European Journal of Cardiovascular Medicine

In the intricate theatre of neuromuscular maladies, there exists an enigmatic and recalcitrant disorder, Myasthenia Gravis (MG), an acquired autoimmune ailment wherein the sovereign dominion of voluntary musculature is insidiously undermined by the malevolent subversion of neuromuscular transmission. This derangement, begotten by antibodies directed with baleful precision against components of the postsynaptic membrane—most often the acetylcholine receptor (AChR)—manifests in progressive muscular enfeeblement, the gravest of which can threaten respiration and deglutition with perfidious subtlety.

In an intriguing alliance, MG oft conjoins its pathophysiological design with thymoma, a neoplasm of the thymic epithelium, whose anterior mediastinal abode harbors the genesis of autoimmunity in many afflicted souls. Approximately one-fifth to three-fifths of thymoma patients exhibit MG, while conversely, thymomas are discerned in one-tenth to one-third of MG sufferers [1,2]. This intertwined diad, termed Thymoma-Associated Myasthenia Gravis (TAMG), invites surgical intercession—thymectomy—which in numerous cases heralds symptomatic abatement, albeit not without peril and unpredictability, especially in post-operative respiratory tribulations and failure to wean [3].

Thymomas, though indolent in their progression, are capricious in their behavior, often exhibiting pleural, pericardial, or diaphragmatic dissemination, rarely extending beyond the thoracic confines [4,5]. They are notorious for their association with paraneoplastic syndromes, particularly MG, and exhibit histological variability under the WHO classification, with the Masaoka-Koga system reigning supreme in staging. Despite the lack of randomized trials and the rarity of cases, surgical resection remains the linchpin of curative intent, with chemoradiation playing ancillary roles as context dictates.

The Myasthenia Gravis Foundation of America (MGFA), in its learned deliberations, has endeavored to codify definitions and guidance for therapy, elucidating constructs such as Minimal Manifestation Status (MMS), impending and manifest crisis, refractory MG, and the indications for novel biologics including rituximab and eculizumab. This treatise, born of clinical experience at a major Eastern Indian tertiary centre, seeks to elucidate the prevailing diagnostic and therapeutic paradigms in patients presenting with thymic masses and/or myasthenia gravis, capturing within its academic compass both the ancient heritage of the thymus and the modern arsenal of medical and surgical weaponry.

AIMS AND OBJECTIVES

To conduct an exhaustive clinical appraisal of individuals presenting with either Myasthenia Gravis or thymic tumours.

To delineate and analyse diagnostic modalities and laboratory adjuncts in the assessment of said conditions.

To evaluate the role and efficacy of pharmacological regimens including cholinergic and immunosuppressive interventions.

To chronicle the operative intricacies and perioperative management of thymectomy, inclusive of post-extubation outcomes.

To institute longitudinal surveillance upon subjects subjected to surgical resection for thymoma or MG.

This scholarly investigation was wrought upon the canvas of a tertiary academic medical centre—IPGME&R and SSKM Hospital, Kolkata—spanning the temporal breadth of 2021 to 2024. Ethical clearances were procured, and written informed consents were obtained with the gravitas befitting such intimate explorations into human affliction.

The cohort comprised patients presenting with clinical symptomatology indicative of MG, thymic masses, or both. Inclusion necessitated serological evidence of AChR antibodies, radiological confirmation of anterior mediastinal opacities, and/or electromyographic decremental responses. Patients were subjected to exhaustive preoperative evaluations, including computed tomography (CT) of the thorax, pulmonary function testing (PFT), and AchR-Ab quantification.

Surgical intervention, when indicated, encompassed transcervical or transsternal thymectomy, performed under general anesthesia with meticulous dissection of the thymic tissue and its associated fat. Post-operative vigilance was exercised regarding respiratory sufficiency, ventilatory dependence, and occurrence of crisis. Follow-up evaluations at monthly intervals included clinical assessment and antibody titres.

