Table 3.
COVID-19 and MS: Cases of para- and post-infectious disease development, relapse or pseudo-relapse.
| References | Number of patients | Diagnosis | Gender | Age | Ethnicity | Clinical presentation | Method of COVID-19 diagnosis | DMT before COVID-19 infection | Time from diagnosis of COVID-19 to clinical onset | CSF SARS-CoV-2 qPCR | Treatment | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Case reports | ||||||||||||
| Moore et al. (77) | 1 | New onset | M | 28 | NA | Brainstem syndrome (vertigo, oscillopsia, diplopia, facial numbness) | Clinical criteria | None | Neurological symptoms appeared 10 days after COVID-19 symptoms | Negative | IVMP 1 g/day for 3 days followed by prednisone taper | Improved |
| Pignolo et al. (79) | 2 | 1 new onset, 1 relapse | M, F | 21,52 | NA | Hand paresthesia and facial nerve palsy; Right-sided weakness and clumsiness | Clinical criteria, serology | None (new onset) Cladribine (relapse) |
MS onset a few days after COVID-19; MS relapse 2 months after COVID-19 | Negative in one case (new onset), NA in the other | IVMP 1 g/day for 5 days | Relapse- fully resolved, new onset disease- partial recover |
| Fragoso et al. (66) | 1 | New onset | F | 27 | Caucasian | Left side dysesthesia | Clinical criteria | None | 6 months | Negative | NA | NA |
| Wildemann et al. (81) | 1 | MS relapse and Takotsubo cardiomyopathy | F | 39 | NA | Brainstem syndrome (dizziness, diplopia, dysarthria, dysphagia) | SARS-CoV-2 PCR | DMF | 10 days | Negative | IVMP 2 gr/day for 5 days + PLEX (seven courses) | Slow improvement |
| Yavari et al. (82) | 1 | New onset | F | 24 | NA | Diplopia, facial nerve palsy, fingertips paresthesia | SARS-CoV-2 PCR | None | 1 month | NA | IVMP 1 gr/day for 4 days | Improved |
| Palao et al. (78) | 1 | New onset | F | 29 | NA | ON | SARS-CoV-2 serology | None | 2–3 weeks | Negative | IVMP 1 gr/day (treatment duration not reported) followed by oral prednisolone taper | Improved |
| Florae et al. (65) | 1 | Relapse *3 weeks post-partum |
F | 40 | Caucasian | Right sided paresthesia and motor disability | SARS-CoV-2 PCR | None | No systemic symptoms, tested positive on swab PCR upon admission | NA | IVMP 1 gr/d for 3 days; hydroxychloroquine 4 g/day, lopinavir/ritonavir 4 tablets/day for 10 days, and azithromycin 1 g/day, for 3 days | Remission of neurological deficit after 2 weeks |
| Khair et al. (86) | 1 | CIS | M | 8 | NA | Double vision, worsening fine motor skills, and ataxic gait | Clinical criteria | None | 1 month | NA | NA | NA |
| Kataria et al. (69) | 3 | Pseudo-relapse | 2M, 1F | 65, 52, 69 | NA | Fatigue, general weakness | SARS-CoV-2 PCR | GA | Concomitant | NA | Only COVID-19 management | Improved to baseline status |
| Barzegar et al. (57) | 1 | Relapse | F | 42 | NA | Muscle aches, gait difficulty, sensory disturbances, and weakness on the right side | SARS-CoV-2 PCR | Fingolimod | Neurological symptoms preceded COVID-19 symptoms by 6 days | NA | Initially IVMP 1 gr/d for 3 days; then azithromycin, ceftriaxone, hydroxychloroquine, oseltamivir, and piperacillin/tazobactam | Gradual improvement |
| Domingues et al. (63) | 1 | CIS | F | 42 | NA | Left side paresthesia | Clinical criteria | None | Concomitant | Positive | No steroids, COVID-19 management not detailed | Full recovery |
| Jaisankar et al. (67) | 1 | Pseudo-relapse | M | 45 | Caucasian | Dysphagia, altered mental status, general deterioration | SARS-CoV-2 PCR | None | COVID-19 diagnosed 2 weeks prior to neurological deterioration. *Also diagnosed with acute renal failure, anemia, PE and sepsis. | NA | IVMP (dose and duration not reported). Received fluids, packed red blood cells and transfusions, anticoagulants, ciprofloxacin | Ongoing disability |
