Approach to Patients with Seizures and Epilepsy: A Guide for Primary Care Physicians.

Seizures and epilepsy are common neurologic conditions that are frequently encountered in the outpatient primary care setting. An accurate diagnosis relies on a thorough clinical history and evaluation. Understanding seizure semiology and classification is crucial in conducting the initial assessment. Knowledge of common seizure triggers and provoking factors can further guide diagnostic testing and initial management. The pharmacodynamic characteristics and side effect profiles of anti-seizure medications are important considerations when deciding treatment and counseling patients, particularly those with comorbidities and in special populations such as patient of childbearing potential.

Danger in plain sight: determining who is at highest risk for cefepime induced neurotoxicity and its associated morbidity and mortality.

Cefepime is a fourth-generation cephalosporin that is widely used to treat sepsis but is associated with a potentially dangerous neurotoxicity syndrome, cefepime-induced neurotoxicity (CIN). As a result, patients treated with cefepime may be at higher risk for morbidity, including seizures, and mortality. Though the recent ACORN trial concluded that cefepime does not increase the risk of mortality, most of these patients were not critically ill or elderly, two of the most at risk populations for CIN. Further, diagnosis may be difficult in the critical care setting as patients may have multiple reasons for encephalopathy. Therefore, this population in particular should be studied and monitored closely for CIN. Importantly, there are not well defined diagnostic criteria for CIN to guide evaluation and management. Defining the risk factors for CIN and using laboratory and EEG to help support the clinical diagnosis could be helpful in early recognition of CIN to help institute treatment and to rule out seizures. In this mini review, we highlight risk factors for CIN, discuss the possible value of EEG, and propose a diagnostic and management approach in the evaluation and management of CIN.

Lateralized Rhythmic Delta Activity and Lateralized Periodic Discharges in Critically Ill Pediatric Patients.

PURPOSE: To evaluate the clinical and electrographic characteristics of critically ill pediatric patients with lateralized rhythmic delta activity (LRDA) and compare them with patients with lateralized periodic discharges (LPDs). METHODS: This was a retrospective study examining consecutive critically ill pediatric patients (1 month-18 years) with LRDA or LPDs monitored on continuous electroencephalography. Clinical, radiologic, and electrographic characteristics; disease severity; and acute sequelae were compared between the two groups. RESULTS: Of 668 pediatric patients monitored on continuous electroencephalography during the study period, 12 (1.79%) patients had LRDA and 15 (2.24%) had LPDs. The underlying etiologies were heterogeneous with no difference in the acuity of brain MRI changes between both groups. Lateralized rhythmic delta activity and LPDs were concordant with the side of MRI abnormality in most patients [85.7% (LRDA) and 83.3% (LPD)]. There was no difference in the measures of disease severity between both groups. Seizures were frequent in both groups (42% in the LRDA group and 73% in the LPD group). Patients in the LPD group had a trend toward requiring a greater number of antiseizure medications for seizure control (median of 4 vs. 2 in the LRDA group, p = 0.09), particularly those patients with LPDs qualifying as ictal-interictal continuum compared with those without ictal-interictal continuum (p = 0.02). CONCLUSIONS: Lateralized rhythmic delta activity and LPDs are uncommon EEG findings in the pediatric population. Seizures occur commonly in patients with these patterns. Seizures in patients with LPDs, especially those qualifying as ictal-interictal continuum, showed a trend toward being more refractory. Larger studies are needed in the future to further evaluate these findings.

Continuous Electroencephalography (EEG) Protocol Improves Seizure Detection in Children on Extracorporeal Membrane Oxygenation.

BACKGROUND / OBJECTIVE: Seizures are a complication for pediatric patients requiring extracorporeal membrane oxygenation (ECMO). There are no standardized guidelines regarding continuous electroencephalography (EEG) monitoring to detect seizures in these patients, and the impact of protocolized monitoring has not been evaluated. Here we examined the effects of continuous EEG protocol implementation in our pediatric ECMO population. METHODS: Retrospective chart reviews were conducted on 57 patients who underwent extracorporeal membrane oxygenation and concurrent continuous EEG out of 165 patients supported on extracorporeal membrane oxygenation. Timing of continuous EEG initiation and seizures detected by continuous EEG was determined for 5 years prior to and 15 months after protocol implementation. RESULTS: Protocol implementation was associated with increased ECMO-supported patients who were concurrently monitored by continuous EEG. Time from ECMO cannulation to continuous EEG initiation was shorter (median 7 hours after versus 16.2 hours before; P < .001). Patients who had ongoing seizures at the start of continuous EEG recording decreased from 64% preprotocol to 0% postprotocol (P < .001), and there was an associated earlier time to break in status epilepticus postprotocol. Seizures were detected past 48 hours after cannulation in 50% of patients in the postprotocol group. CONCLUSIONS: Protocol implementation resulted in earlier continuous EEG initiation and more EEGs initiated before seizure onset with evidence of altered seizure dynamics. Although current recommendations suggest that continuous EEG duration of 24-48 hours results in seizure detection for >90% of critically ill adults, longer monitoring may be needed to reliably detect seizures in children supported with ECMO, particularly if monitoring is initiated earlier in the post-cannulation period.

