key: cord-0734807-mmjowh15 authors: Asadi-Pooya, Ali A. title: Seizures associated with coronavirus infections date: 2020-05-11 journal: Seizure DOI: 10.1016/j.seizure.2020.05.005 sha: 2183fbce28120bf5260e62b6d9dec87bb6298122 doc_id: 734807 cord_uid: mmjowh15 Neurotropic and neuroinvasive capabilities of coronaviruses have been described in humans. Neurological problems found in patients with coronavirus infection include: febrile seizures, convulsions, loss of consciousness, encephalomyelitis, and encephalitis. Coronavirus disease (COVID-19) is caused by SARS-COV2. In severe cases, patients may develop severe pneumonia, acute respiratory distress syndrome, and acute cardiac injury. While seizures and status epilepticus have not been widely reported in the past five months since the onset of COVID-19 pandemic, patients with COVID-19 may have hypoxia, multiorgan failure, and severe metabolic and electrolyte disarrangements; hence, it is plausible to expect clinical or subclinical acute symptomatic seizures to happen in these patients. One should be prepared to treat seizures appropriately, if they happen in a patient who is already in a critical medical condition and suffers from organ failure. Coronavirus is one of the major viruses that primarily targets the human respiratory system. Previous outbreaks of coronaviruses include the severe acute respiratory syndrome (SARS) in J o u r n a l P r e -p r o o f of coronavirus infection is coronavirus disease that is caused by SARS-CoV2; it is the causative agent of a potentially fatal disease 1 . The symptoms of COVID-19 infection appear after an incubation period of about five days. The most common symptoms at the onset of COVID-19 illness are fever, cough, and fatigue; other symptoms include sputum production, headache, hemoptysis, diarrhea, and dyspnea. In severe cases, patients may develop severe pneumonia, acute respiratory distress syndrome, organ failure, and acute cardiac injury 1 . The first cases were reported in December 2019 1 ; however, when the MEDLINE (accessed from PubMed) was searched, from inception to May 3, 2020, with the key word "COVID 19", surprisingly 8,767 articles were yielded. This shows that COVID-19 pandemic is of great global public health concern. Coronaviruses have been associated with neurological manifestations in patients with respiratory tract infections 2 . Neurotropic and neuroinvasive capabilities of coronaviruses have been described in humans. Upon nasal infection, coronavirus enters the central nervous system (CNS) through the olfactory bulb, causing inflammation and demyelination. Once the infection is set, the virus can reach the whole brain and cerebrospinal fluid (CSF) in less than seven days 2 . Neurological problems found in patients with coronavirus infection include: febrile seizures, convulsions, change in mental status, encephalomyelitis, and encephalitis 2 . In this narrative review, the evidence on the occurrence and management of seizures in patients with various coronavirus (CoV) infections will be discussed. In one study of 70 patients with Middle East respiratory syndrome (MERS)-CoV infection, six people (8.6%) had seizures and altered mental status was reported in 26% of the patients (18 patients) 6 . MERS-CoV infection is a serious disease that may affect multiple organs and may cause pulmonary, renal, hematological, gastrointestinal, and neurological (e.g., seizures, intracerebral hemorrhage, etc.) complications 6, 7 . Furthermore, there are reports of seizures associated with other types of coronavirus infection 8 . In one study of viral etiological causes of febrile seizures for respiratory pathogens in 174 children, in patients younger than 12 months, CoV-OC43 was the most common etiology 9 . In addition, in young children, CoV-HKU1 infection is also associated with febrile seizures generally cause enteric and respiratory diseases in animals and humans 11 . Most coronaviruses share a similar viral structure and infection pathway; therefore, the infection mechanisms previously found for other coronaviruses may also be applicable for SARS CoV2. A growing body of evidence shows that neurotropism is one common feature of coronaviruses 2,11 . One study, specifically investigated the neurological manifestations of COVID-19 and could document CNS manifestations in 25% of the patients [headache (13%), dizziness (17%), impaired consciousness (8%), acute cerebrovascular problems (3%), ataxia (0.5), and seizures (0.5%)] 12 . There is also a report of meningitis/encephalitis associated with SARS-CoV2 accompanied by seizures (SARS-CoV2 RNA was detected in the CSF) 13 . Another report describes a patient affected by COVID-19 whose primary presentation was a focal status epilepticus 14 . Therefore, it is reasonable to expect that some patients with COVID-19 develop seizures as a consequence of hypoxia, metabolic derangements, organ failure, or even cerebral damage that may happen in people with COVID-19 ( Figure 1 ). Seizures may happen as a result of an acute systemic illness, a primary neurological pathology, or a medication adverse-effect in critically ill patients and can present in a wide array of symptoms from convulsive activity, subtle twitching, to lethargy 15 . In critically ill patients, untreated isolated seizures can quickly escalate to generalized convulsive status epilepticus or, more