The cases are summarized in Table 1. None of these individuals had any history of COVID-19 infection. Cerebrospinal fluid (CSF) analysis, performed in Cases 2, 4, and 5, is shown in Table 2. A narrative of each case is provided below. In the Albany, NY and Boston, MA areas, COVID-19 vaccination was made available to the public on December 14 and 15, 2020, respectively.

Table 1 Subject’s characteristics Full size table

Table 2 Cerebrospinal fluid results Full size table

Case 1

A 35-year-old Caucasian woman was initially diagnosed with clinically isolated demyelinating syndrome (CIS) 11 years ago after she developed a left optic neuritis and brain MRI lesions. She was placed on weekly intramuscular interferon beta-1a. Despite starting disease-modifying therapy, she developed new brain lesions 10 months later, and she was diagnosed as converted to relapsing–remitting multiple sclerosis (RRMS). She preferred to remain on the same therapy. She was stable for 3 years and then developed a symptomatic partial myelitis associated with an acute enhancing MRI lesion in the cervical spinal cord. Her symptoms resolved after 3 days of high dose (1000 mg daily) intravenous methylprednisolone (IVMP). Her disease-modifying therapy was switched to natalizumab which led to a long period of disease stability at an Expanded Disability Status Scale (EDSS) score [57] of 1.0 with no evidence of clinical or MRI disease activity over the next 7 years. She received the first dose of the Moderna COVID-19 vaccine on January 5, 2021, and the second dose 28 days later. The second dose led to mild systemic side effects lasting only for 1 day. Twenty-one days after the second dose, she developed new neurologic symptoms; neurologic examination showed ataxia/dysmetria in the right upper extremity, and mild gait ataxia, with an EDSS score of 2.5. She received 2 days of 1000 mg IVMP per day based on the assumption that this was an MS relapse. MRI showed a new T2 hyperintense lesion in the right cerebellum that enhanced with gadolinium (Fig. 1). There were no other MRI changes compared to pre-pandemic imaging (Fig. 1). Serum JC virus and natalizumab neutralizing antibodies were negative. She then received 3 more days of high dose IVMP with rapid improvement of neurologic symptoms. Follow up MRI, 30 days after symptom onset, showed nearly complete resolution of the cerebellar lesion gadolinium enhancement (Fig. 1). During this entire episode she remained on monthly natalizumab and was able to work full time, having missed only 1 day of work during this period. Follow-up examination, 62 days after symptom onset, showed return of EDSS score back to the 1.0 baseline. She reported that all new neurologic symptoms had fully resolved.

Fig. 1 Serial 3 T MRI scans in case 1. Axial (a) and sagittal (e) T2 FLAIR MRI obtained 18 months prior to onset of new neurologic symptoms show two typical MS lesions in the corpus callosum, but no lesions in the cerebellum. Axial (b) and sagittal (f) T2 FLAIR and T1 post-gadolinium axial (c) and sagittal (g) MRI after COVID-19 vaccination and new neurologic symptom onset showing a new 1.5 × 1.4 × 1.9 cm T2 hyperintense lesion in the cerebellum with open-ring enhancement. Axial T1 post-contrast MRI (d) obtained 30 days after symptom onset, and after high dose intravenous methylprednisolone, shows nearly complete resolution of the gadolinium enhancement of the lesion. Her other MS lesions remained stable: sagittal STIR (h) and axial T2 (i) of the cervical spinal cord show a T2 hyperintense demyelinating lesion (white arrow). T2 FLAIR of the brain (j–o) show numerous typical MS lesions including one in the right cerebellum (white arrow) Full size image