EEG Correlates of Qualitative Hypermetabolic FDG-PET in Patients With Neurologic Disorders.

Background and Objectives: Case reports and case series have described fluorodeoxyglucose (FDG)-PET findings in critically ill patients with rhythmic or periodic EEG patterns, with one reporting that metabolic activity increases with increasing lateralized periodic discharge (LPD) frequency. However, larger studies examining the relationship between FDG-PET hypermetabolism and rhythmic or periodic EEG patterns are lacking. The goal of this study was to investigate the association of FDG-PET hypermetabolism with electroencephalographic features in patients with neurologic disorders. Methods: This was a single-center, retrospective study of adult patients admitted with acute neurologic symptoms who underwent FDG-PET imaging and EEG monitoring within 24 hours. Subjects were divided into 2 groups based on their FDG-PET metabolism pattern: hypermetabolic activity vs hypometabolic or normal metabolic activity. Chi-square tests and logistic regression were used to determine the relationship of FDG-PET metabolism and EEG findings. Results: Sixty patients met the inclusion criteria and underwent 63 FDG-PET studies and EEGs. Twenty-seven studies (43%) showed hypermetabolism while 36 studies (57%) showed either hypometabolism or no abnormalities on FDG-PET. Subjects with hypermetabolic FDG-PET were more likely to have electrographic seizures (44% vs 8%, p = 0.001) and LPDs with/without seizures (44% vs 14%, p = 0.007), but not other rhythmic or periodic EEG patterns (lateralized rhythmic delta activity, generalized periodic discharges, or generalized rhythmic delta activity). Subjects with hypermetabolism and LPDs were more likely to have concurrent electrographic seizures (58% vs 0%, p = 0.03), fast activity associated with the discharges (67% vs 0, p = 0.01), or spike morphology (67% vs 0, p = 0.03), compared with subjects with hypometabolic FDG-PET and LPDs. Discussion: Adults admitted with acute neurologic symptoms who had hypermetabolic FDG-PET were more likely to show electrographic seizures and LPDs, but not other rhythmic or periodic EEG patterns, compared with those with hypometabolic FDG-PET. Subjects with hypermetabolic FDG-PET and LPDs were more likely to have LPDs with concurrent electrographic seizures, LPDs with a spike morphology, and LPDs +F, compared with subjects with hypometabolic FDG-PET.

Acute Toxicity and Triphasic Waves-The Example of Cefepime.

PURPOSE: Triphasic waves (TWs) have been associated with a host of medication toxicities, and cefepime has emerged recently as a frequently encountered offending agent. This investigation aims to evaluate cefepime-induced encephalopathy and to report the associated clinical, EEG expression with TWs, and the radiologic findings. METHODS: A retrospective multicenter observational study examining adult patients with cefepime-induced encephalopathy with generalized periodic discharges on either routine or continuous EEG between January 2014 and January 2020. Clinical, electrographic, and radiologic data were collected. Patients in whom cefepime was not the sole causative factor for their encephalopathy were excluded. RESULTS: Twenty-seven patients with cefepime-induced encephalopathy marked by generalized periodic discharges with triphasic morphology were identified at both centers, whereas no patients were presenting with generalized periodic discharges without TWs. Patients had a median age of 63 years (interquartile range, 56-73). Fifty-six percent of the cohort (15 patients) were <65 years of age. Eighteen patients (67%) had either acute or chronic kidney impairment (either acute kidney injury or chronic kidney disease or both), whereas 81% had preexisting white matter disease on brain imaging. Of these, 14 patients (51%) were classified as either moderate or severe. In the majority of the patients, TWs were either state-dependent or stimulus-sensitive, and in one third of them presented only as stimulus-induced pattern. All patients improved with discontinuation of cefepime. CONCLUSIONS: Cefepime toxicity should be considered in the differential diagnosis in encephalopathic patients with TWs. The presence of preexisting white matter disease in these patients should heighten the degree of suspicion, especially in younger patients and patients without renal dysfunction.

Anesthesia-Associated Periodic Discharges.

