Neurological infections in 2021: a spotlight on India

In 2021, the second wave of COVID-19, associated with the devastating delta variant, swept across India. As of Nov 18, 2021, 34 478 517 cases of COVID-19 were confirmed in India, with 464 623 deaths. 2021 also witnessed an unprecedented nested epidemic of COVID-19-associated mucormycosis that predominantly affected the Indian subcontinent. By July 15, 2021, India had recorded 45 374 cases of COVID-19-associated mucormycosis and around 4300 deaths related to this fungal infection.¹

What led to the deadly outbreak of COVID-19-associated mucormycosis in India in 2021? An analysis² of the epidemiology of this fungal infection showed that diabetes is the most important risk factor, but that pulmonary and disseminated cases of this infection, and overall mortality, are lower in India compared with the rest of the world. In another epidemiological study in India from 2021,³ the presence of hypoxaemia and improper use of steroids was independently associated with COVID-19-associated mucormycosis compared with mucormycosis not associated with COVID-19.

Analyses of COVID-19 treatment protocols used in India this year4, 5 showed that indiscriminate use of corticosteroids, poor control of hyperglycaemia (in people with known or newly diagnosed diabetes), impaired immunity, blanket use of antibiotics, high intake of zinc, prolonged hospital stay, use of industrial oxygen, and ventilators with defective humidifiers were associated with the outbreak of COVID-19-associated mucormycosis. Moreover, COVID-19-related complications, such as cytokine storm, associated hyperglycaemia, and multiorgan dysfunction, have provided a near-perfect acidotic milieu for unabated growth of mucormycetes.

Involvement of the CNS has been shown to significantly affect survival of patients with COVID-19-associated mucormycosis.⁶ One hypothesis on how mucormycosis might have spread to the CNS in patients with COVID-19 involves hyperglycaemia-induced upregulation of endothelial glucose-regulated protein (GRP78) receptors. These receptors might facilitate adhesion as well as tissue invasion by mucormycetes, which could aid entry of this pathogen into the nasal sinuses, lungs, and brain.4, 5, 7 Statins have been suggested as a treatment to modulate GRP78 receptors and prevent invasive spread of the fungus.⁷

© 2022 Idrees Mohammed/Sputnik/Science Photo Library

The pathophysiology of CNS involvement in mucormycosis was proposed in a report from the Collaborative OPAI-IJO Study on Mucormycosis in COVID-19 (COSMIC) study,⁶ which—with 2826 patients—is the largest case series of COVID-19-associated mucormycosis to date. In patients with rhinocerebral mucormycosis, after initial nasal mucosal localisation, the fungus is believed to be able to reach the paranasal sinuses and further into the sphenopalatine fossa, which serves as the reservoir for subsequent spread to the CNS. The route of involvement of the CNS occurs maximally via the cavernous sinus (seen in approximately 70% of cases), followed by the cribriform plate (22% of cases) and pterygopalatine fossa (12% of cases), with instances of involvement of more than one route.⁶ These data consolidate our understanding of the pathogenesis of fungal spread across bony conduits or deficient barriers and through the vessels, showing the angioinvasive properties of mucormycetes. Transneuronal spread might also be seen, with permeation of the optic nerve, trigeminal nerve, and facial nerve.

Findings from the COSMIC study also showed that facial pain and headache were the most common neurological symptoms of rhinocerebral mucormycosis.⁶ An eschar over the nose, conjunctival chemosis, proptosis, and palate perforation were indicative of rhinocerebral mucormycosis.⁶ Cranial nerve palsies, ranging from cranial mononeuropathy to involvement of almost all the cranial nerves of one side (Garcin syndrome), dominate the gamut of neurological manifestations.⁶ Orbital apex syndrome and cavernous sinus syndrome have been noted as the most common patterns of multiple cranial nerve palsies.⁶ Isolated involvement of the optic nerve, facial nerve (in the infratemporal fossa), and oculomotor nerve has also been observed.⁷ Additionally, posterior ischaemic optic neuropathy or central retinal artery occlusion have been found as other reasons for optic nerve involvement in COVID-19-associated mucormycosis.6, 8

Neurovascular complications associated with COVID-19-associated mucormycosis range from watershed infarcts to intracranial haemorrhage. The internal carotid artery—although coursing through the cavernous sinus—was reported to be invaded by fungal hyphae,⁹ leading either to stenosis or complete occlusion. In another observational study from eastern India,¹⁰ fungal spread to the clivus in sphenoid sinus mucormycosis increased the likelihood of basilar artery involvement. Fungal infiltration of the arterial wall could result in the formation of a mycotic aneurysm and cause subarachnoid haemorrhage. Several neuroimaging abnormalities have been noted in patients with COVID-19-associated mucormycosis, such as basal meningeal enhancement, entrapment of cranial nerves, watershed infarcts, areas of cerebritis, and cerebral abscesses.2, 3, 6, 10

The unprecedented rise in COVID-19-associated mucormycosis in 2021 highlights the perils of unmonitored comorbidities, indiscriminate use of medications, and the lack of appropriate preparedness to tackle a preventable and dreadful disease. A focus on improving pharmacy inventory management and a multidisciplinary approach is needed to prevent future errors.