American Journal of Emergency Medicine 39 (2021) 125-128

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American Journal of Emergency Medicine

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Covid-19 associated Guillain-Barre Syndrome: Contrasting tale of four patients from a tertiary care centre in India

Satyan Nanda, Rahul Handa ?, Atul Prasad, Rajiv Anand, Dhruv Zutshi, Sujata K. Dass, Prabhjeet Kaur Bedi, Aarti Pahuja, Pankaj Kumar Shah, Bipan Sharma

Department of Neurology, BLK Super Speciality Hospital, New Delhi, India

a r t i c l e i n f o

Article history:

Received 16 July 2020

Received in revised form 1 September 2020 Accepted 10 September 2020

a b s t r a c t

Background: Globally, more than 12 million people have been infected with COVID -19 infection till date with more than 500,000 fatalities. Although, Covid-19 commonly presents with marked respiratory symptoms in the form of cough and dyspnoea, a neurotropic presentation has been described of late as well.

Objective: In this brief communication we report four cases of Covid-19 who presented to our hospital with fea- tures suggestive of Guillain-Barre Syndrome (GBS).

Discussion: The mechanisms by which SARS-CoV-2 causes neurologic damage are multifaceted, including direct damage to specific receptors, cytokine-related injury, secondary hypoxia, and retrograde travel along nerve fi- bres. The pathogenesis of GBS secondary to Covid-19 is not well understood. It is hypothesised that viral illnesses related GBS could be due to autoantibodies or direct neurotoxic effects of viruses.

Conclusion: Nervous system involvement in Covid-19 may have been grossly underestimated. In this era of pan- demic, it is very important for the physicians to be aware of association of GBS with Covid-19, as early diagnosis and treatment of this complication could have gratifying results. To the best of our knowledge, this is the first such case series of Guillain-Barre Syndrome associated with Covid-19 to be reported from India.

(C) 2020

Introduction

Globally, more than 12 million people have been infected with COVID -19 infection till date with more than 500,000 fatalities [1]. Al- though, evolution in COVID-19 research is taking place at a rapid pace, new findings have to be thoroughly checked before any conclusion or treatment protocol is made or modified [2]. Although, Covid-19 com- monly presents with marked respiratory symptoms in the form of cough and dyspnoea, a neurotropic presentation has been described of late as well [3]. Guillain Barre Syndrome (GBS) is best described as an acute inflammatory polyradiculoneuropathy clinically characterised by areflexia and progressive weakness of arms and legs. Though, many rare variants of GBS have been described, the commonly observed sub- types such as Acute Motor Axonal Neuropathy (AMAN), Acute Motor Sensory Axonal Neuropathy (AMSAN) and Acute Inflammatory Demye- linating Polyradiculoneuropathy (AIDP) tend to fulfil the above- mentioned criteria [4]. In this brief communication we report four cases of Covid-19 who presented to our hospital with features sugges- tive of GBS.

* Corresponding author.

E-mail address: rahulhanda0411@gmail.com (R. Handa).

Case 1

A 55-year-old female with background history of Diabetes Mellitus, Hypertension and Cholelithiasis presented with chief complaints of fever 10 days back lasting for 3 days, pain abdomen for 5 days; acute onset rapidly progressive symmetric weakness of all four limbs for 3 days (lower limbs followed by upper limbs). There was no history sug- gestive of cranial nerve, bowel or bladder involvement. On examination, patient was hemodynamically stable with 98% oxygen saturation (SpO2) on room air. Cranial nerve examination was normal. Motor ex- amination revealed generalised hypotonia, Grade 2/5 power in both lower limbs proximally and Grade 3/5 distally, while both upper limbs power was grade 4/5 proximally and grade 3/5 distally as per Medical Research Council (MRC) grading. Deep tendon reflexes were universally absent and plantar response was flexor bilaterally. Sensory examination was normal. Her single breath count (SBC) was 26. Her routine blood in- vestigations including complete blood count, liver and kidney function tests were normal. Viral markers including Human Immunodeficiency Virus, Hepatitis B Surface antigen (HBsAg) and Hepatitis C Virus (HCV) antibody were negative. Serum vitamin B12 levels and Thyroid function tests were normal whereas Glycosylated Hemoglobin (HbA1c) was elevated (9.4 %). Covid-19 testing was positive by reverse transcription polymerase chain reaction (RT-PCR). Inflammatory markers were universally elevated (Tables 1 and 2). Chest X ray was

