Guillain–Barre Syndrome in a Post-COVID-19 Patient who had Rhino-Orbital Mucormycosis

Sir, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with many neurologic complications like encephalopathy, arterial and venous strokes, intracerebral hemorrhage, transverse myelitis, anosmia, ageusia, Guillain–Barre syndrome, critical illness polyneuropathy, and critical illness myopathy, myositis, and rhabdomyolysis.[1,2] During the coronavirus disease 2019 (COVID-19) pandemic, India witnessed an epidemic of another life-threatening disease, “rhino-orbital-cerebral mucormycosis.” Mucormycosis is an angioinvasive disorder that can rapidly lead to massive destruction of nasal sinuses, orbit, and oral cavity and eventually spread to the brain. A variety of risk factors have been identified including uncontrolled diabetes, corticosteroids, tocilizumab, mechanical ventilation, and prolonged oxygen therapy.[3-5] We report an unusual case of post-COVID rhino-orbital mucormycosis, who subsequently developed Guillain–Barre syndrome. A 46-year-old man presented with weakness in all four limbs for 2 days’ duration. Previously, he suffered from fever, cough, and myalgia for 5 days. His nasal/throat swabs tested positive for SARS-CoV-2 infection. During illness, he developed hypoxia with oxygen saturation falling below 90%; so, supplemental oxygen at 2–3 L/min was administered at home with the help of oxygen cylinders. In addition, he also received oral methylprednisolone (16 mg/day), which he continued along with other symptomatic treatments. Sixteen days later (on 05/10/2021), the patient reported right frontal headache along with drooping right eyelid. He developed an ulcer on the inner aspect of the upper lip. Cranial magnetic resonance imaging showed destructive lesions in the maxillary and frontal sinuses, also invading the medial wall of the right orbit and the right medial rectus [Figure 1, lower panel]. A diagnosis of rhino-orbital mucormycosis was made. On 06/02/2021, endoscopic sinus debridement of nasal sinuses was done. Histopathology of debrided tissues confirmed mucormycosis [Figure 1, right upper panel]. The patient received parenteral liposomal amphotericin B (5 mg/kg/day) for 2 weeks. He got relief from headache and was discharged with advice to continue oral posaconazole (300 mg once a day). Subsequently, he noted pain inside the mouth. Again (on 07/01/2021), a computed tomography of nasal sinuses was done, which showed destruction of the bilateral maxilla, frontal bone, and ethmoid sinus wall with associated soft tissue. He was examined in the Oral and Maxillofacial Surgery Department. He had grayish/black lesions over the hard palate and molar teeth [Figure 1, left and middle-upper panel]. Debridement of dead tissues of the palate and jaw was done. He was continued on oral antibiotics, oral posaconazole, and nasogastric tube feeding. The present illness started on 07/11/2021 when he noticed bilateral weakness in all the limbs. In the next 2 days, he required support to get up and for all his daily activities. The neurologic examination showed intact higher mental function. He had partial ptosis of the right eye with normal ocular movements. Other cranial nerves were normal. Motor examination revealed areflexic motor quadriparesis. The sensory examination was normal. The plantar reflexes were flexor. His blood parameters revealed total leukocyte count 10,900 cells/mm3 (71% polymorphs), platelet count 114,000/µl, random blood sugar 135 mg/dL, hemoglobin A1c (HbA1c) 5.7%, serum sodium 130 mmol/L, serum potassium 3.7 mmol/L, blood urea 29 mg/dL, serum creatinine 0.69 mg/dL, D-dimer 0.51 µg/mL, B12 167 pg/mL, and folate levels 35 nmol/L. His liver function and thyroid function tests were normal. The enzyme-linked immunoassay tests for hepatitis B, hepatitis C virus, and human immunodeficiency viruses I and II were negative. Reverse transcription polymerase chain reaction (RT-PCR) test was negative. Cerebrospinal fluid examination revealed cytoalbuminic dissociation (protein 120 mg/dL and cells less than 5/mm3). A nerve conduction study revealed a demyelinating pattern. We promptly treated the patient with intravenous