Chronic long‐COVID syndrome: A protracted COVID‐19 illness with neurological dysfunctions

Abstract After almost a year of COVID‐19, the chronic long‐COVID syndrome has been recognized as an entity in 2021. The patients with the long‐COVID are presenting with ominous neurological deficits that with time are becoming persistent and are causing disabilities in the affected individuals. The mechanisms underlying the neurological syndrome in long‐COVID have remained obscure and need to be actively researched to find a resolution for the patients with long‐COVID. Here, the factors like site of viral load, the differential immune response, neurodegenerative changes, and inflammation as possible causative factors are debated to understand and investigate the pathogenesis of neuro‐COVID in long‐COVID syndrome.

therapies in long-COVID syndrome to minimize the disabilities resulting in the affected patients. Additionally, a history of pre-COVID existing neurological deficit should be taken into account to identify newer neurological sign and symptoms caused by COVID. A differential diagnosis with post-traumatic stress disorder (PTSD) caused by the pandemic appears to be important.
Also feature like facial drooping, and speech-related deficits which are potential signs of stroke can be blunted by a patient's face mask, wearing of which is common during the COVID-19 pandemic. 3

| S ITE S OF VIR AL LOAD AND THEIR S I G NIFI C AN CE IN NEURO -COVID
Central to the understanding of the neurological deficits caused by SARS-CoV-2 is the ability of this virus to seed specific sites in human tissues, which can enable its access to the central nervous system (CNS). Nasal and oral cavity are known sites of SARS-CoV-2 seeding from which samples are collected to diagnose COVID-19. The nasal cavity, in particular, is anatomically extended to regions bearing neurological tissues like olfactory mucosa (OM), and across the cribriform plate, at the root of the nose ( Figure 1A), to the olfactory bulb (OB) and frontal lobe of the brain ( Figure 1A-A1). Though the oral cavity has no direct extensions to the CNS, the infection of the nerve terminals in the mouth via retrograde neuronal transport can enable the SARS-CoV-2 to reach cardinal regions of the CNS like the brainstem ( Figure 1A). 2 Common to both of the above routes is its extension to the lungs ( Figure 1B), which is a known organ to be involved in SARS-CoV-2 infection in acute as well as long-COVID.

| PROG RE SS IVE NEU ROTROPI C DEG ENER ATIVE EFFEC TS OF SAR S -CoV-2
One of the possible reasons for the observation of neurological deficits in long-COVID 4 ( Figure 1C), is a possibly a slowly progressive degenerative effect of the SARS-CoV-2 following the neuronal entry.

| P OSS IB LE ROLE OF THE INFL AMMATORY RE S P ON S E TO SAR S -CoV-2 INFEC TI ON IN C AUSATI ON OF THE CN S MANIFE S TATI ON IN LONG -COVID
The immunologically mediated cytokine release by glia and lympho-

| PER S IS TEN CE OF VIR AL LOADS AT IMMUNOLOG IC ALLY PRIVILEG ED S ITE S
Among diverse reasons for incomplete clearance of SARS-CoV-2 from the human body by the immune system after 2-3 weeks of the COVID-19 infection is the possible ability of the virus to reside at immunologically privileged sites, from where its arrival into the circulation can lead to a protracted course of illness leading to long-COVID.
The eyes, lacrimal sac, 8 testes, and placenta are few examples where SARS-CoV-2 can conceal itself, but why this is not the case with patient's not exhibiting long-COVID remains to be resolved.

| D ISCUSS I ON AND CON CLUS I ON
The magnitude with which the human immune system would respond to COVID-19 differs from person to person for few apparent reasons, that includes, (a) the viral load, (b) the ACE2 expression levels in the tissues, and (c) the diversity of immune response. 9 It appears that following an acute phase if the removal of SARS-CoV-2 is not substantial enough, the sub-acute infection persists and becomes chronic to exhibit as long-COVID. Of the sites that suffer the effects of the residual virus and the inflammation that accompanies it, the CNS is the most venerable tissue. The latter is because of the inability of the neurons to regenerate following damage caused by either the virus (Figure 1, C1) or cytokines generated by the lowgrade inflammation (Figure 1, C2). Other tissues that can regenerate following the cellular injury, do not dominate the symptomatic picture of long-COVID as a partial restoration of function is likely following COVID-19. The finding that vaccinations help some patients with long-COVID, 7 needs in-depth research to find the support the vaccination offers to a chronic symptomatic long-COVID patient at the pathogenetic level. Stimulation of a weakly provoked immune system to eradicate the virus seems to be one possibility, but other mechanisms may be at play that is yet to be elucidated in long-COVID. The neurological deficits in long-COVID 4 were predicted to impose a huge burden on the healthcare profession and it now is proving itself a major cause of disability in the post-acute-COVID patient group.

| FUTURE DIREC TIONS
Research that includes long-COVID patients with neurological deficits for understanding the basic underlying pathogenesis of neuro-COVID is needed and the NeuroCOVID project is one example. 4 The biological fluids of these patients need to be fully analyzed for cytokines. Imaging the CNS to notice morphological changes induced in long-COVID is also required as the images can be compared in the coming years to see if the findings progress or remain static. Clinical assessment and appropriate treatment regimens are also essentially needed as if not halted in time, the neurological deficits may become a permanent disability that would not revert. F I G U R E 1 Long-COVID: CNS Access and NeuroCOVID syndrome. SARS-CoV-2 viral loads can follow anatomical pathways from the nasal cavity to the brain (A-A1) via the cribriform plate of the ethmoid bone (A1) and the lungs via respiratory passages (B). Patients in long-COVID report diverse neurological signs and symptoms (C-list) that can be due to slow neuronal damage (C1) (neurodegeneration) or due to lowgrade inflammation and cytokine-mediated damage (C2). SARS-CoV-2 has been isolated from beneath the cribriform plate and the neurons of the frontal lobe in COVID-19 patients