The vegetative stateBMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c3765 (Published 02 August 2010) Cite this as: BMJ 2010;341:c3765
All rapid responses
The excellent review of the vegetative state by Monti, Laureys and
Owen was a timely reminder of the many difficulties in making the
diagnosis and prognosis of severe brain damage.1 Those difficulties make
clinical trials difficult to design and analyse, but one trial has
recently shown that zolpidem is effective in a considerable proportion of
ambulant patients to complement earlier cases of recoveries from
Conducted by the University of Pretoria, South Africa the study found
efficacy in 10 out of 23 patients with brain damage who had been
identified as neurologically disabled by scoring less than 100/100 on the
Barthel Index. Causes of their brain damage were stroke (n = 12),
traumatic brain injury (n = 7), anaphylactic hypoxia (n = 2), drugs
overdose (n = 1) and birth injury (n = 1). Outcome measures were Single
Photon Emission Computerised Tomography (SPECT) scans before and during
treatment that were read by 3 experienced assessors who did not know
whether they were pre-dose or after zolpidem. They designated a scan as
improved when two or more assessors detected reductions in non-functioning
areas of brain damage, which occurred in 10 (43%) patients' scans. The
Tinetti Falls Efficacy Scale (TFES) was used to evaluate clinical progress
since it is well-validated reliable, widely accepted and has appropriate
sensitivity.14,15 Mean overall improvement after zolpidem on TFES was
11.3%, from 73.4/100 to 62.1/100 (p = 0.0001. Wilcoxon signed rank test).
The 10 scan improvers' change was 19.4% (+/- 16.75 SD) compared with 5.1%
(+/- 5.17) in the 13 non-improvers (p = 0.0081, 2-sample t-test with
unequal variance). The authors concluded that "This prospective
study adds further evidence to previous reports of zolpidem efficacy in
patients with established brain damage".
The first vegetative state (PVS) patient was a 28 year-old male
patient (LV) in South Africa who had been in PVS for 3 years after severe
brain trauma in a road accident.3 He was restless one evening to the
point of self-injury so he was sedated with 10mg oral zolpidem. Some 20
minutes later and to onlookers' amazement he awoke and recognised his
mother, actually greeting her by name. His aware state disappeared after
2-3 hours but reappeared after a second dose the next day, a pattern of
response followed by fading that recurred whenever he was dosed and at no
other time, making it clear that zolpidem was the only likely cause. The
story made headlines which led to LV having SPECT scans (Fig 1) that
clearly show tissue that was non-functioning before dosing becoming
active after dosing, which is clear, objective evidence of a significant
functional change. This had never been seen previously so the
dysfunctional areas had been considered to be irretrievably dead until
then. The same unexpected changes appeared in two more patients and were
published in 2006.4
Other reports appeared from the USA, France, Israel, China and Singapore
of dramatic recoveries from vegetative states due to trauma or prolonged
hypoxia.5-12 Most included objective scan evidence of improved brain
function. All reported beneficial effects appearing soon after dosing that
faded as the medication was eliminated from the body and returned after
each dose, even when the interval between them was several weeks.9 The
time of onset, between 20 and 40 minutes after dose, the duration,
intensity and waning of effect all matched the known pharmacokinetics of
oral zolpidem, while a physiological phenomenon would have been more
sustained. Broadly they were consistent with the n-of-1 criteria that
Glasziou et al reported as helping to identify apparently anecdotal
reports that constitute significant clinical evidence.13
Clinical Reasons for Limited Use
There are clinical reasons for this surprisingly slow adoption by the
medical profession; one being that a minority of patients respond. The
only PVS study found just one responder in 15 patients, but the authors
commented that "clinically significant responses to zolpidem among
individuals with disorders of consciousness do occur".16
Responses are often subtle so easily missed or masked by sedation. For
example a stroke patient had fluent conversational speech but difficulty
comprehending specific words with word-finding difficulties and semantic
paraphrasias.17 Another stroke victim detected no effect herself but her
family noticed that she was more animated and used her normal vocabulary
in telephone calls. Later her handwriting improved, being more legible and
in horizontal lines. (Personal communication). Sceptics might argue that
this was a normal recovery but in each case the patient's family saw the
effects only after dosing followed by regression.
Sedation may mask beneficial effects and responses may be unexpectedly
delayed since one 85 year old stroke patient did not respond until the 8th
day of treatment.
Some doctors won't use an approved medication for a new indication, so
called off-label prescribing, even though it is common and entirely legal
provided that they are sure it is in their patient's best interest.
