Background

Electroencephalography (EEG) is a clinical neurophysiology tool used to evaluate cerebral cortex activity that possesses demonstrated efficacy for the diagnosis, monitoring, and prognosis of brain disorders in critically ill patients [1,2,3,4]. Guidelines of the International Federation of Clinical Neurophysiology and the American Society of Clinical Neurophysiology provide standardized methods for EEG recording and analysis in intensive care unit (ICU) patients [1, 5,6,7]. EEG analysis relies mainly on the analysis of basic parameters such as the dominant frequency of background activity and its continuity, reactivity to stimuli, and the symmetry and occurrence of paroxysmal activities [1, 2, 8,9,10,11]. Many abnormal EEG patterns predict a poor outcome in critically ill patients [11,12,13,14,15,16,17,18,19,20,21,22,23]. Several EEG scores have been described [2, 4, 22, 24,25,26]. Several studies point out that electroencephalographic reactivity (EEG-R) or the absence thereof was particularly useful for prognostication in patients with impaired consciousness [8, 27,28,29,30]. Although there is no consensus regarding the definition or the methods to use in assessing EEG-R, EEG-R could be defined as diffuse and transient changes in scalp recorded EEG activity in response to sensorial external stimuli. Such stimuli may be auditory (clap** and loudly calling the patient’s name), nociceptive (pinching of limbs or nipples, compression of the fingernails or of the periosteal surfaces of bones) [31], or visual (spontaneous or forced eye opening, intermittent photic stimulation) [29, 31,32,33,34,35,36,37,38,39]. The amplitude and/or frequency of EEG activity may change in response to external stimulation (Fig. 1). However, EEGs merely exhibiting stimuli-induced rhythmic, periodic, or ictal discharges [36] or muscle activity or eye blink artifacts are not considered as reactive by many authors [1, 5,6,7]. Because visual analysis of reactivity is prone to subjectivity [40,41,42], automated quantitative approaches have been proposed [37]. EEG-R to nociceptive, auditory, and/or photic stimulation requires the functional integrity of peripheral sensory pathways, the brainstem, subcortical structures, and the cerebral cortex. Absent EEG-R could therefore result from a severe dysfunction of any of these structures, precluding the cortical activation by the afferent somatosensory stimuli [43]. The importance of EEG-R in predicting patient outcome in postanoxic coma has been documented in many studies since the 1960s [14, 41, 44,45,46]. Lack of EEG-R has been shown to be of prognostic value in postanoxic, posttraumatic, or hepatic encephalopathies [3, 8, 16, 27,28,29, 47]. The present review highlights and discusses the mechanisms and particular usefulness of EEG-R for determining the prognosis of patients with impaired consciousness.

Fig. 1
figure 1

Example of a reactive electroencephalogram (EEG) following auditory stimulation (claps) of a patient with impaired consciousness. Upper: A 20-second epoch EEG sample showing a diffuse and synchronous slowing of the EEG background activity, appearing immediately after the auditory stimulus (claps) in an ICU patient with sepsis-associated encephalopathy. Recording: 20 mm/s, sensitivity: 10 μV/mm; filter settings: 0.5–70 Hz. Lower: EEG spectral power featuring topographic map** of power of each main EEG frequency band (delta, theta, and alpha) computed 10 seconds before and 10 seconds after the auditory stimulus onset (claps). EEG changes from a theta-dominant frequency (before stimulation) into a delta-dominant one (after stimulation). Higher-power values are shown in warm colors, and cool colors depict lower power

Full size image

Methods

We systematically searched the literature in the PubMed database for published reports pertaining to the use of EEG-R in outcome prediction in patients with impaired consciousness, from inception until March 2018, using the following search terms: (EEG reactivity OR electroencephalogram reactivity OR reactive EEG) AND (coma OR anoxic OR cerebral anoxia OR hypoxia OR post anoxic coma OR resuscitation OR cardiac arrest OR traumatic brain injury OR TBI OR encephalopathy OR unconscious OR vegetative state OR unresponsive wakefulness syndrome OR minimally conscious state) AND (outcome OR prognosis OR prognostication OR prediction OR predictive value OR mortality OR survival OR awakening). The search yielded 202 articles. Of these, we excluded non-English-language articles (n = 25) as well as those for which no full text was available (n = 28). Of the 149 remaining articles, we included 80 publications covering assessment of EEG-R and its impact on the prognosis of patients with impaired consciousness. Among these 80 publications were 17 review articles, 2 systematic reviews [32, 48], and 61 clinical investigation papers. We then carefully read and scrutinized all of these latter 61 articles.

