The lack of an approved treatment for promoting return of consciousness in patients in vegetative state (VS) and minimally conscious state (MCS) raises the question of whether or not off-label prescription of stimulants should be encouraged. For specialists working in brain injury, the decision is more related to which drug to use. Unfortunately, there are many patients without access to specialists with expertise in pharmacological management who may as a consequence never be treated with any pharmacological agent. Although, there are sufficient leads from neuroanatomical, functional and clinical data to create a theoretical support for off-label prescription, the uncertain prognosis of VS-MCS in addition to the lack of strong evidence to suggest which drugs might be indicated for particular conditions raises treatment decision concerns.
One of the most difficult situations to face in medicine is when previously healthy subjects suddenly experience a severe trauma and die. Sometimes, though, surviving can be even worse. Some patients may receive the proper acute care treatment to live, although remaining unaware. The natural evolution in those patients is discouraging. Only around 24% of VS traumatic patients (The Multi-Society Task Force on PVS, 1994) and 50% of MCS (http://www.coma.ulg.ac.be/images/COMA_OUTCOME.pdf) patients improve spontaneously at a one-year follow-up. Worldwide, health support for the patients is highly variable. In developed countries with private health insurance, VS-MCS patients may receive an expedited subacute brain trauma neurorehabilitation approach, which consists of a multisensory stimulation program and a quick organization of a home-based or long term care facility discharge. If the health system is public (still in developed countries) chances to receive or not the standard of brain trauma neurorehabilitation are equally distributed. The situation gets worse in undeveloped countries where one can hardly find a brain trauma neurorehabilitation unit and exceptionally few patients can access them. The future of any VS-MCS patients without access to a specialist is generally predictable: they are managed by a large group of physicians not involved in brain injury (i.e., primary physicians or specialists in Internal Medicine). Most of the time, these physicians assume that since there is lack of an approved treatment to regain consciousness there is no need for treatment beyond avoiding infections and maintaining the patients` nutritional status. In this sense, VS-MCS patients become an abandoned population because if there is no potential to improve, they are free to spontaneously develop progressive and severe spasticity (the decision to use botulinum neurotoxin A or intrathecal baclophen is always made by a specialist). This is why such patients end up laying uncomfortably in their orthopedic beds or wheelchairs receiving only very basic support from physiotherapy. Brain injury not only affects the injured persons; the expansion wave normally reaches the surrounding family nucleus and friends who see their own lifestyles changed in many ways.
It is important to state that when a VS-MCS patient reaches a specialist without too much doubt he/she will receive an off-label prescription of stimulants in addition to the stimulation program. However, in the case of those patients that skip the specialist chances of being treated in this manner are generally reduced. Since we are dealing with a small population of patients that represent a heavy social burden it should not be so difficult to avoid such asymmetries. The question then is double; on one hand, is off-label prescription of stimulants a correct procedure? Or, is it correct to not prescribe them? In this dilemma, there clearly has to be one answer.
In the absence of a goal-standard of treatment off-label prescription of stimulants should be the subsequent procedure if there is logical foundation for doing so. One logic may be that VS-MCS patients are in the worst neurological condition a person can be, awake but unresponsive (or at least not consistently responsive or fully responsive), and no matter which stimulant is chosen by the specialist, none entails a major risk. This is a very humanistic point of view but far from science. Another logical view may be specialist`s clinical impression that VS-MCS patients seem to have greater chances to remain unaware for a longer period of time without the use of stimulants, an argument a bit more scientific but still unproven. However, truth is that there is a theoretical framework to support off-label use of stimulants, which allows one to claim that unless a VS-MCS patient has proved to be unresponsive to stimulants he/she has to be considered a patient with an uncertain prognosis (i.e., they may or they may not respond). Then, and following this statement, avoiding prescription of a stimulant should not be considered as a correct practice.
