Continuing Education Activity

Triphasic waves are abnormal electroencephalogram (EEG) waveforms seen with a multitude of clinical conditions including encephalopathy and structural brain lesions. They are non-specific, high amplitude, sharply contoured waves with a unique morphology. They were believed to be pathognomonic of hepatic encephalopathy. However, they can be seen with any metabolic encephalopathy and many other conditions. This activity reviews the evaluation and management of triphasic waves and highlights the role of the interprofessional team in evaluating and treating patients with this EEG finding.

Objectives:

• Identify the significance and key concepts of triphasic waves on an EEG.
• Describe the differential diagnosis of triphasic waves.
• Outline the clinical significance of triphasic waves on an EEG and the management of potential underlying etiologies.
• Review interprofessional team strategies for improving care coordination and communication to advance the management of patients with triphasic waves and improve outcomes.

Introduction

Triphasic waves are abnormal electroencephalogram (EEG) waveforms seen in association with multiple clinical conditions, including encephalopathy and structural brain lesions, among others. They are nonspecific, high amplitude sharp/sharply contoured waves with three distinctive phases. The main phase is surface positive with a high amplitude (greater than 70 microvolts), preceded by a low amplitude negative deflection and followed by a slow rising broad negative deflection. They were initially believed to be pathognomonic of hepatic encephalopathy; however, they can be seen in any metabolic encephalopathy (in fact, more common with renal than hepatic conditions) and some other conditions. They may be considered a subset of generalized periodic discharges (GPDs).[1][2]

This EEG pattern was first described by Foley in 1950. It was an EEG recording of a patient with hepatic encephalopathy. The author described the waveforms as "blunted and spike waves."[3] There is an abundance of literature in the 1950s on this topic, and most of the literature then suggested this finding to be specific to hepatic encephalopathy. It was felt to represent high mortality with severe liver conditions like portal cirrhosis, metastatic liver disease, infective hepatitis, etc.[4] At that time, EEG was used to diagnose early stages of hepatic encephalopathy and as a tool to guide treatment with medications like neomycin. The term triphasic waves was first coined in 1955 by Bickford and Butt, given the three-phase morphology.[5]

Issues of Concern

Pathophysiology: Triphasic waves are not seen in a normal awake state and are only seen in patients with altered levels of consciousness. It is hypothesized that they occur due to structural or metabolic abnormalities affecting the thalamocortical relays.[6]

EEG Characteristics: These waveforms have 3 phases with a total duration of 300 to 600 milliseconds. They are high amplitude, sharply contoured waves, with the duration of each phase longer than the next. The first phase is always negative; the second wave is positive, displaying the highest amplitude (greater than 70 microvolts), with a third slow negative deflection. The triphasic waves usually repeat periodically at a rate of 0.5 Hz to 2 Hz. They are seen diffusely with synchronous bifrontal and central predominance and display a fronto-occipital time lag.[7][8]

Atypical triphasic waves: Distinguishing triphasic waves from ictal EEG patterns has always been a topic of discussion and concern for experts. This led to reports by different authors of typical and atypical (likely epileptic) triphasic waves. Atypical features include localization (bifrontal/frontopolar, parietal, and temporal predominance in epileptiform triphasic waves as opposed to frontocentral with typical triphasic activity), contour (a more blunt contour with typical triphasic activity) and duration (around 300 milliseconds with typical triphasic and less than 200 milliseconds with epileptiform or atypical triphasic activity). Typical triphasic waves can be altered by external stimuli (EEG reactivity) and usually display a fronto-occipital delay.[9][1]

Etiology: The most common cause of triphasic waves is encephalopathy, which could be related to metabolic, toxic, or other etiologies illustrated in the list below.[10][6][11][12][13]

1. Ictal or postictal state
2. Serotonin syndrome
3. Maple syrup urine disease
4. Naproxen overdose
5. Lithium toxicity
6. Antibiotics such as cefepime
7. Hyperthyroidism
8. Hypothyroidism
9. Hepatic encephalopathy
10. Hypernatremia
11. Hyponatremia
12. Hypercalcemia
13. Hypoglycemia
14. Pregabalin toxicity
15. Hyperosmolar state
16. Azotemia

Structural abnormalities can also cause triphasic waves. These were first described by Aguglia in 1990.[14] These patients do not usually have asterixis, given the absence of significant metabolic derangements. The structural abnormalities associated EEG triphasic waves include: 

1. Cerebral abscess
2. Thalamic gliomas
3. Craniopharyngioma
4. Pontine stroke
5. Cerebral carcinomatosis
6. Multifocal cerebral lymphoma
7. Creutzfeldt-Jakob disease (CJD)
8. Alzheimer and other neurodegenerative diseases
9. Head trauma
10. Subdural hematoma
11. Carcinomatous meningitis

