Introduction

Guillain-Barré Syndrome (GBS) is an acute autoimmune neurological disease, which is usually symmetrical and progresses from the lower to the upper limbs.¹ It usually occurs after a viral or bacterial infection. The prevalence in the world is 1-2 cases per 100,000 people. Currently, five variants of GBS are recognised:²

• Acute inflammatory demyelinating polyneuropathy (AIDP): high prevalence in Europe and North America. It is the most common form of the condition and accounts for more than 90% of GBS cases
• Acute motor axonal neuropathy (AMAN)
• Acute motor-sensory axonal neuropathy (AMSAN)
• Acute autonomic neuropathy
• Miller-Fisher Syndrome (MFS)

Miller-Fisher Syndrome (MFS) is one of the rare variants of GBS. Although the prognosis is most of the time excellent, MFS can lead to severe complications. One major concern is respiratory muscle weakness, which can become a life-threatening condition.¹ Thus, the American Society for Apheresis (ASFA) has settled plasmapheresis as the first-line therapy for GBS and its variant, Miller-Fisher Syndrome.² 

Overview of Miller-Fisher syndrome

Epidemiology

Miller-Fisher Syndrome has a global prevalence of about 1 per 100,000 people per year. Its prevalence varies by region, with the incidence of Asia and South America reaching 15-40% of cases.³ MFS is twice as common in males compared to females. The mean age of onset is estimated to be around 45 years. It often follows a preceding infection, with respiratory infections reported in 56–76% of cases.. MFS appears to have a seasonal pattern, with a higher incidence during autumn and winter, likely due to the increased prevalence of viral infections that act as triggers.² 

Physiopathology and underlying mechanisms

MFS is an autoimmune disease that results in molecular mimicry, a phenomenon in which the immune system mistakenly attacks self-tissues due to structural similarities between microbial antigens and host molecules. The anti-GC1b antibodies produced are directed against the gangliosides, which are abundant in nerves III, IV and VI. The membranes of these gangliosides are similar to the pathogen's lipo-oligosaccharide, triggering an immune-mediated attack on the nervous system. The myelin sheath insulates the axons, the elongated portions of the neuron located in the center of the neuron cells. Thereby, axonal damage may cause neurologic symptoms such as ophthalmoplegia, ataxia, and areflexia. Nevertheless, it must be noted that MFS is not a hereditary or infectious disease. Rather, it is an autoimmune response often triggered by a preceding infection or other immunological stimuli.²

Causes

MFS typically follows a preceding infection, with symptom onset usually occurring within a few days to four weeks after exposure to a triggering pathogen.³ Despite the precise cause being unknown in most cases, several infectious agents have been implicated, including:

• Campylobacter jejuni: the most common pathogen accounting for 25-50% of cases and causes diarrheal illness
• Haemophilus influenzae: implicated in respiratory tract infections
• Cytomegalovirus (CMV): a viral trigger linked to post-infectious autoimmunity
• Epstein-Barr virus (EBV): known for infectious mononucleosis
• Other less common aetiological agents: measles, Mycoplasma pneumoniae, Zika virus, Chikungunya virus

Other factors that may increase the risk of MFS include:^1,3

• Certain drugs such as heroin, isotretinoin and streptokinase 
• Surgical procedures and bone marrow transplantation
• Immunomodulatory treatments, like TNF-alpha inhibitors

Symptoms and clinical presentation

Miller-Fisher Syndrome comprises of three characteristic symptoms:³

• Ophthalmoplegia (fatigue of eye muscle): weakness or paralysis of the eye muscles, leading to abnormal movements of the eye and double vision (diplopia)
• Ataxia: lack of limb coordination
• Areflexia: absence or reduction of deep tendon reflexes

Other less common features that can be manifested are:

• Facial weakness – leading to difficulty swallowing (dysphagia) and facial muscle weakness
• Limb weakness – although less prominent, some mild limb weakness may develop
• Respiratory muscle involvement – rare but potentially life-threatening, as weakness of the diaphragm and intercostal muscles may lead to respiratory failure

Differential diagnosis

• GBS-MFS Overlap Syndrome: a condition where MFS coexists with GBS, leading to more extensive limb weakness
• Bickerstaff Brainstem Encephalitis (BBE): Shares clinical similarities with MFS but includes central nervous system (CNS) involvement, such as altered consciousness and Babinski sign
• Other Neurological Disorders that may resemble MFS include: myasthenia gravis, diphtheria, brainstem stroke, brainstem encephalitis, basal meningitis

Complementary exams

While MFS is primarily a clinical diagnosis, additional tests can help confirm the condition and rule out differentials:

• Anti-CQ1b Antibodies: non-specific for MFS⁴
• Analysis of the cerebrospinal fluid (CSF): high levels of protein, normal white blood cells (WBCs)
• Electromyography (EMG) and Nerve Conduction Studies (NCS): absence of sensory nerve action potentials (SNAPs) reflects impairment of reflex pathways
• Magnetic resonance imaging (MRI) of the brain: normal in MFS

Importance of the treatment

Early treatment is crucial to reduce disease severity and speed up recovery in Miller-Fisher Syndrome (MFS). While supportive care is essential for managing symptoms and preventing complications, specific immunomodulatory therapies have shown efficacy. Evidence supports the following:

