Pharmacological management of seizures in patients with COVID-19: a systematic review

Background: Some patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported to exhibit neurological symptoms such as seizures and impaired consciousness. Our study reviews reported cases to assess the pharmacological approach to managing seizures in SARS-CoV-2 patients and associated outcomes. Methods: A systematic review of case reports on the incidence of seizures following coronavirus disease 2019 (COVID-19) among patients that reported use of antiepileptic drugs (AEDs) in management was performed by using the PRISMA (preferred reporting items for systematic reviews and meta-analysis) guidelines. Databases used included EMBASE, PubMed, SCOPUS, and Google Scholar. Data was presented as qualitative and descriptive data. Results: In total, 67 articles were selected for full-text assessment, of which 18 were included in the final review. Patients had a median age of 54 years, most of whom were male. Remdisivir, dexamethasone, Laninamivir, hydroxychloroquine, azithromycin, and Lopinavir-ritonavir were common agents used in the management of COVID-19. Most patients presented with either generalized tonic-clonic seizures or status epilepticus. Most patients received levetiracetam as drug choice or as part of their regimen. Other AEDs commonly prescribed included midazolam and sodium valproate. Some patients received no antiepileptic drug therapy. Most of the patients who died had more than one comorbidity. Also, most of the patients who died received COVID-19 treatment drugs. None of the patients who received midazolam as drug choice or as part of their regimen developed recurrent seizures in contrast to patients who received levetiracetam and sodium valproate as drug choice or as part of their regimen. Interestingly, none of the patients who received no AEDs suffered recurrent seizures or died. Conclusions: Standard guidelines for managing seizures in COVID-19 patients may be required. A limitation of this review is that it involved the use of case reports with no controls and a small number of patients.

SARS-CoV-2 has been proposed to enter the central nervous system (CNS) either via systemic vascular dissemination or by crossing the cribriform plate of the ethmoid bone (Baig et al., 2020). The latter mechanism is speculated to contribute to anosmia experienced by a quarter of patients (Baig et al., 2020). Similar to SARS-CoV-1, the new SARS-CoV-2 is believed to make its way into biological cells via the angiotensin-converting enzyme 2 (ACE2) receptor (Lan et al., 2020).
Although few cases have been reported, studies indicate that seizures may occur early in the disease process. Nevertheless, the presence of seizures bears heavily on the management and outcome of patients with SARS CoV-2. Recurrent or prolonged seizures, as occurs in status epilepticus, may contribute to or worsen hypoxic encephalopathy, cerebrovascular events, and cytokine storms that can further lead to acute seizures (Bartiromo et al., 2020).
Further to this, COVID-19 may be more difficult to treat in patients exhibiting seizures than in other patients. Antiepileptic drugs (AEDs) tend to cause complex drug-drug interactions and adjustment of these drugs may be necessary to prevent heart, liver, or kidney complications that may occur in patients with severe COVID-19 (Asadi-Pooya et al., 2020). No special guidelines currently exist for management of seizure symptoms in COVID-19. Hence, seizures in patients are controlled with currently available AEDs based on seizure types exhibited by patients. We provide a review of publications on cases of seizure disorders reported in patients with COVID-19, the pharmacological approach to management and outcomes on mortality exploring implications on management of patients. In the wake of a pandemic that has prompted experimental clinical therapy, reviews of the prevailing practices may provide information to guide clinical decision-making. Our objective was therefore to assess which antiepileptic medication or medications are most effective for managing seizures occurring in patients with COVID-19.

Strategy for literature search
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to perform a systematic review of the literature (Moher et al., 2010). Comprehensive electronic literature searches were performed in EMBASE, PubMed, SCOPUS, and Google Scholar to identify articles that covered the neuropathological symptoms in COVID-19. This review primarily aimed to synthesize information on seizure-related complications in patients with COVID-19.
The search included articles published in the English Language from January to December, 2020. Keywords used included 'neurology' or 'neurological manifestations' or 'nervous system', 'neuropathy' or 'nerves' and 'COVID-19' or 'SARS-CoV-2' and 'antiepileptic drugs' or 'antiseizure drugs'. A combination of keywords and MeSH terms were applied to maximize the output from literature findings. The full search string for the database search was COVID-19* OR SARS-CoV-2* OR AND neurological manifestations* OR nervous system* AND antiepileptic drugs* OR antiseizure drugs*. The bibliography list of selected articles were screened by reading through the corresponding abstracts in order to identify additional appropriate studies. Screening was done by JPO and disagreements were resolved by all authors. As seizure complications were rare in COVID-19, all articles reporting seizures were included. We included all types of articles or preprints (from the bioRxiv) that met the following criteria: reported the incidence of seizures following COVID-19 among patients of all ages or reported the use of antiepileptic drugs (AEDs) in the management of COVID-19-related seizures. Studies that reported on patients with a history of seizure disorders were excluded from the study. Only reported cases of seizure complications for which explicit temporal or causal association with COVID-19 infection could be determined were included in the review. Animal studies were excluded. All studies selected were initially managed using Microsoft Word v16.45. This review has not been registered and a review protocol was not prepared.