Differential Diagnosis: Multiple EEG abnormalities can mimic triphasic waves. Despite the presence of certain EEG characteristics that can help differentiate typical triphasic waves from other waveforms, EEG and clinical expertise are warranted. Typical triphasic waves may be difficult to be clearly differentiated from nonconvulsive status epilepticus (NCSE), especially if the frequency is higher than 1 Hertz.[15][1] Administration of benzodiazepines (BZD) or, more importantly, non-sedating anti-seizure medications (NSASMs) can help differentiate NCSE from typical triphasic waves.[16][17]

The following are some of the normal and abnormal EEG waveforms that could mimic triphasic waves:    

1. Nonconvulsive status epilepticus (NCSE)
2. Interictal epileptiform discharges (IED)
3. Generalized spikes and waves
4. generalized periodic discharges (GPDs)
5. Lateralized periodic discharges (LPDs)
6. Bilateral independent periodic discharges (BIPDs)
7. Diffuse slowing
8. 6 Hz spike and wave (phantom spike and wave) 
9. Wicket waves (Wicket Rhythm)
10. Rhythmic mid-temporal theta of drowsiness (RMTD)
11. Subclinical rhythmic electroencephalographic discharges of adults (SREDA)

Workup: Neuroimaging, preferably a brain magnetic resonance imaging (MRI) scan, is warranted when no clear evidence of encephalopathy is established. A hyperintense T1 signal in globus pallidus can be found in patients with hepatic encephalopathy. As described above, non-metabolic etiologies can lead to triphasic EEG waves and should be suspected in the absence of metabolic encephalopathy. Additional workup must be directed towards possible underlying etiologies. A complete blood count and a comprehensive metabolic panel will be very helpful to evaluate for renal and liver functions and infectious and electrolyte abnormalities. When appropriate, a toxicology screen to evaluate for toxic metabolites contributing to encephalopathy must be obtained. Blood levels of home medications must be considered, specifically the antiepileptic and antipsychotic medications. Repeat EEG is often recommended, especially in the absence of clinical improvement. Long-term video EEG monitoring is considered particularly in the setting of atypical triphasic waves or when considering medical treatment with BZD or NSASM if an NCSE is suspected (with NCSE, both clinical and electrographic improvements or appearance of previously absent, normal EEG background activity, should be documented prior to confirmation of the diagnosis). Differentiating GPDs with triphasic morphology from GPDs without triphasic morphology is sometimes difficult, but the interrater agreement between competent electroencephalographers is very high. A longterm EEG is needed at times in such cases.[17][18] 

Prognosis: Sutter et al. conducted a 9-year cohort study to evaluate the significance of triphasic EEG waves in patients with acute encephalopathy presenting to Johns Hopkins Bayview Medical Center. High odds of death were found in the presence of non-reactive EEG patterns, which is a new finding not reported previously. A trend suggested that patients with reversible conditions did better than patients with underlying structural brain pathologies. Most of the studied patients turned out to have more than one underlying condition, with a third displaying a neuroradiological finding.[2] 

Treatment: Typical triphasic waves do not require treatment, but rather treatment must be directed toward the etiology. With hepatic encephalopathy, treatment must be directed toward identifying and treating precipitating factors that cause hepatic encephalopathy. In addition, medications like lactulose to lower ammonia are important as it draws the ammonia into the colon and promotes excretion.[19] Supportive care and correction of electrolyte abnormalities and treatment of infectious etiologies as appropriate can help with the resolution of triphasic waves. Triphasic waves can also be used as a guide for treatment in addition to laboratory workup.

Clinical Significance

It is important to identify triphasic waves and differentiate them from normal EEG variants and other abnormal EEG waveforms. The absence of asterixis in a patient with triphasic waveforms must warrant neuroimaging to evaluate for structural abnormalities, which can cause triphasic waves. It is important to understand that triphasic waves are not specific to any disease or pathology. These waveforms may also be seen in association with subclinical status epilepticus. Hence, careful consideration must be made to evaluate for subclinical status epilepticus and to follow other EEG guidelines, including rhythmicity, change in morphology, evolution, and correlation with clinical changes.[8] Response to stimulation methods routinely utilized in unresponsive patients like nailbed pressure, etc., must be used when reviewing the EEG tracings as it affects prognosis. When triphasic waves are noted on the EEG, they must always be clinically correlated. When triphasic waves are present in an individual with acute encephalopathy, it often indicates a more significant impairment and prolonged hospital course. Non-reactive EEG patterns with triphasic activity in patients presenting with acute encephalopathy are associated with increased odds of mortality. When patients with severe encephalopathy have generalized periodic discharges (GPDs), long-term EEG monitoring should be considered at times to exclude seizures.[18]  

Enhancing Healthcare Team Outcomes

Identification and management of patients with triphasic EEG activity require an interprofessional team approach involving EEG technicians, nurses, and physicians of different specialties (neurologists, intensivists, emergency physicians, and others). An interprofessional team approach could help improve outcomes for patients with accurate identification and treatment of underlying pathology. The education of the caregivers managing such patients is equally important. Adequate training in the interpretation of EEG and triphasic waves will help the clinical team to provide optimal care for these patients.