From the Ophthalmology Department, Cheltenham General Hospital, Cheltenham, United Kingdom.
Address correspondence to Michael S. Wertheim, MRCOphth, Ophthalmology Department, Cheltenham General Hospital, Sandford Road, Cheltenham, GL53 7AN, United Kingdom.
We describe a child who presented with bilateral sixth nerve palsies before the development of ataxia. A diagnosis of Miller–Fisher syndrome was made. Miller–Fisher syndrome is a rare condition that may present to an ophthalmology department and should therefore be considered in the differential diagnosis of any ophthalmoplegia in childhood. The presence of bilateral sixth nerve palsies in children is unusual and the diagnosis of Miller–Fisher syndrome should only be sought after having excluded more serious conditions, including trauma, cerebrovascular disease, neoplasia, demyelination, meningitis, and encephalitis.
A 5-year-old boy presented to our eye department with a 1-day history of sudden onset of horizontal diplopia. The presenting complaint included a 10-day history of nausea and vomiting associated with a fever. He complained of abdominal pain and lethargy. Ophthalmic examination showed the presence of bilateral sixth nerve palsies (Figure) with the absence of papilledema. The rest of his eye examination was normal. The patient was admitted to the pediatric ward for further investigation.
Figure. The patient in the primary position of gaze. This photograph was taken 1 week after his second infusion of intravenous immunoglobulin. The left abducens nerve palsy has started to resolve.
Further neurological examination revealed that he had areflexia of both lower limbs, and over the next 2 days progressively worsening ataxia was noted. Magnetic resonance imaging of his brain was normal with no white matter lesions or evidence of demyelination. Electroencephalogram showed a slightly slowed background pattern compatible with a mild encephalopathy. A lumbar puncture (with normal opening pressure) showed 133 white cells (> 90% lymphocytes), no red cells, and a glucose level of 4.2 mmol/L. His cerebrospinal fluid protein level was raised at 1.14 g/L (normal range: 0.15 to 0.40 g/L) and the cerebrospinal fluid lactate and blood lactose levels were both normal. There was no evidence of oligoclonal bands in his cerebrospinal fluid. All investigations for possible infectious causes of encephalitis were negative. A preliminary diagnosis of Miller–Fisher syndrome was reached and the patient was administered intravenous immunoglobulin at 1 g/kg for 2 days. The diagnosis was confirmed when his ganglioside antibody GQ1b was positive with a titre of 1:200. The patient made a full neurological recovery.
Miller–Fisher syndrome was first described in 1956 as a polyneuropathy characterized by limb ataxia, areflexia, and ophthalmoplegia. It is regarded as a localized variant of Guillain–Barré syndrome, which classically causes an ascending flaccid paralysis without brainstem involvement or ophthalmoplegia. Miller–Fisher syndrome also shares many features with Bickerstaff’s brainstem encephalitis, in which a reduced level of consciousness or long tract signs accompany ophthalmoplegia and ataxia.
The incidence of Miller–Fisher syndrome in children has not been published. The incidence of Guillain–Barré syndrome in children has been reported as 1 in 100,000.1 The incidence of Miller–Fisher syndrome as a proportion of Guillain–Barré syndrome has been reported as 6% in a European study,2 suggesting an overall incidence of less than one in a million. Although the incidence of Guillain–Barré syndrome around the world is reported fairly consistently, the incidence of Miller–Fisher syndrome as a proportion of Guillain–Barré syndrome has been reported as up to 25% in Japan,3 suggesting regional variation in the incidence of Miller–Fisher syndrome.
The classic presentation of Miller–Fisher syndrome is an acute onset of ophthalmoplegia, ataxia, and areflexia, often following a respiratory or gastrointestinal infection. Miller–Fisher syndrome may present in a more limited form or with clinical features overlapping with the related conditions of Guillain–Barré syndrome or Bickerstaff’s brainstem encephalitis. The main supportive laboratory findings in Miller–Fisher syndrome are an elevated cerebrospinal protein level and high titres of the anti-GQ1b antibody. Cerebrospinal protein elevation has been reported in 59% of Miller–Fisher syndrome cases during the first 3 weeks of the illness.4 However, during the first week of the illness, elevated cerebrospinal protein was present in only 25% of cases, rising to 84% in subsequent weeks. In the same study, high anti-GQ1b antibody titres were present in 81% during the first week of the illness.4 Elsewhere, the sensitivity of anti-GQ1b has been reported as greater than 90%.5 The implication is that anti-GQ1b is a more sensitive investigation in the acute phase of the illness.
In common with Guillain–Barré syndrome and Bickerstaff’s brainstem encephalitis, Miller–Fisher syndrome is typically preceded by a respiratory or gastrointestinal infection. Positive serology for Haemophilus influenzae or Campylobacter jejuni has been identified in 20% of Miller–Fisher syndrome cases.6 Many other bacterial and viral infections have been implicated as antecedents to Miller–Fisher syndrome and Guillain–Barré syndrome. The presence of a preceding illness is central to current pathogenic hypotheses in Miller–Fisher syndrome. It is suggested that molecular mimicry or cross reactivity links the ganglioside GQ1b and the bacterial lipopolysaccharides of C. jejuni.7 A growing body of evidence suggests that anti-GQ1b antibodies block neuromuscular transmission8 and the levels of GQ1b ganglioside are found to be higher in the third, fourth, and sixth cranial nerves compared to unaffected nerves.8 It is therefore hypothesized that the preceding infection triggers an immunological mechanism that interferes with neuromuscular transmission at specific sites.
The typical course of Miller–Fisher syndrome is benign and prognosis for a full neurological recovery is good. In one series of 50 patients with Miller–Fisher syndrome, all had returned to normal activity and were almost free of ataxia at 6 months.3 This series included 28 patients who received only conservative management. Recovery of ophthalmoplegia was reported to occur at a median of 88 days (range: 29 to 165 days). The support for use of immunomodulatory treatments, such as intravenous immunoglobulin or plasma exchange, is largely extrapolated from trials of Guillain–Barré syndrome.9 Plasma exchange in Miller–Fisher syndrome has been reported to confer no benefits when compared to those who receive no immunomodulatory therapy,9 whereas the use of intravenous immunoglobulin is only demonstrated in case reports.10 We elected to treat this case with intravenous immunoglobulin and a rapid recovery of clinical features was noted within 2 days.
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