Overview

What is Miller-Fisher syndrome?

Miller-Fisher syndrome (MFS) is a rare variant of Guillain-Barré syndrome (GBS). Guillain-Barré syndrome is an autoimmune polyneuropathy a disorder affecting multiple nerves. It is usually caused by an infection which results in the formation of rogue antibodies that attack our nerves, leading to muscle weakness and other neurological symptoms. MFS occurs in only 1 or 2 people per 1,000,000 globally per year. Interestingly, 25% of all MFS cases are seen in East Asia compared to just 5% in the Western population.¹

Risk factors for Miller-Fisher syndrome

People assigned male at birth (AMAB) are twice as likely as people assigned female at birth (AFAB) to develop MFS. The average age of developing MFS is 44 but can range between the early thirties to late fifties. The following factors are thought to increase the risk of MFS development:^1,2

• Heroin use
• Certain medications including isotretinoin and Tumor Necrosis Factor (
  TNF-alpha) antagonist therapy
• Hodgkin’s lymphoma
• Previous bone marrow transplant
• Autoimmune disease, for example, sarcoidosis or lupus
• Recent surgery
• Epidural anesthesia

Causes of Miller-Fisher syndrome

Typically, infections are the main trigger for MFS. Like GBS, the most common bacterial trigger is Campylobacter jejuni. Other triggers include Human Immunodeficiency Virus (HIV), Epstein-Barr (EBV) and Zika virus. Neurological symptoms appear 7 days after the infection but can take up to 4 weeks. The infection causes the body to produce the incorrect antibodies that attack the nerves, not the infection.³

Symptoms of Miller-fisher syndrome 

MFS presents with at least two of the following clinical symptoms:^1,4

• Ophthalmoplegia: weakness or paralysis of the muscles controlling the eyes
•  Ataxia: problems with coordination, balance, and speech
•  Areflexia: reduced or a loss of the skeletal muscle reflex response

Cerebrospinal fluid (CSF) analysis 

Cerebrospinal fluid (CSF) is a clear, colourless fluid that circulates in and around your brain and spinal cord to form the central nervous system (CNS). CSF protects your CNS from impact or injury, removes waste products, and supplies the essential nutrients properly regulating it.⁵ 

What is the importance of CSF analysis?

Examining a CSF sample can help get an informed diagnosis of MFS. The findings from this test will allow the clinician to differentiate between other neurological conditions that present with the same clinical triad of symptoms. In addition, CSF analysis provides a detailed profile of the CSF, providing information about various biomolecular levels that can be compared to the diagnostic reference levels (DRLs).¹

Diagnostic procedures

Lumbar puncture technique

A lumbar puncture, or spinal tap, can diagnose MFS by taking a CSF sample. In some cases, high pressure outside of the brain (intracranial pressure) is associated with MFS. This technique can relieve this pressure, resulting in normal CSF levels. Consult your healthcare provider before this procedure, as it is not recommended for individuals with severely high intracranial pressure, bleeding complications or inflammation at the insertion site.⁶

Severe complications of this procedure are rare because the site of the spinal cord ends above where the CSF is extracted in the lumbar region, preventing harm. Patients may feel a brief pain as the needle is inserted, and a shooting pain down the leg if the needle touches the nerve root, that quickly subsides.

A “post-lumbar puncture headache” usually occurs following the procedure, and can be accompanied by headaches, nausea, fast heart rate, low blood pressure, or neck stiffness, usually resolving within five days. Immediate medical attention is required for rare cases of bleeding, inflammation or other complications.^7,8

CSF analysis methods

Protein quantification determines CSF protein levels using electrophoresis, which applies an electrical field to separate proteins. This technique is also valuable in diagnosing neurological conditions such as Alzheimer’s Disease. Electrophoresis also identifies specific proteins like immunoglobulins, indicating CNS inflammation, and is commonly associated with multiple sclerosis.⁹

Additionally, red and white blood cells can be counted using automated techniques. A complete cell count provides an overall profile of the red and white blood cells in the sample. On the other hand, a differential cell count yields percentages of various white blood cell types, aiding the diagnosis by ruling out specific patterns of elevated cell types.^10,11

