Microbes and Infectious Diseases

Corona virus disease 2019 (COVID-19) is a multisystem disease with many unusual presentations reported worldwide. Though it mostly involves the respiratory systems, it has also potential to invade neurological system. It can spread from respiratory systems to the central nervous system. Here we report a case of 70 years old female who was diagnosed as COVID-19 case by molecular diagnosis and admitted with the features of acute ischemic stroke and later developed severe pneumonia also. The lady had radiological evidence of acute ischemic stroke and severe pneumonia as well as elevated D-dimer, lymphopenia, raised erythrocyte sedimentation rate, high C reactive protein (CRP) and serum ferritin. She was managed symptomatically for both pneumonia and acute stroke. Our case emphasizes that cerebrovascular disease in COVID-19 may simultaneously develop, increased C reactive protein, serum ferritin and D-dimer may contribute to the hypercoagulability and in the formation of acute ischemia. Elderly patients with co-morbidities like hypertension, diabetes, vascular disease, dyslipidaemia may contribute to acute stroke in addition to coronavirus disease pathology. Chowdhury MR et al./ Microbes and Infectious Diseases 2021; 2(3): 392-399 COVID-19 infection associated with presence of vascular risk factors such as hypertension, ischemic heart disease, diabetes mellitus and chronic kidney disease [9]. It has been observed that SARS-CoV-2 virus can cause a cytokine storm through ACE-2 receptor binding leading to a hypercoagulable state and increased incidence of vascular thrombosis in patients suffering from COVID-19 [10]. The aim to report this case, to describe the clinical characteristics of the patient during presentation, treatment response of the case, choice of anti-thrombotic and to provide possible evidence that SARS-CoV-2 induced inflammation and hypercoagulability contributed to an increased risk for cerebral arterial thrombosis resulting acute ischemic stroke in our patient. Another aim is to familiarize our fellow colleague to share the experience of unusual presentation of COVID-19 with multiple co-morbidities presenting with cerebrovascular complications. Case presentation A 70-year-old woman presented to the Medinova Specialized Hospital, Feni Bangladesh on July,16, 2020 with the complains of sudden onset of left sided weakness for 4 hours, inability to speak and deviation of the face for same duration. On query her attendants also told that she was suffering from high grade intermittent fever for last 7 days, for that she had to take paracetamol three to four times daily and dry cough for 5 days without any expectoration of sputum or shortness of breath. She had no history of haemoptysis, loss of consciousness, headache, dizziness, chest pain, diarrhea or arthralgia or any unusual symptoms. Exploration of past medical history included hypertension for 10 years, diabetes mellitus for 8 years initially controlled on dieting and oral hypoglycemic agents later on subcutaneous insulin for last 4 years. She also suffered from ischemic heart disease and was taking nitroglycerin 2.6mg, trimetazidine 35mg, bisoprolo 5mg, aspirinclopidogrel 150mg combination and a lipid lowering drug atorvastatin 20mg in the last 5 years. She reported no cerebrovascular or peripheral vascular disease. On admission, physical examination revealed a temperature of 102 F, agitated, moderate anemia, blood pressure of 170/110 mm of Hg, pulse of 108/min with normal rhythm and volume, respiratory rate was 20 breath/min and oxygen saturation was 86% on room air put on supplemental oxygen through a simple face mask though the patient have no acute dyspnea, Glasgow coma scale (GCS) was 9/15. Neurological examinations of the patient revealed left sided weakness of the limbs and the limb muscle strength was (MRC grading) was 3. The right leg and arm were unaffected, speech was not fluent with tongue and facial deviation. National institutes of Health Stroke Scale (NIHSS) score was 16. There was also incontinence of urine requiring an immediate catheterization. There was no leg edema, cardiac