Triphasic Waves: Swinging the Pendulum Back in this Diagnostic Dilemma

Commentary

Response Rates to Anticonvulsant Trials in Patients with Triphasic-Wave EEG Patterns of Uncertain Significance.

O'Rourke D, Chen PM, Gaspard N, Foreman B, McClain L, Karakis I, Mahulikar A, Westover MB. Neurocrit Care 2016;24:233–239.

BACKGROUND: Generalized triphasic waves (TPWs) occur in both metabolic encephalopathies and non-convulsive status epilepticus (NCSE). Empiric trials of benzodiazepines (BZDs) or non-sedating AED (NSAEDs) are commonly used to differentiate the two, but the utility of such trials is debated. The goal of this study was to assess response rates of such trials and investigate whether metabolic profile differences affect the likelihood of a response. METHODS: Three institutions within the Critical Care EEG Monitoring Research Consortium retrospectively identified patients with unexplained encephalopathy and TPWs who had undergone a trial of BZD and/or NSAEDs to differentiate between ictal and non-ictal patterns. We assessed responder rates and compared metabolic profiles of responders and non-responders. Response was defined as resolution of the EEG pattern and either unequivocal improvement in encephalopathy or appearance of previously absent normal EEG patterns, and further categorized as immediate (within <2 h of trial initiation) or delayed (>2 h from trial initiation). RESULTS: We identified 64 patients with TPWs who had an empiric trial of BZD and/or NSAED. Most patients (71.9%) were admitted with metabolic derangements and/or infection. Positive clinical responses occurred in 10/53 (18.9%) treated with BZDs. Responses to NSAEDs occurred in 19/45 (42.2%), being immediate in 6.7%, delayed but definite in 20.0%, and delayed but equivocal in 15.6%. Overall, 22/64 (34.4%) showed a definite response to either BZDs or NSAEDs, and 7/64 (10.9%) showed a possible response. Metabolic differences of responders versus non-responders were statistically insignificant, except that the 48-h low value of albumin in the BZD responder group was lower than in the non-responder group. CONCLUSIONS: Similar metabolic profiles in patients with encephalopathy and TPWs between responders and non-responders to anticonvulsants suggest that predicting responders a priori is difficult. The high responder rate suggests that empiric trials of anticonvulsants indeed provide useful clinical information. The more than twofold higher response rate to NSAEDs suggests that this strategy may be preferable to BZDs. Further prospective investigation is warranted.

The nature, origin, and etiology behind the generation of triphasic waves (TW) have occupied neurophysiologists for decades. This seemingly clear and self-descriptive—yet elusive—term has given us reassurance and uncertainty intermittently over the years as it has evolved from being associated with very specific metabolic conditions to being widely associated (in a less specific manner) to a diverse group of conditions ranging from metabolic, autoimmune, toxic or degenerative encephalopathies, postictal states, and active ictal manifestations.

TW are defined by their typical morphology, characterized by a predominant surface positive wave, preceded and followed by smaller surface negative deflections, conferring them a triphasic appearance. The contour of the waves is blunt and broad, not easily mistaken for epileptiform interictal discharges. Other characteristics of the pattern include their periodic presentation (1–2.5 Hz) and generalized distribution, usually showing a geographic time lapse from anterior to posterior in bipolar longitudinal montages. TW are often overriding abnormal and slow EEG background activity. They are seen only in adult humans, notoriously absent in children and animal models.

TW were first described in 1955 by Brickford and Butt (1), and the controversy about their meaning keeps going to this day. Their initial and best known association is with hepatic encephalopathy. TW were not only considered a phenomenon pathognomonic to the condition but were associated with a very specific stage within the progression of the disease and closely related to elevated ammonia levels (2). Later studies have highlighted the likely coexistence of structurally diffuse white matter lesions in combination with metabolic abnormalities of diverse etiology that results in this very specific pattern (3).

