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Transient acetylcholine receptor-related myasthenia gravis, post multisystem inflammatory syndrome in children (MIS-C) temporally associated with COVID-19 infection
Abstract
We report on a unique case of a 7-year-old girl with new onset ocular myasthenia gravis shortly after recovery from multisystem inflammatory syndrome in children (MIS-C) temporally associated with SARS-CoV-2 infection. The diagnosis of myasthenia gravis was based on suggestive symptoms of fatigable bilateral orbital ptosis, diplopia, positive ocular cold compression test and serum acetylcholine receptor antibody positivity, as well as a favourable treatment response to pyridostigmine. The addition of corticosteroids and methotrexate resulted in complete resolution of the ocular signs.
... (9) , opisując w latach 2020 i 2021 chorych z nowo rozpoznaną MG po COVID-19, przedstawiły ich jako pierwsze przypadki na świecie, przy czym biorąc pod uwagę daty publikacji pierwszeństwo należy przyznać włoskim badaczom z Katanii, Rzymu i Padwy (7) . Dotychczas opisano 23 chorych (11 kobiet i 12 mężczyzn) w wieku 6-83 lat (mediana 61 lat), u których ujawnienie MG miało związek czasowy z zakażeniem SARS-CoV-2, a jej rozpoznanie zostało potwierdzone (z wyjątkiem jednego chorego) badaniem obecności przeciwciał (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) (tab. 2). ...
... Po miesiącu uzyskano ustąpienie objawów ocznych i poprawę siły mięśniowej kończyn, a w surowicy nie wykryto już AChRAb. Stopniowo odstawiono leki, nie obserwując nawrotów (16) . Druga pacjentka, 6-letnia dziewczynka, trafiła z powodu MIS-C o podobnym przebiegu klinicznym do szpitala w Ankarze w Turcji. ...
... mimikra molekularna, czyli podobieństwo pomiędzy epitopami wirusa SARS-CoV-2 i receptora nikotynowego acetylocholiny oraz MuSK na płytce nerwowo-mięśniowej, prowadzące do produkcji przeciwciał reagujących ze składnikami błony komórkowej komórki mięśniowej na skutek zakażenia koronawirusem. Innymi zjawiskami immunologicznymi związanymi z inicjowaniem autoagresji są rozprzestrzenianie się epitopów (epitope spreading) i okazjonalna aktywacja (bystander activation) (12,15,16,20,24,26) . Ponadto również niektóre leki, stosowane wcześniej w leczeniu COVID-19, takie jak hydroksychlorochina i azytromycyna, mogą przyczyniać się do zaburzenia funkcji złącza nerwowo-mięśniowego (15) . ...
SARS-CoV-2 infection often causes neurological symptoms and complications. Those associated with the production of anti-acetylcholine receptor antibodies are rare. The aim of the study was to present a case of transient myasthenia gravis as a possible complication of COVID-19. A 1.5-year-old boy was admitted on day 7 of varicella due to poor general condition and anuria. On examination, he presented with dehydration, fatigue, sleepiness, and bilateral ptosis. High titre of serum anti-SARS-CoV-2 antibodies was revealed with a history of viral infection 2 weeks prior. An initial diagnosis of encephalitis was made and treatment was started. Despite clinical improvement, gait disturbances and ptosis persisted and the boy was sent for further neurological evaluation. High titre of anti-acetylcholine receptor antibodies (2.98 nmol/L; normal <0.50 nmol/L) confirmed myasthenia gravis, but no treatment was started. Symptoms and antibodies resolved after 3 and 4 months, respectively. A follow-up after one year showed no recurrences. Conclusion: Transient, self-limiting myasthenia gravis may develop in a child as a complication of viral infection, including COVID-19.
... Eight (16%) were conducted in North America (United States: 6 [5,[77][78][79][80][81], Mexico: 1 [82], and Colombia: 1 [83]). One (2%) was conducted in South Africa [84], one (2%) was multicentre [85], and four (8%) studies were unidentifiable [9,11,86,87]. Thirty-five (70%) studies were case-reports [10,11,45,46,52,55,[57][58][59][60][61][62][64][65][66][68][69][70][71][72][73][74][75][76][77][78][79]81,82,84,86,87], seven (14%) were prospective cohorts [43,44,47,49,50,67,83], six (12%) were retrospective cohorts [5,9,48,53,63,85], one (2%) was a crosssectional study [7], and one a (2%) was case-control study [51]. ...
... One (2%) was conducted in South Africa [84], one (2%) was multicentre [85], and four (8%) studies were unidentifiable [9,11,86,87]. Thirty-five (70%) studies were case-reports [10,11,45,46,52,55,[57][58][59][60][61][62][64][65][66][68][69][70][71][72][73][74][75][76][77][78][79]81,82,84,86,87], seven (14%) were prospective cohorts [43,44,47,49,50,67,83], six (12%) were retrospective cohorts [5,9,48,53,63,85], one (2%) was a crosssectional study [7], and one a (2%) was case-control study [51]. Fifteen (30%) studies examined anti-NMDAR [10,43,50,52,[55][56][57]62,68,70,73,76,77,82,86], seventeen (34%) examined anti-AChR [11,46,58,59,61,[64][65][66]71,72,74,[78][79][80][81]84,87,88], seven (14%) examined anti-AngII [7,9,45,[47][48][49]51], six (12%) examined anti-GAD [53,60,61,67,69,85], and ten (20%) studies examined a range of GPCR-AAbs [7,9,44,45,47-49, 60,69,75]. ...