PURPOSE: Anesthetic agents have been widely used in the treatment of refractory status epilepticus and the medical management of increased intracranial pressure whenever the goal is therapeutic burst suppression. Periodic patterns typically consisting of generalized periodic discharges (GPDs) following emergence from anesthesia have been described in several case reports. However, their clinical significance and in particular whether these patterns are epileptiform remains unclear. METHODS: This is a single-center, retrospective, observational study examining EEG patterns following emergence from pharmacologically induced burst suppression. Clinical and EEG data were collected. Patients who developed GPDs following anesthetic wean were compared with those who did not. RESULTS: Over 4.5 years, 14 patients developed GPDs related to anesthetic withdrawal. The GPDs had a frequency between 0.5 and 2.5 Hz. Generalized periodic discharges related to anesthetic withdrawal were transient, with a median duration of 40 hours (interquartile range, 24-48 hours). Notably, in all patients, the pattern was stimulus dependent. When compared with a control group of 19 consecutive patients who did not develop a generalized periodic pattern in the context of the anesthetic wean, there was no significant difference in the status epilepticus relapse between the two groups (29% vs. 44%; P = 0.63). Patients in the GPD group were more likely to be on pentobarbital (93% vs. 58%; P = 0.05) and were more likely to have concomitant systemic infection treated with antibiotics compared with the control group (86% vs. 42%; P = 0.02). CONCLUSIONS: Generalized periodic patterns are common following the wean of intravenous anesthetics (particularly pentobarbital) and likely represent a transitional encephalopathic state in a subset of patients. Their morphology is distinct and can be differentiated from the reemergence of status epilepticus (if the latter was the indication for anesthetic treatment). Failure to recognize this pattern may lead to prolonged unnecessary treatments if it is mistaken for the emergence of seizure activity. The presence of concomitant systemic infection and associated antibiotic treatment may be risk factors for the development of this pattern.

Ketogenic Diet Therapy for the Treatment of Post-encephalitic and Autoimmune-Associated Epilepsies.

Introduction: Acute Encephalitis is associated with a high risk of acute symptomatic seizures, status epilepticus, and remote symptomatic epilepsy. Ketogenic diet therapies (KDT) have been established as a feasible and safe adjunctive management of refractory- and super-refractory status epilepticus. However, the role of KDT in the chronic management of Post-encephalitic epilepsy (PE) and autoimmune-associated epilepsy (AE) is unknown. This study aims to investigate the use of KDT in patients with PE and AE. Methods: A retrospective single-center case series examining adult patients with PE and AE treated with the modified Atkins diet (MAD), a KDT commonly used by adults with drug-resistant epilepsy. Results: Ten patients with PE and AE who were treated with adjunctive MAD were included. Four patients had either confirmed or presumed viral encephalitis, five patients had seronegative AE, and one patient had GAD65 AE. The median latency between starting MAD and onset of encephalitis was 6 years (IQR: 1-10). The median duration of MAD was 10 months (IQR: 3.75-36). Three patients (30%) became seizure-free, one patient (10%) achieved 90% seizure freedom, and three patients (30%) achieved a 50-75% reduction in their baseline seizure frequency, while three patients (30%) had no significant benefit. Overall, seven patients (70%) achieved ≥50% seizure reduction. Conclusion: In addition to its established role in the treatment of RSE, KDT may be a safe and feasible option for the treatment of chronic PE and AE, particularly in those with prior history of SE. Prospective studies are warranted to explore the efficacy of KDT in management of patients with PE and AE.

Are Triphasic Waves Different From Generalized Spike-Wave Discharges?

SUMMARY: Generalized periodic discharges with triphasic morphology were previously referred to as triphasic waves but have now been subsumed into the ACNS classification as generalized periodic discharges. Although triphasic waves and generalized spike-wave complexes may resemble each other and hence may be incorrectly identified in comatose critically ill patients, many authors believe that there are different entities, with definable morphologic and clinical differences attributable to each waveform. The occurrence of both patterns in the same patient is extremely rare with only a single prior case report. Here the authors report a patient with typical triphasic waves and generalized spike-wave complexes and highlight the morphologic and EEG differences between the two patterns. The occurrence of both waveforms in the same EEG recording supports the notion of different cerebral generators and pathways, further differentiating rather than merging these morphologies.

Lateralized Rhythmic Delta Activity in Patients With Infectious or Autoimmune Insular Lesions.

