In 1956, Miller-Fisher syndrome (MFS) was conceptualised as a “unique entity within the Guillain Barré syndrome (GBS) spectrum” by the man after whom the disease was named (the Canadian neurologist, Miller Fisher).¹ It is typically considered to be one of the four main subtypes of Guillain Barré Syndrome (GBS).^1,2,3 However, MFS is an incredibly rare subtype of GBS, with a global prevalence of 1 in 1,000,000 compared to the 1 to 2 people per 100,000 for all GBS subtypes, so there is scarce data available on MFS.^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 to statistics/data non-specific to any one subtype of GBS rather than just MFS.

Understanding Miller-Fisher syndrome 

MFS is a rare, neurodegenerative, autoimmune condition, usually only ever responsible for one acute episode of symptoms (monophasic/non-relapsing), which normally occurs 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 the damage is done via antibodies). Antibodies are a class of weapon (a protein) made by your immune system in order to fight any one specific species of pathogen. However, autoimmune diseases can begin when antibodies end up accidentally targeting certain structures in your own cells. In MFS, the structures that are targeted are located on your nerves.

Specifically in MFS, these antibodies are believed to damage nerves by causing demyelination.⁸ Demyelination is when damage occurs to a structure surrounding our nerves called the ‘myelin sheath’. In simple terms, the myelin sheath is like the plastic insulation around copper wires (where the copper wire 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 in which demyelination caused by MFS subtype can affect:

• Motor neurons: nerves that carry messages out from the brain and spinal cord to the muscles. Damage to motor neurons gives rise to symptoms such as weakness and paralysis
• Sensory neurons: these send signals received from skin and muscles (such as pain) back to the brain and spinal cord. When damaged, symptoms such as numbness may arise

These two main nerve types exist outside of the central nervous system (CNS), which refers to the brain and spinal cord, in the peripheral nervous system (PNS), which extends through the body. This is also affected in other GBS subtypes. However, unlike other subtypes, research suggests that other brain structures, such as the brainstem, are affected in MFS.²

In addition, EEG, MRI and CT scan findings have documented central nervous system involvement in MFS, demonstrating that it is more of a complex subtype.^2,9 However, none of the GBS subtypes affect the autonomic nervous system, which regulates involuntary fight or flight processes such as heart rate.²

Symptoms of MFS

The main triad of symptoms which indicate MFS are:

• Ataxia: loss of coordination and balance
• Areflexia: absent tendon reflexes
• Ophthalmoparesis: weakness or paralysis of eye muscle(s) leading to trouble with eye movement⁴

Other common MFS symptoms include:

• Difficulty breathing
• Dysphagia: difficulty swallowing 
• Diplopia: double vision
• Headache
• Nasal-sounding voice
• Difficulty moving facial muscles; this can also lead to dysarthria (difficulty with speech articulation) 
• Tingling and numbness (especially in the face)
• Ptosis; drooping of the upper eyelid
• Pupillary involvement such as areflexia/mydriasis: the pupil(s) fail(s) to constrict in response to light and remain(s) dilated. This may lead to light sensitivity
• Nystagmus: involuntary, rapid and repetitive eye movements (such as shaking or jerking) in either horizontal, vertical or, even, rotary (clockwise/anti-clockwise) directions
• Anisocoria: different sized pupils^10-18

Neurological examination findings

Cranial nerves

Involvement of the cranial nerves is a common indication of MFS. Examination can reveal various degrees of paralysis across the face and eyes which can correlate to various cranial nerves (such as the third, fourth, sixth, and seventh cranial nerves).¹⁹ Sometimes, paralysis is observed on both sides of the face, although this does not occur in all cases.^18,20

Furthermore, an examination may include the dilute pilocarpine test, which shows whether chronically dilated pupils are due to a problem with nervous signal transmission or not.¹⁸ Should pilocarpine not cause the pupil to constrict, then the neurologist may deduce that the symptom is not necessarily caused by MFS-related demyelination.

Another form of neurological examination for detecting and locating facial nerve dysfunction is nerve conduction study with magnetic stimulation.²¹ This technique is particularly useful since it can detect affected nerves, even when there are no clinical symptoms such as paralysis.