... Thirty-five (70%) studies were case-reports [10,11,45,46,52,55,[57][58][59][60][61][62][64][65][66][68][69][70][71][72][73][74][75][76][77][78][79]81,82,84,86,87], seven (14%) were prospective cohorts [43,44,47,49,50,67,83], six (12%) were retrospective cohorts [5,9,48,53,63,85], one (2%) was a crosssectional study [7], and one a (2%) was case-control study [51]. Fifteen (30%) studies examined anti-NMDAR [10,43,50,52,[55][56][57]62,68,70,73,76,77,82,86], seventeen (34%) examined anti-AChR [11,46,58,59,61,[64][65][66]71,72,74,[78][79][80][81]84,87,88], seven (14%) examined anti-AngII [7,9,45,[47][48][49]51], six (12%) examined anti-GAD [53,60,61,67,69,85], and ten (20%) studies examined a range of GPCR-AAbs [7,9,44,45,47-49, 60,69,75]. Of the 13 patients with NMDAR-related encephalitis, 8 were female and 5 were male, whereas of the 20 patients with AchR-related myasthenia gravis, 10 were male and 10 were female. ...
Introduction
There are an increasing number of reports of autoantibodies (AAbs) against host proteins such as G-protein coupled receptors (GPCRs) and the renin-angiotensin system (RAS) in COVID-19 disease. Here we have undertaken a systematic review and meta-analysis of all reports of AAbs against GPCRs and RAS in COVID-19 patients including those with long-COVID or post-COVID symptoms.
Methods
PubMed, Embase, Web of Science, and Scopus databases were searched to find papers on the role of GPCR and RAS AAbs in the presence and severity of COVID-19 or post- COVID symptoms available through March 21, 2023. Data on the prevalence of AngII or ACE, comparing AngII or ACE between COVID-19 and non-COVID-19, or comparing AngII or ACE between COVID-19 patients with different disease stages were pooled and a meta-analysed using random- or fixed-effects models were undertaken.
Results
The search yielded a total of 1042 articles, of which 68 studies were included in this systematic review and nine in the meta-analysis. Among 18 studies that investigated GPCRs and COVID-19 severity, 18 distinct AAbs were detected. In addition, nine AAbs were found in case reports that assessed post- COVID, and 19 AAbs were found in other studies that assessed post- COVID or long- COVID symptoms. Meta-analysis revealed a significantly higher number of seropositive ACE2 AAbs in COVID-19 patients (odds ratio = 7.766 [2.056, 29.208], p = 0.002) and particularly in severe disease (odds ratio = 11.49 [1.04, 126.86], p = 0.046), whereas AngII-AAbs seropositivity was no different between COVID-19 and control subjects (odds ratio = 2.890 [0.546–15.283], p = 0.21).
Conclusions
GPCR and RAS AAbs may play an important role in COVID-19 severity, the development of disease progression, long-term symptoms COVID and post- COVID symptoms.
... Myasthenia gravis is caused by the production of antibodies against nicotinic receptors in the neuromuscular junction, which reduces the number of functioning receptors by competitive blockade, increased receptor degeneration, or complement-mediated lysis of receptors [4,5]. In most of the patients, after the tests the presence of these antibodies was found [6][7][8][9][10] and one patient developed another type, anti-MusK, which blocks the formation of acetylcholine complexes in the synapses. In a study by Frida Essajee et al., experts from Stellenbosch University [8] described the recurrence of ocular myasthenia gravis caused by SARS-CoV-2 infection, resulting from the presence of ACE 2 receptors (angiotensin-converting enzyme 2), which are necessary for virus binding by cells. ...
... In most of the patients, after the tests the presence of these antibodies was found [6][7][8][9][10] and one patient developed another type, anti-MusK, which blocks the formation of acetylcholine complexes in the synapses. In a study by Frida Essajee et al., experts from Stellenbosch University [8] described the recurrence of ocular myasthenia gravis caused by SARS-CoV-2 infection, resulting from the presence of ACE 2 receptors (angiotensin-converting enzyme 2), which are necessary for virus binding by cells. COVID-19 has a high affinity for these receptors, causing inflammation. ...
... There is a need for further research in this area. It is also not precisely known how and whether SARS-CoV-2 may trigger myasthenia gravis in subjects who did not suffer from it before [6][7][8]11,12]. It also noted the increasing occurrence of COVID-19 related multi-system inflammatory syndrome (MIS-C) among children in Africa. ...
