The Coronavirus disease 2019 (COVID-19)—initially defined as an acute respiratory syndrome—is now widely considered as a systemic disease. Several neurologic troubles were reported and could be either mild such as headache, dizziness, or anosmia, or more serious like seizure or cerebral ischemic stroke.1 Confusion is reported in severe forms of the disease; however, it seems uncommon in most COVID-19 patients.
We describe here an unusual clinical picture with acute confusion as main symptom and atypical EEG, a posteriori diagnosed as encephalitis related to COVID-19.
A 78-year-old man with controlled high blood pressure and regular follow-up for a non–end-stage chronic kidney disease because of nephroangiosclerosis was admitted to Tenon Hospital (Paris, France) on March 5, 2020 because of acute confusion, cognitive troubles, and behavioral disorders. The patient was previously autonomous and in healthy condition. Initial physical examination was unremarkable with no fever, no anosmia, and no respiratory, cardiovascular, or digestive symptoms. Neurologic assessment was normal except for a decreased Mini-Mental State Examination (15/30). Blood tests did not show any hepatic, ionic, or inflammatory abnormalities. There was no worsening of the usual kidney function. HIV and syphilis tests were also negative.
EEG was realized assuming potential nonconvulsive seizures for which diazepam injection was ineffective. It showed synchronous and continuous exclusively bifrontal periodic small sharp waves occurring on a normal wakefulness and sleep background activity (Fig. 1). This unusual EEG pattern was described as synchronous bifrontal lateralized periodic discharges (LPD) and raised the hypothesis of atypical presentation of encephalitis. Spinal puncture showed a clear cerebrospinal fluid (CSF), with protein concentration of 0.3 g/L, 1 leukocyte/mm3, and normal lactate and glucose concentrations. Cultured CSF remained negative for bacteria and various viral tests, including varicella-zoster virus, HSV, and cytomegalovirus, and syphilis serologic testing was negative. The detection of 14-3-3 protein was also negative. The patient improved spontaneously during the next days while a fluctuating mild confusion remained. He was discharged on March 10, 2020, with an MRI prescription. However, after discharge, recurrence of confusion occurred, leading to loss of autonomy. On March 20, 2020, he was readmitted for acute renal failure because of extracellular dehydration with a history of psychomotor retardation with no food or drink intakes for a few days and a total weight loss of 7 kg. A fever of 39°C was noticed without any respiratory symptoms. Coronavirus disease 2019 infection was diagnosed on the basis of suggestive “ground glass opacities” in the chest computed tomography and a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction method from a nasopharyngeal sampling. The patient completely improved with symptomatic treatment and rehydration and was discharged on March 29, 2020. In a follow-up visit on May 7, 2020, his Mini-Mental State Examination was normal (29/30) with a normal EEG (no longer synchronous bifrontal LPDs). Of note, previous frozen CSF sample was tested negative for severe acute respiratory syndrome coronavirus 2, and noninjected brain MRI—realized on April 10, 2020—was normal.
Our report described one of the rare cases of encephalitis related to COVID-19, with only confusion and cognitive troubles as clinical symptoms for several days. The link with COVID-19 seems most likely even if confusion preceded fever by at least 15 days, but also lung, gut, and potentially kidney damages. Other causes of acute confusion such as metabolic disorder, drug intoxication, and cerebral lesion were ruled out.
Of notice, only few COVID-19 cases were admitted to Paris hospitals in early March conversely to east of France and the lockdown was decided on March 17, 2020. Severe acute respiratory syndrome coronavirus 2 polymerase chain reaction method was not performed during the first hospital stay because COVID-19 diagnosis was considered mostly for upper tract and respiratory infections or diarrhea but not confusion alone.
The originality of our report is based on EEG characteristics with unusual synchronous exclusively bifrontal LPDs. Indeed, periodic activities in EEG are widely regrouped under the term of LPDs (or periodic lateralized epileptiform discharges in the former terminology), which is a rare and nonspecific EEG pattern, usually lateralized or focal, and supposed to be the result of changes of the excitatory neurotransmission of cortical/subcortical cells in case of acute and potentially ischemic/necrotic brain lesions.2,3 Lateralized periodic discharges could be seen, for example, in case of ischemic strokes, fast-growing brain tumors, or abscesses, but it is also highly evocative of viral encephalitis—especially herpetic encephalitis in which the LPDs is typically over the temporal region4—Lateralized periodic discharges could also be bilateral—symmetric or asymmetric but typically asynchronous—and so called BIPDs or have a generalized and synchronous cortical distribution (generalized periodic discharges) with possible prominence in a focal or bifocal regions. These aspects are more likely to be seen in case of anoxic–ischemic encephalopathy, Creutzfeldt–Jakob disease, or in very rare viral encephalitis like subacute sclerosing panencephalitis caused by measles virus.5 An extremely rare variant of LPDs called stimulus-induced rhythmic, periodic or ictal discharges was reported as a possible ictal pattern but its significance is still debated and undefined. In our case, LPDs were continuous and stimulus independent.
Data about EEG in COVID-19 are scarce. Most of EEG were performed in confused patients in intensive care units and showed a high prevalence of nonspecific changes and slowing,6,7 probably because of the coexistence of several factors impacting the EEG background activity such as metabolic abnormalities, hypoxemia, and/or the use of anesthetic drugs.8 Few seizures cases starting in frontal–temporal regions were also reported,9–11 thus raising the issue of an anterior brain tropism of the virus that could account for the high prevalence of anosmia in COVID-19 patients with possible dysfunctions or damages of the orbitofrontal lobes.12,13 However, although severe acute respiratory syndrome coronavirus 2 was found postmortem in neural and capillary endothelial cells of the frontal lobe tissue in one patient,14 in most cases, a direct brain effect of the virus on brain cells seems unlikely. Alternatively, brain microvascular and/or immunologic/inflammatory reversible dysfunctions are suggested by current normal MRI7,10 with various nonspecific lesions reported only in three cases,9,11,15 and no severe acute respiratory syndrome coronavirus 2 detection in the CSF, except for only one patient.11 In our case, the frontal projection of the synchronous LPDs with normal CSF and MRI—altogether with the microvascular fragility related to the nephroangiosclerosis and the ad integrum recovery of confusion and EEG—is in accordance with this latter hypothesis and suggests that frontal cortical and/or subcortical involvement could be an underestimated aspect of COVID-19.
Our case pinpoints the onset of confusion and/or cognitive troubles as a potential COVID-19 initial clinical picture underlying the interest to perform an EEG in such settings looking at potential abnormal pattern such as synchronous bifrontal LPDs.
The authors would like to thank Mrs. A Bouzerau for her valuable contribution to this work.
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