Objective Most SARS‐CoV‐2‐infected individuals never require hospitalization. However, some develop prolonged symptoms. We sought to characterize the spectrum of neurologic manifestations in non‐hospitalized Covid‐19 “long haulers”. Methods This is a prospective study of the first 100 consecutive patients (50 SARS‐CoV‐2 laboratory‐positive (SARS‐CoV‐2+) and 50 laboratory‐negative (SARS‐CoV‐2‐) individuals) presenting to our Neuro‐Covid‐19 clinic between May and November 2020. Due to early pandemic testing limitations, patients were included if they met Infectious Diseases Society of America symptoms of Covid‐19, were never hospitalized for pneumonia or hypoxemia, and had neurologic symptoms lasting over 6 weeks. We recorded the frequency of neurologic symptoms and analyzed patient‐reported quality of life measures and standardized cognitive assessments. Results Mean age was 43.2 ± 11.3 years, 70% were female, and 48% were evaluated in televisits. The most frequent comorbidities were depression/anxiety (42%) and autoimmune disease (16%). The main neurologic manifestations were: “brain fog” (81%), headache (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%), with only anosmia being more frequent in SARS‐CoV‐2+ than SARS‐CoV‐2‐ patients (37/50 [74%] vs. 18/50 [36%]; p < 0.001). Moreover, 85% also experienced fatigue. There was no correlation between time from disease onset and subjective impression of recovery. Both groups exhibited impaired quality of life in cognitive and fatigue domains. SARS‐CoV‐2+ patients performed worse in attention and working memory cognitive tasks compared to a demographic‐matched US population (T‐score 41.5 [37, 48.25] and 43 [37.5, 48.75], respectively; both p < 0.01). Interpretation Non‐hospitalized Covid‐19 “long haulers” experience prominent and persistent “brain fog” and fatigue that affect their cognition and quality of life.

Objective We characterized the evolution of neurologic symptoms and self‐perceived recovery of non‐hospitalized COVID‐19 “long haulers” 6–9 months after their initial Neuro‐COVID‐19 clinic evaluation. Methods In this follow‐up study on the first 100 patients, 50 SARS‐CoV‐2 laboratory‐positive (SARS‐CoV‐2 + ), and 50 laboratory‐negative (SARS‐CoV‐2 − ), evaluated at our Neuro‐COVID‐19 clinic between May and November 2020, patients completed phone questionnaires on their neurologic symptoms, subjective impression of recovery and quality of life. Results Of 52 patients who completed the study (27 SARS‐CoV‐2 + , 25 SARS‐CoV‐2 − ) a median 14.8 (range 11–18) months after symptom onset, mean age was 42.8 years, 73% were female, and 77% were vaccinated for SARS‐CoV‐2. Overall, there was no significant change in the frequency of most neurologic symptoms between first and follow‐up evaluations, including “brain fog” (81 vs. 71%), numbness/tingling (69 vs. 65%), headache (67 vs. 54%), dizziness (50 vs. 54%), blurred vision (34 vs. 44%), tinnitus (33 vs. 42%), and fatigue (87 vs. 81%). However, dysgeusia and anosmia decreased overall (63 vs. 27%, 58 vs. 21%, both p < 0.001). Conversely, heart rate and blood pressure variation (35 vs. 56%, p = 0.01) and gastrointestinal symptoms (27 vs. 48%, p = 0.04) increased at follow‐up. Patients reported improvements in their recovery, cognitive function, and fatigue, but quality of life measures remained lower than the US normative population ( p < 0.001). SARS‐CoV‐2 vaccination did not have a positive or detrimental impact on cognitive function or fatigue. Interpretation Non‐hospitalized COVID‐19 “long haulers” continue to experience neurologic symptoms, fatigue, and compromised quality of life 14.8 months after initial infection.

As of May 2022, there have been more than 527 million infections with severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) and over 6.2 million deaths from Coronavirus Disease 2019 (COVID-19) worldwide. COVID-19 is a multisystem illness with important neurologic consequences that impact long-term morbidity and mortality. In the acutely ill, the neurologic manifestations of COVID-19 can include distressing but relatively benign symptoms such as headache, myalgias, and anosmia; however, entities such as encephalopathy, stroke, seizures, encephalitis, and Guillain-Barre Syndrome can cause neurologic injury and resulting disability that persists long after the acute pulmonary illness. Furthermore, as many as one-third of patients may experience persistent neurologic symptoms as part of a Post-Acute Sequelae of SARS-CoV-2 infection (Neuro-PASC) syndrome. This Neuro-PASC syndrome can affect patients who required hospitalization for COVID-19 or patients who did not require hospitalization and who may have had minor or no pulmonary symptoms. Given the large number of individuals affected and the ability of neurologic complications to impair quality of life and productivity, the neurologic manifestations of COVID-19 are likely to have major and long-lasting personal, public health, and economic consequences. While knowledge of disease mechanisms and therapies acquired prior to the pandemic can inform us on how to manage patients with the neurologic manifestations of COVID-19, there is a critical need for improved understanding of specific COVID-19 disease mechanisms and development of therapies that target the neurologic morbidities of COVID-19. This current perspective reviews evidence for proposed disease mechanisms as they inform the neurologic management of COVID-19 in adult patients while also identifying areas in need of further research.

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Background Persistent viral RNA shedding of SARS-CoV-2 following COVID-19 has increasingly been recognized, with limited understanding of its implications on outcomes in hospitalized COVID-19 patients. Methods We retrospectively assessed for persistent viral shedding across Northwestern Medicine Healthcare (NMHC) patients between March and August 2020. We assessed for predictors of persistent viral shedding, in-hospital delirium, and six-month mortality using binary logistic regression. Results Of the 2,518 hospitalized patients with an RT-PCR-confirmed diagnosis of COVID-19, 959 underwent repeat SARS-CoV-2 RT-PCR at least fourteen days from initial positive testing. Of those, 405 (42.2%) patients were found to have persistent viral shedding. Persistent viral shedding was associated with male sex, increased BMI, diabetes mellitus, chronic kidney disease, and exposure to corticosteroids during initial COVID-19 hospitalization. Persistent viral shedding was independently associated with incidence of in-hospital delirium after adjusting for factors including severity of respiratory dysfunction (OR 2.45; 95% CI 1.75, 3.45). Even after adjusting for age, severity of respiratory dysfunction, and occurrence of in-hospital delirium, persistent viral shedding remained significantly associated with increased six-month mortality (OR 2.43; 95% CI 1.42, 4.29). Conclusions Persistent viral shedding occurs frequently in hospitalized COVID-19 patients and is associated with in-hospital delirium and increased six-month mortality. Supplementary Information The online version contains supplementary material available at 10.1007/s11357-022-00561-z.