The appearance of the SARS-CoV-2 virus initiated many studies on the effects of the virus on the human body. So far, its negative influence on the functioning of many morphological and physiological units, including the nervous system, has been demonstrated. Consequently, research has been conducted on the changes that SARS-CoV-2 may cause in the cholinergic system. The aim of this study is to review the latest research from the years 2020/2021 regarding disorders in the cholinergic system caused by the SARS-CoV-2 virus. As a result of the research, it was found that the presence of the COVID-19 virus disrupts the activity of the cholinergic system, for example, causing the development of myasthenia gravis or a change in acetylcholine activity. The SARS-CoV-2 spike protein has a sequence similar to neurotoxins, capable of binding nicotinic acetylcholine receptors (nAChR). This may be proof that SARS-CoV-2 can bind nAChR. Nicotine and caffeine have similar structures to antiviral drugs, capable of binding angiotensin-converting enzyme 2 (ACE 2) epitopes that are recognized by SARS-CoV-2, with the potential to inhibit the formation of the ACE 2/SARS-CoV-2 complex. The blocking is enhanced when nicotine and caffeine are used together with antiviral drugs. This is proof that nAChR agonists can be used along with antiviral drugs in COVID-19 therapy. As a result, it is possible to develop COVID-19 therapies that use these compounds to reduce cytokine production. Another promising therapy is non-invasive stimulation of the vagus nerve, which soothes the body’s cytokine storm. Research on the influence of COVID-19 on the cholinergic system is an area that should continue to be developed as there is a need for further research. It can be firmly stated that COVID-19 causes a dysregulation of the cholinergic system, which leads to a need for further research, because there are many promising therapies that will prevent the SARS-CoV-2 virus from binding to the nicotinic receptor. There is a need for further research, both in vitro and in vivo. It should be noted that in the functioning of the cholinergic system and its connection with the activity of the COVID-19 virus, there might be many promising dependencies and solutions.
... Neuromuscular complications of COVID-19 pose a unique challenge for physicians worldwide. New onset ocular MG has been reported in patients with proven COVID-19 infection [79][80][81][82][83]. The incidence of MG was found to be marginally higher in patients with COVID-19 infection compared with general population (0.087% and 0.07%, respectively) [84]. ...
... All patients had elevated titers of antiacetylcholine receptor (AchR) antibodies. Two cases occurred following a complicated admission with multisystem inflammatory syndrome in children, which recently has been recognized by Centers for Disease Control and Prevention as a COVID-19 sequela [80,81]. ...
The COVID-19 pandemic has led to the identification of new disease phenotypes associated with infection by the SARS-CoV-2 virus. This includes multiple neuro-ophthalmological sequelae, which have been associated with COVID-19 infection and administration of COVID-19 vaccines. Some of these associations have a plausible pathophysiological link to the infection or vaccination but true causation has yet to be established. We review the literature for associations reported between COVID-19 infection or vaccination and neuro-ophthalmic sequelae and review the potential pathophysiological processes that may underlie these associations.
... 6 A single pediatric patient with transient myasthenia gravis has been reported after multisystem inflammatory syndrome in children (MIS-C). 7 MIS-C is defined as a novel entity within 2-6 weeks of initial SARS-CoV-2 exposure and is characterized by an uncontrolled inflammatory response with multiorgan failure. 8 The use of proteomics, RNA sequencing, autoantibody arrays, and B-and T-lymphocyte repertoire analysis have characterized factors contributing to hyperinflammation and vascular injury. ...
... 16 The only pediatric patient reported to date was a 7-yearold girl who developed new-onset transient ocular myasthenia gravis with an AChR Ab-positive titer of 0.51 nm/L (normal: <0.39) shortly after recovery from severe MIS-C, ICU-acquired weakness, post-COVID-19 myositis, with a time lag between initial symptoms of 18 days. 7 Although she responded initially to pyridostigmine, corticosteroid and methotrexate were given due to suboptimal response, and there was complete resolution of the symptoms 1 month after discharge. Anti-AChR Ab and SARS-CoV-2 antibody tests were negative, leading to slow discontinuation of pyridostigmine and corticosteroids. ...
Neurologic complications have been associated with multisystem inflammatory syndrome in children, possibly involving autoimmune mechanisms. Here, we report a 6-year-old girl who developed myasthenia 11 weeks after severe acute respiratory syndrome coronavirus 2 infection and 8 weeks after the onset of severe multisystem inflammatory syndrome in children.
... Approximately 47 % of the patients were males, and 58 % were aged above 50 years. Patient outcomes improved to varying degrees, except in two cases where treatment outcomes were not described [10,[42][43][44][45][46][47][48][49][50][51][52][53][54]. SARS-CoV-2 infection may be involved in the pathogenesis of MG. ...
COVID-19 posed a major challenge to the healthcare system and resources worldwide. The popularization of vaccines and the adoption of numerous prevention and control measures enabled the gradual end of the COVID-19 pandemic. However, successive occurrence of autoimmune diseases in patients with COVID-19 cannot be overlooked. Long COVID has been the major focus of research due to the long duration of different symptoms and the variety of systems involved. Autoimmunity may play a crucial role in the pathogenesis of long COVID. Here, we reviewed several autoimmune disorders occurring after COVID-19 infection and the pathogenesis of long COVID.
... MG subsequent to a viral infection has been previously reported following Epstein-Barr and Varicella-Zoster infections (Shah et al., 2022). Thus, unsurprisingly, new onset MG after SARS-Cov-2 infection has been reported with patients commonly testing positive for AChR Ab in the setting of ocular and bulbar symptoms (Huber et al., 2020;Restivo et al., 2020;Sriwastava et al., 2020;Assini et al., 2021;Essajee et al., 2021;Karimi et al., 2021). And although cases with positive MUSK antibodies have been documented as well, these appear to be less common (Figure 2) (Assini et al., 2021). ...
