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Thread: The Minimally Conscious State

  1. #1

    The Minimally Conscious State

    The Minimally Conscious State
    18 May 2011
    Wise Young PhD MD

    A man recently called me concerning his mother who had cardiac arrest and suffered hypoxic brain damage. She is two and a half months after her injury, responds on all four limbs to stimulus, opens her eyes but does not seem to see or fixate, and is not consistently responsive to voice or music. She seems to have sleep and wake cycles. He wanted to know whether stem cells could do anything, whether growth and other hormones would help, what drugs may be useful. I tried to explain what I know about such states and thought that I would summarize it here.

    Consciousness is poorly understood state of the brain where awareness of feelings, wakefulness, sense of self, and executive control of the mind is present. Many scientists have proposed various theories of consciousness, none of which seem to account for all the observations and none that have provided clear therapeutic interventions that can restore consciousness to those who have lost consciousness.

    Brain injury causes lapses of consciousness. People and animals also undergo sleep states that includes state of restricted consciousness. A variety of drugs can cause unconsciousness, including alcohol, sleeping drugs, opioids, and other drugs that inhibit neural activity. Of course, anesthesia produces unconsciousness or various states of altered consciousness.

    No single theory explains all these states of altered consciousness. However, of the theories that have been proposed, I prefer one proposed by Rodolfo Llinas (with whom I had obtained my PhD). He proposed that consciousness results from rhythmic activities of thalamic activity, synchronizing cortical activity in a frequency range of 30-90 Hz (called gamma frequency). This theory explains why disruptions of thalamic activity causes loss of consciousness.

    When the thalamus has been damaged to the extent that it can no longer produce this rhythmic activity to synchronizing the various parts of the brain, consciousness is lost. To restore thalamic activity, some investigators have tried to do "deep brain stimulation" or DBS in the gamma frequency. This may "wake" some patient from coma but the efficacy of such stimulation is low and difficult to predict.

    DBS is sometimes combined with pharmacological stimulation such as citicoline, a drug that has been reported to shorten coma and to hasten recovery from minimally conscious state. The electrodes were placed in the anterior intralaminar thalamic nuclei and adjacent paralaminar regions. Stimui were biphasic, square-wave pulses (90 µsec/phase in 100 µsec trains, intertrain rate 130 pulses/sec with intertrain interval of 1.25 seconds).

    In a widely publicized case, Schiff, et al. (2007) studied a 38-year old man who was minimally conscious for 6 years after a traumatic brain injury. Following implantation and therapy, the researchers reported improvement in level of arrousal (sustained eye opening, head turning to voice), functional limb movements, ability to feed orally, and improvements in the JK coma Recovery Scale. The patient was eventually able to name objects with his hands and feed himself.

    Oliverira & Fregni (2011) recently reviewed the literature and found 8 studies that focused on treatment of the vegetative state (VS) or minimally conscious state (MCS). According to the paper, 10,000-25,000 adults and 4000-10,000 chilren are in a persistent vegetative state in the United States. The treatments include levodopa, amantadine, zolpidem, baclofen, dorsal column stimulation, and deep brain stimulation. The side-effects were mild but the effects were also generally small, i.e. 15% of the patients may improve.

    One study by Kanno, et al. (2009) in Japan used dorsal column stimulation of 202 patients. Of these patients, 38 showed motor improvement to object manipulation and non-international movement; 39 experienced improvement to intelligible verbalization and 163 showed no improvement. This was not a controlled study and it is not clear whether this number of patients would have recovered without the dorsal column stimulation.

    In minimally conscious states, two obstacles must be overcome to achieve consciousness. The first is getting the thalamus working sufficiently to restore gamma rhythmic activities to synchronize the cortex. The second is having sufficient memory function (hippocampus) for the person to remember the awareness. Without both of these function, meaningful consciousness is difficult to achieve.

    To my knowledge, there is no credible evidence in animal or human studies to suggest that stem cell therapies will restore consciousness or otherwise improve minimally conscious patients. Because unconsciousness is difficult to model in animal models, there is no animal study of stem cell transplants and their effects on consciousness. Encinas, et al. (2011) did reported that electrical stimulation of the thalamus stimulates neurogenesis in the hippocampus in mice.


    1. Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker K, Berber M, et al. (2007). Behavioral improvements with thalamic stimulation after severe traumatic brain injury. Nature 448: 600-603.

    2. Sen AN, Campbell PG, Yadla S., Jallo J, Shran AD (2010). Deep brain stimulation in the management of disorders of consciousness: a review of physiology, previous reports, and ethical considerations. Neurosurg. Focus 29: E14.

