Post-COVID-19 Multisystem Inflammatory Syndrome-Related Cerebral Infarction in a Pediatric Patient Managed with Decompressive Craniectomy

Introduction: Most people who are infected with the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are asymptomatic or present with mild upper respiratory symptoms. This is especially true in the pediatric population; however, rarely, a massive cytokine storm can develop, causing multisystem inflammatory syndrome associated with COVID (MIS-C). Furthermore, children may also suffer from acute ischemic strokes secondary to SARS-CoV-2 infection. Case Presentation: Here, we present a 2-year-old male who was admitted to the hospital with MIS-C and evidence of a previous SARS-CoV-2 infection. On postadmission day 2, the patient was in cardiogenic shock, had acute kidney injury, liver dysfunction, and metabolic acidosis. He had concurrent altered mental status, and his computed tomography scan showed ischemic infarcts in the territory of the right middle cerebral artery and superior cerebellar artery bilaterally. Magnetic resonance angiography confirmed occlusion of the right middle cerebral artery and right superior cerebellar artery. He underwent an emergent decompressive craniectomy due to rapid deterioration and cerebral edema. After the procedure, he continued to improve and was discharged with moderate disability that improved during outpatient rehab. Conclusion: Though rare in children, SARS-CoV-2 can lead to AIS, especially in the presence of underlying risk factors such as MIS-C and hypercoagulopathy. AIS can be associated with severe mortality and morbidity; however, even in this severe case of AIS, the patient was successfully treated with a decompressive craniectomy.


Introduction
When severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first emerged, the virus was thought to only target the respiratory system via the angiotensin-converting enzyme 2 receptor causing COVID-19. Though this remains the predominant presentation of COVID-19, there are increasing reports of extra-respiratory manifestations of the disease [1,2]. Early in the COVID-19 pandemic, there were reports of patients presenting or developing arterial ischemic stroke (AIS) secondary to COVID-19 [3][4][5]. Most concerning of these reports was the prevalence of AIS in young adults under 50 as well as in children [2,6].
karger@karger.com www.karger.com/pne In children and adolescents, most COVID-19 infections are asymptomatic or present with mild upper respiratory symptoms. A rare but severe complication of postinfectious COVID-19 is multisystem inflammatory syndrome (MIS-C). MIS-C is a diffuse inflammatory response that affects multiple organ systems including the cardiac, gastrointestinal, and mucocutaneous systems [7]. It is also thought to cause a hypercoagulopathic state due to an angiotensin-converting enzyme 2-mediated cytokine storm and has been associated with increased thromboembolic events [1]. Recently, there are increasing reports of pediatric incidence of AIS thought to be secondary to COVID-19 and MIS-C [1,2]. Here we report a child who presented with MIS-C following COVID-19 and developed a cerebral and bilateral cerebellar infarction with rapid neurologic deterioration necessitating emergent decompressive craniectomy (DC).

