COVID-19-associated Miller-Fischer syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyed Arash Javadmoosavi, MD[2]

Synonyms and keywords: MFS, fisher syndrome

Overview

Miller Fisher Syndrome (MFS) is an acute peripheral neuropathy that can develop after exposure to a viral or bacterial infection. It includes triad of ophthalmoplegia, areflexia and ataxia. In COVID-19 pandemic period, while COVID-19 typically presents with fever, shortness of breath (SOB) and respiratory symptoms, MFS with prior history of COVID-19 has been seen in several cases all around the world. One retrospective study in 214 patients has shown that 8.9 % of COVID-19 patients have reported peripheral neurological symptoms.

Historical Perspective

• The first reported case of MFS with a history of COVID-19 was detected in January 2020 in Shanghai, who was a middle-aged woman diagnosed with MFS presented with areflexia, acute weakness in both legs and severe fatigue.
• Further reports were announced by medical groups in Spain and the USA which presented neuro-ophtalmological symptoms.

Classification

• MFS is a rare variant of Guillain-Barre syndrome, characterized by ophtalmoplegia, areflexia and ataxia.

Pathophysiology

• Miller Fisher Syndrome (MFS) is related to dysfunction of third, fourth, and sixth cranial nerves.
• A typical serological finding in patients with MFS and prior history of covid-19 is antibodies against GQ1b ganglioside, though negative test for antibodies does not rule out the diagnosis.
• The presence of ophthalmoparesis in MFS is related to a action of anti-GQ1b antibodies on the neuromuscular junction between the cranial nerves and ocular muscle. ELISA test is positive in 70% to 90% of patients.

Causes

• Although Miller Fisher Syndrome (MFS) has been detected in some patients with COVID-19, other viral and bacterial infections can also cause MFS:
  • Influenza Virus
  • Cytomegalovirus
  • Zika virus
  • Mycoplasma
  • Campylobacter

Differentiating COVID-19-associated Miller-Fischer syndrome from other Diseases

MFS must be differentiated from other diseases that cause ophthalmoplegia, areflexia, and ataxia, such as:

Diseases	History and Physical								Diagnostic tests		Other Findings
	Motor Deficit	Sensory deficit	Cranial nerve Involvement	Autonomic dysfunction	Proximal/Distal/Generalized	Ascending/Descending/Systemic	Unilateral (UL) or Bilateral (BL) or No Lateralization (NL)	Onset	Lab or Imaging Findings	Specific test
Guillian-Barre syndrome	+	-	-	-	Generalized	Ascending	BL	Insidious	CSF: ↑Protein ↓Cells	Clinical & Lumbar Puncture	Progressive ascending paralysis following infection, possible respiratory paralysis
Acute Flaccid Myelitis	+	+	+	-	Proximal > Distal	Ascending	UL/BL	Sudden	MRI (Longitudinal hyperintense lesions)	MRI and CSF PCR for viral etiology	Drooping eyelids Difficulty swallowing Respiratory failure
Adult Botulism	+	-	+	+	Generalized	Descending	BL	Sudden	Toxin test	Blood, Wound, or Stool culture	Diplopia, Hyporeflexia, Hypotonia, possible respiratory paralysis
Infant Botulism	+	-	+	+	Generalized	Descending	BL	Sudden	Toxin test	Blood, Wound, or Stool culture	Flaccid paralysis (Floppy baby syndrome), possible respiratory paralysis
Eaton Lambert syndrome	+	-	+	+	Generalized	Systemic	BL	Intermittent	EMG, repetitive nerve stimulation test (RNS)	Voltage gated calcium channel (VGCC) antibody	Diplopia, ptosis, improves with movement (as the day progresses)
Myasthenia gravis	+	-	+	+	Generalized	Systemic	BL	Intermittent	EMG, Edrophonium test	Ach receptor antibody	Diplopia, ptosis, worsening with movement (as the day progresses)
Electrolyte disturbance	+	+	-	-	Generalized	Systemic	BL	Insidious	Electrolyte panel	↓Ca++, ↓Mg++, ↓K+	Possible arrhythmia
Organophosphate toxicity	+	+	-	+	Generalized	Ascending	BL	Sudden	Clinical diagnosis: physical exam & history	Clinical suspicion confirmed with RBC AchE activity	History of exposure to insecticide or living in farming environment. with : Diarrhea, Urination, Miosis, Bradycardia, Lacrimation, Emesis, Salivation, Sweating
Tick paralysis (Dermacentor tick)	+	-	-	-	Generalized	Ascending	BL	Insidious	Clinical diagnosis: physical exam & history	-	History of outdoor activity in Northeastern United States. The tick is often still latched to the patient at presentation (often in head and neck area)
Tetrodotoxin poisoning	+	-	+	+	Generalized	Systemic	BL	Sudden	Clinical diagnosis: physical exam & dietary history	-	History of consumption of puffer fish species.
Stroke	+/-	+/-	+/-	+/-	Generalized	Systemic	UL	Sudden	MRI +ve for ischemia or hemorrhage	MRI	Sudden unilateral motor and sensory deficit in a patient with a history of atherosclerotic risk factors (diabetes, hypertension, smoking) or atrial fibrillation.
Poliomyelitis	+	+	+	+/-	Proximal > Distal	Systemic	BL or UL	Sudden		PCR of CSF	Asymmetric paralysis following a flu-like syndrome.
Transverse myelitis	+	+	+	+	Proximal > Distal	Systemic	BL or UL	Sudden	MRI & Lumbar puncture	MRI	History of chronic viral or autoimmune disease (e.g. HIV)
Neurosyphilis	+	+	-	+/-	Generalized	Systemic	BL	Insidious	MRI & Lumbar puncture	CSF VDRL-specifc CSF FTA-Ab -sensitive	History of unprotected sex or multiple sexual partners. History of genital ulcer (chancre), diffuse maculopapular rash.
Muscular dystrophy	+	-	-	-	Proximal > Distal	Systemic	BL	Insidious	Genetic testing	Muscle biopsy	Progressive proximal lower limb weakness with calf pseudohypertrophy in early childhood. Gower sign positive.
Multiple sclerosis exacerbation	+	+	+	+	Generalized	Systemic	NL	Sudden	↑CSF IgG levels (monoclonal)	Clinical assessment and MRI	Blurry vision, urinary incontinence, fatigue
Amyotrophic lateral sclerosis	+	-	-	-	Generalized	Systemic	BL	Insidious	Normal LP (to rule out DDx)	MRI & LP	Patient initially presents with upper motor neuron deficit (spasticity) followed by lower motor neuron deficit (flaccidity).
Inflammatory myopathy	+	-	-	-	Proximal > Distal	Systemic	UL or BL	Insidious	Elevated CK & Aldolase	Muscle biopsy	Progressive proximal muscle weakness in 3rd to 5th decade of life. With or without skin manifestations.

