COVID-19-associated Guillain-Barre syndrome
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.[1]
- 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.[2]
- In June 2020,the very first case of COVID-19 associated Guillain-barre syndrome in the United States was reported.[3]
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%).[4]
- 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 [5].
- 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.[6][7]
- 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[7].
- 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:[8][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]
| 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:[5]
- 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 [2].
- 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.[24]
- Another case of Guillain–Barre syndrome with COVID-19 has been reported in Iran[25].
- One case of Guillain–Barre syndrome with COVID-19 was reported in the UK.The patient was a 49-year-old man of South Asian descent with no medical history and reported a 3-week history of shortness of breath, headache and cough.He came to emergency department with worsening cough and distal lower limb paraesthesia during the previous week, resulting in difficulty mobilising.[26]
- There was also one case of SARS-CoV-2 infection associated Guillain-Barre syndrome in a child.The patient was an eleven year old boy who presented with typical features of GBS.The diagnosis of the SARS-CoV-2 infection was confirmed by oropharyngeal swab on reverse transcription polymerase chain reaction assay.[27]
- Familial occurrence of Guillain-Barré syndrome after COVID-19 infection has also been reported.2 members of a family affected by COVID-19 presented with ascending paresthesia with the final diagnosis of Guillain-Barre syndrome.The patient was a 38-year-old man who presented with a history of ascending paresthesia and bilateral facial droop for 5 days before admission and was treated with a diagnosis of Guillain-Barre syndrome, his 14-year-old daughter also presented with a history of progressive paresthesia and weakness. Similar to her father, the paraclinical evaluations were consistent with Guillain-Barre syndrome.[28]
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.[29][2]
- The only US patient with COVID-19 associated GBS briefly required mechanical ventilation and was successfully weaned after receiving a course of Intravenous Immunoglobulin.[3]
Diagnosis
History and Symptoms:
- The most common symptoms of Guillain-Barre syndrome are
- 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
- Less common symptoms of Guillain Barre syndrome include:
- Dysautonomic features
- Symptoms of papilledema such as
- Headache
- Visual disturbance[30]
- Involuntary facial movement [31]
- Hearing loss[32]
- Difficulty speaking (vocal cord paralysis)
- Mental status changes
- 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.[2]
| Patient no. | Onset of neurologic symptoms |
Neurologic Signs & Symptoms [33] |
|---|---|---|
| 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.[3].
- The unique clinical features in the US case are urinary retention secondary to dysautonomia and ocular symptoms of diplopia.[3]
Laboratory Findings
- The findings of five Italian patients with Guillain- Barre syndrome after the onset of COVID-19 infection:[2]
| Patient no.[2] | CSF findings [2] |
Antiganglioside Antibodies [2] |
MRI Findings[2]
|
|---|---|---|---|
| 1 |
|
Negative |
|
| 2 |
|
Not tested |
|
| 3 |
|
Negative |
|
| 4 |
|
Not tested |
|
| 5 |
|
Negative |
|
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 with COVID-19 associated Guillain-Barre syndrome were treated with intravenous immune globulin (0.4 g/kg/day).[34]
- Plasmapheresis can also be done in patients with COVID-19 associated Guillain-Barre Syndrome.
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.[35]
- According to the CDC, the measures to prevent the spread the COVID-19 infection include:[36]
- 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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|pmc=value (help). PMID 32563019 Check|pmid=value (help). - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Toscano, Gianpaolo; Palmerini, Francesco; Ravaglia, Sabrina; Ruiz, Luigi; Invernizzi, Paolo; Cuzzoni, M. Giovanna; Franciotta, Diego; Baldanti, Fausto; Daturi, Rossana; Postorino, Paolo; Cavallini, Anna; Micieli, Giuseppe (2020). "Guillain–Barré Syndrome Associated with SARS-CoV-2". New England Journal of Medicine. 382 (26): 2574–2576. doi:10.1056/NEJMc2009191. ISSN 0028-4793.
- ↑ 3.0 3.1 3.2 3.3 "First Reported US Case of Guillain-Barré Linked to COVID-19".
- ↑ Lin JJ, Hsia SH, Wang HS, Lyu RK, Chou ML, Hung PC; et al. (2012). "Clinical variants of Guillain-Barré syndrome in children". Pediatr Neurol. 47 (2): 91–6. doi:10.1016/j.pediatrneurol.2012.05.011. PMID 22759683.
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|pmc=value (help). PMID 32445789 Check|pmid=value (help). - ↑ Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B (February 2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. PMC 7159299 Check
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|pmc=value (help). PMID 32312628 Check|pmid=value (help). - ↑ 8.0 8.1 Kira R (February 2018). "[Acute Flaccid Myelitis]". Brain Nerve (in Japanese). 70 (2): 99–112. doi:10.11477/mf.1416200962. PMID 29433111.
- ↑ Hopkins SE (November 2017). "Acute Flaccid Myelitis: Etiologic Challenges, Diagnostic and Management Considerations". Curr Treat Options Neurol. 19 (12): 48. doi:10.1007/s11940-017-0480-3. PMID 29181601.
