The patient was given a trial of pyridostigmine that had no effect and was then prescribed 20 mg prednisone daily. Four months after the initial prescription, he had 3 mm of right ptosis. Abduction of the right eye and depression of the left eye had greater range. The left hypertropia had decreased from 18 to 6 PD in primary position, and in downgaze, his left hypertropia had decreased to 5 PD.
Two assays for acetylcholine receptor antibodies were negative. Single-fiber electromyography of the right and left frontalis muscles was performed on 2 separate occasions and was normal. Repetitive stimulation of the left facial nerve at 3 Hz did not show any decrement of the compound muscle action potential. A CT of his chest and MRI of the brain were unremarkable.
One month later, prednisone was stopped because of confusion and depression. Four months after stopping steroid therapy, examination showed 4 mm of right ptosis; diminished abduction of the right eye; and limited adduction, abduction, and depression of the left eye. The left hypertropia now measured 20 PD in primary position.
A biopsy of the left vastus lateralis was performed. Ragged red fibers were noted with modified Gomori trichrome stain, and ragged blue fibers in the nicotinamide adenine dinucleotide hydrogen (NADH) and succinic acid dehydrogenase (SDH) stains. Many cytochrome oxidase-negative muscle fibers were identified (Fig. 3). There was no evidence of inflammation. Electron microscopy showed subsarcolemmal accumulations of mitochondria with focal subsarcolemmal splitting; mitochondria displayed considerable pleomorphism and most contained rectangular crystalline inclusions. Mitochondrial DNA analysis was negative for deletions or point mutations of MELAS 3243, 3271 or MERFF 8344, and nuclear DNA analysis was negative for POLG and Twinkle mutations. Free and total carnitine levels were very low, at 3 and 4 μmol/L, respectively, and he was started on carnitine supplementation. Electrocardiogram was normal.
On 3 examinations over the subsequent 2 years, his right ptosis varied slightly from 3 to 5 mm and he remained with a 16-20 diopter left hypertropia in primary position, with exotropia varying from 0 to 18 PD in right gaze. He had occasional complaints of right leg weakness but no clear evidence of paresis in his limbs.
Our patient presented with weakness of the levator palpebrae superioris and lateral rectus muscle of the right eye and of the medial rectus, inferior rectus, and orbicularis oculi of the left eye. Prednisone improved his ptosis by history, and examination confirmed better abduction of the right eye and depression of the left eye during treatment, which deteriorated again when prednisone was stopped. Subsequent examinations also showed variability of right ptosis and extraocular movement, notably his exotropia in right gaze.
The patient we describe did not have myopathic features on electromyography but then neither do a third of patients with mitochondrial myopathy (1). He did not have mitochondrial DNA deletions but not all cases of CPEO do: some can have point mutations (8,9) and sometimes with overlapping features of other mitochondrial syndromes, such as MELAS or MERRF (10-12). Our patient's complex partial seizures differed from the epilepsies of these classic mitochondrial syndromes, but mitochondrial dysfunction may be a contributing factor in some cases of temporal lobe epilepsy (13). Regardless, his muscle biopsy showed clear features of a mitochondrial myopathy, and his metabolic assays revealed a carnitine deficiency, a secondary phenomenon in some mitochondrial myopathies (1,14,15) but not in myasthenia.
Response to prednisone is typical of inflammatory or autoimmune muscle disorders, including myasthenia gravis. However, in other disorders, such as Duchenne muscular dystrophy, prednisone can also improve muscle function (16). The effect of steroids in mitochondrial myopathies is less clear. In vitro studies have suggested possible beneficial effects of methylprednisolone on mitochondrial function (17). Anecdotal reports suggest that steroids improve weakness in some patients with mitochondrial myopathy (14,18,19) but not others (2,3,20). In addition, there are descriptions of mitochondrial damage and CPEO-like signs evolving in patients on chronic steroid therapy (21). Whether our patient truly improved on prednisone can be questioned as some of his signs fluctuated without treatment. However, his left hypertropia was a relatively stable deficit that did show a documented decrease during the time he was taking prednisone and deterioration after he stopped.
Clinically, a steroid-responsive pattern of highly asymmetric lid with facial and ocular motor weakness with variable signs between examinations strongly suggests myasthenia gravis. Negative results of antibody testing and electrophysiology should not dissuade one from the diagnosis, given the high rate of false-negative results when myasthenia is purely ocular (22,23). Our case illustrates the potential of mitochondrial myopathy to simulate features of myasthenia, including marked asymmetry, variability, apparent response to steroid therapy, and lack of myopathic signs on electromyography.
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