COVID-19 infection has had a profound impact on society. During the initial phase of the pandemic, there were several suggestions that COVID-19 may lead to acute and protracted neurologic sequelae. For example, peripheral neuropathies exhibited distinctive features as compared to those observed in critical care illness. The peripheral nervous system, lacking the protection afforded by the blood–brain barrier, has been a particular site of sequelae and complications subsequent to COVID-19 infection, including Guillain-Barre syndrome, myasthenia gravis, and small fiber neuropathy. We will discuss these disorders in terms of their clinical manifestations, diagnosis, and treatment as well as the pathophysiology in relation to COVID-19.
... The study showed that all patients tested positive for acetylcholine receptors antibodies. 9 Children with myasthenia gravis are more prone to COVID-19 complications. It was found that less than 50% of children had severe respiratory infections using only non-invasive ventilation. ...
Myasthenia gravis (MG) is an autoimmune disease involving the postsynaptic receptors in the neuromuscular junction, characterized by weakness of the muscles. Ocular myasthenia gravis is a subtype of disease where weakness of oculomotor muscles usually occurs with the presence of ptosis. MG is considered a rare disease in pediatric age groups. Acetylcholinesterase inhibitors and immune-modifying medications are usually the mainstays of medication. We report here, a case of a 2-year-old that presented with ptosis and was diagnosed as ocular myasthenia gravis. Our case report describes the clinical presentation, diagnostic tests, and treatments followed.
... Some reports described an ocular motor cranial nerve palsy with or without cranial nerve enhancement on MRI, as well as in association with Miller Fisher/ Guillain-Barré syndromes and myasthenia gravis with and without seropositivity. Brown syndrome (23), ocular inflammatory syndrome, and Tolosa-Hunt syndrome have also been reported (24)(25)(26)(27)(28)(29). A good number of the cases described (including the myasthenia) have been transient; however, no head-to-head comparison of symptom duration or final outcomes are available. ...
... There were 6 descriptive studies about new-onset of MG after COVID-19 infection. The similar structure from acetylcholine receptor and SARS-CoV-2 receptor, activation latent autoimmune disease, and hyperinflammation (such as multisystem inflammatory syndrome in children) may be the possible explanation of it [9,19,40,41,45,47,50]. This condition requires the use of mechanical ventilation, sedating, and paralytic drugs. ...
Introduction
Viral infection such as coronavirus disease 2019 (COVID-19) can exacerbate and aggravate neurological disorders due to autoimmune etiology like myasthenia gravis (MG). Experimental therapies used in COVID-19 are also factors that can cause the worsening of MG symptoms. This review aimed to assess and conclude the research-based study systematically to analyze the relationship of MG and COVID-19.
Method
This study was conducted in accordance to Cochrane handbook for systematic reviews and the guideline of preferred reporting items for systematic review and meta-analysis (PRISMA) and synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. Inclusion criteria in this review were primary studies of every design, articles published in English around January 2000–October 2021, and the study used human as subject. A systematic literature finding was applied in 15 electronic scientific resources. The authors evaluated the study quality and risk of bias of each retrieved article.
Results
The authors found the study through electronic scientific resources that met inclusion and exclusion criteria. The authors evaluated 362 articles identified in literature searching, 22 articles met the criteria for this review and then underwent the evaluation of study quality and risk of bias.
Conclusion
COVID-19 infection can increase the risk of new-onset MG, myasthenic crisis, respiratory failure, and mortality rate due to cytokine storm in MG patients. The management of COVID-19 patients with MG is tailored to each person and based on national guidelines and local expert recommendations.
... Сообщалось о случае транзиторной миастении у 7-летней девочки в Южной Африке [9]. На 4-й день после появления катарально-респираторной симптоматики у пациентки развился мультисистемный воспалительный синдром у детей. ...
... There have been various case reports of COVID-19 infections in patients with pre-existing MG that have been published [2,3]. There is only few reported cases in the literature with new onset MG following COVID-19 .In literature, clinical manifestations of new onset MG were generally mild and was due to antibody formation against the postsynaptic acetylcholine receptor and muscle specific kinase receptor [1,[4][5][6]. To our knowledge, none of the patients in the literature had a thymoma. ...
COVID-19 pandemic is caused by highly infectious SARS-CoV-2. Observational studies have documented several neurological complications or associations either during or after the COVID-19. Some of them, have reported some case reports regarding COVID-19 in patients with a known history of myasthenia gravis (MG) but new onset of autoimmune MG in patients with COVID-19 is scarcely reported. Here, we report two novel cases of new-onset autoimmune MG following COVID-19 and describe the clinical and paraclinical findings in the context of other scarce reported cases.
... In Myasthenia Gravis, an autoimmune pathology that affects communication between the nervous system and muscles, the muscle junction that generates pain, weakness, and inability to move can be treated with infrared, 1 MHz pulsed ultrasound, with a pulse cycle of 48 Hz, intensity of 0.8 W cm −2 and 5 min per region. A single case of a child with new onset of ocular myasthenia gravis shortly after recovery from multisystem inflammatory syndrome associated with SARS-CoV-2 infection has been reported [57]. ...
