posterior face of the sternum until the right pleura releasing lower thymic horns. After that, controlateral right-side thymectomy was continued into the neck to include the upper horns and finally it was removed with an endocatch bag. Histopathological examination showed a benign thymic hyperplasia. There were no perioperative and postoperative complications. The discharge was on IV post-operative day. After thymectomy, patient reported an improvement in symptoms and stopped medical therapy with pyridostigmine.
VATS and Robotic thoracoscopic thymectomy have increasingly taken hold in recent years. The surgical treatment offered to patient an improvement in clinical status. Surgery by robotic assistance has demonstrable advantages, including three-dimensional visualization and articulating instruments. Left lateral approach provided excellent visualization of the thymic veins, anonymous vases and phrenic nerves. Three-dimensional visualization as well as articulating arms greatly facilitated the dissection compared with standard thoracoscopic technique. In Literature very few series of robotic approach for surgical treatment of JMG in children are reported, for these reasons further studies are needed.

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^☆: Supported in part by an unrestricted departmental Grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc, New York, and by NIH/NEI core Grant P30-EY06360 (Department of Ophthalmology).

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Pediatric Myasthenia Gravis☆

Introduction

Section snippets

Pathophysiology

Demographics

Clinical Presentation

Diagnosis

Acetylcholinesterase Inhibitors

Immunosuppressive Agents

Ophthalmic Outcomes

Conclusions

Ophthalmology

J Neuroimmunol

Lancet Neurol

J Neuroimmunol

J Neurol Sci

J Autoimmun

Pediatr Neurol

Pediatr Neurol

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Neuromuscul Disord

Neuromuscul Disord

Clin Neurophysiol

Pediatr Neurol

J Pediatr

J Neurol Sci

Pediatr Neurol

J Neurol Sci

Brain Dev

Pediatr Neurol

Transfus Med Rev

Autoimmun Rev

Lancet Neurol

Pediatr Neurol

Neuromuscul Disord

Autoimmune myasthenia gravis in childhood

Semin Neurol

Myasthenia gravis and pregnancy: Clinical implications and neonatal outcome

BMC Musculoskelet Disord

Neonatal myasthenia gravis: Report of two cases and review of the literature

Pediatrics

Acquired myasthenia gravis in childhood

Curr Opin Neurol

Update on juvenile myasthenia gravis

Curr Opin Pediatr

Juvenile myasthenia gravis: Three case reports and a literature review

J Child Neurol

Myasthenia gravis and associated autoimmune diseases in childhood

J Child Neurol

Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: Ten new aquaporin-4 antibody positive cases and a review of the literature

Mult Scler

The incidence of myasthenia gravis: A systematic literature review

Neuroepidemiology

A systematic review of population based epidemiological studies in myasthenia gravis

BMC Neurol

The epidemiology of myasthenia gravis in central and western Virginia

Neurology