Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly evolved into a worldwide pandemic. COVID-19 predominantly affects the respiratory system and patients typically present with a cough, sore throat, fever, fatigue and breathing difficulties [1]. However, since Mao for the first time reported there is evidence of neurological involvement in COVID-19 [2], neurologic complications are increasingly recognized in the coronavirus disease 2019 (COVID-19) pandemic [3,4,5,6]. In detail, several pieces of evidence suggested potential neurologic complications of SARS-CoV-2 infection include anosmia, ageusia, anorexia, myalgias, headache, dizziness, meningoencephalitis, altered consciousness, Guillain–Barré syndrome, syncope, seizure, and stroke [7, 8].

As a rare illness, acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the central nervous system (CNS) that predominantly affects children [9]. However, several studies reported an increased incidence of ADEM after SARS-CoV-2 epidemics around the world. More recently, numerous case report/series have described cases of ADEM linked to SARSCoV-2 infection, which suggests a possible association between ADEM and SARS-CoV-2 infection [10,11,12,13,14,15].

Until now, no systematic review has conducted to review the available information on the reports of ADEM associated with the COVID-19 infection. This study aims to perform a systematic review of all published studies on SARS-CoV-2-related ADEM and give a comprehensive overview of the demographic characteristics, clinical features, diagnostic investigations, and outcome of SARS-CoV-2-related ADEM patients. At the same time, we also compare the clinical features of SARS-CoV-2-associated ADEM to the classical form of ADEM. The current study may get a better understanding of the acute and post-infectious manifestations of SARS-CoV-2-associated ADEM to guide long-term management and health service reorganization.


This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [16, 17]. A PRISMA-P checklist has been provided as an online supplementary file. We conducted a thorough literature review in June 2021 using keywords (including all commonly used abbreviations of these terms) used in the search strategy were as follows: (“acute demyelinating encephalomyelitis;” OR “acute haemorrhagic leukoencephalitis”) AND (“COVID-19”OR “SARS-CoV-2”). We searched PubMed and Web of Science databases for identifying case series and case reports published between December 1, 2019, to June 5, 2020. Suitable references were also identified in the authors’ archives of scientific literature on ADEM. At least two independent reviewers independently screened all publications, including title and abstract, to determine whether studies include cases. Further case reports and case series studies were obtained by reference tracing of retrieved articles. We restricted our search to studies published in English. Publications that were not peer-reviewed were excluded from this study. For each case, we extracted data concerning demographic and clinical variables, results of diagnostic investigations, and outcome. Searches were performed by SAR, AA, and MF. The selection of relevant articles was shared with all authors.

According to our search criteria, we found 246 studies from PubMed and Web of Science. Duplicate studies, studies with missing clinical data, review articles and articles unrelated to our study objective were excluded and 31 full-text literatures were reviewed in accordance with our study objective.


A total of 48 patients with COVID-19 diagnosed with ADEM/AHLE were used for analyses from the 37 case reports and case series published between December 1, 2019, to June 5, 2020. The demographic data, the clinical, laboratory and imaging findings of the 48 patients are detailed in Table 1 and summarised in Tables 2 and 3.

Table 1 Demographic and clinical characteristics of ADEM and AHNE/AHLE With Evidence of SARS-CoV-2 infection
Table 2 Clinical and demographic characteristics of the 48 patients with SARS-CoV-2 and ADEM/AHLE
Table 3 Clinical and Laboratory Findings in the 48 Patients with SARS-CoV-2 and ADEM/AHLE

Epidemiological distribution and demographic characteristics of the patients

Of the 48 ADEM cases identified from 37 studies, 26 patients (54%) were male and 18 patients (38%) were female, with a male to female sex ratio of 1.4:1; median age was 44 (1.4–71) years. 9 patients (20%, 9/45) were children. Of the 9 children patients, their median age was 8 years (age range 1.4–13 years), 6 patients (75%, 6/8) were female, and 2 patients (25%, 2/8) were male, with a female to male sex ratio of 3:1. Adult to children ratio is 4:1(36/9), indicating that SARS-CoV-2-related ADEM predominantly affects adults after than children.

Overall, patients were reported from 10 countries but mostly from Europe (43.7%, 21/48) and especially from UK (25.0%). In details, patients were originally from USA (n = 13), United Kingdom (n = 12), Italy (n = 5), Brazil (n = 4), India (n = 3), Iran (n = 3), Singapore (n = 3), France (n = 3), Canada (n = 1), and Greece (n = 1) (Table 2).

