Elsevier

The Lancet Neurology

Volume 18, Issue 6, June 2019, Pages 600-614
The Lancet Neurology

Review
Therapeutic interventions in patients with prolonged disorders of consciousness

https://doi.org/10.1016/S1474-4422(19)30031-6Get rights and content

Summary

The management of patients with severe brain injuries and prolonged disorders of consciousness raises important issues particularly with respect to their therapeutic options. The scarcity of treatment options is challenged by new clinical and neuroimaging data indicating that some patients with prolonged disorders of consciousness might benefit from therapeutic interventions, even years after the injury. Most studies of interventions aimed at improving patients' level of consciousness and functional recovery were behavioural and brain imaging open-label trials and case reports, but several randomised controlled trials have been done, particularly focused on the effects of drugs or use of non-invasive brain stimulation. However, only two studies on amantadine and transcranial direct current stimulation provided class II evidence. Although new therapeutic approaches seem to be valuable for patients with prolonged disorders of consciousness, optimised stimulation parameters, alternative drugs, or rehabilitation strategies still need to be tested and validated to improve rehabilitation and the quality of life of these patients.

Introduction

A lot of work has been done on the accurate diagnosis of patients with disorders of consciousness1, 2 to establish prognostic indicators3, 4 and to understand the neural correlates of consciousness.5 This work is crucial because misdiagnosis can lead to important medical decisions, such as withdrawal of life-sustaining care.6 Disorders of consciousness include coma (unwakefulness, reflex behaviours only), unresponsive wakefulness syndrome (previously known as vegetative state; wakefulness but reflex behaviours only), and minimally conscious state (clinical demonstration of signs of consciousness).7, 8 Once patients recover functional communication or object use, they emerge from the minimally conscious state. Additional entities have been proposed when dissociation occurs between clinical diagnosis and neuroimaging results showing atypical brain activation, including minimally conscious state* and cognitive motor dissociation (panel 1; figure 1).14, 18 Patients who have recovered from coma can remain severely disabled for several months, years, or even decades.

With regards to therapeutic options, only a few studies have investigated the treatment of patients with disorders of consciousness. Following a landmark paper on amantadine in 2012,22 this field has evolved rapidly, with new therapeutic approaches being tested and reported, but patients' clinical management remains challenging, mostly because these patients cannot communicate and are dependent on others for care. The 2018 American practice guidelines for patients with disorders of consciousness23 only recommend amantadine for patients with unresponsive wakefulness syndrome and minimally conscious state 4–16 weeks after a traumatic brain injury on the basis of one randomised controlled trial.22 Given that the guidelines were developed on the basis of strict inclusion and exclusion criteria (eg, a minimum of 20 patients included, all at least 28 days after injury), many studies failed to meet their inclusion criteria and were not reported in these recommendations. In this Review, we critically evaluate the available therapeutic options for patients with prolonged disorders of consciousness (ie, more than 28 days) that have been studied in the past 6 years. We discuss pharmacological and non-pharmacological interventions with the strongest evidence and for which robust randomised controlled trials have been published. If no randomised controlled trials were available, we present open-label studies and anecdotal case reports with careful interpretation, because they might still provide insightful results to guide future research. We also report neuroimaging and neurophysiological results associated with positive treatment responses.

Section snippets

Pharmacological treatments

Amantadine (dopamine agonist and NMDA antagonist),22, 24, 25, 26 intrathecal baclofen (GABA agonist),27 zolpidem (non-benzodiazepine GABA agonist),28, 29, 30, 31, 32 midazolam (benzodiazepine GABA agonist),33 and ziconotide (calcium channel blocker)34 have been used to improve consciousness and functional recovery in patients with disorders of consciousness.

Non-pharmacological interventions

Non-pharmacological interventions have also been attempted to improve consciousness and functional recovery in patients with disorders of consciousness. These include non-invasive brain stimulations (eg, transcranial direct current stimulation, repeated transcranial magnetic stimulation, transcutaneous auricular vagal nerve stimulation, and low intensity focused ultrasound pulse), invasive brain stimulation (ie, deep brain stimulation or vagal nerve stimulation), and sensory stimulation

Transcranial direct current stimulation

A double-blind randomised controlled trial59 tested the effect of prefrontal transcranial direct current stimulation (ie, anode over the left dorsolateral prefrontal cortex for 20 min at 2 mA) on 55 patients, both in acute and prolonged disorders of consciousness (1 week to 26 years after injury). At the group level, behavioural improvements, as measured by the Coma Recovery Scale-Revised,46 were reported for patients in a minimally conscious state, but not for those with unresponsive

Invasive brain stimulation

A 7-year well-designed prospective open-label study89 on the effects of deep brain stimulation of the thalamic reticular nuclei in patients with disorders of consciousness (>6 months after injury) reported that only five (13%) of 40 patients met the inclusion criteria (eg, EEG desynchronised activity <5% of the recorded time, somatosensory and auditory evoked potentials evoked on at least one side). Of the five eligible patients, two did not receive surgery owing to issues with the legal

Sensory stimulation programmes

Stimulation programmes include, among others, motor-based therapy, auditory-based training, music therapy, and multi-sensory training programmes.

In a single-blind randomised controlled trial,86 the effects of conventional tilt table and its combination with a stepping device were assessed in 50 patients with disorders of consciousness (1–6 months after injury). Behavioural improvements were reported in both groups at the end of the 3-week intervention period and at the 3-week follow-up. No

Conclusions and future directions

Management of patients with disorders of consciousness is challenging because of the absence of communication, the scarcity of interaction with their environment, and their severe motor disability. Adapted therapeutic approaches that do not require patients' active participation need to be developed rapidly. Present findings suggest that some patients might benefit from rehabilitative interventions,62, 86, 87 even years after the brain injury.59, 63, 65 As highlighted in the American practice

Search strategy and selection criteria

We searched PubMed for articles published in English between Jan 1, 2013, and Oct 31, 2018, using the following search terms: “disorders of consciousness”, “vegetative state”, “unresponsive wakefulness syndrome” or “minimally conscious state”, and “therapy”, “treatment”, “therapeutics”, “revalidation”, or “drugs”. Of 558 papers, 45 matched our inclusion criteria: clinical trial, open label study, observational study, and case report using validated behavioural tools to evaluate therapeutic

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