EEG to detect early recovery of consciousness in amantadine-treated acute brain injury patients

INTRODUCTION

Disorder of consciousness (DOC) is common in patients with acute brain injury (ABI) and it weighs heavily in goals of care discussion.¹ Dopaminergic agents to support recovery have shown encouraging results in chronic DOC following traumatic brain injury (TBI) and are currently the most promising candidates to also support recovery during the acute post injury phase.² Amantadine is a neurohormonal modulator that increases the concentration of dopamine at the synaptic cleft. Behavioural assessments of consciousness alone are often operator dependent, time consuming to obtain and may miss patients with covert consciousness.³ Our hypothesis is that resting Electroencephalogram (EEG) features follow a predictable course preceding behavioural recovery in patients with acute non- hypoxic-ischaemic brain injury receiving amantadine and may serve as biomarkers for recovery of consciousness.

METHODS

We studied 44 patients with ABI that were not following commands and were on EEG monitoring before and after the start of amantadine. A full description of the methods is available in the online supplementary file.

RESULTS

Study cohort

From a cohort of 44 patients, 30 (68%) recovered consciousness prior to hospital discharge (online supplementary tables S1, S2).

Baseline predictors of recovery

Age, focal versus diffuse brain injury and admission Glasgow Coma Score were not associated with recovery of command following. Presence of sleep structures in the EEG (spindles and K-complexes) prior to starting amantadine was independently associated with recovery of command following (online supplementary table S3). Average spectrogram plots for each EEG recording classified according to the ‘ABCD’ model representing thalamocortical integrity were generated (figure 1A, online supplementary figure).⁴ The percent of patients that recovered command following did not increase hierarchically with higher ‘ABCD’ levels (figure 1B). Power spectral density analysis of the EEG prior to starting amantadine revealed higher frontocentral gamma and beta frequencies for patients that recovered command following (figure 1C).

Figure 1.

(A) ‘ABCD’ patterns representing the thalamocortical integrity. Caption: thalamocortical integrity according to the ‘ABCD’ model. ‘A’ type represents a complete loss of corticothalamic integrity (<4 Hz frequencies only). ‘B’ type represents a low level of afferent input to neocortical neurons resulting in oscillations of layer V pyramidal cells in the frequency range of theta—arrow—(5–7 Hz frequencies). ‘C’ type represents a deafferented thalamus fires in burst mode and the afferent volley of synaptic activity with intact neocortical regions ‘thalamo-cortical dysrhythmia’—first and second arrows—(theta and beta frequencies). ‘D’-type spectrum represents a normal corticothalamic integrity with a normal firing of the thalamus and normal resting cortical oscillations—arrow—(alpha and beta frequencies). Patterns ‘A’ and ‘B’ are examples of two patients who did not recover consciousness prior to discharge. Patterns ‘C’ and ‘D’ are examples of two patients who recovered consciousness prior to discharge. (B) recovery of command following among patients using the ‘ABCD’ model. Caption: distribution of recovery of command following among different ‘ABCD’ patterns at baseline, days 1–7, more than 7 days after starting amantadine, and the best ‘ABCD’ pattern during admission. the ‘A’ type represents a complete loss of corticothalamic integrity (<4 Hz frequencies only). the ‘B’ type represents a low level of afferent input to neocortical neurons resulting in oscillations of layer V pyramidal cells in the frequency range of theta (5–7 Hz frequencies). the ‘C’ type represents a deafferented thalamus firing in burst mode and the afferent volley of synaptic activity with intact neocortical regions ‘thalamo- cortical dysrhythmia’ (theta and beta frequencies). the ‘D’-type spectrum represents a normal corticothalamic integrity with a normal firing of the thalamus and normal resting cortical oscillations (alpha and beta frequencies). (C) Averaged power spectral density maps prior to starting amantadine Caption: averaged power spectral density maps for beta (right side) and gamma (left side) before starting amantadine in patients who recovered command following versus patients who did not. the statistically significant difference (p<0.05) electrodes are circled.

Amantadine response

Age and the cumulative dose of amantadine were independently associated with recovery of command following. Sleep features on EEG at any time and development of a posterior dominant rhythm (PDR) after starting amantadine were associated with recovery of command following. Increases in the PDR frequency were not associated with recovery of consciousness (online supplementary table S4). Presence of PDR, sleep structures, reactivity to stimulation and absence of epileptiform discharges during admission were only associated in the univariate analysis (online supplementary table S2). Seven days after starting amantadine, a pattern indicating higher levels of anterior forebrain corticothalamic integrity (patterns ‘C’ and ‘D’) emerged for those patients with later behavioural recovery (figure 1B). The best recorded ‘ABCD’ score tracked with a hierarchical increase of the percentage of patients that would ultimately follow commands from 50% for pattern A to just below 80% for pattern D. All patients indicating a high degree of thalamocortical integrity (patterns ‘C’ and ‘D’) documented after 7 days of amantadine recovered command following prior to discharge. A full description of the results is available online supplementary file.

DISCUSSION

Our data suggest that EEG may be a promising biomarker for recovery of in-hospital command following in patients with ABI who are treated with amantadine. Baseline EEG findings such as sleep structures and higher frequency frontocentral power (beta- gamma spectrum) may allow patient selection following ABI in clinical practice and in future clinical trials. In addition to the cumulative amantadine dose, improved thalamocortical integrity on follow- up EEGs tracks with clinical recovery of command following.

The largest trial to date evaluating the effectiveness of amantadine in improving recovery from vegetative (vs) and minimally conscious states was conducted in patients with TBI 4–16 weeks after the injury. The study identified faster recovery measured by the disability rating scale during a 4- week period of amantadine therapy. However, during a 2- week washout period, a slower recovery rate was seen in the amantadine group compared with placebo.² This slower recovery on amantadine discontinuation was also seen in another randomised controlled study.⁵ Neither study used EEG. Case reports have implicated background changes and decreased slowing on EEG in unconscious patients treated with amantadine.

In the present study, we found that the presence of a PDR prior to the start of amantadine was associated with a higher chance of command following prior to discharge. We did not see an increase in PDR frequencies to be associated with recovery of command following during amantadine treatment. Our ‘ABCD’ model was consistent with predominantly higher frequencies in those who recovered command following. Thalamocortical connectivity may not be static and can be detected by spectrogram analysis of the EEG. The fact that we found transition between the hierarchical scale of EEG patterns to correlate with behavioural recovery supports that re- establishing thalamocortical connectivity during recovery in patients treated with amantadine administration may be detected by an EEG biomarker.

Limitations

First, the EEG data were limited by the retrospective nature of the study and the EEG indication which may lead to a selection bias. Second, our cohort did not include a comparative group without amantadine treatment. However, the study highlights the potential use of EEG as a biomarker for recovery of consciousness in patients receiving amantadine. Third, the duration of treatment in our study was relatively short when compared with the treatment duration in the randomised control trial by Giacino et al.² Fourth, command following was assessed as surrogate for recovery of consciousness.³ Fifth, the relatively small sample size limited our ability to control for confounders in this cohort of patients who had predominantly stroke. In summary, this study suggests the potential use of EEG characteristics as a biomarker for recovery of consciousness in patients with ABI receiving amantadine. Further prospective studies with serial EEG recording and longitudinal behavioural assessments are needed to verify and extend our findings.