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 Table of Contents  
REVIEW
Year : 2022  |  Volume : 1  |  Issue : 2  |  Page : 57-79

A scoping review of treatments for the vegetative and minimally conscious states


School of Nursing, MGH Institute of Health Professions, Boston, MA, USA

Date of Submission01-Jun-2022
Date of Decision07-Jun-2022
Date of Acceptance14-Jun-2022
Date of Web Publication29-Jun-2022

Correspondence Address:
John Wong
School of Nursing, MGH Institute of Health Professions, Boston, MA
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2773-2398.348252

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  Abstract 


Disorders of consciousness (DoC) including the vegetative state, now known as unresponsive wakefulness syndrome, and the minimally conscious state lead to profound disability among affected individuals while placing a major burden on health care facilities, the economy, and society. Efficacious treatment strategies are necessary to alleviate these strains, but standardized, evidence-based protocols for the treatment of DoC are lacking. Progress towards this end remains difficult when considering the current dearth of comprehensive scoping review articles to organize and present the existing literature. The present scoping review seeks to fill this gap while presenting an up-to-date comprehensive compilation of current treatment strategies and their efficacy for vegetative state/unresponsive wakefulness syndrome, and minimally conscious state. To accomplish this, an examination of the existing literature between 2011 and 2021 was conducted using the PubMed database to compile and present current treatment strategies and their efficacy amongst patients in vegetative state/unresponsive wakefulness syndrome and minimally conscious state. Of the 112 articles collected, 32 reported successful treatment, 69 reported some incremental benefits of treatment, and 11 identified no benefit of treatment. Overall, sensory stimulation, transcranial direct current stimulation, transcranial magnetic stimulation, spinal cord stimulation, vagus nerve stimulation, rehabilitation programs, cranioplasty, and pharmacological treatments with zolpidem, amantadine, baclofen, midazolam, and clonazepam dose reduction coupled with neurorehabilitation were associated with successful treatment of DoC. Given the personal, societal, and economic burden associated with DoC, further research is warranted to determine and protocolize evidence-based strategies for effective treatment of those with DoC.

Keywords: disorders of consciousness; nervous system; pharmacological; rehabilitation programs; sensory stimulation; unresponsive wakefulness syndrome


How to cite this article:
Morris B, Wong J. A scoping review of treatments for the vegetative and minimally conscious states. Brain Netw Modulation 2022;1:57-79

How to cite this URL:
Morris B, Wong J. A scoping review of treatments for the vegetative and minimally conscious states. Brain Netw Modulation [serial online] 2022 [cited 2022 Aug 13];1:57-79. Available from: http://www.bnmjournal.com/text.asp?2022/1/2/57/348252




  Introduction Top


Disorders of consciousness (DoC) describe a spectrum of disorders that includes coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), and minimally conscious state (MCS) (Billeri et al., 2019). Coma is defined as a state of unconsciousness with a complete lack of awareness and wakefulness typically lasting less than 2–4 weeks at which point the patient either recovers or progresses into a VS/UWS or MCS (Mayo Clinic, 2020; National Health Service, 2021). VS/UWS is characterized as a condition of wakefulness with a complete lack of discernable conscious awareness of self and environment, while MCS is described as a condition of clear but minimal and variable signs of conscious environmental interaction in which the presence of at least one behavioral sign of consciousness is detectable (Giacino et al., 2012; Billeri et al., 2019; National Health Service, 2021). Further, a persistent or permanent vegetative state (PVS) is defined as VS lasting 6 months or more when caused by non-traumatic brain injury (TBI) or 12 months or more when caused by TBI (National Health Service, 2021). In the continuum of DoC, those in VS/UWS may improve to an MCS which has been further subdivided into MCS–, or MCS without language capabilities, and MCS+, or MCS with language capabilities (Edlow et al., 2021). Advancing along the DoC continuum is an emergence from MCS (EMCS) which is achieved with the recovery of functional object use as well as functional communication (Giacino et al., 2012).

DoC are caused by injury or damage to the brain in areas responsible for consciousness (National Health Service, 2021). Causes can be divided into TBI, non-TBI, and progressive brain damage (National Health Service, 2021). TBI occurs when the brain is damaged by an outside force or trauma such as in a fall, traffic accident, violent assault, sports related injury, or explosion (Mayo Clinic, 2020; National Health Service, 2021). On the other hand, non-TBIs are most often a result of cerebral hypoxia or conditions that attack the brain itself including stroke, myocardial infarction, meningitis, encephalitis, drug overdose, poisoning, drowning, suffocation, and aneurysm (National Health Service, 2021). Finally, progressive brain damage may take a more indolent course and is often caused by Alzheimer’s disease, Parkinson’s disease, and brain tumors (National Health Service, 2021). In a 2012 study across 15 Belgian neurorehabilitation expertise centers, the 1-year recovery from VS/UWS of traumatic etiology was 37% to 52%, while recovery from non-traumatic etiologies was 0% to 21% (Bruno et al., 2012). Older sources report that 50% of patients in a VS for at least 4 weeks will regain consciousness after 1 year (Levin et al., 1991). Patients in an MCS have a higher rate of recovery compared to VS though severe disabilities persist in approximately 50% of those who have recovered consciousness (Giacino and Kalmar, 1997; Lammi et al., 2005; Katz et al., 2009; Luauté et al., 2010).

Recommended therapeutic options for those in VS/UWS or MCS are scarce and often based on case reports. In fact, treatment with N-methyl-D-aspartate antagonist and indirect dopamine agonist, amantadine, was the only therapeutic option recommended by the American Practice Guidelines for DoC in 2018 (Giacino et al., 2012, 2018). These recommendations were limited to patients with traumatic VS/UWS or MCS between 4- and 16-week following injury and were found to be drug dependent with gains gradually dissipating upon discontinuation of treatment (Giacino et al., 2018). Within these 2018 American Practice Guideline recommendations, authors caution clinicians to recognize and understand the lack of sufficient evidence to support the use of many supposed treatment strategies that may result in harm to the patient without evidence of efficacy (Giacino et al., 2018). These recommendations, or lack thereof, underscore the shortage of evidence-based treatment strategies and the need for further research in this area.

While leading to profound disability among affected individuals, DoC place a major burden on health care facilities, the economy, and society at large leading to great resource utilization (Oldershaw et al., 1997; Eapen et al., 2017). To alleviate these strains, efficacious treatment strategies must be uncovered, protocolized, and implemented. Ongoing research is underway to further understand the mechanisms that govern these disorders and their often unpredictable recovery as well as possible treatment targets and strategies. Unfortunately, while technological advancements have been made, difficulties in precise diagnosis, prognostication, underlying mechanisms of disease, and therapeutic approaches persist and underlay the lack of standardized and proven treatment protocols among these patients. Among treatment strategies under investigation include sensory stimulation, transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), spinal cord stimulation (SCS), pharmacologic therapies, assistive technologies, rehabilitation programs, symptom management, music therapy, animal therapy, and use of personal objects. In this scoping review, we aim to present these currently available treatment strategies for patients with VS/UWS and MCS as well as to discuss their efficacy in recovery of consciousness.[143]


  Data and Methods Top


A scoping review of the literature to determine current treatment strategies for VS/UWS and MCS was conducted between September 15, 2021 and October 26, 2021 using the PubMed database. Articles were filtered for date of publication between 2011 and 2021. An electronic search of the database on PubMed was conducted using the keywords including “treatments for vegetative state,” “treatments for unresponsive wakefulness syndrome,” “treatments for minimally conscious state,” “treatments for disorders of consciousness,” “pharmacologic treatments for disorders of consciousness” to gather articles relevant to the present research question. Duplicate articles were removed and the remaining articles were assessed for inclusion and exclusion criteria to determine eligibility. Inclusion criteria included quantitative and qualitative controlled trials, randomized controlled trials, case reports, letters to the editor, and observational studies written in English, focusing on patients in VS/UWS or MCS, and discussing specific treatment strategies for PVS/VS/UWS and/or MCS. Articles were excluded if not in English, if the patient population included patients with a diagnosis of coma, TBI but not PVS/VS/UWS or MCS, if the patient population included pregnant women, and if an article was determined to be an opinion piece. After all articles were assessed for eligibility, 112 articles were included in the final analysis as shown in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram (Tricco et al., 2018) ([Figure 1] and Additional file 1[Additional file 1]). Data were then collected, reviewed, and categorized by research design, DoC studied, and treatment strategy. Finally, data were summarized to report and discuss findings that elucidate the currently available treatments and their efficacy for VS/UWS and MCS.
Figure 1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram.

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In this scoping review, treatment strategies were divided into three categories based on efficacy. First, ultimate success of treatment was defined as a change in clinical diagnosis from VS/UWS to MCS, MCS to EMCS, or a general emergence into consciousness from either disorder of consciousness. Second, treatment was considered beneficial for improvement and recovery of consciousness if incremental improvements were appreciated in any item contained in the Coma Recovery Scale-Revised (CRS-R), a standardized measurement tool that assesses cognition, language, vision, perception, communication, and functional mobility to diagnose, monitor recovery, predict outcomes, and measure success of treatments in those with DoC (Bodien et al., 2020). This assessment tool contains subscales of auditory, visual, motor, and oromotor/verbal function as well as communication and arousal which are used to evaluate behaviors mediated by the brainstem, subcortical, and cortical brain regions (Bodien et al., 2020). Therefore, as these items reflect improvement status in persons with VS/UWS or MCS, studies that reflect improvement in any of these items following intervention were assessed as beneficial for recovery while those that do not reflect improvement in these items will be deemed non-efficacious. Thus, the categories into which the success of each treatment strategy was grouped include successful/efficacious treatment, beneficial treatment, and non-efficacious or not beneficial treatment.


  Results Top


The literature related to treatment strategies for VS/UWS and MCS published between 2011 and 2021 was reviewed using the PubMed database. Keywords yielded a total of 7301 articles of which 1251 publications were review, systematic review, or meta-analysis articles and were thus excluded. Exclusion of opinion pieces and filtering for controlled trials, randomized controlled trials, case reports, and observational studies yielded 6050 publications. After duplicate articles were removed, the remaining publications assessed for eligibility according to the inclusion and exclusion criteria above. After all articles were assessed according to these criteria, 134 articles were evaluated for eligibility. Of these 134 articles, 112 included non-pregnant patients in a VS/UWS or MCS that underwent a specific intervention assessed for its efficacy in the treatment of these DoC. These 112 articles were included in the final analysis.

Research design

Among the 112 articles included in the present scoping review, 30 were randomized controlled trials including crossover trials, 28 were case studies, 26 were quasi-experimental studies, 9 were cohort studies, 5 were observational studies, 5 were experimental studies with an ABA-type design, 4 were letters to the editor, 3 were retrospective audit studies, and 2 were correlational studies [Table 1].
Table 1: Study designs of the included articles

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Patient population

Each article focused on a patient population in VS/UWS, MCS, or a combination of patients in a VS/UWS and MCS. Among the 112 articles, 36 studied participants in a VS/UWS, 28 studied participants in MCS, and 48 studied both participants in a VS/UWS as well as those in an MCS.

