In this study, we matched 200 consecutive cEEG patients with GPDs to controls based on age, category of presenting illness, and level of consciousness. GPDs had a significant association with NCSz (26.5% with GPDs vs 7.5% of controls) and NCSE (21.5% vs 6.5%), but not CSz. In both groups, one-third of patients had CSz at some point, and <6% had CSz during cEEG. Just over half of patients with GPDs had no seizures at any time. Seizures in those with GPDs were more likely to be delayed, with the first seizure occurring >24 hours after the start of cEEG in about one-quarter of patients (vs 6% of controls). Contrary to our hypothesis, GPDs were not independently associated with worse outcome. While 41.0% with GPDs died during hospitalization and an additional 40.0% were severely impaired at discharge, there was no difference in outcome compared to matched controls without GPDs. When CA patients were excluded, GPDs were associated with increased mortality on univariate analysis. Multivariate predictors of poor outcome overall were coma, sepsis, CA, and NCSE, but not GPDs.
details prior studies of GPDs.8–11
Of note, there were significantly more women in our GPD group compared with controls (60% vs 46%). In 2 prior studies,9,11
women also comprised more than half (57.1%), but these were not controlled cohorts. There are several possible explanations for this observation—hormonal, genetic, epidemiologic—but these remain speculative.
Major findings and comparison of studies on generalized periodic discharges
GPDs remain relatively uncommon, but were seen in approximately 4.5% of more than 3,000 consecutive inpatients undergoing cEEG, compared with 0.06%–0.24% undergoing routine EEG.8,10,11
As cEEG use becomes more widespread, GPDs are likely to be detected with increasing frequency, similar to experience with NCSz.3,14
In our study, 46.0% with GPDs had seizures overall and 23.5% had SE; during cEEG, most seizures were NCSz and would have gone unrecognized without cEEG, consistent with other investigations.3,14,15
In a prior GPD series,9
32.0% had SE. However, in their cohort, 40.0% had a history of prior seizures (vs 6.5% in our study). In a second study,8
89.2% had seizures within 48 hours of EEG: 32.4% had SE during the EEG, 21.5% had CSz after EEG, and 35.2% had myoclonic jerks (“myoclonic status”16
). Their cohort was quite different from ours: chronic conditions associated with myoclonic seizures were included, such as subacute sclerosing panencephalitis (SSPE; 29.7%, their largest subgroup) and CJD (10.8%), which in our study were absent (SSPE) or rare (CJD; 3.5%). Neither study included control groups. We found that when controlling for age, category of presenting illness, and level of consciousness, only NCSz and NCSE, not CSz, were associated with GPDs.
Overall in-hospital mortality for GPD patients was 41.0% (65.5% with CA and 36.8% without CA). A prior study9
documented 64.0% mortality, but anoxia comprised 40.0% of the patients (vs 14.5% in our study). Excluding those, 46.7% of their patients died, similar to our results. A second study8
documented a mortality of 48.7%, but while their cohort included a similar proportion of CA patients as ours (18.9%), it included 7 with burst-suppression patterns, which we excluded. Burst-suppression is associated with poor outcome, especially after CA, and all 7 patients died. Excluding burst-suppression, mortality in their cohort was 36.7%. One GPD subgroup11
had 29.7% mortality after up to 1 year follow-up, lower than ours perhaps because 5/17 of these patients had so-called chronic (>8 weeks) GPDs. Again, these prior studies had no control groups. Despite the relatively poor outcomes, when we matched patients for age, category of presenting illness, and level of consciousness, there was no definite independent association between GPDs and outcome, although a small association remains possible.
The role of underlying illness and its severity in determining outcome in this cohort of mostly critically ill patients is underscored by multivariate analysis in which coma, sepsis, and CA were significant predictors of poor outcome. In addition, we found that NCSE confers independent risk of poor outcome once age, category of presenting illness, and level of consciousness are controlled. This is consistent with a prior report of NCSE after control of CSE.17
Both delays to diagnosis of NCSE and duration of NCSE have been reported to be associated independently with mortality in patients with acute neurologic injury.18
Periodic epileptiform discharges or electrographic seizures have also been shown to be independent risk factors for poor outcome in medical ICU patients without acute neurologic injury undergoing cEEG.19
Our center has reported that periodic epileptiform discharges independently associate with poor outcomes in poor-grade SAH and ICH, but when stratified, only lateralized discharges maintain this association, not generalized discharges. While overall outcome was not associated with GPDs in our current study, GPDs were strongly associated with NCSz and NCSE.