Support for off-label use of stimulants in VS-MCS
The first thing to highlight is that there is no animal model of long term disorders of consciousness (i.e., VS and MCS). Nevertheless, during the last 15 years there has been an increasing knowledge of the clinical diagnosis and the underlying mechanisms on VS-MCS. It seems clear from behavioral and functional data that what is mainly occurring in these traumatic patients corresponds to a lack of cognitive integration. After a severe TBI, the brain behaves like multiple islands represented by pools of neurons devoted to different cognitive aspects that cannot act in conjunction (Schiff et al., 2002; Laureys et al., 2004; Owen et al., 2006; Boly et al., 2007). Neuropathological studies show that one of the most important phenomena occurs at the thalamic level (Adams et al., 2000), and this is why there is a correlation between abnormal thalamic diffusivity on DTI and the clinical diagnosis of either VS or MCS (Fernández-Espejo et al., 2011). All current evidence points towards a dynamic alteration of the thalamus to ensemble cognitive information from associative cortices in the frontal and parietal lobes (Laureys et al., 2000). In addition, there is an alteration of the neuroreceptors in the brain of VS-MCS patients, where it is possible to observe a reduction in the expression of dopamine receptors at the pre- and post-synaptic level (Donnemiller et al., 2000). From the clinical point of view and to further support this reduction, it is interesting that more than 80% of VS-MCS patients that have responded to stimulants have received a dopaminergic agent. Some of them with l-dopa (Haigh and Ruess, 1990; Wolf and Gleckman, 1995; Matzuda et al., 2003; Krimchansky et al., 2004), others with Bromocriptine (Passler and Riggs, 2001), Amantadine (Zafonte et al., 1998; Meythaler et al., 2001, Patrick et al., 2006), Apomorphine (Fridman et al., 2009; Fridman et al., 2010) and Pramipexol (Patrick et al., 2006).
This available information has made it possible to consider the dopaminergic deficiency model in VS-MCS patients as the one having the most logical support. Additionally, this framework mirrors Parkinson’s disease (PD), the most well known model of dopaminergic deficit, although, a clear limitation exists in this comparison as the dominant deficit in PD affects the motor domain but does not produce severe alteration of consciousness. One physiopathological theoretical solution to this problem may be that in VS-MCS the transmission is also affected at the connection between the thalamus and the nigrostriatal circuit, through the dopaminergic mesothalamic system, that exceeds the typical nigriostriatal alteration of PD (Fridman et al., 2009). This model fits well with the target location for deep brain stimulation chosen in VS-MCS patients (Schiff et al., 2007).
Can we standardize off-label choice?
Although for the time being we cannot standardize the off-label choice, this should not be an impediment to share our experiences and discuss our opinions. Of the several dopaminergic drugs that have already been tried in VS-MCS patients, Amantadine seems to be the weakest. The fact that Amantadine is useful in PD at early stages when there are mild clinical signs and symptoms raises the question of whether VS-MCS patients are only expressing a mild dopaminergic deficit or that Amantadine has an idiosyncratic unknown mechanism of action over them. But if this is not the case, we should not expect a major or fast response using it.
Fortunately, the results of the first double blind placebo controlled multicenter study within this population of patients are near completion. Bromocriptine and Pramipexol are mostly used at the later stages of PD, when the dopaminergic deficit is much more marked. However, they are normally used as co-adjuvant medications of l-dopa therapy (Goetz et al., 2005), but they are not effective as monotherapy. Indeed, only two drugs have shown to have major efficacy at this late stage of PD as monotherapy: l-dopa (Goetz et al., 2005) and Apomorphine (Manson et al., 2002), and responses to either of them are considered in the differential diagnosis of PD and Parkinsonism (i.e., levodopa test and apomorphine test). Therefore, if there is a likelihood that in VS-MCS there is a major alteration of the dopaminergic system it seems reasonable to try one or the other.
Personal experience and impressions
I believe there is a major dopaminergic deficit in VS-MCS traumatic patients, and following this posit consider that a patient should not be deemed unresponsive to stimulants unless a strong dopaminergic drug fails to restore consciousness. During the last 10 years Apomorphine has been my drug of choice for stimulation. However, while waiting for the corresponding IRB and Health Administration approvals, as well as acquiring further support for the use of Apomorphine, I treated all of my VS-MCS patients with l-dopa (data still unpublished). Most of those cases seemed to improve more than spontaneously, as previously suggested (see above), but when high doses were reached (up to 2000 mg). In order to reach such doses with l-dopa more than three weeks were needed in order to avoid dopamine related side-effects of emesis, hypotension and diarrhea. Although the scheme is feasible, it is very demanding for nurses: l-dopa needs to be administered every three hours during the awake-part of the circadian rhythm and requires disconnection of feeding 45 minutes in advance of each dose, aswell as restoration 45 minutes after to evade interference on its absorption when combined with proteins.