Treatment strategies

Of the 112 articles that met selection criteria, 7 discussed sensory stimulation programs, 34 discussed treatment strategies involving stimulation of the nervous system including tDCS (n = 13), TMS (n = 9), SCS (n = 8), deep brain stimulation (DBS) (n = 1), DBS with SCS (n = 1), left ear caloric vestibular stimulation (n = 1), and vagus nerve stimulation (n = 1). One article discussed transcranially focused extracorporeal shock waves (TESWT) while another discussed bilateral, transcranial near-infrared light-emitting diode irradiation to the forehead. Further, 30 articles discussed pharmacologic approaches to treatment of VS/UWS and MCS using zolpidem (n = 11), amantadine (n = 7), baclofen (n = 3), midazolam (n = 1), levodopa (L-dopa) (n = 1), botulinum toxin (n = 2), intranasal nerve growth factor (n = 1), clonazepam dose reduction followed by neurorehabilitation (n = 1), and autologous bone marrow transplantation (n = 3). The remaining articles focused on treatment strategies including the use of assistive technology (n = 4), rehabilitation programs (n = 19), music therapy (n = 8), animal therapy (n = 3), acupuncture (n = 3), personal or autobiographical objects (n = 1), and cranioplasty (n = 1). Details of these studies can be found in Additional Table 1[Additional file 2].

Major findings

Sensory stimulation

Sensory stimulation programs differ based on the form of stimulation provided but are based on the premise that an enriched environment will improve brain plasticity and recovery of patients with DoC (Schnakers et al., 2016). Sensory stimulation is offered in various modalities including unimodal, multimodal, multisensory, social-tactile, auditory, personally affective, familiar auditory sensory training (FAST) programs, and more (Lotze et al., 2011; Noé et al., 2012; Pape et al., 2015; De Tanti et al., 2016; Cheng et al., 2018; Sullivan et al., 2018; De Luca et al., 2021).

Among 112 articles included in the present scoping review, seven studied the effects of sensory stimulation on VS/UWS or MCS (Lotze et al., 2011; Noé et al., 2012; Pape et al., 2015; De Tanti et al., 2016; Cheng et al., 2018; Sullivan et al., 2018; De Luca et al., 2021). Two articles focused on patient populations in VS (De Tanti et al., 2016; Sullivan et al., 2018), one focused on a patient population in MCS (De Luca et al., 2021), and four focused on both patient populations in PVS/VS and MCS (Lotze et al., 2011; Noé et al., 2012; Pape et al., 2015; Cheng et al., 2018). Of these seven articles, six reported improvements in measures of consciousness while one suggested that sensory stimulation may not be adequate to restore consciousness (Lotze et al., 2011; Noé et al., 2012; Pape et al., 2015; De Tanti et al., 2016; Cheng et al., 2018; Sullivan et al., 2018; De Luca et al., 2021). Further, three of these seven articles described a sensory stimulation program that resulted in successful treatment with recovery of consciousness, three described programs that resulted in beneficial effects of treatment, and one described a program where no benefit of treatment was appreciated (Lotze et al., 2011; Noé et al., 2012; Pape et al., 2015; De Tanti et al., 2016; Cheng et al., 2018; Sullivan et al., 2018; De Luca et al., 2021).

In a case report of a 15-year-old female who recovered consciousness after 7 years in a VS, De Tanti et al. (2016) reported that a specialized treatment team with constant sensory stimulation may have been an important factor in recovery. Though recovery of consciousness could not be directly attributed to a particular intervention, a skilled interdisciplinary team equipped with the expertise to manage patients with severe acute brain injury and associated neurosurgical complications along with constant sensory stimulation through all sensory channels seemed to be a critical component of this patient’s recovery of consciousness (De Tanti et al., 2016). In a case report of a 69-year-old male in MCS, advanced emotional audio-visual stimulation was shown to significantly improve behavioral responsiveness and cognition as well as caregiver’s distress compared to conventional rehabilitation strategies but did not result in a change in clinical diagnosis or emergence (De Luca et al., 2021). Therefore, this treatment strategy was beneficial but not necessarily successful and authors suggest it may be a useful adjunct to therapy among those in MCS (De Luca et al., 2021).

In a study that assessed the use of sensory stimulation combined with a social-tactile intervention among seven patients in PVS and MCS, researchers found a significant change in diagnosis along with improvements in motor function with five patients recovering from PVS to MCS and one patient remaining in MCS upon study completion (Lotze et al., 2011). Similarly, Noé et al. (2012) reported that 7 participants emerged from MCS, and 1 emerged from VS following an integrative multisensory program of daily physical rehabilitation and multimodal sensory stimulation in their prospective cohort study of 32 participants. Both Pape et al. (2015) and Sullivan et al. (2018) studied FAST programs in a double-blind randomized placebo-controlled trial and a blinded crossover case study, respectively. In one study among both patients in VS and MCS, FAST was associated with significantly improved arousal and awareness as indicated by higher scores on the Coma-Near-Coma scale which reflects response consistency according to the subject’s ability to follow auditory commands, visually track, localize to sounds, vocalize, and respond to touch and pain (Pape et al., 2015). A second study found significant neurobehavioral and neurophysiological improvements, particularly auditory-language gains, following FAST in their blinded crossover case study of a 31-year-old male in VS (Sullivan et al., 2018). In both studies, FAST was beneficial for recovery but could ultimately not be considered a successful treatment strategy at this point.

Conversely, one article that assessed the efficacy of a sensory stimulation program among both patients in VS and MCS concluded that sensory stimulation program may not be adequate to restore consciousness (Cheng et al., 2018). In this interventional clinical trial with a time series design, Cheng et al. (2018) found that sensory stimulation program may improve behavioral responsiveness in MCS with increased arousal and oromotor functions; still, as discussed, treatment was considered inadequate for consciousness recovery and thus deemed non-efficacious.

tDCS

tDCS is a method of neurostimulation that delivers low current constant electrical stimulation to areas of the brain via scalp electrodes (Eapen et al., 2017). This technique has been studied since the 1960s and employs anodal and cathodal polarities with excitatory and inhibitory effects on the cerebral cortex, respectively, which alters membrane resting potentials, neuronal excitability, and neuronal firing rates (Nitsche and Paulus, 2000; Nitsche et al., 2003; Lang et al., 2007).

In the present review, 13 articles presented the efficacy of tDCS as a treatment option for VS/UWS or MCS. TDCS was associated with successful treatment in one of these articles with eight describing benefits of treatment but no change in clinical diagnoses or emergence into consciousness (Angelakis et al., 2014; Thibaut et al., 2014, 2017; Bai et al., 2017a; Dimitri et al., 2017; Martens et al., 2018; Cavinato et al., 2019; Straudi et al., 2019; Tzur et al., 2020), and four articles finding no benefit of treatment (Estraneo et al., 2017; Martens et al., 2019; Wu et al., 2019; Martens et al., 2020). Of note, in the single article that described successful treatment with tDCS, recovery of consciousness occurred in MCS patients but not VS/UWS patients (Thibaut et al., 2014).

Of these 13 articles, 5 studied the effects of tDCS among patients in MCS (Dimitri et al., 2017; Thibaut et al., 2017; Martens et al., 2018; Straudi et al., 2019; Tzur et al., 2020). Dimitri et al. (2017) conducted a case study of a 20-year-old female in MCS following anoxic brain damage who was treated with tDCS and psychosensory stimulation. While the patient remained in MCS following treatment, authors noted improvement and maintenance of alertness as well as improved muscle hypertonia (Dimitri et al., 2017). A randomized controlled trial by Martens et al. (2018) studied home-based tDCS in MCS patients. Researchers found home-based tDCS improved recovery and signs of consciousness in patients with chronic MCS and was a feasible strategy for use by caregivers outside of the hospital (Martens et al., 2018). In an open-label pilot electroencephalogram (EEG)-tDCS study to evaluate the effects of bilateral M1 anodal tDCS on adults with MCS following severe TBI, Straudi et al. (2019) reported new signs of consciousness in 8 out of 10 participants with gains in auditory function being most significant. These signs of consciousness recovery were sustained for at least 3 months (Straudi et al., 2019). A randomized double-blind sham-controlled crossover study by Thibaut et al. (2017) studied the effects of repeated prefrontal tDCS on recovery in MCS patients in which 5 days of repeated left prefrontal tDCS led to improvement in consciousness recovery in 56% of patients who were considered “responders” to treatment. This improvement was noted for up to 1 week following the end of stimulation (Thibaut et al., 2017). Tzur et al. (2020) also focused on the effects of tDCS in a case report of a 26-year-old male with MCS which found that treatment with tDCS may promote neural reactivity and responses linked to enhanced awareness. As the benefit of therapy was appreciated but overt emergence or change in clinical diagnosis did not occur, these studies are considered evidence of the beneficial effects of tDCS towards recovery, but ultimately not successful treatment as determined by the present scoping review

Eight articles studied the effects of tDCS on the recovery of patients in both VS/UWS as well as those in MCS (Angelakis et al., 2014; Thibaut et al., 2014; Bai et al., 2017a; Estraneo et al., 2017; Cavinato et al., 2019; Martens et al., 2019, 2020; Wu et al., 2019). In a prospective case series trial with 12 months of follow-up time, Angelakis et al. (2014) studied the impact of tDCS on persons in PVS/UWS and MCS. Improvement was seen in all MCS participants immediately following tDCS treatment with two MCS patients emerging into consciousness by the 12-month post-stimulation follow-up (Angelakis et al., 2014). While one patient in PVS/UWS recovered to MCS following treatment, no other PVS/UWS participants showed recovery by 12-month follow-up (Angelakis et al., 2014). Bai et al. (2017a) also found differences in treatment efficacy between patients in VS and MCS after receiving “real” versus sham tDCS sessions. Significant differences between local cerebral excitability among persons in VS and MCS were detected following “real” tDCS (Bai et al., 2017a). For the first time, this study presents evidence that tDCS may modulate cortical excitability in persons with MCS which may contribute to and be beneficial for recovery (Bai et al., 2017a). Both Cavinato et al. (2019) and Thibaut et al. (2014) studied the effect of left dorsolateral prefrontal cortex tDCS on recovery of persons with VS/UWS and MCS in a randomized double-blind crossover study and sham-controlled randomized double-blind crossover trial, respectively. Cavinato et al. (2019) found that tDCS produced EEG changes in brain areas involved in arousal and cognitive-emotional processing. Their findings suggested that tDCS is a potentially useful therapy for patients who retain some level of consciousness as significant clinical improvements were observed in participants with MCS; however, no benefit was observed in unresponsive participants (Cavinato et al., 2019). Similarly, Thibaut et al. (2014) reported that signs of consciousness were detected in 43% of MCS participants and 8% of VS/UWS participants following tDCS. Authors conclude that treatment may transiently improve level of consciousness in MCS; however, significant improvement was not detected in VS/UWS participants (Thibaut et al., 2014).

In contrast, Estraneo et al. (2017), Martens et al. (2019), Martens et al. (2020), and Wu et al. (2019) did not appreciate significant recovery for VS/UWS or MCS patients following tDCS. In a double-blind crossover study, Estraneo et al. (2017) did not find short-term benefit of repeated tDCS among patients in VS and MCS. Similarly, after a single tDCS session in a randomized double-blind sham-controlled crossover pilot study, Martens et al. (2019) found no evidence of improved behavioral function though 2 out of 10 subjects demonstrated a new sign of consciousness following tDCS. In another randomized double-blind sham-controlled crossover trial by Martens et al. (2020), network-based frontoparietal tDCS did not promote recovery when results were analyzed on a group level. However, when results were analyzed on an individual participant level, new behaviors suggestive of conscious awareness became evident in five participants (Martens et al., 2020). Accordingly, authors concluded that the efficacy of tDCS varies between patients (Martens et al., 2020). Finally, a randomized, sham-controlled trial conducted by Wu et al. (2019) to study the effects of repetitive dorsolateral prefrontal cortex tDCS among patients in UWS and MCS found that anodal tDCS to the left dorsolateral prefrontal cortex more effectively increases cortical excitability than anodal tDCS to the right dorsolateral prefrontal cortex. Still, significant behavioral gains were not observed at the group level with only one patient demonstrating a positive outcome (Wu et al., 2019).