Case 2

A 26-year-old white Hispanic woman presented with 2 days of new visual symptoms involving the right eye. Her symptoms began with mild blurring, which progressed over the next few days to worsening blurriness and pain with eye movement OD. Fourteen days prior to symptom onset, she had finished a full COVID-19 vaccination course. She received the first dose of the Moderna COVID-19 vaccine on December 27, 2020, and the second dose 29 days later without any significant immediate side effects after vaccination. She had a negative COVID-19 nasal PCR test on Jan 26, 2021, 1 day after the second vaccine dose. She had no significant past medical history. On examination, she had a relative afferent pupillary defect (RAPD), decreased visual acuity (20/50) and color desaturation OD. Visual field assessment showed a monocular central/inferior monocular deficit. MRI (Fig. 2) showed multiple T2 hyperintense periventricular, subcortical, posterior fossa, and spinal cord lesions with morphology suggesting MS. After gadolinium administration, two of the lesions enhanced (one each in the brain and spinal cord). Other inflammatory and infectious blood studies including antinuclear antibody, anti-neutrophil cytoplasmic antibody, and Lyme titer were unremarkable. Lumbar puncture performed 4 days after symptom onset (Table 2), showed an elevated IgG index (CSF/serum) at 1.27 (normal ≤ 0.85) and an elevated cell count. The CSF was otherwise normal on protein and glucose, without oligoclonal bands. She received 5 days of 1000 mg IVMP, 3 days after symptom onset, leading to gradual improvement of her symptoms. At follow-up visit, 14 days after symptom onset, she had returned to baseline and neurologic examination was normal. Given her clinical presentation and MRI findings, she was diagnosed with RRMS and started MS disease-modifying therapy. She showed a positive serum SARS-CoV-2 spike antibody, suggesting humoral immunity to the SARS-CoV-2 virus, when checked 8 months after completing COVID-19 vaccination (608.70 U/mL–negative < 0.80 U/mL).

Fig. 2 Serial 3 T MRI scans in case 2, obtained 2 days after symptom onset. Spinal cord sagittal STIR (a, d) and axial T2 (b) obtained 3 days after symptom onset, motion degraded, showing T2 hyperintense focal lesions suggestive of multiple sclerosis at C1-2 (d, blue arrow), C3-4 (a/b, white arrows), and T4-5 (a, blue arrow). After gadolinium administration, the spinal cord lesion at C4-5 enhanced on T1 images (c, white arrow). Brain sagittal (e–h) and axial (i, j) T2 FLAIR show multiple periventricular and subcortical lesions suggestive of multiple sclerosis (white arrows), with one of them likely active (j, blue arrow) because of enhancement on axial T1 post contrast (k, white arrow) compared to isointense appearance on T1 non contrast images (l). Consistent with the acuteness of the enhancing lesion, note the reduced signal (restricted diffusion) on the apparent diffusion coefficient map (m, blue arrow). No clear right optic nerve T2 abnormality or enhancement was detected (not shown) Full size image

Case 3

A 24-year-old Vietnamese woman presented with new onset left eye vision changes. She had a history of RRMS with symptom onset 9 years previously with sensory symptoms/paresthesias in the right face and upper extremity, followed by diplopia 5 years later. This second event led to an RRMS diagnosis. One year later, disease-modifying therapy with fingolimod was started. She had a stable disease course with no disability (EDSS 0), except for an episode of numbness in her left lower extremity with no new MRI lesions after 2 years of fingolimod treatment. This resolved after 3 days of IVMP. In the fourth year of fingolimod treatment, she had routine MRI that showed stable MS findings (Fig. 3). Sixty days later, she had received two doses of the Pfizer COVID-19 vaccine, the first dose on April 10, 2021, and the second dose 21 days later, without any systemic side effects. One day after the second dose, she developed new visual symptoms in the right eye with blurred vision and pain on eye movement. When examined 5 days after symptom onset, monocular decreased visual acuity (20/30), RAPD, and red desaturation were noted OD. There were no other neurologic symptoms or abnormalities on examination. MRI of the brain and orbit showed several new enhancing brain lesions without any optic MRI abnormalities (Fig. 3). She had a negative COVID-19 nasal PCR test on May 8, 2021, 7 days after completing vaccination. She was treated with 3 days of 1000 mg IVMP and her visual acuity improved to 20/25 OD. At follow-up, 11 days after discharge, she returned to baseline with a visual acuity of 20/20 bilaterally (EDSS 0). She showed a positive serum SARS-CoV- 2 spike antibody on May 20, 2021, (940.20 U/mL-negative < 0.80 U/mL) suggesting an adequate humoral immunity to the virus after vaccination.