With the ubiquitous use of continuous video EEG (CVEEG) within the intensive care setting, we have also become progressively aware of the presence of subclinical EEG seizures as the underlying cause of altered mental status in the critically ill population. Nonconvulsive status epilepticus (NCSE) is found in 8 to 20 percent (4) of critically ill patients with altered mental status and subclinical seizures in up to 10 to 50 percent (4, 5). Definite seizure patterns seen in the intensive care unit (ICU) include repetitive rhythmic spike or sharp wave discharges at a frequency >3 Hz or the abrupt appearance of evolving rhythmic activity. There are also EEG patterns of unclear significance; generalized periodic discharges (GPDs) is one such pattern. The clinical value of GPDs as a predictor or surrogate for epileptic seizures is uncertain (6, 7). Not surprisingly, GPDs (as have other periodic discharges) have been associated with increased mortality in the ICU. The most frequent substrate for the development of seizures and NCSE among the critically ill is the coexistence of an acute structural brain lesion in combination with infectious, metabolic, toxic, autoimmune, or respiratory abnormalities.

The questions remain: Are some or all TW a form of epileptic or ictal pattern in the critically ill? Are all GPDs, in the end, GPEDs (generalized periodic epileptiform discharges)?

Let's start by addressing how skillful we are in recognizing TW. In other words: Do we know them when we see them? Are we talking about the same thing when we read TW on EEGs? Some of the characteristics of EEG activity that can help differentiate GPEDs from TW include: 1) A sharper, more complex and narrower morphology; and 2) lack of response to stimulation. Both are more likely to be seen in the context of epileptiform discharges (8) than in TW. The Critical Care EEG Monitoring Research Consortium (CCEMRC) has undertaken the task of describing, analyzing, and classifying EEG patterns seen in critically ill patients without making assumptions regarding etiology or prognostic factors—the characteristics most likely to have clinically relevant significance and facilitate reliable interpretation. In relation to GPDs, they found a high interrater agreement (IRA) for the localization as “generalized” and the periodicity of the discharges but only fair IRA for the description as TW amongst 11 expert EEG readers (9).

O'Rourke et al. set themselves to answer this specific question through a retrospective model of a treatment trial. They reviewed the responses of 64 patients with EEGs interpreted as TW to a diagnostic/therapeutic challenge with benzodiacepines (BDZ) or nonsedating antiseizure medications (NSAEDs). They found 34.4% positive response to either drug or a combination of the treatments. Immediate responses were seen in 18.9% of the patients treated with BDZ and 6.7% of the patients treated with NSAEDs. A higher proportion (34.4%) of patients ultimately showed a positive response after a longer trial of BDZ or NSAEDs; however, as TW tends to be a fluctuating pattern; the course of patients in an intensive care setting, under appropriate care, is one of improvement over days. These delayed responses are difficult to interpret.

The study has limitations inherent to its design; however, it does make a point: Some of our critically ill patients with structural brain lesions and a combination of metabolic/infectious/toxic derangements are at risk for subclinical seizures and NCSE; in some, TW may be the EEG expression of the epileptic activity. Further, this is possible only because they used NSAEDs and took into account clinical improvement; the modification of TW patterns by the use of BDZ alone is frequent but likely represents a higher level of sedation and not clinical improvement.

It would be interesting to consider this question in a prospective way and have a control group that does not receive BDZ or NSAED, as long as the EEG shows no other interictal or ictal epileptiform abnormalities. This will require defining the responder time of the trial and also taking into account, in addition to metabolic markers, any medications known to be associated with GPDs, such as lithium, cefepime, and baclofen, among others.

It seems we are at risk of swinging the pendulum to the other extreme by suggesting all patients with TW need to have a BDZ/NSAED trial or that all TW (or GPDs) are GPEDs. It is pertinent to remember that AEDs are easy to start and difficult to stop, mostly when dealing with patients with chronic metabolic conditions and brain injury. The risks of acutely worsening the patient's condition with the introduction of medication they may not need—as well as the risk of overuse of long-term AEDs—are not trivial and include higher mortality and longer hospital stay, side effects, and medication interactions, along with psychosocial and economic consequences. In the absence of clinical seizures (most patients with GPDs never clinically seize), the goal for medication treatment and discontinuation will always remain uncertain.

In the end, TW are an EEG manifestation of encephalopathies of diverse etiologies; prognosis depends almost exclusively on the prognosis of the underlying cause. So, treating the pattern with sedation or specific antiepileptic medications may change the EEG pattern, but it solves the problem only when the ultimate cause of the encephalopathy is addressed. Sometimes, the cause of the encephalopathy is underlying seizures or NCSE and, in these cases, treatment trials are very well indicated.