Clinical features of SARS-CoV-2-associated ADEM

Most common manifestations of COVID-19 included fever (66.0%, 23/35),cough (27.0%, 13/35), dyspnoea (24.0%,11/35), anosmia/hyposmia (14.0%, 5/35) (17.0%, 6/35), myalgia (14.0%, 5/35), fatigue (11.0%, 4/35), lethargy(9.0%, 3/35) and rash (6.0%, 2/35). Six patient [18,19,20,21,22,23] did not present any sign related to COVID-19. The diagnosis of SARS-CoV-2 infection was made by positive RT-PCR of nasopharyngeal swab in 18 (78%) patients (sometimes after repeated tests) and when negative by in 5 (21%) patient. SARS-CoV-2 RT-PCR with sputum exam was positive in 1 (3%) patients, and when positive by serology in 3 (10%) patient.

34 (71.0%) had ADEM while 14 (29.0%) were of AHLE. In all (n = 48) but one patients [14], ADEM manifestations developed after those of COVID-19. Differently, the temporal relationship between onset of COVID-19 symptoms and ADEM was not reported or not calculable in 16 patients (24.4%) [8, 11, 13, 15, 18, 20, 22, 24,25,26,27,28]. COVID-19 symptoms began concurrent in one case [23]. The mean interval between onset of COVID-19 and ADEM symptoms in the remaining 31 patients was a mean 24.7 days (range 1–214 days).The most prominent reported clinical features are those of acute meningoencephalitis, including encephalopathy (59%), headache (15%), seizures (11%) and fever (66%) (Table 3). Other clinical manifestations at onset included sensory symptoms (11%, 5/46), hemiplegia (8.7%, 4/46),leg weakness (8%, 3/46), tetraparesis (4%, 2/46), arm weakness (4%, 2/46),facial weakness (4%, 2/46), hyporeflexia or areflexia (4%, 2/46).Gait ataxia is the most another commonly reported clinical features of SARS-CoV-2-related ADEM (13%, 6/46).

Results of CSF, biochemical, and neuroimaging investigations

CSF was examined in all (81.0%, 39/48) except six of the patients [11, 13, 29,30,31], and was not reported in three patients [26, 27]. Increased protein level were present in 15 patients (38%, 15/39), and normal protein level were present in 13 patients (33%, 13/39) with a median CSF protein of 376.0 mg/dl (min: 15, max: 2340 mg/dl) (Tables 1 and 3).The pleocytosis was evident in 12/31 cases (39%). The search for the viral RNA in CSF was positive in three patients (14.0%, 3/22) [24, 32, 33]out of all 22 cases in whom was done. AQP4 antibodies were tested in 19 patients, being negative in all. MOG antibodies were searched in 19 patients, being positive in one case [34]. Furthermore, CSF SARS-CoV-2 RNA was not reported or not calculable in 23 patients.

In 44 patients (92%, 44/48), head MRI was performed. The deep white matter is the most frequently involved (43%, 19/44), followed by corpus callosum (32%, 14/44) and subcortical white matter (23%, 10/44). Brainstem is another frequently involved (20%, 9/44). The brain lesions occurring in SARS-CoV-2-ADEM involve the periventricular white matter relatively frequently (18%, 8/44). The cerebellum is less frequently involved (14%, 6/44) (Tables 1 and 2), often symmetrically [9], while deep gray matter are present to a lesser extent (5%, 2/39). Contrast enhancement was reported in 17 cases (89%, 17/19). Spinal MRI scans were performed in a minority of the patients (12.5%, 6/48).

Management of SARS-CoV-2-ADEM and patient outcomes

All the patients except ten [12, 21, 22, 24, 26, 27, 30] were treated with specific treatment (79.0%, 38/48). 23 patients were treated with intravenous methylprednisolone (IVMP) (61%, 23/38) 0.13 patients were treated with intravenous immunoglobulin (IVIg) (34%, 13/38); and five received plasma exchange (13%, 5/38). Eleven received combined IVMP and IVIg (29%, 11/38). 31 (64%) of patients had a poor outcome on discharge from hospital. Five (10.4%) patients died in hospital.


In current analysis, we identified and reviewed a total of 48 cases of ADEM with COVID-19 from 37 studies identified worldwide through different case series and reports. The cases were categorized into two groups for further statistical analysis, “ADEM” versus “AHLE”. The novel addition to our review was for the first time reviewed clinical features, results of diagnostic investigations, and outcome in 48 cases of COVID-19-associated ADEM spectrum.

Classic ADEM is an immune-mediated, inflammatory demyelinating disease of the central nervous system (CNS) that usually affects children and young adults after an infection or vaccination [9, 35]. The mean age of onset of classic ADEM is between 3.6 and 7 years [36]. We found significant differences between COVID-19-associated ADEM and classic ADEM in age at onset; the mean age for COVID-19-associated ADEM was 44 years. In the present study, mean age at onset in patients with COVID-19-associated ADEM largely older that of classic ADEM subjects, indicating that an adult age range might be affected (Table 4). Although ADEM has no obvious gender predominance, a slight male prevalence is reported in a few paediatric series [37]. We found a slightly higher prevalence of COVID-19-associated ADEM in males compared to females (male:female ratio is 1.4:1), which is consistent with the literature in general.

