Miller Fisher Syndrome (MFS) is a very rare disease which affects nerves. MFS often impacts ocular motility. This is due to ophthalmoparesis, meaning weakness or paralysis of eye muscles, which leads to trouble with eye movement. 

Why does the GBS keep coming up when searching for Miller Fisher Syndrome?

In 1956, MFS was classified “as a unique entity within the […] spectrum” of Guillain-Barré Syndrome (GBS) by the very man after whom the disease is named (the Canadian neurologist, Miller Fisher).¹ Since then, there have been conflicting “interpretations of the nature of the Miller Fisher syndrome”.²

However, when reading up on Miller Fisher Syndrome (MFS), one is most likely to find sources quoting MFS as being one of the four 4 main subtypes of GBS.^1-3

Since MFS is such an incredibly rare subtype of GBS, having “a worldwide prevalence of 1 in 1,000,000” compared to the 1 to 2 people per 100,000  for all/any GBS subtype(s), data on MFS is relatively hard to come by.^1,4-7 For instance, a MFS literature review conducted in 1992 stated that only 223 cases of MFS had been published in the 36 years following a report in 1956.² This sparsity of data, therefore, is why this article may refer, in some instances, to statistics/data non-specific to any one subtype of GBS rather than just MFS.

Of course, this article’s aim is only to investigate the impact of MFS on ocular motility; any statistics non-specific to MFS, used in this article, are only intended to help the reader gauge an approximation of whatever matter it is that is being discussed.

Understanding Miller Fisher Syndrome 

Pathophysiology

MFS is a rare neurodegenerative autoimmune condition, usually only ever responsible for one episode of symptoms (monophasic/non-relapsing) and normally occurring after a recent infection.

The words ‘autoimmune’ and ‘immune-mediation’ are often used to describe MFS. These words convey that MFS is a disease where your own body is responsible for the damage that is done (in this case, to the nervous system). 

In MFS, the most established and thoroughly studied mechanisms with which the body does damage to nerves are ‘antibody-mediated’ (meaning a mechanism whereby damage is done ‘via antibodies’); antibodies are a class of weapon made by your immune system in order to fight any one specific species of germ, however, autoimmune diseases can begin when antibodies end up accidentally targeting certain structures in your own cells (i.e. different structures on your nerves in MFS).

To be specific, in MFS, these antibodies are believed to damage nerves by causing their demyelination.⁸ Demyelination is when damage is done to a structure surrounding our nerves called the ‘myelin sheath’. 

In simple terms, the myelin sheath serves an analogous role to that of plastic insulation around copper wires (in this analogy, it is the copper wire which represents the nerve). Damage to the myelin sheath, therefore, results in the reduced conductivity of electrical signals through the nerve.

There are two main nerve types which demyelination caused by MFS subtype can affect:

• Sensory neurones; these send signals received from sensory organs (such as pain from the skin) back to the brain and spinal cord. In MFS, when damaged, symptoms such as numbness may arise

In the context of the impact of MFS on ocular motility, the reader should know that the optic nerve, despite being a sensory nerve, is unaffected by MFS. This is particularly good news, since the optic nerve is responsible for actually sending electrical/visual signals to the brain; the brain makes sense of the signals and generates for us the images we call ‘sight’.Therefore, damage to the optic nerve would most likely result in at least some form of vision loss (this is not a symptom of MFS).

• Motor neurones: nerves that carry messages/orders out from the brain and spinal cord to muscles. Damage to motor neurons gives rise to symptoms such as weakness and paralysis. In MFS, damage to the cranial nerves is the main cause of any impact on ocular motility. Despite being in the head, the cranial nerves are not part of the brain or spinal cord. 

These two main nerve types mostly exist outside of the Central Nervous System (CNS = the brain + spinal cord) and are also affected in other GBS subtypes. In MFS, however, there is also involvement of other aspects of the nervous system, with there being “evidence for involvement of brainstem structures in the Miller Fisher syndrome.” Likewise, EEG, MRI and CT scan findings have been “reported as evidence for a central nervous system involvement” in MFS.^2,9 Therefore, in addition to cranial nerves, brainstem structures, which are well established as being involved in pathways that control eye movement, are likely to be another culprit for any loss or abnormality of ocular motility in MFS.

Again, unlike other GBS subtypes, MFS does not “ever show the involvement of the autonomic system”² (the autonomic system comprises nerves associated with internal organs).