Motor system examination

Examination of individuals with MFS may often reveal the reduction or, even, the absence of some deep tendon reflexes.^18,19 One specific case described the absence of deep tendon reflexes throughout the body.²² Individuals with MFS may also show decreased strength and muscle tone upon examination, which can indicate the involvement of the motor system.²⁰ 

Additionally, individuals may exhibit increased distal motor latencies (meaning longer times taken for nervous signals to activate neuromuscular junction) and, therefore, induce a response in the muscle, indicating motor system degeneration.²³ Furthermore, individuals with MFS may show absent H-reflexes and reduced persistence of F-wave responses in various nerves.²²

Sensory system examination

Many cases of MFS have demonstrated decreased sensory nerve conduction speed with disease progression.²³ Such measurements may be recorded in various nerves including the tibial, peroneal, sural, median and ulnar nerves (see image above).^23,24

Similarly, studies have revealed reduced sensory nerve action potentials (the number of nerve signals, as opposed to how fast it travels) in MFS patients.²⁵

Furthermore, patients’ reports of pinprick sensations and other sensory disturbances are indicators of sensory system involvement due to MFS, though these are less frequently reported.²³ 

Coordination and gait

Aside from non-technical diagnostic tests such as the Romberg Test, other analyses such as postural body sway analyses may serve as more accurate indicators of any neurological abnormalities.²⁴ In fact, in one study it was shown that 72% of cases of MFS underwent body sway analyses which indicated dysfunction of the proprioceptive afferent system; part of the nervous system that sends sensory signals about where a limb is in space.²⁴

Furthermore, should examination reveal issues such as truncal ataxia (instability of the trunk) the neurologist may suspect CNS involvement, and perform additional tests. It has been suggested that somatosensory evoked blink response might also be an indication of central nervous system involvement.^18,26

MRI

Commonly, an T1 MRI scan is performed; which highlights fatty tissue within the brain. MFS patients may demonstrate “increased signal intensity in cerebral white matter, brainstem and cerebellum” areas.”²³ Similar findings are shown with T2 MRI as well.²⁴ In one case, “after intravenous injection of dimeglumine gadopentetate all lesions showed T1 shortening, confirming blood-brain barrier breakdown.”²³ Another case, using a T1-weighted MRI and a double dose of double-dose gadolinium (an MRI contrast) showed neuropathy of the 3rd, 6th, and 7th cranial nerves on both sides of the face.¹⁹ However, there is also evidence to suggest that most individuals with MFS do not show MRI abnormalities.^24,25

Electrogram tests

Though there has been previous use of electronystagmography for MFS patients, electromyograms (EMG) and electroencephalograms (EEG) have been used in diagnosis more recently.^{20, 27,28} In one study, EEG recordings showed diffuse slowing, which is the slowing of certain types of brain waves in 25% of 32 MFS patients.²⁴

Another study using EMG found neuromuscular junction dysfunction in an individual with MFS, indicating that the signals between the nervous system and muscles were not working properly.² To be specific, nerves to the frontalis muscle, the muscle in the forehead, were particularly affected.”^22,29 Another study also used single-fibre EMG findings as a basis to establish peripheral nerve dysfunction.³⁰

Cerebrospinal spinal fluid CSF

Cerebrospinal fluid (CSF) analysis is a very common diagnostic tool for Miller-Fisher Syndrome and helps to differentiate it from other conditions.²⁸ CSF analysis usually reveals elevated protein levels, with a normal or mildly elevated white blood cell count.^18,22,28,29 Similarly, CSF transthyretin concentration has been found to be significantly elevated in those with MFS.²⁵

FAQs

What is MFS?

A rare autoimmune condition affecting nerves, marked by ataxia, areflexia, and ophthalmoparesis.

How is it diagnosed?

Through neurological exams, nerve conduction studies, MRI, and CSF analysis.

Is treatment available?

Yes, with supportive care and immunotherapy, most patients recover well.

Summary

Miller-Fisher Syndrome (MFS) is a rare autoimmune disorder distinct from other Guillain Barré Syndrome (GBS) subtypes, characterized by a specific triad of neurological symptoms. Accurate diagnosis through neurological examinations and diagnostic tests is essential for effective management and patient recovery.