Fig. 3 Serial 3 T MRI scans in case 3. Baseline scan: sagittal STIR (a) and axial T2 (b) of the cervical spinal cord and axial (c–e, k, n) and sagittal (f) T2 FLAIR MRI of the brain obtained 70 days prior to onset of new neurologic symptoms, showing multiple T2 hyperintense demyelinating lesions in the brain and one lesion in the spinal cord (blue arrows). Post-vaccination scan: axial (g–i, l, o) and sagittal (j) T2 FLAIR of the brain 6 days after new neurologic symptom onset and 7 days after COVID-19 vaccination, showing multiple new T2 hyperintense lesions (white arrows: new lesions, blue arrows: old lesions). T1 post-gadolinium axial images (m, p) show enhancement (white arrows) of two of the new FLAIR lesions. Spinal cord imaging was not obtained post vaccination due to the isolated visual symptoms Full size image

Case 4

A 64-year-old Caucasian man with no history of neurologic diseases, received the first dose of the Pfizer COVID-19 vaccine on April 2, 2021 without any immediate side effects post vaccination. Eighteen days after the first vaccine dose, he developed pain and paresthesia in his upper abdomen. Over the next 4 days, he developed right lower extremity numbness and weakness. His symptoms progressed to pain and numbness in the bilateral lower extremities, saddle anesthesia, sphincter dysfunction, and balance/gait difficulty. He required a cane to walk 200 feet. Brain and spinal cord MRI, 9 days after symptom onset, showed a minimally expansile central spinal cord edema-like T2 hyperintensity extending from the cervical spinal cord to the conus, with patchy areas of gadolinium enhancement, consistent with longitudinally extensive transverse myelitis (Fig. 4). Brain lesions were also demonstrated, suggesting demyelination (Fig. 4). Lumbar puncture, performed 9 days after symptom onset (Table 2), showed that CSF cells, protein, glucose, and IgG index were unremarkable, without oligoclonal bands. Neuromyelitis optica (NMO) antibody was strongly positive [serum titer > 1:100,000 (reference range < 1:5); CSF 1:128 (reference range < 1:2)]. He had positive SS-A/SS-B antibodies and underwent a salivary gland biopsy, which was consistent with Sjogren’s disease (focal lymphocytic sialadenitis and mild atrophic changes). He had negative COVID-19 nasal PCR tests on April 27, 2021 and May 1, 2021. The patient was treated with 3 days of 1 g IVMP with a partial response, followed by five sessions of plasma exchange. He showed improvement of his bowel/bladder symptoms and pain, with EDSS score improved to 3.5 from 6.0 when he was symptomatic. Residual symptoms included moderate sensory symptoms, mild right sided weakness, and bladder symptoms. The patient did not receive a second dose of the vaccine upon advice from his neurologist. Treatment with rituximab was initiated.

Fig. 4 3 T MRI scans in case 4. Cervical and thoracic spinal axial T2 (a) and sagittal STIR (b, d), obtained 8 and 9 days after neurologic symptom onset, show longitudinally extensive high signal abnormalities with cord swelling in the thoracic spinal cord (white arrows). Gadolinium-enhanced sagittal (c) and axial T1 (e–g) images show patchy posterior lesion enhancement at T1/2-T5 and T9-T10/11 (blue arrows). Brain axial (h, i) and sagittal (j, k) T2 FLAIR obtained 9 days after onset of new symptoms, showing multiple T2 white matter signal abnormalities in the corpus callosum with extension into the left frontal and parietal white matter, suggestive of demyelination. Brain imaging with gadolinium showed the lesions to be non-enhancing (not shown) Full size image

Case 5

A 33-year-old Caucasian man with no significant past medical history received the first dose of the Pfizer COVID-19 vaccine on December 18, 2020, with limited side effects (arm pain). The second dose was administered 20 days later. One day after the second vaccine dose, he developed unilateral painless blurring of vision. Examination showed a visual acuity of 20/50 OS. Brain MRI, 39 days after symptom onset, demonstrated multiple T2 hyperintense white matter lesions with a single gadolinium-enhancing lesion consistent with an active demyelinating process (Fig. 5). CSF studies, obtained 40 days after symptom onset (Table 2), showed more than five oligoclonal bands with elevated IgG index. He had a normal CSF cell count, protein, and glucose. NMO serum antibody was negative. He was treated with 3 days of 1000 mg IVMP followed by an oral prednisone taper. Seven days later, left eye visual acuity improved to 20/30 OS with poor low contrast visual acuity but no red color desaturation or RAPD. Thirty days later, visual symptoms returned to normal (acuity 20/20 OU), and he was started on disease modifying therapy.