INTRODUCTION: Lateralized rhythmic delta activity (LRDA) is a rare pattern on the ictal-interictal continuum (IIC) encountered in critically ill patients. Its association with acute seizures is yet to be fully explored. Insular involvement is a common finding in patients with infectious and autoimmune encephalitis. The association between acute insular lesions and the ictal-interictal continuum, particularly LRDA, has not been explored before. METHODS: A case series of 4 patients with either herpetic or autoimmune encephalitis and prominent insular cortex involvement who had LRDA when monitored on continuous EEG is being presented. RESULTS: Two patients had herpetic encephalitis and 2 patients had autoimmune encephalitis. All patients had either clinical or electrographic seizures with 1 patient progressing into new-onset refractory status epilepticus. CONCLUSION: LRDA can be seen in patients with insular cortex acute inflammation. In this group of patients, LRDA may be associated with a higher risk of acute seizures. The presence of this otherwise not clearly epileptiform pattern should raise the clinical suspicion for the development of acute seizures. Patients with LRDA and ipsilateral insular lesions should be carefully monitored for the development of recurrent electrographic or electroclinical seizures and status epilepticus.

Acute and Long-Term Outcomes of Lateralized Rhythmic Delta Activity (LRDA) Versus Lateralized Periodic Discharges (LPDs) in Critically Ill Patients.

BACKGROUND: To assess the acute and long-term outcomes for patients with lateralized rhythmic delta activity (LRDA) compared to patients with lateralized periodic discharges (LPDs). METHODS: A single-center retrospective study examining consecutive patients older than 10 years who had LRDA, LPDs, or both on continuous electroencephalographic (cEEG) between 12/01/2015 and 12/31/2017. Outcomes included inpatient mortality, functional outcome at follow-up, inpatient electrographic seizures, and the presence of new epilepsy at follow-up. Patients were classified into 4 groups: LRDA-only (without LPDs), LPDs-only (without LRDA), LRDA/LPDs, and control (without LRDA or LPDs). RESULTS: Twenty-nine patients (2.7%) were in the LRDA-only group, 76 (7%) patients were in the LPDs-only group, and 25 (2.3%) patients had both patterns (LRDA/LPDs group). 68 patients were identified as a control group. Only one patient (3%) in the LRDA-only group died during their hospitalization, compared to 21 patients (28%) in the LPDs-only group, 2 (8%) LRDA/LPDs group and 7 (10%) in the control group (p 0.003). Patients in the LPDs-only group had three times higher odds of adjusted mortality compared to the control group (p 0.05), while there was no difference in the mortality odds between the LRDA-only and control groups. Patients with LRDA-only had higher odds of good functional outcome at clinic follow-up (p 0.04). When compared to control, patients with both IIC patterns (LRDA/LPDs group) had 24.3 higher odds of acute electrographic seizures (p < 0.001), followed by patients in LPDs-only (OR 12.6, p < 0.001) and then LRDA-only (OR 9.4, p = 0.002). The odds of developing epilepsy following discharge were not increased in patients with either LRDA or LPDs (p = 0.9). CONCLUSIONS: Patients with LRDA had superior functional outcome compared to a higher mortality for patients with LPDs. Patients with both patterns had the highest odds of acute seizures, followed by those with only LPDs and then patients with only LRDA. There was no difference in the odds of developing new epilepsy compared to control with any IIC pattern. We hypothesize different underlying mechanisms of injury leading to the observed electrographic patterns.

Periodic Discharges: How to Approach, When to Treat.

The use of continuous EEG monitoring has expanded in the last decade, allowing the recognition not only of nonconvulsive seizures but also of the relatively high prevalence of periodic and rhythmic EEG patterns. Periodic discharges are a fairly common EEG pattern and often present a therapeutic challenge when encountered. We will consider five associations of these periodic discharges: ictal, acute seizures, epileptogenic, injurious, and epiphenomenal. We present the challenges and unanswered questions pertaining to periodic discharges, along with several next steps and future directions to help enhance our understanding of periodic discharges. We also present an algorithmic approach to management centered on clinicoelectrographic and clinicoradiologic data.

The ketogenic diet all grown up-Ketogenic diet therapies for adults.

The use of ketogenic diet therapies (KDT) in adults has expanded in the last two decades and has been accompanied by a surge of new retrospective as well as prospective studies evaluating its efficacy in adults with epilepsy. In this review article, we will highlight the recent clinical trials and advances in the use of the ketogenic diet therapy (KDT) in adult patients with epilepsy. We will analyze the responder rate in regard to the epilepsy syndrome (focal vs generalized) to identify adults who are optimal to consider for KDT. In addition to its role in treating patients with chronic epilepsy, we will explore the emerging use of the KDT in the critical care setting in adults with refractory and super-refractory status epilepticus as well as other neurologic disorders. Finally, we will discuss special considerations for the use of KDT in adults with epilepsy including its potential long-term effects on bone and cardiovascular health, and its use in pregnancy.