Symptoms

The main triad of symptoms which indicate MFS are:⁴

• Ataxia: loss of coordination and balance
• Areflexia: absent tendon reflexes
• Ophthalmoparesis: weakness or paralysis of eye muscle(s) leading to trouble with eye movement (ocular motility)

Other common MFS symptoms include:^10-15

• Difficulty breathing
• Dysphagia: Difficulty swallowing 
• Diplopia: Double vision
• Headache
• Nasal voice
• Difficulty moving facial muscles; this can also lead to dysarthria (difficulty with articulation)
• Tingling and numbness (especially in the face)
• Ptosis: drooping of the upper eyelid

Ocular Motility Disorders in MFS 

There are various ways in which ocular motility may be affected as a result of MFS. In all of these instances, it is the motor neurons or other similar nervous structures in control of the contraction of the Extraocular Muscles (EOMs; muscles attached to the outside of the eyeballs), which become the victim of demyelination.

Depending on the extent of demyelination and consequent EOM weakness (ophthalmoparesis), MFS may result in varying degrees of restriction to the range of eye motion. Most cases may result in complete EOM paralysis (ophthalmoplegia). 

In broader terms, deterioration in ocular motility may cause reading and visual tracking (especially that of moving objects) to become difficult. This, in turn, may affect their ability to focus. Furthermore, double vision may often lead to headaches.

Impact on Specific Eye Movements

There are 3 pairs of muscles which control the movement of each eye:

Designed by brgfx / Freepik

• The contractions of the lateral and medial rectus muscles result in the horizontal movement of the eyes; these muscles are attached to the sides of the eyeballs
• The contractions of the superior and inferior rectus muscles result in the vertical movement of the eyes; the muscles are attached at the top and bottom of the eyeballs
• The oblique muscles contract to rotate the eyeballs in either the clockwise or anti-clockwise directions; this rotation is limited to 5° to 7°

These muscles are controlled by three pairs (one of each pair for each eye) of cranial nerves, namely, the oculomotor nerves (cranial nerve III), the trochlear nerves (cranial nerve IV), and the abducens nerves (cranial nerve VI). When any one of these nerves experiences demyelination, then the muscle(s) to which it leads receive(s) a weaker or no signal. 

In a 2019 paper investigating the “Pattern of Extraocular Muscle Involvements in Miller Fisher Syndrome” it was found that the “lateral rectus muscle is the most-involved and last-to-recover EOM in ophthalmoplegia”, followed by the superior, inferior and medial rectus muscles, “with similar involvement frequencies”.¹⁶

Involvement of these four muscles results in:

• Horizontal Gaze Palsy: limitations in lateral eye movements
• Vertical Gaze Palsy: limitations in upward and downward eye movements

Another EOM which can also become affected by the demyelination of the oculomotor nerve is called the Levator Palpebrae Superioris. It is responsible for pulling up the upper eyelid, and, therefore, some cases of MFS present ptosis.

Furthermore, MFS has been linked to a peculiar condition called Internuclear Ophthalmoplegia (INO), whereby the coordination between the eyes is impaired. This happens when the Medial Longitudinal Fasciculus (MLF) nerve becomes demyelinated. 

This nerve exists in the brainstem and connects the oculomotor nerve of one eye with the abducens nerve of the other eye; this connection means that when looking left, for example, the outside muscle (lateral rectus) of the left eye contracts at the same time as the inside muscle (medial rectus) of the right eye.

There are three main manifestations of INO:

• Both eyes are able to look to the right; only the left eye is able to look to the left while the right eye continues to gaze straight ahead
• Both eyes are able to look to the left; only the right eye is able to look to the right, while the left eye continues to gaze straight ahead
• Only the right eye can look to the right, while the left eye is stuck looking ahead, and only the left eye can look to the left, with the right eye stuck looking ahead

FAQs 

What is the main cause of Miller-Fisher Syndrome?

Most cases of MFS follow a recent infection, which then triggers an antibody-mediated autoimmune response against the myelin sheath of various nerves.

Can MFS-related eye movement problems be completely cured?

Following treatment with IV immunoglobulins or plasmapheresis, most patients should expect almost full recovery within a few weeks to months.

What are the first signs of MFS affecting the eyes?

Patients may first experience difficulty with concentration, reading, and headaches. 

Summary

Miller Fisher Syndrome (MFS), a rare Guillain-Barré Syndrome (GBS) subtype, primarily affects ocular motility due to demyelination of cranial nerves. Symptoms include ataxia, areflexia, and ophthalmoparesis, causing eye movement, reading, and visual tracking difficulties. Recovery typically occurs within weeks to months.