Hope for Patients With Prolonged Disorders of Consciousness

April 25, 2019

New therapeutic approaches are providing hope that patients with prolonged disorders of consciousness can show improvement and can benefit from various interventions even years after the injury, a review of the field indicates.

"I don't want to give false hope to families of patients with prolonged consciousness disorders, but we are finding that there are things we can do for these patients. As a medical field, it has historically been viewed as one with no hope. But we are now proving this to be wrong," lead author Aurore Thibaut, PhD, University of Liège, Belgium, told Medscape Medical News.

"In the past few years, there have been a few cases where patients have regained consciousness after many years, and these cases have rejuvenated interest in the field," she said.

"We see many patients who have loss of consciousness for many years. We want to do something for them — try new therapeutic approaches," Thibaut added. "It might not be possible for these patients to make a full recovery, but it is likely that some of them will be able to have some improvement in movement or communication with therapeutic input."

The review was published online in Lancet Neurology on April 16. It reports latest results with drug therapy, noninvasive brain stimulation, and sensory stimulation programs for these patients.

"These interventions have been all associated with increased signs of brain activity, showing that we should not just leave these patients in bed alone 24 hours a day," Thibaut said.

They need "long-term, active rehabilitation," she added. "The brain can respond to these rehabilitation treatments, so we shouldn't give up on these patients."

The review explains that disorders of consciousness include coma, characterized by unwakefulness and only reflex behaviors; unresponsive wakefulness syndrome (previously known as vegetative state), characterized by wakefulness but with only reflex behaviors; and minimally conscious state, characterized by clinical demonstration of signs of consciousness.

Very few controlled studies of therapeutic options have been conducted, but following publication of a landmark article on amantadine (multiple brands) in 2012, this field has evolved rapidly, with new therapeutic approaches being tested and reported, the authors state.

The 2018 American practice guidelines for patients with disorders of consciousness only recommend amantadine for patients who have unresponsive wakefulness syndrome and minimally conscious state 4 to 16 weeks after having a traumatic brain injury. The recommendation is based on one available randomized trial.

However, Thibaut and colleagues note that many studies failed to meet the strict criteria for inclusion in the guidelines. The current review was undertaken to critically evaluate therapeutic options for patients with prolonged disorders of consciousness that have been studied in the past 6 years. The review included open-label studies and anecdotal case reports, "as they still provide insightful results to guide future research," the authors write.

Drug Therapy

The only drug that has been recommended in guidelines is amantadine. It was recommended after publication of a randomized trial involving 184 patients who experienced prolonged disorders of consciousness after experiencing traumatic brain injury (28 to 112 days after injury). In that trial, the patients who received amantadine (up to 200 mg twice a day for 4 weeks) recovered faster than the patients who received placebo, as determined on the basis of measurements using the Disability Rating Scale.

Two case reports of the use of amantadine for patients with nontraumatic brain injury have also been published. In these trials, amantadine showed positive effects for patients in a minimally conscious state. These findings should encourage the development of a randomized controlled trial of amantadine involving patients with disorders of consciousness with causes other than traumatic brain injury, the review says.

The hypnotic zolpidem (multiple brands) has been associated with improvements in scores on the Coma Recovery Scale–Revised in a small percentage of patients in two placebo-controlled trials. In addition, there has been a case report of a patient with unresponsive wakefulness syndrome (>3 years after cardiac arrest) who recovered consciousness after receiving a higher dose of the drug (30 mg).

Neuroimaging studies have identified an increase in brain activity, mainly in prefrontal regions, after zolpidem administration. "Determining the behavioural and physiological profile of zolpidem responders is crucial to better identify the patients that could benefit from this treatment," the report states.

Other drugs that have been reported to stimulate the recovery of consciousness in a few uncontrolled studies or case reports include intrathecal baclofen (multiple brands), midazolam (multiple brands), and ziconotide (Prialt, TerSera Therapeutics LLC). "These anecdotal findings need to be confirmed with randomized controlled trials," the authors say.

