The world of neurology is a maze of big words, complex disease mechanisms and, sometimes, confusingly similar symptoms. It’s a good thing, therefore, that we live in the 21st century: the age of the internet, where information is so abundant. What better stage, therefore, to distinguish between two rather similar neurological diseases, with one being very rare (Guillain-Barré Syndrome) and the other being even more so (Miller-Fisher Syndrome)?

Please read ahead to both distinguish the differences and assess the similarities between these two otherwise elusive diseases.

Autoimmune nature

In 1956, Miller Fisher Syndrome was “[classified] as a unique entity within the GBS spectrum” 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 Guillain-Barré Syndrome (GBS) and MFS, one is likely to find many sources that quote GBS as having 4 main subtypes, with one of these being MFS.^{1, 2, 3}

This categorisation is certainly neither without robust evidence nor sound reason. Only a glance over the scientific literature will yield an appreciation of the extent of the two diseases’ similarities. 

Indeed, both terms (GBS and MFS) describe rare neurodegenerative autoimmune conditions, both are usually only ever responsible for one episode of symptoms (monophasic/non-relapsing) and occur after a recent infection. GBS and MFS even have the same recommended course of treatment.

Despite these similarities, there are some key differences between the two, especially in their pathophysiologies (disease mechanisms), symptoms, and global impacts.   

Pathophysiology

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

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

There are two main nerve types which other GBS subtypes and the MFS subtype can affect; some subtypes solely affect motor neurones while others also affect sensory neurones:

• Motor neurons are nerves that carry messages/orders out from the brain and spinal cord to muscles. Therefore, damage to motor neurons gives rise to symptoms such as weakness and paralysis
• Sensory neurons 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

In GBS, there are subtypes such as ‘Acute Motor Axonal Neuropathy’ (AMAN), which only affects motor neurons and others such as Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) and Acute Motor and Sensory Axonal Neuropathy (AMSAN), which can affect both sensory and motor neurons.

In any of these cases, GBS only affects the Peripheral Nervous System (PNS),⁴ The PNS comprises nerve fibres and nerve cell bodies that exist outside of the spinal cord and the brain.⁵ 

On the other hand, while MFS does affect the PNS, such as the “neuromuscular junction between the cranial nerves and ocular muscles in CN III, IV, and VI”^1,6,7,8, there is also “evidence for involvement of brainstem structures in the Miller Fisher syndrome.”² Likewise, EEG, MRI and computed tomography findings have been “reported as evidence for a central nervous system involvement”² in MFS. Such evidence suggests that MFS not only affect the PNS.

Furthermore, there are two ways in which GBS or MFS can damage nerves:

Demyelination: this 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.

Axonal neuropathy: this is when damage is done to the nerve cell itself (or, better said still, to the part of the nerve which carries the signal). In our analogy, findings strongly suggest that MFS is caused by demyelination,⁹ just like the AIDP GBS subtype, and unlike the AMSAN and AMAN GBS subtypes.

Common triggers

GBS “is a typical post-infectious disorder”¹⁰ and MFS is also post-infectious in the majority of cases, with “the respiratory tract ([…]59.2%[of cases]) [as] by far the most common site of infection.”²

In both GBS and MFS, there are several associated microorganisms, “most notably Campylobacter jejuni,  Zika virus”¹¹, “human immunodeficiency virus (HIV), as well as Haemophilus influenzae”.^1,6,12 Furthermore, both GBS and MFS have also been associated with SARS-CoV2 (COVID-19) infection.^1,12,13 Other analyses showed evidence that patients suffering GBS subtypes had previously been infected with Mycoplasma pneumoniae, hepatitis E virus, cytomegalovirus, and Epstein-Barr virus.^14,15

Having said this, GBS patients do not always report having had a recent infection; one paper from 2016 suggested that up to 40% (<40%) of patients do not report “antecedent infectious symptoms”¹⁶. Similarly, one source demonstrated that in 12.6% of MFS cases, “no preceding illness was mentioned”.²

Such incidents, where no prior infection is reported, may be explained by “exposure to toxins [or] genetics.”¹

Various sources show a range of “other risk factors associated with [MFS]”:^6,17,18

“Other risk factors associated with the disease [(MFS)] include the use of certain drugs (heroin, suramin, streptokinase, and isotretinoin), use of TNF-alpha antagonist therapy, other concurrent autoimmune diseases (systemic lupus, Hodgkin disease, and sarcoidosis), surgery, epidural anesthesia, bone marrow transplant, and immunisations.”

