key: cord-0846692-u5mmnd0s authors: Bhagat, Riwaj; Kwiecinska, Barbara; Smith, Nolan; Peters, Matthew; Shafer, Christopher; Palade, Adriana; Sagi, Vishwanath title: New-Onset Seizure With Possible Limbic Encephalitis in a Patient With COVID-19 Infection: A Case Report and Review date: 2021-03-01 journal: J Investig Med High Impact Case Rep DOI: 10.1177/2324709620986302 sha: 72da87548389f82cfa8570e5a5eaa66d7d43ac54 doc_id: 846692 cord_uid: u5mmnd0s With the outbreak of COVID-19 (coronavirus disease 2019) as a global pandemic, various of its neurological manifestations have been reported. We report a case of a 54-year-old male with new-onset seizure who tested positive for severe acute respiratory syndrome coronavirus 2 from a nasopharyngeal swab sample. Investigative findings, which included contrast-enhancing right posterior temporal lobe T2-hyperintensity on brain magnetic resonance imaging, right-sided lateralized periodic discharges on the electroencephalogram, and elevated protein level on cerebrospinal fluid analysis, supported the diagnosis of possible encephalitis from COVID-19 infection. The findings in this case are placed in the context of the existing literature. In December 2019, coronavirus disease 2019 (COVID- 19) emerged from Wuhan as a global pandemic. 1 It is a clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a positive-sense RNA virus. 2 Several neurological manifestations have been associated with COVID-19, among which hyposmia, headache, myalgia, hypogeusia, and altered sensorium are commonly identified. 3 New-onset seizures or breakthrough seizure of previously known epilepsy patients are a less common manifestation of COVID-19. 4, 5 Likewise, there is sparse literature on new-onset seizure with encephalitis from COVID-19. 6 We present a case of new-onset seizure likely secondary to possible limbic encephalitis in a patient with acute COVID-19 infection, along with an updated review. A 54-year-old African American male was evaluated in the emergency department (ED) after a 5-minute episode of loss of consciousness without convulsion preceded by sudden onset of a nonradiating pressure type holocranial headache along with diaphoresis, palpitation, and nausea. He was then working in his normal state of health at the hospital cafeteria and the event was witnessed by his coworkers. He regained consciousness without confusion. Fifteen minutes later, he had a generalized convulsion lasting 1 minute followed by 15 minutes of post-ictal confusion as described by the nurse. The patient could not recall any aura before seizure. He did not bite his tongue or become incontinent in either of the events. His past medical history included paroxysmal atrial fibrillation (PAF), hypertension, glucose-6-phosphate dehydrogenase deficiency, and hepatosteatosis. He did not report any past or family history of seizures and no risk factors for these. He was compliant on apixaban 5 mg 2 times daily as his home medication for PAF. He was afebrile, normotensive, and had an irregularly irregular pulse rate of 110 beats per minute. During the initial neurological examination, he was drowsy, oriented to time, place, and person with intact language, cranial nerves, motor, sensory, and cerebellar functions. He had no neck rigidity. He was treated with 2 mg of intravenous (IV) lorazepam and 1-g loading dose of IV levetiracetam in the ED. The patient tested positive for SARS-CoV-2 infection in real-time reverse transcription polymerase chain reaction analysis taken from nasopharyngeal swab. Chest X-ray was unremarkable. Arterial blood gas analysis showed respiratory acidosis (pH 7.21, pCO 2 [partial pressure of carbon dioxide] 69.8, pO 2 [partial pressure of oxygen] 84.2, bicarb 28, and Thyroid function test, serum angiotensin-converting enzyme, cardiac troponins, urine toxicology, and analysis were unremarkable. Magnetic resonance imaging (MRI) of the brain showed increased signal in diffusion-weighted imaging (DWI) without apparent-diffusion coefficient correlation in the posterior aspect of right medial temporal lobe and para-hippocampal gyrus with associated T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) signal hyperintensity. Repeat imaging 2 days later showed persistent findings with associated contrast enhancement ( Figure 1 ). Computed tomography of the head and neck and transthoracic echocardiogram were unremarkable. Lumbar puncture was done after 24 hours before starting heparin drip without complications. Cerebrospinal fluid (CSF) analysis showed zero white blood cell and red blood cell count, protein 108 mg/dL (ref = 15-45 mg/dL), immunoglobulin G index 0.8 HI (ref = 0.0-0.7 HI), and glucose 56 mg/dL. CSF culture/stain, herpes simplex virus (HSV) 1 and 2, cryptococcal antigen, and cytology were negative. No definitive autoantibodies were detected in the CSF that included anti-amphiphysin, anti-ANNA-1/2/3, anti-AGNA-1, anti-CASPR2, anti-CRMP-5, anti-GAD-65, anti-GRAF1, anti-IgLON5, anti-MPR1, anti-LGI1, anti-mGluR1, anti-NIF, anti-NMDA-A, anti-PCA-Tr, anti-PCA-1, and anti-PCA-2. Electroencephalogram (EEG) showed right posterior quadrant lateralized periodic discharges with a frequency of 0.5 to 1 Hz, accompanied by focal delta slowing, but no electrographic seizures for the 1 hour duration of the study (Figure 2 ). During 4 days of hospitalization, the patient was initially treated with high-flow oxygen for hypoxia in the intensive care unit and was later transitioned to room air by maintaining his oxygen saturation above 93%. Atrial fibrillation with rapid ventricular rate was treated with an amiodarone drip and a heparin drip, which was later transitioned to oral diltiazem and apixaban. Levetiracetam was continued for seizure prophylaxis. He remained afebrile, normotensive, and had no further seizure. He had no cognitive or neurological deficits at the discharge. Common central nervous system (CNS) manifestations of COVID-19 incorporate ischemic stroke, CNS inflammation, encephalopathy, and myelitis. 