key: cord-0917567-hwogtlml authors: Memon, Anza B.; Al-Hader, Rami; Patel, Suresh; Malik, Shaneela; Megally, Mary; Steijlen, Kara; Suri, Ritika R.; Corrigan, John title: Late-onset rapidly progressive MRI- negative-myelitis after COVID-19 illness date: 2021-01-22 journal: Clin Neurol Neurosurg DOI: 10.1016/j.clineuro.2021.106513 sha: 0010d989cfae87853f2351a37e002edb03bf397f doc_id: 917567 cord_uid: hwogtlml • Atypical presentation of myelitis raises concern for a slow or delayed immune-mediated pathogenesis that could occur in response to the SARS-CoV-2 virus or antiviral antibodies. • This case highlights the need for physician vigilance in recognizing post-COVID-19 myelitis even months after initial infection. • MRI-negative partial myelitis that progressed to complete myelitis. Several neurological manifestations in association with the coronavirus disease 2019 (COVID-19) 1 ,2 have been reported. Cases of post-infectious transverse myelitis (TM) and para-infectious TM associated with COVID-19 have been published, and longitudinally extensive 3, 4 , acute necrotizing 5 , and multifocal TM cases have also been reported 6 . Other viral pathogens that can be causative of TM include herpes simplex, Epstein-Barr, varicella-zoster, cytomegalovirus, hepatitis B, Zika, dengue, and chikungunya viruses 7 . Flaviviruses (yellow fever, tick-borne encephalitis, Japanese encephalitis, West Nile, dengue, and Zika viruses) and coronaviruses (Middle East respiratory syndrome, SARS-CoV-1, and SARS-CoV-2 viruses) are RNA based respiratory viruses with neurotropic properties that allow them to bypass or alter the immune mechanisms, which can lead to viral-induced neurological manifestations. 8 The host-virus interaction triggers the immune mechanisms, and genetics may play an important role too. Therefore, it is interesting that only some individuals develop neurological manifestations after infection with potentially neurotropic pathogens. Here, we report a case of late-onset rapidly progressive MRI-negative-myelitis after infection. This case is compelling, as the patient presented with myelopathic symptoms 9 weeks after COVID-19 illness, which was unrecognized for 3 months due to negative results from an extensive neurological workup for myelitis, which led to diagnostic uncertainty. This case highlights the need for physician vigilance in recognizing post-COVID-19 myelitis even months after initial infection. J o u r n a l P r e -p r o o f A 65-year-old woman with a history of borderline diabetes and obesity (BMI 45.6) was referred to the neuroimmunology clinic to evaluate idiopathic magnetic resonance imaging (MRI) negative TM. In early April 2020, the patient became sick with symptoms concerning for COVID-19 illness. She had chills, headache, cough, shortness of breath, fever, anorexia, and taste loss. She was prescribed prednisone and antibiotics for one week and was recommended by her primary care physician to self-quarantine. She was advised to go to the emergency department (ED) for care after her symptoms worsened. SARS-CoV-2 testing was not done at that time. The patient made a full recovery after 2 weeks and did not require hospitalization. The patient remained in good health until June 12, 2020, when she started having numbness in her feet that gradually ascended to her trunk. Simultaneously, she noticed strange vibrations inside her body upon neck flexion (Lhermitte's phenomena). She had an imbalance and weakness in her legs that led to falls. The patient also reported bladder (urinary incontinence) and bowel dysfunction (constipation) and saddle anesthesia. She had a televideo-visit with a neurologist on July 15, 2020 and she was recommended to seek an urgent ED visit to evaluate myelopathy. The patient presented to the ED the same day, and the Neurology Department was consulted. Neurologists noted upon examination that the patient had normal upper and lower extremity strength with diffusely brisk reflexes and positive Hoffman's sign bilaterally. She had a sensory level at T10 with diminished pinprick sensation. Temperature sensation was normal with loss of vibratory sensation and impaired proprioception distally at her toes. The patient had a wide-based cautious gait with a positive Romberg's sign. She was admitted to the observation unit for 24 hours. The patient had magnetic resonance imaging (MRI) of the cervical, thoracic, and lumbar spine (1. The patient reported no family history of cancer, and computed tomography (CT) imaging of the