| Karsidag et al. (68) | 2 | Two patients with new-onset MS (*+1 ADEM) | 1F, 1M | 42, 32 | NA | Jaw and left facial pain and paresthesia; numbness in left jaw | Clinical criteria | None | 2–3 weeks; 4 months | 1 Negative, 1 Positive | 1-IVMP 1 gr/d for 7 days; 1- IVMP 1 gr/d for 10 days | Improved |
| Möhn et al. (76) | 1 | Relapse | M | 42 | NA | Gait and limb ataxia | SARS-CoV-2 PCR | Teriflunomide | Neurological symptoms preceded COVID-19 by 3 weeks | NA | IVMP 1 gr/d for 4 days | Initial improvement, then worsened concomitantly to COVID symptoms |
| Finsterer (84) | 1 | Relapse | F | 27 | NA | TM | Clinical criteria | IFNβ-1a | 2 weeks | NA | CS | Slow improvement |
| Observational case series and cohort studies of MS patients | ||||||||||||
| Khurana et al. (71) | 5 RRMS patients | 1 relapse | 3F, 2M | Mean (SD) age 35.60 (13.94) | NA | NA | SARS-CoV-2 PCR | Treated with DMT, type not specified | NA | NA | NA | NA |
| Maghzi et al. (73) | 3 RRMS, 1 SPMS, 1 RIS | No relapses | 3M, 2F | Mean 53.6 | NA | NA | SARS-CoV-2 PCR | Teriflunomide | NA | NA | NA | NA |
| Mantero et al. (74) | 7 RRMS patients | No relapses. 1 pseudo-relapse | 5F, 2M | Mean 35.9 ± 11.4 | NA | Left hand paresthesia | Clinical criteria | DMF | Concomitant | NA | NA | NA |
| Conway et al. (60) | 72 RRMS, 21 SPMS, 8 PPMS, 2 CIS, eight related disorders | 2/111 (1.8%) relapses, 19 (17.2%) pseudo-relapses and 27 (24.3%) with worsening of pre-existing MS symptoms. Five patients (4.5%) had new MRI lesions on T2 or T1Gd scans | 85 females (77%) | Mean age 49 (SD 12.2) years | NA | NA | Clinical criteria | NA | NA | NA | NA | |
| Chyzhyk et al. (59) | 17 relapsing MS patients | No clinical or radiological signs of MS disease activity During 6 months of observation |
4M, 13 F | Mean age 38 ± 7.6 years | NA | NA | Clinical criteria | Treated with DMT, type not specified | NA | NA | NA | |
| Czarnowska et al. (61) | 426 individuals with MS | 27 patients (6.34%) had a relapse at 3 months after the initial infection | 142M, 284F | Mean 40.27 ± 10.12 | NA | Symptoms during the relapse were as following: pyramidal track symptoms (16 people), cerebellar symptoms (eight people), sensory deficit (four people), brainstem symptoms (3 people), urinary incontinence (1 person) | SARS-CoV-2 PCR (n = 361), SARS-CoV-2 serology (n = 24) or combination of tests | Interferon beta (n = 77); GA (n = 43); DMF (n = 171); teriflunomide (n = 34); fingolimod (n = 16); natalizumab (n = 29); ocrelizumab (n = 29); cladribine (n = 7); alemtuzumab (n = 1); mitoxantrone (n = 1); ozanimod (n=12); other (n = 12); none (n = 4) *Type of DMT in patients who relapsed not specified |
The mean time for relapse occurrence after the SARS-CoV-2 infection was 43 days | All treated with IVMP 3–5 gr | NA | |
| Michelena et al. (75) | 41 MS patients with confirmed COVID-19 diagnosis | 25 patients (61%) reported neurological worsening, three patients (7.7%) met criteria for relapse | 24 F, 17M | Mean 42.9 years (SD 11.3) | NA | Motor (n = 12) Sensory (n = 10) Visual (n = 7) Balance disorders (n = 3) Memory (n = 6) Fatigue (n = 13) | SARS-CoV-2 PCR | 35 treated with DMTs (23-oral DMTs, 4-injectables, 8-monoclonal antibodies) | Concomitant (n = 16), within the 1st month (n = 5), beyond the 1st month (n = 4) | NA | CS (type, dose, and duration not reported) | NA |
| Luetic et al. (72) | 17 RRMS and 1 RIS patients | No MS relapses occurred during or after COVID-19 course. | 13 F, 5M | Mean 41.2 ± 12.6 | NA | NA | 11- SARS-CoV-2 PCR; 8- Clinical criteria | Teriflunomide | NA | NA | NA | NA |
