CLINICAL REVIEW For the full versions of these articles see bmj.com

The vegetative state Martin M Monti,1 Steven Laureys,2 Adrian M Owen1

1MRC Cognition and Brain Sciences The vegetative state may develop suddenly (as a conse- Unit, Cambridge CB2 7EF quence of traumatic or non-traumatic brain injury, such SOURCES AND SELECTION CRITERIA 2 Coma Science Group, Cyclotron as hypoxia or anoxia; infection; or haemorrhage) or gradu- This paper is largely based on a personal database of Research Center and Neurology articles from all three authors, including the most recent Department, Université de Liège, ally (in the course of a neurodegenerative disorder, such published work in primary research journals as well as Bât B30 Allée du 6 août no 8, as Alzheimer’s disease). Although uncommon, the condi- recent and influential reviews and chapters on the subject. B-4000 Liège, Belgium tion is perplexing because there is an apparent dissocia- Correspondence to: M M Monti We also searched PubMed using the keyword “vegetative [email protected] tion between the two cardinal elements of consciousness: ! state” and the limits “classical article, review and meta- awareness and wakefulness. Patients in a vegetative state analysis” Cite this as: BMJ 2010;341:c3765 appear to be awake but lack any sign of awareness of them- doi: 10.1136/bmj.c3765 selves or their environment.w! Large retrospective clinical audits have shown that as many as "#% of patients with a What is the vegetative state and what is it not? diagnosis of vegetative state may in fact retain some level The $##% guidance from the UK’s Royal College of Physi- of consciousness. Misdiagnosis has many implications for cians on diagnosing and managing the permanent vegeta- a patient’s care—such as day to day management, access tive state defines it as “a clinical condition of unawareness to early interventions, and quality of life—and has ethical of self and environment in which the patient breathes and legal ramifications pertaining to decisions on the dis- spontaneously, has a stable circulation, and shows cycles continuation of life supporting therapies.$ w$-w" of eye closure and opening which may simulate sleep and Overall, our understanding of the vegetative state is waking.”% Three main clinical features define the vegeta- incomplete. Although we know quite a lot about the neu- tive state: (a) cycles of eye opening and closing, giving the ropathology underlying the vegetative state, our ability to appearance of sleep-wake cycles (whether the presence of assess (un)consciousness and cognitive function in the eye opening and closing cycles actually reflects the pres- clinic is extremely limited, as highlighted by the high rate ence of circadian rhythms is unclearw& w'); (b) complete of misdiagnosis. lack of awareness of the self or the environment; and (c) complete or partial preservation of hypothalamic and SUMMARY POINTS brain stem autonomic functions.% " The guidelines from The vegetative state is a complex neurological condition the Royal College of Physicians consider a vegetative state in which patients appear to be awake but show no sign of to be persistent when it lasts longer than a month and awareness of themselves or their environment permanent when it lasts longer than six months for non- bmj.com archive Current clinical methods of diagnosis are limited in scope, traumatic brain injuries and one year for traumatic brain evidenced by a high rate (about 40%) of misdiagnosis injuries.% Guidelines published in the United States, how- Previous articles in this (that is, patients who are aware are considered to be ever, consider that for non-traumatic brain injury a per- series unconscious) manent vegetative state exists after only three months." ! Management of The main causes of misdiagnosis are associated with Although both the persistent and the permanent veg- alopecia areata a patient’s disability (such as blindness), confusion in etative states are often abbreviated to “PVS,” authors of (BMJ 2010;341:c3671) terminology, and lack of experience of this relatively rare condition a letter in the BMJ in $### suggested that to avoid con- ! Investigation and Furthermore, standard behavioural assessments cannot fusion the abbreviation should be used exclusively to management of distinguish an aware (that is, minimally conscious) but indicate a permanent vegetative state.w) The American congestive heart failure completely immobile patient from a non-aware patient Congress of Rehabilitation Medicine suggested that the (BMJ 2010;341:c3657) (one with vegetative state) cause of injury (traumatic, anoxic) as well as the time ! Obstetric anal In such behaviourally non-responsive patients, functional elapsed since onset of the condition should be docu- sphincter injury neuroimaging methods (such as magnetic resonance mented, as both are important for prognosis.w* (BMJ 2010;341:c3414) imaging or electroencephalography) can detect residual Experts have suggested that the vegetative state should cognition and awareness and can even establish two way be seen as part of a continuous spectrum of conditions, ! Perioperative acute communication, without requiring any behavioural output kidney injury from patients often referred to as disorders of consciousness, in which (BMJ 2010;341:c3365) Current guidelines should therefore be modified to include someone’s wakefulness and/or awareness are impaired & ' ! Huntington’s disease functional neuroimaging as an independent source of after severe brain injury (figure, table !). This sugges- (BMJ 2010;340:c3109) diagnostically relevant information tion is consistent with the idea that awareness and una- wareness are part of a continuum, and it highlights the

