COVID-19 Update [June '22]

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

In this month’s Neurology and COVID-19 review, we’ve included several points of interest that have arisen in the literature and news, including pediatric neurologic complications of COVID-19, long-term neurologic outcomes of intubated COVID-19 patients, and SARS-CoV-2 antigenemia in the CNS.

In part due to generally less severe disease in the pediatric populations, neurologic complications in pediatric COVID-19 patients have so far received less attention than adult issues.  However, recent publications have detailed the neurological manifestations in pediatric COVID-19 patients. An article in the Journal of Pediatricsdetails a case series of neuroimmunologic complications related to COVID-19 in patients less than 18 years of age. In this study, 19 children were described who had a history of SARS-CoV-2 with a variety of associated neuroimmunologic manifestations, including acute disseminated encephalomyelitis (ADEM), cerebellar ataxia, neuromyelitis optica spectrum disorder (NMOSD), optic neuritis, and encephalopathy.  Imaging was abnormal in 14/19 patients, with evidence of ADEM, cytotoxic lesions of the corpus callosum, cerebellitis, and myelitis among other abnormalities. Of the 19 patients, 17 were treated with an anti-inflammatory medication such as IV-methylprednisolone or IVIG, and all patients had favorable outcomes at one month (Aubart 2022). It is also worth noting that neurological symptoms such as headache, meningeal signs, encephalopathy, and others may occur as manifestations of multi-system inflammatory syndrome in children (MIS-C), a novel disease associated with COVID-19 which shares similarities to Kawasaki syndrome (Lee 2022). An article published this month from Germany addressed post-acute COVID sequelae and noted that about 2% of patients less than 18 years of age develop long-COVID, and that the incidence was higher in the older pediatric patients (ages 13-18), consistent with several other recently published studies (Kostev 2022). Symptoms of post-acute sequelae of SARS-CoV-2 (PASC) may include new daily persistent headache, as illustrated in another case series of pediatric patients (Simmons 2022).  These findings are of concern, as many children remain unvaccinated, with the American Academy of Pediatrics reporting less than a third of US children between the ages of 5-11 having completed a 2-dose vaccination regimen (https://www.aap.org/.../children-and-covid-19-vaccination-trends/ ⧉ ).  This may be due to a variety of reasons, such as delayed vaccination approval (and COVID-19 vaccination in children under 5 still awaiting approval by the FDA), but underscores the fact that pediatric patients are indeed at risk of contracting SARS-CoV-2 and may suffer neurologic consequences or long-COVID, even though it may be less common than in adults.

Another topic of interest this past month has been regarding neurologic outcomes in intubated COVID-19 patients. In the Annals of Neurology, a retrospective study of 795 intubated patients with severe COVID-19 and impaired consciousness evaluated the time to recover the ability to follow commands after intubation.  On average, these patients took 30 days to recover the ability to follow commands, with worsening hypoxemia correlating with longer times of recovery.  These findings are of significance, as goals of care discussions for critically ill, intubated patients often take place early in intensive care units, typically within 1-2 weeks of intubation. However, the findings in this paper suggest that critically ill COVID-19 patients may need a longer time to recover meaningful consciousness, and that goals of care discussions should reflect these considerations (Waldrop 2022).

One issue that has concerned clinicians taking care of COVID-19 patients with neurologic manifestations is the lack of CNS-specific diagnostics, as these patients almost never have evidence of SARS-CoV-2 RNA in cerebrospinal fluid (CSF).  However, a recent study looked at a SARS-CoV-2 antigen detection in CSF using a novel ultrasensitive assay in a cohort of COVID-19 patients, including about 23 with neurologic symptoms and 21 without.  In this cohort, SARS-CoV-2 nucleocapsid antigen (N-Ag) was detected in 31 of 35 COVID-19 patients’ CSF samples (with none detected in control CSF), and SARS-CoV-2 spike antigen (S-Ag) was detected in only one COVID-19 patient; in all patients, SARS-CoV-2 RNA was negative in CSF.  Interestingly, the CSF N-Ag levels did not correlate with neurologic symptoms or severity of COVID-19.  Although the significance of this ultrasensitive assay is still to be determined, the improved capability to detect SARS-CoV-2 antigen in the CSF may lead to better markers of neurologic disease and prognosis in COVID-19 disease (Edén 2022).