Results

Data on the prognostic value of EEG-R in patients with impaired consciousness were explicitly reported in only 42 of the papers [8, 28, 30, 33, 37, 38, 44, 49,50,51,52,53,54,55,56,57,58,59,60,113, 114]. The reticular nucleus of the thalamus (RN) surrounds the rostral and lateral surfaces of the dorsal thalamus. The RN contains exclusively GABAergic neurons and, via extensive inhibitory outputs, modulates all incoming sensory information on its way to the cerebral cortex [115]. The RN therefore plays a critical role in controlling the firing patterns of ventroposterior thalamic neurons and is thought to play a critical role in controlling thalamocortical rhythm [116]. The RN plays a crucial role in selective attention and consciousness because it can inhibit the area of the thalamus from which the initial information came and can influence the flow of information between the thalamus and cortex [117]. Increases in low-frequency cortical power may be due to a shift in thalamic neuron activity from a state dominated by tonic firing to one in which there is an increase in low-threshold spike burst firing [118]. Low-threshold calcium bursts occur when thalamocortical relay cells are in a state of hyperpolarization; there is evidence that the RN is capable of entertaining this “burst-firing mode” [119], and it is argued that the RN serves to maintain the low-frequency thalamocortical oscillations (4–10 Hz) [120, 121]. Aberrations and alterations in these thalamocortical loops is characteristic of several central nervous system disorders, particularly disorders of consciousness [122], because human perceptions arise from ongoing activity within recurrent thalamocortical circuits [123]. The lack of EEG-R observed in critically ill patients may result from altered modulation of thalamocortical loop activity by the afferent sensorial input due to the neural impairment [118]. This unresponsiveness of the thalamocortical rhythm’s synchronization or desynchronization [107, 113, 124] to sensorial stimuli reveals cerebral impairment and is strongly associated with patient outcome [14, 16, 18, 72, 84]. Moreover, the same EEG pattern may have a different prognostic value, depending on the presence or lack of EEG-R [44, 46, 125].

Fig. 2
figure 2

Example of a nonreactive electroencephalogram (EEG) following painful stimulus (pinching) in a patient with impaired consciousness. Upper: A 20-second epoch EEG sample showing generalized pseudoperiodic discharges of spikes with no change after the painful stimulus (pinching) in a postanoxic ICU patient. Recording: 20 mm/s, sensitivity: 10 μV/mm; filter settings: 0.50–70 Hz. Lower: EEG spectral power featuring topographic map** of power of each main EEG frequency band (delta, theta, and alpha) computed 10 seconds before and 10 seconds after the painful stimulus. No significant EEG frequency band power change was observed after the painful stimulus. Higher-power values are shown in warm colors, and cool colors depict lower power

Full size image
Fig. 3
figure 3

Schematic representation of pathways that convey somatosensory and auditory information to the cerebral cortex. The dorsal column-medial lemniscus system (solid black line), anterolateral-extralemniscal system (broken line), and auditory-lateral lemniscal system (orange colored solid line) are shown

Full size image

Most studies of EEG-R do not mention the exact time at which reactivity was evaluated; however, it is well known that EEG features may change during the acute stage, especially in the first 24–48 hours after cardiac arrest [75, 126, 127]. The impact of the recovery of EEG-R on patient prognosis was recently demonstrated by Bagnato et al. [33], who reported that only patients with consciousness improvement showed the reappearance of EEG-R. Nine of the 16 patients with consciousness improvement, corresponding to 81.9% of patients who did not show EEG-R at admission, had reappearance of EEG-R at the 6-month follow-up. On the contrary, none of the patients without consciousness improvement showed reappearance of EEG-R. Repeated standard EEG or continuous EEG monitoring is then recommended in order to closely follow trends of the EEG changes in acute patients [27, 128,129,130].

It should be mentioned that EEG background activity and SSEPs are other neurophysiological parameters with robust outcome-predictive values in patients with impaired consciousness [1, 128, 131]. EEG background activity reflects spontaneous global cerebral functioning. It usually worsens by slowing down, decreasing amplitude, flattening, and discontinuing according to the severity of brain dysfunction [1, 5]. Worsened EEG background activity has been associated with unfavorable outcome in several studies [26, 75, 85, 130, 132]. Reduced EEG amplitudes and delta frequencies correlated with worse clinical outcomes, whereas alpha frequencies and reactivity correlated with better outcomes in patients with disorders of consciousness admitted for intensive rehabilitation [50]. Low-voltage or flat EEG background activity, burst suppression, and burst suppression with identical bursts are constantly associated with unfavorable outcome in postanoxic coma patients [75, 130, 132]. Spontaneously discontinuous background predicted unfavorable outcome with a false-positive rate of about 7% (95% CI, 0–24%) [16], whereas a continuous background predicted awakening with positive predictive values of 92% (95% CI, 80–98%) [133] and 72% (95% CI, 55–88%) [75]. SSEPs explore the functional integrity of the somatosensory pathways from the peripheral level to the cortical one through the brainstem and subcortical levels. The ability of absent SSEPs to detect patients at risk for poor neurological outcome appears to be robust [134]. Bilateral absent cortical components of SSEPs were associated with no awakening in anoxic coma, but normal SSEPs had less predictive capacity in the same cohort [135] because only 52% of patients with normal SSEPs awoke from coma [135]. In patients with TBI, normal SSEPs after TBI are associated with a 57% chance of good recovery, whereas bilateral absent SSEPs are associated with only a 1% chance of functional recovery [135, 136]. When combined with absent EEG-R, the prognostic value of SSEPs further increased [137]. Although there is no systematic study comparing the prognostic value of EEG background activity, SSEP, and EEG-R, available data and guidelines suggest that a combined multimodal assessment with these tests increases the accuracy of outcome prediction in patients with impaired consciousness [5, 128, 138,139,140].

Conclusions

This review emphasizes that whatever the etiology, patients with impaired consciousness featuring a reactive EEG are more likely to have favorable outcomes, whereas those with a nonreactive EEG are prone to unfavorable outcome. EEG-R is, then, a valuable prognostic parameter and warrants a rigorous assessment. However, current assessment methods are heterogeneous, and no consensus exists. Standardization of stimulation and interpretation methods is needed. Furthermore, it should be stated that all other EEG basic parameters, such as the dominant frequency or the continuity, warrant assessment in order to provide a fully integrated interpretation.