Differential diagnosis in ptosis and ophthalmoplegia: mitochondrial disease or myasthenia?

Abstract

Sirs: One of the commonest phenotypes of mitochondrial disease is generalised fatigue with ptosis and a chronic progressive external ophthalmoplegia. The main differential diagnosis in these patients is with myasthenia gravis (MG). Ocular symptoms are the most common presentation of MG [1] and in up to 48% of patients are the only clinical manifestation [2]. Correct diagnosis is vital both to provide the best treatments and to avoid side effects from inappropriate ones [3]. We reviewed the records of 430 patients with proven mitochondrial disease on the basis of muscle histochemistry or mitochondrial DNA analysis to determine how many had originally been diagnosed with MG. Eighty-one of our patients had first presented with ptosis or ophthalmoplegia. Of these, a relatively small number, 15, had been investigated for possible MG as part of their diagnostic workup, and 5 (6.2%) had been given a primary diagnosis of MG. Table 1 shows the extra-ocular clinical features of the patients both at the time of diagnosis with MG and at subsequent diagnosis with mitochondrial disease. The average time between the initial diagnosis of MG and the subsequent diagnosis of mitochondrial disease was 3.6 years (range 1–9). Three of these patients had a single largescale deletion of mitochondrial DNA, and in two multiple deletions of the mitochondrial genome were found. All of the five patients initially diagnosed with MG had negative anti-acetylcholine receptor antibodies Table 2. Three patients were reported as having had a positive response to tensilon, although in one patient a repeat test was negative. Only three patients had undergone the more sensitive test of single fibre electromyography of orbicularis oculi. In one patient the initial result was reported as being consistent with myasthenia gravis on the basis of increased jitter (but with no blocking); this was subsequently repeated and reported as normal. All five patients had been treated with oral anticholinesterases. In one, an initial but shortlived symptomatic improvement was recorded. Three patients had received prolonged courses of oral steroids because of poor response to anticholinesterase treatment and one patient had undergone thymectomy. The differential diagnosis between mitochondrial disease presenting as ptosis and external ophthalmoplegia and myasthenia gravis can be difficult. The presenting clinical features of all the patients were entirely compatible with MG. Indeed, the majority reported variability in symptoms, often regarded as a hallmark of MG. Even those symptoms, which became apparent years later, such as proximal weakness and dysphagia, are common in MG. The investigations performed were similarly ambiguous; although all patients had negative anti-acetylcholine receptor antibodies, these are negative in up to 50% of ocular MG. Three had a positive tensilon test and one a suggestive single fibre EMG. Whilst all of these were probably false positives, an intriguing possibility is that these patients had disturbed neuromuscular transmission as a direct result of their mitochondrial disease. Blocking mitochondrial function in vitro leads to reduced phasic acetyl choline vesicle release [4] and changes in neuromuscular transmission similar to antibody mediated MG. Families with proven mitochondrial disease show minor but definite abnormalities on single fibre electromyography [5–7]. There are also anecdotal reports of symptomatic improvement in patients with mitochondrial disease given anticholinesterases [8], including one patient in this study. Although these drugs are as likely as any other to produce a placebo effect, these remain interesting observations. Our study emphasises the need to consider mitochondrial disease in the differential diagnosis of ocular MG, especially in those patients in whom symptoms do not respond well to treatment. R. G. Whittaker (&) AE A. M. Schaefer R. W. Taylor AE D. M. Turnbull Mitochondrial Research Group School of Neurology Neurobiology and Psychiatry University of Newcastle upon Tyne Newcastle upon Tyne NE2 4HH, UK Tel.: +1-91-2228334 Fax: +1-91-2228553 E-Mail: r.whittaker@ncl.ac.uk LETTER TO THE EDITORS J Neurol (2007) 254:1138– 1139 DOI 10.1007/s00415-006-0484-5