The authors from the United States presented a series of three women aged 26, 43, and 44 years who developed hemorrhagic myelitis within 4 weeks after being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The presence of hemorrhage was identified on precontrast T1-weighted, susceptibility-weighted, and gradient echo sequences. Unlike typical inflammatory or demyelinating myelitis, clinical recovery was poor in all cases. The disease responded poorly to immunosuppressive therapies, resulting in residual quadriplegia or paraplegia.
There are a limited number of reports of para/postinfectious hemorrhagic myelitis dating back to 1915, with histopathology demonstrating hemorrhagic changes involving the gray matter, early necrotizing features and perivascular lymphocytic infiltration. Para/postinfectious hemorrhagic myelitis has been reported in patients infected with herpes viruses and in those with immunocompromised conditions. A few noninfectious cases were associated with vaccination (papilloma and influenza viruses) and comorbid systemic lupus erythematosus. The main differences between hemorrhagic myelitis and inflammatory or demyelinating myelitis are the severity of the neurologic deficit, low clinical response to immunosuppressive therapy, and the long-term disability. It is proposed that several mechanisms contribute to hemorrhagic myelitis, including direct neuroinvasive viral mechanisms, para/postinfectious inflammatory cascades, complement activation, vasculopathy and coagulopathy.
Case series
Case 1
Ten days after developing symptoms of upper respiratory tract infection, a 43-year-old woman was admitted for acute bilateral weakness of the lower extremities, urinary retention, and ascending sensory loss. She tested SARS-CoV-2 positive by nasopharyngeal swab reverse transcription polymerase chain reaction. The neurologic examination showed flaccid paraplegia and sensory level at T4. The magnetic resonance imaging (MRI) of the spine after 24 hours revealed contrast enhancement and central T2-weighted hyperintensity at C5-T12. The CSF demonstrated an increase in erythrocytes (226/μL), pleocytosis (949 leukocytes/μL, 93% neutrophils), an elevated protein level (210 mg/dL), and elevated immunoglobulin (Ig) G index (0.82). Other analyses of the CSF, including the meningoencephalitis panel, viral tests (herpes simplex virus, varicella zoster virus and SARS-CoV-2) showed negative results. Antineural antibody panel tests for autoimmune myelopathy, human immunodeficiency virus (HIV) serology, antinuclear antibodies, aquaporin–4 IgG, and myelin oligodendrocyte glycoprotein antibodies were negative. Platelets, prothrombin time, and activated partial thromboplastin time were normal.
Prophylactic subcutaneous enoxaparin was administered. After receiving intravenous methylprednisolone (IVMP) for 5 days, her condition deteriorated to quadriplegia and respiratory failure, so plasmapheresis was initiated. After 11 days, the control MRIs of the spine and brain showed an extension of T2-weighted hyperintensity upward into the brainstem, and new hemorrhage. After 12 days, a control CSF analysis showed 5 erythrocytes/μL, 5 leukocytes/μL (51% lymphocytes), 31 mg/dL of protein, and elevated IgG index (1.09). The patient was treated with intravenous immunoglobulins, and with another 5-day course of IVMP, followed by oral prednisone. Despite this, she remained quadriplegic and mechanically ventilated. After 2 months, neuroimaging showed improvement in lower cervical T2-weighted hyperintensity and evolving susceptibility-weighted imaging hypointensity in the medulla. At three months, the expanded disability status scale (EDSS) was 9.0.
Case 2
After three weeks of symptomatic SARS-CoV-2 infection, a 44-year-old woman with a history of right lower extremity weakness and paresthesia developed new ascending bilateral paresthesia in the lower extremities. The neurologic examination showed normal muscle strength, hyperreflexia, and sensory level at T8. After a month, MRI of the spine demonstrated expansile T2-weighted hyperintensities at T6-8 and T9-10 with contrast enhancement. The MRI of the brain revealed multiple periventricular and pericallosal nonenhancing T2-weighted lesions. The CSF analysis showed 94 erythrocytes/μL, 7 leukocytes/μL (94% lymphocytes), 32 mg/dL of protein, elevated IgG index (1.77), and serum-unmatched oligoclonal bands. The CSF bacterial stain and culture, and tests for cytomegalovirus, herpes simplex virus, and varicella zoster virus were all negative. The HIV serology, antinuclear antibodies, aquaporin–4 IgG, and myelin oligodendrocyte glycoprotein antibodies were all negative. Platelets, PT, and APTT were normal.
She received IVMP for 3 days, but after 15 days she developed paraplegia and urinary retention. After 9 weeks, the MRI revealed a near-confluent progression of T2-weighted hyperintensity at C2-L1 with patchy contrast enhancement. She received another 5-day course of IVMP and plasmapheresis, followed by oral prednisone. She also received rituximab-pvvr. After 4 months, MRI revealed an evolution to chronic hemorrhage at T6-T7. At approximately 8 months, she remained paraplegic. At 1 year, MRI showed myelomalacia at T5-T9.
Case 3
A woman aged 26 years was admitted for COVID-19 myocarditis, cardiogenic shock, and multiorgan failure. 5 months before symptoms of SARS-CoV-2 infection, she was vaccinated with the adenovirus-vectored COVID-19 vaccine (Janssen Biotech). The patient was treated with dexamethasone for 10 days. After four weeks, she developed acute ascending sensory loss, followed by flaccid paraplegia and areflexia. The CSF analysis conducted 3 days after the onset of neurologic symptoms showed 23 erythrocytes/μL, 3 leukocytes/μL (75% neutrophils), 36 mg/dL of protein, and matched oligoclonal bands.
After 9 days, MRI of the spine showed expansile T2-weighted hyperintensity with precontrast T1 hyperintensity and microhemorrhage on T2-weighted sequences. After 19 days, CSF analysis showed 2 erythrocytes/μL, 1 leukocyte/μL (55% lymphocytes), 36 mg/dL of protein, and slightly elevated IgG index (0.67). The viral tests of CSF for the cytomegalovirus, herpes simplex virus, varicella zoster virus, and Epstein-Barr virus showed negative results. Serum HIV and antinuclear antibodies showed negative results. Platelets, PT, and APTT were normal. Serum aquaporin–4 IgG, and myelin oligodendrocyte glycoprotein IgG antibodies were all negative. A prophylactic subcutaneous heparin was administered. She received IVMP, followed by oral prednisone. The neuroimaging at 2 months showed persistent hemorrhage. At 5 months, she remained paraplegic.
The authors stated that five other cases of hemorrhagic myelitis following SARS-CoV-2 infection have been previously reported. The MRI findings and clinical outcomes in these studies were similar to those reported in this study. On MRI, myelitides were predominantly longitudinally extensive. The treatment included steroids, plasmapheresis and rituximab, but minimal or no improvement was observed during follow-up. The neurologic outcomes were severe, very similar to those seen in this study.
The authors concluded that hemorrhagic myelitis is uncommon in clinical practice, but may occur in a para/postinfectious setting, such as post–SARS-CoV-2. The severity of systemic symptoms due to initial viral infection does not seem to be correlated with hemorrhagic myelitis in cases of SARS-CoV-2 infection. Therefore, in case of suspected myelitis following the SARS-CoV-2 infection, it is imperative to conduct a gradient echo sequences with MRI of the spinal cord to detect any potential hemorrhage.
This article was published in Neurology.
Journal Reference
Tolja K et al. Pearls & Oy-sters: Hemorrhagic Myelitis Following SARS-CoV-2 Infection. Neurology 2023;101;e672-e676 (Open Access)Â http://n.neurology.org/content/101/6/e672.full