SPECT scans like those in Fig 1 showed for the first time that apparently
dead areas are actually dormant so Clauss coined the term neurodormancy.20
As zolpidem is a GABA agonist he proposed that GABA mediates protective
mechanisms during severe oxidative stress and once in place it outlives
the hypoxic period. Some recent supporting evidence is slow wave activity
within a brain-damaged area that is consistent with the known effects of
GABA and which disappeared when the patient was given zolpidem17
suggesting that zolpidem retains enough affinity for GABA receptors to
break the cycle. One may therefore speculate that enhancing GABA activity
during hypoxic episodes could have a useful protective effect. Then there
is the obvious challenge to discover another agonist that lacks zolpidem's
The main conclusion is that the potential benefit is so large and the
evidence sufficiently sound for this discovery to deserve priority funding
of its development.
Secondly, it is an important avenue for research.
1. Monti Laureys and Owen
2. Clauss RP, Goldenpfennig WM, Nel HJ, Sathekge MM, Venkannagari RR.
Extraordinary arousal from semi-comatose state on zolpidem: A case report.
South African Medical J 2000, 90(1): 68- 72.
3. Clauss RP and Nel HW. Drug induced arousal from the permanent
vegetative state. Neurorehabilitation , 2006, 21, 23-28.
4. Cohen L, Chaaban B, Haberl MO. Transient Improvement of Aphasia with
Zolpidem. N Engl J Med. 2004, 350(9) 949-950.
5. Shadan FF, Poceta JS, Kline LE. Zolpidem for Postanoxic Spasticity.
Southern Med J. 2004, 97(8) 791-792.
6. Brefel-Courbon C, Payoux P, Ory F, Sommet A, Slaoui T, Raboyeau G,
Lemesle B, Puel M, Montastruc JL, Demonet JF, Cardebat D. Clinical and
Imaging evidence of zolpidem effect in hypoxic encephalopathy. Ann Neurol.
2007, 62(1) 102.
7. Cohen SI, Duong TT. Increased Arousal in a Patient with anoxic brain
injury after administration of zolpidem. Am J Phys Med Rehabil. 2008,
87(3) 229- 231.
8. Shames JL & Ring, H (2008). Transient reversal of anoxic brain
injury-related Minimally Conscious Ref 8 - State after zolpidem
administration: A case report. Arch Phys Med Rehabil. 2008, 89 386-388.
9. Du B, Shan A, Yang D, Xiang W. Induced arousal following zolpidem
treatment in a vegetative state after brain injury in 7 cases : Analysis
using visual single photon emission computerized tomography and digitized
cerebral state monitor. Neurl Regeneration Research. 2008, 3/1 (94096),
10. Adamiak G, Stetkiewicz A, Lewandowska A, Borkowska A. An extraordinary
improvement of neurological condition following zolpidem administration to
a patient with ischemic cerebellar stroke, secondary hydrocephalus and
brain stem damage: a case report. Post Psychiatr Neurol 2009, 18(3): 303-
11. Alisky JM. Minimally-responsive head injury survivors may have chronic
catatonia reversed years after an accident. Singapore Med J. 2009,
12. Glasziou P et al. 2007. When is Randomised trial unnecessary? Picking
signal from noise. BMJ 344, 349-51, 17th February
13. Nyakale NE, Clauss RP, Nel HW, Sathekge MM. Clinical and Brain
SPECT scan response to zolpidem in patients after brain damage.
Arzneimittel Forschung. 2010, 60 (4): 177-81.
14. Tinetti ME, Mendes de Leon CF, Doucette JT et al. Fear of falling and
fall-related efficacy in relationship to functioning among community-
living elders. J Gerontol 1994; 49: M140-M147.[
15. Yardley L, Beyer N, Hauer K, Kempen G, Piot-Ziegler C and Todd C
Development and initial validation of the Falls Efficacy Scale-
International (FES-I). Age and Ageing 2005 34(6):614-619.
16. Whyte J, Myers R. Incidence of clinically significant responses to
zolpidem among patients with Disorders of Consciousness: A preliminary
placebo controlled trial. American Journal of Physical Medicine and
Rehabilitation. 2009, 88 (5): 410-418.
17. Hall SD, Yamawaki N, Fisher AE, Clauss RP, Woodhall GL, Stanford IM.
GABA(A) alpha-1 subunit mediated desynchronization of elevated low
frequency oscillations alleviates specific dysfunction in stroke--a case
report. Clin Neurophysiol. 2010, 121(4):549-55.
The following website written by Dr R Clauss contains a complete list
of references and a description of the discovery, the GABA theory of brain
dormancy and several patient-responders.
The author has 30 years experience of clinical pharmacology in the
pharmaceutical industry and over 5 years working on the zolpidem project.
He has a small shareholding in the company ReGen Therapeutics who holds
the patent rights and would also have a small royalty income if the
product ever makes substantial sales. He now acts as Medical Director for
ReGen on a pro bono basis.