Typical findings 

The findings normally associated with MFS are:^12,13

• Elevated protein levels between: a high protein concentration surpassing the normal reference range are detected in roughly half of MFS patients. Albuminocytologic dissociation (ACD) is a hallmark feature of MFS, with an elevated protein level with normal white blood cell levels
• Normal white blood cell count
• Absence of oligoclonal bands: oligoclonal bands refer to the healthy immunoglobulins produced by the immune system to fight any infection

 Interpretation of CSF results

• Elevated protein levels: the increase in CSF protein is thought to reflect the disruption of the blood-nerve barrier caused by antibody-mediated inflammation of nerve roots
• Normal white blood cell count: in the case of Miller-Fisher syndrome, a normal white cell count eliminates any possible lingering infection in the body, hence why it is not typically elevated¹³
• Absence of oligoclonal bands: reduced immunoglobulins support the fact that MFS is a condition affecting the body outside of the brain and spinal cord. Absent immunoglobulins limit the neutralisation of the harmful, anti-Ganglioside antibodies (GQ1b). Intravenous immunoglobulin therapy can help address this deficiency by providing the body with the ability to combat the damaging anti-GQ1b antibodies efficiently¹⁴

Diagnostics and differential diagnosis

Diagnostic criteria

The diagnosis of MFS is clinical and reliant on the clinical symptoms and physical examination of the patient. It can be supported with laboratory analysis of extracted cerebrospinal fluid samples, as previously discussed. Cerebrospinal fluid analysis remains unchanged in 10% of patients, whilst others may show a mild change in blood cell count studies.

Supportive testing, including the following, should be used to support a comprehensive, distinguished diagnosis of MFS:³

• Nerve conduction study: measures how well your nerves are functioning
• Serological testing: this is serum testing for anti-GQ1b antibodies. This is the most effective test for MFS
• Electromyography (EMG): detects how well your muscles work in response to nervous stimulation. In patients with MFS, this can show sensory nerve abnormalities
• CT scan
• MRI scan

Distinguishing Miller-Fisher syndrome from other disorders 

Other diagnoses that can be mistaken for MFS include Bickerstaff Brainstem Encephalitis (BBE), pharyngeal-cervical-brachial (PCB) variant of GBS and other neuromuscular autoimmune disorders. Effectively distinguishing between the MFS, BBE and PCB requires other tests because of the common presence of anti-GQ1b antibodies.^15,16,17

Bickerstaff Brainstem Encephalitis (BBE):

• The MRI scan in MFS patients is typically normal, whereas BBE presents abnormal signals in the brainstem
• Testing for hyperreflexia is crucial as BBE presents hyperactive reflexes unlike the areflexia shown in MFS patients
• Altered consciousness is indicative of BBE, where consciousness is unchanged in MFS patients
• Identifying where GQ1b is localised in the body can also differentiate between BBE and MFS, as MFS affects the peripheral nervous system, by altering balance and coordination, and BBE only affects the brain and spinal cord

Pharyngeal-cervical-brachial (PCB) variant of GBS:

• MFS affects the upper body first but PCB affects lower body limbs first and spreads upwards to the arms and face. PBS also causes arm and neck weakness
• Symptoms of PCB therefore involve numbness and tingling of hands or feet, and pain in the back, legs, or arms. Overlapping symptoms with MFS, include problems with eye movement, blurry vision, and loss of coordination in the arms and legs.

Risks of CSF analysis

Analysing CSF to aid in diagnosis is generally a low-risk procedure. Nevertheless, certain individuals with specific conditions should exercise greater caution because of potential complications:¹⁸

• Tumour in the back of the brain which is pressing down on the brain stem
• Blood clotting problems
• Low platelet count, termed “thrombocytopenia”
• Individuals taking blood thinners, aspirin, clopidogrel, or other similar drugs that decrease the formation of blood clots

Summary

Miller-Fisher syndrome (MFS) is a rare form of Guillain-Barré syndrome (GBS), triggered by an infection, leading the immune system to attack the nerves, and causing neurological symptoms and weakness. A cerebrospinal fluid (CSF) analysis by a lumbar puncture can aid a MFS diagnosis. Typical findings include an increased protein level and unchanged white blood cells, termed  “albuminocytologic dissociation” and a lack of oligoclonal bands. However, CSF analysis alone is insufficient and requires combined testing of Anti-GQ1b antibodies, CT/ MRI scans, and nerve conduction studies to eliminate any other diseases with similar symptoms.