Specific treatments

1. Intravenous Immunoglobulin (IVIG)
   • First-line therapy
   • Works by neutralizing pathogenic antibodies through immunomodulation
   • Typically administered over five days⁵
2. Plasmapheresis (Plasma Exchange, TPE)
   • Therapeutic plasma exchange removes circulating autoantibodies
   • May be used alone or in combination with IVIG
   • Recommended by the American Society for Apheresis (ASFA) as a Grade I therapy for Guillain-Barré Syndrome (GBS) and its variants, including MFS⁶

Supportive care

• Multidisciplinary management (neurologists, physiotherapists, psychologists)
• Physical therapy to aid recovery and prevent muscle deconditioning
• Psychological support to address anxiety and stress

Prognosis

• Generally excellent, with complete or near-complete recovery
• Median time to improvement: 4–5 days (range: 2–21 days)
• Full recovery typically within 8–12 weeks
• Recurrence occurs in ~3% of cases, but it remains mild and self-limiting⁷

Overview of plasmapheresis

Definition and procedure

Apheresis is a blood treatment based on the removal of harmful elements from the blood, i.e., a blood purification therapy. According to the recommendations of the American Society For Apheresis (ASFA), two modalities of apheresis can be performed in the cases in GBS and its variants:²

• Therapeutic Plasma Exchange (TPE): involves removing the patient’s plasma and replacing it with a substitute (e.g., albumin or donor plasma). According to ASFA, TPE is a ‘’strong recommendation with high-quality evidence’’ in the treatment of Guillain-Barré Syndrome
• Immunoadsorption (IA): IA selectively removes immunoglobulins (IgG, IgA, and sometimes IgM) without the need for plasma replacement. The plasma is centrifuged, it is then passed to adsorber columns which can remove immunoglobulins. Here, the quality of evidence is still moderate but with strong recommendations according to ASFA

TPE and the IA have the same modality of treatment. However, IA does not require other plasma replacement products.

The material

1. Therapeutic Plasma Exchange (TPE):
   In TPE, the liquid part of the blood (plasma) is replaced to remove harmful substances. The type of fluid used depends on hospital rules, availability, and cost. The most common replacement is albumin, but fresh frozen plasma, a mix of both, Gelofusine (a cheaper option), or even salt water (saline) can also be used²
2. Immunoadsorption (IA):
   IA is a similar treatment but isn’t used everywhere, as it depends on whether it’s approved in a country and how much the healthcare system can afford. It doesn’t usually require plasma. Special filters, called columns, are used to remove bad antibodies. Doctors also keep an eye on fibrinogen levels (a blood-clotting protein), since some filters might remove it by accident

Differences between the two treatments

Immunoadsorption, in contrast to TPE, avoids certain risks associated with the infusion of external plasma. Specifically, IA reduces the following risks:²

1. Risk of intolerability (allergic reactions): IA bypasses the need for external plasma, reducing the risk of allergic reactions associated with plasma components
2. Risk of spreading infectious agents: since IA does not rely on the use of external plasma, the risk of transmitting infectious agents from donor plasma, which depends on the conservation and manipulation of the plasma, is minimized
3. Coagulation risks: the need for external plasma in TPE introduces the risk of coagulation abnormalities, which IA avoids

Complications

Generally, patients tolerate plasmapheresis well. The following complications rarely occur are not life-threatening:⁸

• Hypotension: due to the retrieval of blood from the body (48,83%)
• Paresthesia: impairment of sensitivity presenting as tingling or numbness in the upper or lower limbs (41,86%)
• Rare complications: allergic reactions (4,65%), fever (2,33%), abdominal cramps (2,3%)

Predictive factors of success

One important predictive factor of success studied in certain treatments is the Neutrophil-Lymphocyte Ratio (NLR). Studies have shown that a significantly low NLR is associated with a better outcome in patients, indicating that this ratio could be a useful marker for predicting treatment success.⁹

Comparison with other treatment modalities

1. IV immunoglobulin (IVIG) - Several studies did not demonstrate a significant difference between intravenous immunoglobulin and plasmapheresis. Moreover, the hospital stay length and the time of respiratory support have no statistical difference¹⁰ 
2. Corticosteroids - Although corticosteroids are commonly used to reduce inflammation in various disorders, they are ineffective in MFS¹

 Summary

Ten Key Facts to Keep in Mind with Plasmapheresis in the Management of Miller-Fisher Syndrome (MFS)

• MFS overview: Miller-Fisher Syndrome (MFS) is an acute autoimmune neurological disease
• Geographic prevalence: It is rare in the European region but more prevalent in Asian and South American countries, with an incidence rate ranging from 15-40%
• Gender ratio: The male-to-female ratio is approximately 2:1
• Recovery outlook: MFS generally has an excellent and complete recovery rate, although there is a 20-40% chance of respiratory failure in some cases
• Need for treatment: Supportive care alone is not sufficient for treating MFS
• Therapeutic modalities: Plasmapheresis and intravenous immunoglobulin (IVIG) are the two main treatment options for MFS
• First-line therapy: The American Society for Apheresis (ASFA) recommends plasmapheresis as the first-line therapy for MFS
• Types of apheresis: Two types of apheresis are used in MFS: TPE (Therapeutic Plasma Exchange), commonly referred to as plasmapheresis, and IA (ImmunoAdsorption), which is used less frequently
• Complications of TPE: Plasmapheresis (TPE) can lead to benign complications, which are generally not life-threatening
• Comparative effectiveness: No significant difference has been found between intravenous immunoglobulin (IVIG) and plasmapheresis in terms of treatment efficacy for MFS