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Table 1

Clinical and laboratory parameters of four cases presenting with Covid-19 associated GBS.

normal. Contrast enhanced Magnetic Resonance Imaging (MRI) of the spine was suggestive of degenerative changes in the spine (Table 2). Nerve Conduction Study (NCS) of both upper and lower limbs was sug- gestive of pure motor axonal polyneuropathy. CSF examination done on fourth day of hospitalisation showed albumino-cytological dissociation (Table 2). After informed consent the patient was started on IV Immu- noglobulin (IVIG): 0.4 g/kg body weight per day for five days. In view of a possibility of Covid-19 associated hypercoagulable state (elevated D Dimer) she was also given therapeutic anticoagulation. There was no further progression of her symptoms after starting IVIG and the patient was discharged after 10 days of hospital stay with Grade 4/5 power in both lower limbs and Grade 4+/5 power in both upper limbs.

Case 2

A 72-year-old male, known case of hypertension for 5 years on treat- ment, presented to the emergency department of our hospital with chief complaints of fever 6 days back lasting for 2 days, cough since past 3 days associated with progressive weakness of all four limbs since past 2 days. He had lost the ability to walk independently since 1 day. There was no history suggestive of cranial nerve involvement, di- arrhoea, bowel and bladder symptoms, or dog bite. On examination, pa- tient was hemodynamically stable and afebrile. Neurological examination revealed no cranial nerve involvement. Motor examina- tion showed generalised hypotonia, Grade 2/5 power in both lower limbs and grade 3/5 in both upper limbs as per MRC grading. Deep

Table 2

Laboratory parameters, Imaging and clinical outcomes of four cases presenting with Covid-19 associated GBS.

tendon reflexes were universally absent and plantar response was

flexor bilaterally. The sensory examination was normal. His SBC was

12. His routine blood investigations including complete blood count, serum sodium and potassium, liver and kidney function tests were nor- mal. Viral markers including Human Immunodeficiency Virus, Hepatitis B Surface antigen (HBsAg) and Hepatitis C Virus (HCV) antibody were negative. Serum B12 levels and Thyroid function tests were normal. Covid-19 testing was positive by RT-PCR technique. Contrast MRI of whole spine was suggestive of degenerative changes in the spine (Table 2). CSF examination showed albumino-cytological dissociation and inflammatory markers were elevated (Tables 1 and 2). Chest X ray showed bilateral ill-defined inhomogeneous infiltrates involving predominantly the upper lobes. IVIG therapy was started at a dose of

0.4 g/kg/day for five days. NCS was suggestive of severe demyelinating sensori-motor polyneuropathy affecting all 4 limbs with evidence of conduction block involving both ulnar nerves. Despite being on IVIG and supportive treatment for Covid-19, the patient had worsening of power in both upper and lower limbs and developed severe respiratory distress requiring intubation and mechanical ventilation. His respiratory involvement (chest infiltrates due to Covid-19) also continued to worsen and the patient expired after 7 days of hospital admission.