Clinical presentation 

There are several symptoms which can indicate the onset of GBS:^{1,19,20,21,22}

• Growing weakness and/or tingling sensations in the legs and, sometimes, the arms. This normally ascends upwards (i.e. beginning in the toes or fingers and moving upwards towards the thighs or shoulders)
• Numbness (not present in AMAN GBS)
• Hyporeflexia/Areflexia; weak or absent tendon reflex
• Pins and needles in the extremities 
• Tripping
• Pain
• Dysautonomia (dysfunction of the nerves serving the internal organs); the most common dysautonomic symptom is sinus tachycardia (a type of fast heartbeat)

In GBS, “dysautonomia affects 65 % of patients.”²² A 2013 article also pointed out that other less common autonomic symptoms include:²²

“Bradycardia, labile blood pressure with hypertension and hypotension, orthostatic hypotension, cardiac arrhythmias, neurogenic pulmonary oedema, changes in sweat, and in less than 5 % of cases bladder (urinary retention) and gastrointestinal (constipation, ileus, gastric distension, diarrhoea, faecal incontinence) dysfunction.”

MFS, on the other hand, does not “ever show the involvement of the autonomic system, which is typical of the Guillain-Barre syndrome”² where indicating MFS are:⁶

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

Other common MFS symptoms include:

• Difficulty breathing
• Dysphagia: difficulty swallowing 
• Diplopia: double vision
• Difficulty moving facial muscles; this can also lead to dysarthria(difficulty with articulation) 
• Tingling and numbness (especially in the face)

Variations in epidemiology

GBS is a very rare condition with an estimated 100,000 cases per year worldwide,⁴ only occurring in 1 to 2 people per 100,000^1,6,12,17, but MFS is even rarer and “has a worldwide prevalence of 1 in 1,000,000.” ^1,6,7 Both diseases have a similar age onset; MFS had a mean age of 43.6 years and GBS had a mean age of 40 years.^2,22 One report evidenced MFS as having a male-to-female ratio of 2:1 while another report found that in GBS, “all ages are affected with slightly more people assigned male at birth (AMAB) than people assigned female at birth (AFAB).”²² Another report found that in all subtypes of “GBS incidence increased by 20% for every 10-year increase in age; the risk of GBS was higher for people AMAB than people AFAB.”²³

Global impact and variations in risk

The area of the world you’re from can have a huge bearing on the probability of suffering any one of the subtypes of GBS:²⁴

• 90% of GBS cases in Europe and North America are AIDP; less than 10% are AMAN
• “22-46% of cases in China, Japan, India, Southeast Asia, and Mexico” are AIDP, while AMAN accounts for 30-65% of cases in these countries

Furthermore, the Miller-Fisher Syndrome subtype of GBS, “makes up about 5 % of the cases of GBS in most countries, but about 25 % in Japan”.^6,22,23

Other sources place the percentage incidence of MFS in Asian countries slightly higher at  “ 15-20 % of GBS cases.”^1,12

Summary

Miller-Fisher Syndrome (MFS) and Guillain-Barré Syndrome (GBS) are rare autoimmune neurological conditions. Both often follow infections and involve immune-mediated nerve damage. While GBS primarily affects peripheral nerves, MFS can also impact the central nervous system. GBS causes muscle weakness and autonomic dysfunction, whereas MFS is characterised by ataxia, areflexia, and ophthalmoparesis.

FAQs

What are the primary symptoms of MFS and GBS?

MFS is characterised by ataxia, areflexia, and ophthalmoparesis; GBS can cause tingling, ascending limb weakness and, in severe cases, difficulty breathing.

How are MFS and GBS diagnosed?

MFS and GBS are diagnosed through clinical examination, nerve conduction studies, cerebrospinal fluid analysis, and specific antibody tests.

What treatments are available for MFS and GBS?

IV Immunoglobulins or plasma exchange.