Epidemiology and Demographics

• While the incidence of MFS is one or two-person per million each year, the prevalence of MFS associated with COVID-19 is still unknown.

Risk Factors

• There are no established risk factors for MFS associated with COVID-19.

Screening

• There is insufficient evidence to recommend routine screening for patients with MFS caused by COVID-19.

Natural History, Complications, and Prognosis

• There is an increased risk of death in patients over the age of 60-year-old. Hence, the mortality rate is estimated to be 3.6%.
• Risk factors for severe illness and poor prognosis include:
  • Old age
  • Male gender
  • Patients with
    • Diabetes Mellitus
    • Hypertension
    • COPD
    • CKD

Diagnosis

Diagnostic Study of Choice

• Although the diagnosis of COVID-19 is based on respiratory symptoms, it can be associated with neurological symptoms, which overlap the diagnosis of MFS.
• Consequently, inpatient with prior history of COVID-19, other neurologic diseases should be ruled out and anti-GQ1b antibody test should be considered.
• Also, in new patients with suspicious symptoms for COVID-19 and neurological symptoms, a nasal swab test and neurological examination should be considered.
• MRI may be performed as a part of the diagnostic workup. Although in majority of cases no abnormality is detected, enlargement and prominent enhancement in orbits and retro-orbital region has been reported in some cases..

History and Symptoms

Symptoms of covid-19 associated with MFS include:

• Respiratory system symptoms
  • shortness of breath
  • cough
• Neurological symptoms
  • headache
  • ataxia
  • ophthalmoplegia
  • areflexia

Physical Examination

• Patients with covid-19 associated with MFS present various signs and symptoms related to systematic and neurological presentation. Hence physical examination should be performed based on signs and symptoms include:

Vitals

Abnormal signs associated with covid-19:

• Tachycardia
• Tachypnea
• Fever

Neurological

• Eye dropping
• Blurry vision
• Paresthesia
• Decreased sensation
• Myalgia
• Weakness of breathing muscle

Laboratory Findings

• Laboratory findings consistent with the diagnosis of COVID-19 include positive PCR nasal swab.
• Laboratory tests for neurological signs are not diagnostic and should be used with other clinical parameters. They include:
  • Ganglioside (GM1) Antibodies, IgG and IgM
  • GD1b Antibody, IgM
  • GQ1b Antibody, IgG

Electrocardiogram

• There are no ECG findings associated with COVID-19.

X-ray

• Chest X-ray is less sensitive in detection of COVID-19 in comparison with CT.
• However, in some cases lung consolidation and patchy peripheral opacities corresponding to ground glass opacities has been reported.

Echocardiography or Ultrasound

• Lung ultrasound may be helpful in the evaluation of patients with COVID-19. It indicates :

• Multiple B-lines
  • Ranging from focal to diffuse with spared areas
• Irregular and thickened pleural lines
• Subpleural consolidations
• Alveolar consolidations
• Bilateral A-lines

CT scan

The preliminary findings of CT in COVID-19 associated with MFS include:

• Bilateral ground glass opacities
• Air space consolidation
• Bronchovascular thickening
• Traction bronchiectasis

MRI

• Brain MRI may be helpful in the diagnosis of MFS in patients with prior history of COVID-19 and neurological manifestations.
• Although there can be no abnormalities, multiple cranial nerve enhancement has been reported in some patients.

Other Diagnostic Studies

• There are no other diagnostic studies associated with COVID-19 with MFS manifestations.

Treatment

Medical Therapy

• No specific treatment and vaccine exists for covid-19 yet.
• However, patients with moderate to severe ARDS and respiratory manifestations can benefit from Mechanical ventilation and extracorporeal membrane oxygenation (ECMO).
• In some patients the combination of antiviral therapies like protease inhibitors, ritonavir, and lopinavir (100-400mg/day) indicated partial success in treatment of COVID-19.
• Remdesivir (100-200mg/day), a drug originally developed to treat Ebola virus, showed positive results against SARS-CoV-2.
• Dexamethasone (6mg/day) has been announced as an effective treatment in patients with systematic manifestations.

Surgery

• Surgical intervention is not recommended for the management of covid-19.

Primary Prevention

• Effective measures for the primary prevention of covid-19 include hand-washing, wearing of face masks, social distancing, avoidance of large gathering and self-isolation for patients who have mild symptoms.

References

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