Case 3

A 55-year-old male, known case of Diabetes mellitus, hypertension and chronic kidney disease on maintenance haemodialysis (3/week) presented to OPD with chief complaints of difficulty in walking since 3 days and mild weakness of upper extremities since 1 day. He had his- tory of cough and sore throat 1 week back for 2 days. There was no his- tory suggestive of cranial nerve involvement, diarrhoea, bowel and bladder symptoms, or dog bite. On examination, patient was hemody- namically stable and afebrile. Neurological examination revealed no cranial nerve involvement. Motor examination showed generalised hy- potonia, grade 3/5 power in both lower limbs proximally and 4-/5 dis- tally. Upper limb motor examination showed grade 4/5 power bilaterally as per MRC grading. Deep tendon reflexes were absent in both lower limbs and 1+ in both upper limbs. Plantar response was flexor bilaterally. The sensory examination was abnormal with glove and stocking pattern sensory loss (position sense and pain) and positive Romberg’s test. His SBC was 22. He underwent routine blood investiga- tions which showed microcytic/hypochromic anaemia, raised blood Urea (61 mg/dL) and Creatinine levels (4.74 mg/dL). Potassium was el- evated (5.82 mmol/L) with elevated HbA1c (8.4 %). Viral markers in- cluding HIV, HBsAg and HCV antibody were negative. Serum vitamin B12 levels and Thyroid function tests were normal. Covid-19 testing was positive by RT-PCR technique. MRI screening of whole spine showed mild degenerative changes with no cord hyperintensity (Table 2). CSF examination showed albumino-cytological dissociation with elevated inflammatory markers (Tables 1 and 2). Chest X ray was normal. NCS was suggestive of axonal sensorimotor polyneuropathy af- fecting all 4 limbs. IVIG therapy was started on Day 2 of hospital admis- sion and 2 g/kg body weight of same was given over 5 days. Patient had good neurological improvement and was discharged by 9th day with power of grade 4+/5 in both upper limbs and grade 4/5 in both lower limbs.

Case 4

A 49-year-old male, known case of hypertension on treatment, pre- sented to the neurology outpatient department (OPD) with chief com- plaints of fever 10 days back which lasted for 2 days followed by 4 days history of progressive lower limb weakness and 2 days history of facial weakness. On examination, patient was hemodynamically sta- ble, afebrile with 98% SpO2 on room air. Neurological examination re- vealed bilateral lower motor neuron facial palsy (right > left). Upper limb power was normal across all joints; both lower limb power:

proximal: 3/5; distal: 4/5 as per MRC grading. The Deep tendon reflexes were absent in lower limbs and normal in upper limbs. Sensory exami- nation was normal. Routine blood investigations including complete blood count, serum sodium and potassium, liver and kidney function tests were normal. Viral markers including HIV, HBsAg and HCV anti- body were negative. Serum vitamin B12 levels and Thyroid function tests were normal. Covid-19 testing was positive by RT-PCR technique. NCS was suggestive of pure motor demyelinating polyneuropathy in- volving all 4 limbs. Contrast MRI of whole spine showed mild degener- ative changes of the spine (Table 2). CSF examination showed albumino-cytological dissociation with mildly elevated inflammatory markers in the blood (Tables 1 and 2). Chest X- ray showed evidence of bilateral lower and midzone infiltrates. IVIG was given at 0.4 g/kg body weight/day for 5 days with other supportive treatment. Good neurological improvement was observed over the next 5 days and patient was discharged after 7 days. At the time of discharge patient had 4+/5 power in both lower limbs with mild residual facial palsy.

Discussion

A member of the beta-coronaviridae family, SARS-CoV-2 is an enveloped, non-segmented, single-stranded, positive-sense RNA virus. The mechanisms by which SARS-CoV-2 causes neurologic damage are multifaceted, including direct damage to specific receptors, cytokine- related injury, secondary hypoxia, and retrograde travel along nerve fi- bres [5]. Three of the above cases presented with neurological com- plaints and had no respiratory features secondary to Covid-19, and these were the ones who did quite well with treatment. One patient who presented with respiratory complaints and X-ray changes along with neurological deficits continued to deteriorate even after starting treatment for both GBS and Covid-19, and eventually succumbed to the disease.

In the past GBS has been associated with a number of viral infections, most recently to Zika virus [6]. The pathogenesis of GBS secondary to Covid-19 is not well understood. It is well documented that the cross immunity which plays an important role in GBS secondary to bacterial infections such as C. jejuni may not be the main reason behind GBS as- sociated with viral infections namely Dengue and Zika. It is hypothesised that viral illnesses related GBS could be due to autoanti- bodies or direct neurotoxic effects of viruses [7]. Although, our patients had positive PCR throat swab test, their CSF examination did not show any raised cell count and contrast MRI of the spine did not show any en- hancement of caudal nerve roots, thus favouring immune mediated hy- pothesis. This was further strengthened by an excellent response to IVIG, thus favouring an immune mediated pathogenesis rather than di- rect viral damage.