immunoglobulins 0.4 g/kg/day for 5 days. The patient improved and became independent in all his daily activities. He was discharged with the advice to continue oral posaconazole 300 mg/day.Figure 1: Upper panel: Photograph of the oral cavity shows fungal invasion of the hard palate and molar teeth and collection of debrided tissue (left- blank arrows). Histopathology of debrided tissue shows aseptate and branching hyphae, confirming the diagnosis of mucormycosis (hematoxylin and eosin stain; ×40- middle and right). Lower panel: T2-weighted fat-suppressed (middle) and T1-weighted, fat-suppressed contrast-enhanced MR images (left and right) show extensive involvement of the maxillary sinuses (white arrows), palate, right orbit (black arrow), and the surrounding tissues (white arrowheads). MR = magnetic resonanceThis is an unusual case because of three reasons. Firstly, this is the only post-COVID-19 case reported so far that has two serious complications sequentially, rhino-orbital mucormycosis and then Guillain–Barre syndrome. Secondly, rhino-orbital-cerebral mucormycosis possibly was a trigger for Guillain–Barre syndrome. Thirdly, this patient developed rhino-orbital-cerebral mucormycosis despite any major abnormality in the blood glucose levels. In the second wave of COVID-19, India faced an unexpected epidemic of mucormycosis (black fungus). Mucormycosis is caused by ubiquitous fungi, which are collectively called mucormycetes. Common species Rhizopus and Mucor are the most frequent fungi, which are responsible for human mucormycosis in certain high-risk persons. Persons with severe COVID-19 (requiring oxygen support), those on prolonged corticosteroid use, and those with uncontrolled diabetes mellitus are particularly vulnerable to developing rhino-orbital-cerebral mucormycosis. In the majority of cases, HbA1c level was more than 10%. Patients with diabetic ketoacidosis are highly susceptible to developing mucormycosis.[6,7] The indiscriminate use of corticosteroids in managing COVID-19, coupled with subsequent uncontrolled diabetes mellitus, is believed to be a significant factor contributing to the surge in mucormycosis cases in India. A retrospective study involving 58 COVID-19–associated mucormycosis patients revealed a median HbA1c value of 10.5% (with a mean of 10.44 ± 2.84 mg%). Similarly, an analysis of 101 documented mucormycosis cases found that 80% of patients had preexisting diabetes, while approximately 15% presented with diabetic ketoacidosis. These findings underscore the link between poorly controlled diabetes, exacerbated by the use of corticosteroids, and the heightened susceptibility to mucormycosis in the context of COVID-19. This emphasizes the need for cautious and targeted corticosteroid administration and vigilant diabetes management to mitigate the risk of mucormycosis complications.[8,9] Our patient did not have any abnormality in blood glucose levels. Guillain–Barre syndrome is a commonly reported neurologic complication of COVID-19. Freire et al., in a review of 82 published cases, noted that Guillain–Barre syndrome develops up to 90 days (median 11 days) after the onset of COVID-19. Both para-infectious and post-infectious types of Guillain–Barre syndrome have been recorded. Post-infectious Guillain–Barre syndrome develops in real-time polymerase chain reaction test–negative patients generally after 3 weeks of initial COVID-19. COVID-19 associated with Guillain–Barre syndrome is thought to be triggered by the phenomenon of molecular mimicry. In addition, immune-mediated injury during cytokine storm and direct vial invasion of peripheral nerves were also considered putative mechanisms for Guillain–Barre syndrome in COVID-19.[10,11] Given the late development of rhino-orbital-cerebral mucormycosis in the post-COVID-19 period, we speculate that Guillain–Barre syndrome might have been triggered by Mucor spp. Mucor spp. have vasoinvasive properties, and in many cases, Mucor fungemia has been demonstrated.[12] In conclusion, this case was unique in the sense that so far, no COVID-19 case has had two concomitant severe complications. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.