Chronic Neurological Sequelae
The long-term neurological impact of COVID-19 is uncertain, but it is already apparent that a range of signs and symptoms emerge among patients hospitalized with COVID-19 while non-hospitalized patients also exhibit neurological disorders that arise after the acute COVID-19 illness phase (Figure 3). The lingering or delayed neurological syndromes have been termed long COVID or post-acute sequelae of SARS-CoV-2 (PASC) and are composed of a wide range of symptoms and signs including neurocognitive symptoms with associated impaired performance on neuropsychological testing. Of note, neurocognitive and mood alterations among ICU survivors are well recognized phenomena, often attributed to sedating medications as well as systemic inflammation and neuronal injury. Notably, these ICU-related effects can confound the evaluation of chronic sequelae among survivors of severe acute COVID-19. A study evaluating patients with COVID-19 at 2–3 months post-hospitalization (approximately a third of patients required ICU) reported that those patients reported significantly higher rates of depressive symptoms and decreased quality of life compared to age- and comorbidity-matched controls. Moreover, abnormalities in visuospatial and executive function were detected among COVID-19 survivors compared to controls when assessed by the Montreal Cognitive Assessment tool (MoCA), recapitulating clinical experience of patients with post-COVID-19 who report apathy, short-term/working memory difficulties and 'brain fog' after SARS-CoV-2 infection.[39,101] A recent study of patients post-COVID-19 without hospitalization reported 'brain fog', headache, anosmia, dysgeusia and myalgia as the predominant persisting symptoms. Over half of hospitalized COVID-19 patients report significant fatigue months after discharge, particularly among those who required admission to the ICU. Similarly, persistent psychological distress is reported by half of hospitalized patients with COVID-19-related ICU admission as well as those COVID-19 patients not requiring the ICU. A retrospective cohort analysis of over 200 000 patients in the UK found that 12.8% of patients with COVID-19 received a new neurological or psychiatric diagnosis in the 6 months after initial infection. In the same study, nearly half of ICU-COVID-19 survivors had a neurological or psychiatric illness at 6-month follow-up, of which half were new diagnoses. Of note, frontotemporal FDG hypometabolism reported for acute COVID-19, discussed previously, was also observed among COVID-19 patients with cognitive symptoms >3 weeks after initial illness, accompanied by brainstem and thalamus hypometabolism in 'long COVID' patients, compared to controls. A separate study of eight patients in the subacute and chronic stages of recovery from COVID-19 observed a similar pattern of bilateral frontoparietal hypometabolism, which resolved at the 6-month follow-up assessment and was accompanied by improved MoCA scores. FDG-PET imaging is a potentially useful research tool although it is not validated for diagnosis of COVID-19 related neurocognitive impairments, which require clinical evaluation. Future studies of cognitive impairment in COVID-19 survivors must take into account the fact that hospitalization for any infection is associated with an increased 10-year risk of dementia, particularly vascular dementia and Alzheimer's disease.
Chronic neurological sequelae of COVID-19. Several long-term neurological syndromes result from SARS-CoV-2 among hospital- and community-treated patients, termed long COVID or post-acute sequelae of COVID-19 (PASC). These syndromes include neurocognitive, mood and sleep disorders, dysautonomia, diverse pain syndromes, as well as marked exercise intolerance and fatigue. These protracted syndromes remain to be fully defined in longitudinal cohort studies.
Patients with COVID-19 also develop autonomic instability that manifests as tachycardia, postural hypotension, hypertension, postural orthostatic tachycardia syndrome, low-grade fever with associated bowel, bladder or sexual dysfunctions.[106,107] Cardiac MRI of COVID-19 survivors at 2–3 months after symptom onset showed evidence of fibrosis and inflammation, which was correlated with serum inflammatory markers (e.g. CRP, calcitonin), possibly accounting for the exercise intolerance reported by patients.
The spectrum of symptoms described in long COVID has prompted comparisons with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). Indeed, the overlap in symptoms between post-acute COVID-19 syndromes and ME/CFS is remarkable for the shared symptomatology including fatigue, autonomic instability, post-exertional myalgia or weakness as well as neurocognitive impairments.[36,102,108] Nonetheless, other viral illnesses (e.g. Dengue, West Nile disease, mononucleosis) are also associated with substantial disabilities that resemble the previous symptom complex. The precise diagnosis and management of neurological symptoms in long COVID is an emerging area of study, which is in evolution as more studies become available. Important caveats in considering persistent or delayed neurological disorders related to COVID-19 include the contribution of comorbid illnesses and their associated therapies to neurological disease as well as the potential for uncovering previously unrecognized illnesses.