Noninvasive Brain Stimulation

Use of transcranial direct current stimulation has resulted in improvement in signs of consciousness in five randomized controlled trials involving patients who were in a minimally conscious state.

"Although the sample sizes were relatively small and the field of non-invasive brain stimulation for patients with disorders of consciousness is still in its infancy, transcranial direct current stimulation seems a promising treatment approach for patients in a minimally conscious state," the review states.

"Patients with prolonged disorders of consciousness can show clinical improvements after transcranial direct current stimulation, such as the recovery of object manipulation or functional communication, even years after the brain injury, but a continuous application of transcranial direct current stimulation seems to be required."

The prefrontal cortex seems to be the best target for stimulation. Clinical improvement following transcranial direct current stimulation seems to require partial functional and structural preservation of the dorsolateral prefrontal cortex and other brain regions crucial in consciousness recovery, such as the precuneus and the thalamus.

Within the growing field of noninvasive brain stimulation, transcranial direct current stimulation is the only intervention that has resulted in a clinical effect in multiple randomized controlled trials, specifically in patients in a minimally conscious state, the review notes.

However, not all patients respond, its effects are limited to the recovery of a few signs of consciousness, and the changes are transient. Therefore, the technique needs to be optimized to induce long-lasting, clinically meaningful improvements, the authors comment.

They suggest that in the future, stimulation could be tailored using individual structural brain changes, as determined on the basis of neuroimaging findings.

Of note, no side effects have been reported in all studies of repeated transcranial magnetic stimulation studies.

"The area of transcranial direct current stimulation is now moving very fast," Thibaut added. "I think this is where the future lies. We can target a specific region of the brain, and new devices are being developed that can stimulate several regions, thus increasing activity across the entire brain network.

"If used with MRI, it is possible to target the stimulation to the location of brain lesions," she added. "These noninvasive brain stimulation techniques also have very few side effects, so are very promising indeed."

With regard to the other noninvasive interventions, repeated transcranial magnetic stimulation did not have a significant effect at the group level in any randomized controlled trials, the review states. However, preliminary results of uncontrolled studies with this approach suggest that many parameters (eg, target area, frequency, or duration of stimulation) could be optimized to enhance its efficacy.

Other noninvasive brain stimulation approaches that in case reports have resulted in improvement include focused ultrasound pulse targeting of the central thalamus, transcutaneous auricular vagal nerve stimulation, and caloric vestibular stimulation.

Invasive brain stimulation (requiring surgical implantation of electrodes) of the thalamic reticular nuclei has resulted in small behavioral improvements, but the authors say this approach seems limited to a small proportion of patients with prolonged disorders of consciousness.

They add that no sham-controlled trial has been published on deep brain stimulation involving patients with disorders of consciousness, and there are many clinical and ethical issues associated with this approach, such as the risk for infection and consequent clinical deterioration, that need to be addressed.

Sensory Stimulation Programs

One small, double-blind, randomized controlled trial suggested that auditory stimulation, in which stories involving autobiographical events were told to patients by relatives, could speed up recovery for patients with prolonged disorders of consciousness. Uncontrolled studies have also suggested improvements with other sensory stimulation programs, including motor-based therapy, auditory-based training, music therapy, and multisensory training programs.

"Present findings suggest that some patients might benefit from rehabilitative interventions, even years after the brain injury," the authors conclude.

However, the results need to be confirmed in larger studies and cannot yet be translated directly into clinical practice.

"Given the promising effects of some treatments in patients with prolonged disorders of consciousness, we are convinced that the field of therapeutic interventions will make important progress in the years to come," they write.

Thibaut has received grants from the Belgian National Funds for Scientific Research, the European Union's Horizon 2020 Framework Program for Research and Innovation, the Luminous project, the James McDonnell Foundation, the Mind Science Foundation, the Belgian government, Fondazione Europea di Ricerca Biomedica, the Bial Foundation, and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Lancet Neurol. Published online April 16, 2019. Abstract

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