apex in normal position, first and second heart sounds were normal without any added sound, there were no carotid bruits, xanthelasma or xanthoma anywhere in the body. Lungs auscultation showed few scattered course crackles over the both lung fields. Real time polymerase chain reaction (RT-PCR) from nasopharyngeal swab sample was found positive on the following day. Computed tomography of Brain (Ct scan of Brain) without contrast was performed immediately which revealed large hypodense areas noted at right temporo-parietal region, diffuse hypodensities at subcortical and periventricular white matter of both cerebral hemispheres suggesting large acute infarct at right temporoparietal region with age related generalized cerebral and cerebella atrophy with white matter ischemic change and features of normal pressure hydrocephalus (Figure 1A & B). Following RTPCR positive result, high resolution computed tomography of chest (HR CT of Chest) also performed which revealed multifocal ground glass opacity areas intermixed with irregular increased attenuated areas, fibrotic bands and early sub segmental consolidations are seen at multiple segments of both lungs predominantly distributed at peripheral, peri bronchoalveolar and subpleural regions. The ground glass density involved approximately 30% of lung volume (Figures 2 & 3). Other significant laboratory findings included (Table 1); hemoglobin was 7.9gm/dl, packed cell volume (PCV) was 26.0%, erythrocyte sedimentation rate (ESR) was 55 mm in 1 hour, total white blood cell count (WBC) was 23,400/cmm with 88% neutrophils and 8% lymphocytes in differential counts, platelet count was 340,000/cmm, serum creatinine was 1.2 mg/dl with estimated GFR was 87 ml/min/1.73m, C reactive protein was 87mg/L, alanine aminotransferase was 14 U/L, serum lactate dehydrogenase was 565 U/L, serum ferritin was 1000ng/ml, D-dimer was 2.69 mg/l, serum urea was 34 mg/dl, serum calcium was 6.4 mg/dl, troponin I was <0.01 ng/ml, N terminal Pro393 Chowdhury MR et al./ Microbes and Infectious Diseases 2021; 2(3): 392-399 brain natriuretic peptide (NT-Pro-BNP) was 410 pg/ml, serum sodium was 136 mmol/l, potassium was 3.6mmol/l, random blood sugar was found 18.0 mmol/l on admission. Trans thoracic echocardiography showed concentric hypertrophy with normal left ventricular function (Ejection fraction 64%) and inferior wall motion abnormality. She was started on low molecular weight heparin, enoxaparin 60mg subcutaneous 12 hourly, aspirin 75mg, oral favipiravir 1600mg loading dose followed by maintenance dose of 600 mg twice daily for 10 days according to national guideline of Bangladesh, Intravenous antibiotic ceftriaxone 2gm twice daily with oral clarithromycin twice daily for possible bacterial co-infection, continuous infusion of short acting insulin was started and corticosteroid, dexamethasone for 5 days along with her regular antihypertensive losartan potassium50mg/hydrochlorothiazide 12.5mg, clopidogrel 75mg, nitroglycerine2.6mg, trimetazidine 35mg, bisoprolol5mg and atorvastatin 20 mg daily. She was put on nasogastric tube for maintaining adequate feeding. She was admitted in isolation unit and started on supplemental oxygen therapy via simple face mask at 5L/min. She positively responded to treatment meanwhile after 5 days sudden desaturation occurred requiring supplemental oxygen 25L/min through High flow nasal canola for five days and starting antiviral remdesivir for 5 days according to national guideline without any adverse events. After that she was maintaining saturation above 92% with a nonther mask with 10-12 L/min oxygen. Alternate day electrocardiogram showed no new ischemic change or arrhythmia. She was given 2 units of packed cell blood transfusion during her hospital stay. She remained on regular physiotherapy, speech therapy and chest therapy during her hospital stay. After 17 days stay in the hospital, her clinical and laboratory parameters improved along with slight radiological (X ray chest) improvement (Figure 4). The patient-maintained saturation above 92% on room air without supplemental oxygen therapy. Her nasogastric tube was withdrawn and