Neurological Complications Among Native Americans with COVID-19: Our Experience at a Tertiary Care Academic Hospital in the U.S.

OBJECTIVE: To study the central nervous system (CNS) complications in patients with COVID-19 infection especially among Native American population in the current pandemic of severe acute respiratory syndrome virus (COVID-19).
METHODS: Patients with confirmed COVID-19 infection at University of New Mexico hospital (UNMH) were screened for development of neurological complications during Feb 01 to April 29, 2020 via retrospective chart review.
RESULTS: Total of 90 hospitalized patients were screened. Out of seven patients, majority were Native Americans females, and developed neurological complications including subarachnoid hemorrhage (SAH), Intraparenchymal hemorrhage (IPH), Ischemic stroke (IS) and seizure. All 7 patients required Intensive care unit (ICU) level of care. Patients who developed CNS complications other than seizure were females in the younger age group (4 patients, 38-58 years) with poor outcome. Out of 7, three developed subarachnoid hemorrhage, two developed ischemic infarction, and four developed seizure. Two patients with hemorrhagic complication expired during the course of hospitalization. All three patients with seizure were discharged to home.
CONCLUSION: Patients with serious CNS complications secondary to COVID-19 infection were observed to be Native Americans. Patients who developed hemorrhagic or ischemic events were observed to have poor outcomes as compared to patients who developed seizures.

Introduction

Severe acute respiratory syndrome (SARS-CoV-2), termed as COVID-19 has affected millions of people worldwide. It originated in the city of Wuhan, China and was formally declared as a pandemic by World Health Organization (WHO) on March 11th 2020. It has affected more than five million people and more than 100,000 deaths so far in United States.

Neurological complications seen in COVD-19 include involvement of both central nervous system (CNS) and peripheral nervous system (PNS). According to a recent study, neurological symptoms were seen in approximately 36% of the patients diagnosed with COVID-19. Commonly reported CNS symptoms were dizziness, headache, metabolic encephalopathy, taste impairment, smell impairment, vision impairment and neuralgia. Serious neurological complications such as stroke, and seizure, were also reported. , Recent weekly report by centers for disease control and prevention (CDC) reported 0.7% of the US population experienced central nervous system (CNS) complications.

We share a case series of seven patients, all except one of whom, were Native Americans (NA), and experienced CNS complications during the admission of COVID-19.

Methods

Retrospective chart review of patients, admitted to University of New Mexico Health Science Center (UNMH) between Feb 01 to April 29, 2020, was done. Patients diagnosed with COVID-19 via reverse transcriptase-polymerase chain reaction (RT-PCR) from nasal swab were screened for development of neurological complications (ischemic stroke, intracerebral hemorrhage, sub-arachnoid hemorrhage, seizure, and encephalitis). Patients with peripheral neurological symptoms such as nerve pain, tingling and/or minor CNS symptoms like headache, mild dizziness, altered mental status without focal neurological signs, or metabolic encephalopathy, were excluded. The study was approved by UNMH institutional review board and was granted a waiver of informed consent (Fig. 1, Fig. 2 ).

Fig. 1

(Case # 2): (A) Non-contrast CT- head axial section showing right cerebral hemispheric hypo-attenuation with hemorrhagic transformation (B) Diffusion weighted image (DWI) axial section and (B) Apparent diffusion coefficient (ADC) axial image of post- hemi-craniectomy MRI brain without contrast showing acute ischemic stroke involving right cerebral hemisphere

Fig. 2

(Case # 3): MRI brain without contrast (A) DWI axial image and (B) ADC axial image showing acute infarct in right cerebellar hemisphere. Figure I (Case # 1): Non-contrast CT head axial sections showing bilateral subarachnoid hemorrhage occupying cerebral sulci. Figure II (Case # 4): Non-contrast CT head showing right frontal and parietal hypo-attenuation with hemorrhagic transformation extending into bilateral lateral ventricles.

Results

A total of 90 patients with confirmed COVID-19 were screened. Out of 90 patients, 53(59%) were NA, 25(28%) were Caucasian, 4(4%) were African-American and 8(9%) were others. Seven out of ninety (8%) were found to have neurological manifestations including SAH, IPH, IS and seizures, were included. Mean age was 55 years and majority (5 out of 7) were female Table 1 . Six patients were Native Americans (NA) and one was Caucasian. All patients presented with symptoms of COVID-19 infection including fever, cough, shortness of breath and general body malaise. Five patients required emergent intubation. All 7 patients required intensive care unit (ICU) level of care.

