EEG findings in acutely ill patients investigated for SARS-CoV-2/COVID-19: A small case series preliminary report

1 INTRODUCTION

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections (COVID-19) and the grave prognosis in certain people who manifest more severe illness and rapid decline urges for the identification of early predictors of outcomes and progression as these predictors may lead to more effective interventions to improve chances for rapid recovery. While the initial reports of COVID-19 illness highlighted the respiratory decline, multi-system organ failure and resultant mortality, particularly in vulnerable populations, reports on neurological manifestations are currently emerging.^1-7 A report from China on 214 COVID-19 patients indicated that more severely affected COVID-19 patients were more likely to have neurological involvement (45.5% in severe vs 30.2% in less severe COVID-19-positive individuals), including acute cerebrovascular diseases (5.7% vs 0.8%), impaired consciousness (14.8% vs 2.4%) and skeletal muscle injury (19.3% vs 4.8%).¹ Additional neurological manifestations included epilepsy (0.5%), peripheral nervous system disorders and muscle injury.¹ In a retrospective study of 274 patients who were either deceased (n = 113) or recovered and discharged (n = 161), disorders of consciousness upon admission were far more prevalent among the deceased (22%) than the recovered patients (1%) and hypoxic encephalopathy was seen in 20% of the deceased.² Altered mental status, presenting with delirium or encephalopathy, is a recognized neurological manifestation among COVID-19 patients;⁸ this may stem from the many metabolic derangements, cardiorespiratory disturbances, the ongoing viral infection and cytokine storm, or the coagulopathy that may be present in the acute phase of the illness. Whether and when direct transmission of the virus to the CNS and associated regional neurotropism may also contribute to this encephalopathy or other CNS neurological manifestations is unclear.

Our hospital network has been operating within the epicenter of the COVID-19 pandemic. Systematic testing for COVID-19 has been has been performed beginning in early March 2020 when the first cases were recognized in New York. To minimize healthcare personnel's exposure to high risk for COVID-19 transmission patients, we have utilized an 8-channel headband EEG system (8ch-EEG), Ceribell rapid response EEG that can be quickly applied by personnel without having prior training as EEG technologists.^{9, 10} We report our first findings from medically indicated EEG studies, performed predominantly using 8ch-EEG, on admitted acutely ill COVID-19 PUIs. We found that a sizeable proportion of COVID-19-positive patients had suspicion for seizures and/or epileptiform discharges (EDs) in their EEG compared to COVID-19-negative patients, albeit these differences did not reach statistical significance. The findings are discussed in the context of clinical indication, respiratory status, prior medication and additional relevant history.

2 METHODS

3 RESULTS

3.5 EEG findings

EEGs were uniformly abnormal with a slow and disorganized background, usually symmetric but no electrographic seizures were recorded (Table 1, Figure 1). However, 9/22 (40.9%) COVID-19-positive patients had sporadic EDs, reported as frontal sharp waves in 8/9 patients (88.9%). The frontal sharp waves were bilateral and symmetric in 3/8, bilateral asymmetric in 5/8 and unilateral in 2/8. Left temporal sharp waves were seen in one COVID-19-positive patient with prior history of epilepsy. EDs were reported in only one COVID-19 negative patient with bilateral asymmetric frontal sharp waves and triphasic waves. Generalized rhythmic delta slowing, maximal frontal, was seen in 3/22 and intermittent left temporal rhythmic delta in 1/22 COVID-19-positive patients, respectively. In COVID-19-negative patients, 1/6 had generalized rhythmic delta slowing. No electrographic seizures were captured.

Overall, COVID-19-positive patients tended to have more sporadic EDs than COVID-19-negative, even if exposure to sedatives or ASMs or prior history of epilepsy was taken into consideration (Table 1). Renal insufficiency or hepatic dysfunction was common in both patients with and without EDs. However, many patients with suspicion of clinical seizure-like events were placed on ASMs prior to EEG, which may have reduced the likelihood of detecting epileptiform discharges. The rates of patients who had either suspicion for clinical seizure-like events or EDs in their EEG were not significantly different between COVID-19-positive (77.3%) and COVID-19-negative (50%) patients (P = .3107).

