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Acute transverse myelitis with Dysautonomia following SARS-CoV-2 infection: A case report and review of literature

Objective To report a unique case and literature review of post COVID-19 associated transverse myelitis and dysautonomia with abnormal MRI and CSF findings. Background Coronavirus disease have been reported to be associated with several neurological manifestations such as stroke, Guillain-Barré syndrome, meningoencephalitis amongst others. There are only few reported cases of transverse myelitis with the novel coronavirus (n-CoV-2) and only one reported case identifying dysautonomia in COVID-19 patient. Here, we identify a COVID-19 patient diagnosed with acute transverse myelitis in addition to dysautonomia following with complete resolution of symptoms. Method A retrospective chart review of a patient diagnosed with post SARS-CoV-2 infection acute transverse myelitis and dysautonomia, and a review of literature of all the reported cases of transverse myelitis and COVID-19, from December 1st, 2019 till December 25th, 2020, was performed. Conclusion To our knowledge, this is the first reported case of transverse myelitis and dysautonomia in a patient with SARS-CoV-2 infection, who responded to intravenous methyl prednisone and bromocriptine. Follow-up imaging of the spine showed complete resolution of the lesion. Further studies would be recommended to identify the underlying correlation between COVID-19 and transverse myelitis.

Here we present a case of acute transverse myelitis and dysautonomia involving the cervical and thoracic spinal cord following SARS-CoV-2 infection, with complete recovery following treatment with intravenous steroid.

Case report
A 41-year-old man with no significant past medical history presents to the emergency department (ED) with new onset paresthesia (numbness and tingling) in bilateral upper and lower extremities along with urinary and fecal retention which stared two days prior to his presentation. Of note, he had visited his primary care clinic few weeks ago for headache, nausea and low-grade fever; and was tested for COVID-19 which turned out to be positive. He had an exposure to his friend who had mild COVID like symptoms. He did not require any intervention at that time and was asked to self-quarantine for a period of two weeks. During this span, he experienced mild symptoms of fatigue, myalgia, and low-grade fever. He presented at nearest emergency department with difficulty in voiding urine, and vomiting a week after his diagnosis; for which he underwent straight catherization after which he was discharged.
He was doing fine until the second week after diagnosis; when he was brought to the ED second time with headache, acute onset low-grade fever, extreme fatigue, retention of urine, neck and mid-thoracic back pain with generalized weakness. In the ED, he had foley catherization and was admitted for further management. He also complained of no bowel movement for more than a week, and new onset of numbness since few days which he described as patchy in distribution; involving right side of his face along with right side involvement of upper and lower extremities. He also mentioned tingling in right lower extremity and difficulty in ambulating requiring assistance for walking. He denied any vision changes, difficulty in swallowing or speech, shortness of breath, chest pain, and loss of smell or taste sensation. There was also no history of preceding diarrhea, recent vaccinations or any trauma.
On arrival, he was lethargic, oriented x3, afebrile and vitals were stable. Physical examination demonstrated cranial nerves were intact, however motor strength showed MRC grade of 4/5 throughout right lower extremity. Upper motor neuron signs were present in bilateral lower extremities with Grade 3+ reflex, positive bilateral Babinski reflex and decreased sensation in right lower extremity with sensory level at T6. Proprioception and vibration sensation were intact.
Serum NMO/AQP4, MOG antibodies (Ab), HTLV I/II Ab, MTB PCR, lymphocytic choriomeningitis virus (titer <1:10), listeria Ab, west nile virus IgM, IgG and PCR, were all negative. Myelin basic protein, serum and CSF autoimmune panel were negative including anti-NMDAreceptor, anti-CASPR2, anti-LGl1, anti-GABAB-receptor, anti-AMPA. Overall, findings were compatible with inflammatory central nervous system disorder and the presentation was thought to be from post viral transverse myelitis.
The patient was initiated on intravenous methyl prednisone and was managed with foley catheter placement for neurogenic bladder. Patient reported gradual improvement in symptoms at day 6 of admission, with improved mentation, increase in muscle strength and decrease in paresthesia. Repeat MRI of the cervical and thoracic spine was performed on day 10 of admission, which showed interval resolution of previously identified signal abnormalities in the cervical and thoracic spine (Fig. 2). Following 5 days of intravenous methyl prednisone, he was transitioned to oral prednisone taper. He was categorized as mild COVID-19 based on IDSA/ATS guidelines (Metlay et al., 2019). Of note, during the course of admission on day 4, patient had unstable blood pressure and episodes of tachyarrhythmias concerning for dysautonomia. Patient had frequent episodes of transient elevations in blood pressure ranging in 160 s to 180 s, and asymptomatic sinus tachycardia in 120 s. He was started on IV labetalol 10 mg push and was switched to IV enalapril 1.25 mg q6 hourly and as needed. He was also started on oral amlodipine 10 mg daily and oral bromocriptine 2.5 mg q8 hourly. Dysautonomia eventually resolved by the time of discharge, and amlodipine as well as bromocriptine were discontinued.
Patient was discharged to skilled nursing facility on day 15 with oral prednisone for 3 weeks. He continued to show improvement in sensory and motor deficits. However, urinary retention persisted, which required indwelling foley catheter on discharge. Patient was followedup with his urologist within a week of discharge and his foley catheter was removed. The patient will be followed up in neurology clinics in 6 weeks. Though NMO antibody tests were negative, NMOSD can still be considered in the differentials and so a repeat MRI spine including cervical and thoracic will be performed; along with repeat serum NMO antibody test on the patient's follow-up visit.