started oral feeding with supervision, she can walk little with help and near fluent language, but urethral catheterization could not possible to off due to urinary incontinence following failed attempt of withdrawal. On August 4,2020, she was discharged from hospital with a hemodynamic stable condition though follow up RT–PCR for coronavirus could not done due to changing discharge criteria in the national guideline of Bangladesh. She was advised for 14 days home isolation and a follow up visit after 14 days in the outpatient department. Table 1. Clinical laboratory finding from hospital (Day 1-Day 17) :( July,16, 2020-August,04,2020). Measurement (Reference range) Day 1 Day 8 Day 18 Hemoglobin (Female 11-16gm/dl) 7.9gm/dl 9.2mg/dl 9.1gm/dl Erythrocyte Sedimentation rate (ESR) (0-15 mm in 1 hour) 55mm in 1 hour 87mm in 1 hour 49mm in 1 hour Total White blood cell count (WBC)(400011,000/cmm) 23,400/cmm 18,700/cmm 15,000/cmm Neutrophils (Differentials)(40-75%) 88% 79% 71% Lymphocytes (Differential) 08% 14% 11% Haematocrit (37-47%) 26% 28.8% 28% Platelet count (150,000-400,00/cmm 340.000/cmm 290,000/cmm 272,000/cmm Sodium(135-145nmol/L) 136.0nmol/L 138nmol/L 134nmol/L Potassium (3.5-5.0nmol/L) 3.60nmol/L 4.5nmol/L 4.9nmol/L Chloride(98-107nmol/L) 106nmol/L 109nmol/L) 102nmol/L Serum calcium (8.1-10.4mg/dl) 6.4mg/dl Serum creatinine (0.5-1.2mg/dl) 1.2mg/dl 1.0mg/dl 1.2mg/dl Blood urea nitrogen (BUN)(6.0-21mg/dl) 12.7mg/dl Total Bilirubin (0.2-1.2mg/dl) 1.2mg/dl 1.3mg/dl Blood Urea(10-50mg/dl) 34mg/dl 41mg/dl Prothrombin time (Control 13.sec) 17.0 sec 14.0sec 18.0 sec Alanine aminotransferase (Female up to 32 U/L) 14U/L 32U/L C reactive protein (less than 6mg/L) 87mg/l 43.6mg/l 42.8mg/ml D-dimer (<0.5 mg/ml) 2.69 mg/l 2.1mg/l 0.9mg/l Activated plasma thromboplastin time (APTT)(25-35) Control:32 Patient:21 Control:32

Cerebral venous thrombosis, an unusual rare causes of stroke, frequently occurs in female gender and young age group [8][9][10][11].The features of CVT ranges from non-specific neurological symptoms and signs [12] including headache, vomiting, seizures, to focal neurological deficits, [11] such as motor weakness (present in up to 40% of patients), visual field loss and sensory symptoms.However, infection with SARS-CoV-2 reported to be associated with neurological manifestations, (e.g.febrile seizures, convulsions, changes in the mental status and encephalitis) [1, 10,13,14].Neurologic sequelae such as anosmia, headache, dizziness and altered

A B S T R A C T
Newly recognized pandemic infectious disease COVID-19 (Corona-virus disease) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).This viral infection causes hypercoagulability and inflammation leading to increased incidence of both arterial and venous thrombotic events (VTEs).Therefore, patients infected with this novel virus seem to be at higher risk of thrombotic events (TEs) resulting in thromboembolic diseases, especially stroke and pulmonary embolism, or even cerebral venous sinus thrombosis (CVST).We report a case of 42-year-old female, presented with features of venous thrombotic events (extensive dural venous sinus thrombosis) and was subsequently found to have COVID-19 positive by reverse transcriptase-polymerase chain reaction (RT-PCR) test.The case report indicates CVST might be an unusual manifestation of COVID-19.Cerebral venous sinus thrombosis even presents as an initial symptom of COVID-19 without significant respiratory symptoms.Early diagnosis and treatment with thrombolytic agent in case of SARS-CoV-2 infection result in reduced morbidity and mortality.We recommend further studies to establish SARS-CoV-2 virus (the COVID-19 disease) as a known risk factor for CVST.sensorium may occur due to direct viral infection or as secondary complications of SARS-CoV-2.Moreover, neurotropic and neuro-invasive capabilities of coronaviruses have been described in humans [2,11,14,15] .We present a unique case of a 42-year-old COVID positive female with features of extensive dural venous sinus thrombosis.This study was approved by the local research ethics committee.Written informed consent was obtained from the patient.