He is the guarantor of the accuracy of this article
Dr J A Sutton. MD(London), FFA. Email: firstname.lastname@example.org
The Author grants a worldwide licence to the Publishers and its
licensees in perpetuity, in all forms, formats and media (whether known
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The author has a small shareholding in the company that has the rights to develop zolpidem for treating brain injuries
Competing interests: No competing interests
The World Medical Association's Statement on persistent vegetative
state, adopted by the 41st World Medical Association Assembly, Hong Kong,
September, 1989 (1) established the following guidelines:
"These rare examples notwithstanding, the data indicate that
unawareness for six months predicts nonrecovery or overwhelming disability
with a high degree of certainty regardless of the nature of the insult to
the brain. Therefore, a conservative criterion for the diagnosis of PVS
would be observed unawareness for at least 12 months although cognitive
recovery after six months is exceedingly rare in patients over 50.
"The risk of prognostic error from widespread use of the above
criterion is so small that a decision that incorporates it as a prognostic
conclusion seems fully justifiable. A physician's determination that a
person is unlikely to regain consciousness is the usual prelude to
deliberations about withdrawing or withholding life support. Although the
family may be the first to raise the issue, until a physician has ventured
an opinion about prognosis, the matter of withholding treatment is not
generally considered. Once the question of withholding or withdrawing life
support has been raised, its legal and ethical dimensions must be
If we accessed the Medical World Association's site today we can
verify that the Statement on persistent vegetative state, was rescinded from
the Policies of the WMA during the General Assembly that took place in
Santiago, Chile, in October of 2005.
Probably the reason for the rescinding is the absence in the Statement
of any mention of the patient's autonomy and his/her expressed wishes.
Two points to emphasize:
1.- This Statement has coexisted for more than two decades with
the World Medical Association Declaration on the Rights of the Patient
(2), where the Right to self-determination is principal.
2.- There has been no publicity on the rescinding of the Statement
and continues considering it effective (3)
(accessed Aug 11,2010).
(accessed Aug 11,2010).
3. Bernat JL. Chronic disorders of consciousness. Lancet.
Competing interests: No competing interests
Monti et al quote the Andrews paper on misdiagnosis of vegetative
state uncritically. The 43% error rate observed by Andrews is to my mind
excessive; for example 9/17 misdignosed cases were referred in vegetative
state for less than 12 months, so at least some can have been expected to
recover some awareness during the assessment period. However errors do
occur in the differentiation of the two states, and you would expect
centres of excellence to be better than a district general hospital, but
in my experience the error rate is much lower.
The paragraph 'time spent in vegetative state' in this article is slightly
misleading, better I suggest to say 'the chance of recovery of
consciousness by one year' rather than 'at' one year.
It is slightly odd that these authors leave out their work on the
conscious perception of pain in minimally conscious state, this is one of
the most significant practical differences between vegetative state and
minimally conscious state. For example it impacts significantly on quality
of life in people in minimally conscious state with tracheostomies who
need regular endotracheal suction.
Finally there is an odd comment at the end, asking what it would be like
to be in a vegetative state, surely what the authors mean to ask is what
it is like to be in a minimally conscious state? By definition people in
vegetative state have no awareness.
Competing interests: No competing interests
This call for modification of current guidelines of Vegetative State
(VS) is laudable and timely.1 Error rate of 40% in diagnosing VS is
worrying. The survival of patients with severe brain injury will keep on
rising, thanks to increasing expertise of Neurosurgeons, ITU, Heli-
transport and other systems of NHS. Therefore, incidence and prevalence
will go up. There will be a rise in legal challenges and carers /
professionals’ distress as well.
The recent trend of primary and secondary care managers’ push for
repatriation of patients, from regionally based neurosurgical facilities
to local Neuro-rehabilitation Units, with a diagnosis of VS or Minimally
Conscious State, in the drive to save money is not well thought through.
Are they aware of the profound ethical and legal implications of such
misdiagnoses and “treatment” in local District hospitals albeit this ticks
the box of “care nearer home”?
I hope Monti et al’s call will be supported to have a comprehensive look
in the diagnostic criteria, evaluation of efficacy of current
rehabilitation “treatments”. One way to save money is to stop providing in
-effective treatments! More research is needed to look into the efficacy
of computer-brain interface and impact of current treatments of minimally
conscious state eg “sensory stimulation” therapy through appropriate brain
imaging. These will help the frontline staff at District hospital
Rehabilitation Units to engage better with the carers and the managers.
Can we think of better term than the Vegetative State with a perceived
1Martin M Monti, Steven Laureys, Adrian M Owen. The vegetative state. BMJ
As Director / Consultant of Neurorehabilitation Unit, the author is on the frontline to deliver new service initiative including CS, PVS.
Competing interests: No competing interests