- ↑ Messacar K, Schreiner TL, Van Haren K, Yang M, Glaser CA, Tyler KL, Dominguez SR (September 2016). "Acute flaccid myelitis: A clinical review of US cases 2012-2015". Ann. Neurol. 80 (3): 326–38. doi:10.1002/ana.24730. PMC 5098271. PMID 27422805.
- ↑ Chong PF, Kira R, Mori H, Okumura A, Torisu H, Yasumoto S, Shimizu H, Fujimoto T, Hanaoka N, Kusunoki S, Takahashi T, Oishi K, Tanaka-Taya K (February 2018). "Clinical Features of Acute Flaccid Myelitis Temporally Associated With an Enterovirus D68 Outbreak: Results of a Nationwide Survey of Acute Flaccid Paralysis in Japan, August-December 2015". Clin. Infect. Dis. 66 (5): 653–664. doi:10.1093/cid/cix860. PMC 5850449. PMID 29028962.
- ↑ Messacar K, Asturias EJ, Hixon AM, Van Leer-Buter C, Niesters H, Tyler KL, Abzug MJ, Dominguez SR (August 2018). "Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality". Lancet Infect Dis. 18 (8): e239–e247. doi:10.1016/S1473-3099(18)30094-X. PMID 29482893. Vancouver style error: initials (help)
- ↑ Chen IJ, Hu SC, Hung KL, Lo CW (September 2018). "Acute flaccid myelitis associated with enterovirus D68 infection: A case report". Medicine (Baltimore). 97 (36): e11831. doi:10.1097/MD.0000000000011831. PMC 6133480. PMID 30200066.
- ↑ "Botulism | Botulism | CDC".
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- ↑ Walling AD, Dickson G (February 2013). "Guillain-Barré syndrome". Am Fam Physician. 87 (3): 191–7. PMID 23418763.
- ↑ Gilhus NE (2011). "Lambert-eaton myasthenic syndrome; pathogenesis, diagnosis, and therapy". Autoimmune Dis. 2011: 973808. doi:10.4061/2011/973808. PMC 3182560. PMID 21969911.
- ↑ Krishnan C, Kaplin AI, Deshpande DM, Pardo CA, Kerr DA (May 2004). "Transverse Myelitis: pathogenesis, diagnosis and treatment". Front. Biosci. 9: 1483–99. PMID 14977560.
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- ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430.
- ↑ "Frontiers | Neurological Manifestations of COVID-19 (SARS-CoV-2): A Review | Neurology".
- ↑ Tiet, May Yung; AlShaikh, Nazar (2020). "Guillain-Barré syndrome associated with COVID-19 infection: a case from the UK". BMJ Case Reports. 13 (7): e236536. doi:10.1136/bcr-2020-236536. ISSN 1757-790X.
- ↑ Rasker, Johannes J; Emad, Yasser; Bamaga, Ahmed; Saad, Ahmed; Ragab, Yasser; Zakaria, Fairouz; Khalifa, Maher (2020). "Guillain-Barre Syndrome Associated with SARS-CoV-2 Detection and a COVID-19 Infection in a Child". Journal of the Pediatric Infectious Diseases Society. doi:10.1093/jpids/piaa086. ISSN 2048-7193.
- ↑ Paybast, Sepideh; Gorji, Reza; Mavandadi, Shirin (2020). "Guillain-Barré Syndrome as a Neurological Complication of Novel COVID-19 Infection". The Neurologist. 25 (4): 101–103. doi:10.1097/NRL.0000000000000291. ISSN 2331-2637.
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- ↑ Joynt, R. J. (1958). "Mechanism of Production of Papilledema in the Guillain-Barre Syndrome". Neurology. 8 (1): 8–8. doi:10.1212/WNL.8.1.8. ISSN 0028-3878.
- ↑ Mateer JE, Gutmann L, McComas CF (March 1983). "Myokymia in Guillain-Barré syndrome". Neurology. 33 (3): 374–6. doi:10.1212/wnl.33.3.374. PMID 6681885.
- ↑ Nelson KR, Gilmore RL, Massey A (August 1988). "Acoustic nerve conduction abnormalities in Guillain-Barré syndrome". Neurology. 38 (8): 1263–6. doi:10.1212/wnl.38.8.1263. PMID 3399076.
- ↑ "Guillain–Barré Syndrome Associated with SARS-CoV-2 | NEJM".
- ↑ van Doorn PA, Kuitwaard K, Walgaard C, van Koningsveld R, Ruts L, Jacobs BC (May 2010). "IVIG treatment and prognosis in Guillain-Barré syndrome". J. Clin. Immunol. 30 Suppl 1: S74–8. doi:10.1007/s10875-010-9407-4. PMC 2883091. PMID 20396937.
- ↑ "NIH clinical trial of investigational vaccine for COVID-19 begins | National Institutes of Health (NIH)".
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