Case study
On 15 th May 2020, a 42-years-old obese woman (BMI 29) with no significant past medical history or comorbidities presented with the complains of gradual onset of severe headache for 3 days and gradual onset of left sided weakness for same duration.She was referred to a nearby tertiary Medical College Hospital by an internal medicine specialist on that day, with the suspicion of cerebrovascular disease (subarachnoid haemorrhage).
On admission, she was afebrile, had a normal sinus rate and rhythm of heart, no respiratory difficulties, with no altered vision or seizure.Her history explored having no comorbidities like hypertension, diabetes mellitus, any prothrombotic condition, any history of cardiac or cerebral disease or any drug history related to the disease (oral contraceptives) or any relevant family history.On examination, her vital signs were blood pressure (BP) 130/80 mm of Hg, pulse 68/min regular with normal volume, body temperature was 99 • F, respiratory rate was 16/min but the patient was looking ill with little agitating behaviour with other normal parameters in general examinations.
Neurological evaluation revealed left sided weakness as evidenced by decreased muscle power on the left side (both upper and lower limb -3/5 MRC-grade 3), sensory intact, planter extensor in the left side and involvement of the bladder requiring urethral catheterization.Moreover, no cerebellar sign was found but funduscopic examination showed bilateral early papilloedema.Meanwhile, her oxygen saturation was fluctuating from admission to onward following days, from 89% to 96% on room air, requiring supplemental oxygen by simple face mask at a rate of 4 to 6 l/min.However, she had history of taking paracetamol 500 mg QDS and azithromycin 500 mg OD for five days prior to hospitalization due to sore throat which were improved within this time.
She underwent emergency head computed tomography (CT) with contrast (on 16 th May) to diagnose the underlying pathology, extensive hyper densities at dural venous sinuses were found, more marked at straight and posterior part of the superior sagittal sinuses associated with dilatation of venous sinuses (Figure1).Prominent superficial cortical vein was also noted at both cerebral hemispheres.After intravenous contrast, filling defect were noted at dural venous sinuses (enclosed photograph).
On the following day, thrombophilia screening test and other relevant investigations were done to find out the underlying causes of thrombosis.Laboratory findings are reported in table (1).
Meanwhile, reverse transcriptasepolymerase chain reaction (RT-PCR) was done on 16 th May due to suspicion of COVID-19 and tested positive on 17 th May 2020.However, her treatment was on going with enoxaparin 60mg s/c 12 hourly, paracetamol 1 gm IV 08 hourly, phenobarbitone IV 12hourly.After the report of RT-PCR she was shifted to an isolation unit of a dedicated COVID-19 hospital and treated according to National Guidelines on Clinical Management of Coronavirus Disease 2019.Treatment was started with oral favipiravir loading dose (1600 mg day 1) followed by maintenance dose (600mg BD Day 2 -Day 10).Her condition improved from day four and headache was totally subsided on 6 th day of treatment.
Furthermore, physiotherapy was started and left sided weakness gradually improved.On 25 th May she was discharged from the hospital with the advice of 10 days home isolation and the prescribed treatment was oral Rivaroxaban 20mg daily for 45 days, oral anticonvulsant levetiracetam 500mg 12 hourly, paracetamol , antioxidant Vit E and Vit C and also advised for follow up sample test for COVID-19 after isolation completion.Follow up sample was not tested due to protocol change according to national guideline and complete recovery of the patient.