The post-COVID-19 condition or ‘long COVID’ is a clinical and scientific challenge for society. In this regard, patients after COVID-19 recovery show a vast range of sequels including muscular, articular lesions, neurological, dermatological, and pulmonary issues. These clinical consequences are issues in the present and for the future. In this case, rehabilitation therapies based on photobiomodulation and combined therapies arise as excellent tools to solve it. Herein, we describe and discuss the perspectives on the use of light-based therapies such as photobiomodulation, photodynamic therapy and combined vacuum and laser therapy for rehabilitation of patients who present some sequelae of the COVID-19 infection. We did not intend to produce a comprehensive review; instead we highlight the most important and clinical protocols against these sequels. Moreover, the principles and mechanism of action of each light-based technique proposed were reported and discussed.
... New onset myasthenia gravis (MG) post-COVID-19 infection in a pediatric patient has also been reported. The patient developed acetylcholine receptor antibody positive ocular MG 72 h after resolution of multisystem inflammatory syndrome in children (MIS-C) secondary to COVID-19 [15]. Multiple cases of MG in adult patients after COVID-19 have been published [16,17]. ...
Since the emergence of SARS-CoV-2, several studies have been published describing neuromuscular manifestations of the disease, as well as management of pre-existing pediatric neuromuscular disorders during the COVID-19 pandemic. These disorders include muscular dystrophies, myasthenic syndromes, peripheral nerve disorders, and spinal muscular atrophy. Such patients are a vulnerable population due to frequent complications such as scoliosis, cardiomyopathy, and restrictive lung disease that put them at risk of severe complications of COVID-19. In this review, neuromuscular manifestations of COVID-19 in children and the management of pre-existing pediatric neuromuscular disorders during the COVID-19 pandemic are discussed. We also review strategies to alleviate pandemic-associated disruptions in clinical care and research, including the emerging role of telemedicine and telerehabilitation to address the continued special needs of these patients.
... COVID-19 was declared as a pandemic by WHO on March 11th, 2020. To date, accumulating evidence has confirmed that SARS-CoV-2 is linked to MG. 10 case reports of new-onset MG following COVID-19 have been analyzed with the following features: mean age 51 years, male gender (6), time interval between COVID-19 and MG (5-56 days), generalized (7), bulbar and/or ocular symptoms (5), anti-AChR antibodies (9) and anti-muscle specific kinase antibodies (anti-MUSK) (2) (93,94). ...
Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and abnormal fatigability due to the antibodies against postsynaptic receptors. Despite the individual discrepancy, patients with MG share common muscle weakness, autoimmune dysfunction, and immunosuppressive treatment, which predispose them to infections that can trigger or exacerbate MG. Vaccination, as a mainstay of prophylaxis, is a major management strategy. However, the past years have seen growth in vaccine hesitancy, owing to safety and efficacy concerns. Ironically, vaccines, serving as an essential and effective means of defense, may induce similar immune cross-reactivity to what they are meant to prevent. Herein, we outline the progress in vaccination, review the current status, and postulate the clinical association among MG, vaccination, and immunosuppression. We also address safety and efficacy concerns of vaccination in MG, in relation to COVID-19. Since only a handful of studies have reported vaccination in individuals with MG, we further review the current clinical studies and guidelines in rheumatic diseases. Overall, our reviews offer a reference to guide future vaccine clinical decision-making and improve the management of MG patients.
Background
Following the COVID-19 pandemic, there are many chronically ill Long COVID (LC) patients with different symptoms of varying degrees of severity. The pathological pathways of LC remain unclear until recently and make identification of path mechanisms and exploration of therapeutic options an urgent challenge. There is an apparent relationship between LC symptoms and impaired cholinergic neurotransmission.
Methods
This paper reviews the current literature on the effects of blocked nicotinic acetylcholine receptors (nAChRs) on the main affected organ and cell systems and contrasts this with the unblocking effects of the alkaloid nicotine. In addition, mechanisms are presented that could explain the previously unexplained phenomenon of post-vaccination syndrome (PVS). The fact that not only SARS-CoV-2 but numerous other viruses can bind to nAChRs is discussed under the assumption that numerous other post-viral diseases and autoimmune diseases (ADs) may also be due to impaired cholinergic transmission. We also present a case report that demonstrates changes in cholinergic transmission, specifically, the availability of α4β2 nAChRs by using (-)-[ ¹⁸ F]Flubatine whole-body positron emission tomography (PET) imaging of cholinergic dysfunction in a LC patient along with a significant neurological improvement before and after low-dose transcutaneous nicotine (LDTN) administration. Lastly, a descriptive analysis and evaluation were conducted on the results of a survey involving 231 users of LDTN.
Results
A substantial body of research has emerged that offers a compelling explanation for the phenomenon of LC, suggesting that it can be plausibly explained because of impaired nAChR function in the human body. Following a ten-day course of transcutaneous nicotine administration, no enduring neuropathological manifestations were observed in the patient. This observation was accompanied by a significant increase in the number of free ligand binding sites (LBS) of nAChRs, as determined by (-)-[ ¹⁸ F]Flubatine PET imaging. The analysis of the survey shows that the majority of patients (73.5%) report a significant improvement in the symptoms of their LC/MEF/CFS disease as a result of LDTN.
Conclusions
In conclusion, based on current knowledge, LDTN appears to be a promising and safe procedure to relieve LC symptoms with no expected long-term harm.