Fig. 5 3 T MRI in case 5. Brain: axial (a–c) T2 FLAIR obtained 39 days after new neurologic symptom onset, showing periventricular and juxtacortical T2 lesions typical of multiple sclerosis; note one of the lesions ring-enhances with gadolinium (d, white arrow). Spinal cord: thoracic sagittal STIR (e) shows a T2 hyperintense spinal cord lesion suggestive of multiple sclerosis (white arrow). No cervical spinal cord enhancing lesions or new cervical spinal cord T2 lesions were seen (not shown) Full size image

Case 6

A 44-year-old Caucasian woman had her first MS symptoms at age 20 when she developed optic neuritis. She was diagnosed with RRMS 2 years later but remained off disease-modifying therapy despite having active disease with several relapses. She started intramuscular interferon beta-1a at age 29 but this was poorly tolerated. One year later, she had an episode of myelitis and was place on glatiramer acetate for a few months and was again unable to tolerate injections. Her neurological complaints resolved, and she remained off disease-modifying therapy for the next 14 years with stable disease clinically (EDSS 0) and by MRI. She had a small gadolinium-enhancing lesion in the right pericallosal white matter reported on brain MRI 2 years prior to this presentation but without any new neurological symptoms, followed by stable subsequent imaging. She received the first dose of the Moderna COVID-19 vaccine on January 24, 2021, followed by a second dose 30 days later. She had a transient low-grade fever after the second dose, but no other systemic symptoms. Six days after the second vaccine dose, she developed new neurological symptoms including numbness that ascended from her feet to the middle of her waist without any bowel or bladder incontinence. On exam, she had an EDSS score of 1.5 with mild right deltoid and iliopsoas weakness, brisk deep tendon reflexes, and slightly diminished sensation to pinprick in the left back. MRI, 1 day after symptom onset, showed a new enhancing lesion in the brain (Fig. 6). She was treated with 3 days of 1000 mg IVMP and, 30 days later, the neurologic exam returned to normal (EDSS 0); she was started on disease-modifying therapy.

Fig. 6 3 T MRI scans in case 6. Axial (a) and sagittal (c) T2 FLAIR of the brain obtained 1 day after new neurologic symptom onset showing stable burden of periventricular and juxtacortical T2 lesions when compared to previous imaging 2 years prior to symptom onset (not shown). There is a new 3-mm gadolinium enhancing lesion in the centrum semiovale, adjacent to the falx in the left cerebral hemisphere (b, white arrow). No new spinal cord lesions were noted by MRI during this episode (not shown) Full size image

Case 7

A 48-year-old Caucasian woman was diagnosed with a clinically isolated demyelinating syndrome (CIS) in the setting of sensory complaints 8 years previously. Her MS disease-modifying therapy history included a 9-month course of dimethyl fumarate which was poorly tolerated, followed by 6 years of glatiramer acetate. At her last neurologic visit (May 2019), she had clinical and MRI stability. Her baseline MS symptoms included sensory symptoms, occasional Lhermitte's symptoms, and decreased visual acuity OD (20/25); her EDSS score was stable at 1.0 for many years. When the pandemic started in early 2020, she decided to discontinue disease-modifying therapy. She received the first dose of the Pfizer COVID-19 vaccine on March 5, 2021, which was initially well tolerated. Fifteen days after the first vaccine dose, she developed a painful sensation behind her right eye, worsening with eye movement. She also noted increased Lhermitte’s phenomenon and new balance difficulty with occasional tripping. Brain MRI showed three new T2 hyperintense white matter lesions compared to prior imaging 2 years earlier (Fig. 7). Gadolinium was not administered with the new scan. All post-vaccination neurologic symptoms showed improvement after 3 days of high dose oral corticosteroids (1000 mg methylprednisolone daily) but she continued to have persistent mild symptoms. She received the second dose of the vaccine, 30 days after the first dose, without any new symptoms. At follow-up, 90 days after the initial event, EDSS score was 1.5, and the patient reported improvement but felt worse than her pre-vaccination baseline.