Discussion
Current pandemic infectious disease COVID-19, when symptomatic, typically presents with systemic and respiratory manifestations [2,[15][16][17].Emerging data also suggested that this disease can present with neurological manifestations, in fact there are few studies about neurologic complications of COVID-19 [1, 10,13,14].Angiotensin converting engyme-2 (ACE2) is identified as the receptor for SARS-CoV-2, which is present in nervous system and skeletal muscles, hence this virus can infect these systems as well as the respiratory tract [14].SARS-CoV-2 can also cause overproduction of proinflammatory cytokines (tumor necrosis factor [TNF], IL-6, and IL-1β) resulting in cytokine storm and damage to the coagulation system causing release of D-dimer and platelet abnormalities.It increases the risk of abnormal blood clotting leading to deep vein thrombosis or pulmonary embolism [1,10].Moreover, with COVID-19, development of severe hypoxemia in some patients results in thrombus formation under hypoxic conditions [18].However, to the best of our knowledge our patient is the first reported case of CVT associated with COVID-19 in Bangladesh.This case illustrates a number of diagnostic challenges, in particular presentation with isolated neurological findings.Our patient was admitted with the diagnosis of suspected CVT (confirmed subsequently), presenting features were gradual onset of severe headache with left sided weakness.Further history later on revealed mild sore throat was present five days prior to hospital admission.The suspicion of COVID-19 occurred later in the hospital due to clinical presentation of the patient without any significant correlation of thrombosis related disease but recently increasing COVID-19 cases in her surroundings residence and clinical interest of the treating physician as well as some published case reports.
Cerebral venous thrombosis is a rarely documented early presentation of COVID-19 [3].However, incidence of CVT among female sex and young age patients is much higher than male sex and other age groups.In this case report, we found a female patient of 42 years of age suddenly developed CVT that correspond to previous study findings [9,10,12].However, hypercoagulability of SARS-CoV-2, manifests as an increase in Ddimer, lactate dehydrogenase (LDH) and prolonged coagulation times, which are also associated with more severe disease [3].In this case, patient had normal coagulation time and little raised LDH level.However, D-dimer level, was slightly elevated suggesting a hypercoagulable state [13].
This case demonstrates presence of thrombolytic (VTE) effect, dural venous sinus thrombosis, in the cerebral venous system in absence of additional risk factors other than obesity.Moreover, the family history of hypercoagulability, prior history of DVT, Cardiovascular disease, cancer, collagen vascular diseases and acquired causes like brain tumor, head trauma, local central nervous system infection, none of which were present in this patient.That indicates venous sinus thrombosis might occur secondary to the hyper inflammatory state during COVID-19 [2].So, we may consider COVID-19 as an independent risk factor for CVT.Furthermore, patients may present with thromboembolic complications, (such as CVT) prior to respiratory symptoms.So, this case report also highlights the importance of identifying CVT as a presenting sign of COVID-19 patient who presented with headache, which is also similar finding as study conducted by Hemasian and Ansari [13].
Regarding treatment, the selection of anticoagulants for managing a patient of VTEs associated with COVID-19 is a matter of debate [19].Both unfractionated heparin and low molecular weight heparins (LMWH) are used in acute CVST.Emerging evidence suggests that various heparins can bind to the COVID-19 spike proteins, help downregulate IL-6, and directly dampen immune activation.In our patient we started treatment with LMWH enoxaparin instead of unfractionated heparin as the patient clinical condition was stable and there were no other comorbidities.

Conclusion:
Cerebral venous sinus thrombosis is an unusual manifestation of COVID-19 and few cases reported already worldwide.Cerebral venous sinus thrombosis even presents as an initial symptom of COVID-19 without significant respiratory symptoms.Early diagnosis and treatment with thrombolytic agent could significantly reduce morbidity and mortality.We recommend further studies to establish the COVID-19 disease as a known risk factor for CVST.

Figure 1 .
Figure 1.Pictures of computed tomography with contrast.