What is miller-fisher syndrome (MFS)

Miller-Fisher syndrome (MFS) is a rare neuronal disorder, classified as an acute inflammatory demyelinating polyneuropathy (AIDP). It is a variant of another rare neuronal disease called Guillain-Barré syndrome (GBS). The GBS classification group 2014 classified both GBS and MFS within a continuous spectrum as they had similar clinical features but differences in treatment, pathogenesis and prognosis. MFS typically occurs more in persons assigned male at birth (AMAB) than in persons assigned female at birth (AFAB). It can affect people of all age groups, but it roughly affects persons assigned male at birth at an age of 43.6 years. Its worldwide incidence is approximately 1 in 1,000,0000 and is more prevalent in Asian countries than in the Western world.¹

MFS is a particularly interesting case as its onset is due to preceding viral and bacterial infections, which cause respiratory and gastrointestinal diseases. Cases peak within the autumn–winter months, which correlates with peak respiratory infection cases.

Clinical features 

The clinical features of MFS are:² 

• Acute ophthalmoplegia: weakness of the extraocular muscle which is responsible for eye movement
• Ataxia: The Abnormal, uncoordinated movements and poor balance, along with trouble walking without supports; this is the most severe symptom out of the three 
• Areflexia: the loss of deep tendon reflexes responsible for motor functions 

Kuwubara et al. (1999) concluded that MFS affects the proprioceptive afferent system, responsible for motor skills, and ataxia is correlated with the abnormalities of the afferent fibre found in our muscles, which is the reason for weakness. Areflexia, on the other hand, involves dysfunction in the peripheral nervous system and axonal neuropathy. Additionally, other symptoms could be present including:³ 

• Ptosis, where one or both upper eyelids droop
• Facial nerve palsy
• Sensory deficits
• Hyposthenia, characterised by a lack of strength and weakness

Diagnosis

The diagnosis of MFS includes history taking, physical examinations, and examination of the cerebrospinal fluid (CSF). Patients with MFS might have elevated CSF protein concentrations. A positive test for anti-GQ1b antibodies is a more accurate sign of MFS. MFS isn’t typically associated with any brain imaging, but an MRI scan is typically used to rule out the possibility of mass lesions in the brain stem or the cerebellum. Neuronal electrophysiological studies are normally used to look at alterations in GBS but not MFS. Furthermore, tests for infectious agents linked to MFS, like Campylobacter jejuni or Haemophilus influenzae, can help establish a confirmation of MFS.^1,3

Infectious agents associated with MFS

Campylobacter jejuni

Campylobacter jejuni (C. jejuni) is the most common infectious agent found in MFS patients. In a study in 1995, with 96 GBS and 7 MFS patients, 2 of the 7 MFS patients were infected with C. jejuni. C. jejuni is part of the species Campylobacter, which can cause diarrheal diseases caused by the consumption of raw milk, uncooked poultry, and contaminated water. The illness can last from 5 to 7 days. C. jejuni is prevalent in food animals, like cattle and poultry and can transmit to humans via the consumption of contaminated or improperly cooked food.⁴

Symptoms begin 1 week after the incubation period and affect the gastrointestinal tract, specifically the jejunum and ileum, but can extend to the colon and rectum. They invade and destroy epithelial cells, which attract mucus. In turn, the bacterium then uses its flagella, responsible for movement, to adhere to the mucus or epithelial cells. Once they adhere, they release a toxin, which can cause cell death, blood and inflammation within the small intestine. The symptoms of the infection include bloody diarrhoea, cramping, abdominal pain, nausea and headaches. Infection can require rehydration, but antibiotics should be used as a last resort if symptoms don’t improve.⁴ 

Haemophilus influenzae

Haemophilus influenzae (H. influenzae) is another common infectious agent involved with MFS. Koga et al. (2001) identified 7% of 70 MFS patients’ blood serum to have evidence of H. influenzae. It is a bacterial species, classified into encapsulated and non-encapsulated types. The most common one is H. influenzae type b, which affects children and immunocompromised individuals. The bacterium causes infections like pneumonia or meningitis.⁵ 

