key: cord-0777665-q0b1aum0 authors: Cristian, Deana; Bagatto, Daniele title: Severe stroke in patients admitted to intensive care unit after COVID-19 infection: pictorial essay of a case series date: 2021-12-13 journal: Brain Hemorrhages DOI: 10.1016/j.hest.2021.12.002 sha: 1bb4e95243f6182ebde4dea798252daf9d87866a doc_id: 777665 cord_uid: q0b1aum0 Patients infected by COVID-19 could require intensive care unit admission especially due to acute respiratory failure. However, neurological manifestations are very common. Among these, ischemic stroke or cerebral hemorrhage may have unfavorable outcome. The mechanisms leading to cerebral damage by SARS-CoV2 are still under debate. One of the most accepted theories implies an endothelial activation which in turns increase the risk of thrombus formation with the development of stroke, either ischemic or hemorrhagic. The more severe the COVID-19 disease, the higher the risk of stroke. Stroke in ICU patients are not frequent, but cerebral hemorrhage has devastating effects with high mortality. In these pictorial essay of case reports, main clinical aspects are discussed, along with a summary of the evidence about pathophysiology and treatment of these patients. The COVID-19 pandemic has put national health systems under stress, especially in terms of patient admittance, mostly for severe cases requiring intensive care unit (ICU) beds 2 . Unfortunately, ICU bed availability has not always been able to meet demand, leading to unintentional deaths outside ICUs 3 . The reason for ICU admittance for COVID-19 patients is severe acute respiratory failure. Neurological involvement has been frequently reported, however, the main symptoms of which are anosmia, dysgeusia, headache, mental confusion and seizures 4 . Stroke is another cerebral complication of COVID-19, placing patients at risk of loss of life. The treatment of stroke complications also entails some logistical aspects, such as a dedicated COVID-team 5 . Neurological manifestations of COVID-19 have been extensively studied, and various theories have been put forward to explain the behavioral changes 6 . In the ICU, patients with severe acute respiratory failure require sedation for mechanical ventilation. Neurological evaluation thus becomes difficult, especially for deeply sedated patients, with the consequence that some neurological signs and symptoms can be missed 7 . Critical care physicians have seen an increase in the number of patients with acute stroke related to severe COVID-19 infection 8 . These should be taken into consideration as long as the COVID-19 pandemic continues, not only in patients with a severe manifestation of viral infection but also in those experiencing mild SARS-CoV2 symptoms 9 . This pictorial review presents five case reports describing the different possible manifestations of stroke in critically ill patients infected with SARS-CoV2, diagnosed with real-time PCR on nasopharyngeal swabs. A summary of the main pathophysiological and treatment aspects is also provided. Since only anonymous data are included in this work, the requirement for an Ethics Committee was waived. General informed consent for publication was obtained whenever possible. A 45-year-old woman was admitted to the emergency department (ED) of a spoke center due to disartria. She had been complaining of headaches in the previous days. Forty-two days prior to hospital admittance, she had tested positive for COVID-19 (real-time PCR nasal swab) and had suffered a mild case of anosmia. Her past medical history was unremarkable. An immediate head computed tomography (CT) scan revealed cerebral venous thrombosis with a small hemorrhagic focus in the left temporal lobe (Figure 1 , A-B-C). She was then transferred to the hub center where she underwent endotracheal intubation due to her reduced level of consciousness. In the meantime, unfractioned heparin infusion was commenced as the first line treatment. She was also given mannitol as an anti-edema therapy. After 24 hours, a control CT scan demonstrated increased signs of intracranial hypertension. Following a multidisciplinary discussion between a neurologist, a neurosurgeon and a critical care physician, it was decided to monitor intracranial pressure with an intraparenchymal probe. This did not reveal any intracranial hypertension, and was removed after five days. After four days of unfractioned heparin, the patient's therapy was switched to enoxaparin 6000 international units (IU) every 12 hours. At day 12, a tracheostomy was performed due to the slow recovery of consciousness and a concomitant need for mechanical ventilation for ventilator-associated pneumonia. The patient was transferred to the neurology unit at day 20, and to a rehabilitation unit at day 36. She was finally discharged at day 78 with mild neurological deficits including expressive aphasia and partial epilepsy with clonic hemifacial spasms. Chronic medications included levetiracetam 1500 mg bid and warfarin. A 55-year-old man with a history of arterial hypertension and psoriasis was admitted to the ED due to worsening headache, nausea, diplopia and postural instability. Glasgow coma scale