Myasthenia gravis (MG) is defined as an autoimmune neuromuscular disorder where autoantibodies disrupt synaptic transmission at the neuromuscular junction by targeting the acetylcholine receptor (AChR), muscle-specific kinase (MuSK), or other proteins related to the AChR complex. This disruption leads to characteristic muscle weakness and rapid fatigability. Clinically, MG is classified based on the age of onset into three distinct categories: early-onset MG (younger than 50 years), late-onset MG (between 50 and 64 years), and very-late-onset MG (65 years and older). We present a rare case of an 81-year-old man who presented with dysarthria, shortness of breath, diplopia, and oropharyngeal dysphagia to both solids and liquids for approximately seven days and was noted to be more progressive in the last 48 hours prior to his presentation to the emergency room. Upon arrival at the emergency room, he complained of shortness of breath and diplopia. Of note, approximately four months prior to this admission, he was diagnosed with COVID-19 pneumonia and was treated appropriately with remdesivir and corticosteroids. He had an uneventful COVID-19 pneumonia hospitalization and was discharged home. Given the progressive nature of his symptomatology, particularly dyspnea, he was transferred to the ICU for further evaluation and treatment. Laboratory results were positive for AChR binding, blocking, and modulating antibodies, confirming the diagnosis of MG. The patient received treatment consisting of pyridostigmine, a pulse dose of methylprednisolone, and intravenous immunoglobulin (IVIG) therapy. This case is unique and highlights a case of a very late onset of MG and the manifestation of new-onset MG four months following COVID-19. Additionally, this patient had a very delayed onset of MG symptoms, as he presented four months after his infection with COVID-19, compared to the average onset of reported cases of post-COVID MG being four to eight weeks post-infection with COVID-19. This uniquely delayed onset, occurring beyond a three-month window post-COVID-19 infection, aligns with the criteria established by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) for a diagnosis of “Post-COVID Condition,” also known as “Long COVID.” This case illustrates the intricate link between post-viral states and autoimmune responses, particularly in geriatric patients. The pathophysiology linking COVID-19 to MG primarily involves immune dysregulation triggered by the viral infection, which may disrupt immune tolerance and lead to clinical autoimmunity. This case stresses the need for vigilance in diagnosis and managing neurological complications in the context of viral respiratory illnesses, particularly in vulnerable populations.
Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction caused by a B-cell-mediated, T-cell-dependent immunologic attack at the end plate of the postsynaptic membrane. Attack on muscle acetylcholine receptors (AChR) of the postsynaptic membrane due to the AChR, muscle-specific tyrosine kinase, or lipoprotein receptor-related peptide 4 antibodies lead to symptoms of painless, fluctuating weakness of muscle groups and often begins with ocular signs and symptoms. Coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus closely related to SARS-CoV. Serious neurologic complications are infrequent and diverse with reported cases of stroke, encephalitis/meningitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, ataxia, and unspecified limb weakness. MG is a rarely reported sequela of COVID-19 infection. To date, there are 15 reported cases of post-COVID-19 MG. In this article, we present a case of post-COVID-19 MG and a concise review of other reported cases. An 83-year-old Caucasian male with a medical history of atrial fibrillation status post-ablation and non-ischemic cardiomyopathy was initially admitted for COVID-19 pneumonia. He was treated with remdesivir, convalescent plasma, and supplemental oxygen therapy but did not require invasive mechanical intubation. One month after discharge, he started experiencing fatigue with muscle weakness and progressive dyspnea. He progressed to develop dysphonia, especially at the end of the day. After extensive workup, he was diagnosed with MG with a positive antibody against the AChR. The chronological events of developing slowly worsening muscular weakness after recovering from COVID-19 infection and positive AChR antibody led to the diagnosis of post-COVID-19 new-onset MG. Post-COVID-19 fatigue, long-term use of steroids, and intensive care unit-related physical deconditioning ....
Myasthenia gravis (MG) is a rare, long-term neuromuscular disorder that can affect individuals of any age. In Japan, the Omicron variant of coronavirus disease 2019 (COVID-19) began spreading in 2022, and many cases of neurological symptoms caused by the virus have been reported. Although COVID-19 has been reported to exacerbate MG in adults, there are no reports on the effects of COVID-19 on the MG symptoms of pediatric patients. We report the case of a 6-year-old girl with a 3-year history of MG who presented to our hospital with symptom exacerbation after COVID-19 infection. Four days before admission, she developed fever with a runny nose and cough. Three days before admission, she developed severe bilateral blepharoptosis and progressive limb weakness, and 2 days before admission, she was diagnosed with COVID-19 by SARS-CoV-2 antigen test. Physical examination revealed moderate blepharoptosis and mild bilateral upper and lower limb weakness. We diagnosed her with worsening MG due to COVID-19, and she was administered 400 mg/kg intravenous immunoglobulin (IVIG) daily for 5 days with continued oral corticosteroids and tacrolimus. The patient's symptoms improved promptly after admission and, at discharge 7 days after admission, her symptoms had significantly improved. During the 1-month outpatient follow-up period, she remained stable and the anti-acetylcholine receptor (AchR) antibody level was reduced to 14.6 nmol/L (from 18.5 nmol/L on admission). Our case suggests that COVID-19 exacerbates MG in both children and adults.
Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction caused by a B-cell-mediated, T-cell-dependent immunologic attack at the end plate of the postsynaptic membrane. Attack on muscle acetylcholine receptors (AChR) of the postsynaptic membrane due to the AChR, muscle-specific tyrosine kinase, or lipoprotein receptor-related peptide 4 antibodies lead to symptoms of painless, fluctuating weakness of muscle groups and often begins with ocular signs and symptoms. Coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus closely related to SARS-CoV. Serious neurologic complications are infrequent and diverse with reported cases of stroke, encephalitis/meningitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, ataxia, and unspecified limb weakness. MG is a rarely reported sequela of COVID-19 infection. To date, there are 15 reported cases of post-COVID-19 MG. In this article, we present a case of post-COVID-19 MG and a concise review of other reported cases. An 83-year-old Caucasian male with a medical history of atrial fibrillation status post-ablation and non-ischemic cardiomyopathy was initially admitted for COVID-19 pneumonia. He was treated with remdesivir, convalescent plasma, and supplemental oxygen therapy but did not require invasive mechanical intubation. One month after discharge, he started experiencing fatigue with muscle weakness and progressive dyspnea. He progressed to develop dysphonia, especially at the end of the day. After extensive workup, he was diagnosed with MG with a positive antibody against the AChR. The chronological events of developing slowly worsening muscular weakness after recovering from COVID-19 infection and positive AChR antibody led to the diagnosis of post-COVID-19 new-onset MG. Post-COVID-19 fatigue, long-term use of steroids, and intensive care unit-related physical deconditioning can be confounders in the clinical presentation of post-COVID-19 new-onset MG. Careful history-taking and meticulous assessment of chronological events are needed to diagnose this rare entity.
Purpose of review:
We set out to describe efferent neuro-ophthalmological complications that have been reported in association with coronavirus disease 2019 (COVID-19) infection. We describe syndromes affecting ocular motility and elaborate on mechanisms of disease, including para-infectious inflammation, hypercoagulability, endothelial damage, and direct neurotropic viral invasion. Despite global vaccination programs, COVID-19 continues to pose an international threat that may rarely result in diplopia or nystagmus.
Recent findings:
Efferent complications include cranial nerve palsies leading to diplopia, either isolated or in association with Miller Fisher syndrome. Nystagmus has been observed in the setting of hemorrhagic acute necrotizing encephalopathy and brainstem infarcts, and opsoclonus syndrome has been described.
Summary:
Observed neuro-ophthalmic associations need to be confirmed through larger comparative studies. Meanwhile, the range of possible complications should be recognized by neurologists and ophthalmologists alike, to facilitate faster diagnosis and treatment of both COVID-19 and its neuro-ophthalmic manifestations.
Introduction:
Coronavirus disease 2019 (COVID-19) has spread around the world and caused hundreds of thousands of fatalities across a wide spectrum of patients with varying severity and presenting complaints. The discussion of the ability of this disease to cause significant illness in patients with various risk factors such as myasthenia gravis is important to help guide physicians on recognition and treatment options as the pandemic matures.
Case report:
Here we discuss a single case of isolated COVID-19 infection that precipitated a myasthenic crisis with no other clinical sequelae in a patient who presented to the emergency department (ED). This report highlights some of the initial difficulties and delay in diagnosis encountered earlier in the pandemic with limited testing supplies and processing labs; however, prompt ED recognition and treatment still led to a favorable outcome.
Conclusion:
The patient recovered during this initial presentation and was successfully treated with plasma exchange and steroids only. It is important to recognize that myasthenia gravis patients may represent a uniquely vulnerable population that requires enhanced surveillance and screening to prevent significant morbidity and mortality. This case describes how even a mild infection with no significant clinical sequelae or significant signs on imaging studied can precipitate a crisis event.
The novel coronavirus outbreak of SARS-CoV-2 first began in Wuhan, China, in December 2019. The most striking manifestation of SARS-CoV-2 is atypical pneumonia and respiratory complications; however, various neurological manifestations are now well recognized. Currently, there have been very few case reports regarding COVID-19 in patients with a known history of myasthenia gravis. Myasthenia gravis (MG) causes muscle weakness, especially respiratory muscles, in high-risk COVID-19 patients, which can lead to severe respiratory compromise. There are few reported cases of severe myasthenia crisis following COVID-19, likely due to the involvement of the respiratory apparatus and the use of immunosuppressive medication. We report the first case of ocular MG developing secondary to COVID-19 infection in a 65-year-old woman. Two weeks prior to hospitalization, the patient suffered from cough, fever, and diarrhea and was found to be positive for COVID-19 via a nasopharyngeal RT-PCR swab test. The electrodiagnostic test showed decremental response over more than 10% on repetitive nerve stimulation test of orbicularis oculi. She tested positive for antibodies against acetylcholine receptor. COVID-19 is known to cause the release of inflammatory cytokines, leading to immune-mediated damage. MG is an immune-mediated disorder caused by molecular mimicry and autoantibodies against the neuromuscular junction.
Currently, there are scarce data on how COVID-19 affects people with myasthenia gravis. Theoretically, there is a higher risk of experiencing severe manifestations of COVID-19 due to the common use of immunosuppressive drugs and potential respiratory failure in relation to respiratory muscle weakness. This is one of the early cases of COVID-19 reported in association with myasthenia gravis. Here, we highlight the prognosis, discuss the pathophysiological mechanisms, and prompt the consideration of convalescent plasma therapy in myasthenia gravis patients with concomitant COVID-19.
