External and internal ophthalmoplegia, facial diplegia, ataxia and exaggerated deep tendon reflexes associated with anti-GQ1b antibodies: a new variant of acute ophthalmoparesis

Ian Morrison, Saif S.M. Razvi, Richard A. Metcalfe and Rod Duncan
Department of Neurology
Institute of Neurological Sciences
Southern General Hospital
1345 Govan Road
Glasgow G51 4TF
United Kingdom

Address for correspondence:
Ian Morrison
Department of Neurology
Institute of Neurological Sciences
Southern General Hospital
1345 Govan Road
Glasgow G51 4TF
United Kingdom
Phone: 0044 141 2012494
Fax: 0044 141 2012510
Email: ian_m@doctors.org.uk


Abstract

We present the case report of a patient with antibodies to ganglioside GQ1b, who presented with pupillary areflexia, external ophthalmoplegia, ataxia, brisk deep tendon reflexes and facial muscle diplegia following a viral illness. The patient was diagnosed with acute ophthalmoparesis, which is a rare variant of Miller Fisher syndrome that has been characterised recently. We describe a unique presentation of this rare condition, and consider the range of presentations that can occur in association with antibodies to the GQ1b ganglioside.

Keywords: Miller Fisher syndrome, acute ophthalmoparesis, facial paresis, internal ophthalmoplegia, GQ1b antibody

 

A 29-year old previously well male farmer developed horizontal diplopia on wakening in the morning. The diplopia was static and accompanied by mild unsteadiness. Prior medical history included an upper respiratory tract illness two weeks previously. The patient denied recreational drug misuse. He smoked twenty cigarettes a day and drank 16 units of alcohol a week. There was no history of rash, tick bites or exposure to pesticides.

On assessment, he was alert and oriented. He had bilateral sixth nerve palsies with bilateral dilated pupils (10 millimetre and equal), which were non-reactive to light and accommodation. Visual acuity, colour vision and discs were normal. Examination of arms and legs demonstrated normal tone and power with symmetrical exaggerated deep tendon reflexes and flexor plantar responses. There was subtle in-coordination and gait ataxia. Sensory examination was normal.

Figure 1:
Bilateral failure of abduction of eyes accompanied by dilated areflexic pupils on looking to left (A) and right (B)


Blood tests including erythrocyte sedimentation rate, C-reactive protein and thyroid function were normal. Serum protein electrophoresis, complement levels, Borrelia burgdorferi serology, Campylobacter serology, anti-acetylcholine receptor antibody titres, anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were normal. Computed tomographic and magnetic resonance imaging (with Gadolinium) of brain was normal. Cerebrospinal fluid (CSF) analysis demonstrated normal cell counts (< 5 white cells and < 5 red cells per cubic millimetre), CSF protein 0.23 gram per litre and CSF glucose 4.3 millimol per litre (serum glucose 8.3 millimol per litre). CSF virology was negative for Enterovirus, Herpes simplex, Varicella, Human Herpes Virus 6 and 7, Cytomegalovirus, Epstein-Barr virus and Mumps. CSF Treponemal serology was negative. Limb nerve conduction, sensory potentials, and electromyographic studies performed on fourth day after symptom onset were normal.

The patient then developed bilateral third and fourth nerve palsies. At this stage, serological examination revealed positive anti-glycolipid IgG antibody titre to GQ1b (1/1600, normal range <1/500) while other anti-ganglioside antibody titres were negative. A diagnosis of acute ophthalmoparesis (AO) was made, and the patient was treated with a course of intra-venous immunoglobulin (1) (2 gram / kilogram body weight administered over five days).

The patient subsequently developed bi-facial paresis and was treated with a second course of intra-venous immunoglobulin. Resolution of ataxia and facial paresis followed shortly after. Deep tendon reflexes and pupillary reflexes returned to normal with minimal improvement of external ophthalmoplegia. Review two months later demonstrated residual but improved external ophthalmoplegia. Repeat serological assay did not show elevated titres to anti-ganglioside antibodies.

Miller Fisher syndrome (MFS) is a variant of Guillain-Barré syndrome (GBS), presenting with the clinical triad of: ataxia, areflexia and ophthalmoplegia (Fisher, 1956). Other features outwith the original description by Fisher are now considered to be part of the clinical syndrome, including weakness of other cranial nerves, and pupillary abnormalities. (2;3) MFS is associated with antibodies to complex gangliosides, in particular GQ1b, in approximately 90% of cases.(4;5) These antibodies are thought to arise through a process of molecular mimicry often as a result of antecedent infection with Campylobacter jejuni, Epstein Barr virus, and cytomegalovirus.(6) Human oculomotor nerves are enriched with complex gangliosides and antibody binding to these sites may account for the clinical manifestations of MFS.(5)

Like Bickerstaff’s brainstem encephalitis (BBE), AO shares many of the clinical features of MFS, including antibodies to complex gangliosides and ophthalmoplegia. (1;7) The clinical syndrome of AO is varied, but bilateral sixth nerve palsies will often occur prior to the involvement of other extra-ocular nerves, and cases have been described in association with pupillary areflexia, or facial muscle diplegia with ataxia(8;9). Although hyperreflexia is uncommon in GBS and its variants, cases have been reported with brisk reflexes, especially following Campylobacter enteritis (10-12). It has been suggested that hyprerreflexia occurs as a consequence of spinal inhibitory interneuron dysfunction and hyperexcitability of motor neurones (12).

The overlap between the clinical presentations of AO, MFS and BBE have led authors to propose the concept of an “anti-GQ1b IgG antibody syndrome”. This highlights the close aetiological relationship between these conditions by classifying patients with anti-GQ1b antibodies and ophthalmoplegia together, and recognising the wide variation of symptoms that are often seen in association with antibodies to the GQ1b ganglioside. (13;14) However, it is difficult to classify this as a new clinical syndrome as the outcome of anti-GQ1b IgG antibody syndromes is not uniform, and largely dependent on the presenting features.(15)

We believe our patient is the first report in the literature of AO associated with pupillary areflexia, external ophthalmoplegia, ataxia, brisk deep tendon reflexes and facial muscle diplegia, illustrating the broad range of presentation in AO and anti-GQ1b antibody associated syndromes.

 

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