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Statin-Associated Myasthenia Gravis

Report of 4 Cases and Review of the Literature

Purvin, Valerie MD; Kawasaki, Aki MD; Smith, Kyle H. MD; Kesler, Anat MD

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doi: 10.1097/
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Over the past few years an increasing number of studies have demonstrated that inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, termed statins, are effective in lowering levels of total cholesterol and LDL-cholesterol27 and are also associated with a reduction in the incidence of both coronary heart disease30 and cerebrovascular disease3. As a result of this strong evidence of therapeutic benefit, there has been a tremendous increase in the number of these agents prescribed since their initial release in 1987. Because hypercholesterolemia and atherogenesis are chronic conditions, lifelong treatment is generally required. It is thus important that statins demonstrate a positive safety profile. Clinical trials have demonstrated that statins are generally well tolerated, with an adverse event profile that includes a variety of gastrointestinal side effects and elevated transaminase levels in some individuals. The most serious adverse reaction is myotoxicity, with a reported incidence of 1%-7%1. Recently, authors of a few individual case reports8,23,24 have suggested that a myasthenic syndrome may be associated with statin medications, but this association is not well documented. We describe 4 patients who developed symptoms of myasthenia gravis shortly after initiation of statin treatment.


Case 1

This 55-year-old man with hypertension, idiopathic membranous nephropathy, and hyperlipidemia developed fluctuating ptosis and vertical diplopia 1 week after starting rosuvastatin. Two weeks later he also developed weakness with chewing and mild dysphagia. Examination 3 months after onset showed left upper lid ptosis with marked variability and fatigability. There was moderate limitation of supraduction of the right eye and markedly reduced adduction of the left eye with a 25-diopter exotropia in primary position. An edrophonium chloride test was positive, acetylcholine receptor (AChR) binding antibodies were mildly elevated at 0.06 nmol/L (normal < 0.02 nmol/L) and a single fiber electromyogram (EMG) showed increased jitter. A computed tomographic (CT) scan was negative for thymoma. The statin was discontinued 2 weeks later. Treatment with pyridostigmine improved his ptosis but not his ophthalmoplegia. Five months after onset (6 weeks after stopping the statin) he was started on prednisone. After 3 months of prednisone therapy, examination showed completely normal ocular motility and lid function. His prednisone dose was slowly tapered and he continued to do well. Fourteen months after onset he remained asymptomatic on 5 mg of prednisone on alternate days. One year after onset, AChR antibodies were found to be normal.

Case 2

A 70-year-old man with hyperlipidemia and coronary artery disease developed persistent though variable vertical diplopia and difficulty pursing his lips (fatigue with whistling) 1 week after starting rosuvastatin. Examination 3 months later revealed 2-diopter right hypertropia that increased to 6 diopters on right gaze with mild underaction of the right inferior rectus muscle. A magnetic resonance imaging (MRI) scan of the head, thyroid function tests, and erythrocyte sedimentation rate were normal. AChR binding antibodies were elevated at 7.86 nmol/L (normal < 0.02 nmol/L) and a CT scan of the chest was normal. Four months after onset of symptoms the statin was discontinued and he was treated with pyridostigmine. After 7 months of treatment he remained only mildly symptomatic and AChR antibodies remained elevated. There was only a flick right hyperphoria in primary position that increased to 4 diopters on right gaze with no ductional deficit. AChR antibodies were repeated and again found to be elevated at 18.0 nmol/L (normal < 0.1 nmol/L).

Case 3

This 71-year-old hypertensive man developed bilateral ptosis and hoarseness 2 weeks after starting simvastatin. His symptoms improved each morning upon awakening and worsened later in the day. Examination 1 year later showed bilateral ptosis worse on the left with a positive Cogan lid twitch sign and bilateral orbicularis weakness. A single fiber EMG showed increased jitter, AChR antibodies were negative, and creatine kinase levels were normal. He noted improvement in symptoms within 2 weeks of stopping the statin, and was almost completely asymptomatic within 2 months. Examination showed good levator and orbicularis function and normal ocular alignment and rotations. A subsequent rechallenge with pravastatin led to a recurrence of his myasthenic symptoms.