4 DISCUSSION

We present the first preliminary case series report of EEG findings in patients under investigation for COVID-19 who presented with altered mental status, encephalopathy or suspicion for seizures and demonstrates evidence of EDs. Seizure-like behaviors prompting EEG investigation were common (63.6%) in COVID-19-positive patients and sporadic epileptic abnormalities were seen in 40.9%, predominantly in the form of frontal sharp waves. The sporadic EDs did not appear to correlate with the presence of renal insufficiency or hepatic dysfunction or the use of sedatives and ASMs. We did not see electrographic seizures in this cohort, possibly because patients had already been started on ASMs before the study. A single case report of COVID-19 encephalopathy with left temporal EDs ipsilateral to an old encephalomalacia has been recently reported,¹¹ while in a group of 8 COVID-19 patients with encephalopathy, EEGs showed slowing without EDs.⁸

Frontal sharp waves, bilateral symmetric or asymmetric, were the predominant ED pattern, suggesting a frontal epileptogenic focus or dysfunction. It is intriguing that the frontal focus suggested in our study may be consistent with the idea of entry into the brain through the nasopharyngeal mucosa or via the olfactory nerves. The rapid clinical decline of certain COVID-19 infected patients is multifactorial. It has been recently proposed that the neuroinvasive potential of the virus may also contribute by invading the central nervous system (CNS), such as brainstem, leading to the rapid respiratory decline of certain patients.⁴ In support of the CNS invasion potential of the virus, intranasally delivered SARS-CoV or Middle East Respiratory Viral syndrome coronavirus (MERS-CoV) viruses can enter the mouse brain possibly via transsynaptic transfer through the olfactory nerves^{12, 13} or through the hematogenous route. SARS-CoV may subsequently spread to other brain regions, including brainstem, thalamus, or limbic regions.¹³ The olfactory or taste deficits in the early stages of COVID-19 have triggered the speculation that peripheral sensory nerves are the points of entry and subsequent transsynaptic transfer to the brain. However, ageusia or anosmia may not be necessarily followed by neurological decline. Hematogenous transmission is another route of possible viral entry into the brain that has been proposed for similar viruses, potentially rendering patients with blood brain barrier disruption more vulnerable.¹⁴

In humans, COVID-19 virus has very rarely been detected by PCR in the cerebrospinal fluid (CSF).^{3, 15} The poor availability of COVID-19 CSF testing so far and the efforts to minimize unnecessary exposure of healthcare personnel to COVID-19 has limited lumbar punctures to patients with increased clinical suspicion of meningoencephalitis. There are anecdotal reports of two patients with meningitis/encephalitis, one of whom had seizures, who tested COVID-19 positive in their CSF.^{3, 5} Furthermore, a 24-year-old man presenting with seizures, meningoencephalitis, and abnormal hippocampal MRI signal also had COVID-19-positive CSF, even though his nasopharyngeal swab had been negative.¹⁵ Yet, in 7 COVID-19-positive patients with encephalopathy, CSF was negative for COVID-19.⁸ It is currently unclear which factors render certain COVID-19-positive patients susceptible to CNS viral transmission, and if less invasive tests than CSF studies might identify early biomarkers predicting such adverse outcomes.

CNS viral infections as well as activation of neuroinflammatory pathways are known to lower the threshold for seizures and potentially facilitate epileptogenesis in certain individuals.^{16, 17} Seizures have been reported in other viral encephalitides with variable prevalence depending on the virus.¹⁸ Case reports of NCSE or seizures have been reported in MERS infections,^{19, 20} Influenza A H1N1 infection-related altered mental status,^21-25 and Influenza A H3N2 encephalitis.²⁶ EEG findings were predominantly background slowing occasionally with variable or unclear localization of epileptic activities. Similar to the rare case reports of CSF findings in COVID-19 infected patients with seizures,^{15, 27, 28} CSF abnormalities are not always seen in patients with viral encephalitides and seizures even if the virus is detected,^{3, 24} alerting the medical community that CSF testing for COVID-19 should be considered if clinically suspected.