Table 4 Comparation of clinical characteristics of SARS-CoV-2-ADEM with typical ADEM

In the typical presentation of ADEM, neurological symptoms develop 7–14 days following an infection and may involve headache, emesis, meningismus, and alterations in behaviour and level of alertness s [35]. Common neurological exam findings include altered mental status, ataxia, and extremity weakness. A latency period between the onset of the ADEM symptoms and onset of COVID-19 has been reported in different papers (Table 1). The present cohort has shown an average latency of 25 days from the onset of COVID symptoms to the presentation of ADEM. The mean latency ranged between a duration of 0 to 214 days. We did not found significant differences between COVID-19-associated ADEM vs. classic ADEM in neurological symptoms and signs at onset.

The diagnosis of ADEM is based on a combination of clinical features, supported by MRI findings. Brain MRI T2-weighted and fluid-attenuated inversion recovery (FLAIR) images typically demonstrate multiple hyperintense bilateral, asymmetric patchy and poorly marginated lesions [37], which typically involve the subcortical and deep white matter [9, 37,38,39,40]. The brain lesions occurring in ADEM more frequently affect the deep gray matter and cortex [41] and less frequently involve the periventricular white matter [42] and corpus callosum [41].The deep gray matter is frequently involved (40–60%), often symmetrically [43]. In our population, most common brain lesions resemble those of classic ADEM, i.e. the distribution of lesions more frequently affect subcortical and deep white matter (Tables 3 and 4). Compared to the lesions observed in classic ADEM, the brain lesions occurring in COVID-19-associated ADEM more frequently involve the periventricular white matter (18%) and corpus callosum (32%), and less frequently affect the deep gray matter (5% vs. 40–60%). The reported frequency of gadolinium-enhancing lesions in classic ADEM is highly variable between studies (10–95%) [43], largely overlapping with the percentages in our cohort (89%).

CSF examination reveals inflammatory findings in most ADEM patients [44], consisting of elevated protein levels (15–60%) and lymphocytic pleocytosis (25–65%). In our population, increased protein level was present in 38% patients, and normal protein level were present in 33% patients. The pleocytosis was evident in 39% cases. These results indicated that we did not found an obvious discrepancy concerning CSF findings between classic ADEM and COVID-19-associated ADEM. First-line acute treatment of classic ADEM generally consists of IVMP at a dose of 30 mg/kg/day (maximum 1000 mg/day) for 3–5 days, followed by an oral prednisone taper for 4–6 weeks [9]. 61% patients were treated with IVMP, which overlapping with the percentages in classic ADEM [43]. The use of IVIg is usually considered a second-line treatment option for ADEM patients who do not respond to or who deteriorate after intravenous steroids, which has proven effective in about 40–50% of steroid-resistant patients [43]. 34% of patients were treated with IVIg, indicating that a high percentage use of IVIg for the treatment of COVID-19-associated ADEM.

Patients with classic ADEM usually have a good outcome with a complete recovery. The outcome seems to be better in children than in young adults, especially for the disease course, recovery, and mean duration of hospitalization [45]. Unlike typical ADEM, most of COVID-19-related ADEM have a relatively poor outcome, with mortality rates of 10% (Table 4). In analogy to classic ADEM, only 15% COVID-19-associated ADEM subjects have a full recovery (15% VS 47–89%). In this regard, cases with COVID-19-associated ADEM need a higher rate of ICU management.

Our study had several strengths. Major strengths of our review are the inclusion of a high number of patients, together with an in-depth analysis of the clinical features of COVID-19-associated ADEM for the first time. This is among the first studies focused on comparing the clinical presentation, management and outcomes in COVID-19 patients who were diagnosed with ADEM, highlighting on differences with classic ADEM. Our study should be considered in light of several limitations. First, cases included in this review were identified through a comprehensive search of databases using a systematic search strategy. There is a possibility of missing out new upcoming studies because of the evolving nature of the COVID-19 pandemic. Second limitation associated with this systematic review is the concern notably restriction of the search to the PubMed and Web of Science, inclusion of articles published only in English, and heterogeneity of included studies.


In conclusion, based on the systematic review of 48 cases, we showed the clinical picture of COVID-19-associated ADEM, and revealed that although rare, ADEM can be associated with SARS-CoV-2 infection. SARS-CoV-2-ADEM seems to share most features of classic ADEM, with a moderate discrepancies from the classical ADEM. In analogy to classic ADEM, COVID-19-associated ADEM have a more longer duration between the onset of the antecedent infective symptoms and the start of ADEM symptoms, the older age distribution of the patients, relatively poor outcome, a lower full recovery rate, a more frequently brain lesions involved the periventricular white matter and corpus callosum, and less frequently affected the deep gray matter.