Case 4

This 56-year-old woman developed myasthenia in 1978 manifest as variable ptosis and diplopia. She had a positive edrophonium chloride test and was treated with pyridostigmine with good response. Three years later she was able to discontinue treatment. She remained asymptomatic until 2003, when she experienced recurrence of these symptoms associated with mild weakness of the legs and neck 1 week after beginning pravastatin. AChR binding antibodies were elevated at 17.5 nmol/L (normal < 0.4 nmol/L). A CT scan of the chest revealed no evidence of thymoma. The pravastatin was discontinued after only 2 weeks of treatment. After the patient was started on Mestinon and intravenous immunoglobulin, the symptoms improved but did not completely resolve. Approximately 3 months later she developed Hashimoto thyroiditis and fulminant thyroid-related orbitopathy that was treated with corticosteroids and orbital decompression. She was tapered off the prednisone after 14 months, and shortly thereafter experienced a recurrence of the myasthenic symptoms.


A few cases of myasthenic weakness associated with the use of statins have been reported previously8,23,24. Parmar and associates24 described a 67-year-old woman who developed generalized and ocular weakness within 3 months of starting atorvastatin. Discontinuation of treatment brought improvement but symptoms recurred within 2 to 3 months of starting 3 different statin medications. Examination showed "strikingly fatigable myogenic ptosis"and variable horizontal and vertical strabismus. Repetitive stimulation and edrophonium chloride testing were apparently not performed and AChR antibodies were not detected. The authors' classification of this case as myasthenia has been challenged based on the absence of supportive evidence10.

Cartwright et al8 reported a 55-year-old man who developed dysarthria 1 week after beginning treatment with atorvastatin. His dysarthria spontaneously resolved 1 week after stopping the medication, but rechallenge with 3 other statin drugs over the next 8 months caused the same symptom. He subsequently experienced recurrent dysarthria 3 months after being off all statins, at which time repetitive stimulation testing was positive, AChR antibodies were elevated, and he demonstrated a positive response to pyridostigmine. The authors concluded that the statin precipitated symptomatic exacerbation of underlying subclinical myasthenia, although the patient did not have a history of preexisting myasthenic symptoms.

In addition, Negevesky et al23 described a 60-year-old woman who developed external ophthalmoplegia 2 months after beginning treatment with atorvastatin. Additional neurologic deficits included vertigo, ataxia, and paresthesias. An edrophonium chloride test was negative and EMG with repetitive stimulation was normal, but AChR antibodies were elevated. The clinical findings improved within 2 days of discontinuing the statin and by 10 weeks later her neurologic deficits and antibody levels had returned to normal. The authors did not designate the case as myasthenia but the ophthalmoplegia and presence of AChR antibodies were suggestive of the disorder. The clinical findings in our 4 patients lend further support for an association between statin use and myasthenic weakness.

Based on a review of our 4 patients and 2 of the previously reported patients, a clinical picture of statin-associated myasthenia emerges, although with some variability (Table 1). (We excluded the patient reported by Negevesky et al23, who had other nonmyasthenic neurologic symptoms.) All 6 patients developed the generalized form of myasthenia. AChR antibodies were present in 4 of the 6 patients. This number is comparable to the prevalence of such antibodies in spontaneous myasthenia gravis, in which 80%-90% of patients are antibody positive22,31. Five of 6 patients noted onset of myasthenic symptoms within 2 weeks of initiating statin treatment (1 week in 4 patients, 2 weeks in 1). The sixth patient had symptom onset 3 months after statin initiation.

Characteristics of 6 Patients With Statin-Associated Myasthenia Gravis

Some degree of recovery after discontinuing medication occurred in 5 patients. Recovery was complete in 1 patient (reference 24), substantial in 1 (Case 2), and partial in 2 (Cases 3 and 4). The 1 patient who did not exhibit recovery (Case 1) was started on corticosteroids 6 weeks after stopping the statin, and it is possible that he might have shown spontaneous clinical improvement had treatment been withheld for a longer period. Three patients (Cases 3 and 4 and reference 8) to date have experienced a recurrence that was not precipitated by rechallenge with a statin.

The variability in the clinical picture of these patients could be in part due to differences in the underlying mechanism responsible for muscle weakness associated with statin use. One possible mechanism is a primary statin myotoxicity that exacerbates weakness in a patient who has underlying myasthenia gravis; the second possible mechanism is a true statin-induced, antibody-mediated myasthenia. Below we review the evidence for each of the 2 possible mechanisms in further detail.

