The 2019 novel coronavirus disease with secondary ischemic stroke: two cases report

Background : The 2019 novel coronavirus disease is an outbreak of respiratory illness rst detected in Wuhan, China in the end of Dec, 2019. The older patients complicated with underlying diseases are reported more likely to have clinical symptoms. But its secondary lesion is rarely reported. Case presentation : We reported two cases of coronavirus infected pneumonia with acute ischemic stroke in patients at their middle-age. In both 2019 coronavirus diseases cases, neurological physical examination are normal before infection. Lymphocytopenia and high expression of cytokines and D-dimer were found from serum clinical laboratory test at admission. The tongue palsy, dysarthria and limb muscle weakness are initial manifestations in one week after 2019 novel coronavirus infection. The head CT and head/neck arterial CTA showed small-vessel occlusion. The patients were diagnosed with coronavirus diseases with secondary acute ischemic stroke. They were treated with tiroban and followed up with daily aspirin and atorvastatin. Conclusion : The present cases suggest that secondary ischemic stroke, which mainly manifested as small-vessel occlusion, should be considered for coronavirus disease patients with prompt diagnosis and treatment.

followed up with daily aspirin and atorvastatin.
Conclusion : The present cases suggest that secondary ischemic stroke, which mainly manifested as small-vessel occlusion, should be considered for coronavirus disease patients with prompt diagnosis and treatment.

Background
On 31 December 2019, a novel type of coronavirus disease (COVID-19) has broken out from Wuhan, China. So far, the global number of con rmed reported cases of COVID-19 has surpassed 150000 in 143 countries over the world [1] . The main clinical manifestations of this disease are lung symptoms such as fever, cough and wheezing [2,3] . Those patients with many concomitant diseases tend to develop into severe critically ill and likely to die of acute respiratory distress. Ling et al found 36% of the hospitalized patient had neurological manifestation such as headache and dizziness [4] . A large-scale epidemiologic study shown 1.5% of the COVID-19 patient has a history of cerebrovascular disease [2] . But the secondary lesion is rare reported. Here is a case report of two con rmed patients of COVID-19 with acute ischemic stroke at their middle age. These two patients got intensive care in the isolation ward and have been discharged from hospital recently.

Case 1
A 45-year-old male was admitted for fever over one week on 5 Jan, 2020. The vital signs from a general physical examination were 38.3 degree for body temperature, 110 times/min for pulse, 24 times/min for breathing rate and 125/72 mmHg for blood pressure. The patient reported no history of hypertension, diabetes, hyperlipidemia, heart disease and no history of smoking and drinking. His neurological examination on admission was normal. The clinical serum laboratory examination showed an increased serum amyloid protein (SAA) of 288.42 mg/L (normal range 0-10mg/L), C reactive protein (CRP) of 25.17 mg/L (normal range 0-10 mg/L), D-dimer of 15.21 mg/L (normal range 0-0.5 mg/L) and brinogen (FIB) of 4.87 G/L (normal range 2-4 G/L). The levels of serum cytokines are also increased extremely, including IL-8 of 438.20 pg/ml (normal range 0-62 pg/ml), IL-10 of 836.50 pg/ml (normal range 0-9.1 pg/ml) and IL-6 of 962.70 pg/ml (normal range 0-7 pg/ml). The white blood cell was normal together with lymphocytopenia (0.64 G/L, normal range 0.8-4 G/L). The levels of glucose, lipid and homocysteine are normal. The chest computed tomography (CT) scans showed typical bilateral patchy shadowing ( Figure   1). The real-time RT-PCR assay for 2019-nCoV test is positive.
The patient was treated with oxygen therapy, ribavirin (0.5g, i.v. drip, Q12h), and venous rehydration solution. In the morning of 6 Jan, the patient presented unclear spitting words and left limb progressive of 36.60 pg/ml (normal range 0-5 pg/ml) and IL-10 of 26.70 pg/ml (normal range 0-9.1 pg/ml) are increased. The levels of glucose, lipid and homocysteine are normal. The COVID-19 were diagnosed with typical bilateral patchy shadowing from chest CT ( Figure 4) and positive RT-PCR assay test. The head CT on 10 Feb presented right basal ganglia infarction ( Figure 3B). The patient was treated with oxygen therapy, ribavirin (0.5g, i.v. drip, Q12h), and venous rehydration solution, following by daily aspirin (100mg, p.o.), plavix (75mg, p.o.) and atorvastatin (20mg, p.o.). During hospitalization, the patient didn't have a fever again and the lung symptoms get relieved obviously. But the neurological function defects get recovery gradually. The patient discharged on 1 Mar with mild dysarthria. The left limb muscle strength score is 4, NIHSS score is 5 and MRS score is 3.