The demographic distribution revealed a preponderance of males, with a mean age of affliction within the fourth decade of life. Clinical features most frequently included ptosis, diplopia, dysphagia, and dyspnea. Approximately 30% of the study population experienced antecedent myasthenic crises.

Serological investigations demonstrated elevated AChR antibodies in the vast majority, with titers correlating with clinical severity. CT imaging frequently revealed homogenous anterior mediastinal masses suggestive of thymoma. Preoperative pharmacological preparation included pyridostigmine, corticosteroids, and in select cases, plasmapheresis or intravenous immunoglobulin.

Thymectomy was successfully accomplished in all operable patients. Histopathological analysis confirmed thymoma in over half the cases, while the remainder revealed thymic hyperplasia. The mean day of extubation post-thymectomy was three, while discharge was effected around the fifth post-operative day. Postoperative myasthenic crisis occurred in a minority and was managed with ventilatory support and immunotherapy.

Follow-up spanning six to eighteen months demonstrated a statistically significant diminution in antibody titres and symptomatic relief, with nearly 70% achieving MMS or better.

In the vast, intricate, and oft-bewildering arena of autoimmune pathology, wherein the physiological sanctity of self-recognition is treacherously betrayed by its own custodians, the disease entity designated as Myasthenia Gravis (MG) stands as an enigmatic exemplar of immunological misapprehension—one which, with unrelenting subterfuge, undermines the very instruments of volitional expression: the skeletal musculature. A condition both humbling and haughty, MG strips its sufferers of the simplicity of breath and movement, not through the attrition of time or injury, but through the surreptitious sabotage of synaptic function by antibodies forged in the crucible of thymic misdirection [1].

It is, perhaps, within the thymus—once thought a transient organ of childhood, a vestige of embryonic immunopoiesis—that this malevolent script is first penned. The thymus, situated in solemn obscurity within the anterior mediastinum, possesses in its epithelium both the capacity to instruct and to corrupt. It is now irrefutably known that thymic epithelial cells (TECs), in both hyperplastic and neoplastic states, may present self-antigens—particularly acetylcholine receptor (AChR) peptides—in aberrant contexts, failing to enact central tolerance, and instead licensing the maturation of autoreactive T lymphocytes [2,3].

The observed concurrence between thymoma and MG—a partnership of immunopathology and oncology—is neither accidental nor superficial. Between 10–30% of patients afflicted with MG are found to harbour thymomas, while 20–60% of those diagnosed with thymoma exhibit clinical or serological evidence of MG [1,4]. This bi-directional association gives rise to the clinical entity known as Thymoma-Associated Myasthenia Gravis (TAMG), wherein the thymic neoplasm is not merely an anatomical anomaly but a pathogenic catalyst.

Thymomas, in their variegated histomorphological guise—classified meticulously by the WHO into types A through B3 and carcinoma—exhibit a duality of behaviour: indolent in growth yet insidious in immunological consequence [5]. Their frequent association with paraneoplastic syndromes, particularly MG, has been well documented, with certain subtypes (e.g., WHO Type B2 and B3) more closely correlated with autoimmunity [6]. The Masaoka-Koga staging system, though anatomical in its orientation, remains clinically salient, especially in prognosticating recurrence and guiding adjunctive therapy [7].

Thymectomy, therefore, emerges not merely as a resective surgical act but as an immunotherapeutic intervention—an ablative ritual whereby the presumed nidus of aberrant autoimmunity is extirpated. The profound physiological and prognostic implications of this surgical undertaking were immortalized in the landmark randomized controlled trial by Wolfe et al., which demonstrated that extended transsternal thymectomy, when performed in non-thymomatous MG patients under 65 years of age with generalized disease and positive AChR antibodies, significantly improved clinical outcomes and reduced corticosteroid dependency [10]. This trial, and others before it, lend empirical gravitas to a therapeutic tradition long held as dogma but only recently codified by statistical rigor [8,10].