Data extraction
Data was extracted with the aid of a pre-designed data extraction form. Data extraction from full text of eligible articles was done independently by two investigators (PKM and NOA). The following data were obtained: author, country of report,

Amendments from Version 1
This version contains corrections of clerical errors, updates of the introduction, methods and discussion sections of the original manuscript. Inconsistencies in number patients and publications reviewed have been corrected. The introduction has been updated to clarify the purpose of the review. The grading system i.e. The Murad tool used to grade the reports as fair quality vs good/excellent quality has been updated in the study characteristics section. Table 1 has been updated to show that the seizure histories of patients 9 and 10 were not reported and negative respectively. The use of 'nil of note' and 'no' in Table 1 has all been changed to 'nil of note' for consistency. ROSC has been defined in Table 1. Laminavir has been corrected to Laninamivir throughout the manuscript. The discussion has been updated to explore possible reasons for all the patients who did not receive AEDs, did not suffer recurrent seizures and also survived as well as midazolam's effect on mortality. Finally, Four more references have been added.
Any further responses from the reviewers can be found at the end of the article REVISED demographic details, the number of patients with COVID-19 having seizure complications, frequency and prevalence of seizures, electroencephalogram (EEG), neuroimaging and/or other laboratory investigations associated with other neuropathological symptoms, management strategies and outcomes. Accuracy of extracted data was rechecked by a third independent investigator. Investigators made every effort to prevent data duplication. Quality of the included cases was assessed based on Consensus-based Clinical Case Reporting (CARE) guidelines for case reports by ensuring the selected cases met the criteria as stated in the 2013 CARE checklist.

Data synthesis and statistical analyses
Studies were first tabulated as qualitative data as selected studies were case reports. Given the small number of cases, descriptive analysis was performed to generate frequencies and percentages. All analyses and data visualisation were conducted using STATA version 13 (StataCorp, College Station, TX, USA).

Study characteristics
A search of literature yielded 249 citations. Following duplicates removal, and titles and screening of abstracts, 67 articles were selected for full-text assessment. Subsequent to full-text evaluation, 18 articles were used for the final review ( Figure 1). Characteristics of the included articles are provided in Table 1. All articles were case reports/series. One article was a multicenter study. Three case reports were of fair quality whereas all other studies were graded to be of good or excellent quality according to the Murad tool for methodological quality and risk of bias. Studies were considered as "poor," "moderate/fair," or "good/excellent" quality when 3 or fewer, 4, or 5 of the criteria were fulfilled, respectively (Murad et al., 2018).

Patient characteristics
The 18 articles reported incidence of seizure complications among 29 patients with COVID-19 from ten countries (USA

Seizure types and antiepileptic drugs administered
The distribution of the types of seizures presented by the patients are summarized in Figure 2a. Most patients presented with either generalized tonic-clonic Seizures (9/29; 31%) or status epilepticus (9/29; 31%). Two patients presented with non-convulsive status epilepticus while one patient suffered refractory status epilepticus. The majority (19/29; 65.5%) of patients received levetiracetam as drug choice or as part of their regimen (Figure 2b). Moreover, 17.2% (5/29) and 13.8% (4/29) received midazolam and sodium valproate as drug choice or as part of their regimen, respectively, whereas 17.2% (5/29) received no drug therapy (Figure 2).

