Miller-Fisher Syndrome in Association With Enterovirus Infection

Case Report

A 10-year-old boy was admitted to the pediatric department with a 24-hour history of headache, dizziness, and transient dysarthria. He also mentioned that he had diplopia 12 hours earlier, which lasted for about 1 hour. From the recent history he had gastroenteritis 7 days prior to the admission, which lasted 2 days. He had not taken any medications at that time. He was fully vaccinated for his age. There was no history of head injury.

On examination, he was alert and afebrile, with normal respiratory rate, blood pressure, and oxygen saturation. His left pupil was dilated with normal fundoscopy. A few hours after admission, he developed blepharoptosis of the left side, diplopia, and ataxic gait, whereas the deep tendon reflexes of the lower extremities were not elicited. The initial investigations showed the following results: hemoglobin 13.4 g/dL, hematocrit 38.5%, platelets 256 000/μL, leucocytes 8250/μL, neutrophils 48%, lymphocytes 44%, monocytes 8%, C-reactive protein 1 mg/L, glucose 98 mg/dL, blood urea nitrogen (BUN) 34 mg/dL, creatinine 0.4 mg/dL, aspartate transaminase 47 U/L, alanine aminotransferase 28 U/L, γ-glutamyl transferase 7 U/L, alkaline phosphatase 249 U/L, sodium 144 mmol/L, and potassium 4 mmol/L. A lumbar puncture yielded sterile cerebrospinal fluid with no cells and normal protein (14 mg/dL) and glucose concentrations (61 mg/dL). Polymerase chain reaction of cerebrospinal fluid for herpesvirus 1, herpesvirus 2, Toxoplasma, Bartonella, Borrelia, and Mycoplasma was negative. However, polymerase chain reaction of cerebrospinal fluid for enteroviruses (polioviruses, coxsackieviruses A and B, and echoviruses) was positive. Furthermore, polymerase chain reaction of cerebrospinal fluid and blood for common bacteria (Haemophilus influenza, pneumococcus, meningococcus, Listeria) was negative. Polymerase chain reaction of a throat specimen for Mycoplasma pneumoniae was also negative. No enteric pathogen, including Campylobacter jejuni, was isolated from the stool analysis, and polymerase chain reaction of stools for enteroviruses was negative. Magnetic resonance imaging (MRI) of brain and cavernous sinuses as well as magnetic resonance angiogram were normal. Chest radiograph was also normal. Electromyography and nerve conduction studies of upper and lower extremities were within normal limits. With the clinical suspicion of Miller-Fisher syndrome (external ophthalmoplegia, ataxia, loss of tendon reflexes), serum antibodies against gangliosides were also tested at Great Britain. The antibodies anti-GQ1B were positive (titer 1/1600), whereas the anti-GM1 antibodies were negative.

The patient was initially put on ceftriaxone intravenously, which was stopped the third day when the results of polymerase chain reaction of cerebrospinal fluid and blood for common bacteria became available. The second and the third day of admission, intravenous immunoglobulin was administered at a dose of 1 g/kg per day, with the clinical suspicion of Miller-Fisher syndrome. The patient was discharged home on day 12, remaining areflexic in lower extremities, but without signs of ophthalmoplegia and ataxia.

On follow-up 4 months later, the patient was fine and the tendon reflexes of lower limbs were normally elicited.

Discussion

Miller-Fisher syndrome has been mainly associated with preceding C jejuni infection. ⁵ However, other infectious agents ^6,7 such as bacteria (Haemophilus influenzae, Streptococcus pyogenes, M pneumoniae, Chlamydia pneumoniae, Salmonella enteritis, Escherichia coli) and viruses (Epstein-Barr virus, cytomegalovirus, varicella virus, and mumps virus) have also been implicated. To the best of our knowledge, this is the first report of a typical Miller-Fisher syndrome in a child with Enterovirus infection. However, isolated acute ophthalmoparesis associated with anti-GM1, anti-GD1a, and anti-GD1b antibodies, after Enterovirus infection, was previously described in a 6-year-old girl. ⁸ Actually, that patient ⁹ might be considered, according to the authors, as having had an atypical form of Miller-Fisher syndrome without ataxia and areflexia. It should be also mentioned that enterovirus 71, which causes epidemics of hand–foot and mouth disease in young children, can induce Guillain-Barré syndrome. ⁹

In our case, Enterovirus was isolated from cerebrospinal fluid. Although the isolation of the virus from the cerebrospinal fluid is equivalent with neuroinfection, the clinical course of our patient indicates immunopathology as the major factor of the disease pathogenesis, taking into consideration that the brain magnetic resonance was normal, with no signs of virus-induced damage. On the contrary, the patient had positive antiganglioside antibodies, which are present in the majority of Miller-Fisher cases. It was shown that the production of antiganglioside antibodies was mediated by a GQ1b epitope of the lipopolysaccharide fractions from the Campylobacter, ⁶ in the cases where the preceding infection was attributed to C jejuni. We assume a similar molecular mimicry between Enterovirus and the nerve tissue, although this possibility has not been substantiated by any experimental studies.

Cerebrospinal fluid albuminocytological dissociation was not found in our patient, but this finding is not considered necessary for the documentation of the Miller-Fisher syndrome diagnosis. Such a dissociation was observed in 66 of 110 adults with Miller-Fisher syndrome described by Odaka et al. ³

Miller-Fisher syndrome seems to be a self-limiting condition. ⁶ However, intravenous immunoglobulin has been used, ⁶ mainly from extrapolation of data from studies in Guillain-Barré. We also followed this therapeutic approach, and the patient had a remarkable improvement.

In conclusion, the possibility of a preceding enteroviral infection should be carefully investigated in cases presenting with the classic triad of Miller-Fisher syndrome, as enteroviruses could be a trigger for the development of this syndrome.