| Etemadifar et al. (64) | A retrospective cohort study comparing the risk of relapse in RRMS patients with (n = 56) and without COVID-19 (n = 69) *Within 6 months from COVID |
4 patients in the MS-COVID-19 group (7.14%) had a relapse compared to 18 patients in the RRMS without COVID-19 group (26.09%). Incidence rate ratio: 0.275; p = 0.026 | COVID-19 group: 40 F/15 M; non COVID-19 group: 62 F/ 7 M | COVID-19 group: 36.89 (±9.06); non-COVID-19 group: 36.19 (±8.97) | NA | 2-limb paresthesia, 1-diplopia, 1-lower extremity weakness | SARS-CoV-2 PCR | Teriflunomide (n = 3); fingolimod (n = 9); DMF (n = 22); AZA (n = 5); Interferon ß 1b (n = 3; Interferon ß 1a (n = 6); GA(n = 3); RTX (n = 3); NTZ (n = 2) *Type of DMT in patients who relapsed not specified |
Only reported that the 4 relapses in COVID-19 confirmed patients occurred after COVID-19 diagnosis | NA | NA | NA |
| Etemadifar et al. (83) | A prospective-retrospective hybrid single center cohort study comparing the risk of relapse during 1 year pre- and post-COVID-19 period in 53 RRMS patients *Some patients may have been included in the previous study by the same first author |
11 patients (20.75%) in the post-COVID-19 period and 16 patients (30.19%) in the pre-COVID-19 period experienced a relapse (p = 0.30) | 45 F, 8M | Mean 38.42 (SD 8.77) | NA | NA | Clinical criteria or SARS-CoV-2 PCR *Number of patients in each group not specified |
IFN beta (n = 4); DMF (n = 21); teriflunomide (n = 1); GA (n = 1); fingolimod (n = 12); RTX (n = 9); AZA (n = 2); none (n = 3) | NA | NA | NA | NA |
| Barzegar et al. (58) | A retrospective observational study comparing the relapse rate among 41 MS patients with confirmed COVID-19 during a pre-defined at-risk period (from 2 weeks before to 5 weeks after COVID-19) and the previous 2 years | Five patients had a relapse during the defined at-risk period. Other two patients had neurological worsening that did not meet clinical relapse definition. Increased relapse rate during the at-risk period (RR: 2.566, 95% CI: 1.075–6.124, P = 0.034) | 31 females, 10 males | Mean 35.10 ± 9.20 | NA | NA | SARS-CoV-2 PCR | NA | All relapses occurred after the onset of COVID-19 (Mean 3.2 weeks, range 1–5 weeks) | NA | NA | |
| Paybast et al. (85) | 202 MS patients followed for 1 year | 25 patients developed COVID-19, of which 1 (4%) had a relapse | 164F, 37M | 38.09 ± 10.44 | NA | TM | SARS-CoV-2 PCR | NA | NA | NA | PLEX | NA |
| General observational studies | ||||||||||||
| Sandoval et al. (80) | 13 pediatric patients with confirmed COVID-19 and new-onset neurological manifestations | 1 patient with new-onset multifocal demyelination consistent with MS | M | 14 | ON, sixth nerve palsy, asymmetric paraparesis | SARS-CoV-2 PCR | None | No systemic symptoms, tested positive on swab PCR upon admission | NA | IVMP (dose and duration not reported) | Significant clinical improvement) | |
| Khedr et al. (70) | 439 patients with confirmed/probable COVID-19 | 2 MS relapse (among those with probable COVID-19, n = 62) | NA | NA | NA | NA | SARS-CoV-2 PCR | NA | NA | NA | NA | NA |
| Dhillon et al. (62) | Case series of 29 inpatients presented with COVID-19 and neurological disorders, 2 MS patients | 1 MS relapse | M | 56 | White | Worsening of limb weakness and dysarthria | SARS-CoV-2 PCR | NA | NA | NA | NA | Ongoing disability |
CIS, clinically isolated syndrome; DMT, disease modifying therapy; ON, optic neuritis; TM, transverse myelitis; IVMP, intravenous methylprednisolone; CS, corticosteroids; PLEX, plasma exchange.