Discussion And Conclusions
We report 2 cases of COVID-19 in patients with acute ischemic stroke. Previous studies have paid a lot of attention to multiple organs except for lung were also involved in COVID-19 [5] . Recently Hu et al found neurological symptoms existed in one third of hospitalized patients [4] . The other previous studies on coronavirus induced diseases (such as SARS [6] , MERS [7] ) also shown cases of central nervous system damage.
From the history of these two patients, their neurological physical examination showed normal before 2019-nCoV infection. The initial speculation is the acute ischemic stroke is a secondary lesion after COVID-19 in one week. The possible mechanism might because of coronavirus attacks the human body through the angiotensin-converting enzyme-2 (ACE2) [8] that distributed on blood vessel and multiple organs [9] . Then the virus trigger cytokine cascade that could aggravate ischemic brain damage and increase the risk of intracerebral hemorrhage [10] and blood coagulation disturbances. This hypothesis supported by highly expression of cytokines and D-dimer from these two patients to a certain degree. From the head CT scan and head/neck atrial CTA examination, the COVID-19 induced acute ischemic stroke mainly manifested as small-vessel occlusion according to TOAST classi cation. Notably, these two patients were at middle-age and should had a lower risk of stroke. They didn't show any symptoms of deep venous thrombosis in spite of high levels of D-dimer, either. We suspected that the small-vessel occlusion was secondary lesion following coagulopathy during 2019-nCoV infection. Unfortunately, we could not have more exhaustive neurological examinations during this hospitalization because of the special infectious circumstances. So there are still some concerns need to clarify between coagulopathy induced increased D-dimer and the virus-induced ischemic stroke from the view of clinical application.
To take consider of the possibility of small-artery occlusion developed into progressive stroke, we use tiro ban instead of aspirin and chloropidore with the informed consent in case 1. The patient's neurological function got recovery rapidly in 2 days. Such platelet glycoprotein II.b/III.a receptor antagonists could act on the nal common channel of thrombosis. Their e cacy compared with aspirin could be investigated in future study.
It's worth mention that these are the only two cases of COVID-19 with secondary acute ischemic stroke out of 764 hospitalized patients in Hubei Provincial Hospital of Integrated Chinese and Western Medicine till 9 Mar, 2020. We suggest early diagnosis and treatment should be consider for COVID-19 patients with secondary ischemic stroke, which mainly manifested as small-vessel occlusion.  The head CT and head/neck arterial CTA of case 1 infected with 2019-nCoV. A: head CT on 6 Jan, 2020, Illness day 8, B: Repeat head CT on 8 Jan, 2020, Illness day 10; C: head arterial CTA on 6 Jan, 2020, Illness day 8, D: neck arterial CTA on 6 Jan, 2020, Illness day 8.

Figure 3
The head/neck atrial CTA and head CT of case 2 infected with 2019-nCoV. A: head CTA on 17 Jan, 2020, routine surgical evaluation before thyroid cancer removal surgery, B: head CT on 10 Feb, 2020, Illness day 9. Figure 4 CT imaging of case 2 infected with 2019-nCoV on 10 Feb, 2020, Illness day 9.