COVID-19 Ischemic Strokes as an Emerging Rehabilitation Population: A Case Series.

There is emerging literature that coronavirus disease 2019 infections result in an increased incidence of thrombosis secondary to a prothrombotic state. Initial studies reported ischemic strokes primarily occurring in the critically ill coronavirus disease 2019 population. However, there have been reports of ischemic strokes as the presenting symptom in young noncritically ill coronavirus disease 2019 patients without significant risk factors. Further characterization of the coronavirus disease 2019 stroke population is needed. We present four cases of coronavirus disease 2019 ischemic strokes occurring in patients aged 37-68 yrs with varying coronavirus disease 2019 infection severities, premorbid risk factors, clinical presentations (eg, focal and nonfocal), and vascular distributions. These cases highlight the heterogeneity of coronavirus disease 2019 ischemic strokes. The duration of the coronavirus disease 2019-related prothrombotic state is unknown, and it is unclear whether patients are at risk for recurrent strokes. With more coronavirus disease 2019 patients recovering and being discharged to rehabilitation, physiatric awareness of this prothrombotic state and increased incidence of ischemic strokes is essential. Because of the variable presentation of coronavirus disease 2019 ischemic strokes, clinicians can consider neuroimaging as part of the evaluation in coronavirus disease 2019 patients with either acute focal or nonfocal neurologic symptoms. Additional studies are needed to clarify prothrombotic state duration, determine prognosis for recovery, and establish the physiatrist's role in long-term disease management.

Introduction

The coronavirus disease of 2019 (COVID-19) is an illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has resulted in 7,273,958 cases and 413,372 deaths worldwide as of June 11th, 2020.[1] Commonly encountered symptoms include cough, fever, myalgia, and fatigue. More severe infections can lead to pneumonia, acute respiratory distress syndrome (ARDS), and multi-system organ failure.[2] Recent studies have reported an increased incidence of thrombosis associated with COVID-19 infections.[2-4] It is currently unknown if this prothrombotic state is due to the virus itself, a cytokine storm with resulting systemic inflammatory response, or endovascular dysfunction.[3] The most common thrombotic complication is pulmonary embolism, accounting for 87% of thrombotic events.[4] However, there have been increasing reports of ischemic strokes occurring with COVID-19 infections that may be part of the hypercoagulable spectrum of this disease.[2,4-9]

Infection with severe acute respiratory syndrome (SARS), a closely related coronavirus, has been associated with large vessel ischemic strokes in 2.4% of cases.[10] Initial studies showed that neurologic symptoms were a feature of COVID-19 infections, with ischemic strokes reported in 3-5% of hospitalized patients, primarily occurring in the critically ill.[2,8] However, there have been increasing reports of COVID-19 ischemic strokes as the presenting symptom in young non-critically ill patients without significant risk factors.[5-7,9] Further characterization of COVID-19 ischemic stroke patients is needed to elucidate pathophysiology, identify risk factors, and develop management strategies.

Case Presentations

We present four patients who developed acute ischemic strokes during the course of their COVID-19 infection (Table 1). The first case was a 54-year-old male with undiagnosed hypertension who presented with dysarthria, hemiparesis, and decreased level of consciousness, found to have sustained basilar and right superior cerebellar artery infarctions (Figure 1A). The second case was a 37-year-old male with undiagnosed type 2 diabetes who presented with aphasia, hemiparesis, and hemi-sensory loss, found to have a left middle cerebral artery infarction (Figure 1B). The third case was a 65-year-old male with undiagnosed type 2 diabetes who presented after a motor vehicle accident with altered mental status and respiratory distress, subsequently requiring intubation due to COVID-19 related ARDS. Initial neuroimaging showed no acute intracranial abnormalities. He was unresponsive when sedation was held on hospital day four and magnetic resonance imaging (MRI) showed bilateral multifocal subcortical infarctions (Figure 1C). The fourth case was a 68-year-old female with a history of hypertension and diabetes with COVID-19 respiratory symptoms, who required intubation due to ARDS. She developed septic shock, multi-system organ failure, and decreased command following on hospital day eight, with MRI showing a right posterior cerebral artery infarction (Figure 1D). None of the patients had a history of smoking, illicit drug use, or alcohol abuse. All patients had elevated ferritin, fibrinogen, c-reactive protein (CRP), and d-dimer levels. Stroke treatment included mechanical thrombectomy, intravenous tissue plasminogen activator, and/or aspirin. Computed tomography angiography (CTA) of the head and neck showed no significant atherosclerosis, stenosis, or dissections. Cardiac telemetry showed either normal sinus rhythm or sinus tachycardia. Echocardiograms performed showed no vegetations or thrombi. Patient outcomes varied including death, discharge home, or discharge to rehabilitation.

