COVID-19-associated Guillain-Barre syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rinky Agnes Botleroo, M.B.B.S.,Niloofarsadaat Eshaghhosseiny, MD[2], Fahimeh Shojaei, M.D.

Synonyms and keywords:

Overview

The coronavirus (COVID-19) pandemic originated in Wuhan (China) on December 2019.Although respiratory complications are more common, neurological manifestations are also increasingly reported. Guillain-Barre syndrome is preceded by upper respiratory infection or gastrointestinal illness. In June 2020,the very first case of COVID-19 associated Guillain-barre syndrome in the United States was reported. The polyneuropathy in Guillain–Barre syndrome is believed to be due to cross-immunity against epitopes of peripheral nerve components that it shares with the epitopes on the cell surface of bacteria that produces an antecedent infection. If left untreated, COVID-19 associated GBS may cause respiratory failure. The classic clinical manifestations of Guillain-Barre syndrome is progressive, ascending, symmetrical flaccid limbs paralysis.

Historical Perspective

• COVID-19 (SARS-CoV-2) outbreak initiated in December, 2019 in Wuhan, Hubei Province, China.

• In northern Italy five patients developed Guillain–Barré syndrome after the onset of coronavirus disease 2019 (Covid-19) from February 28 through March 21, 2020.
• In June 2020,the very first case of COVID-19 associated Guillain-barre syndrome in the United States was reported.

Classification

• There is no established system for the classification of COVID-19 associated Guillain-Barre Syndrome .
• Guillain-Barre Syndrome its self may be classified into various subtypes: Demyelinating polyneuropathy (67.4%), acute axonal neuropathy (7.0%), Miller Fisher syndrome (7.0%), Bickerstaff brainstem encephalitis (7.0%), pharyngo-cervical-brachial variant (4.7%), and polyneuritis cranialis (4.7%).

• To view the classification of COVID-19, click here.

Pathophysiology

• Guillain–Barre syndrome causes immune-mediated damage to the peripheral nerves that usually follows gastrointestinal or respiratory illnesses.
• The polyneuropathy in Guillain–Barre syndrome is believed to be due to cross-immunity against epitopes of peripheral nerve components that it shares with the epitopes on the cell surface of bacteria that produces an antecedent infection .
• Most common antecedent infections are Campylobacter jejuni ,Zika virus and influenza virus.
  
• The mechanism of Guillain–Barre syndrome in patients infected with COVID-19 is not fully understood yet.
• COVID-19 stimulates inflammatory cells and produces various inflammatory cytokines and as a result, it initiates immune-mediated processes.
• Molecular mimicry as a mechanism of autoimmune disorder plays an important role in formation of Guillain–Barre syndrome.
• It is not yet clear whether COVID-19 induces the production of antibodies against specific gangliosides that usually appear with certain forms of Guillain–Barre syndrome.
• In the future further investigations should be conducted about the mechanism of GBS in patients with COVID-19 for better understanding.

Causes

• COVID-19 associated Guillain-Barre syndrome may be caused by SARS-CoV-2 virus.
  

Differentiating COVID-19-associated Guillain-Barre syndrome from other Diseases

GBS should be differentiated from other causes of muscle weakness, hypotonia and flaccid paralysis:

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.

• COVID-19 associated Guillain-Barre syndrome:
  • It has been reported in Northern Italy,United States, Iran
  • Affects mostly elderly people
  • More males are affected than females
  • Presence of Fever, cough, dyspnea, ageusia, hyposmia before the onset of GBS
  • Takes 5-14 days to develop GBS
  • Facial Diplegia common
  • Dysautonomia less common
  • Outcome is poor, residual weakness, dysphagia, long ICU stay

• Differentiating from Typical Guillain-Barre syndrome:
  • Typical Guillain-Barre syndrome occurs worldwide
  • Affects all age groups,
  • Male 1.5 times more affected than females,
  • Presence of preceeding respiratory/gastrointestinal illness
  • Takes less than 6 weeks to develop GBS from initial illness
  • Facial Diplegia common
  • Dysautonomia common
  • Prognosis is good, persistent disability in 20%-30% cases
    

• Differentiating from Zika virus-related Guillain-Barre syndrome:
  • Zika virus-related Guillain-Barre syndrome was reported in Latin America, Europe, East Asia, North America
  • Affects Middle aged people to elderly people
  • Males are more affected than females
  • Presence of fever, headache, rash, arthralgia, diarrhea, conjunctivitis before the onset of Guillain-Barre syndrome
  • Takes 0–10 days to develop Guillain-Barre syndrome
  • Facial Diplegia common >50% cases
  • Dysautonomia common up to 30% cases
  • Outcome is good, half may require ICU care

Epidemiology and Demographic

• Five cases of Guillain-Barre syndrome (GBS) in patients with COVID-19 has been reported in three hospitals in Northern Italy from February 28 through March 21, 2020.
• Four of these patients had a positive nasopharyngeal swab for SARS-CoV-2 at the onset of the neurologic syndrome, and one had a negative nasopharyngeal swab and negative bronchoalveolar lavage but subsequently he developed a positive serologic test for the virus .
• The first official case of Guillain-Barre syndrome (GBS) associated in patients with COVID-19 in the United States has been reported by neurologists from Allegheny General Hospital in Pittsburgh, Pennsylvania in June,2020.
• The patient was a 54-year-old man who was transferred to Allegheny General Hospital after developing ascending limb weakness and numbness that followed symptoms of a respiratory infection.
• The man reported that his wife was tested positive for COVID-19 infection and that his symptoms started soon after her illness.
• Later he also tested positive for COVID-19.
• Another case of Guillain–Barre syndrome with COVID-19 has been reported in Iran.