Case Report
An otherwise healthy 2-year-old male presented to the emergency department (ED) via ambulance for a high fever (105.9°F). On presentation, the patient's grandmother also reported he had a 5-day history of earache, anorexia, toothache, and swollen posterior cervical lymph node in addition to the fever. The patient's family had tested positive for COVID-19 2 weeks prior, and the patient had mild upper respiratory symptoms during this time; however, he was not tested for COVID-19. Repeat temperature taken in the ED at arrival was 104.8°F. The patient was given a bolus of Tylenol which dropped his temperature to 101°F. Pertinent laboratory work results are shown in Table 1. The patient was positive for the SARS-CoV-2 IgG antigen, and polymerase chain reaction for SARS-CoV-2 was negative. He was transferred to the pediatric floor for continued care.
The following day, postadmission day (PAD) 1, the patient deteriorated with signs of MIS-C, decreased liver function, hypoperfusion signs including acute kidney injury, altered mental status, cardiogenic shock, and metabolic acidosis. Notable laboratory test results at this time are shown in Table 2. The patient was transferred to the pediatric intensive care unit for higher level of care. Due to his altered mental status and lethargy, he had a computed tomography scan which indicated acute ischemic infarcts to the right middle cerebral artery territory and bilateral cerebellar hemispheres (shown in Fig. 1). Other notable findings included cerebral edema and a 12 mm right to left midline shift. Following the scan, the patient was anisocoric with a sluggish right pupil at 6 mm and left pupil at 3 mm with a Glasgow Coma Scale (GCS) of 7. He was intubated on fentanyl and vecuronium, given 3% NaCl, hyperventilated, and sent for a stat magnetic resonance imaging (MRI). Magnetic resonance angiography was postponed until after surgery because of the rapid neurological deterioration; however, MRI was still obtained in order to get a full understanding of the extent of damage to better plan for surgery and medical management. MRI indicated severe swelling in the right middle cerebral artery territory with limited swelling in cerebellar hemispheres (shown in Fig. 2). Due to the severity of cerebral swelling, associated midline shift, uncal herniation, and rapid neurologic deterioration, the patient was taken to the operating room for emergent right-sided DC and placement of an extraventricular drain and intracranial pressure monitor. Following surgery, the patient's skull flap was cryogenically stored in a sterile peel pack at −81°C.
Post decompression, the patient was sedated on fentanyl and versed, so neurologic status could not be assessed; however, his anisocoria decreased to between 4 and 5 mm in his right pupil. Mean intracranial pressure was 15 ranging between 13 and 18 and mean cerebral perfusion pressure was 70 ranging between 67 and 75. He was started on heparin continuous infusion for MIS-Crelated hypercoagulability. Additional postoperative laboratory tests showed elevated coagulopathy markers including elevated D-dimer, PT, and CRP with low fibrinogen. Laboratory tests also showed no underlying coagulopathies. Magnetic resonance angiography showed occlusion of both the right middle cerebral artery and the right superior cerebellar artery (shown in Fig. 3). Magnetic resonance venography showed no evidence of dural venous sinus thrombosis.
The patient continued to improve following decompression. Coagulation and inflammatory markers began to improve on PAD 4 with a decrease in D-dimer to 10,019 ng/mL and a decrease in C-reactive protein to 3.7 mg/dL. The patient was switched from  heparin to enoxaparin, and sedation began to be weaned on PAD 7. On PAD 9, sedation continued to be weaned; he had a GCS of 12 and began his first day of rehab. Due to the patient's rapid recovery and need for extensive rehab following the AIS, the patient returned to the OR to undergo cranioplasty on PAD 10. On PAD 18, his extraventricular drain was removed, and he was subsequently transferred from the pediatric intensive care unit to the pediatric floor with a GCS of 15. He was then discharged to an outside inpatient rehab facility on PAD 21. At the time of his discharge, the patient had a GCS of 15 with ongoing moderate leftsided hemiparesis. He continued anticoagulation therapy and was discharged on enoxaparin. He presented for follow-up at the neurosurgery clinic after completing rehab 6 months later at age 3. There was marked improvement in left-sided hemiparesis which is currently mild; however, his grandmother stated the patient no longer sleeps well and has angry outbursts. He continues to take enoxaparin for anticoagulation and continues speech and occupational therapy on an outpatient basis.