    3. Oliveira L, Fregni F (2011). Pharmacological and electrical stimulation in chronic disorders of consciousness: new insight and future directions. Brain Inj. 25: 315-27.

    4. Kanno T, Morita I, Yamaguchi S, Yokoyama T, Kamei Y, Anil SM, Karagiozov KL (2009). Dorsal column stimulation in persistent vegetative state. Neuromodulation 12: 33-39.

    5. Encinas et al. Neurogenic hippocampal targets of deep brain stimulation. J Comp Neurol (2011) vol. 519 (1) pp. 6-20
    Last edited by Wise Young; 05-18-2011 at 11:26 AM. Reason: corrected traumatic spinal cord injury to traumatic brain injury (Schiff)

  2. #2
    What is the proposed mechanism for the paradoxical efficacy of zolpidem in reversing PVS?

  3. #3
    Quote Originally Posted by PaidMyDues View Post
    What is the proposed mechanism for the paradoxical efficacy of zolpidem in reversing PVS?
    Zolpidem binds specifically to omega 1 subunit of the GABA A receptor. I am not sure that anybody knows precisely why blockade of this receptor results in reversal of the persistent vegetative state (PVS). I attach a paper that describes a case report of its use.

    Unfortunately, the evidence that Zolpidem that does reverse PVS is not robust. I found three papers of its use for traumatic brain injury [1-3]. As you can see, most of these are case reports instead of controlled clinical trials. In 2004, Claus & Nel [4] in the Royal Surrey County Hospital in UK reported that zolpidem showed better brain spect scans after administration of zolpidem. Cohen & Duong, et al. [5] in 2008 reported a 35-year old man with anoxic injury and treated with twice daily with zolpidem responded with dramatic improvement in alertness, speech, and gait. In the same year, Shames & Ring [6] reported a case of 50-year old woman who was minimally conscious at 18 months after severe anoxic brain injury. Apparently, within 45 minutes after the initial dose of 5-10 mg, the patient ceased athetoid movements, regained speaking ability and ability to perform various tasks including self-feeding. Whyte, et al. in 2009 [7] did a small randomized placebo-controlled crossover trial in 15 minimally conscious participants and found that only one of 15 showed clinically significant response. In 2010, Snyman, et al. [8] studied 3 children that were had coma or near-coma. The patients showed *reduced* responsiveness and blood flow did not increase.

    The data is not impressive.



    1. Nyakale NE, Clauss RP, Nel W and Sathekge M (2010). Clinical and brain SPECT scan response to zolpidem in patients after brain damage. Arzneimittelforschung 60: 177-81. Nuclear Medicine Department, University of Pretoria, South Africa. Previous reports document transient improvements after daily zolpidem (CAS 82626-48-0) in patients with brain damage. This multi-patient study evaluates the response to zolpidem in neurologically disabled patients, using 99mTcHMPAO brain SPECT scans and clinical rating scales. METHOD: 23 of 41 consecutive adult patients, at least 6 months after brain damage were identified as neurologically disabled patients by scoring less than 100/100 on the Barthel Index. Causes of their brain damage included stroke (n = 12), traumatic brain injury (n = 7), anaphylaxis (n = 2), drugs overdose (n = 1) and birth injury (n = 1). The selected 23 patients had a baseline 99mTcHMPAO brain SPECT scan before starting daily zolpidem therapy and a second within two weeks of therapy, performed 1 h after 10 mg oral zolpidem. Scans were designated as improved when at least two of three assessors detected improvement after zolpidem. The rest were designated non improved. After four months daily zolpidem therapy, patients were rated on the Tinetti Falls Efficacy Scale (TFES) before and after zolpidem. The TFES ratings were compared using a Wilcoxon non parametric signed rank test. Scan improvers were compared with non improvers, using a two sample t test with unequal variance. RESULTS: Mean overall improvement after zolpidem on TFES was 11.3%, from 73.4/100 to 62.1/100 (p = 0.0001). 10/23 (43%) patients improved on SPECT scan after zolpidem. Their mean TFES improvement was 19.4% (+/- 16.75) compared with 5.08% (+/- 5.17) in 13/23 non improvers (p = 0.0081). CONCLUSION: This prospective study adds further evidence to previous reports of zolpidem efficacy in patients with established brain damage.