With Apomorphine it is possible to skip these limitations of l-dopa; it can be raised to high doses (8 mg/hour) in less than one week; and feeding does not interfere with apomorphine absorption since it is given subcutaneously and continuously with an infusion pump. Thus, nurses have to just turn the pump on at 8:00 AM and take it off at 8:00 PM. There is no diarrhea at all, but there is a greater likelihood of vomiting which can be reduced with the prophylactic use of antiemetic agents such as Domperidone. Probably the major limitation of Apomorphine is that it is not a famous drug. In the U.S. it is almost exotic, only approved for erectile dysfunction and in Europe it is well-known but only in the movement disorders field. As a Neurologist, I first encountered apomorphine during my residency training program. Its marked effects in PD can be seen as quickly as 20 minutes after the subcutaneous injection. I have tried it in several VS-MCS cases and have seen improvement in all patients except one. Since these patients received Apomorphine in an open-label fashion I will only refer to two cases where the nature of their response makes a placebo effect or spontaneous recovery unlikely. My first case was an impressive clinical proof of dopaminergic deficit (Fridman et al., 2009). The patient remained in a MCS for 104 days after a severe TBI. During this period he had received Methylphenidate (15mg qd for 12 days) and Bromocriptine (10mg qd for 8 days) without any response. However, in less than 24 hours of apomorphine infusion, again on day 104, he started to obey commands, and in less than one week to verbally communicate. If Apomorphine was disconnected during the awake-part of the cycle, patient showed “off” phenomenon that was reversed when Apomorphine was again administered. In addition, he presented dyskinesias with high doses of apomorphine (8 mg/h), a well known consequence of dopaminergic denervation (Jenner, 2003). Fast response, “on-off” phenomena, and dyskinesias are three very clear signs of an existing dopaminergic deficiency that could be overcome with Apomorphine. The second patient was my last experience some weeks ago in collaboration with Dr. Magnus Esbjörnsson in Sweden (data still unpublished). We treated a patient that remained in MCS for 126 days after a severe TBI and who had previously never received any type of stimulant medication. He started to follow some commands during the initial 24 hours, to reach, grasp and manipulate an object in 4 days, and make attempts to communicate in less than one week. The patient presented “off” phenomenon as well, and dyskinesias while raising Apomorphine to 5mg. Although in this last case the clinical response seems to be less spectacular than the first patient, he displayed one more time the three evidences that there is a failure in the dopaminergic system, and that this deficit can be replaced.
Our population belongs to a vulnerable group of patients, in part, due to their inability to sign an informed consent form. Normally, families demand the use off-label stimulants. By regulatory laws, the industry should not promote off-label use of medicines. On the other hand, by medical ethics and in view of the lack of approved drugs, we cannot deny to any of those families the possibility of treating a patient until a goal-standard is set. Off-label prescription in our patients would not interfere with the pursuit of the final objective; that is, to find the goal standard.
In this article, I have shared my personal experience with stimulants for VS-MCS patients. A methodology to collect information in a structured fashion (i.e. VS-MCS off-label global data base) to share data and knowledge should be advocated. This may not allow us to recognize the real population of responders (for this we will still need double-blind placebo controlled trials) but it may help to discriminate those patients that are refractory. In other words, what would happen if a refractory patient to one drug later responds to another stimulant?
Although from a research point of view, such a procedure (prescription of stimulants in an open label way) can be seen as primitive, trial and error may help those patients who are waiting for a goal-standard of treatment. Dr. Sacks opinion about his famous experience with l-dopa in a group of patients with sequelae of lethargic encephalitis is worth reading (Sacks, 1983): “These were not "ordinary" patients with Parkinson's disease: they had far more complex pathophysiological syndromes, and their situations were more complex”; "I was faced by scientific and human complexities, complexities and perplexities of a sort which had not arisen in previous trials of levodopa, or, indeed, of any treatment in the past. Thus there was an element of the extraordinary, the unprecedented, the unpredictable. I was setting out, with my patients, on an uncharted sea....”. Our patients in VS-MCS are not that far from those patients, and we do not have an approved treatment as of yet.
I am thankful to Dr. Nathan Zasler for his helpful comments and for the manuscript editing. EAF is supported by a Fondation pour la Recherche Médicale.
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