Muscle toxicity constitutes the most common adverse reaction to the use of statins11,12,16. Symptoms range from mild cases with myalgias but no objective abnormalities to those with severe rhabdomyolysis leading to renal failure and occasionally death19. In the case of cerivastatin, this complication was sufficiently severe to warrant withdrawal of the drug from the market5. The mechanism is not entirely clear and may be multifactorial22. In addition to changes in muscle membrane composition and/or function, there is increasing evidence that statins cause mitochondrial dysfunction11. Particular interest has focused on possible depletion of coenzyme Q, which is used by mitochondria for normal cellular respiration21. Results of muscle biopsy in patients with statin myopathy have shown mitochondrial dysfunction26, and muscle symptoms in some individuals have been improved by coenzyme Q supplementation9. Muscle biopsy has not revealed evidence of inflammatory infiltration17. Whatever the precise mechanism, it is possible that statin myotoxicity could exacerbate weakness in a patient with underlying myasthenia.

Alternatively, statins might cause myasthenia by inducing antibodies directed at the neuromuscular junction. There have been several reports of patients who developed other autoimmune disorders while taking statins for varying periods of time28. These hypersensitivity reactions have included lupus-like syndromes1,4,28, angioedema13, vasculitis28, polymyalgia rheumatica28, hypereosinophilic syndrome28, and dermatomyositis20,29. The Compendium of Pharmaceuticals and Specialties15 includes a "hypersensitivity syndrome" associated with the use of HMG-CoA reductase inhibitors, and the manufacturers of these medications list such complications in their product monographs and adverse drug reaction surveillance data28. These complications have been considered rare. Rudski et al28 have pointed out that autoantibody formation tends to increase with age and that major trials investigating the efficacy and safety of these drugs have been limited to patients younger than 75 years old. As these agents are used more in elderly individuals, such complications may occur more frequently. In our patients 1-3, who did not have a preexisting history of neuromuscular disease, it is possible that the statins induced de novo formation of antibodies directed at the neuromuscular junction, thus causing myasthenia.

There is precedent for drug-induced antibodies causing a clinical disorder of the neuromuscular junction, most notably in the case of penicillamine-induced myasthenia. The evidence that penicillamine induces the production of AChR antibodies is strong32. Such antibodies have been found in 90% of patients with penicillamine-induced myasthenia14. Furthermore, 70% of these patients experience spontaneous resolution within the first year of discontinuing penicillamine therapy compared with only 8% of patients with idiopathic myasthenia gravis2. This spontaneous improvement includes resolution of signs and symptoms, reduction of AChR antibody levels, and reversal of electrophysiologic abnormalities18. Nearly all patients with penicillamine-induced myasthenia gravis do not require long-term anticholinesterase or corticosteroid therapy, in contrast to most patients with the idiopathic form of the disease32. A similar capacity to induce AChR antibody formation has been attributed to phenytoin sodium7 and trimethadione6,25 but with fewer reported cases. The causal relationship for these medications has been deemed "probable" rather than "definite"32.

The actual incidence of statin-related myasthenia is unknown. In some previous cases of presumed statin-induced autoimmune disease, the interval between starting the drug and onset of symptoms was considerably longer, ranging from 6 months to 6 years28. In these cases the compelling evidence for a causal association was the improvement or resolution of clinical manifestations that occurred after cessation of the medication. There may be more cases of myasthenia either induced or aggravated by statins that could only be identified by stopping the suspect medication. While we would not consider the use of statins to be contraindicated in patients with known myasthenia, we would recommend that these patients be closely observed for possible worsening of their neuromuscular function after initiating treatment.

In summary, we have identified 4 patients in whom myasthenic symptoms developed within 1-2 weeks of starting therapy with some form of statin medication. In 1 patient the drug appears to have exacerbated underlying myasthenia, whereas in the 3 other patients de novo antibody formation due to statin treatment seems to be the most likely mechanism. Recovery, either partial or complete, typically occurs following discontinuation of the responsible medication. Unfortunately, patients who exhibit this myasthenic response to 1 statin may have the same response to other drugs in this family. Recommendations for managing these patients must be individualized, taking into consideration the potential risks and benefits of treatment.


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