    2. Singh R, McDonald C, Dawson K, Lewis S, Pringle AM, Smith S and Pentland B (2008). Zolpidem in a minimally conscious state. Brain Inj 22: 103-6. Department of Rehabilitation Medicine, Astley Ainslie Hospital, Edinburgh, UK. BACKGROUND: Case reports of the use of zolpidem in Permanent Vegetative States (PVS) have led to interest by the media and court judgements defining treatment with such drugs. It is uncertain whether this paradoxical effect of zolpidem in raising consciousness may be evident in other low awareness states such as Minimally Conscious State (MCS). CASE STUDY: This study treated a 44 year old male with MCS some 4 years after his traumatic brain injury with zolpidem for 1 week on and 1 week off treatment. Assessment with a number of tests by blinded therapists showed that his scores were no better on zolpidem and in some cases were worse on treatment. CONCLUSIONS: Ideally a series of individuals is required to assess the effect of zolpidem, but in the light of positive spin stories in the media, negative case reports should also be highlighted. It is imperative that medical treatment in all instances and certainly in low awareness states and end of life decisions is always based on firm evidence.

    3. Yang W, Dollear M and Muthukrishnan SR (2005). One rare side effect of zolpidem--sleepwalking: a case report. Arch Phys Med Rehabil 86: 1265-6. Department of Neurology and Rehabilitation, University of Illinois, Chicago, IL, USA. Zolpidem is an imidazopyridine agent indicated for the short-term treatment of insomnia. Sleepwalking is a rare side effect of zolpidem. A review of the literature produced only 2 cases. We report a case of a male rehabilitation inpatient in his mid fifties with a history of alcoholism and traumatic brain injury who had undergone a right hip hemiarthroplasty. He had no history of somnambulism or insomnia but walked in his sleep on 2 nonconsecutive nights after taking zolpidem. He had exhibited no such behavior before taking zolpidem, on the intervening night that was he was not given medication, and after the medication was discontinued. We conclude that zolpidem can cause sleepwalking, and patients who have suffered a brain injury may be more susceptible to this side effect. Here we describe the clinical presentation and review the relevant literature on zolpidem and sleepwalking.

    4. Clauss RP and Nel WH (2004). Effect of zolpidem on brain injury and diaschisis as detected by 99mTc HMPAO brain SPECT in humans. Arzneimittelforschung 54: 641-6. Nuclear Medicine Department, Royal Surrey County Hospital, Guildford, Surrey (United Kingdom). The study investigates the effect of zolpidem (CAS 82626-48-0) on brain injuries and cerebellar diaschisis. Four patients with varied brain injuries, three of them with cerebellar diaschisis, were imaged by 99mTc HMPAO Brain SPECT before and after application of zolpidem. The baseline SPECT before zolpidem showed poor tracer uptake in brain injury areas and cerebellar diaschisis. After zolpidem, cerebral perfusion through brain injury areas improved substantially in three patients and the cerebellar diaschisis was reversed. Observations point to a GABA based phenomenon that occurs in brain injury and diaschisis that is reversible by zolpidem.

    5. Cohen SI and Duong TT (2008). Increased arousal in a patient with anoxic brain injury after administration of zolpidem. Am J Phys Med Rehabil 87: 229-31. Division of Physical Medicine and Rehabilitation, Department of Orthopedic Surgery, Stanford University, California, USA. A 35-yr-old man sustained an anoxic brain injury resulting from cardiac arrest, with subsequent extreme lethargy and lack of response to stimuli. The patient's lethargy was unresponsive to trials of several medications in attempts to increase arousal. Administration of twice-daily zolpidem 8 mos after injury resulted in a dramatic increase in the level of alertness, including improved speech and gait. When the patient was not able to receive zolpidem for a brief period, the patient's lethargy returned, and he became bedbound until the medication was resumed.

    6. Shames JL and Ring H (2008). Transient reversal of anoxic brain injury-related minimally conscious state after zolpidem administration: a case report. Arch Phys Med Rehabil 89: 386-8. Day Rehabilitation Center, Maccabi Health Services, Rishon Lezion, Israel. Zolpidem is a unique nonbenzodiazepine sedative hypnotic drug that selectively binds to omega-1 gamma-aminobutyric acid receptors in the brain. Although used for years in Israel and abroad for insomnia, there have been periodic reports of unusual or remarkable neurologic effects in patients with various brain pathologies. Here, we report on a 50-year-old woman 18 months after severe anoxic brain injury in a minimally conscious state. Residual deficits included mutism, athetoid movements of the extremities, and complete dependence for all personal care. After the administration of 5 to 10mg of zolpidem, within 45 minutes, the patient's condition improved markedly, including the cessation of athetoid movements, regained speaking ability, and ability to perform various tasks including self-feeding. These effects lasted 3 to 4 hours, after which the patient returned to her former state. This effect was repeatable on a daily basis. Existing evidence and possible mechanisms to explain zolpidem's effects in brain injury are described.

