Association of Clinical, Biological, and Brain Magnetic Resonance Imaging Findings With Electroencephalographic Findings for Patients With COVID-19

Key Points Question Can electroencephalography (EEG), combined with clinical, biological, and magnetic resonance imaging (MRI) analyses, help to better characterize patients with neurologic coronavirus disease 2019 (COVID-19) and diagnose specific COVID-19–related encephalopathy? Findings Neurologic manifestations, biological findings, EEG findings, and brain MRI images were analyzed in a cohort study of 78 adult patients with COVID-19. Nine patients had no identified cause of brain injury, as revealed by biological and MRI findings; their injury was defined as COVID-19–related encephalopathy. Meaning This study suggests that, although neurologic manifestations, EEG findings, and MRI findings may appear heterogeneous and nonspecific, multimodal monitoring may better identify patients with COVID-19–related encephalopathy and guide treatment strategy.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may damage the central nervous system (CNS). 1,2 Brain magnetic resonance imaging (MRI) results or cerebrospinal fluid findings may be suggestive of encephalitis or may be normal for patients with CNS symptoms. 3,4 Electroencephalography (EEG) is a tool to identify neurologic injury and understand underlying mechanisms. At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, periodic EEG discharges with triphasic morphologic characteristics were reported in 1 patient with alteration of consciousness, 5 with unremarkable results of cerebrospinal fluid analysis and brain MRI. Frontal periodic EEG discharges were further reported in 5 critically ill patients with COVID-19. 6 To our knowledge, few studies have evaluated EEG findings together with clinical, biological, and MRI findings in patients with COVID-19, and these studies did not show evidence of specific patterns. [7][8][9] Here, we aimed to better characterize patients with neurologic COVID-19 and, possibly, to identify a subgroup of patients with COVID-19-related encephalopathy (CORE). We combined EEG with clinical, biological, and MRI findings in a cohort study of 78 patients. We had 3 main goals: (1) to provide a description of the clinical symptoms and the biological, EEG, and MRI patterns observed in these patients, including their frequency and their prognostic value; (2) to analyze EEG patterns in light of MRI, clinical, and biological findings; and (3) to further define CORE.

Study Design and Participants
We included all consecutive adult inpatients with confirmed COVID-19 1 (based on the results of a nasopharyngeal reverse transcription-polymerase chain reaction test or a chest computed tomography scan) who underwent EEG for neurologic symptoms in the Pitié-Salpêtrière Neurophysiology Department between March 30 and June 11, 2020. This study received approval from the Sorbonne Université Ethic Committee. All patients or relatives provided written consent.
The study design and report are in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Data Collection
Electroencephalography was performed over 20 minutes with SystemPlus Evolution (Micromed) using 8 to 21 channels, and the results were analyzed prospectively in a longitudinal bipolar montage. 10 Demographic, clinical, and biological data were extracted from the electronic medical records. Clinical evaluation was performed before EEG, and then we reviewed neurologic symptoms and summarized into syndromes. For patients who had another neurologic evaluation before hospital discharge, we reported the proportion of patients with a total recovery of neurologic symptoms and the association of persistent neurologic symptoms with patient autonomy. Magnetic resonance imaging scans were performed using the 3.0-T MRI system (Premier; GE Healthcare) with a 48-channel receive head coil. 3 Electroencephalographic features were analyzed in light of clinical and biological characteristics and the therapeutics received on the day of EEG. We performed a detailed analysis of biological findings and focused on all disturbances (hyponatremia, hypocalcemia, renal insufficiency, hepatic dysfunction, hypercapnia, and hyperosmolarity; Table 1 11 ) that were able to induce an encephalopathy pattern during EEG. If one of these disturbances was reported, the patient was classified as a patient with biological abnormality. Similarly, we reported all drugs taken by the patient at time of EEG. If the patient was under sedation or taking drugs with possible CNS adverse effects (antibiotic, pain medication, or psychotropic medications), we considered the possibility that the EEG findings may be affected by these drugs. 12

Statistical Analysis
Pairwise comparisons were performed using t tests or Mann-Whitney tests when appropriate to evaluate the association of an intensive care unit (ICU) stay with EEG findings or the prognostic significance of EEG alterations. We performed univariable logistic regression analyses to identify paraclinical variables that differ between patients with CORE and other patients. The sequential rejective Benjamini-Hochberg test procedure was used to correct for multiple comparisons. Next, in the cohort of the 57 patients who underwent both EEG and brain MRI, we performed a backward stepwise logistic regression procedure to select the variables most associated with CORE (n = 5).
We then used a multivariable logistic regression model with the 5 variables previously selected.
The performance of the model was evaluated according to the area under the receiver operating characteristic curve. We also reported sensitivity and specificity. To evaluate the classification performance, we performed a 100-fold cross-validation. Our data set was partitioned into 2 folds: 70% of the patients were used for training, and 30% for testing. All P values were from 2-sided tests and results were deemed statistically significant at P < .05. Analyses were performed with R software, version 3.5.0 (R Foundation for Statistical Computing).

