key: cord-0873913-7uwjxpln
authors: Fredrich, Sarah; Greenberg, Benjamin M; Hatanpaa, Kimmo J
title: Neurological infections in 2020: COVID-19 takes centre stage
date: 2020-12-16
journal: Lancet Neurol
DOI: 10.1016/s1474-4422(20)30451-8
sha: 30b4d42de1a661cb29ebbafcbc7ba33f2f1098cf
doc_id: 873913
cord_uid: 7uwjxpln

nan

Although there have been many contributions to advance our understanding of neurological infections in 2020, the year has been dominated by research focused on the neurological consequences of COVID-19. Multidisciplinary studies are ongoing to better differen tiate the direct effects of severe acute respiratory syn drome coronavirus 2 (SARS-CoV-2) versus its secon dary effects (PMC7184392, NCT04386083, and CTRI/2020/07/026339). Nevertheless, it has become clear that there is a striking incidence of neurological involvement in this disease, the symptoms of which span reversible anosmia, stroke-related disability, and death. [1] [2] [3] Dry cough, fever, dyspnoea, nausea, emesis, and fatigue are common symptoms of SARS-CoV-2 infection 1 -a profile shared with numerous viral infections. However, anosmia and ageusia, which have now been documented in ample research, 1, 2, 4 are symptoms more distinctive of SARS-CoV-2 infection than other common viral infections, and the implications of these symptoms drive our understanding of the unique pathophysiology of COVID-19. In one of the largest studies to date, 3191 individuals infected with SARS-CoV-2 were surveyed to assess the prevalence of anosmia and ageusia. 488 (15·3%) individuals were found to have one or both of these symptoms; in most cases, taste and smell were fully recovered 7 days after onset on average. 1 Smaller studies have shown anosmia to be much more prevalent and the heralding symptom of SARS-CoV-2 infection, 5 therein identifying a potential source of viral replication and CNS invasion.

Subsequently, hypotheses emerged regard ing the poten tial for viral neurotropism and a direct route of entry into the CNS from the olfactory bulbs. In an imaging study 6 of 23 patients with confirmed SARS-CoV-2 infection with clinical anosmia, SARS-CoV-2-related olfactory dys func tion was differentiated from other viral olfactory dysfunction in several crucial ways. Postviral anosmia in the setting of upper respiratory tract infections is usually related to mucosal congestion and nasal obstruction, resulting in a conductive olfactory loss; however, few patients with SARS-CoV-2-related anosmia had sinonasal symptoms, suggesting that mucosal congestion is an unlikely aetiology for anosmia in these cases. 6 Olfactory epithelium support-cells residing in the olfactory cleft express the angiotensin-converting enzyme 2 receptor, identified as the binding antigen for SARS-CoV-2. 6 Imaging of the olfactory cleft showed olfactory cleft opacification in 17 (74%) of cases. 6 Moving proxi mally, olfactory nerve filia clumping, sug gestive of inflammation, was observed in eight (35%) of patients, and olfactory bulb signal abnormalities, indicating degenera tion or micro haemorrhage, were seen in 21 (91%) individuals. Within the CNS, hyperintense T2 or fluidattenuated inversion recovery signals in the olfactory cortex were found in five (22%) individuals.

An association has been shown between SARS-CoV-2 infection and acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 7 extending the viral pathogenic effects to the peripheral nervous system. In a case series of five individuals with AIDP and SARS-CoV-2 infection, the latency between res pira tory symptom and neurological symptom onset was 14-30 days. 7 Most patients presented with the classical findings of AIDP, with ascending paraparesis and hyporeflexia, conduction blocks and increased latency on nerve con duction studies, and albuminocytological dissociation in the Sturti/Getty Images www.thelancet.com/neurology Vol 20 January 2021 CSF. 7 However, uniquely to SARS-CoV-2-associated AIDP, patients also showed elevated systemic or CSF levels of IL-6 and IL-8, implicating an overactive inflammatory response in the pathogenesis of AIDP in these patients.

Stroke has been identified as an independent risk factor for death in individuals with SARS-CoV-2 infection. 2 Although it remains unclear whether the incidence of stroke in people with SARS-CoV-2 infection is higher than in those with other severe viral illnesses, SARS-CoV-2-related neurovascular complications appear to have a unique mechanism also tied to inflammation. Neuro imaging has revealed multivascular infarcts in the absence of common cardioembolic mechanisms. 2 Micro bleeds are concurrently seen, indicat ing potential small vessel involve ment. Furthermore, vessel wall sequence MRI revealed contrast enhancement of the medi um and large arterial vessel walls in these patients. 2 This finding, coupled with the absence of CSF inflammatory markers and SARS-CoV-2-specific IgG antibodies, further supports the hypothesis for a systemic rather than CNS-specific inflam matory response contributing to a hypercoagulable state and endo thelial cell dysfunction. 2 An autopsy of one individual additionally showed systemic endotheliitis. 2 Brain autopsy studies 8 have described pathological changes that have been attributed to the direct effects of SARS-CoV-2 infection in the brain; however, these studies lacked controls. An exception was a brain autopsy study 8 of seven patients with SARS-CoV-2 infection comparing the findings with 13 control patients, defined as SARS-CoV-2-negative patients who died of sepsis or died suddenly without a systemic inflam matory response. The most common brain autopsy findings in patients with SARS-CoV-2 infections are also commonly seen in patients who die of other severe illnesses. 9 Therefore, neuropathological changes such as reactive gliosis, mild chronic perivascular inflam matory infiltrates, and acute hypoxic-ischaemic injury in patients with SARS-CoV-2 infections probably reflect critical illness-related, nonspecific changes rather than specific abnormalities induced by the virus.

Through the efforts of researchers worldwide, we have gained foundational insights into the patho physiology of COVID-19. Indeed, the virus has proven to be of its own kind, displaying a spectrum of potential pathogenetic mechanisms including delayed para infec tious demyelinat ing and axonal injury, viral inva sion, hyperactive inflammatory response, and endothelial dys func tion. With neurological conse quences span ning the entire neuroaxis, the importance of continued research efforts to combat this public health crisis can not be overstated. 

Prevalence and duration of acute loss of smell or taste in COVID-19 patients

Large and small cerebral vessel involvement in severe COVID-19: detailed clinical workup of a case series

History of stroke is independently associated with in-hospital death in patients with COVID-19

Smell and taste dysfunction in patients with COVID-19: a systematic review and meta-analysis

Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms

Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia

Clinical neurophysiology and cerebrospinal liquor analysis to detect Guillain-Barré syndrome and polyneuritis cranialis in COVID-19 patients: a case series

Autopsy findings in COVID-19-related deaths: a literature review

Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology