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: Covid‐19 can involve multiple organs including the nervous system. We sought to characterize the neurologic manifestations, their risk factors, and associated outcomes in hospitalized patients with Covid‐19.Methods: We examined neurologic manifestations in 509 consecutive patients admitted with confirmed Covid‐19 within a hospital network in Chicago, Illinois. We compared the severity of Covid‐19 and outcomes in patients with and without neurologic manifestations. We also identified independent predictors of any neurologic manifestations, encephalopathy, and functional outcome using binary logistic regression.Results: Neurologic manifestations were present at Covid‐19 onset in 215 (42.2%), at hospitalization in 319 (62.7%), and at any time during the disease course in 419 patients (82.3%). The most frequent neurologic manifestations were myalgias (44.8%), headaches (37.7%), encephalopathy (31.8%), dizziness (29.7%), dysgeusia (15.9%), and anosmia (11.4%). Strokes, movement disorders, motor and sensory deficits, ataxia, and seizures were uncommon (0.2 to 1.4% of patients each). Severe respiratory disease requiring mechanical ventilation occurred in 134 patients (26.3%). Independent risk factors for developing any neurologic manifestation were severe Covid‐19 (OR 4.02; 95% CI 2.04–8.89; P < 0.001) and younger age (OR 0.982; 95% CI 0.968–0.996; P = 0.014). Of all patients, 362 (71.1%) had a favorable functional outcome at discharge (modified Rankin Scale 0–2). However, encephalopathy was independently associated with worse functional outcome (OR 0.22; 95% CI 0.11–0.42; P < 0.001) and higher mortality within 30 days of hospitalization (35 [21.7%] vs. 11 [3.2%] patients; P < 0.001).Interpretation: Neurologic manifestations occur in most hospitalized Covid‐19 patients. Encephalopathy was associated with increased morbidity and mortality, independent of respiratory disease severity.

In less than 6 months, the severe acute respiratory syndrome‐coronavirus type 2 (SARS‐CoV‐2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID‐19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS‐CoV‐2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus‐induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID‐19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID‐19 is associated with dysfunction of smell and taste, muscle injury, the Guillain‐Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID‐19 poses a global threat to the entire nervous system. Although our understanding of SARS‐CoV‐2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID‐19. ANN NEUROL 2020;88:1–11 ANN NEUROL 2020;88:1–11

Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus. We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chain-reaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus–related polyomavirus, was used as a control. We determined JC virus–specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences. After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P=0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P=0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus–specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML. Subclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus–specific cellular immune response.

Background Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease of the brain, caused by reactivation of the polyomavirus JC (JCV). PML has classically been described in individuals with profound cellular immunosuppression such as patients with AIDS, haematological malignancies, organ transplant recipients or those treated with immunosuppressive or immunomodulatory medications for autoimmune diseases. Methods and case reports The authors describe five HIV seronegative patients with minimal or occult immunosuppression who developed PML including two patients with alcoholic cirrhosis, one with untreated dermatomyositis and two with idiopathic CD4⁺ T cell lymphocytopenia. The authors performed a review of the literature to find similar cases. Results The authors found an additional 33 cases in the literature. Of a total of 38 cases, seven (18.4%) had hepatic cirrhosis, five (13.2%) had renal failure, including one with concomitant hepatic cirrhosis, two (5.2%) were pregnant women, two (5.2%) had concomitant dementia, one (2.6%) had dermatomyositis, and 22 (57.9%) had no specific underlying diagnosis. Among these 22, five (22.7%) had low CD4⁺ T cell counts (0.080–0.294×10⁹/l) and were diagnosed as having idiopathic CD4⁺ lymphocytopenia, and one had a borderline CD4⁺ T cell count of 0.308×10⁹/l. The outcome was fatal in 27/38 (71.1%) cases within 1.5–120 months (median 8 months) from onset of symptoms, and 3/4 cases who harboured JCV-specific T cells in their peripheral blood had inactive disease with stable neurological deficits after 6–26 months of follow-up. Discussion These results indicate that PML can occur in patients with minimal or occult immunosuppression, and one can revisit the generally accepted notion that profound cellular immunosuppression is a prerequisite for the development of PML.