Risk Factors

• There are no established risk factors for COVID-19 associated Guillain-Barre syndrome.

Screening

• There is insufficient evidence to recommend routine screening for COVID-19 associated Guillain-Barre Syndrome.
  

Natural History, Complications, and Prognosis

• If left untreated, COVID-19 associated GBS may cause respiratory failure.
• Among the five Italian patients of Covid-19 associated GBS two patients had poor outcome including ICU admission due to respiratory failure,they remained in intensive care after 4 weeks of treatment ;two patients had mild improvement and receiving physical therapy, and one was discharged walking independently.
• The only US patient with COVID-19 associated GBS briefly required mechanical ventilation and was successfully weaned after receiving a course of Intravenous Immunoglobulin.

Diagnosis

History and Symptoms:

• The classic clinical manifestations of Guillain-Barre syndrome is
  • Progressive, ascending, symmetrical flaccid limbs paralysis
  • Areflexia or hyporeflexia and with or without cranial nerve involvement, which can progress over the course of days to several weeks
• In the Italian cases, Guillain-Barre syndrome symptoms began 5-10 days after the first COVID-19 symptoms.
• The first symptoms of GBS were lower limb weakness in four patients and facial diplegia with subsequent ataxia and paresthesia in one patient.
• Four patients had generalized flaccid tetraparesis or tetraplegia that developed over 3 to 4 days.
• No patient had dysautonomic features.

Patient no.	Onset of neurologic symptoms	Neurologic Signs & Symptoms
1	7 days after fever, cough, ageusia	Flaccid areflexic tetraplegia evolving to facial weakness, upper limb paresthesia(36 hr), and respiratory failure(day 6)
2	10 days after fever and pharyngitis	Facial diplegia and generalized areflexia evolving to lower limb paresthesia with ataxia (Day 2)
3	10 days after fever and cough	Flaccid tetraparesis and facial weakness evolving to areflexia (day 2) and respiratory failure( day 5)
4	5 days after cough and hyposmia	Flaccid areflexic tetraparesis and ataxia (day 4)
5	7 days after cough,ageusia and anosmia	facial weakness,flaccid areflexic paraplegia(day 2-3) and respiratory failure (day 4)

• In the US case, the deficits in the 54 year old man were characterized by quadriparesis and areflexia, burning dysesthesias, mild ophthalmoparesis, and dysautonomia.
• He did not have the loss of smell and taste documented in other COVID-19 patients..
• The unique clinical features in the US case are urinary retention secondary to dysautonomia and ocular symptoms of diplopia.

Laboratory Findings

• The findings of five Italian patients with Guillain- Barre syndrome after the onset of COVID-19 infection:

Patient no.	CSF findings	Antiganglioside Antibodies	MRI Findings
1	Day 2(first lumbar puncture): Protein level: Normal; No cells; Negative PCR assay for SARS-CoV-2 Day 10(second lumbar puncture): Protein level:101mg/dl; White cell count 4per mm3; Negative PCR assay for SARS-CoV-2	Negative	Head: Normal Spine: Caudal nerve roots enhanced
2	Day 3 Protein level :123mg/dl; No cells were found; PCR assay was negative for SARS-CoV-2	Not tested	Head: Bilateral enhancement of Facial nerve Spine: Normal
3	Day 3 Protein level :193mg/dl; No cells were found; PCR assay for SARS-CoV-2 negative	Negative	Head: Normal Spine: Caudal nerve roots enhanced
4	Day 5: Protein level: Normal; No cells; PCR assay for SARS-CoV-2 was negative	Not tested	Head: Normal Spine:Normal
5	Day 3 Protein level: 40mg/dl; WBC count 3 per mm3; PCR assay for SARS-CoV-2 was negative	Negative	Head: Not performed Spine:Normal

Electrocardiogram

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

X-ray

• There are no x-ray findings associated with COVID-19 associated Guillain-Barre Syndrome.

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound findings associated with COVID-19 associated Guillain-Barre Syndrome.

Treatment

Medical therapy

• All patients were treated with Intravenous Immune globulin
• Plasmapheresis can also be done

Surgery

• Surgical intervention is not recommended for the management of COVID-19 associated Guillain-Barre Syndrome.

Primary Prevention

• The disease itself is associated with COVID-19 infection and it is believed that preventing the spread of the infection itself is the most promising primary prevention strategy at the moment.
• There have been rigorous efforts in order to develop a vaccine for novel coronavirus and several vaccines are in the later phases of trials.
• According to the CDC, the measures to prevent the spread the COVID-19 infection include:
  • Frequent handwashing with soap and water for at least 20 seconds or using a alcohol based hand sanitizer with at least 60% alcohol.
  • Staying at least 6 feet (about 2 arms’ length) from other people who do not live with you.
  • Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs.
  • Cleaning and disinfecting.

Secondary Prevention

• There are no established measures for the secondary prevention of COVID-19 associated Guillain-Barre Syndrome.

References

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