Statistics from Altmetric.com
Acute cerebrovascular disease, particularly ischaemic stroke, has emerged as a serious complication of COVID-19.1 However, the mechanism and optimal management of this remain incompletely understood. In the pulmonary and cardiac circulation, there is evidence that thrombotic complications may relate to endothelial inflammation and injury but evidence for this in the cerebrovascular system is limited.2 We demonstrate direct imaging evidence of vasculitis in a patient with COVID-19 complicated by multiple territory ischaemic strokes which responded to steroids and targeted interleukin-1 (IL-1) and interleukin-6 (IL-6) inhibition.
A 64-year-old man with type 2 diabetes mellitus, hypertension, hypercholesterolaemia and ischaemic heart disease was admitted with a 5-day history of dry cough and fever. He was diagnosed with COVID-19 pneumonia requiring early intubation, mechanical ventilation, inotropic support and haemofiltration for acute kidney injury. Blood tests showed lymphopenia (0.6×109/L), elevated C-reactive protein (196 mg/L), renal dysfunction (creatinine 156 μmol/L) and raised D-dimer (>20 000 µg/L). Given this, and his need for continuous renal replacement therapy, the patient was systemically heparinised. SARS-CoV-2 infection was confirmed with nasopharyngeal swab reverse-transcriptase PCR testing.
On day 24 of admission, following a sedation hold, he was not appropriately responsive with Glasgow Coma Scale 8 (E4, V2, M2) and episodic clonic movements of the proximal upper limbs. The patient was on aspirin and intravenous heparin at this time.
MRI brain demonstrated abnormal signal, variable restricted diffusion and peripheral enhancement in the left occipital and right parietal, occipital and temporal lobes (figure 1). Appearances were consistent with multiple subacute infarcts in the right middle cerebral artery (MCA) and both posterior cerebral artery (PCA) territories. Magnetic resonance angiography showed occlusion of the right PCA and left PCA. Postcontrast volume T1 SPACE MRI sequence revealed long segment, abnormal concentric, vessel wall enhancement of both MCAs, anterior cerebral arteries (ACAs), vertebral arteries and the basilar artery (figure 1). Appearances suggested a diffuse intracranial vasculitis complicated by multiterritory infarcts.
Virology screen showed evidence of prior hepatitis C virus (viral RNA not detected in blood) and varicella-zoster virus infection but no signs of active infection. Enterovirus, hepatitis B and HIV serology were negative. antinuclear (ANA), anti-neutrophil cytoplasmic (ANCA) and antiphospholipid antibodies were negative. Complement and immunoglobulin levels were normal. Cerebrospinal fluid sampling was not performed as this was felt to be unsafe due to cerebral swelling. A diffuse, attenuated slow wave pattern was observed on EEG, with no underlying epileptiform activity, consistent with severe non-specific cerebral dysfunction.
The patient was treated with intravenous methylprednisolone (1 g daily for 3 days) then oral prednisolone (60 mg daily). Levetiracetam was given for seizure management. Acyclovir and ceftriaxone were prescribed empirically. Clinical assessment 6 days later revealed spontaneous eye opening with no fixation, intact brainstem reflexes and withdrawal to painful stimuli. Following multidisciplinary discussion which included the potential impact of the preliminary positive hepatitis C serology, an off-label trial of the IL-1 receptor antagonist anakinra was given at a dose of 200 mg two times a day.
Follow-up MRI on day 42 of admission (on the fifth day of anakinra treatment) showed no new infarcts, reduction in cerebral swelling and persistent abnormal vessel wall enhancement. Neurological improvement was observed, with the patient now localising to painful stimuli. In light of a negative hepatitis C viral RNA test, biological therapy was switched to the IL-6 antagonist tocilizumab 8 mg/kg intravenous, to be repeated every 4 weeks. Neurological assessment 3 days later (day 47) showed further improvement with the patient able to obey commands, speak in single words and sit out of bed. Since then, the patient’s condition continued to improve with resolution of AKI and successful wean from ventilation. Imaging on day 57 showed evidence of treatment response, with resolution of the abnormal MCA and ACA vessel wall enhancement (figure 1) and reduction in the vertebrobasilar vessel wall enhancement.
The patient improved, becoming more alert, with limited but appropriate speech, orientation to place and person, and return of movement in all four limbs. We plan to continue monthly tocilizumab infusions with a slow steroid wean.
Our finding of intracranial vessel wall enhancement in a patient with COVID-19 and subacute multiterritory ischaemic strokes provides direct mechanistic evidence that acute cerebrovascular complications in COVID-19 may be in part related to arteritis. This aligns with early postmortem data suggesting SARS-CoV-2 infection may directly impact brain endothelial cells and supports the theory that COVID-19 may be associated with multisystem endothelial inflammation.3 This is supported by the observation that acute respiratory distress syndrome (ARDS) in COVID-19 is associated with endothelial inflammation and thrombosis.2 ACE 2 receptors expressed in the endothelial cells of multiple organs, including the brain, have been postulated as the entry point for SARS-CoV.2 Despite these advances in understanding, the exact mechanism for endothelial inflammation and injury, either from direct infection or from a hyperinflammatory response, remains unclear.
Optimal therapeutic intervention in COVID-19-related cerebrovascular disease is uncertain. These early findings rationalise trials of therapies to reduce endothelial inflammation in addition to treatments that tackle direct endothelial infection and viral replication. In our case, a trial of the recombinant IL-1 antagonist anakinra was felt justified due to its potential neuroprotective effect and early evidence of therapeutic benefit in other COVID-19-related vascular inflammatory syndromes. In a retrospective cohort study of 29 patients with COVID-19 and ARDS, anakinra treatment was associated with improved survival and recovery.4 The switch to tocilizumab therapy was driven by its recognised efficacy in large vessel vasculitis and preliminary evidence in severe COVID-19 infection.5 In our case of presumptive COVID-19-related intracranial vasculitis, the clinical and radiological evidence of treatment response to steroid therapy and IL-1 and IL-6 pathway antagonism adds further weight to the potential benefit of immunosuppression and raises broader questions about optimal treatment in other COVID-19 associated cerebrovascular diseases. Exploration of the possible benefit of anticytokine drugs and antiviral therapies is urgently needed. This is perhaps especially indicated in vulnerable patients, like ours, with comorbidities that cause background endothelial dysfunction, linked with poorer outcomes in COVID-19.
Contributors LD, CC, CB and CG conceived the case report. CC obtained written consent from the patient’s next-of-kin. LD, CC, KK, NG, JV and JH cowrote the first draft. LD, DM and BJ sourced and reported high-quality images for this study. RC, CB, JP, TY, JM and CG revised the manuscript for important intellectual content. All authors have read and approve the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Next of kin consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.