Table 1

Clinical Characteristics of Four COVID-19 Positive Patients with Ischemic Strokes

Figure 1

A-D: Axial magnetic resonance diffusion weighted images of four COVID-19 positive patients with acute ischemic strokes; A. Patient 1, multiple areas of restricted diffusion of the bilateral cerebellum and midline paramedian pons with minimal mass effect; B. Patient 2, restricted diffusion within the left middle cerebral artery distribution involving the temporal lobe, parietal lobe, and subcortical structures including the putamen; C. Patient 3, numerous scattered punctate foci of restricted diffusion primarily within the subcortical white matter of the bilateral cerebral hemispheres; D. Patient 4, diffusion restriction within the right posterior cerebral artery territory involving the medial aspect of the right occipital lobe.

Discussion

COVID-19 ischemic strokes are poorly understood with multiple proposed mechanisms for associated neurologic manifestations. Coronaviruses, including COVID-19, are thought to have direct neuroinvasive properties resulting in symptoms including encephalopathy and seizures.[2,10] However, the relationship between the development of ischemic strokes and the neuroinvasive properties is unclear. Recent literature suggests a prothrombotic state is the more likely mechanism.[7] Autopsy findings of COVID-19 patients showed pulmonary thrombotic microangiopathy on histological evaluation.[11] While brain tissue was not evaluated, a similar process of thrombi formation is possible within the cerebral vasculature. In addition, coagulation cascade and inflammatory marker abnormalities seen in COVID-19 patients, such as elevated CRP, ferritin, d-dimer and fibrinogen levels, reflect a prothrombotic state.[3] These findings, present in the aforementioned cases, may have contributed to the development of COVID-19 ischemic strokes. Interestingly, the prothrombin time (PT) can be paradoxically prolonged in COVID-19 patients, as seen in these four cases. [3] However, the association between the prolonged PT and the prothrombotic state is currently unclear.

Of note, each presented patient had risk factors that could have contributed to the development of strokes independent of COVID-19 infection. All patients had either premorbid or undiagnosed hypertension and/or diabetes, with two patients being greater than 55 years of age. However, it is currently unknown if the presence of these classic stroke risk factors predisposes patients for ischemic events during COVID-19 infections. Additional stroke etiologies in these patients were considered and assessed during their hospital course. CTA of the head and neck in all patients showed no significant atherosclerotic disease, stenosis, or dissection. Also, none of the patients had premorbid or new onset arrhythmias, including atrial fibrillation, and echocardiograms showed no evidence of vegetations or thrombi. Finally, none of these patients sustained episodes of significant hypotension or cardiac arrest that could have resulted in ischemic cerebral injury.

The presented cases highlight the spectrum of COVID-19 ischemic strokes. Both young and elderly patients had varying COVID-19 infection severities and infarct locations. Most of the published cases reported anterior circulation large vessel infarctions of either the middle cerebral or posterior cerebral arteries, seen in cases two and four, respectively.[5-7] Posterior circulation infarctions, seen in case one, were less frequently reported.[7,9] In addition, there have been documented cases of multifocal strokes occurring in critically ill COVID-19 patients, as seen in case three.[9] Medical histories varied among the previously reported cases with all currently presented cases having either premorbid or undiagnosed medical conditions including diabetes or hypertension.[5-7,10] Our cases detailed two non-critically ill patients less than 55 years of age who presented to the hospital due to stroke symptoms, compared to the two critically ill patients greater than 55 years of age who developed strokes during their hospitalization. The first and second cases had focal neurologic defects that were consistent with the involved vascular distributions. However, cases three and four experienced non-focal, encephalopathic manifestations that led to additional neuroimaging and subsequent stroke diagnosis. The current cases also highlight the wide age range of patients susceptible to COVID-19 ischemic strokes, consistent with the current literature.[5-7,9]

Conclusion

With more recovering COVID-19 patients being transferred to post-acute care, physiatric knowledge of increased thrombotic risk in this population is essential. The duration of the COVID-19 prothrombotic state is currently unknown and it is unclear if patients are at increased risk for recurrent strokes. Therefore, clinicians have a key role in educating patients about thrombotic events associated with COVID-19 infection. In addition, a recent publication described thirteen COVID-19 patients exhibiting encephalopathic features with 100% of patients showing abnormalities on MRI, including acute ischemic strokes.[12] This supports a role for neuroimaging in the post-acute setting for COVID-19 patients with new onset of either non-focal or focal neurologic findings. Decreased inpatient bed availability and closed outpatient facilities due to infection control measures have made access to rehabilitation challenging. However, physiatrists must advocate for appropriate rehabilitation to maximize patient recovery. This case series highlights the broad clinical spectrum of COVID-19 ischemic strokes, reported in patients 37 to 68 years of age of varying COVID-19 infection severities, clinical presentations (e.g. focal and non-focal), and vascular distributions. Prospective studies of COVID-19 stroke patients are needed to fully understand long-term risks, manifestations, and appropriate physiatric management of this emerging rehabilitation population.