TMS

TMS is a non-invasive form of neuromodulation in which magnetic fields are used to stimulate brain areas using a magnetic stimulator connected to a copper wire coil which is topically applied to the scalp (Eapen et al., 2017). Repetitive and quickly changing magnetic stimulation affects cortical processes and has been reported to modify neural plasticity and conduction resulting in neurobehavioral improvements (Pape et al., 2015; Eapen et al., 2017). Of the 36 articles that discussed central nervous system stimulation for the treatment of DoC, 9 articles reported results of TMS with 4 focusing on patients in VS (Pistoia et al., 2013; Cincotta et al., 2015; Jang and Kwon, 2020; Zhang et al., 2021), 1 focusing on patients in MCS (Piccione et al., 2011), and 4 discussing both patients in VS/UWS and MCS (Manganotti et al., 2013; Pape et al., 2015; Liu et al., 2016; He et al., 2018). Of these nine articles, one found evidence to support the successful treatment of PVS with TMS (Jang and Kwon, 2020), seven found some benefits of therapy for those in VS/UWS or MCS (Piccione et al., 2011; Manganotti et al., 2013; Pistoia et al., 2013; Pape et al., 2015; Liu et al., 2016; He et al., 2018; Zhang et al., 2021), and one found no benefit of treatment with TMS (Cincotta et al., 2015).

Jang and Kwon (2020) conducted a case report of a 45-year-old male treated with TMS for PVS. Authors reported a change in clinical diagnosis from PVS to MCS following rTMS of the right dorsolateral prefrontal lobe combined with pharmacologic treatment in this patient indicating the success of treatment (Jang and Kwon, 2020). While receiving only pharmacologic therapy, the patient’s CRS-R score remained the same; however, when rTMS was added, the patient demonstrated improvement in higher cognition (Jang and Kwon, 2020).

Seven articles found evidence to support beneficial impacts of TMS among persons in VS/UWS or MCS (Piccione et al., 2011; Manganotti et al., 2013; Pistoia et al., 2013; Pape et al., 2015; Liu et al., 2016; He et al., 2018; Zhang et al., 2021). In a sham-controlled randomized crossover trial by He et al. (2018) that looked at 20 Hz repetitive TMS (rTMS) on VS, MCS, and EMCS, one of six patients showed sustained behavioral and neurophysiological changes after rTMS while the remaining five patients showed local brain reactivity but non-significant EEG changes. Authors concluded that rTMS may increase awareness and arousal (He et al., 2018). Similar results were found in a correlational study by Manganotti et al. (2013) that evaluated the therapeutic effects of high-frequency TMS on patients in VS and MCS. In this study assessing six patients in VS or MCS, authors measured sustained behavioral and neurophysiological changes in one MCS patient whose EEG showed emergence of fast activity and increase in slow activity after rTMS (Manganotti et al., 2013). While authors found some significant electrophysiological changes in VS and MCS patients after a single session of 20 Hz rTMS over the motor cortex, no significant sustained clinical or EEG changes were seen in the other five patients (Manganotti et al., 2013). Still, these results are encouraging and represent a therapeutic strategy that may benefit recovery given that at least one patient made behavioral and neurophysiological gains (Manganotti et al., 2013). Liu et al. (2016) also tested high-frequency rTMS among patients in VS and MCS following head injury in a sham-controlled study. Researchers found varying effects of rTMS on cerebral blood flow (CBF) depending on level of consciousness in patients with these DoC (Liu et al., 2016). While no significant changes in CRS-R scores were observed in either VS or MCS patients, significant increases in peak systolic velocity and mean flow velocity of the left middle cerebral artery occurred in MCS patients (Liu et al., 2016). CBF is associated with neural activity through a concept known as “neurovascular coupling”; thus, it can be reasoned that these increases in peak systolic velocity and mean flow velocity may indicate increased neural activity related to rTMS (Liu et al., 2016). These changes did not occur in VS patients (Liu et al., 2016). In a study by Pape et al. (2015) that tested combination therapy with rTMS and amantadine in an alternate treatment-order within-subject baseline-controlled trial of VS and MCS patients following TBI, meaningful neurobehavioral gains were observed in 75% of treatment segments studied including rTMS, amantadine, and combined rTMS + amantadine. These changes suggest that modulation of neural activity and communication vital to the process of neurobehavioral recovery occurs with this treatment strategy (Pape et al., 2015). Auditory-language gains more than doubled in participants who received rTMS prior to the combined rTMS and amantadine treatment compared to those who received amantadine prior to the combined rTMS and amantadine treatment though evidence ultimately suggested that both conditions resulted in improved auditory-language skills (Pape et al., 2015). Further, rTMS + amantadine treatment resulted in increased social interaction with nonfamiliar people and increased physical manipulation and nonspecific sensory stimulation during rTMS (Pape et al., 2015). Results suggest that combined therapy with rTMS and amantadine may improve neurobehavioral recovery though further research is indicated (Pape et al., 2015).

A case report of a 70-year-old male in MCS with hemorrhagic etiology also found beneficial effects of rTMS that suggested rTMS may improve awareness and arousal in those with MCS (Piccione et al., 2011). In a cross-sectional survey by Pistoia et al. (2013), corticomotor facilitation induced by TMS (TMS-CF) was assessed in combination with three conditions to evaluate its ability to promote motor behaviors: at rest, with execution of a motor task, and with imitation of a demonstrated action. While TMS-CF combined with rest or execution conditions showed no change, changes in motor evoked potentials (MEPs) associated with behavioral improvements were seen in four patients when TMS-CF was combined with the imitation condition (Pistoia et al., 2013). Authors suggest that imitation provided a visual stimulus along with TMS-CF which may have promoted recovery of motor behaviors as imitation provided patients an association between planning a movement and executing it (Pistoia et al., 2013). Also testing combined therapy with encouraging results, Zhang et al. (2021) conducted a prospective open randomized controlled single-center clinical trial among PVS patients to test the impact of combined rTMS and conventional rehabilitation. After 30 and 60 days of treatment, the experimental group receiving rTMS of the dorsolateral prefrontal cortex with conventional rehabilitation had CRS-R and EEG grading measures that were significantly higher than the control group which received false stimulation combined with conventional rehabilitation (Zhang et al., 2021). Findings suggest that rTMS combined with conventional rehabilitation promotes recovery of consciousness in patients in PVS (Zhang et al., 2021).

On the other hand, in a randomized sham-controlled study with a crossover design, Cincotta et al. (2015) studied the effect of 20 Hz rTMS among patients in VS and found no benefit of therapy when rTMS was conducted using conventional coils.

SCS and DBS

SCS involves the surgical implantation of a spinal cord stimulator that can be programmed to send various frequencies and amplitudes of electricity directly to the spinal cord (Sivanesan; Bai et al., 2017b). SCS controls the excitability and firing rate of neurons in the spinal cord with different results based on the frequency of stimulation such that low frequency (10–40 Hz) results in excitatory effects and high-frequency stimulation (> 60 Hz) results in inhibitory effects (Yampolsky et al., 2012; Bai et al., 2017b). This is a minimally invasive procedure that is favored for being less invasive and simpler compared to DBS (Yamamoto et al., 2012, 2013; Bai et al., 2017b). DBS is a more invasive method in which a deep brain stimulator is surgically implanted and then utilized for brain stimulation (Eapen et al., 2017).

Eight articles discussed the efficacy of SCS (Yamamoto et al., 2012, 2017; Bai et al., 2017b; Liang et al., 2018; Si et al., 2018; Zhang et al., 2018; Xu et al., 2019; Wang et al., 2020a), one discussed the efficacy of combined SCS and DBS (Yamamoto et al., 2013), and one discussed the efficacy of DBS alone (Chudy et al., 2018). Amongst these 10 articles, all measured some therapeutic benefit related to intervention with 5 articles indicating successful treatment and 5 articles indicating beneficial treatment (Yamamoto et al., 2012, 2013, 2017; Bai et al., 2017b; Chudy et al., 2018; Liang et al., 2018; Si et al., 2018; Zhang et al., 2018; Xu et al., 2019; Wang et al., 2020b). One study discussed patients in VS, three discussed patients in MCS, and the remaining six discussed both patients in VS/UWS and MCS (Yamamoto et al., 2012, 2013, 2017; Bai et al., 2017b; Chudy et al., 2018; Liang et al., 2018; Si et al., 2018; Zhang et al., 2018; Xu et al., 2019; Wang et al., 2020b).

In an interventional study based on a retrospective study of 12 participants in VS that received cervical SCS (cSCS), Xu et al. (2019) found that patients’ CRS-R scores improved significantly from baseline following treatment. Five patients reached outcomes that were considered “responsive” with three patients recovering consciousness and two patients recovering from VS to MCS (Xu et al., 2019). Seven patients were considered unresponsive with six remaining in VS and one passing away (Xu et al., 2019). Further, authors found the etiology of VS to be significantly associated with the response to cSCS such that those with etiologies of ischemia or anoxia had poorer outcomes (Xu et al., 2019). In a long-term interventional study of patients in MCS, Yamamoto et al. (2012) reported that, following SCS, 7 out of 10 patients recovered consciousness regaining the ability to communicate and perform motor activities including use of objects. A 22.2% increase in CBF was seen during cSCS compared to pre-stimulation CBF in MCS subjects and, overall, cSCS resulted in diffusely increased CBF (Yamamoto et al., 2012). Another study by Yamamoto et al. (2017) presented the efficacy of cSCS among VS and MCS patients reporting recovery in three VS patients who remained bedridden and seven MCS patients who were all able to emerge from a bedridden state within 12 months of therapy. Increased CBF and induced upper extremity muscle twitches were observed with cSCS at five hertz (Yamamoto et al., 2017). Further, at five hertz of cSCS, notable recovery of consciousness and motor function of the upper extremities compared to lower extremities occurred in MCS patients (Yamamoto et al., 2017). Authors conclude that MCS patients may be good candidates for cSCS therapy which findings suggest is a promising neuromodulation and neurorehabilitation strategy (Yamamoto et al., 2017).

A study by Yamamoto et al. (2013) looked at combined therapy with SCS and DBS for the treatment of persons in VS and MCS. In this clinical trial, researchers reported eight of 21 patients in VS showed recovery and demonstrated the ability to follow verbal instructions following treatment (Yamamoto et al., 2013). Further, patients in MCS who fulfilled electrophysiological inclusion criteria showed great functional improvement following DBS and SCS (Yamamoto et al., 2013). The efficacy of DBS among patients in VS and MCS was also studied by Chudy et al. (2018) who reported improvement in consciousness in four of fourteen participants (29%), three of which were in the VS or MCS due to ischemic encephalopathy. Of these four participants, consciousness was regained in three MCS patients, two of which regained the ability to walk, speak, and live independently while the third remained bound to a wheelchair (Chudy et al., 2018). Further, one patient in VS regained consciousness and the ability to respond to simple commands (Chudy et al., 2018). No significant improvement was seen in seven patients while three died due to sequelae of their disorder (Chudy et al., 2018). Authors concluded that, for patients exhibiting some inclusion criteria, DBS may be a fruitful treatment option (Chudy et al., 2018).