Clinical features include high-grade fever, chills, coughing, shortness of breath, and chest pain. Another subtype is Non-typeable Haemophilus Influenzae (NTHi), which possesses properties that prevent the bacteria from being encapsulated, which increases bacterial proliferation. H. influenzae can be transmitted via inhaling air droplets produced by an infected individual.⁵

Epstein-barr virus

Koga et al. (2005) found no difference in Epstein-Barr virus (EBV) infection frequency between MFS patients and healthy people. Although the evidence is mixed, EBV is still believed to play a role in causing MFS. It is part of the herpes virus family, with a double-stranded DNA virus, which infects B lymphocyte cells. Nearly 95% of adults in the world have been at some point infected with EBV, transmission can occur via deep kissing or food-sharing. A special feature of EBV is their ability to remain in B cells and become latent, reactivating infection when triggered.⁶

Cytomegalovirus

Cytomegalovirus (CMV) can have a wide range of responses, from asymptomatic in healthy individuals to severe end-organ dysfunction in immunocompromised patients, with 59% of the world’s population older than 6 years old exposed to CMV in their lifetime. Transmission of CMV is normally via contact with fluids like blood products, breastfeeding, or sexual transmission.

Infections commonly associated with salivary glands, like EBV or CMV, can often remain latent and become reactivated at any time.⁷ 

Zika virus

Zika virus is primarily transmitted by mosquitoes but can also be transmitted through person-to-person contact, blood transfusion, organ transplantation, and maternal-foetal transmission. 80% of patients infected with Zika are asymptomatic, but clinical features to look out for via the CDC are fever with a rash, arthralgia (joint stiffness), conjunctivitis, myalgia (muscle ache and pain), and headaches lasting from several days to weeks. Pregnant women should be careful, as it can cause serious birth defects in the brain and eyes. Zika can also be associated with GBS, and there’s evidence that it can cause MFS as well.⁸

Pathogenesis

It is believed that C. jejuni and H. Influenzae have lipo-oligosaccharide (LOS), a glycolipid which is expressed in gram-negative bacteria with a similar structure to the GQ1b ganglioside, which many studies like Chiba et al. (1993) used anti-GQ1b monoclonal antibodies and found high levels of GQ1b expressed on the neuromuscular junctions (NMJ) of the cranial nerves; another study done in 1997 done by the same researcher, also found it expressed in the nerves of the human extraocular muscles, responsible for eye movement. Furthermore, Goodyear et al. (1999) found that mAbs are bound to the gangliosides on NMJs.

It is hypothesised that the B cells and helper T cells are involved, that as the infection of C. jejuni or H. influenzae subsides their LOS acts as antigens taken up by B cells and presented to helper T cells, which results in the production of anti-GQ1b/GT1a antibodies, which can target not only the infectious agents, but also target the GQ1b found on the NMJ of the cranial nerves. Once bound, they cause the NMJ to release excessive amounts of acetylcholine (ACh), important for nerve communication, which blocks the neuromuscular transmission, causing effects of muscle paralysis. This theory has been termed as ‘molecular mimicry’.⁹

Summary

Miller-Fisher syndrome is a rare neuronal condition, a variant of GBS. Its clinical features include ophthalmoplegia, ataxia and areflexia, all associated with muscle weakness in the eyes and weakness in the coordination of muscles in the body. MFS is caused by preceding infections, which commonly cause respiratory or gastrointestinal infections. The main agents include the bacterium C. jejuni and H. influenzae. The structure of lipo-oligosaccharides has a similar structure to the GQ1b ganglioside on nerves, in which antibodies are produced, that not only target the infection but also start targeting the gangliosides on the nerves, causing muscle paralysis and weakness, ultimately damaging the nervous system.