The present investigation corroborates these observations, demonstrating that thymectomy, when undertaken with judicious preoperative preparation—often including corticosteroids, intravenous immunoglobulin (IVIg), or plasmapheresis—results in a high rate of post-operative symptom stabilization, as evidenced by the attainment of Minimal Manifestation Status (MMS) in a significant proportion of our cohort. Nevertheless, this therapeutic odyssey is not without its perils. The perioperative period is fraught with potential calamities: myasthenic crisis looms as a shadow over intubation and extubation, its risk compounded by pre-existing bulbar or respiratory involvement [3,9].

The immunopathological foundations of MG are intricate and labyrinthine. It is now well established that the disease is mediated primarily by immunoglobulin G1 and G3 subclass autoantibodies directed against the extracellular domains of the AChR in 80–85% of generalized MG patients [6,14]. These antibodies engage in complement activation, culminating in the assembly of the membrane attack complex (MAC), thereby inflicting structural dissolution upon the post-synaptic membrane, diminishing both AChR density and endplate potential [16].

Yet MG is no monolith. The phenotypic and serological diversity is astonishing in scope. Patients seronegative for AChR antibodies may be found to possess antibodies against muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (Lrp4), or agrin—each conferring distinct clinical and prognostic implications. MuSK-MG, for instance, characterized by IgG4 subclass antibodies that do not activate complement, exhibits a predilection for bulbar musculature and tends to be refractory to standard immunosuppressants, yet often responds dramatically to rituximab [12,18].

Furthermore, pediatric MG—termed Juvenile Myasthenia Gravis (JMG)—presents a discrete epidemiological and immunological profile. It is notably more prevalent in East Asian populations and frequently manifests with ocular involvement. Despite the increased likelihood of spontaneous remission, JMG necessitates timely intervention, particularly to forestall irreversible developmental sequelae such as amblyopia [15].

The histopathological examination of the thymus in MG patients reveals compelling insights. In early-onset disease, thymic hyperplasia with germinal center proliferation is the norm, whereas late-onset MG and TAMG are often associated with thymoma or involuted thymic architecture [6,11]. The presence of germinal centers serves as an anatomical testament to intrathymic B cell activation and antibody production, with antigen-presenting cells and follicular helper T cells (Tfh) orchestrating the autoimmune concerto [19].

Molecular analyses further deepen our understanding of MG's etiopathogenesis. Studies have unveiled polymorphisms in the HLA locus—particularly HLA-DR3 and HLA-B8—as well as non-HLA genes such as CTLA4 and TNFRSF11A, all of which confer susceptibility to MG [13]. The autoimmune regulator (AIRE) gene, which governs central tolerance by promoting the ectopic expression of tissue-restricted antigens in thymic medullary epithelial cells, is often aberrantly expressed in thymoma, facilitating the escape of autoreactive clones [19].

Our findings, drawn from a demographically heterogeneous Indian population, reflect these global trends, while also highlighting regional nuances. For instance, the predominance of late-onset male patients in our thymomatous cohort aligns with the Western experience, whereas the seropositivity rates and antibody titers among juveniles more closely mirror East Asian data [6,13,15].

In the postoperative surveillance of thymectomy patients, a consistent decrement in AChR antibody titers has been observed, often correlating with clinical improvement. However, titers alone do not dictate outcome; clinical judgment must guide therapy. This necessitates continued immunosuppression in selected patients, with agents ranging from corticosteroids and azathioprine to newer biologics such as eculizumab—a monoclonal antibody against complement protein C5, which has shown efficacy in refractory AChR-MG [3].

It must be underscored that the triumph of thymectomy is not absolute. A subset of patients—particularly those with MuSK-MG, seronegative MG, or late-onset thymoma—may exhibit incomplete or absent remission despite surgical extirpation. For such patients, a tailored regimen of immunomodulation remains paramount [11,12].

In the closing contemplation of this scholarly pursuit, wherein the confluence of clinical science, immunological insight, and operative stratagem has been scrutinized with unwavering rigour, it may be asserted—without equivocation—that the management of thymic mass lesions and Myasthenia Gravis (MG) constitutes a formidable, yet profoundly conquerable, domain within the higher order of cardiothoracic surgical medicine.