Bai et al. (2017b) studied the efficacy of SCS among MCS patients and found that SCS may modulate brain function which authors believe may be related to the activation of the formation-thalamus cortex network. In this study, the use of different frequency parameters of SCS yielded differing EEG results in the frontal region thereby indicating that the effects of SCS may vary by frequency in MCS patients (Bai et al., 2017b). Liang et al. (2018) also studied SCS among MCS patients reporting that SCS improved brain activity particularly in the frontal and occipital regions. Researchers found that, following SCS, information integration became more complex with more cortical area engagement thus supporting the use of this treatment method (Liang et al., 2018). In an experimental pilot study of VS and MCS patients, Si et al. (2018) reported that SCS at 70 Hz and 100 Hz led to significantly increased hemodynamic responses in the prefrontal cortex, a crucial brain area to consciousness. Responses were frequency specific with the best hemodynamic responses seen when SCS was provided at 70 Hz at which frequency there was significant improvement in functional connectivity between the prefrontal and occipital regions of the brain (Si et al., 2018). Authors suggest that increased cerebral blood volume and improved transmission of information through the reticular-formation-thalamus-cortex pathway may underlie these improvements (Si et al., 2018). Another study presenting the efficacy of SCS among VS/UWS and MCS patients was discussed by Wang et al. (2020b) who conducted an interventional study using permutation entropy as a measure to quantify brain response to SCS. Authors found that permutation entropy increased in all patients following SCS and was associated with short-term changes in neural activities (Wang et al., 2020b). However, more significant changes occurred in subjects in MCS compared to those in VS/UWS, particularly in frontal brain regions, which highlights a potential difference in treatment efficacy between patients with differing DoC (Wang et al., 2020b). Zhang et al. (2018) tested the efficacy of SCS on the recovery of patients in VS and MCS with a slightly more narrowed focus in that researchers paid particular attention to the inter-stimulus interval parameter of SCS. In this preliminary interventional study, authors found that the shorter inter-stimulus interval parameters of SCS improved blood volume in the prefrontal cortex, a brain area important to consciousness (Zhang et al., 2018). Findings were more significant in groups with a favorable prognosis as determined by Glasgow Outcome Scale (Zhang et al., 2018).

Other methods of stimulation

Caloric vestibular stimulation is a technique whereby thermal current is injected into the ear which interacts with the endolymph therein which alters the firing rate of the vestibular nerve stimulating a chain of events that results in reactivity of the distal frontal-parietal and striatal networks which are involved in goal directed behavior and arousal (Vanzan et al., 2017). Left ear vestibular stimulation was discussed as a treatment strategy for MCS in a single-case prospective controlled (ABAB) efficacy study by Vanzan et al. (2017). In their article, authors describe the potential of this treatment as a beneficial strategy for MCS patients as both participants studied showed behavioral improvement that occurred during treatment (Vanzan et al., 2017). However, these improvements were not sustained upon cessation of stimulation (Vanzan et al., 2017). Still, and encouragingly, improvements in participants’ level of awareness and responsiveness were partially irreversible in at least one of the two participants indicating some benefits of therapy (Vanzan et al., 2017).

Activation of the thalamo-cortical network via Vagus nerve stimulation involves the surgical implantation of a stimulation device which is then used to stimulate the Vagus nerve at varying intensities (Corazzol et al., 2017). In a case study of an individual in VS, Vagus nerve stimulation was associated with recovery of consciousness such that the patient transitioned from VS to MCS after 1 month of treatment (Corazzol et al., 2017). This patient exhibited reproducible improvements in arousal, attention, body motility, and visual pursuit with stimulation promoting the spread of cortical signals and increased metabolic activity resulting in improved behavioral function (Corazzol et al., 2017). Thus, authors conclude that Vagus nerve stimulation may improve recovery of consciousness (Corazzol et al., 2017).

In a longitudinal observation study by Lohse-Busch et al. (2014), TESWT were evaluated to determine therapeutic benefit for persons in UWS following TBI or overdose. Researchers found a 135.9% improvement on the German Coma Remission Scale and a 43.6% improvement on the Glasgow Coma Scale after two to four years and an average of 5.2 series of treatments with TESWT (Lohse-Busch et al., 2014). A 64.3% improvement was also noted in motor areas of the German Coma Remission Scale. Based on clinical improvement of the five patients included in this study, clinicians were able to remove percutaneous endoscopic gastrostomy feeding tubes from three patients and noncommunication was initiated in four patients (Lohse-Busch et al., 2014). Overall, authors concluded that TESWT benefited all patients studied (Lohse-Busch et al., 2014).

Nawashiro et al. (2012) conducted a case study of a 40-year-old male in a PVS following severe TBI to assess the recovery benefit of bilateral, transcranial near-infrared light-emitting diode irradiation to the forehead. Authors found that 146 treatments over a duration of 73 days increased CBF by 20% and may lead to improved neurological condition for persons in PVS that is beneficial for recovery (Nawashiro et al., 2012).

Pharmacologic therapy

Among 112 articles included in the present scoping review, 30 presented pharmacologic therapies for VS/UWS or MCS including eleven articles on zolpidem, seven articles on amantadine (plus one previously discussed above thus not included in the total number of articles discussing pharmacologic therapies), three articles on baclofen, one article on midazolam, one article on L-dopa, two articles on botulinum toxin, one article on clonazepam dose reduction followed by neurorehabilitation, one article on intranasal nerve growth factor, and three articles on autologous bone marrow transplantation.

Zolpidem

Zolpidem is a gamma-aminobutyric acid (GABA) agonist and sedative-hypnotic that was incidentally administered to a patient in VS with positive effect thus leading to its further study among patients in DoC (Clauss et al., 2000; Eapen et al., 2017; Sutton and Clauss, 2017). Since then, it has been suggested that zolpidem may improve arousal in patients in DoC. In the present review, eleven articles presented zolpidem as a treatment strategy for DoC with five discussing its efficacy for patients in PVS/VS (Rodriguez-Rojas et al., 2013; Du et al., 2014; Machado et al., 2011, 2014; Calabrò et al., 2015), three discussing its efficacy for patients in MCS (Appu and Noetzel, 2014; Chatelle et al., 2014; Delargy et al., 2019), and three discussing its efficacy for patients in VS/UWS and MCS (Thonnard et al., 2013; Whyte et al., 2014; Khalili et al., 2020). Further, two of eleven articles reported successful treatment (Appu and Noetzel, 2014; Khalili et al., 2020), eight reported some benefits of treatment (Machado et al., 2011, 2014; Rodriguez-Rojas et al., 2013; Chatelle et al., 2014; Du et al., 2014; Whyte et al., 2014; Calabrò et al., 2015; Delargy et al., 2019), and one reported no benefit of treatment (Thonnard et al., 2013).

Studies by Appu and Noetzel (2014) and Khalili et al. (2020) reported successful treatment of DoC using zolpidem. In a case report of a 16-year-old female in MCS following anti-N-methyl-N-aspartate receptor encephalitis, zolpidem treatment was begun on hospital day 42 and led to immediately improved lucidity, accelerated recovery from MCS, and dramatically reduced length of hospital stay with the patient’s discharge occurring on hospital day 55 (Appu and Noetzel, 2014). Zolpidem treatment was weaned 3 weeks following discharge and the patient exhibited almost complete recovery approximately six months after discharge (Appu and Noetzel, 2014). Authors concluded that zolpidem would be a reasonable adjunct to treatment for patients in MCS (Appu and Noetzel, 2014). In a prospective clinical trial by Khalili et al. (2020), a change in clinical diagnosis from VS to MCS occurred in 50% of patients with statistically significant differences in motor scores after 2 weeks of zolpidem treatment. Further, 50% of VS patients demonstrated an improvement in their level of consciousness and motor function following treatment (Khalili et al., 2020).

Calabrò et al. (2015), Du et al. (2014), Machado et al. (2011), Machado et al. (2014), and Rodriguez-Rojas et al. (2013) reported beneficial, but not overtly successful, effects of zolpidem treatment among patients in PVS/VS. Zolpidem was found to increase awareness and wakefulness as well as improve consciousness and arousal in a case report of a 52-year-old female in VS following cardiac arrest (Calabrò et al., 2015). Further, in a study of 165 patients by Du et al. (2014), zolpidem treatment improved brain function, and did so in a rapid rather than gradual manner. Authors reported that benefit was greater in those who suffered brain injury to non-brain stem areas compared to those with primary and secondary brain stem injuries (Du et al., 2014). In further support of zolpidem’s efficacy among patients in PVS/VS, a case report of a 21-year-old female by Machado et al. (2011) found significant signs of behavioral arousal following zolpidem administration including spontaneous eye movements and yawning. Arousal reached its height rapidly, from 20-45 minutes after administration (Machado et al., 2011). This study highlights the brain-heart connection and was the first to describe the use of heart rate variability to assess response to zolpidem treatment among PVS patients (Machado et al., 2011). In another study by Machado et al. (2014), researchers describe a prospective two-period crossover double-blind randomized controlled trial in which treatment with zolpidem led to time-related signs of arousal including behavioral signs, activation of EEG cortical activity, and a vagolytic chronotropic effect. Authors suggest this demonstrated arousal may be related to improvements in brain function and propose that zolpidem be added to rehabilitation programs for DoC (Machado et al., 2014). In a fifth study presenting the efficacy of zolpidem treatment in a case report of a 21-year-old female in PVS following stroke, Rodriguez-Rojas et al. (2013) found that zolpidem treatment led to increased blood oxygen level dependent signal changes which relate to CBF and support the hypothesis that zolpidem increases brain activation and promotes awareness in patients with PVS.

Similarly, Chatelle et al. (2014) and Delargy et al. (2019) reported beneficial effects of zolpidem treatment among patients in MCS. In a randomized, double-blind 2-day protocol study of three patients in MCS following anoxic events, treatment with zolpidem resulted in clinically significant behavioral improvement as evidenced by fluorodeoxyglucose-positron emission tomography imaging which noted metabolic activation of the prefrontal cortices (Chatelle et al., 2014). Using a slightly different therapeutic approach, Delargy et al. (2019) studied the efficacy of zolpidem treatment combined with an interdisciplinary team in a single case study of a 44-year-old female in MCS with hemorrhagic etiology. Authors reported that zolpidem treatment improved awareness but that this improvement faded following the completion of therapy (Delargy et al., 2019). However, combined zolpidem treatment and interdisciplinary team over the 8-week study period led to functional and communicative improvements that were durably highlighting the beneficial impact of a skilled interdisciplinary team (Delargy et al., 2019).

While Whyte et al. (2014) report evidence to support the efficacy of zolpidem on consciousness recovery, Thonnard et al. (2013) found no clinically significant improvement following zolpidem treatment in their prospective open-label study of 60 patients in VS/UWS and MCS. In a placebo-controlled double-blind single-dose crossover study of 84 patients in either VS or MCS, Whyte et al. (2014) report that 5% of participants benefited from zolpidem treatment as evidenced by increased movement, social interaction, command following, attempts to communicate, and functional object use. Of note, authors did note that mild adverse events occurred more often in the zolpidem group compared to the control group (Whyte et al., 2014).