As time goes on in this pandemic, we are learning better how to care for and diagnose neurologic complications of COVID-19 in patients of all age groups.  However, there are still many gaps in our knowledge of this fairly new disease, and neurologists must remain vigilant, particularly for populations at risk of being overlooked including children.

References

• Aubart M, Roux CJ, Durrleman C, Gins C, Hully M, Kossorotoff M, Gitiaux C, Levy R, Moulin F, Debray A, Belhadjer Z, Georget E, Kom Tchameni R, Blanc P, Wehbi S, Mazeghrane M, Tencer J, Gajdos V, Rouget S, De Pontual L, Basmaci R, Yacouben K, Angoulvant F, Leruez-Ville M, Sterlin D, Rozenberg F, Robert M, Zhang SY, Boddaert N, Desguerre I. Neuro-inflammatory disease following SARS-CoV-2 infection in children. J Pediatr. 2022 May 13:S0022-3476(22)00426-7. doi: 10.1016/j.jpeds.2022.05.018. Epub ahead of print. PMID: 35577119; PMCID: PMC9106400. 10.1016/j.jpeds.2022.05.018 ⧉

• Lee KH, Li H, Lee MH, Park SJ, Kim JS, Han YJ, Cho K, Ha B, Kim SJ, Jacob L, Koyanagi A, Shin JI, Kim JH, Smith L. Clinical characteristics and treatments of multi-system inflammatory syndrome in children: a systematic review. Eur Rev Med Pharmacol Sci. 2022 May;26(9):3342-3350. doi: 10.26355/eurrev_202205_28754. PMID: 35587087. 10.26355/eurrev_202205_28754 ⧉

• Kostev K, Smith L, Koyanagi A, Konrad M, Jacob L. Post-COVID-19 conditions in children and adolescents diagnosed with COVID-19. Pediatr Res. 2022 May 14:1–6. doi: 10.1038/s41390-022-02111-x. Epub ahead of print. PMID: 35568733; PMCID: PMC9107066. 10.1038/s41390-022-02111-x ⧉

• Simmons AC, Bonner A, Giel A, Pezzano A, Rothner AD. Probable New Daily Persistent Headache After COVID-19 in Children and Adolescents. Pediatr Neurol. 2022 Apr 28;132:1-3. doi: 10.1016/j.pediatrneurol.2022.04.009. Epub ahead of print. PMID: 35598584. 10.1016/j.pediatrneurol.2022.04.009 ⧉

• Waldrop G, Safavynia SA, Barra ME, Agarwal S, Berlin DA, Boehme AK, Brodie D, Choi JM, Doyle K, Fins JJ, Ganglberger W, Hoffman K, Mittel AM, Roh D, Mukerji SS, Der Nigoghossian C, Park S, Schenck EJ, Salazar-Schicchi J, Shen Q, Sholle E, Velazquez AG, Walline MC, Westover MB, Brown EN, Victor J, Edlow BL, Schiff ND, Claassen J. Prolonged Unconsciousness is Common in COVID-19 and Associated with Hypoxemia. Ann Neurol. 2022 Jun;91(6):740-755. doi: 10.1002/ana.26342. Epub 2022 Apr 21. PMID: 35254675; PMCID: PMC9082460. 10.1002/ana.26342 ⧉

• Edén A, Grahn A, Bremell D, Aghvanyan A, Bathala P, Fuchs D, Gostner J, Hagberg L, Kanberg N, Kanjananimmanont S, Lindh M, Misaghian S, Nilsson S, Schöll M, Sigal G, Stentoft E, Studahl M, Yilmaz A, Wang M, Stengelin M, Zetterberg H, Gisslén M. Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms. JAMA Netw Open. 2022 May 2;5(5):e2213253. doi: 10.1001/jamanetworkopen.2022.13253. PMID: 35604688. 10.1001/jamanetworkopen.2022.13253 ⧉