By Prof. Avindra Nath and Dr Bridgette Jeanne Billioux, Tropical and Geographical Neurology Specialty Group

This past month, there were several interesting articles focused on the neurologic manifestations and outcomes of hospitalized COVID-19 patients.  We also found updates and new insights on some COVID-related neurologic sequelae.

An interesting study regarding hospitalized COVID-19 patients was an international multicenter prospective observational study which looked at the neurologic manifestations.  Out of over 16,000 patients diagnosed with COVID-19 across various sites over the span of a year, serious neurological complications were found in 12.9% of patients, including 10.2% with encephalopathy at admission, and 2.0% with stroke, 1.5% with seizures, and 0.4% with meningitis/encephalitis at admission.  Patients with serious neurological manifestations were more likely to be admitted to the ICU, and also had higher 28-day mortality than the hospitalized COVID-19 patients without these neurologic manifestations (Cervantes-Arslanian 2022). Another study looked at patients hospitalized with COVID-19 who had either encephalopathy or encephalitis, and evaluated CSF and serum inflammatory markers and markers of axonal damage during acute illness and through 18 months of follow-up.  This study found that patients with COVID-19 related encephalopathy (n=25) or encephalitis (n=14) had elevated levels of many different cytokines when compared to controls, including IL-6, IL-8, IL-18 in both serum and CSF; macrophage chemoattractant protein 1 (MCP1) in CSF alone; and neurofilament-Lightchain (NfL) and  IL-10, among others, in serum alone.  No neuronal autoantibodies were found in either cohort. These patients were followed for 18 months and assessed for neurologic disability. Interestingly, only the levels of NfL and 14-3-3 correlated significantly with the degree of disability at 18 months, indicating that the degree of acute neuronal damage may be more predictive of prognosis compared to the degree of acute inflammation during COVID-19 (Guasp 2022).

As mentioned in last month’s review, there is growing concern for potential cognitive decline in patients who have recovered from COVID-19, though to date, relatively few studies have rigorous neurocognitive data to explore this possibility.  This month, a new study was published in Lancet eClinical Medicine detailing the cognitive follow up of 46 adults (average age 51 years, range 28-83) who were hospitalized for COVID-19.  In the 6-10 months after admission for COVID-19, these patients were assessed with a battery of computerized cognitive tests using the Cognitron platform, as well as a variety of supplemental scales to assess for mood disorder, anxiety, or PTSD.  In comparison to the matched control group, the participants who were hospitalized for COVID-19 scored significantly worse on testing overall and were slower in their responses than was expected.  In particular, tasks specific for higher cognitive functions such as spatial planning, analogical reasoning, and word recall were more notably affected in the COVID-19 cohort when compared to controls.  Not surprisingly, acute illness severity correlated with worse scores, but mental health issues were not found to correlate with the cognitive scores.  Though this is a relatively small study, it is further evidence that COVID-19 survivors may have cognitive deficits that may require medical attention and long-term follow-up (Hampshire 2022).

Disrupted olfaction has long been an intriguing complication in COVID-19.  A recent post-mortem study on the olfactory tissue of patients with COVID-19 has shed some new light on the nature of the olfactory disturbances. In this study, the olfactory tract tissues from 23 patients who died from COVID-19 and 14 matched controls were assessed by histopathology, electron microscopy, digital droplet PCR, and immunohistochemistry.  No obvious histopathologic abnormalities were found in COVID-19 olfactory autopsy material, nor were increases in lymphocytic infiltration, microglia, nor reactive astrocytosis.  However, on electron microscopic analysis, patients who died from COVID-19 were found to have axonal pathology in the olfactory neurons that ranged from mild to severe axonal injury, which was significantly worse when compared to matched autopsy controls.  When comparing clinical data, individuals who had complained of loss of smell had greater evidence of axonal damage on EM. Individuals with COVID-19 were also found to have evidence of endothelial injury of the olfactory microvasculature in comparison to controls (Ho 2022).

Finally, another interesting sequel of COVID-19 was highlighted, in the form of a sleep disorder. Sleep disturbances have been noted frequently post-COVID, but a recent study was undertaken to evaluate the onset of restless legs syndrome (RLS) in patients with long COVID (LC).  In this questionnaire-based study, 136 participants with long COVID were assessed for evidence of restless legs syndrome before and after COVID-19 and compared to 136 control participants.  The study found that RLS prevalence in their COVID-19 cohort was similar to that of the background population prior to developing COVID-19; however, after developing long-COVID, this prevalence in this group increased, particularly in the female participants (5.7% pre-LC to 14.8%).  Given the fact that RLS has been reported after other viral infections, there may be some link between post-infectious immune/inflammatory factors and the development of RLS in these cases; however, this requires additional study (Weinstock 2022).

Together, the ability of levels of NfL, which is a marker of axonal injury, to predict long term outcome and the demonstration of axonal damage in the nasal mucosa suggest that axonal injury maybe a key pathophysiological process in long term outcome of patients with COVID-19. These long-term outcomes may include neurocognitive deficits and restless legs syndrome. This will require  additional long-term studies and continued medical support of these patients.



  • Cervantes-Arslanian AM, Venkata C, Anand P, Burns JD, Ong CJ, LeMahieu AM, Schulte PJ, Singh TD, Rabinstein AA, Deo N, Bansal V, Boman K, Domecq Garces JP, Lee Armaignac D, Christie AB, Melamed RR, Tarabichi Y, Cheruku SR, Khanna AK, Denson JL, Banner-Goodspeed VM, Anderson HL 3rd, Gajic O, Kumar VK, Walkey A, Kashyap R. Neurologic Manifestations of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Hospitalized Patients During the First Year of the COVID-19 Pandemic. Crit Care Explor. 2022 Apr 25;4(4):e0686. doi: 10.1097/CCE.0000000000000686  ⧉. PMID: 35492258; PMCID: PMC9042584.
  • Guasp M, Muñoz-Sánchez G, Martínez-Hernández E, Santana D, Carbayo Á, Naranjo L, Bolós U, Framil M, Saiz A, Balasa M, Ruiz-García R, Sánchez-Valle R; Barcelona Neuro-COVID Study Group. CSF Biomarkers in COVID-19 Associated Encephalopathy and Encephalitis Predict Long-Term Outcome. Front Immunol. 2022 Apr 11;13:866153. doi: 10.3389/fimmu.2022.866153 ⧉. PMID: 35479062; PMCID: PMC9035899.
  • Hampshire A, Chatfield DA, MPhil AM, Jolly A, Trender W, Hellyer PJ, Giovane MD, Newcombe VFJ, Outtrim JG, Warne B, Bhatti J, Pointon L, Elmer A, Sithole N, Bradley J, Kingston N, Sawcer SJ, Bullmore ET, Rowe JB, Menon DK; Cambridge NeuroCOVID Group, the NIHR COVID-19 BioResource, and Cambridge NIHR Clinical Research Facility. Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort. EClinicalMedicine. 2022 May;47:101417. doi: 10.1016/j.eclinm.2022.101417 ⧉. Epub 2022 Apr 28. PMID: 35505938; PMCID: PMC9048584.
  • Ho C, Salimian M, Hegert J, et al. Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19. JAMA Neurol. Published online April 11, 2022. doi:10.1001/jamaneurol.2022.0154 ⧉
  • Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. Restless legs syndrome is associated with long-COVID in women. J Clin Sleep Med. 2022 May 1;18(5):1413-1418. doi: 10.5664/jcsm.9898 ⧉. PMID: 35484639.