Amantadine

Amantadine is a dopamine agonist and N-methyl-D-aspartate antagonist that also possesses antagonistic action against acetylcholine which in turn further augments its dopaminergic effects (Gao et al., 2020a). This medication has been associated with enhanced neurotransmission and employed as a sort of “wake-up” treatment for patients in DoC owing to its arousal effects (Eapen et al., 2017; Chen et al., 2019; Gao et al., 2020a). It is the only recommended therapy included in the 2018 American Practice Guidelines for individuals with DoC published by Giacino et al. (2018). This recommendation was based on the results of one study by Giacino et al. (2012) which is discussed herein. Seven articles presented amantadine as a treatment strategy for VS/UWS or MCS plus one article by Pape et al. (2015) previously discussed above (Giacino et al., 2012; Avecillas-Chasín and Barcia, 2014; Estraneo et al., 2015; Lehnerer et al., 2017; Chen et al., 2019; Bender Pape et al., 2020; Gao et al., 2020a, b). Of these seven articles, four discussed its efficacy among patients in VS/UWS (Lehnerer et al., 2017; Tricco et al., 2018; Chen et al., 2019; Gao et al., 2020a, b), two among patients in MCS (Avecillas-Chasín and Barcia, 2014; Estraneo et al., 2015), and one among patients in VS/UWS and MCS (Giacino et al., 2012). All articles reported some level of recovery following amantadine treatment with four articles reporting successful treatment and three reporting beneficial effects of treatment (Giacino et al., 2012; Avecillas-Chasín and Barcia, 2014; Estraneo et al., 2015; Lehnerer et al., 2017; Chen et al., 2019; Gao et al., 2020a, b).

Amantadine treatment among patients with traumatic VS/UWS and MCS was discussed in an influential international, multicenter, randomized, controlled trial by Giacino et al. (2012) which formed the basis for the 2018 American Practice Guidelines. Compared to placebo, amantadine therapy initiated between 4 and 16 weeks following brain injury among patients with VS/UWS and MCS significantly accelerated functional recovery during the active 4-week treatment period (Giacino et al., 2012). This rapid functional recovery included consistent response to commands, speech gains, and functional object use indicating emergence from VS/UWS and MCS during the 4-week treatment period (Giacino et al., 2012). However, authors found this emergence to be drug dependent as recovery slowed with discontinuation of therapy and benefits virtually disappeared by 6-week follow-up (Giacino et al., 2012). While treatment with amantadine was successful during active treatment, the described loss of benefit with discontinuation of therapy represents a major limitation. Long-term benefits of amantadine remain to be seen; however, authors recommend its use for the acceleration of early recovery among patients in VS/UWS and MCS (Giacino et al., 2012).

Gao et al. (2020a, b) studied the efficacy of amantadine treatment in adults in PVS and UWS, respectively. In a retrospective controlled study by Gao et al. (2020a), 50% of PVS participants in the amantadine group regained consciousness five months after onset of PVS but remained severely disabled while 50% of PVS participants did not recover consciousness and remained in PVS. Researchers suggest that treatment with amantadine may accelerate consciousness recovery in PVS and requires further investigation (Gao et al., 2020a). In an observational study of UWS patients by Gao et al. (2020b), consciousness improved in all seven participants 3–6 days after beginning amantadine treatment. In this study, five patients regained consciousness, recovered left aphasia, hemiplegia, and other associated sequelae while two patients improved from UWS to MCS (Gao et al., 2020b). Similarly, Lehnerer et al. (2017) described a case report of a 36-year-old female in PVS who was treated with amantadine and subsequently recovered consciousness 16 days into treatment and full orientation within three months. Moderate motor deficits and minor cognitive dysfunction remained but the patient improved dramatically and was able to speak, eat independently, and stand with assistance (Lehnerer et al., 2017).

Chen et al. (2019) studied “wake up treatment” with amantadine treatment and rehabilitation training in a case study of a 52-year-old individual in VS following TBI. After 3 months of treatment, fMRI elucidated increased brain activation in areas that correspond to task instructions indicating a positive effect of amantadine treatment and rehab training on brain function (Chen et al., 2019).

Avecillas-Chasín and Barcia (2014) and Estraneo et al. (2015) studied the efficacy of amantadine treatment among patients in MCS. In a case report of a 49-year-old female in MCS with hemorrhagic etiology, researchers found treatment with amantadine 100 mg twice daily improved consciousness such that the patient developed the ability to open her eyes spontaneously and follow commands after 3 days of treatment (Avecillas-Chasín and Barcia, 2014). Dose increase to 150 mg twice daily resulted in further gains including the ability to follow commands, engage in visual pursuit, use objects, communicate through gesturing, and recognize relatives. When treatment was stopped, the patient’s condition deteriorated, and functional gains were again lost. However, after reinitiating amantadine treatment and then slowly tapering back down, the patient was withdrawn successfully and able to maintain improvement. Therefore, the authors suggested that amantadine may be a safe and effective treatment for the recovery of patients with MCS when dopamine circuits are preserved. Estraneo et al. (2015) also appreciated a dose-dependent effect of amantadine among MCS patients in their case report of a 57-year-old female. Researchers reported improvements in arousal, auditory, visual, and motor scales with amantadine 50 mg twice daily while further recovery was seen with up-titration to 100 mg twice daily (Estraneo et al., 2015). At this increased dose, the patient emerged from MCS after gaining the ability to communicate and use functional objects. However, dosage reductions due to side effect development resulted in the patient’s return to baseline function which support amantadine’s role in recovery while highlighting a barrier to its use.

Baclofen

Baclofen is a selective GABA-B receptor agonist that has been used for many years in the treatment of spinal cord and cerebral spasticity via the placement of an intrathecal baclofen (ITB) pump (Al-Khodairy et al., 2015). ITB treatment for DoC was discussed in two articles, both of which reported successful treatment (Margetis et al., 2014; Al-Khodairy et al., 2015). In a case report by Al-Khodairy et al. (2015), a 26-year-old male patient in an MCS was treated with ITB pump implantation less than 10 months following injury. Following initiation of ITB therapy, the patient swiftly and somewhat unexpectedly emerged from MCS demonstrating behavioral gains, decreased spasticity, improved attention, concentration, and auditory and verbal comprehension (Al-Khodairy et al., 2015). Authors concluded that treatment with ITB pump may improve cognition, augment recovery and facilitate recovery from DoC (Al-Khodairy et al., 2015). Similarly, Margetis et al. (2014) studied chronic ITB via an ITB pump in a prospective, open-label observational study in which two patients showed significant improvement consistent with emergence from MCS, four patients showed no change, and two patients required ITB pump removal due to complications. As two of eight participants experienced a change in clinical diagnosis from MCS to EMCS, results suggest that ITB therapy was successful for the recovery of MCS patients in this study (Margetis et al., 2014).

Baclofen and ziconotide

Lanzillo et al. (2016) evaluated the efficacy of combined ITB and ziconotide treatment in a case report of a 42-year-old male in UWS. Ziconotide is an analgesic medication used to treat chronic pain chosen by researchers in this study for its pain-relieving qualities along with its low risk of negative cognitive or adverse effects in attempt to relieve pain related to rehabilitative treatments (Lanzillo et al., 2016). In this case report, authors found that pain is an important aspect of DoC and their treatment with ziconotide along with ITB may improve recovery outcomes (Lanzillo et al., 2016). Ziconotide was found to have synergistic antispastic effects when combined with ITB which together led to clinical improvement, a result authors suspect may be largely related to pain relief (Lanzillo et al., 2016). Thus, combined therapy with ITB and ziconotide was found to be beneficial for recovery from UWS though was not overtly successful according to this article (Lanzillo et al., 2016).

Midazolam

Midazolam is a benzodiazepine often used for its sedative properties (Mayo Clinic, 2020). Treatment using midazolam was discussed in one article by Carboncini et al. (2014) that presents a case report of a 43-year-old male in MCS following TBI. More than 1 year following injury, midazolam was administered for sedation during routine imaging which subsequently and surprisingly led to the patient’s emergence into consciousness with the ability to interact with persons around him and demonstration of memory gains (Carboncini et al., 2014). However, improvement was transient lasting for approximately 2 hours (Carboncini et al., 2014). Improvements recurred with subsequent midazolam administration which led to improved patient cooperation, awareness, speech, memory, command following and understanding, and eventually full recovery of the patient’s ability to interact with the environment (Carboncini et al., 2014). Authors report this is the first study to demonstrate paradoxical behavioral reaction to midazolam which they refer to as an “awakening” effect though there was a question of whether the patient was truly in MCS at baseline (Carboncini et al., 2014).

L-Dopa

As a precursor of dopamine, norepinephrine, and adrenaline neurotransmitters, L-dopa has been utilized in the treatment of patients in DoC (Eapen et al., 2017). Treatment of patients with MCS following TBI using L-dopa was discussed in one article by Fridman et al. (2019) which found that the administration of L-dopa reversed the dopamine deficit measured in many patients with MCS and subsequently restored its biosynthesis by providing substrate. Authors suggest that L-dopa administration may benefit patients in MCS resulting in increased brain and behavioral function through improvement in dopamine dysfunction (Fridman et al., 2019). Authors also suggest that interruption in dopamine activity to the central thalamus may be an important element in the pathophysiology of MCS (Fridman et al., 2019).

Botulinum toxin

Botulinum toxin has been included in larger multifactorial treatment protocols for patients in DoC largely related to its effects on muscle spasticity (Vainshenker et al., 2017). In the present scoping review, two studies focused on treatment strategies that included botulinum toxin in a larger treatment protocol for the treatment of patients with VS or MCS with one finding some benefits of therapy (Vainshenker et al., 2017) and the second finding no benefit (Wheatley-Smith et al., 2013). In a longitudinal case report of a 39-year-old female in VS following TBI whose treatment included botulinum toxin, authors found that botulinum toxin reduced hyperafferentation of spastic muscles which authors suggest is likely related to this patient’s improvement in cognitive functional state (Vainshenker et al., 2017). Data supports the claim that botulinum toxin benefits recovery of patients in VS though was not associated with emergence of consciousness or a change in clinical diagnosis (Vainshenker et al., 2017). Conversely, Wheatley-Smith et al. (2013) conducted a retrospective audit study of patients in VS and MCS whose treatment included botulinum toxin in combination with physiotherapy, manual stretching and passive movements, and casting and splinting in which no patients recovered consciousness to emerge from VS or MCS.

Clonazepam dose reduction

In a case report of a 27-year-old man who emerged from VS 19 months following injury, authors identified a reduction in clonazepam dosing followed by conventional comprehensive neurorehabilitation to be a major potential causative factor in this patient’s recovery (Illman and Crawford, 2018). Clonazepam is a benzodiazepine often used in the treatment of seizures and panic attacks owing to its ability to reduce abnormal electrical brain activity (American Society of Health Systems Pharmacists, 2021). Authors describe marked improvement with increased arousal and ability to respond to functional objects as well as visually track and localize objects on command following clonazepam dose reduction (Illman and Crawford, 2018). This improvement was classified as emergence from VS to MCS in this patient and thus a change in clinical diagnosis indicating successful treatment. The authors of this study suggested that reduction in clonazepam dosing was an important factor in consciousness recovery.

