What is Miller Fisher Syndrome (MFS)?

MFS is a rare variant of Guillain-Barré syndrome, a category of diseases that cause dysfunction in multiple nerves in response to a trigger by the immune system after an infection.¹ It is important that we can identify the changes that occur in the body as a result of this disease.

Autoimmune nature of MFS 

MFS is believed to develop as a result of the immune system being triggered inappropriately after an infection like HIV, Epstein-Barr virus and Campylobacter jejuni enteritis. On the surface of cells, there are substances called antigens which indicate to the body whether or not something in your body may or may not be harmful. In MFS, a cross reaction occurs between antigens on peripheral nerve cells, the cells that make up the peripheral nervous system, and components in a virus through a process called molecular mimicry.¹

This is where the foreign antigen has the same structure as the antigens on the surface of a person's own cells. This cross-reaction can cause a sustained inflammatory response.² The immune system will activate lipo-oligosaccharides, a glycolipid component found on the outer membrane of bacteria and viruses, on the membrane of the virus, which are similar in shape to ganglioside, a sugar attached to fat which contains sialic acid, in the infected person.^1,3 This leads to the production of autoantibodies called anti-GQ1b against the ganglioside GQ1b, these antibodies attack the person instead of a microbe. Anti-GQ1b antibodies are found in the cerebrospinal fluid of almost 85% of patients with MFS These antibodies are very successful at binding to the gangliosides and cause a blockade of the movement of an electrical impulse along the axons.⁴ This disrupts normal muscle function.

What areas of the brain are affected by the antibodies?

Three distinct areas are affected by the autoantibodies. These are:

• The juxtaparanodal region, where the myelin sheath, the protective membrane that wraps around parts of the nerve cells to increase the speed at which signals can travel between nerve cells, attaches to the axolemma, the plasma membrane of an axon
• The paranodal region where the myelin sheath is attached to the axolemma but is not organised into a compact structure
• The node of Ranvier, where the axolemma is not lined with myelin and is in direct contact with the extracellular fluid

The region that is most important to the conduction of an action potential is the paranodal region. The paranodal axon glial, non-neuronal cells that provide support and protection to neurons in the central and peripheral nervous system, leads to the formation of ion channel clusters which propagate an action potential. GQB1 gangliosides stabilise paranodal formation, and GQ1b autoantibodies act against this formation.⁴ Microscopic examination shows there is patchy and extensive segmental demyelination, damage to myelin sheath, of axons in Schwann cells, glial cells in the peripheral nervous system, cytoplasm caused by the invasion of macrophages and lymphocytes. This affects motor and sensory roots in the peripheral nervous system as well as cranial nerves.¹ In MFS, there is dysfunction in the lower cranial nerves: the third, fourth and sixth. Facial nerves are also affected.

Levels of anti-GQ1b antibody reflect the severity of a patient’s symptoms, particularly ophthalmoplegia. As symptoms lessen, there is a marked decrease in antibodies in serum samples. This indicates how central the antibodies are to the pathophysiology and development of the syndrome.

What symptoms does this syndrome cause?

Ophthalmoparesis

Dysfunction of muscles in the eye is caused by muscle weakness.⁵ This includes upper eyelid jerks and eyelid retraction.⁶ This is thought to be caused by the direction of action of anti-GQ1b antibodies on the neuromuscular junction, the connection between the terminal end of a motor nerve and muscle, between the cranial nerves and ocular muscles.¹ 

Ataxia

Absence of voluntary muscle coordination and loss of control of movement that affects gait stability, speech and eye movement. This is caused by autoantibody action in the cerebellar and sensory areas of the brain.⁶ The loss of the fat-rich insulating material called myelin around nerves causes skeletal muscles to not function properly.¹ This may lead to an inability to walk without support.

Osteotendinous areflexia

Lack of response to stimuli at the point where the tendon inserts onto bone. This is caused by peripheral nerve dysfunction, including disturbance in the axons and abnormal conduction in peripheral sensory fibres.^6-8

Other symptoms include: poorly reactive pupils, facial and mild limb weakness, paresthesia ( pins and needles)¹²

Levels of anti-GQ1b antibody reflect the severity of a patient’s symptoms, particularly ophthalmoplegia. As symptoms lessen there is a marked decrease in antibodies in serum samples. This indicates how central the antibodies are to the pathophysiology and development of the syndrome.¹⁸

What other causes are there of MFS?