Table 1

Clinical characteristics of COVID-19 cases presenting with neurological manifestations.

Age	Case # 1	Case # 2	Case # 3	Case #4	Case # 5	Case # 6	Case # 7
	CVA				Seizures
Age	38	47	39	58	75	77	53
Gender	Female	Female	Female	Female	Female	Male	Male
Ethnicity	Native American	Native American	Native American	Native American	Native American	Caucasian	Native American
BMI	55.0	27.5	23.5	24.3	29.0	25.3	22.4
Comorbid medical conditions	Obesity, Asthma, Anxiety, DepressionDiabetes	Alcohol use disorder in remission	Hands and feet birth defectDiabetes	No past medical history	Hypertension, Diabetes mellitus, complicated ventral hernia repair	Hypertension, Diabetes Mellitus, hyperlipidemia, Chronic obstructive pulmonary disease, major depressive disorder	Alcohol use disorder in remission, traumatic brain injury
Home medications	Ibuprofen, Asthma inhalers, Monteleukast	None	None	None	Insulin, Lisinopril, Metformin, Aspirin	Metformin, Albuterol, Amitryptyline, Aspirin, Pregabalin, Tamsulosin, Furosemide	Escitalopram, Multivitamin
Presenting vitals
Blood pressure (mmHg)	119/74	128/68	93/86	101/74	98/76	117/64	129/78
Pulse (bpm)	106	86	106	140	98	99	82
Temperature (°C)	36.0	37.6	36.1	37.9	37.3	36.4	36.2
O2 sat	90%	74	69	84	93	65	95%
COVID-19 presentation	Fever, cough, Shortness of Breath, chest pain, Chills, Myalgia	Fever, Cough,	Fever, cough, shortness of breath, chills, fatigue	Fever, Cough, shortness of breath	Fever, Abdominal pain	Shortness of breath	Fever
Labs:
WBC (N/L %)	10.7 (93/4)	10.6 (81/11)	20 (N/A)	16.2 (N/A)	6.8 (54/38)	20 (91/3)	15.1 (85/8)
Platelets	263	302	342	239	370	225	227
PT/INR (sec/ratio)	13.2/1.1	15.3/1.3	11.4/1.0	13.0/1.1	15.0/1.3	12.6/1.1	12.6/1.1
ESR (mm/hr)	46	57	7.6	N/A	N/A	111	N/A
CRP	17.8	5.4	0.4	N/A	N/A	25.4	<0.3
LFTs	AST:295	AST:28	AST:22	AST:101	AST:70	AST:148	AST:24
	ALT:86	ALT:26	ALT:17	ALT:75	ALT:31	ALT:45	ALT:15
	ALP:137	ALP:60	ALP:219	ALP:85	ALP:100	ALP:129	ALP:77
	TB:0.5	TB:1.0	TB:0.6	TB:0.5	TB:0.9	TB:0.4	TB:1.0
	TP:8	TP:6.8	TP:7	TP:6.2	TP:8.1	TP:7	TP:6.9
	AlB:3	AlB:2.5	AlB:2.5	AlB:1.9	AlB:2.5	AlB:2.1	AlB:3.1
D-dimer (ng/ml)	421	1,380	2,061	1,425	1,535	1,113	1,680
Ferritin (ng/ml)	397	N/A	N/A	N/A	N/A	N/A	N/A
HbA1c (%)	7.3	6.3	16.8	5.9	10.0	6.6	N/A
LDL (mg/dl)	N/A	46	35	N/A	77	67	N/A
Hyper-coagulable panel (U/ml)	N/A	N/A	Positive anti-cardiolipin	N/A	N/A	N/A	N/A
Vasculitis panel (titre)	N/A	ANA, Anti-DNA positive	N/A	N/A	N/A	N/A	N/A
Ethanol Level	Not detected	Not detected	Not detected	Not done	Not done	Not detected	Not detected
Urine Toxicology screen	N/A	N/A	Positive benzodiazepine	Not done	Not done	UDM: neg	Positive oxycodone
Chest Imaging Findings:	Multifocal pneumonia	Mild bibasilar atelectasis	Multifocal pneumonia	Multifocal pneumonia	Left ground glass opacity	Multifocal pneumonia	Bibasilar atelectasis
Emergent Intubation on presentation	No	Yes	Yes	Yes	No	Yes	Yes
DVT prophylaxis on presentation	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Onset of neurological symptoms from COVID symptoms	Day 16	Day 6	Day 5	Day 19	Day 7	Day 3	Day 16
Neurological presentation	AMS, Not following commands, GCS: 2T1	AMS, dilated pupil, GCS: 3T6	AMS, Seizures, GCS: 2T6	AMS, Fixed pupil, Not following commands, GCS:1T1	AMS, Seizure	AMS, seizure	AMS, Status epilepticus
Neuro-imaging findings
NCCT	bilateral SAH	Right IPH with IVH and SAH	Not done	Right large IPH with IVH and SAH with midline shift and herniation.	Unremarkable	Non- specific right corona radiata calcificationq	Unremarkable
CTA Head & Neck	Not done	No LVO, AVM or dissection	No LVO or critical stenosis	Not done	Not done	Not done	Not done
MRI brain	Not done	Right cerebral hemisphere infarct with HT	Right cerebellar hemisphere infarct	Not done	No acute abnormality	No abnormality	No Abnormality
MRA or MRV brain	Not done (see supplementary figure 1)	Right sigmoid and transverse sinus thrombosis (See figure 1)	Not done (see figure 2)	Not done (see supplementary figure 2)	Not done	No sinus venous thrombosis, or critical stenosis, subtel vasogenic edema can be seen with seizures	Not done
Vascular territory involved in ischemic stroke	-	Right Middle Cerebral Artery	Left Middle Cerebral and Anterior Cerebral Artery	Right Posterior Inferior Cerebellar Artery	-	-	-
EKG findings on admission	Sinus tachycardia with non-specific T wave abnormalities	Normal Sinus rhythm with prolonged Qtc of 495	Sinus tachycardia with left axis deviation	Sinus tachycardia with left axis deviation and low voltage QRS complexes	NSR with no specific ST changes unchanged from prior EKG	NSR with PVCs	NSR with prolonged QTC of 533
EEG Findings	Non-epileptiform activity	Not done	Burst suppression, no epileptiform activity	Not done	No interictal epileptiform or seizure activity	Low amplitude diffuse theta and delta with superimposed beta activity	No epileptiform activity
Treatment of neurological disease	BP control	Anticoagulation, BP control, seizure prophylaxis	Antiepileptic, Anticoagulation and high intensity statin	Antiplatelet and Statin	Antiepileptic and sedation	Antiepileptic and sedation	Antiepileptic and sedation
Neurological intervention	None	Emergent decompressive hemicraniectomy with anterior temporal lobectomy and evacuation of IPH	None	Emergent decompressive hemicraniectomy	None	None	None
Length of stay (ICU) (days)	19 (17)Expired	13 (3)Discharged SNF	N/A Still admitted	14 (14)Expired	11 (3)Discharged	16 (14)Discharged	6 (2)Discharged