Intranasal nerve growth factor

Nerve growth factor is a neurotrophin, a vital group of proteins that regulate the development, growth, differentiation, survival, function, and plasticity of neurons which assist in the restoration of neuronal function after injury (Huang and Reichardt, 2001; Chiaretti et al., 2017). Chiaretti et al. (2017) describe a case report of a four-year-old male in UWS following TBI who was treated with intranasal nerve growth factor. Following treatment, functional assessment, electrophysiological studies, and clinical status improved with improvements observed in voluntary movements, facial mimicry, phonation, attention and verbal comprehension, ability to cry, cough reflex, oral motility, capacity to feed, and urinary and bowel functions (Chiaretti et al., 2017). These results led authors to conclude that nerve growth factor may be neuroprotective for those in UWS, and results support the benefit of intranasal nerve growth factor therapy (Chiaretti et al., 2017).

Autologous bone marrow transplantation

Among 30 articles that discussed pharmacologic treatments for PVS/VS/UWS or MCS, three reported the effects of autologous bone marrow transplantation as a treatment strategy for PVS/VS (Tian et al., 2013; Fauzi et al., 2016; Liem et al., 2020). All three studies concluded that this treatment strategy improved recovery though not to the point of emergence into consciousness or change in clinical diagnosis (Tian et al., 2013; Fauzi et al., 2016; Liem et al., 2020). In a case report of two patients in PVS following stroke, intraventricular transplantation of autologous bone marrow mesenchymal stem cells via a subcutaneously placed Ommaya reservoir was employed for the treatment of PVS (Fauzi et al., 2016). Authors reported no adverse events related to this treatment during the 1-year follow-up concluding that treatment was safe, simple to perform, and led to improved neurologic and functional status (Fauzi et al., 2016). Tian et al. (2013) also tested the effect of autologous bone marrow mesenchymal stem cell therapy in a clinical trial containing patients in PVS as well as those with disturbance of motor activity following TBI. In their study, authors reported that improved consciousness including responsive eyeball tracking, groaning, and tearing was seen in 45.8% of patients with PVS (Tian et al., 2013). Authors note younger age and the initiation of treatment as soon as possible following injury may lead to higher treatment efficacy (Tian et al., 2013). Similarly, Liem et al. (2020) conducted a prospective case series study of five patients in VS following anoxic brain injury that were subsequently treated with autologous bone marrow-derived mononuclear cell transplantation. Authors found that all participants made improvements in gross motor function, cognition, and muscle spasticity 6 months following bone marrow-derived mononuclear cell transplantation with no serious adverse effects observed (Liem et al., 2020). One of five patients showed dramatically improved cerebral atrophy and three showed marked improvements in communication (Liem et al., 2020). Overall, authors suggest bone marrow-derived mononuclear cell transplantation is safe and may lead to improvements in cognition, motor function, and muscle spasticity in children in a VS (Liem et al., 2020).

Assistive technology

Among 112 articles included in the present scoping review, four reported the effects of assistive technology on the recovery of persons in MCS (Lancioni et al., 2012, 2015, 2017; Müller-Putz et al., 2012). Three articles concluded that assistive technology provided some benefits for recovery (Lancioni et al., 2012, 2015, 2017) while one presented somewhat puzzling results reporting some benefits of therapy while cautioning the need for further information before conclusions could be drawn (Müller-Putz et al., 2012).

In a case report of a 53-year-old female in MCS following TBI, Lancioni et al. (2012) studied the effect of microswitch technology and contingent stimulation on development of adaptive responding, consolidation and maintenance of responses, and demonstration of learning and discrimination through response-consequence awareness was studied. Following treatment protocol, the patient demonstrated adaptive engagement with stimuli suggestive of an awareness of the links between her responses and contingent stimulation (Lancioni et al., 2012). In this way, she exhibited behavior suggestive of learning (Lancioni et al., 2012). Authors conclude that this method of adaptive responding to contingent stimulation might contribute to improved alertness and arousal in DoC patients related to its promotion of learning and self-determination (Lancioni et al., 2012). This concept was further studied in another study by Lancioni et al. (2015) that employed an ABAB design to further elucidate the effect of assistive technology on the promotion of response and stimulation control in adults in an MCS with hemorrhagic, TBI, anoxic, and ischemic etiologies. Results supported and added to previous study findings in that there was an increased frequency of responses indicating that microswitch assistive technology may promote functional responses and control of stimulation which may increase alertness, self-determination, and personal involvement/enjoyment (Lancioni et al., 2015). These factors may, in turn, augment recovery from MCS (Lancioni et al., 2015). A third study by Lancioni et al. (2017) sought to further elucidate the effects of assistive technology using a microswitch aided program on the recovery of adults in MCS with hemorrhagic, ischemic, encephalopathy, and encephalitis etiologies. In a single subject ABAB study design, authors found that response frequencies and thus input from participants in response to stimuli were increased in all participants during the experimental phase (Lancioni et al., 2017). Data suggested that the microswitch aided program helped effectively train MCS individuals to develop improved control over responses and stimulation (Lancioni et al., 2017). These data support previous work studying similar technologies by the same authors (Lancioni et al., 2012, 2015, 2017).

In slight contrast, Müller-Putz et al. (2012) tested the effects of a novel auditory single switch brain computer interface on recovery of persons in MCS and found that further research was required before conclusions could be drawn regarding benefit of this technology. Still, results showed significant differences in response to deviant and frequent tones on EEG in all patients (Müller-Putz et al., 2012). While results are encouraging, further research will be required to assess whether this technology improves recovery of consciousness in persons in MCS (Müller-Putz et al., 2012).

Rehabilitation, positioning, and symptom management

Nineteen articles discussed rehabilitation, positioning, and symptom management strategies for the treatment of VS/UWS and MCS (Okubo, 2011; Eifert et al., 2013; Howell et al., 2013; Klein et al., 2013; Wheatley-Smith et al., 2013; León-Carrión et al., 2014; Krewer et al., 2015; Thibaut et al., 2015a, b; Eilander et al., 2016; Frazzitta et al., 2016; Jang et al., 2016a, b; Steppacher et al., 2016; Baricich et al., 2017; Jang and Kwon, 2020; Lee et al., 2020; Sattin et al., 2020; Gurin et al., 2022). Of these nineteen articles, fourteen discussed the efficacy of rehabilitation, neurorehabilitation, or physiotherapy-based treatments for VS and/or MCS with nine articles demonstrating successful treatment (Klein et al., 2013; León-Carrión et al., 2014; Baricich et al., 2017; Sattin et al., 2020), four demonstrating some benefits (Eifert et al., 2013; Howell et al., 2013; Eilander et al., 2016; Jang et al., 2016a, b; Steppacher et al., 2016; Jang and Kwon, 2020; Lee et al., 2020; Gurin et al., 2022), and one article demonstrating no benefit towards treatment (Wheatley-Smith et al., 2013).

Recovery from VS to MCS was described in a case report of a 54-year-old patient in VS who received comprehensive rehabilitation therapy as well as in a case report of a 59-year-old male in VS who received comprehensive rehabilitative therapy including neurotropic drugs (modafinil, methylphenidate, amantadine, levodopa, zolpidem, and baclofen), physical therapy, and occupational therapy (Jang et al., 2016a, b). Further, in an observational case report, Jang and Kwon (2020) reported recovery of a 31-year-old female patient in MCS who regained consciousness over approximately six years of comprehensive rehabilitation therapy with neurotropic medications (methylphenidate, amantadine, bromocriptine, pramipexole, and levodopa), physical therapy, and occupational therapy. Sattin et al. (2020) also conducted an observational study of 364 patients in either VS or MCS who received physical and cognitive rehabilitation concluding that rehabilitation treatments are effective and should be included in the treatment plan for patients with VS and MCS. In a case study of a UWS patient 18 years old at the time of injury, gradual improvement to consciousness occurred over 10 years of treatment including multimodal intensive early and late rehabilitation with continued at home treatment and interval hospitalization (Steppacher et al., 2016). At 10 years, while memory remains reduced and speech slow, this patient is able to communicate well using speech, walk, ride a bike, use stairs, live independently, and complete all activities of daily living (Steppacher et al., 2016). Marginal recovery was reported in a prospective cohort study of patients in VS, MCS, or locked in syndrome which tested rehabilitation with passive range of motion and use of tilt table therapy combined with a slow-to-recover brain injury program (Baricich et al., 2017). Over the 4-year study period, 6 of the 49 participants transitioned from VS to MCS, one participant showed a locked in syndrome, eight dropped out, and 29 died (Baricich et al., 2017). At the 36-month mark, 10 VS participants remained, of which 3 transitioned from VS to MCS, 5 remained in VS, and 2 died (Baricich et al., 2017). Overall, authors showed 14.29% recovery of participants who regained consciousness to move from VS to MCS (Baricich et al., 2017).

Interestingly, a retrospective observational study of VS/UWS and MCS patients following coronavirus disease 2019 (COVID-19) infection by Gurin et al. (2022) found that early neurorehabilitation therapy resulted in consciousness recovery in 57% of participants who recovered to MCS or better following neurorehabilitation. Howell et al. (2013) conducted a retrospective cohort study to evaluate the impact of inpatient neurorehabilitation on treatment of patients in VS, MCS, or coma. Researchers reported that 22 patients emerged into consciousness with seven patients reaching a good functional outcome (Howell et al., 2013). Authors concluded that inpatient neurorehabilitation offers hope for functional neurobehavioral improvement though it may take three months to begin to appreciate significant improvement (Howell et al., 2013). Neurorehabilitation was also studied by Klein et al. (2013) in a retrospective single-center cohort study of patients in either VS or MCS with authors findings an improved functional outcome in 19% of patients and an improved behavioral outcome in 39.7% of patients after median neurorehabilitation time of 11 and 9 weeks, respectively. Overall, authors appreciated clinical improvement approximately six months following the start of the neurorehabilitation program (Klein et al., 2013). In a program description and case report of an 18-year-old male in VS, neurorehabilitation integrated into intensive care treatment significantly improved level of consciousness and functional abilities (Eifert et al., 2013). However, this patient had not regained independence with activities of daily living at the time of publication (Eifert et al., 2013). A cross-sectional cohort study was conducted by Eilander et al. (2016) to assess the impact of neurorehabilitation 10–12 years following its completion. At this 10–12-year follow-up, authors found that two thirds of participants who had regained consciousness following the initial intensive neurorehabilitation program were living independently while two thirds of participants who remained in VS/UWS or MCS at program discharge 10–12 years earlier had since died (Eilander et al., 2016).

In a retrospective study on the benefit of neurorehabilitation combined with pharmacologic treatments for those in VS and MCS, Lee et al. (2020) found recovery of consciousness in 46% of subjects who regained consciousness after a median of 200 days during neurorehabilitation. Neurorehabilitation combined with concurrent pharmacologic treatment, stimulation, and neuroimaging which authors collectively termed “The Combined Method” was studied in a case report of a 24-year-old male which found this treatment method to improve posterior and anterior cortical connectivity thus promoting recovery from VS (León-Carrión et al., 2014).

Physiotherapy combined with manual stretching and passive movements, casting and splinting, management of spasticity with Botulinum toxin, and standing interventions for the treatment of patients in VS and MCS was evaluated by Wheatley-Smith et al. (2013) in a retrospective audit study. Following combined therapy, no patients recovered consciousness to emerge from a VS or MCS thus indicating no benefit of therapy.

