Miller Fisher Syndrome

Description

Miller Fisher syndrome (MFS) is a rare variant within the Guillain-Barré syndrome (GBS) spectrum, typically presenting with the triad of ataxia, areflexia, and ophthalmoplegia. It is considered part of the continuum of immune-mediated acute polyneuropathies, alongside GBS and Bickerstaff brainstem encephalitis (BBE).

MFS usually follows an infectious trigger, most commonly Campylobacter jejuni, Haemophilus influenzae, or viral agents. Molecular mimicry leads to autoimmune attack on gangliosides, particularly GQ1b, explaining the cranial and sensory involvement. MFS predominantly affects the cranial nerves III, IV, VI, as well as proprioceptive pathways.

Although initially alarming, MFS has a favourable prognosis, with most patients recovering within 8–12 weeks. Severe forms may involve limb weakness or respiratory compromise, blurring distinctions with GBS variants. MFS is treated supportively, with IVIG or plasma exchange used selectively in severe cases.

Charles Miller Fisher (1913-2012) first formally described this syndrome in 1956, and it has since been recognised as a distinct clinical entity within the GBS spectrum.

Pathogenesis

MFS is thought to result from an aberrant immune response to a preceding infection, particularly involving Campylobacter jejuni, Haemophilus influenzae, or viral agents. Molecular mimicry between bacterial/viral lipooligosaccharides (LOS) and host gangliosides drives the autoimmune process.

• Anti-GQ1b IgG antibodies are detected in ~85% of MFS cases, with 100% specificity.
• GQ1b is highly expressed in:
  • Oculomotor nerves (III, IV, VI) → ophthalmoplegia
  • Muscle spindles and proprioceptive fibres → ataxia
  • Dorsal root ganglia → sensory deficits

Antibody binding at neuromuscular junctions and paranodal myelin results in functional conduction block and reversible nerve dysfunction, without significant axonal loss in most cases.

BBE shares the same anti-GQ1b profile but involves central nervous system involvement (altered consciousness, hyperreflexia).

Clinical Features & Diagnosis

The classical triad of MFS includes:

• Ophthalmoplegia (bilateral, progressing to complete external ophthalmoplegia)
• Ataxia (gait and limb; often severe despite preserved strength)
• Areflexia (present in ~80%, sometimes partial)

Additional features:

• Diplopia (63% in some series — common presenting symptom)
• Facial palsy (30–50%)
• Sensory deficits (20–50%)
• Hyposthenia (~20%)
• Cranial nerve involvement (III, IV, VI; sometimes VII and IX/X)
• Dysarthria, dysphagia in severe cases
• Autonomic dysfunction (less common)

CSF findings:

• Albuminocytologic dissociation (normal cell count with elevated protein) in ~90%, but may be absent early.

Nerve conduction studies:

• Reduced/absent sensory responses without slowing of sensory conduction velocity.

Imaging:

• MRI may show enhancement of cranial nerves or cauda equina.

Brighton criteria (modified for GBS/MFS variants — Fokke et al. 2014):

• Bilateral limb weakness ± cranial nerve involvement
• Decreased/absent deep tendon reflexes
• Monophasic course, nadir within 28 days
• CSF: <50 cells/microlitre; elevated protein in ~49% initially, 88% at 3 weeks
• NCS findings consistent with GBS variant
• Exclusion of alternative causes

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History

1956 – Charles Miller Fisher (1913–2012), Canadian neurologist, publishes An unusual variant of acute idiopathic polyneuritis in New England Journal of Medicine, describing the triad of:

• Total external ophthalmoplegia
• Ataxia
• Areflexia

Complete recovery occurred in each patient; the syndrome appears to be distinct from other forms of polyneuritis.

Fisher CM, 1956

Late 20th century – MFS increasingly recognised as a GBS variant, but some confusion arises in the literature with Bickerstaff brainstem encephalitis (BBE). BBE is a related but distinct entity involving altered consciousness and hyperreflexia, unlike MFS.

1990s onward – Anti-GQ1b antibodies identified as a serological hallmark of MFS, linking pathogenesis to molecular mimicry following infections. Koga et al., Chiba et al. contribute to defining immunological underpinnings.

2014 – The GBS Classification Group recommends viewing MFS and GBS variants as part of a continuous spectrum, given overlapping clinical and immunological features.

Recent decades – Higher incidence of MFS reported in East Asia (up to 15–25% of GBS spectrum cases), with Western incidence around 1–7%.

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Associated Persons

• Charles Miller Fisher (1913-2012)

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Alternative names

• Fisher syndrome

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References

Historical references

• Fisher CM. An unusual variant of acute idiopathic polyneuritis (Syndrome of ophthalmoplegia ataxia and areflexia). NEJM, 1956; 255: 57-65

Eponymous term review

• Bickerstaff ER. Brain-stem encephalitis; further observations on a grave syndrome with benign prognosis. Br Med J. 1957 Jun 15;1(5032):1384-7.
• Chiba A, Kusunoki S, Shimizu T, Kanazawa I. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome. Ann Neurol. 1992 Jun;31(6):677-9. 
• Yuki N, Koga M. Bacterial infections in Guillain-Barré and Fisher syndromes. Curr Opin Neurol. 2006 Oct;19(5):451-7.
• Yuki N, Hartung HP. Guillain-Barré syndrome. N Engl J Med. 2012 Jun 14;366(24):2294-304.
• Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn PA, Jacobs BC. Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain. 2014 Jan;137(Pt 1):33-43. 

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