Discussion
Several studies describing the neurological manifestations of the novel coronavirus disease have been published recently showing its potential to invade both the central nervous system (CNS) as well as the peripheral nervous system (PNS). In one of the most comprehensive reviews on neurological imaging findings and COVID-19 according to our knowledge, we found that more than one third of hospitalized patients with COVID-19 developed some form of neurologic symptoms (Munhoz et al., 2020;Chowdhary et al., 2020;Berger, 2020).
Acute transverse myelitis basically presents with a varied signs and symptoms of sensory, motor and autonomic dysfunction. Pathological changes in the spinal cord tract are seen on spinal imaging, as a result of focal inflammation. As this disorder can lead to debilitating effects and permanent disability, it is quintessential to recognize it early and distinguish it from other neurological entities. The diagnosis of transverse myelitis involves characteristic clinical presentation of bilateral signs and symptoms with a clearly defined sensory level, in addition to evidence on neuroimaging, CSF and serologic studies (Proposed diagnostic criteria and nosology of acute transverse myelitis, 2002). The inclusion criteria of transverse myelitis include the non-specific hyperintense lesion of spinal cord and isolated grey matter involvement which makes the differential of demyelinating diseases less likely as MS affects short segments usually and concerns white matter (Lycklama et al., 2020). Nevertheless, neuromyelitis optica spectrum of disorders (NMOSD) stand as a significant differential due to longitudinally extensive spinal cord involvement but since it is usually seen surrounding the central canal of spinal cord, it can be ruled out in MRI findings to make transverse myelitis the definitive choice of diagnosis    (Kim et al., 2020). Table 2 includes Transverse Myelitis Consortium Working Group criteria which is used for diagnosis of cases of transverse myelitis (Proposed diagnostic criteria and nosology of acute transverse myelitis, 2002). However, on a comprehensive literature review, we found that amongst the ten reported cases of COVID-19 associated transverse myelitis, only 9 could fulfill the criteria. A case report by Zhao et al., did not have adequate investigations or their investigations findings lacked essential data to fulfill all the inclusion criteria for diagnosis of transverse myelitis   (refer Tables 1 and 2). Majority (6 out of 10) of the cases reported a high protein value in CSF, some reported pleocytosis (4 out of 10), while the WBC counts were inconsistent in the majority of the cases. The time elapsed between development of the symptoms suspicious of transverse myelitis and COVID-19 RT-PCR positivity varied between 2 and 12, with an average of ~7 days (refer Table 1).
The age of the patients also varied from 24 to 66 years. All of the patients had development of lower extremity weakness or sensory disturbances as one or the only presenting symptom. The most common MRI finding was hyperintensity in two to three consecutive segments of spinal cord. In our review, amongst all reported cases of post infectious COVID-19 transverse myelitis, only one study by Sarma et al. found to have abnormal enhancement on post contrast study, however the remaining cases did not report any abnormal post contrast enhancement in the spinal cord. Eight out of ten cases received standard doses of steroids and showed significant improvement, however the remaining cases succumbed to death. Moreover, the overall course of seven cases were not severe likely due to timely detection and management (Sarma and Bilello, 2020;Zhao et al., 2020;Chow et al., 2020;Chakraborty et al., 2020;Valiuddin et al., 2020;AlKetbi et al., 2020;Durrani et al., 2020;Munz et al., 2020;Zachariadis et al., 2020;Abdelhady et al., 2020) (refer Table 1).
Various theories have been put forward to explain the unknown pathogenesis of transverse myelitis in COVID-19. Inflammatory processes may be triggered by retrograde transmission of virus through axons starting a demyelinating or inflammatory response (Bohmwald et al., 2020) whereas massive cytokine release as a consequence of systemic inflammation may also affect neuronal tissues. Baig A.M. et al. proposed the relation between COVID-19 and ACE-2 as a theoretical cause of this association (Baig et al., 2020). Transverse myelitis is a potentially serious complication which can be seen temporally associated with COVID-19 infection with serious repercussions if not identified and treated vigilantly.

Conclusion
We report the very first case of acute transverse myelitis with dysautonomia, post SARS-CoV-2 infection. Neurological manifestations can lead to severe debilitating effects and thus it is important for the emergency physicians and the neurologists to act swiftly in recognizing rare entities such as transverse myelitis early in the course of the novel coronavirus infection. Guidelines should be formulated for early imaging and CSF analysis in patients with COVID-19, in order to provide quick and efficient management to these patients. We believe, this case report will not only add to the existing database of COVID-19 and transverse myelitis, but also would serve as a source for researches to conduct more studies in the future.