Three groups presented the effects of position-based therapies for patients in VS and MCS with all three finding some benefits of therapy (Okubo, 2011; Krewer et al., 2015; Frazzitta et al., 2016). Two of three articles focused on patients in VS and MCS (Krewer et al., 2015; Frazzitta et al., 2016) while one article focused only on patients in VS (Okubo, 2011). An early stepping verticalization protocol was tested in a parallel-group single-blind randomized clinical pilot study among VS and MCS patients following severe acquired brain injury (Frazzitta et al., 2016). In this study, short- and long-term functional and neurological benefits were observed with stepping verticalization protocol indicating some efficacy of treatment (Frazzitta et al., 2016). Both Krewer et al. (2015) and Okubo (2011) reported treatment strategies that conferred benefit to recovery of VS or MCS as an adjunct to the treatment plan. In a randomized controlled clinical trial of patients in VS and MCS, Krewer et al. (2015) tested tilt table therapy with and without an integrated stepping device which included conventional tilt table therapy and tilt table therapy with an integrated stepping device. Neither therapy demonstrated a significant change in spasticity for the VS or MCS patients studied (Krewer et al., 2015). However, authors report that the rate of recovery in the conventional tilt table group increased significantly (Krewer et al., 2015). Further, while the tilt table with integrated stepping device did not show significant benefit compared to the conventional tilt table group, verticalization in general was beneficial to this patient population leading authors to recommend its addition to treatment protocols for patients with VS and MCS (Krewer et al., 2015). In another study related to positioning, Okubo (2011) conducted a case study of three VS patients in which researchers tested the efficacy of sitting without back support on recovery. Authors report “at least some improvement” in consciousness with “subtle changes” to “pronounced improvements” in measures such as the Kohnan Prolonged Consciousness Disturbance scale and EEG activity (Okubo, 2011). However, this intervention was costly in terms of time and effort and authors call for further investigation (Okubo, 2011).

Finally, two articles discussed the efficacy of adjunctive treatments for symptom management in VS/UWS and MCS (Thibaut et al., 2015a, b). In a cross-sectional study looking at clinical rehabilitation to manage spasticity among patients in MCS, Thibaut et al. (2015b) found clinical rehabilitation to be helpful in spasticity management which is relevant as improvements in spasticity may improve overall rehabilitation and provide for better recovery and improved quality of life for patients with DoC. Further, spasticity was found to correlate with pain, a meaningful finding as researchers highlighted the importance of pain management as a barrier or facilitator to overall rehabilitation (Thibaut et al., 2015b). Thibaut et al. (2015a) presented a prospective randomized single-blind controlled trial that tested the efficacy of soft splints for symptom management in VS/UWS and MCS patients. Authors found that both soft splinting and manual stretching for 30 minutes led to improved spasticity of the finger flexors and 30 minutes of soft splinting led to improved hand opening ability (Thibaut et al., 2015a). No differences in efficacy were observed between VS/UWS and MCS subjects (Thibaut et al., 2015a).

Music therapy

Music is a form of stimulus known to elicit an emotional response from its listeners which has been shown to benefit cognitive processing in both healthy and diseased brains (Schellenberg, 2006; Koelsch, 2009; Thaut, 2010; Castro et al., 2015). Eight articles presented the effects of music therapy on the recovery of persons with VS/UWS or MCS with two articles reporting successful treatment (Okumura et al., 2014; Castro et al., 2015) and six articles describing some treatment benefit (Lee et al., 2011; O’Kelly et al., 2013; Raglio et al., 2014; Ribeiro et al., 2014; Heine et al., 2015; Steinhoff et al., 2015). No articles reported emergence into consciousness or changes in clinical diagnosis following music therapy.

Castro et al. (2015) and Okumura et al. (2014) explore the effects of music therapy among patients in VS/UWS and MCS reporting efficacious results of treatment. Castro et al. (2015) studied the impact of music therapy on cerebral functioning by measuring subjects’ ability to discriminate their own name (SON) following music therapy. Authors found that discrimination of SON following music therapy was significantly associated with patient outcomes such that all patients who demonstrated discrimination went on to gain additional behavioral responses six months later (Castro et al., 2015). These functional behavioral gains were indicative of MCS or emergence from MCS; therefore, at least a portion of subjects experienced a change in clinical diagnosis or emergence into consciousness indicating successful treatment (Castro et al., 2015). On the other hand, all patients who were unable to discriminate SON in either the music or control conditions, suffered unfavorable outcomes including remaining in the original DoC or succumbing to their illness within 6 months following this study (Castro et al., 2015). Authors suggest that arousal and awareness are likely improved due to personal and emotional aspects of music (Castro et al., 2015). In a study by Okumura et al. (2014), music stimulation was evaluated for its recovery benefit in patients in a VS and MCS following diffuse brain injury. While authors uncovered no significant activation of the temporal superior gyri in VS subjects overall, music stimulation was found to activate the bilateral temporal superior gyri in healthy adults, MCS subjects, and one VS subject (Okumura et al., 2014). Encouragingly, this one VS subject recovered consciousness from VS to MCS following four months of music stimulation (Okumura et al., 2014). Therefore, while some patients did not show benefit of music stimulation, this study still presents encouraging and supportive results for the benefit of music stimulation in persons with DoC (Okumura et al., 2014).

Heine et al. (2015), O’Kelly et al. (2013), and Raglio et al. (2014) also discuss the effects of music therapy amongst patients in VS/UWS or MCS; however, these authors report beneficial results of treatment towards recovery rather than overtly successful therapy. Heine et al. (2015) studied preferred music stimulation among adults in UWS and MCS and found that, compared to control conditions, preferred music showed increased functional connectivity in primary auditory brain cortices linked to consciousness, music perception, and autobiographical memory. O’Kelly et al. (2013) presented an article describing a cohort study as well as three case reports that evaluated the effects of music therapy on patients with VS and MCS by comparing baseline silence with four different auditory stimuli. Like the studies described above, music therapy elicited arousal and selective attention in patients with DoC (O’Kelly et al., 2013). In two case studies on VS patients within this article, discriminatory responses were observed between different music stimuli (O’Kelly et al., 2013). Overall, authors concluded that music therapy may improve or support neuroplasticity to promote functional improvements and call for consideration and further study towards the benefit of its addition to neurorehabilitation for patients with DoC (O’Kelly et al., 2013). Raglio et al. (2014) conducted a controlled observational case study amongst patients in a VS or MCS in which improvements were observed in both VS and MCS patients. Of note, however, greater improvement was reported in the MCS group compared to the VS group (Raglio et al., 2014). Specifically, the MCS group demonstrated improvement in behaviors including eye contact, smiles, communication through use of objects and voice, and decreased demonstration of annoyance or suffering through expressions while the VS group demonstrated only an increase in eye contact (Raglio et al., 2014). Overall, according to their findings, authors concluded that music therapy increases brain activity, reduces stress, potentially promotes relaxation, and could therefore be a beneficial addition to the rehabilitation process among patients with DoC (Raglio et al., 2014).

Studies by Lee et al. (2011), Ribeiro et al. (2014), and Steinhoff et al. (2015) reported the beneficial effects of music therapy among persons in VS/UWS. In a case study of a mid-40-year-old male in VS following hemorrhagic stroke, Lee et al. (2011) found recovery benefits following music therapy though benefits were assessed through measures of cardiovascular and circulatory system activation. Interestingly, authors reported significant cardiovascular and circulatory system activation and enhancement after 14 days of music therapy such that body circulation improved in response to music therapy (Lee et al., 2011). In a pilot study with a quasi-experimental design, Ribeiro et al. (2014) examined the impact of music stimulation on vital signs and facial expression among patients in a VS. Results showed that music stimulation via radio increased systolic blood pressure, heart rate, respiratory rate, and blood oxygen saturation while classical relaxing music reduced respiratory rate and increased blood oxygen saturation, and relaxing music with nature sounds reduced blood pressure, heart rate, and respiratory rate and increased blood oxygen saturation (Ribeiro et al., 2014). While this study did not directly evaluate the effects of music stimulation on consciousness, these results suggest that classical relaxing music and relaxing music with nature sounds stimulation may lead to a state of increased relaxation among VS patients (Ribeiro et al., 2014). In a pilot study assessing the effects of music therapy on UWS patients using positron emission tomography imaging, music therapy was found to activate the frontal, hippocampal, and cerebellar regions of the brain with higher tracer uptake on positron emission tomography imaging after 5 weeks of therapy compared to control group (Steinhoff et al., 2015).

Animal therapy

Animals are known to elicit affection, emotion, and attention as well as caring and social engagement responses (Boitier et al., 2020). For these reasons, animals have been considered useful “partners within therapy” for DoC patients though research demonstrating this relationship is sparse (Boitier et al., 2020). Among the 112 articles, three studied the effect of animal assisted therapy (AAT) or animal presence on recovery of patients with MCS with each finding some level of recovery following treatment yet none described emergence into full consciousness (Hediger et al., 2019; Boitier et al., 2020; Arnskötter et al., 2021).

In a case study of a 28-year-old female in MCS following TBI, Boitier et al. (2020) found that AAT was a beneficial adjunct for recovery increasing awareness and arousal while the animal is present. Hediger et al. (2019) also studied AAT in a randomized two-treatment multi-period crossover trial of MCS patients with TBI and non-TBI. Authors assessed patient responses using behavioral video coding, the Basler Vegetative State Assessment, heart rate, and heart rate variability and found increased behavioral reactions and physiologic arousal during AAT compared to control sessions (Hediger et al., 2019). Authors concluded that these findings suggest that AAT may increase consciousness during treatment sessions (Hediger et al., 2019). Similarly, Arnskötter et al. (2021) aimed to measure the response to interaction with a live animal versus control toy animal in patients in MCS and healthy controls by measuring frontal brain activity using functional near infrared spectroscopy. When patting the live animal versus the control toy animal, three of four subjects demonstrated a stronger hemodynamic response measured by functional near infrared spectroscopy (Arnskötter et al., 2021). Authors appreciated neurovascular reactions that were associated with elevated neural activity in the frontal brain region when MCS patients interacted with animals concluding that live animal interactions were associated with emotional processing (Arnskötter et al., 2021).

Acupuncture

Two articles studied the use of acupuncture for the treatment of adults in VS/UWS and MCS following TBI (Matsumoto-Miyazaki et al., 2016a, b) finding benefit of treatment, while a third article studied the impact of combined Xingnao Kaiqiao acupuncture, oral Angong Niuhuang Wan, and Xingnaojing intravenous drip in a child in PVS reporting emergence into consciousness and thus efficacious treatment (Song et al., 2018).

Matsumoto-Miyazaki et al. (2016a) was the first study to evaluate the effects of acupuncture on spinal motor neurons in persons with DoC using F-wave measurements, a noninvasive method used to measure excitability of spinal motor neurons through evoked electromyography. Compared to controls, a reduction in spinal motor neuron excitability was appreciated via reduced F-wave/M-wave amplitude ratio following acupuncture (Matsumoto-Miyazaki et al., 2016a). These data suggest the benefit of acupuncture for muscle spasticity hypertonia in patients with DoC (Matsumoto-Miyazaki et al., 2016a). In another study by Matsumoto-Miyazaki et al. (2016b), the benefit of acupuncture on recovery from VS and MCS was evaluated using TMS to quantify MEPs indicating the activity of the cortico-spinal tract. Compared to controls, MEP amplitude and MEP/Mmax and therefore cortico-spinal system excitability were significantly increased following acupuncture treatment leading authors to suggest that acupuncture may improve motor function in persons with VS and MCS (Matsumoto-Miyazaki et al., 2016b).