abdomen and pelvis was done to assess possible malignancy, which was negative.Shortly after discharge from the hospital, the patient started using a cane. Brain MRI (1.5 tesla) completed 5 days after her discharge from the hospital showed a small lacunar infarct in the right lateral pontine region (Figure1 E), which did not explain her worsening symptoms. Spinal fluid analysis was recommended, but the patient elected not to undergo this procedure per clinical documentation. The patient presented to the ED again 6 days after her first hospitalization for lower extremity pain, swelling, and progressive motor weakness. On neurological examination during this visit, she was noted to have 4/5 weakness with the right lower extremity hip flexion; the rest of the examination was stable. She had a repeat SARS-CoV-2 nasopharyngeal PCR test, which was negative. In the ED, the patient had pre-syncope (dizziness), tachycardia, chest pain, and acute The patient received catheter-directed, low-dose fibrinolysis via the EKOS catheter for submassive pulmonary embolism and was later started on intravenous heparin. The patient was admitted to the medical intensive care unit for 2 days and transferred to the stepdown unit, where she was observed for an additional 2 days. Her shortness of breath and chest pain improved, and she was discharged home on apixaban 5 mg twice a day. Her pulmonary embolism was thought to have been provoked by limited mobility. After discharge from the hospital, the patient started using a walker. She had an outpatient EMG study done 11 days after discharge from her second hospitalization, which did not indicate peripheral nerve disorders suchneuropathy or myopathy (supplementary table) . The lumbar puncture was on hold because the patient was on anticoagulation therapy. She was prescribed prednisone 60 mg daily for 5 days, followed by a slow taper over one month with no improvement in her symptoms. The patient received outpatient physical therapy but made no progress. The patient then presented to an outside hospital where she had a repeat MRI of the cervical and thoracic spine, which was again reported as normal (we do not have access to the imaging). She was discharged to inpatient rehabilitation, where the patient's condition continued to decline and she became wheelchair-bound by September. Given the lack of abnormal enhancement and restricted diffusion, a demyelinating process was not suspected. Given progressive clinical worsening and abnormal neuroimaging findings, inpatient admission to neurology service was recommended to expedite the lumbar puncture and treatment. The patient underwent lumbar puncture after apixaban was withheld for 48 hours (medication was (supplementary table) . Follow-up MRI of the brain and cervical spine with and without contrast after PLEX was unchanged to slightly improved due to differences in MR magnets and motion suggest stability (Figure, K-M) . MRI thoracic and lumbar spine remained normal. The patient was discharged to inpatient rehabilitation with outpatient neurology follow-up. Per the last conversation with the patient over the phone, she reported that she could move her feet and kick her legs further out, which she could not do before treatment. She can now slowly pull her J o u r n a l P r e -p r o o f legs back and she can stand with bilateral assistance for about one minute. The patient believes that she is very slowly making progress. Our patient presented with late-onset partial myelitis that progressed to complete myelitis over 3 months, which was preceded by the COVID-19 illness 9 weeks before her neurological manifestation. Extensive infectious, inflammatory autoimmune, neoplastic, and paraneoplastic investigations were negative. CSF was positive for West Nile IgG antibody; however, the patient's clinical presentation and EMG results were not suggestive of lower motor neuron illness seen in West Nile virus infection. This could be due to SARS-CoV-2 antibody cross-reactivity with the West Nile Virus, also seen in antibody-induced by other flavivirus infections (e.g. Dengue virus, Although she had positive initial serum mycoplasma IgG test, the repeat antibody tests (IgM and IgG) and a CSF mycoplasma PCR test were negative, which suggests an initial false positive result. This elucidates a possible post-infectious or immune-mediated myelitis after COVID-19 illness. About 30%-60% of idiopathic TM cases are preceded by a gastrointestinal, respiratory, or systemic disease. The onset of infectious myelitis symptoms is typically hours to days, but can be months to years after infection, as seen with human T cell lymphotropic virus-1 (HTLV-1) associated myelopathy. 