Laboratory Analyses of Nervous System Tissues and Fluids
Analyses of CSF from patients with COVID-19 vary widely depending on the associated neurological disorder although pleocytosis, especially lymphocytic, and elevated protein are common findings, particularly among patients with other features of encephalitis. The IgG index is increased in many patients with COVID-19 together with the presence of antiviral and antiviral receptor (e.g. ACE2) antibodies, indicative of intrathecal synthesis.[20,111] In contrast, viral RNA is infrequently detected in CSF using standard RT-PCR protocols,[110,112] although the timing of the CSF collection in relation onset is often not reported. Host innate immune responses were also apparent in CSF from patients with COVID-19 based on reports of neopterin and β2-microglobulin detection in CSF. Similarly, several chemokines and cytokines in CSF have shown to be associated with COVID-19-related neurological disease (e.g. encephalitis) including IL-8, TNF-α, IL-6 as well as neural cell type-specific markers (e.g. GFAP, neurofilament and tau). However, a specific diagnostic profile in CSF for COVID-19 associated neurological disease awaits definition. Antibodies associated with autoimmune encephalitis have been reported concurrently with SARS-CoV-2 infection, including anti-GD1b, -NMDA-R[22,114,115] and -CASPR2. While these reports are intriguing, a direct link between SARS-CoV-2 infection and the development of these autoantibodies has not been established. Interestingly, there are emerging reports of non-neurological autoimmune disorders including psoriatic arthritis, rheumatoid arthritis and immune thrombocytopenic purpura developing after COVID-19. Possible explanations for this phenomenon include transient immunosuppression during acute viral illness, including suppression of regulatory T and B cells resulting in impaired self-tolerance, as has been suggested in other viral infections. In susceptible individuals, the process of immune reconstitution following COVID-19 may 'unmask' autoimmune conditions, including multiple sclerosis and neuromyelitis optica spectrum disorders.[121,122] In contrast, other groups have proposed that T-cell exhaustion might contribute to autoimmune neuropathogenesis in COVID-19.
As with CSF studies, autopsy-based neuropathological findings are diverse. Several variables need to be considered in interpreting the neuropathological findings including the presence and severity of prior or concurrent comorbidities, duration in ICU and ventilator support, concomitant therapies and the circumstances of death. Moreover, for many neuropathological reports of COVID-19, a corresponding clinical phenotype was not observed or reported. Nevertheless, reports range from the findings of absent neuropathology to hypoxic/ischaemia changes, acute infarction and haemorrhagic lesions with endotheliitis. ADEM- and ATM-like findings have been observed in select cases.[60,125] Post-mortem studies of patients with ADEM-associated COVID-19 report periventricular inflammation, characterized by foamy macrophages and axonal injury.[60,126] Conversely, other neuropathological studies have identified lymphocyte-predominant inflammation in the meninges, brainstem and perivascular spaces with significant neuronal and axonal loss. Meningoencephalitis, haemorrhagic posterior reversible encephalopathy syndrome, as well as diffuse leukoencephalopathy and microhaemorrhages have also been reported.[51,128,129] While a number of post-mortem studies indicate there is a paucity of immune cell infiltration within the neuroaxis,[47,51,130] recent studies have found marked microglial activation and CD8+ T cells in the brainstem and cerebellum.[68,131] In fact, one study reported pan-encephalitis in a cohort of patients with severe pulmonary-associated COVID-19. Microscopy in larger studies (n = 43) have described diverse findings including astrogliosis with activated microglia and infiltrating T cells in brain parenchyma, together with ischaemic lesions in a subset of patients.[68,132,133] In one post-mortem study using imaging mass cytometry, distinct neuropathological features within the brainstem and olfactory bulb of COVID-19 patients were identified, including microglial nodules, CD8+ T-cell infiltration, and increased ACE2 expression in blood vessels. These findings were not as pronounced in control patients who had been on ECMO but did not have COVID-19. Nevertheless, some authors have commented that collectively the neuropathological findings, especially microglia activation in COVID-19 resemble that observed in patients with hypoxia and sepsis.[132,134]
Brain. 2022;144(12):3576-3588. © 2022 Oxford University Press