was measured at 15. Forty-five days prior to this visit, the patient presented with a mild COVID-19 infection (cold-like symptoms with no respiratory involvement). An immediate CT head scan revealed a basilar thrombosis (Figure 2 A-B). The patient underwent an angiographic endovascular procedure that reperfused the arterial vessels. However, partial thrombosis at the vertebra-basilar junction persisted. The onset of sudden coma (GCS 3 immediately following angiography) meant that the patient required intubation and mechanical ventilation. He was admitted to the ICU. After 24 hours, a CT-scan revealed a large cerebellar ischemia and hypodensity at the level of the brainstem and thalami. After seven days, the patient was declared brain dead. A 61-year-old man was admitted to the ICU with severe acute COVID-19-related respiratory failure requiring intubation and mechanical ventilation. His medical records included a history of arterial hypertension treated with amlodipine 10 mg once a day. A CT chest scan revealed severe lung injury caused by COVID-19 infection and pulmonary embolism. Enoxaparin 4000 bid was commenced. Mechanical ventilation with deep sedation with muscular paralysis lasted for 12 days due to severe gas exchange impairment. Tracheostomy was performed after this, but sedation continued due to severe refractory hypoxemia. At day 14, sedation was gently withdrawn and neurological evaluation revealed a left hemysindrome. An immediate head CT scan revealed a large stroke due to middle cerebral artery thrombosis, without any sign of bleeding ( Figure 3 ). Antiplatelet therapy was commenced. At day 18, the patient was able to breathe without respiratory support, and at day 20 he was transferred to the neurology unit. Finally, at day 37, he was transferred to the general medicine ward, from where he was discharged to the rehabilitation unit. Neurological examination at hospital discharge revealed mild dysarthria, left facial paralysis (House Brackmann grade 3), plegia of the left arm and weakness of the left leg. A previously healthy 46-year-old man was admitted to the ED due to the sudden onset of left hemiplegia after a headache. The patient tested positive for COVID-19. During admission, GCS decreased rapidly from 15 to 11. He was hence intubated and underwent a CT scan that showed a large right nucleo-capsular hemorrhage with mass effect on the brain (Figure 4 A). No surgical treatment was possible. Blood exams revealed concomitant acute kidney injury (serum creatinine 6.33 mg/dL, blood urea nitrogen 63 mg/dL) and 3.5% of schistocytes and mild thrombocytopenia. Clinicians investigated whether uremic-hemolytic syndrome was the cause. The results of all tests performed (autoantibodies, microbiological and cultural samples) were negative. After two days, transcranial coded color doppler (TCCD) at the bedside revealed impending cerebral circulatory arrest (Figure 4 B) . The patient was diagnosed as brain dead the next day. A 52-year-old man was admitted to the ICU due to coma. He had complained of fever two days previously. No illness was reported in his medical history. On the day of admission to the ICU, he was found unconscious at home with a GCS of 4, and vomiting. He was immediately intubated. After admittance to the ED, the patient tested positive for COVID-19. A CT head scan revealed a subarachnoid hemorrhage (SAH) caused by a small aneurism of the right ophthalmic artery ( Figure 5 A-B) . At the same time, given his positive COVID-19 test and the high value of the D-dimer (see Table 1 ), the patient also underwent a CT thorax scan that revealed a pulmonary embolism (PE), but no lung involvement. The patient never regained consciousness in the ICU, and developed a severe acute respiratory failure caused by SARS-CoV2 infection. He died after 17 days. Intracranial strokes associated with COVID-19 infection have been increasingly reported 10, 11 . Despite the increased risk of thrombotic events leading to an expected higher rate of acute ischemic stroke (AIS) among critically ill COVID-19 patients, a non-negligible number of hemorrhagic cerebral manifestations have been highlighted 12 . COVID-19-associated AIS includes arterial thrombosis due to plaque rupture or embolization. Cases of cerebral vein sinuses thrombosis, which resembles deep vein thrombosis, have also been reported 13 . Angiotensin converting enzyme 2 (ACE2) receptor, due to its presence in neuronal cells, seems to be an entry point to the brain for SARS-CoV-2, explaining neurological symptoms such as anosmia, dysgeusia and headache 14, 15 . However, the etiology of stroke in critically ill COVID-19 patients is probably multifactorial. It seems unlikely that direct cerebral nervous system (CNS) invasion by the virus leads to stroke 16 . The elements of Virchow's triad are blood stasis, endothelial injury and hypercoagulable state, and COVID-19 patients very frequently express all of these 17 . Early on in the pandemic, clinical evidence appeared to support the prothrombotic state of these patients, as well as deep vein thrombosis and pulmonary embolism, especially in the moderate-severe cluster of infected people 18, 19 . Based on these findings, and results from autopsies highlighting a high rate of clinically silent PE, international guidelines recommend starting early with pharmacological venous thromboembolism (VTE) prophylaxis [20] [21] [22] . However, the above case reports also included patients who did not experience severe COVID-19 symptoms; rather, they tested positive for SARS-CoV-2 infection with a mild clinical course and no lung involvement. Evidence supporting an inflammatory state in infected people experiencing mild symptoms could still explain the endothelial injury and hypercoagulable state of the patients in the case reports described 23 . Moreover, studies have been carried out to investigate the potential impact of immunological responses secondary to an exaggerated response to COVID-19 infection, such as hypoxia, oxidative stress, and excessive platelet-induced aggregation on the brain 24 . Unfortunately, there have been many delays in the diagnosis pathway throughout the pandemic, and treatment for AIS has been reported in COVID-19 positive patients, leading to increased disability 25 . Critically ill patients sedated for long periods due to the necessity of mechanical ventilation may likewise make it harder for clinicians to recognize a neurological deficit due to ischemic stroke. For this reason, clinical evaluation should be performed as soon as possible (for instance, periodic lightening of sedation, if possible) in conjunction with multimodal neuromonitoring (TCCD, processed electroencephalogram, near-infrared spectroscopy) 26, 27 . Intracranial hemorrhage (ICH) is less frequent than ischemic strokes in COVID-19 patients. However, ICH is associated with a high mortality rate 28 . At the beginning of the pandemic, an intriguing question was posed by Sharifi-Razavi and colleagues as to whether COVID-19 infection and ICH were coincidental or linked by a causative relationship 29 . In fact, COVID-19 infection is not an immediate cause of ICH unless the patient is undergoing anticoagulation treatmenta recognized risk factor for ICH in SARS-CoV2 infected patients 30 . Microscopic studies have demonstrated that viral inclusion is present within the endothelium of the vascular bed, leading to endotheliitis, loss of barrier function, mononuclear infiltration with subsequent disruption of the vascular wall, and finally haemorrhage 31, 32 . It is also possible that hypercytokinemia induces an activation of the matrix metalloproteinases (MMPs) through IL-1, IL-6, TNF-a group of proteolytic enzymes that disrupt the vessel walls, which may increase the risk of rupture with consequent bleeding. Finally, a hypercoagulation state may also produce thrombotic microangiopathy of the vasavasorum with arterial wall hypoxia, vascular loss of tightness, and rupture 33 . Patients experiencing ICH have poor outcomes, with the literature reporting a mortality rate in up to 50% of cases 34 . Reversal of anticoagulation and pressure control are known factors affecting the outcomes of patients with ICH. These measures are hence strongly recommended for these patients 35 . Critically ill COVID-19 patients also develop severe hypoxemia, an aggravating feature for those experiencing ICH 36 . The literature contains very few SAH case reports of COVID-19 patients, and it remains to be clarified as to whether viral infection may cause SAH 37-39 . Whether COVID-19 patients suffering from any form of stroke are at increased risk of severe sequelae or death compared to patients testing negative for COVID-19 is a matter of debate. Compared with non-COVID-19 patients, those with AIS and COVID-19 infection had a higher mortality in a recent large prospective observational study 40 . These results are in line with the abundance of existing data that uniquely demonstrate that COVID-19-positive patients suffering from AIS have worse outcomes than uninfected patients 41 . There is less data on ICH than AIS in COVID-19 patients. Articles on this topic predominantly involve case studies. However, the higher mortality rate in COVID-19 patients appears confirmed in this population. Moreover, the literature indicates that ICH is more severe in COVID-19 than non-COVID-19 patients. It affects younger patients, and is probably linked to inflammation rather than hypertension 42 . Finally, persistent increased risk of stroke in asymptomatic COVID-19 patients suggests that COVID-19 infection in itselfeither mild or severeplays an important role in triggering the sequence of events leading to cerebral vascular damage 43. In summary, severe stroke among COVID-19 patients has different features including thrombosis of the arterial or venous cerebral compartment, primary ICH, and hemorrhagic transformation from ischemic lesion ( Figure 6 ). Given that COVID-19 is still present worldwide, it should perhaps be included in the differential diagnosis of severe acute stroke patients admitted to the ICU, as well as in COVID-19 patients experiencing mild symptoms with a resolved viral infection and who present with neurological signs. Competing interests: none to declare. Acknowledgements: none. 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