In a case report of a five-year and three-month-old male, authors describe a significant health improvement to a level similar to a healthy child of the same age following treatment with Xingnao Kaiqiao acupuncture, oral Angong Niuhuang Wan, and Xingnaojing intravenous drip (Song et al., 2018). Xingnao Kaigiqao acupuncture was provided for 4 weeks, Angong Niuhuang Wan 0.5 pill was given once daily for a total of three pills, and Xingnoajing intravenous drip 5 mL was administered for 10 days (Song et al., 2018). The patient began to recover after 3 days of treatment, regained consciousness and ability to perform simple tasks after approximately 3 weeks and demonstrated improvement to the level of a healthy child of his age following completion of the 50-day treatment regimen though he still exhibited some fine motor function deficiencies (Song et al., 2018).

Personal objects

One article presented the impact of personal or autobiographic objects on recovery of persons with VS and MCS finding no significant benefit of treatment (Di Stefano et al., 2012). In an interventional clinical trial using a single case design with an A-B-C-B-A paradigm, Di Stefano et al. (2012) tested the impact of enriched stimulation with biographically meaningful objects in an immersive environment on the recovery of patients in VS and MCS. Researchers found that an augmented environment brought about a greater variety of behavioral responses and suggested that such stimulation may improve active behaviors in individuals with VS and MCS (Di Stefano et al., 2012). While not statistically significant, patients in MCS exhibited more behavioral gains than did patients in VS (Di Stefano et al., 2012). Findings suggest that the personal relevance, internal consistency, verbal content, and emotional value of a stimulation program that is personalized are the main factors in determining treatment success (Di Stefano et al., 2012). However, it must be emphasized that the aim of this study was not to evaluate cognitive ability; thus, authors stress that conclusions regarding this outcome cannot be drawn from this data (Di Stefano et al., 2012).

Cranioplasty

In a case report of a 55-year-old male in an MCS with hemorrhagic etiology, cranioplasty was associated with significant improvements in consciousness, cognition, activities of daily living, instrumental activities of daily living on neurological examination, CRS-R, Glasgow Coma Scale, functional independence measure, and mini-mental status exam (Corallo et al., 2015). This patient recovered cognitive, behavioral, and motor functions transitioning from VS to MCS and eventually regaining partial autonomy representing emergence into consciousness (Corallo et al., 2015). Authors claim these gains were “partially related to a proper cranioplasty” and suggest that these findings support the beneficial effect of cranioplasty on neurophysiological and motor function in persons with DoC (Corallo et al., 2015).


  Discussion Top


Standardized, evidence-based protocols for the treatment of DoC are lacking and necessary to address, first and foremost, immense patient and family needs related to DoC, but also the associated societal and economic burdens. This scoping review of the available treatment strategies and their efficacy for recovery among patients in VS/UWS or MCS offers an organized, comprehensive presentation of the literature that may be used to better understand the current state of the literature, knowledge gaps, and areas warranting further study. This review identified a more complete list of numerous articles purporting evidence of successful treatment among patients in VS/UWS or MCS in which some degree of consciousness recovery was appreciated. In an area where evidence-based treatment options are scarce and in high demand, it is necessary to carefully consider all therapeutic options presenting evidence of successful outcomes.

It is important to note that the exact meaning of improvement and recovery differs based on the article studied and the outcomes being measured. Successful treatment is often subjective in the eyes of the researchers. Treatment success for a VS/UWS or MCS can be considered a change in clinical diagnosis from VS/UWS to MCS or MCS to EMCS with emergence into full consciousness marking the ultimate success of treatment. Therefore, efficacy of treatment may be considered in steps such that transition from a VS/UWS to an MCS with the re-emergence of behavioral responses that are repetitive and not reflexive, may be considered successful with the idea that patients may continue to improve with time and further treatment to full emergence into consciousness (Wang et al., 2020a). Still, the ultimate marker of successful treatment is emergence from the disorder of consciousness into a state of arousal, awareness, and consciousness whereby patients regain functional communication and the ability to use functional objects (Nakase-Richardson et al., 2008; Machado et al., 2010). These are the outcomes we strive towards.

However, smaller, more incremental markers of improvement toward the larger goals of change in clinical diagnosis and full emergence into consciousness may also be considered treatment success when the alternative is no improvement at all and there exists no reliable and standardized protocol for treatment. In this case, a treatment strategy may be considered effective if improvements in awareness, neurobehavioral function, and signs of consciousness are appreciated so that the patient is seen to make improvements towards the greater goal of regaining consciousness. To this point, the CRS-R is the most comprehensive, evidence-based, and sensitive behavioral assessment for evaluating consciousness and signs of its re-emergence (Giacino et al., 2004; Estraneo et al., 2019). This behavioral assessment measures these more incremental signs of improvement including cognition, language, vision, perception, communication, and functional mobility and may suggest improvement when overt change in clinical diagnosis or emergence into consciousness is not detected (Giacino et al., 2004). However, further research is needed to determine whether these smaller improvements will eventually lead to further gains and emergence into consciousness. In many cases, authors call for further research which is necessary to fill gaps in our current understanding.

This scoping review has compiled and presented 112 articles that studied treatment strategies for VS/UWS and MCS between 2011 and 2021. Of these 112 articles, 101 described some benefits of the treatment studied while 11 identified no benefit of therapy. Of these 101 articles, 32 reported outcomes that included a change in clinical diagnosis or emergence from the DoC thus indicating a successful and efficacious treatment strategy while 69 discussed treatment strategies that resulted in neurobehavioral gains, improved cognition, recovery of signs of consciousness but not emergence from DoC. Treatment strategies yielding successful results included sensory stimulation, tDCS, TMS, SCS, vagus nerve stimulation, rehabilitation programs, cranioplasty, and pharmacological treatments with zolpidem, amantadine, baclofen, midazolam, and clonazepam dose reduction coupled with neurorehabilitation, which were all associated with changes in clinical diagnosis from VS/UWS to MCS or MCS to EMCS and recovery of consciousness.

Among these successful treatment strategies, comprehensive rehabilitation programs were found to be the treatment strategy that most often resulted in emergence of consciousness with nearly half of collected articles reporting VS/UWS and/or MCS participants recovering consciousness such that there was a change in clinical diagnosis or emergence into full consciousness. Of note, this treatment strategy was the most studied of all strategies collected as part of this review. Perhaps this is because, while not currently standardized, treatment protocols often consist of a variety of interventions that include behavioral, physical, stimulatory, and psychological elements bundled into what is referred to as rehabilitation programs or neurorehabilitation programs. In this multidimensional treatment approach, the care team often consists of a wide range of interdisciplinary members including physicians, specialized nurses, physical therapists, speech and language pathologists, occupational therapists, psychologists, neuropsychologists, case management, and social workers (Eapen et al., 2017). These teams are equipped to handle the myriad needs of patients in VS/UWS or MCS including rehabilitation, acute clinical complications, medication requirements, physical, and neuropsychological needs which may help explain the benefit associated with this type of strategy. It is also worth noting that four of nine articles reporting emergence into consciousness using rehabilitation programs as treatment strategies were case reports of one or two patients rather than larger randomized controlled trials.

SCS was found to be the second most effective treatment strategy associated with emergence into consciousness in half of the articles studied. While questions remain, this treatment strategy is one of the more extensively studied approaches to the treatment of VS/UWS and MCS. Of the five articles that detailed recovery of consciousness associated with SCS, all five were interventional clinical trials of at least nine patients or more. It is possible that this makes the evidence reported by these trials stronger than that of case reports of only one to two participants.

Among therapeutic strategies focusing on stimulation of the nervous system for the treatment of VS/UWS or MCS, tDCS was the most studied. This is perhaps owing to its non-invasive nature, ease of use, portability, and low risk (Eapen et al., 2017). While 13 articles studied tDCS between 2011 and 2021, only 1 reported emergence of consciousness (Angelakis et al., 2014). In this article, benefit of tDCS was greater for patients in MCS compared to patients in VS/UWS supporting previous data suggesting that tDCS is potentially efficacious in the treatment of MCS but not VS/UWS (Angelakis et al., 2014; Thibaut et al., 2014). Further, while not noting emergence into consciousness, eight articles discussed some benefits of tDCS related to improvements in cortical excitability, electrophysiological reactivity, increased arousal and cognitive emotional processing, significant clinical improvements, improved and maintained alertness, improvement in signs of consciousness recovery, and enhanced awareness (Thibaut et al., 2014, 2017; Bai et al., 2017a; Dimitri et al., 2017; Martens et al., 2018; Cavinato et al., 2019; Straudi et al., 2019; Tzur et al., 2020). Again, greater benefit of treatment was observed in MCS patients compared to VS/UWS patients. Still, these incremental improvements may suggest the potential for greater improvement; however, further research is needed to answer this question.

Of the pharmacologic treatments studied between 2011 and 2021, amantadine therapy was associated with recovery of consciousness more often than any other medication studied with three of eight studies reporting emergence from DoC. However, zolpidem, baclofen, and midazolam also resulted in successful treatment with patients emerging from VS/UWS to MCS or MCS to full consciousness.

While technology continues to improve and research is ongoing, limitations in our understanding of pathophysiological mechanisms that underlay DoC, reliably accurate diagnostics, and prognostication persist that make the development and implementation of standardized and efficacious treatment protocols difficult. Wang et al. (2020a) conducted a study to evaluate the rate of misdiagnosis when DoC were diagnosed by clinical consensus versus repeated CRS-R behavioral scale assessments. Researchers found that MCS was clinically misdiagnosed in 38.2% of patients while EMCS was misdiagnosed as MCS in 16.7% of patients and as UWS in 1.1% of patients (Wang et al., 2020a). While improvements in misdiagnosis rates have been seen with emerging technology over the last 10 years, these staggering results underscore persistent limitations in accurate diagnosis of VS/UWS and MCS which in turn lead to limitations in prognostication and prediction of recovery. These limitations have implications on treatment making it difficult to determine appropriate and potentially efficacious strategies that may lead to improvement and recovery. Still, however, the CRS-R is not used routinely in clinical practice but is rather employed most by clinical psychologists and researchers studying these disorders (Wang et al., 2020a). We will conceivably continue to face these challenges until this sensitive test is adopted by more clinicians in the evaluation and continued assessment of patients in VS/UWS and MCS.


  Conclusions Top


In this scoping review, ultimate success of treatment is considered the change in clinical diagnosis from VS/UWS to MCS or from MCS to EMCS as well as a general emergence into full consciousness. While standardized and reliable treatment protocols for the treatment of patients in VS/UWS or MCS do not currently exist, many strategies have been employed and studied to facilitate recovery. Of these, it appears the most successful, efficacious, and well-studied include comprehensive rehabilitation or neurorehabilitation programs, SCS, and pharmacologic therapy with amantadine. However, at this point, further research is warranted in this area, and it would seem irresponsible to rule out the benefit of the abovementioned treatments that also resulted in recovery of consciousness, albeit less often or less well-studied as of yet. As technology and medical capacity to more accurately diagnose, prognosticate, identify biomarkers, evaluate progress, and predict recovery continue to improve, so too will our understanding of DoC and its treatment targets. Given the personal, societal, and economic burden associated with DoC, efficacious treatment strategies are necessary and continued research in this area is warranted.

Author contributions

Review design, literature search guide, and manuscript edit: JW; literature search and manuscript draft: BM. Both authors approved the final version of the manuscript.

Conflicts of interest

None.

Editor note: JW is an Editorial Board member of Brain Network and Modulation. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editorial Board member and his research group.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Additional files

Additional Table 1: Literature review table.

Additional file 1: Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist.



 
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