New-Onset Refractory Status Epilepticus in Children: Etiologies, Treatments, and Outcomes.

OBJECTIVES: To elucidate etiologies, treatment, functional and neurocognitive outcomes of children with new-onset refractory status epilepticus. DESIGN: A single-center retrospective study. SETTING: A tertiary care children's hospital. PATIENTS: All patients between 1 month and 21 years old admitted with new-onset refractory status epilepticus between January 2004 and July 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical presentation, laboratory data, imaging studies, and treatments were collected during hospitalization. Outcomes were assessed at hospital discharge and follow-up in the outpatient neurology clinic based on functional and neurocognitive outcomes as well as development of epilepsy. A total of 674 unique patients presented with status epilepticus of which 40 had new-onset refractory status epilepticus. Patients were classified into either refractory status epilepticus or super-refractory status epilepticus. The etiology of most children with new-onset refractory status epilepticus remained cryptogenic. The most common identified etiology was viral (20%). None of the patients had a contributory positive neuronal antibody test. Several treatments were tried including immunotherapy which was used in half of the patients. Five patients died (12.5%) during the acute phase of their disease, with four lost to follow-up. Twenty out of the remaining 31 patients (65%) developed epilepsy and 18 (58%) had persistent neurocognitive impairment. There was no statistical significant difference in various outcome measures and various etiologies, patients' characteristics, and treatments. CONCLUSIONS: In this single-center cohort, more than half of the children with new-onset refractory status epilepticus did not have an identifiable etiology. Unlike adult patients, the presence of positive neuronal antibody syndrome was rare. There was no difference in outcome between those with or without an identifiable etiology. As expected, patients with super-refractory status epilepticus had worse functional and neurocognitive outcomes. More standardized diagnostic and treatment algorithms are needed along with prospective multicenter studies.

Autoimmune Epilepsy.

The field of autoimmune epilepsy has evolved substantially in the last few decades with discovery of several neural autoantibodies and improved mechanistic understanding of these immune-mediated syndromes. A considerable proportion of patients with epilepsy of unknown etiology have been demonstrated to have an autoimmune cause. The majority of the patients with autoimmune epilepsy usually present with new-onset refractory seizures along with subacute progressive cognitive decline and behavioral or psychiatric dysfunction. Neural specific antibodies commonly associated with autoimmune epilepsy include leucine-rich glioma-inactivated protein 1 (LGI1), N-methyl-D-aspartate receptor (NMDA-R), and glutamic acid decarboxylase 65 (GAD65) IgG. Diagnosis of these cases depends on the identification of the clinical syndrome and ancillary studies including autoantibody evaluation. Predictive models (Antibody Prevalence in Epilepsy and Encephalopathy [APE2] and Response to Immunotherapy in Epilepsy and Encephalopathy [RITE2] scores) based on clinical features and initial neurological assessment may be utilized for selection of cases for autoimmune epilepsy evaluation and management. In this article, we will review the recent advances in autoimmune epilepsy and provide diagnostic and therapeutic algorithms for epilepsies with suspected autoimmune etiology.

Assessing recent suicidal ideation and behavior in the adult epilepsy monitoring unit.

OBJECTIVES: The objective of the study was to describe the prevalence of recent suicidal ideation and behavior in adult patients admitted to a tertiary epilepsy monitoring unit (EMU) and to assess the difference between patients with epileptic seizures, psychogenic nonepileptic spells (PNES), and other inpatient populations. RESULTS: Over the 14-month period, 316 patients were included in the study. One hundred and seventy-nine (57%) were classified as having epilepsy (ES), 116 (37%) with PNES, and 21 (7%) with comorbid ES and PNES (ES/PNES). Overall, 25 patients (8%) were screened positive for suicide risk factors (recent suicidal ideation and/or suicidal behavior). Patients admitted to the EMU had double the risk of suicide ideation and behavior when compared with other inpatient populations. There was no significant difference in the risk of suicidal ideation and behavior among patients with ES, PNES, and comorbid ES/PNES. Patients with comorbid ES/PNES had the highest risk (14%), although this did not reach statistical significance. Across all groups, patients with any comorbid psychiatric disorder had increased rates of suicidal ideation and behavior (11% vs 5%, p = 0.04). CONCLUSIONS: The rate of suicidal ideation and behavior in this sample of EMU patients was higher compared with other inpatient populations. The presence of a psychiatric disorder was independently associated with a higher risk. There was no statistically significant difference in the risk between those with ES and PNES. Screening for suicide risk, suicidal ideation, and behavior is recommended for all patients admitted to the EMU.