9 Several mechanisms are involved in TM's microbial pathogenesis: bystander effects, molecular mimicry, immune complex deposition, and microbial super-antigen mediated inflammation and humoral response. 10 In bystander effects, the pathogen directly invades the CSF or causes indirect damage through an immune-mediated process, as can happen in para-infectious TM. Molecular mimicry is when there J o u r n a l P r e -p r o o f is antigenic similarity between pathogen antigens and the human tissue. 10 Molecular mimicry and immune complex deposition have been elucidated as one of the immunopathogenic processes involved in Mycoplasma pneumoniae post-infectious TM. Another interesting mechanism is the activation of lymphocytes by microbial superantigens that can initiate immunopathogenesis and lead to autoimmune diseases. 11 This has been reported in association with COVID-19 in a 15-year old male patient who was diagnosed with anti-MOG IgG associated bilateral optic neuritis a few weeks after COVID-19 illness. 12 The interesting feature in that case was the patient's normal MRI scans (1.5 tesla magnet) on at least 2 occasions, which was a misleading factor that delayed immunotherapy. MRI-negative myelitis is reported to be associated with anti-MOG autoantibodies, 13 and our patient tested negative for the MOG-IgG antibody. Her repeat MRI scans performed on 3-tesla magnet showed multifocal myelitis affecting the cervical cord. High T2 signal intensity involving the bilateral cortical spinal tracts affecting the posterior limbs of internal capsules extending to the cerebral peduncles, and faintly extending to the pons without associated enhancement. These results raise concern for possible Wallerian degeneration, as the patient did not manifest any features of encephalitis or cranial neuropathies from the brainstem involvement throughout her disease course. We speculate that these results indicate an intense axonal degeneration without demyelination that can be seen in severe viral-induced pathogenesis and therefore was not seen on the MRI scan earlier in our patient's disease course. Pathological processes that extensively affect the corticospinal tracts could raise a concern for rapidly progressive motor neuron disease, such as amyotrophic lateral sclerosis. But our patient's history of ascending sensory paresthesia followed by motor weakness and negative EMG on 2 occasions does not support the diagnosis of motor neuron disease. A similar brain abnormality was reported in another COVID-19 patient, where bilateral corticospinal tract lesions in internal capsules extending to the cerebral peduncles and pons associated with evidence of longitudinally extensive transverse myelitis were seen on spinal neuroimaging. 14 Clinically, this patient behaved differently compared to our patient, as she manifested mild encephalopathy, acute onset of TM 2 weeks after COVID-19 illness, and had a good response to immunotherapy (PLEX). 14 Perhaps one might argue that early initiation of immunotherapy could have changed our patient's clinical outcome. SARS-CoV-1 studies have shown that viral replication can delay the self-reactive T-cell suppression, leading to central nervous system neuroinflammation, demyelination, and axonal damage. 15, 16 Our patient's case highlights several interesting aspects of post-COVID-19 myelitis, including late manifestation of myelitis months after the viral illness, rapidly progressive disease, and MRInegative spinal imaging at the onset of disease that led to diagnostic uncertainty, which dissuaded early initiation of immunotherapy. This atypical presentation of myelitis raises concern for a slow or delayed immune-mediated pathogenesis that happened in response to the SARS-CoV-2 virus or its antibodies. 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Multiple Sclerosis and Related Disorders Frequency and characteristics of MRInegative myelitis associated with MOG autoantibodies A case of possible atypical demyelinating event of the central nervous system following COVID-19 Innate immune responses and Viral-Induced neurologic disease Viral-induced suppression of self-reactive T cells: lessons from neurotropic coronavirus-induced demyelination The authors thank the patient and all the physicians and health personnel involved in the care of this patient.