There are also instances where patients develop autoantibodies to glutamic acid decarboxylase, the enzyme that starts the formation of gamma aminobutyric also known as GABA which is a chemical that stops messages from being transported between brain cells.¹⁰ These autoantibodies disrupt the synthesis of GABA, leading to aberrant neuronal firing.⁴

Some MFS patients do not produce autoantibodies to GQ1b but instead are positive for the lysosomal storage disorder GM1 gangliosidosis GM1, a neurodegenerative condition caused by a deficiency of the enzyme beta galactosidase. This leads to an accumulation of GM1 gangliosides and other substrates in the lysosome, subcellular organelles that break down biological polymers like proteins and carbohydrates, which impair cell function and leads to dysfunction in the nervous system.¹¹ This form exclusively affects men and is associated with lymphoma like Burkitts and diffuse large B cell.⁴

Complement is also thought to play a role in MFS development. The complement system is a network of plasma and membrane proteins that regulate the normal function of the tissue and survey the immune system for any foreign substances. When this system is dysregulated, it can cause autoimmune disease. When GQ1b targets gangliosides, complement is activated. In mouse experiments, these autoantibodies can only damage perisynaptic, near a synapse, Schwann cells when in the presence of complement. Deposition of complement on the surface of Schwann cells can also lead to myelin damage, which precedes infiltration with macrophages and T cells.¹⁴

FAQ’s

How is Miller-Fisher syndrome diagnosed?

A doctor or nurse will ask the patient about symptoms and then perform tests, including: 

• A lumbar puncture (spinal tap), where a thin needle is placed in the lower back and spinal fluid is removed, which will be tested
• A blood test may be performed to identify specific sugar chains that are present in the gangliosides that the body attacks
• Nerve conduction studies are used to show whether the nerves are carrying electrical signals correctly
• Electromyography (EMG), which shows whether muscles are responding to electrical signals coming from nerves in an expected way
• Neuroimaging CT/MRI of the spine, which will reveal if the body is attacking nerve cells in the spinal cord¹

Can COVID-19Covid-19 cause Miller Fisher syndrome?

Human coronaviruses do have the neuroinvasive capacity to induce Guillain Barre type illness as they affect the nervous system directly and indirectly through an inflammatory response.¹⁶ Typically MFS develops 2 weeks after COVID-19 infection.¹⁷ However as of 2021 only 12 patients have developed COVID-19 associated with MFS.

How do you treat Miller Fisher syndrome?

MFS is a self-limiting disease, meaning that it can resolve spontaneously without treatment or intervention.¹ However, treatments can slightly improve patients’ condition and their recovery time.⁴ To treat MFS itself, immunoglobulins are used. This helps the body to expel the GQ1b antibodies that damage the nerves.

Plasma exchange can also be used, which is where a machine will pump blood from the body in order to remove the GQ1b antibodies that are attacking the nervous system. The machine will then return the detoxified blood to the body. If a patient experiences breathing issues, then they may require a breathing tube, which goes down the throat and into the lungs to provide oxygen to the body.

If a patient experiences pain, pain-suppressing medication will be administered that will not cause them to breathe harder.MFS causes muscle weakness and so will require physical and neurological rehabilitation, which usually involves 1-2 weeks of intense rehabilitation with health professionals.¹

What is the recovery time for Miller Fisher syndrome?

Recovery for ataxia takes 35 days, ophthalmoplegia takes 3 months, and areflexia takes, on average, 64 days. Patients can expect to return to their normal activities in an average of 6 months. MFS patients usually have excellent recovery.

What is the prognosis of Miller Fisher syndrome?

The prognosis of MFS is very good, with a case fatality of less than 5%. The most common long-termlong term complicationscomplication areis generalised fatigue and chronic pain.

What is the difference between Bickerstaff encephalitis and Miller Fisher syndrome?

Miller Fisher syndrome and Bickerstaff encephalitis have similar symptoms of ophthalmoplegia and ataxia and are both preceded by an infection but Bickerstaff encephalitis is a pure central nervous system disease whereas Miller Fisher syndrome is an inflammatory neuropathy of the peripheral nervous system.¹⁹

What can be done to prevent the development of Miller-Fisher syndrome?

As bacterial and viral infections cause MFS, if these infections are avoided, the syndrome can also be avoided. This is possible through :

• Improving sanitation by washing hands thoroughly with soap and water before and after handling poultry and raw meat.
• Cooking poultry products thoroughly
• Avoiding the consumption of unpasteurised milk.

Summary 

MFS is a rare neurological condition that causes three main symptoms. It is preceded by an infection that triggers an inappropriate immune response, which leads to the destruction of the myelin sheath. This impairs muscle function.