A Post-Infectious Steroid-Responsive Brainstem Lesion Associated With COVID-19

Abstract

A 51-year-old man developed coma, bilateral pupillary dilation, ophthalmoplegia and quadriplegia 4 weeks after testing positive for COVID-19. MRI demonstrated a symmetric midline pontine non-enhancing T2-FLAIR hyperintense lesion. The patient was treated with intravenous methylprednisolone, which resulted in improvement of his Glasgow Coma Scale (GCS) from 3 to 15 over the next 5 days. To our knowledge, this is the first case of a post-infectious steroid-responsive brainstem lesion associated with COVID-19. The clinical picture best fits in the family of a steroid-responsive encephalopathy and reminds us that COVID-19 may cause severe post-infectious neurological complications.

Dear Editor,

We wish to submit a brief case report entitled “A Post-Infectious Steroid-Responsive Brainstem Lesion Associated with COVID-19” for consideration by the Neurohospitalist.

In this paper, we show a case of a patient who developed coma due to a symmetrical-appearing midbrain lesion 4 weeks after COVID-19 infection who recovered with high-dose intravenous methylprednisolone. It is significant because it confirms the COVID-19 infections can have severe post-infectious neurological complications which may improve with treatment. We believe that this manuscript is appropriate for publication by the Neurohospitalist because it would raise awareness of potential diagnoses and treatments in comatose patients who have had a history of COVID-19 infection.

All authors have contributed substantively to the writing of this article and have given approval of the final version to be published. The patient has given informed consent for publication.

We confirm that this work is original and has not been published elsewhere, nor is it currently under consideration for publication elsewhere.

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors have received no financial support for the research, authorship, and/or publication of this article. The patient gave informed consent for the publication of this article.

Please address all correspondence concerning this manuscript to me at khamidulla.bakhadirov@kp.org.

Thank you for your consideration of this manuscript.

Sincerely,

Khamidulla Bakhadirov, MD

Assistant Professor of Neurology, Boston University Medical School, Department of Neurology, Kaiser Permanente Santa Clara Medical Center

Introduction

In late 2019, coronavirus disease 2019 (COVID-19), a virus with a highly homological sequence to SARS-CoV-1 and MERS-CoV was discovered to cause many unexplained cases of respiratory failure in Wuhan, China.¹ Since then, COVID-19 has become a worldwide pandemic, and there are emerging data that it can cause multiple neurological complications in humans, such as anosmia, dysgeusia, and stroke.² We report a case of post-infectious brainstem lesion associated with COVID-19 that was treated successfully with intravenous methylprednisolone.

Case Description

A 51-year-old man with a past medical history of hypertension and hyperlipidemia presents as a neurological consultation for acute onset of coma, bilateral ophthalmoplegia, and flaccid paralysis of all extremities in setting of a recent COVID-19 infection. He had presented to the emergency department 4 weeks prior with dyspnea, fever, cough, and myalgias. Qualitative PCR testing for COVID-19 via nasal swab was positive on presentation. He had no other significant past medical, family, or psycho-social history. The initial emergency room evaluation showed a normal neurological examination, but hypoxemia on room air. Initial laboratory investigations showed an unremarkable electrolyte panel, and lymphopenia without leukocytosis. His hospital course was complicated by intensive care unit admission for acute respiratory distress syndrome requiring ventilatory support and extensive deep venous thromboses of the internal jugular vein and lower extremities requiring therapeutic anticoagulation. Patient’s respiratory status and mental status were improving on the 4^th week of admission when he became comatose while off all sedatives and paralytics. Examination showed bilateral exophoria, dilated pupillary responses with poor constriction to light, quadriplegia and hyporeflexia. His Glasgow Coma Scale was 3. Computed tomography of the brain showed a midline symmetric hypodensity in the rostral pons (Figure 1). CT angiogram and venogram of the head did not show any vascular abnormalities aside from a known non-occlusive thrombus in the right internal jugular vein. Magnetic resonance imaging (MRI) of the brain revealed a non-enhancing T2-hyperintense pontine lesion (Figure 2). Repeat qualitative PCR testing for COVID-19 via nasal swab was negative. Unfortunately, serum and spinal fluid immunological testing for COVID-19 was unavailable. Lumbar puncture was considered but not performed due to family refusal to consent due to need for systemic anticoagulation. The patient was treated with 1 gram of intravenous methylprednisolone daily for 5 days. Over the treatment course, the patient regained consciousness, and his Glasgow Coma Scale improved to 15. By discharge, he was alert and oriented without aphasia, and had a normal cranial nerve examination. His flaccid quadriplegia had improved, though he still had a mild residual right upper extremity weakness. On outpatient follow-up 2 weeks later, he had no further neurological abnormalities, and thus a follow-up MRI was not obtained for cost-efficient management. Serum testing for aquaporin-4 receptor antibodies and myelin oligodendrocyte glycoprotein (MoG) antibodies returned negative. At 3-month follow-up patient has had no further neurological complications.

Figure 1.

Symmetric-appearing rostral pons hypodensity on computed tomography.

Figure 2.