3 Encephalitis have been a pathological diagnosis usually caused by infection or autoimmune process. Viral encephalitis can be suspected with the clinical picture of fever, headache, altered sensorium or behavior, and seizure. 7 CSF pleocytosis and elevated protein, T2/FLAIR hyperintensity of the temporal lobe, and focal abnormality on EEG support the diagnosis. However, CSF analysis might be normal in 5% to 10% cases or during the early stage of the disease. 7 We lack the brain biopsy finding in our case to yield a definitive diagnosis. Our patient had a new-onset headache, seizure, contrast-enhancing T2 hyperintense lesion in the right medial temporal lobe, LPDs in right temporal leads on EEG, and elevated protein in the CSF with positive SARS-CoV-2 infection, which suggested the diagnosis of possible encephalitis. Though the lack of leukocytosis and mildly elevated protein in the CSF may be a nonspecific finding, however, similar CSF picture can be seen in early encephalitis. There were no metabolic abnormalities, cytokine storm, and cerebral hypoxic changes to attribute for the cause of seizure, which are theorized among the mechanisms of seizure with COVID-19. 6 The lack of restricted diffusion in MRI brain ruled out an acute ischemic stroke. We cannot exclude the possibility of subacute stroke; however, other vascular territories of posterior cerebral artery that supplies medial temporal lobe like midbrain, thalamus, and occipital lobe were unaffected and patient compliance of apixaban for PAF made it less likely diagnosis. The lesion had DWI hyperintensity, which we think was likely secondary to the seizure. Seizure causes transient cytotoxic and vasogenic edema, which can reflect as a hyperintense DWI lesion on MRI of brain. 8 The lack of heterogeneous lesion made brain tumor like low-grade glioma a lesser possibility. Demyelinating CNS diseases like multiple sclerosis usually affects periventricular and juxtacortical regions, which were not present in our case. Finally, CSF analysis showed no evidence of autoimmune antibody associated with encephalitis. We did the systemic review of all cases published in English language with possible meningoencephalitis with COVID-19 to look for the clinical course and associated findings. A systematic review was done using PubMed and EMBASE database from January 2020 to September 2020 using the search terms "COVID-19," " SARS-CoV-2," and "encephalitis," modified as per the requirements for the search tool of each database. We found 14 such cases, which are elaborated in Table 1 . [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] The ages of the 14 cases ranged from 25 to 72 years (median = 45; interquartile range = 33.5-61). Of the 14, nine were males. Most of them initially 10 1 case had rhombencephalitis, 21 and 1 had type 1 mild encephalitis with reversible splenial lesion. 20 One case with left temporal encephalitis had MR spectroscopy finding of elevated choline peak, and decreased N-acetylaspartate peak. Subsequent left temporal frozen biopsy showed concentric lymphocytic infiltration into perivascular spaces with neuronal damage and diffuse hypoxic changes. 15 Most of the patients were managed with empirical antibiotics, acyclovir, hydroxychloroquine, and steroids. Out of 5 cases of new-onset seizures, MRI of the brain was done in 3 cases among which 2 had temporal lobe T2-hyperintense signal changes and 1 had normal findings. Seizures were managed by various anti-epileptics, including levetiracetam, lorazepam, versed, clobazam, and valproate. 9, 12, 13, 15, 17 One case had a refractory focal seizure with concomitant use of hydroxychloroquine. 13 Majority of the patients had good and early recoveries with median time to recovery of 11 days (interquartile range = 3-12.5). 12, 14, 16, 18, 19, 21 Our review suggests, frequent atypical presentation from possible encephalitis with COVID-19, like isolated behavior issues. Altered mental status was the foremost presentation while fever and new-onset seizure was reported in more than one third of the cases. Normal CSF analysis and MRI findings were seen in one third or more cases. Diagnosis of possible meningoencephalitis was made based on the clinical picture and investigations. As in this case, most of the reported cases of COVID associated encephalitis recover quickly with minimal residual deficits. Definitive diagnosis with evidence of SARS-CoV-2 in brain tissue were lacking. Currently, there are numerous medications used for the treatment of COVID-19 infection. Care should be taken while using hydroxychloroquine, as it lowers the seizure threshold and interacts with several antiepileptics. 22 For instance, in a patient with COVID-19 and refractory seizure, hydroxychloroquine may have lowered the seizure threshold. 13 Levetiracetam is the favored antiepileptic medication for treating a seizure in COVID-19 patients, given its least cardiorespiratory adverse effects and drug-drug interactions. 6 Our case adds to the literature on possible encephalitis with new-onset seizure associated with COVID-19. According to existing literature, more than one third of COVID-19 encephalitis cases had a new onset seizure and the majority quickly recovered with minimal residual deficits. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article. Our institution does not require ethical approval for reporting individual case. Informed consent for patient information to be published in this article was obtained. Riwaj Bhagat https://orcid.org/0000-0001-7730-3665 Pandemic potential of 2019-nCoV Clinical characteristics of coronavirus disease 2019 in China Neurological manifestations of COVID-19: a systematic review Seizure as the presenting symptom of COVID-19: a retrospective case series Neurologic manifestations of hospitalized patients with coronavirus disease Seizures associated with coronavirus infections National Encephalitis Guidelines Development and Stakeholder Groups. 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