Overview

Miller-Fisher Syndrome (MFS) is an uncommon variant of Guillain-Barré Syndrome (GBS). It is typically triggered by a bacterial or viral infection, which may enter the body during flu episodes or gastrointestinal distress. MFS is also sometimes referred to as Fisher's syndrome. Classified as an antibody-mediated neurological disorder, MFS is neither transmissible nor contagious.

Patients with MFS experience an immune response in which antibodies mistakenly attack nerve cells instead of bacteria or viruses, leading to muscle weakness. The antibodies primarily target the GQ1b molecule on the neurone’s myelin sheath. 

MFS is known to affect 1 to 2 people per million each year, with a higher prevalence in East Asia and a greater incidence in individuals assigned male at birth (AMAB) than those assigned female at birth (AFAB).¹ In the West, MFS accounts for about 1 to 5% of all GBS cases, meanwhile in the East, it makes up approximately 20%.²

MFS primarily affects the lower cranial and facial nerves, unlike GBS, which is characterised by motor weakness of the limbs. MFS typically presents with two of the three symptoms: ataxia, hyporeflexia (areflexia), and ophthalmoplegia.³

Causes

MFS is triggered by infections from bacteria or viruses. The most common pathogens include:³

• Campylobacter jejuni
• Cytomegalovirus
• Human Immunodeficiency Virus (HIV)
• Epstein-Barr virus
• Zika virus

Accurate diagnosis 

Due to the complexity of diagnosing MFS, it can be mistaken for other neurological disorders. Most patients with the syndrome receive the same treatment as those with GBS, because MFS is a rare variant of GBS, making it much less common. Most patients recover within approximately six months from the onset of symptoms, and the disease has a low relapse rate of around 3%.¹

Relationship to guillain-barré syndrome (GBS)

MFS and GBS are triggered by infections that lead to autoimmune diseases through an immune reaction. In both syndromes, the immune system mistakenly attacks the peripheral nervous system instead of the pathogenic organisms. 

MFS typically affects the upper body first and then gradually begins to affect the lower body, whereas the opposite progression is seen in GBS. GBS is more common than MFS and is more frequently observed in people aged 50 or older.³ 

Clinical presentation of miller-fisher syndrome

Symptoms

Classic symptoms of MFS include:³

• Poor limb coordination 
• Eye muscle weakness, leading to impaired vision
• Reduced or absent tendon reflexes

Symptoms can worsen rapidly over a short period. In some cases, weakness may also affect the facial muscles, including the tongue. With appropriate treatment, symptoms may only persist for a few weeks. However, a delayed or incorrect diagnosis can result in symptoms lasting for several months.

Ophthalmoplegia

Ophthalmoplegia is a common symptom of MFS in the acute phase of the illness. It commonly includes weak pupil reflexes in cases of external ophthalmoplegia; however, about one-third of cases report internal ophthalmoplegia. External ophthalmoplegia involves paralysis of the voluntary extraocular muscles, while internal ophthalmoplegia results from paralysis of the muscles responsible for pupil constriction. Bilateral and symmetrical ophthalmoplegia is frequently observed in MFS however ophthalmoplegia can be unilateral.⁴

Ataxia

Ataxia is characterised by changes in the person’s movement due to muscle weakness and paralysis of the limb muscles. The initial symptoms of ataxia include a lack of coordination, along with speech and balance issues.⁴ There are 2 types of ataxia: hereditary or acquired, and the latter is regularly seen in MFS cases.

Hyporeflexia (Areflexia)

Hyporeflexia (areflexia) is another symptom of MFS. It is the reduction or absence of reflexes, making the patient less aware of their surroundings. It can cause failure of the autonomic nervous system, leading to dysfunction in organs such as the heart, kidneys, glands, and pupils.⁶

Other less common symptoms:⁴

• Droopy eyes (ptosis)
• Blurred vision
• Involuntary eyelid movements
• Minor facial paralysis
• Photophobia (sensitivity to light)
• Severe headaches 

Diagnostic challenges

Diagnosing Miller-Fisher syndrome (MFS) presents challenges for clinicians due to its rarity and the overlap of its symptoms with other neurological diseases. Clinicians must compare MFS symptoms and rule out other conditions such as myasthenia gravis, botulism, basal meningitis, and brainstem stroke, among many others. Neurological examinations are often conducted to achieve a clearer diagnosis.

Additional diagnostic challenges arise from overlapping syndromes, such as cases of acute ophthalmoplegia without ataxia or vice versa. Incomplete or variant forms of MFS can further complicate diagnosis. To ensure an accurate diagnosis, physicians may order a variety of tests, some of which are described below.¹ The Brighton criteria is a series of different tests consisting of laboratory tests, imaging, physical examination, and history taking. These tests are used as a scoring system to diagnose Guillain-Barré syndrome (GBS) and its variants, in this case, Miller Fisher syndrome (MFS), and other conditions.³

Cerebrospinal fluid (CSF) analysis

Analysing the cerebrospinal fluid (CSF) extracted from the spinal cord can reveal markers indicating that a patient may have MFS. Furthermore, testing protein levels and cell count or the presence of albuminocytologic dissociation (ACD) in the CSF at peak disease can differentiate between MFS and GBS.³

Serum analysis

Levels of anti-GQ1b antibodies in the blood serum can also serve as markers for MFS. High levels of these antibodies suggest that the patient may have MFS.⁵

Electrodiagnostic studies (EDX)

Electrodiagnostic studies (EDX) are a combination of nerve conduction studies (NCS) and needle electromyography (EMG). These studies are done to understand the nerves and electrical activity of muscles. In patients with MFS, conduction in motor neurons is typically normal, while conduction in sensory neurons is often abnormal. This sensory neuron dysfunction contributes to poor reflexes.^1,8

Imaging techniques 

CT or MRI scans can reveal any abnormalities of the nerves in the spin and can provide a site for the lesions.^3,4

Differential diagnosis 

MFS may be confused with other disorders that exhibit similar clinical characteristics. Bickerstaff Brainstem Encephalitis (BBE) and MFS patients often present with common symptoms such as ataxia, ophthalmoplegia, and limb weakness. This overlap of clinical symptoms can make it difficult for clinicians to distinguish between BBE and MFS. In both conditions, patients typically have high levels of the anti-GQ1b antibody, similar to those seen in MFS.⁷ However, BBE patients are known to also exhibit hyperreflexia (increased activity of skeletal muscles) and encephalopathy (abnormal brain function), while these symptoms are not present in MFS patients. 

On the other hand, the pharyngeal-cervical-brachial variant of GBS presents sudden weakness in the oropharyngeal, neck, and shoulder muscles, accompanied by dysphagia and facial paresis, while reflexes and strength in the lower limbs remain intact. The sudden appearance of symptoms in these disorders is what differentiates them from MFS, which develops symptoms gradually. Other disorders might include Myasthenia Gravis, Multiple Sclerosis (MS), Wernicke encephalopathy, sarcoidosis and many others.³

Summary 

Miller-Fisher syndrome is a variant of  Guillain-Barré Syndrome and is a rare autoimmune neurological disorder caused by bacterial and viral infections. This condition is difficult to diagnose due to a significant overlap of clinical symptoms and physiological indicators with other neurological conditions; however, some key markers can help narrow down the diagnosis, thereby greatly helping physicians in making a prognosis. The main symptoms include eye muscle weakness, poor limb coordination, and weakened tendon reflexes.