Discussion
This systematic review synthesized evidence on the pharmacological management and outcomes in patients with COVID-19 who experienced seizure disorders. Our findings revealed significant heterogeneity in the pharmacological management of seizures in COVID-19 patients. This may be ascribed to the limited knowledge of the pathophysiology of seizures in COVID-19 patients and the lack of evidence-based guidelines. In all, nearly 1 in 4 patients died which may reflect the poor prognosis and clinical challenge in managing these patients. The study also identified status epilepticus and generalized tonicclonic seizures as the seizure types with highest incidence in COVID-19 patients. Moreover, development of recurrent seizures and mortality appeared to vary according to the AED used.
Researchers have related the incidence of seizures in COVID-19 patients to factors such as multiple organ failure, hypoxia and severe metabolic and electrolyte changes that may be experienced by these patients (Asadi-Pooya et al., 2020). A suggested mechanism by (Nikbakht et al., 2020) associates the incidence of seizures in patients with COVID-19 to increased proinflammatory cytokine (IL-1B, IL-6, TNF-a) levels by microglia/astrocytes in the brain after viral entry through nerve pathways (directly) or ACE2 receptors (indirectly). This results in the elevation of glutamate and aspartate levels, and reduction in levels of Gamma-amino butyric acid (GABA) and disruption of the blood brain barrier (BBB), in the CNS. Levetiracetam is an AED initially approved for partial onset seizure as an adjunct and subsequently as an adjunct in juvenile myoclonic seizures and generalized tonic-clonic seizures in the US. In the European Union, it is used as initial monotherapy in these conditions. With low protein binding and predominant kidney excretion, pharmacokinetic interactions are not a major concern. However, enzyme-inducing AEDs have been shown to cause a reduction in levetiracetam serum levels and promote higher clearance (Abou-Khalil, 2008). Its good pharmacokinetic interaction profile may warrant its use in COVID-19 cases. The mechanism of action of levetiracetam is via binding to SV2A, a synaptic vesicle protein, which results in the reduction of vesicle release rate of neurotransmitters (Lynch et al., 2004).  Levetiracetam has been identified to decrease levels of the cytokines, IL-1B, IL-2 and TNF-a (Himmerich et al., 2013) and may therefore be beneficial in seizure management in COVID-19 patients. However, a study conducted by Li et al. (2013) revealed the role of levetiracetam in inhibiting CD8+ T-Lymphocyte function, which is key in protection against viral infections. The study related this effect to the elevated incidence of upper respiratory tract infections in patients receiving levetiracetam. Administration of levetiracetam in COVID-19 patients may therefore be associated with detrimental respiratory effects and may explain the association between increased mortality and levetiracetam administration in COVID-19 patients with seizures as seen in our study. However, further research will be needed in drawing definite conclusions on this association.
The finding of increased mortality in patients with SE is consistent with the general high mortality associated with SE. Status epilepticus has evidently remained a clinical emergency with poor short-and long-term outcomes as well as high morbidity and mortality in the affected population (Marawar et al., 2018;Stelzer et al., 2015). An acute symptomatic cause such as a CNS infection, as occurs in COVID-19, has been identified as a critical factor related to morbidity. Treatment challenges such as delayed initiation of therapy and lack of effective medication have been identified to be possibly related to higher mortality (Stelzer et al., 2015).

Conclusion
The adequacy of antiseizure medication administered may be of concern and there is a need for the establishment of proper seizure management guidelines in COVID-19.

Study limitation
Our study involved the use of case reports with no controls and a significantly small number of patients.

Data availability
All data underlying the results are available as part of the article and no additional source data are required. patients who were hospitalised due to COVID-19 infections. The reports include those published between January to December 2020. The databases that were searched as well as the search string used is provided to allow reproduction of their work. The authors identify 67 articles which was narrowed down to 19. Based on these reports, the frequency of specific anti epileptic drugs used in case management is clearly reported as well as the type of seizures and patient outcomes. Studies that reported on patients with a history of seizures were excluded. Only cases of seizure complication for which a temporal or causal relationship with COVID-19 infection could be determined were included. This contributed towards focusing the scope of the review. The authors do a good job of pulling out key pieces of information from each report and discuss the potential pathways by which AEDs could overlap with COVID-19. Based on the reports presented as part of the review, the authors conclude that AEDs could potentially be worsening patient outcomes. Although the review is scientifically sound, there are a few outstanding points which could further strengthen the review if addressed. Figure 1 shows that 48 out of 67 retrieved records were excluded. Details on the common reasons for exclusion among the 48 cases that were cut will be useful.
According to the methodology, data extracted included "...frequency and prevalence of seizures, electroencephalogram (EEG), neuroimaging and/or other laboratory investigations associated with other neuropathological symptoms,...". However this information is not included in any of the tables or results presented.