This investigation, conducted amidst the scholastic precincts and surgical corridors of a preeminent tertiary centre of Eastern India, has illuminated the delicate yet consequential interplay between thymic pathology and the autoimmune neuromuscular disorder that is MG. It has become unequivocally evident through our observations that the thymus, far from being a vestigial relic of immunological youth, remains a central architect in the orchestration and dysregulation of immunotolerance. Whether through the chaotic architecture of a neoplastic thymoma or the hyperplastic exuberance of germinal centre proliferation, the gland exerts a potent influence upon the autoimmune cascade that culminates in the fatigability and muscular weakness so characteristic of MG.

Our study reiterates the vital importance of a comprehensive and methodical approach in the evaluation of patients presenting with signs of MG and/or anterior mediastinal masses. The synthesis of clinical vigilance, serological analysis (particularly the identification of AChR and MuSK antibodies), neurophysiological studies such as repetitive nerve stimulation and single-fibre electromyography, and radiological imaging (notably contrast-enhanced CT of the thorax), emerges as the gold standard in accurate and timely diagnosis. Moreover, pulmonary function testing remains indispensable, not only in preoperative risk stratification but also in anticipating the insidious development of myasthenic crisis.

Thymectomy, in its modern incarnation—whether through transsternal, transcervical, or minimally invasive techniques—has been vindicated once more as both a surgical necessity in cases of thymoma and an immunomodulatory adjunct in selected non-thymomatous MG cases. The favourable clinical trajectory observed postoperatively in a majority of our patients, including attainment of Minimal Manifestation Status (MMS), reduced antibody titres, decreased reliance on pharmacotherapy, and improvement in respiratory and bulbar function, substantiates the thymus' culpability in perpetuating the autoimmune dialogue.

Equally significant is the role of preoperative pharmacological conditioning and postoperative immunosuppressive stewardship. The preoperative administration of corticosteroids, cholinesterase inhibitors, IVIg, and plasmapheresis has demonstrably reduced perioperative complications, especially respiratory compromise. Our findings echo global evidence that optimal preparation is paramount in mitigating the hazards of perioperative myasthenic crisis and ensuring timely extubation and discharge.

Furthermore, our results underscore the indispensability of postoperative follow-up. Myasthenia, though often susceptible to remission, is a disease punctuated by caprice. Continued surveillance for relapse, antibody resurgence, and secondary autoimmunity is imperative. Tailored pharmacotherapeutic regimens—spanning corticosteroids, steroid-sparing immunosuppressants, and novel biologics like rituximab and eculizumab—must be employed judiciously and longitudinally, with decisions informed by serological trends, functional recovery, and patient-reported outcomes.

In the regional context, this study represents a seminal contribution to the Indian subcontinent’s growing corpus of myasthenic and thymic literature. The demographic nuances observed—such as male preponderance in thymomatous cases, prevalence of ocular symptoms in juvenile presentations, and the spectrum of antibody positivity—offer invaluable insights for clinicians operating in similar sociocultural and epidemiological milieus.

Ultimately, this investigation affirms the axiom that successful management of thymic masses and MG is not anchored solely in operative intervention, nor purely in pharmacological manipulation, but in the harmonious integration of both—guided by timely diagnosis, surgical precision, immunological insight, and empathetic longitudinal care. The thymus, once dismissed as immunological detritus, has re-emerged as both villain and vessel: a site of pathogenesis, yet simultaneously a target for therapeutic redemption. And in its removal, carefully selected and skillfully executed, lies the potential not merely for symptomatic reprieve, but for immunological recalibration and durable remission.

In this union of surgical and immunological disciplines, and in the light of this study's empirical testament, the clinician is reminded that the human body, even in its rebellion, remains amenable to understanding, to intervention, and—through informed, evidence-based stewardship—to healing.

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