Top-Left: Symmetrical DWI hyperintensity of the rostral pons on magnetic resonance imaging. Top-Right: Corresponding ADC hyperintensity, not suggestive of an acute ischemic stroke. Bottom-Left: T2/FLAIR hyperintenstiy of the rostral pons. Bottom-right: No abnormal enhancement seen on T1-post contrast imaging.

Discussion

Recently, Mao et al detailed neurological manifestations of hospitalized patients with COVID-19, describing complications such as acute cerebrovascular disease, encephalopathy, and skeletal muscle injury.² However, at time of this article, there have been no reports of post-infectious and steroid-responsive brainstem lesions of COVID-19. Our patient had re-tested negative for COVID when he developed neurological complications. Given improvement of his clinical status after administration of steroids, we demonstrated that patients may develop a steroid-responsive encephalopathy weeks after the initial COVID infection has cleared.

With limited investigational data, including lack of CSF analysis due to refusal of family consent, we had a broad differential diagnosis, including ischemic stroke, venous infarction, central pontine myelinolysis, post-infectious autoimmune/inflammatory disease, critical illness neuropathy, and critical illness myopathy. Because the MRI showed a single brainstem lesion that was hyperintense on diffusion weight imaging, and hyperintense on apparent diffusion coefficient, this was possible to be a subacute-chronic ischemic stroke. However, given that he was following commands with no weakness, and then was acutely comatose, a subacute timeline of stroke seemed unlikely. In addition, there was no stenosis or evidence of thrombus on CT angiogram of the head and neck. In brainstem strokes without associated basilar occlusion, it is very atypical to see such a midline and symmetric lesion on MRI. In terms of venous infarction, a computed tomography venogram of the head and neck only showed the known non-occlusive right internal jugular vein thrombosis. Central pontine myelinolysis or osmotic demyelination was considered given the classic midline T2-FLAIR hyperintense brainstem lesion on MRI, but there was no corresponding clinical history. The patient’s chemistry panel, including sodium levels, were checked daily and was within normal limits his entire hospitalization. There was no liver or kidney disease during his admission, and he did not have excessive hyperglycemia to suggest hyperosmolality from an unmeasured solute.³ Other diagnoses on the differential included critical illness myopathy and neuropathy were considered but given the patient had recovered from his COVID infection and did not have weakness or numbness the day before development of acute coma, this was thought to be less likely due to an inconsistent timeline and the presence of a brainstem lesion that could explain his findings. Lastly the brainstem lesion could be indicative of a post-infectious (given repeat COVID testing was negative) inflammatory or demyelinating lesion in the family of ADEM (acute disseminated encephalomyelitis). While acute inflammation or demyelination typically has contrast enhancement, absence of these radiographic signs does not exclude the diagnosis. Given brainstem involvement, a neuromyelitis optica-spectrum disorder or anti-MoG encephalitis was entertained as well.

Limited by the lack of CSF testing, we decided to empirically administer steroids as a post-infectious inflammatory etiology of the brainstem lesion appeared most likely when combining clinical history, physical examination, laboratory data and radiographic findings.⁴ In addition, was no evidence-based treatment to improve deficits from a subacute-chronic ischemic stroke, as patient was already on anticoagulants. The management of critical illness neuropathy and myopathy generally consists of supportive management. If there was a great chance for improved clinical recovery, we believed it would be with steroids. In the case of central pontine myelinolysis, there are some case reports showing improvement with steroids.⁵ In terms of an autoimmune/inflammatory disorder such as ADEM, the treatment with steroids has been associated with substantial clinical improvement in most of these patients⁶ with immunomodulatory therapy (intravenous immunoglobulin or plasma exchange) reserved for patients who have a poor response to steroids.⁷

After a robust and sustained response to steroids that improved the patient’s clinical status, and subsequent negative testing for serum titers of aquaporin-4 receptor antibodies and myelin oligodendrocyte antibodies, we believed this would likely be in the family of a post-infectious inflammatory syndrome due to molecular mimicry which includes diseases such as Bickerstaff encephalitis or ADEM. In these cases, an environmental stimulus such as a viral infection triggers development of an autoimmune reaction which inappropriately the nervous system, with a typical time course of onset averaging 4 weeks after infection While there has been no report of this entity in COVID-19 to our knowledge, there have been case reports of such complications in MERS-CoV which have a highly homological sequence to COVID-19.⁸ In addition, Guillain-Barre syndrome, a disease with a similar mechanism of molecular mimicry, was recently described in association with COVID-19.⁹ However, our case report is limited by lack of cerebral spinal fluid analysis and availability of serum/spinal fluid COVID-19 testing, which makes an inflammatory diagnosis is somewhat questionable. Thus, this case would be best described as a post-infectious steroid-responsive encephalopathy in association with a brainstem lesion.

This case began with a typical COVID-19 hospitalization for acute respiratory syndrome, but was complicated by acute coma, ophthalmoplegia, flaccid quadriplegia, and a pontine hyperintense lesion on MRI. A sustained and robust response to intravenous steroids suggests that a post-infectious inflammatory or autoimmune etiology the most likely diagnosis. Neurohospitalists should be aware of the possibility of post-infectious steroid-responsive encephalopathies in patients with COVID-19 that may lag several weeks after the initial infection.