Table Legend: AMS: altered mental status, BMI: body mass index, BP: blood pressure, CVA: cerebrovascular accident, HbA1c: Hemoglobin A1c, ICU: intensive care unit, LDL: low density lipoprotein, MRI: magnetic resonance imaging, MRA: magnetic resonance angiogram, NCCT: non-contrast Computed Tomography scan, O2 sat: oxygen saturation, P: pulse, PT/INR: prothrombin time/international normalized ratio, T: temperature, WBC: white blood cell count.

Reference Ranges: WBC: 4-11 × 103 /µl, Hgb: 12-16 g/dl, Platelet count: 150-400 × 103 /µl, PT: 9.4-15.4 sec, INR: 0.80-1.30, aPTT: 26-38 sec, Anti-DNA: 0-4 IU/ml, D-dimer: 0-500 ng/ml, Fibrinogen: 170-450 mg/dl, TG: <150 mg/dl, LDL: <100 mg/dl, HDL: >40 mg/dl, Cholesterol: <200 mg/dl, HgbA1c: >6.5%, Anti-cardiolipin antibodies: 0.0-9.9U/ml, Procalcitonin: <10ng/ml, Ferritin: 30-530 ng/ml, Platelet count: 150-450k C-Reactive Protein: <0.3 mg/dl, Erythrocyte Sedimentation Rate:0-28mm/hr, neutrophil E3/uL 1.8-7, lymphocyte 1 – 3.4 E3/ul, AST 6-58 Unit/Liter, ALT 14-67 Unit/Liter, ALP 38-150 Unit/Liter, Total Bili 0.3-1.2 mg/dl, Total protein 6.1-8.2 g/dl, albumin 3.4-4.7 g/dl.