frequently, nonconvulsive status epilepticus (NCSE), which is associated with a high morbidity and mortality 15 . When visiting a patient who is in a critical medical condition and has a change in mental status, it is suggested to make sure that NCSE is not a part of the clinical scenario 16,17 . J o u r n a l P r e -p r o o f Salzburg Consensus Criteria for Non-Convulsive Status Epilepticus is a helpful guide to make a diagnosis of NCSE in critically ill patients 18 . If a patient with COVID-19 develops a clinical or subclinical seizure or status epilepticus, it is very reasonable to start the treatment urgently 19 . In such circumstances, one should try to determine the cause of the seizure and manage the cause [e.g., hypoxia, fever (in children), metabolic derangements, etc.] immediately. However, it is often necessary to start antiseizure medication (ASM) therapy as well; this is to abort prolonged seizures and also to prevent further seizures from happening. When an ASM is initiated, drug factors, such as the onset of action, drug interactions, and adverse effects, and also patient factors, such as age, respiratory, renal, hepatic, and cardiac functions, should be taken into account 20 . Below, is a summary of different scenarios of seizure management in patients, who are critically ill with COVID-19. A. A single seizure less than 5 minutes long: there is no need for rescue treatment with benzodiazepines (these drugs should be used with caution in patients with compromised respiratory function), but an ASM should be started to prevent further seizures from happening. Since these patients are critically ill, a drug with intravenous (IV) formulation is preferable. However, because these patients suffer from severe respiratory and/or cardiac problems, drugs with significant respiratory/cardiac adverse effects (e.g., Phenytoin, Phenobarbital, etc.) should be prescribed cautiously, with clinical monitoring as appropriate. In addition, drugs with significant drug interactions 16, 20, 23 . In any of the above scenarios, a thorough investigation of the underlying cause of the seizure should be performed immediately and an appropriate treatment strategy to resolve that cause should be implemented. New-onset seizures in these patients could be considered as acute symptomatic seizures. Patients with acute symptomatic seizures do not need long-term ASM therapy after the period of acute illness, unless a subsequent seizure occurs 25 . Since the period from the onset of COVID-19 symptoms to death may range from 6 to 41 days 1 , it is reasonable to continue the ASM for about 6 weeks and then tapper and discontinue the drug rapidly in 1-2 weeks. Another important issue is the potential risks associated with COVID-19 in people with epilepsy (PWE). This issue is so important that it deserves a full manuscript, which is beyond the scope of the current work. There are many questions on this topic, which should be answered and clarified. The International League Against Epilepsy (ILAE) has provided valuable resources to tackle some of the important issues on this topic 26 . There is also a valuable review by Dr. French and colleagues on "Keeping people with epilepsy safe during the COVID-19 pandemic" 27 prolongs the QT interval in electrocardiogram (ECG) 28 . Therefore, administering hydroxychloroquine to a patient with epilepsy, who is already taking lacosamide, may carry an added risk and should be done with precaution and ECG monitoring. Also, QT prolongations may occur with azithromycin and chloroquine and some ASMs (e.g., carbamazepine, lacosamide, phenytoin, and rufinamide) may cause cardiac conduction abnormalities. Co-administration of these two groups of drugs should be done cautiously, with ECG monitoring as appropriate 29 31 . This should be investigated in the context of the current pandemic. 3. Should telemedicine be stepped up, or initiated? In the context of a pandemic, telemedicine, particularly video consultations, should be promoted and scaled up to reduce the risk of transmission 32 . Telemedicine has been shown to improve access to specialized care for patients with epilepsy in difficult circumstances (e.g., living in rural areas) in previous studies 33 . However, many countries do not have a regulatory framework to authorize, integrate, and reimburse telemedicine services, including during outbreaks 32 . For countries without integrated telemedicine in their national healthcare system, the COVID-19 pandemic is a call to adopt the required regulatory frameworks for supporting wide adoption of telemedicine 32 . While seizures and status epilepticus have not been addressed appropriately in the past five months since the onset of COVID-19 pandemic, patients with COVID-19 may have hypoxia, multiorgan failure, and severe metabolic and electrolyte disarrangements; hence, it is plausible to expect clinical or subclinical acute symptomatic seizures to happen in these patients. One should be prepared to treat seizures appropriately, if they happen in a patient who is already in a critical medical condition. Detailed clinical, neurological, and electrophysiological investigations of the patients (particularly those with a change in mental status), and attempts to isolate SARS-CoV-2 from CSF may clarify the roles played by this virus in causing seizures. 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