Our report confirms the possible occurrence of ADEM following SARS-CoV-2 infections in adult patients. We reviewed the literature available at the moment of the present report, addressing clinical and CSF findings. We also checked for possible prognostic factors, comparing ADEM and ANHLE patients.
Previous studies have reviewed the cases of ADEM 40–42 and ANHLE40 following COVID-19. However, those studies did not focus on possible disease prognostic factors nor the clinical differences between ADEM and ANHLE. Clinical 43 and radiological 43,44 prognostic factors have been previously proposed for the risk of multiphasic ADEM, both for children and adult pre-pandemic patients 43,44. Conversely, to date, no factor predicting the outcome of the disease was identified. In the present study, we observed that the absence of encephalopathy was associated with a lower risk of a worse clinical outcome in ADEM patients, both in univariate and multivariate analyses. On the opposite, we failed to identified valuable prognostic factors for ANHLE patients. We found that encephalopathy was present in 80% of ADEM and 91.3% of ANHLE patients. This incidence appears to be higher as compared to what was previously reported in pre-pandemic ADEM patients ADEM (20–56%) 3–5. Furthermore, in 50% of ADEM patients and 30.4% of ANHLE patients, difficult awakening from sedation was the presenting neurological symptoms, suggesting the need to promptly investigate encephalopathy in COVID-19 patients.
Despite the growing number of ADEM and ANHLE reports in people with SARS-CoV-2 infection, the development of these neurological complications is very rare. At the time of the present report, the global number of SARS-CoV-2 infections counted from the beginning of the pandemic exceeded 175 million (WHO COVID-19 weekly epidemiological update, edition 44, published 15 June 2021, available at https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---15-june-2021). Against the ample number of SARS-CoV-2 infections, we identified only 43 reported patients who developed ADEM or ANHLE in the context of COVID-19, with a prevalence of about 2.4 cases per 10,000,000 COVID-19 patients. This prevalence is much lower than what is expected in the general population. In a previous study published before the pandemic, the prevalence of ADEM was 3.3 per 100,000 population 45. This 100-fold difference may be at least partially explained by an under-reporting of ADEM/ANHLE cases in COVID-19. Conversely, one could argue that SARS-CoV-2 may be a less effective trigger for ADEM, as compared to other viral infections. While the prevalence of ANHLE is not established, it is usually considered a rare variant of ADEM46. Interestingly, we identified a higher number of ANHLE reports as compared to ADEM. As previously highlighted by Manzano et al., other significant epidemiological differences exist between pre-pandemic ADEM and post-COVID-19 ADEM 40. We observed a higher median age of people with ADEM (55 years vs 33–41 years 3,5,44,47,48) and ANHLE (55 years vs 38 years 46), a shorter lag time between infection and neurological symptoms 47 and a worse prognosis both in terms of high morbidity and mortality 3,5,7,8, and the absence of anti-MOG antibodies in ADEM patients. When comparing ADEM and ANHLE, we observed a higher mortality and worse prognosis trend in ANHLE patients, consistently with previous studies 46.
Our findings should be read in light of the study limitations. These include the small sample size, and the retrospective collection of published reports, which are highly variable in terms of data reporting and quality. Moreover, our analyses concerning prognosis were based on a retrospective categorization of clinical outcomes that may have biased the study. In addition, follow-up periods were mostly short and not clearly specified in most of the studies, being another possible source of bias. Other study limitations are the low number of anti-MOG and anti-AQP testing and the possible under-reporting of ADEM/ANHLE cases.
Despite these limitations, the present study, suggests encephalopathy as a possible prognostic factor in post-COVID-19 ADEM and highlights the possible epidemiological differences between pre-pandemic and post-COVID-19 ADEM in adults. Future prospective multi-center studies are needed to shed light on this rare but yet possible complication of SARS-CoV-2 infection.
Table 1
– Clinical and CSF data of ADEM and ANHLE patients – Data are expressed as percentage or median ± interquartile range. Sample size of the analyses are specified in brackets when the specific variable was not available for all the reported patients. Abbreviations: ADEM = acute disseminated encephalomyelitis, ANHLE = acute necrotizing hemorrhagic leukoencephalitis, CSF = cerebrospinal fluid, na = not applicable, OCB = oligoclonal bands.
| ADEM | ANHLE |
Number of patients (n) | 20 | 23 |
Female (%) | 45% | 47.8% |
Age (years) | 53.5 ± 40-58.25 | 55 ± 46.75–58.25 |
Severity of COVID-19 infection (%): | | |
asymptomatic | 15% | 0% |
mild | 25% | 34.8% |
severe | 0% | 8.7% |
critical | 60% | 56.5% |
Main reason for hospitalization: neurological | 40% | 52.2% |
Lag time between infection and neurological disease (days) | 15.5 ± 9.5–20.5 | 9 ± 2-5-20.75 |
Presence of encephalopathy | 80% | 91.3% |
Presenting with difficult awakening from sedation | 50% | 30.4% |
Presence of spinal cord lesion | 70% (n = 10) | Na |
CSF | | |
OCB presence | 11.8% (n = 17) | 33.3% (n = 3) |
Cells/µl | 3 ± 1.25-6 (n = 19) | 4 ± 3–5 (n = 18) |
protein (mg/dl) | 48.85 ± 35.25–57.5 (n = 19) | 230 ± 80-5-605.5 (n = 18) |
Anti-MOG | 0 % (n = 5) | 0% (n = 1) |
Anti-AQP4 | 0% (n = 6) | 0% (n = 1) |
Neurological clinical outcome: | n = 18 | n = 22 |
complete recovery | 5.6% | 0% |
good recovery | 11.1% | 4.5% |
partial/poor recovery | 55.6% | 59.1% |
no recovery | 16.7% | 0% |
Death | 11.1% | 36.4% |