However, the multiple metabolic and electrolytic abnormalities and ongoing hypoxic, inflammatory/infectious processes may also contribute to the abnormal EEG background. In our study, the presence of EDs was not significantly different between patients with or without renal or hepatic dysfunction. Most of our COVID-19-positive patients had abnormalities in inflammatory markers peripherally or signs of coagulopathy and we therefore cannot exclude that these may have played a pivotal role in activating the EEG. While sharp waves are not always epileptogenic, the relatively high prevalence of clinical seizure-like events at presentation and/or epileptiform EEGs specifically in the COVID-19-positive cohort may suggest a pathogenic role of COVID-19 virus in triggering these potentially epileptiform events. Whether this is a result of direct insult of the virus within the CNS, indirect consequence of the complex systemic effects of the virus, or both needs further investigation. Our study suggests the importance of investigating patients with COVID-19 encephalopathy with EEG studies, when medically safe and indicated. However, both the potential clinical benefit as well as the increased risk of exposure of the EEG technologists to the virus need to be considered. In our center, the 8ch-EEG offered an opportunity to perform such studies while minimizing healthcare personnel's exposure to COVID-19.

We attempted a comparison with COVID-19 negative patients who would have been more likely to have similar clinical presentation and EEG indications as the COVID-19-positive patients. Unfortunately, due to the high prevalence of COVID-19 in our region, the majority of COVID-19 PUIs tested positive, limiting the number of COVID-19 negative patients. As a result, our study was not powered to confirm statistical significance among COVID-19 PUI subcohorts in the rates of EDs or clinical seizure-like events. Larger studies are needed to confirm whether such differences are preferentially associated with COVID-19 infection or are a more general trait of encephalopathy in the setting of viral infections.

Limitations of our study include the small sample size, as discussed previously. While 8ch-EEGs provide a rapid and easy method of EEG monitoring,^{9, 10} the electrode coverage includes 8 bipolar channels (frontal, temporal, occipital), limiting the capacity to fully localize and characterize certain waveforms. In our study, two patients with EDs detected by the 8ch-EEG also had routine and/or cEEG studies that confirmed the presence of EDs. We intentionally compared COVID-positive with COVID-negative patients, because of their similar clinical presentations. COVID-19 negative tests by nasopharyngeal swab have sometimes been reported in patients who eventually tested positive in their CSF.¹⁵ Furthermore, there is a concern that many RT-PCR assays for COVID-19 carry a high false negative rate.^{29, 30} Consequently, these may have created a negative bias reducing the power of detection of cohort differences in our study. However, 5/6 COVID-19 negative patients had bacteremia or viremia and/or pneumonia from other confirmed causes that could explain their course. Finally, the EEG findings were based on the reports of multiple independent board-certified EEG readers. In some – but not all - cases, COVID-19 status was already known at the time of reading and therefore assessment was unblinded. However, the fact that there has not been any prior report on EEG findings in COVID-19-positive patients, except for a single case report,¹¹ reduces the possibility of bias in the EEG interpretation. A prospective large scale study utilizing a more uniform and structured method of EEG scoring as well as subsequent follow up with the classical routine or cEEG to confirm these findings is needed.

Despite these limitations, we believe that this first case series of COVID-19-positive patients with encephalopathy investigated with EEG will be valuable in the clinical management and understanding of the pathophysiology of COVID-19 acute encephalopathy. We offer a first view on a candidate EEG biomarker of COVID-19 acute encephalopathy, frontal sharp waves, that could potentially herald the onset of new epileptic dysfunction. Long-term follow up of these patients as well as larger, powered and adequately controlled studies to validate our findings, test the specific effect of COVID-19, as well as elucidate the pathogenic mechanisms are needed.

CONFLICT OF INTEREST

AS Galanopoulou is co-Editor in Chief of Epilepsia Open and has received royalties for publications from Elsevier and Morgan & Claypool publishers. AD Legatt serves on the editorial board of Journal of Clinical Neurophysiology and has received royalties for a publication from Springer Publishing. He has received consultant’s fees from Brain Sentinel. SR Haut serves on the editorial board of Epilepsy and Behavior. SL Moshé is serving as Associate Editor of Neurobiology of Disease and is on the editorial board of Brain and Development, Pediatric Neurology and Physiological Research. He receives from Elsevier an annual compensation for his work as Associate Editor in Neurobiology of Disease and royalties from two books he co-edited. He has received consultant's fees from UCB and Pfizer. AB Boro is site PI for clinical trials sponsored clinical trials sponsored by Biogen, SK Life Science, Neurelis and UCB. He receives no salary support or other reimbursement for these projects. All funds go to the institution. None of the other authors have conflicts to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.