The first four presenting with SAH, IPH, and IS, were NA females with age range 38 – 58 years. All presented with subjective fevers, shortness of breath and cough. The neurological complication in these four patients was observed between 5-19 days of symptoms onset. Out of other three cases presenting with seizure, two were NA with age range 53-77 years. All three patients required intubation on presentation but two patients required it for seizure and were extubated within 2 days.

All seven patients were on deep venous thrombosis (DVT) prophylaxis with heparin since admission and this was continued appropriately as per clinical needs. None of the patients were treated with therapeutic anticoagulation. Overall length of stay was between 6-19 days and 2-17 days for ICU stay.

Discussion

To the best of our knowledge, this is the first report sharing neurological complications in NA with COVID-19 infection. Native Americans, who make up less than 2 percent of the U.S. population, comprise 10 % of the population in state of New Mexico. Based on the CDC data, mortality among NA is higher compared to other ethnicities. In recent reports, it was acknowledged that due to health care disparities and low socioeconomic status, NA were at increased risk of having conditions associated with COVID-19. Moreover, in general population, NA have a higher incidence of Cerebrovascular accidents (CVA) compared to other ethnic groups. Approximately 59% of patients managed at our center for COVID-19 infection were NA (51 out of 90) and 6 out of 7 patients with neurological complication were NA. Even though we have a small sample size, our data depicts a higher prevalence of neurological manifestations among NA with COVID-19. We believe that this is due to the known higher prevalence of vascular risk factors such as hypertension, smoking, atrial fibrillation, coronary artery disease, obesity, and alcohol abuse among the NA.

It is also worth noting that our patients had some unusual findings, especially the presence of IPH. We could not ascertain why our NA patients had a higher incidence of brain bleeds. Klok et al. suggested that patients with severe COVID-19 have higher risk of thromboembolism due to procoagulant state. Three out of four patients who had CVA, one was found to have venous sinus thrombosis. All of them had elevated d-dimer levels. None of these patients had any atrial arrhythmias or evidence of unstable thrombus or plaques. The ischemic stroke can be partly explained due to pro-thrombotic state with dysregulation of the clotting system secondary to intense inflammation related to cytokine storm leading to thrombus formation. It might be possible that dysregulation of the clotting cascade might have resulted in hemorrhagic transformation. This same mechanism might be responsible for development of spontaneous SAH, though bleeding at other sites were not observed. None of the patients reported in our study or in prior published manuscripts have had subcortical strokes, which negates accelerated atherosclerosis as the cause of stroke in COVID-19 patients.

The three patients in our case series who experienced seizures had underlying risk factors such as hypertension, diabetes and/or history of alcohol abuse. We hypothesize that development of seizure was a secondary response from the underlying severe systemic illness. For all three patients, any structural lesion, vascular abnormality, metabolic cause, toxin induced or infectious etiology other than COVID-19 infection was ruled out. A recent study from China, demonstrated that SARS-CoV-2 was present in cerebrospinal fluid (CSF) of patients with COVID -19 by genome sequencing. A recently published case report from Japan did find viral RNA sequencing from CSF and claimed that the patient had meningitis who presented with seizures. Since most of our patients made clinical recovery with supportive care, further invasive neurological investigation including CSF analyses was not performed, though initial brain imaging and electroencephalogram (EEG) was benign in all three patients.

The understanding of the pathophysiology behind neural involvement in COVID-19 is still in its infancy but various mechanisms have been proposed. Zhao, et al postulated that the virus binds to Angiotensin converting enzyme-2 (ACE2) receptors which are also present in vascular endothelial cells in the brain. This is one of the potential mechanisms, how viruses can breach the blood brain barrier. Giacomelli et al showed presence of anosmia and dysgeusia as one of the early presenting symptoms suggesting involvement of olfactory and gustatory pathway. Further investigations are needed to confirm the exact pathophysiology.

Our study has some limitations. It is a single center retrospective study and this data might not be applicable to the general population as the majority of our patients are NA.

Declaration of Competing Interest

None