2.
Under the study characteristics, there is no basis given for judging case reports as "fair", "good" or "excellent". 3.
The labelling of the flow diagram in figure 1 could be done vertically rather than horizontally, purely for aesthetic reasons and better reading.

4.
Information on seizure history is absent for some of the reported cases (9 and 10).
Considering that this was a critical point in selection of cases, it will be great to know if this information was absent from the primary reports or erroneously left out of the review.

5.
The data in this review clearly shows that all the patients who did not receive AEDs (n = 6), did not suffer recurrent seizures and also survived. This is a curious finding which could have been further explored in the discussion.

6.
Based on the mechanism of action of levetiracetam, the authors propose that "Administration of levetiracetam in COVID-19 patients may therefore be associated detrimental respiratory effects and may explain the association between increased mortality and levetiracetam administration in COVID-19 patients with seizures as seen in our study". Although this is sound, patients that received levetiracetam also showed the highest survival rates among all the patients who received AEDs. A discussion around another AED with a different mechanism of action from levetiracetam and worse survival rates would have enriched the review.

7.
Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others?
information was absent from the primary reports or erroneously left out of the review.

Answer:
The seizure histories of patients 9 and 10 were not reported and negative respectively; the table has been updated accordingly.
6. The data in this review clearly shows that all the patients who did not receive AEDs (n = 6), did not suffer recurrent seizures and also survived. This is a curious finding which could have been further explored in the discussion.
However, it is still unclear what unmet need this review is aiming to answer. Providing more clarification (at least a sentence or two) on the purpose of this review, in our opinion, will underscore the relevance of the review.
What were the criteria for selecting the 4 electronic literature search platforms used for this review? Could more information be garnered from these additional search platforms -the Cochrane Library, Web of Science Core Collection, CENTRAL, and clinicaltrials.gov?

2.
What was the rubric for the grading system for the reports (fair quality vs good/excellent quality)? 3.
There are a number of inconsistencies in the patient and publication counts. Specifically, It is stated that there are 19 studies/references but Table 1 only shows 18 references. 1.
Under patient characteristics, it is stated that the patients were from 9 countries, however, there are 10 countries listed.

2.
The patient count from the patient characteristics section adds up to 29, however, the table only shows data for 28 patients. 3.

4.
In table 1, for patients 9 and 10, are the seizure histories not reported or negative? Please clarify.

5.
The authors stated that there is significant heterogeneity in the pharmacological management of seizures in COVID-19. Was that conclusion based on any inferential statistics run or it was based on the observation from the descriptive statistics? 6.
In patient 16, Moriguchi et al. 1 indicated that the patient received Laninamivir. Is this the same as Laminavir indicated in Table 1? Why is there an asterisk on Laminavir (no information is provided on the use of the asterisk in the table legend)? 7.
The conclusion of the review article could be expounded a little bit further. The authors stated that 'The adequacy of anti-seizure medication administered may be of concern'. How did they come up with this conclusion? 8.
In the title of this review, the authors refer to the pharmacological management of seizures. However, the term, 'pharmacological management' does not just entail the choice of pharmacological agent (which is the highlight of this review), but also the duration of therapy, dose, possible side effects, and other aspects. Thus, in our opinion, the title does not fully represent the content of the review.

Minor Comments
In the co-morbidities column for table 1, different terms have been used to signify no comorbidities -no, nil of note, and none stated. The authors can consider using one term for consistency.

2.
this review? Could more information be garnered from these additional search platformsthe Cochrane Library, Web of Science Core Collection, CENTRAL, and clinicaltrials.gov? same as Laminavir indicated in Table 1? Why is there an asterisk on Laminavir (no information is provided on the use of the asterisk in the table legend)?
Answer: The study reported the use of Laninamivir. This has been made consistent throughout the manuscript. The asterisk was used to indicate the ongoing nature of the case. It has however been removed from the table.
8. The conclusion of the review article could be expounded a little bit further. The authors stated that 'The adequacy of anti-seizure medication administered may be of concern'. How did they come up with this conclusion?