Our case series serves to highlight the heterogeneity in clinical pre- sentation and laboratory parameters of patients with Covid-19 associ- ated GBS (Tables1 and 2). Only one of our patients had cranial nerve involvement (bilateral facial nerve palsy) with no patient developing bulbar symptoms. This was in contrast to typical GBS, wherein cranial nerve involvement is quite common. Less frequent involvement of cra- nial nerves in GBS secondary to Covid-19 is also in contrast to Zika virus associated GBS, where facial and third nerve involvement was quite common [7]. All the above patients had significantly raised pro- inflammatory markers that might suggest a causal link to pro- inflammatory state secondary to Covid-19. Similar rise in inflammatory markers were noted in other case reports as well, and it was hypothesised that these inflammatory mediators and cytokines may play a role in triggering an immune mediated neuropathy [8].

All our patients developed features of GBS, 5-10 days after the onset of Covid-19 symptoms, which is similar to the interval seen with Guillain-Barre syndrome that occurs secondary to other infections [9]. Most of the previous case reports documented a similar interval dura- tion between the onset of Covid-19 symptoms and GBS [2,9]. Three of our patients had an excellent response to IVIG and were ambulatory

without support within 10 days of starting treatment. Previous case re- ports show mixed treatment response with some reporting very good recovery, while others reported minimal or delayed response [9,10].

Conclusion

Nervous system involvement in Covid-19 may have been grossly underestimated. Over the course of this pandemic, an increasing num- ber of Covid-19 patients are being reported with neurological complica- tions. Some of these neurological presentations, in particular GBS has quite effective treatment options. In this era of pandemic, it is very im- portant for the physicians to be aware of the association of GBS with Covid-19, as early diagnosis and treatment of this complication could have gratifying results. It is also important to differentiate GBS from crit- ical illness neuropathy and respiratory distress secondary to Covid-19 itself, as treatment to the above conditions is quite different and inabil- ity to correctly diagnose could lead to significant increase in morbidity and mortality. To the best of our knowledge this case series of Guillain-Barre Syndrome associated with Covid-19 is the first one to be reported from India.

Declaration of Competing Interest

The manuscript, as submitted or its essence in another version, is not under consideration for publication elsewhere, and will not be

published elsewhere while under consideration by AJEM. The authors have no commercial associations or sources of support that might pose a conflict of interest. All authors have made substantive contributions to the study, and all authors endorse the data and conclusions.

References

1. World Health Organization. Coronavirus Disease (COVID-19): Situation Report, 172;

   2020.

   Carrillo-Larco RM, Altez-Fernandez C, Ravaglia S, Vizcarra JA. COVID-19 and Guillain- Barre Syndrome: a systematic review of case reports. Wellcome Open Res. 2020;5: 107.

2. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan. China JAMA Neurol. 2020;77(6):1-9.
3. Piccione EA, Salame K, Katirji B. Guillain-Barre syndrome and related disorders. Neu- romuscular disorders in clinical practice. New York, NY: Springer; 2014. p. 573-603.
4. Bridwell R, Long B, Gottlieb M. Neurologic complications of COVID-19. Am J Emerg Med. 2020;38(7):1549.e3-7.
5. Virani A, Rabold E, Hanson T, et al. Guillain-Barre syndrome associated with SARS- CoV-2 infection. IDCases. 2020;20:e00771.
6. Gupta A, Paliwal VK, Garg RK. Is COVID-19-related Guillain-Barre syndrome differ- ent? Brain Behav Immun. 2020;87:177-8.
7. Benvenuto Angelo, Carella Angelo Michele, et al. Atypical clinical presentation of COVID-19: a case of Guillain-Barre syndrome related to SARS-Cov-2 infection. Curr Tr Clin Med Sci. 2020;2(1).
8. Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barre syndrome associated with SARS-CoV-2. N Engl J Med. 2020;382(26):2574-6.
9. Assini A, Benedetti L, Di Maio S, Schirinzi E, Del Sette M. New clinical manifestation of COVID-19 related Guillain-Barre syndrome highly responsive to intravenous im- munoglobulins: two Italian cases [published correction appears in Neurol Sci. 2020 Jun 8]. Neurol Sci. 2020;41(7):1657-8.