    7. Whyte J and Myers R (2009). Incidence of clinically significant responses to zolpidem among patients with disorders of consciousness: a preliminary placebo controlled trial. Am J Phys Med Rehabil 88: 410-8. Moss Rehabilitation Research Institute, 2nd Floor, West Building, 60 E. Township Line Road, Elkins Park, PA 19027, USA. OBJECTIVES: The common hypnotic, zolpidem, has been reported to temporarily restore consciousness to individuals in the chronic vegetative state. In drug responders, repeated dosing appears to maintain consciousness. The frequency of such responses, however, is unknown and is important both to guide clinical use and to plan further research on the mechanisms underlying drug response. The objectives of this study were to obtain an estimate of the frequency of clinically significant responses among individuals with disorders of consciousness, to determine whether less obvious drug responses are present among "nonresponders," and to identify clinical features characteristic of zolpidem responders. DESIGN: Participants were individuals in the vegetative or minimally conscious state at least 1 month after brain injury. Each participant was studied individually in a double-blind, placebo-controlled, crossover design, once on zolpidem (10 mg per feeding tube) and once on placebo. Each assessment involved baseline administration of the Coma Recovery Scale-Revised, followed immediately by administration of the study drug, followed by 5 hourly readministrations of the Coma Recovery Scale-Revised. A replication pair of assessments was available for drug responders. RESULTS: : One of 15 participants (6.7%) demonstrated a clinically significant response, which altered his assessment from the vegetative state to the minimally conscious state, and this result was repeated in the replication assessment. The remaining 14 participants showed no evidence of a subclinical response to the drug. CONCLUSION: These results confirm that clinically significant responses to zolpidem among individuals with disorders of consciousness do occur in a minority of patients and can be replicated. Failure to find a trend toward improved performance on zolpidem among nonresponders suggests a bimodal rather than a graded response to the drug. The fact that only one drug responder was identified in this small study prevents assessment of features characteristic of drug responders.

    8. Snyman N, Egan JR, London K, Howman-Giles R, Gill D, Gillis J and Scheinberg A (2010). Zolpidem for persistent vegetative state--a placebo-controlled trial in pediatrics. Neuropediatrics 41: 223-7. Rehabilitation Department, The Children's Hospital at Westmead, Westmead, Sydney, Australia. OBJECTIVE: The aim of this study was to determine if zolpidem is associated with improved responsiveness or regional cerebral perfusion in patients with persistent vegetative states. METHODS: Following ethics approval, children with persistent vegetative state were enrolled in a prospective, double-blind, placebo-controlled randomised trial. Patients underwent 2 treatments of 4 days, separated by 10 days. Each child received either a daily dose of zolpidem or placebo with a dosage of 0.14-0.2 mg/kg. Responsiveness and regional cerebral perfusion were the outcomes of interest. These were assessed using the Rancho levels of cognitive functioning scale, the coma/near-coma scale and F (18)-FDG positron emission tomography. These were conducted at baseline and after completion of the treatments. RESULTS: 3 children were enrolled. The Rancho assessment scales showed no change with treatment. The coma/near-coma scale showed a tendency to increase with zolpidem, suggesting reduced responsiveness - when compared to baseline or placebo. The positron emission tomography scans showed no significant changes between treatments. CONCLUSION: Zolpidem was associated with a tendency towards reduced responsiveness in patients with persistent vegetative states. There were no objective changes on positron emission tomography suggestive of an associated increase in cerebral blood flow with zolpidem. It would appear that zolpidem does not offer a beneficial effect in this setting.

  4. #4
    Cardiac arrest results in global ischaemia and death of selectively vulnerable neurons in the CA1 area of the hippocampus and cortical layers 3,5 and 6. Thus far we have booked good results with Pro8-Gly9-Pr010 ACTH4-10, a synthetic short fragment of ACTH in preventing the deleterious effects of global ischemia following cardiac arrest. This drug has shown good clinical results in lowering mortality as well as neurological deficits in a double blind placebo-controlled trial of acute carotid stroke by E Gusev and V.Skvortsova (Brain Ischemia- Kluwer Plenum Academic Publishers, 2003. Administration was within 6 hours of onset at doses of 12 mg daily for 5 days.

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