The earliest observations of GPDs encompassed the original descriptions of SSPE,1,2
as well as their almost pathognomonic presence in the setting of rapidly progressive dementia and myoclonus in sporadic CJD.20,21
Other specific etiologies have included phencyclidine or ketamine toxicity, anesthetic use, and barbiturate overdose.21
GPDs may occur in hepatic and renal disease, CNS infection (herpes simplex encephalitis), hypoxic-ischemic encephalopathy, hypoglycemia, hyperosmolarity, Alzheimer disease, steroid-responsive encephalopathy and autoimmune thyroiditis (or Hashimoto), or with medication toxicity: lithium, ifosfamide, and baclofen.16
Diffuse cerebral gray matter involvement may link these various associated etiologies. The classic pathologic study by Gloor et al.22
demonstrated that diffuse cortical and subcortical gray matter disease was required for the development of bilateral periodic epileptiform discharges; white matter involvement was incidental. Gloor et al. concluded that the electrophysiology reflects an abnormal system in which networks of damaged neurons (either cortical or subcortical) discharge and become aberrantly synchronized, thereby appearing generalized, with relatively fixed discharge intervals related to a prolonged refractory period.
Subsequent to the work of Gloor et al., animal experiments have suggested periodic epileptiform discharges may represent the EEG correlate of dying neurons.23
Alternatively, a hypothetical progression of CSE culminating in a final stage of coma and periodic epileptiform discharges representing ongoing ictal activity has been termed “subtle status epilepticus.”24
As the term has been used in many clinical situations and for many forms of SE without major convulsive movements, we have instead suggested the more specific “status epileptics terminans” for this final smoldering stage of SE.25
These seemingly disparate interpretations of GPDs are not necessarily mutually exclusive. A parsimonious explanation is that periodic epileptiform discharges represent “a dynamic…state in which unstable neurobiological processes create an ictal-interictal continuum” linking neuronal injury to metabolic dysfunction in their pathophysiology.7
In the case of generalized periodic epileptiform discharges, it is possible that a subset may be unrelated to seizures (i.e., not on this ictal-interictal continuum at all), but simply represent the electrophysiologic correlate of metabolic encephalopathy.
GPDs vary in appearance from patient to patient and distinctions have been made based on the presence of slow-wave, spike-wave, or triphasic-appearing waves (TWs) in prior studies.9,10
In one, the amplitude and duration of GPDs were larger and the interdischarge amplitude preserved in patients who subsequently developed SE.9
However, waveform characteristics overlapped extensively, and the differences were not large enough to help at the individual patient level. Particularly in comatose patients, making morphologic distinctions between seizure-related GPDs (which lie along the ictal-interictal continuum) and metabolic encephalopathy-related GPDs (typically called “triphasic waves”) is difficult, if not impossible, in a given patient.9,26
Although some have attempted to use IV benzodiazepine response to help differentiate between the two, metabolic encephalopathy-related GPDs (without evidence of seizures) commonly resolve with benzodiazepines.27
Partly for these reasons, we did not exclude TWs from this study of GPDs. In fact, in our experience, the use of the term “TWs” rather than “GPDs” is related more to clinical history than the waveforms: several of our patients' cEEG reports used both terms at different times, sometimes for similar patterns, in the same 24-hour study. It is possible that some in our cohort had pure metabolic encephalopathy, which provides some limitation to this study. Only carefully designed prospective, blinded studies can address whether EEG alone can help distinguish “TWs” from other forms of GPDs, assuming that there is a fundamental difference. For now, it appears that regardless of morphology, GPDs reflect a common manifestation of a variety of pathologies and are highly associated with NCSz and NCSE.
There are a number of additional limitations to the current study. First, it is retrospective and based on chart review. Second, EEG characteristics, while described by a small group of board-certified electroencephalographers, are prone to low interobserver reliability; standardization of EEG terminology should ultimately remedy this.12
Third, we did not account for specific anesthetic cIV medications, newer AED medications, or clinical response to AEDs. Finally, care of the patients was heterogeneous depending on the setting and nature of the illness, which may have led to different outcomes. Particularly in critically ill patients, withdrawal of care may be a significant determinant of outcome, but was not specifically addressed.
Further questions remain to be answered. Is there a role for AEDs in patients with GPDs before development of unequivocal seizures? Is there any role for attempting to suppress GPDs? Are there subgroups in which GPDs provide independent prognostic information such as after CA9,28,29
? Specific morphologic characteristics of the waveforms need to be studied prospectively and, specifically with regard to cEEG, should be re-evaluated to refine terminology. The American Clinical Neurophysiology Society (ACNS) Subcommittee on Research Terminology for Continuous EEG Monitoring12
provides a framework for the study of periodic epileptiform discharges in the future.
GPDs were highly associated with NCSz and NCSE, but had no definite independent prognostic value. Treatment of the underlying etiology and careful monitoring for and treatment of NCSE are the most important considerations in the care of patients with GPDs. Patients with GPDs should undergo cEEG to identify NCSE, which is independently associated with worse outcome in patients with and without GPDs. We believe aggressive treatment of GPDs should be reserved for cases in which there is definite NCSE based on evolving EEG patterns or clinical features, or if there is evidence of ongoing neuronal injury.30–32