Discussion
Strokes are not commonly encountered in the pediatric population with yearly incidence rates between 1.2 and 2.1 out of 100,000, much lower than the adult population [8,9]. With the rise of the COVID-19 pandemic, neurologic complications, including AIS, became well recognized within the adult population [2]. Slowly, the association with SARS-CoV-2 and AIS was discovered within the pediatric population following few isolated case reports reporting this manifestation of the disease [5,9,10]. A recent multi-institutional international study by Beslow et al. reported the incidence of pediatric AIS to be 0.32% in which the main cause proposed was concurrent SARS-CoV-2 infection. This is slightly lower than a previous study conducted by the same group a year earlier suggesting the incidence was 0.62% [2]. Risk factors of pediatric stroke are also varied from that of the adult population. Determination of risk factors is important as a study by Mallick et al. found that 87% of pediatric stroke cases had at least one identifiable risk factor. The most common risk factors are an underlying nonatherosclerotic arteriopathy, vasculitis secondary to systemic disease, or a concurrent infection [8,10,11]. This is demonstrated in the study by Beslow et al. [2] as they found that in patients who experienced an AIS in which SARS-CoV-2 was thought to be the causative agent, they discerned that the most probable etiology was inflammatory arteriopathy. Similarly, Whitworth et al. [1] found that MIS-C was associated with thromboembolic events in pediatric patients. This is further supported by case reports such as the one by Tiwari et al. [10] which presents a pediatric patient with MIS-C who suffered from AIS [9].
Further, the role of hypercoagulative states cannot be overlooked in pediatric AIS. Other case reports have reported elevated coagulation markers present in pediatric patients with AIS secondary to SARS-CoV-2 infection. Notably, in many cases, both hypercoagulation and inflammation are present. MIS-C typically presents with severe systemic inflammation and hypercoagulopathy [1,6,9,10,12,13]. Despite these associated risk factors and possible mechanisms, the full extent to which SARS-CoV-2 can be attributed to AIS in patients remains unknown [2,6]. The patient in this case presented with MIS-C including elevated inflammatory markers, ESR and CRP, and evidence of hypercoagulability with high D-dimer and low fibrinogen. It is therefore likely that the cause of his AIS was multifactorial and can be attributed to a hyperinflammatory state and a hypercoagulable state due to MIS-C secondary to his previous SARS-CoV-2 infection. Furthermore, with the severity of his underlying condition with laboratory work consistent with MIS-C and coagulopathy, these factors may have attributed to the severity of the AIS necessitating emergent decompression. Different treatment modalities have been utilized in the treatment of pediatric AIS secondary to COVID-19 based on the severity of patient presentation. In many of the case reports reporting on AIS secondary to SARS-CoV-2 as the main contributing factor, the severity is relatively low. Many patients are effectively treated with either anticoagulation or mechanical thrombectomy. Tiwari et al. [10] reported a patient who also presented with MIS-C and was successfully treated with steroids, low molecular weight heparin, remdesivir, and immunoglobulins [2]. Some patients, however, do have severe disease progression following AIS and are not able to be treated successfully via more conservative methods. For instance, Scala et al. reported a patient who initially underwent a successful endovascular thrombectomy. Twelve hours after the procedure, he deteriorated due to massive cerebral edema with 1 cm midline shift and associated uncal herniation. The patient underwent a right-sided fronto-temporo-parietal DC to control cerebral swelling. Follow-up testing revealed elevated coagulation markers and a factor II mutation. Following DC, the patient recovered well with only minor disability [6]. Kihira et al. present a patient with severe COVID-19 leading to cardiogenic shock and a hypercoagulable state. This patient experienced an AIS while undergoing extracorporeal membrane oxygenation. The AIS was severe enough and the patient deteriorated so rapidly that no DC was attempted, and the patient was later declared brain dead [12]. The patient presented here had a severe and rapid onset of AIS with two major vessel occlusions and two locations of infarction. It is unclear whether the cerebellar stroke was secondary to cerebral herniation or underlying arteriopathic process. Unlike the patient presented by Scala et al., our patient did not have time to undergo mechanical thrombectomy prior to DC. Further, his AIS was caught and treated rapidly enough that he was able to be treated successfully. To our knowledge, the patient presented here is the only reported patient with MIS-C to undergo DC following severe AIS. DC is a feasible treatment modality in patients who have severe AIS with MIS-C and hypercoagulopathic states. Our patient had very severe underlying risk factors including MIS-C, hypercoagulopathy, and cardiogenic shock predisposing him to AIS; however, with rapid surgical decompression, he survived with limited disability. Morgan/Collins/Nagy

Conclusion
Here we present the rare case of a patient who necessitated DC following right middle cerebral artery occlusion secondary to MIS-C from previous SARS-CoV-2 infection and a superior cerebellar artery occlusion. He had rapid deterioration with an uncal herniation and 12 mm midline shift secondary to cerebral edema which may have led to his cerebellar AIS. He was treated with a DC and ultimately had good recovery with only minor disability. Even though AIS with SARS-CoV-2 infection as the main contributing factor is rare, occurring in less than 1% of the pediatric cases, severe AIS can occur. Patients with underlying SARS-CoV-2 infection, especially those with severe infection with associated underlying risk factors, can suffer severe AIS and rapid deterioration. Early detection and treatment of these cases can decrease the morbidity and mortality in these patients.

Statement of Ethics
Ethical approval is not required for this study in accordance with local guidelines. Written informed consent was obtained from legal guardian for publication of the details of their medical case and any accompanying images.