We report three critically ill pediatric patients (aged 6–10 years), presenting with features of multisystem inflammatory syndrome in children (MIS-C) from April 4 to May 10, 2020, to a tertiary-care center in New Jersey, United States. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and were previously healthy. Clinical presentations were similar with fever, abdominal pain, gastrointestinal complaints, and/or rash. One patient had altered mental status with cerebrospinal fluid (CSF) findings consistent with aseptic meningitis. Laboratory values were remarkable for high levels of C-reactive protein, D-dimers, B-type natriuretic peptide (BNP), and troponin in all patients. All had low albumin levels. Evaluation for other infectious etiologies was negative. All of the patients were critically ill, requiring admission to the intensive care unit. All had circulatory shock and needed inotropes. Two patients had respiratory failure requiring advanced respiratory support and one had cardiac dysfunction. All patients received steroids, and two received intravenous immunoglobulin (IVIG). One patient received tocilizumab. None of the children died. MIS-C is a recently recognized pediatric illness spectrum in association with SARS-CoV-2 infection, and clinical characterization is essential for understanding disease mechanisms to inform clinical practice.
The coronavirus-19 (COVID-19) pandemic has potential to disproportionately and severely affect patients with neuromuscular (NM) disorders. In a short period of time, it has already caused reorganization of neuromuscular clinical care delivery and education, which will likely have lasting impact on the field. This paper reviews 1) potential NM complications of COVID-19, 2) assessment and mitigation of COVID-19-related risk for patients with pre-existing NM disease, 3) guidance for management of immunosuppressive and immunomodulatory therapies, 4) practical guidance regarding NM care delivery, telemedicine and education, and 5) impact on neuromuscular research. We outline key unanswered clinical questions and highlight the need for team-based and inter-specialty collaboration. Primary goals of clinical research during this time are to develop evidence-based best practices and to minimize morbidity and mortality related to COVID-19 for patients with neuromuscular disorders.
As severe acute respiratory syndrome coronavirus 2 continues to spread worldwide, there have been increasing reports from Europe, North America, Asia, and Latin America describing children and adolescents with COVID-19-associated multisystem inflammatory conditions. However, the association between multisystem inflammatory syndrome in children and COVID-19 is still unknown. We review the epidemiology, causes, clinical features, and current treatment protocols for multisystem inflammatory syndrome in children and adolescents associated with COVID-19. We also discuss the possible underlying pathophysiological mechanisms for COVID-19-induced inflammatory processes, which can lead to organ damage in paediatric patients who are severely ill. These insights provide evidence for the need to develop a clear case definition and treatment protocol for this new condition and also shed light on future therapeutic interventions and the potential for vaccine development.
Translations
For the French, Chinese, Arabic, Spanish and Russian translations of the abstract see Supplementary Materials section.
Objective:
To investigate the association between human parvovirus B19 (B19V) infection in the thymus and myasthenia gravis (MG).
Methods:
The presence of human B19V DNA and protein was assessed in 138 samples, including 68 thymic hyperplasia (39 with MG), 58 thymoma (23 with MG), and 12 normal thymus tissues, by nested polymerase chain reaction, immunohistochemistry, laser capture microdissection, and sequencing in a double-blinded manner.
Results:
B19V DNA was mainly detected in thymic hyperplasia, and the positive rate (41.18%, 28/68) was significantly higher than that in thymoma (3.45%, 2/58) (P<0.001), but not in normal thymic tissues. Correspondingly, the positive rate in thymic hyperplasia with MG (30.77%, 12/39) was significantly higher than that in thymoma with MG (4.35%, 1/23) (P=0.021). However, it was higher in thymic hyperplasia without MG (55.17%, 16/29) than in thymic hyperplasia with MG (30.77%,12/39) (P=0.043). B19V VP1/VP2 protein-positive cells in thymic hyperplasia (63.24%, 43/68) were mainly identified in ectopic germinal centers and thymic corpuscle epithelial cells, but were rare in thymoma (1.72%, 1/58) (P<0.001). Moreover, the positive rate was significantly higher in thymic hyperplasia with MG (74.36%, 29/39) than in thymic hyperplasia without MG (48.28%, 14/29) (P=0.027).
Conclusions:
To our knowledge, the present study is the first to show that human B19V infection is closely associated with thymic hyperplasia and thymic hyperplasia-associated MG, but not related to thymoma or thymoma-associated MG. The findings revealed a previously unrecognized etiopathogenic mechanism of thymic hyperplasia-associated MG, evoking numerous questions that require further investigation.
We report two children with transient myasthenia gravis preceded by viral illnesses. The first is a 5-year-old boy who developed oculobulbar weakness 2 weeks following a varicella-zoster infection. The second is a 4-year-old boy who developed facial diplegia and dysarthria several weeks following a viral pharyngitis. Myasthenia gravis was diagnosed based on the substantial decremental changes on 3 Hz repetitive motor nerve stimulation studies for the first child and on the positive edrophonium test and complete improvement in symptoms during pyridostigmine therapy for both children. In both cases, the symptoms gradually resolved and have not recurred following discontinuation of pyridostigmine. Molecular mimicry between the acetylcholine receptor and viral proteins might provide the nidus for the immune response in this variant of myasthenia gravis.