A rare case of D-penicillamine induced Myasthenia Gravis

INTRODUCTION

D-Penicillamine (DPA) remains one of the most widely prescribed chelating agents, particularly in resource-limited settings, due to its proven efficacy and availability in Wilson’s disease. Wilson’s disease is an autosomal recessive disorder of copper metabolism requiring long-term chelation therapy to prevent progressive hepatic and neurological injury. However, its use is associated with a broad spectrum of adverse effects, including immune-mediated complications that may mimic primary neurological disorders. Myasthenia gravis (MG) is a chronic autoimmune neuromuscular junction disorder characterized by fatigable weakness, most commonly involving extraocular, bulbar, and proximal limb muscles. While MG is classically idiopathic or thymus-associated, several drugs are known to induce or unmask myasthenic syndromes. Among these, DPA is a well-recognized but underappreciated trigger, with reported incidence ranging from 1–7% among treated patients.^1,2

DPA–induced myasthenia gravis typically presents with a predominantly ocular phenotype and is thought to result from drug-mediated immune dysregulation, leading to autoantibody formation against acetylcholine receptors.^3,4 The onset may occur months to years after initiation of therapy, particularly in patients with Wilson’s disease, often leading to diagnostic delay or misattribution of symptoms to hepatic or metabolic causes.^1,2

Recognition of this entity is clinically important, as drug-induced MG is potentially reversible with timely withdrawal of the offending agent and supportive therapy.^1,2 We present a case of DPA–induced ocular myasthenia gravis in a young female with Wilson’s disease, highlighting the diagnostic clues, electrophysiological and serological confirmation, and favorable outcome following drug cessation.

CASE REPORT

A 27-year-old female presented with complaints of fluctuating drooping of eyelids and intermittent double vision, more marked towards the end of the day or after sustained activity for 7 months. There were no complaints of limb weakness, respiratory distress, tremors, dysphagia, drooling, imbalance while walking, or behavioral changes. She was diagnosed with the hepatic form of Wilson's disease and initiated on D-Penicillamine therapy for 2 years.

DISCUSSION

DPA–induced MG is a well-described but frequently underrecognized adverse effect, particularly in patients treated for Wilson’s disease.^1,2 Unlike idiopathic MG, which is commonly associated with thymic pathology and may present with generalized weakness, drug-induced MG typically demonstrates a predominantly ocular phenotype, minimal systemic involvement, and a favorable prognosis following withdrawal of the offending agent.^2,4

The pathophysiological mechanism of DPA–induced MG remains incompletely understood. Proposed mechanisms include drug-mediated alteration of major histocompatibility complex (MHC) molecules and modification of antigenic peptides on antigen-presenting cells, leading to breakdown of immune tolerance and autoantibody formation against acetylcholine receptors [Figure 1].^2-4

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Figure 1 A-C: Pathogenic mechanisms of acetylcholine receptor (AChR) antibodies in Myasthenia Gravis (MG) at the neuromuscular junction (NMJ) (MAC: Membrane activation complex)

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The frequent presence of acetylcholine receptor antibodies, as seen in our patient, supports an immune-mediated process rather than a purely pharmacologic neuromuscular blockade.^3,4

An important diagnostic challenge is the variable latency period between drug initiation and symptom onset. While most cases develop within the first year of therapy, delayed presentations—ranging from several months to many years—have been reported, particularly in Wilson’s disease [Figure 2].^1,2

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Figure 2: Causes of aggravation of neurological symptoms or onset of de novo neurological symptoms in Wilson’s Disease (WD) patients during D-penicillamine (DPA) treatment (WD: Wilson’s disease; ADRs: Adverse drug reactions; MG: Myasthenia gravis)

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This prolonged exposure may contribute to diagnostic delay, with symptoms often misattributed to hepatic encephalopathy, metabolic derangements, or functional disorders. In our case, the onset of ocular symptoms nearly two years after initiation of DPA highlights the need for continued vigilance throughout therapy. Electrophysiological studies and serological testing play a critical role in establishing the diagnosis. The demonstration of a decremental response on repetitive nerve stimulation and elevated acetylcholine receptor antibody titers, coupled with the absence of thymic pathology, supports the diagnosis of drug-induced MG rather than coincidental idiopathic disease.^2,3 The absence of MuSK antibodies further aligns with the predominantly ocular presentation and favorable clinical course.³

Management of DPA–induced MG differs fundamentally from idiopathic MG. Immediate withdrawal of the causative drug is the cornerstone of therapy, often leading to partial or complete remission.^1,2,4 Most patients respond well to acetylcholinesterase inhibitors alone, and immunosuppressive therapy is rarely required.^1,2 The rapid and sustained resolution of symptoms in our patient following DPA cessation reinforces the reversible nature of this condition when promptly recognized.

This case underscores the importance of medication review in patients presenting with neuromuscular junction disorders, particularly in those receiving long-term chelation therapy.

Early recognition of drug-induced MG prevents unnecessary investigations, avoids prolonged immunosuppression, and allows timely modification of therapy for Wilson’s disease with excellent neurological outcomes.^1,2

CONCLUSION

DPA–induced myasthenia gravis is an important, potentially reversible cause of ocular myasthenia in patients receiving long-term chelation therapy for Wilson’s disease. A high index of suspicion is required, as symptom onset may be delayed and presentations are often limited to ocular involvement. Recognition of the temporal drug association, supported by electrophysiological and serological findings, allows prompt withdrawal of the offending agent and leads to excellent clinical outcomes. This case emphasizes the need for routine medication review in neuromuscular presentations and highlights that early identification of drug-induced myasthenia gravis can prevent unnecessary immunosuppression and long-term morbidity.