Clinical Findings
Before the patients underwent EEG, the most frequent neurologic manifestations were delirium  an abnormal EEG background without periodic EEG discharges, epileptic activities, or frontal slow waves (n = 12); and frontal slow waves (n = 47). The latter included an encephalopathy pattern (ie, reactive triphasic or rhythmic diffuse waves with bifrontal predominance; n = 23) and frontal slow waves (unilateral or bilateral and symmetric or nonsymmetric; n = 24) (Figure 1).

Drugs and Biological Findings
Electroencephalographic features were explained according to major confounders at the time of EEG. Fifty-five patients showed biological abnormalities, including dysnatremia, kidney failure, and liver dysfunction, the same day as the EEG procedure. Of 23 patients with encephalopathy, 7 received antibiotics, 1 received a neuroleptic drug, and 4 received light sedation on the day of EEG. 13 Eighteen patients had biological abnormalities (moderate to severe renal insufficiency [n

EEG Results and Related Clinical and Paraclinical Findings
The neurologic manifestations and MRI abnormalities were described according to EEG patterns (eTable in the Supplement). Owing to the large heterogeneity of clinical, MRI, and EEG findings, we were not able to show specific correlations between those findings. Three of 4 patients with epileptic activities detected by EEG had previous seizures, and 5 of 24 patients with EEG frontal abnormalities had frontal syndrome.
An overview of the most specific EEG and brain MRI findings is represented according to clinically defined syndromes in Figure 2. In our cohort, patients with disorder of consciousness, brainstem impairment, or frontal syndrome seemed to more frequently have EEG or MRI abnormalities than those with cerebellar syndrome or psychiatric disorders.
We performed a multimodal evaluation of patients with COVID-19. Their neurologic complications were sometimes associated with ICU complications, preexisting pathologic conditions, toxic or metabolic encephalopathies, or strokes. 1,14 The existence of specific COVID-19 brain complications is still being debated. Eight patients with SARS-CoV-2 infection and irritability, delirium, drowsiness, and new-onset epilepsy were reported. 14 Additional reports further reinforced the hypothesis of brain-specific COVID-19 involvement, including marked brain metabolism changes detected on fluorodeoxyglucose positron emission tomography scans. 18 We defined this brain involvement as CORE. In our study, we showed that patients with CORE mostly had movement     disorders (mainly seizures and/or myorrhythmia), and brainstem impairment (oculomotor disorders such as bobbing) and frontal syndrome (disinhibition and grasping).
Similarly, MRI findings showed both (1) unspecific lesions, such as perfusion abnormalities, and (2) more specific lesions, such as basal ganglia abnormalities, microhemorrhages, corpus callosum injury, and white matter-enhancing lesions. 3 The latter abnormality was the most significant lesion detected on MRI scans in patients with CORE ( Table 2).
The most frequent EEG findings were abnormal background activity (81%) and frontal slow waves (60%). The latter were associated with metabolic and toxic encephalopathies-for which we identified 1 or several factors in most cases-or frontal lesions. Six patients (8%) showed a periodic EEG pattern, predominating in frontal lobes and not explained by MRI findings.
Our results are in accordance with previous reports; a recent meta-analysis reported abnormal background activity in almost all patients (96.1%), 16 while half of all patients had focal slowing that involved the frontal region. 17 A more specific periodic EEG pattern was also reported, with an incidence ranging from 0% to 38% according to the etiologic characteristics. [6][7][8][9]15,16,[19][20][21][22][23] Nevertheless, we found that this periodic EEG pattern had no prognostic value.
Patients with CORE had a periodic EEG pattern more frequently than other patients. All EEG abnormalities from the frontal lobe, coupled with the frontal syndrome noted in patients with CORE, suggest frontal lobe dysfunction, which is reminiscent of the hypothesis of a neuroinvasive entry of SARS-CoV-2 into the brain via the olfactory nerves or via the nasopharyngeal mucosa. 18,26 A change in neuronal excitability, perhaps mediated by specific cytokines, may occur in brain areas close to the nasopharynx, such as the orbitofrontal lobe and the brainstem. Because inflammatory mechanisms, such as cytokine-mediated response or postviral autoimmune process, are suspected, immunomodulator treatments, such as plasma exchanges or intravenous immunoglobulins, may be proposed as early treatment for patients with CORE (Table 2). 26-28

Limitations
This study has some limitations. A relatively small number of patients underwent both EEG and MRI in a single center. There was a lack of systematic follow-up after hospital discharge. There was also a Receiver operating characteristic curve for the model, evaluating the performance of movement disorders, brainstem impairment, frontal syndrome, EEG periodic discharges, and white matter-enhancing MRI lesions to identify patients with COVID-19-related encephalopathy. AUC indicates area under the curve.