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disorder of consciousness, may be confused with veg- Acute brain injury etative state. Patients with locked-in syndrome are both awake and aware, yet they are entirely unable to produce Coma any motor output or they have an extremely limited rep- ertoire of behaviours (usually vertical eye movement or blinking).w!# w!! Locked-in Vegetative Chronic coma Brain syndrome state (very rare) death What causes the vegetative state? In terms of neuropathology, the vegetative state is mostly Minimally conscious state Permanent vegetative state marked by cortical or white matter and thalamic, rather (>3 months if non-traumatic, >1 year if traumatic) than brain stem, injury. A review of the evidence avail- Confusional state able up until !,," highlighted the fact that traumatic injury was found to be associated with diffuse damage to Increasing independence Death subcortical white matter (or diffuse axonal injury). Cases of non-traumatic injury, on the other hand, were found Flow chart of cerebral insult and coma. to have extensive necrosis in the cerebral cortex, almost w9 Adapted from Laureys et al, 2004 always associated with thalamic damage.!# In a more recent survey of patients with brain injury Table 1 | Consciousness and motor behaviour characteristics (n=",), %& ()!%) patients had traumatic brain injury, of in patients with disorders of consciousness and locked-in syndrome whom $& ()!%) had severe diffuse axonal injury and ) !! Consciousness ($#%) had major injury to the cerebral cortex. Among Sleep-wake Motor behaviour the %& patients, the thalamus seemed to be abnormal in Condition cycles Awareness characteristics $* (*#%) and damage to the brain stem was present in Coma No No No purposeful behaviour only & (!"%). In the !" ($,%) patients with non-trau- Vegetative state Yes No No purposeful behaviour matic injury, , ('"%) cases presented with diffuse neo- cortical damage; in all !" cases a profound and diffuse Minimally Yes Partial, Inconsistent but conscious state fluctuating reproducible purposeful neuronal loss was apparent in the thalamus and hippo- behaviour campus. Overall, these lesions effectively render a struc- Locked-in Yes Yes Yes, but limited to eye turally intact cortex unable to function by destroying the syndrome movements (depending connections between cortical areas via the thalamus, as on lesion) well as afferent and efferent cerebral connections.

importance of differentiating the vegetative state from What affects prognosis in patients with a diagnosis of other related neurological conditions that may also fol- vegetative state? low catastrophic brain injury. Three major factors affect the prognosis of patients with vegetative state: time spent in the vegetative state, age, Coma and type of brain injury. Coma is a condition of unresponsiveness in which patients lie with their eyes closed, do not respond to Time spent in the vegetative state attempts to arouse them, and show no evidence of aware- A study of !"# patients showed that time spent in a veg- ness of self or of their surroundings.) Patients lack not etative state is negatively correlated with the chances of only signs of awareness (similar to vegetative state) but recovering independence and consciousness and posi- also wakefulness (unlike vegetative state) regardless of tively correlated with the probability of remaining in a how intensely they are stimulated. Patients typically vegetative state.!$ The role of time in prognosis was con- either recover or progress to a vegetative state (that is, firmed by a large review of '#% adult published cases,!% they show signs of wakefulness) within four weeks.% Irre- from which it was estimated that the chance of regaining versible coma with absent brainstem reflexes indicates independence at one year after injury steadily decreased brain death, which is not the same as a vegetative state.* with time from !*% (one month in the vegetative state), to !$% (three months), and %% (six months). Similarly, Minimally conscious state the chance of recovering consciousness at one year also The minimally conscious state is a condition in which decreased, from "$% to $)% and !$% respectively. The patients appear not only to be wakeful (like vegetative chances of remaining in the vegetative state at one year state patients) but also to exhibit inconsistent (fluctuat- after injury were estimated to increase from !,% to %&% ing) but reproducible signs of awareness (unlike patients and &)% respectively. with vegetative state)., Like the vegetative state, the minimally conscious state may be transitory and pre- Age cede recovery of communicative function or may last Younger patients show better recovery rates.!% In one in definitely. report, for example, the rates of recovering independ- ence at one year decreased from $!% for patients below Locked-in syndrome $# years old to ,% for patients between $# and %, years Locked-in syndrome (or pseudocoma), although not a old and #% for patients above "# years.!$

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rently, the diagnosis of the vegetative state is based on ADDITIONAL EDUCATIONAL RESOURCES two main sources of information: a detailed clinical t
NHS Choices (www.nhs.uk/Conditions/Vegetative-state/ history and careful (but subjective) observation of the Pages/Introduction.aspx)—NHS information about the vegetative state patient’s spontaneous and elicited behaviour. Clinical t
Royal College of Physicians. The vegetative state: assessments involve repeated examinations at different guidance on diagnosis and management. 2003. http:// times of the day because patients who are not in a vegeta- bookshop.rcplondon.ac.uk/contents/47a262a7-350a- tive state may have alternating periods of awareness and 490a-b88d-6f58bbf076a3.pdf. unawareness (and a single examination cannot exclude t
Scholarpedia (www.scholarpedia.org/article/ a state of minimal consciousnesses) as well as circadian Vegetative_state)—Web based encyclopaedia that gives oscillations in levels of wakefulness. Examinations aim a comprehensive, peer reviewed, overview of definitions, to uncover evidence of (a) awareness of the self or the diagnostic criteria, and recent research on vegetative environment; (b) sustained, reproducible, purposeful, or state and related disorders of consciousness voluntary response to visual, olfactory, auditory, tactile, t
Headway (www.headway.org.uk/Core/DownloadDoc. or noxious stimuli; and (c) comprehension of language or aspx?documentID=446)—Fact sheet on coma from the brain injury association Headway, a charity providing expression. If evidence of these exists, the patient is con- help and support to people affected by brain injury sidered to be (minimally) aware. If meaningful “object use” (such as appropriate use of a spoon or comb) or con- sistent communication can also be established, then the Type of brain injury patient is considered to have emerged from a minimally Traumatic brain injuries are associated with better out- conscious state to a condition of severe disability (table comes at one year than non-traumatic injuries, in terms $)., However, if no evidence of awareness can be found, of recovery of independence ($"% v "%) and recovery the patient is considered to be “not aware” and therefore of consciousness (&$% v !%%).% " !% Once permanent in a vegetative state. vegetative state is diagnosed, the chances of recovery are Although several protocols exist for conducting behav- considered to be “extremely low,”" with any further recov- ioural assessments (articles by Giacino et al and Majerus ery being “exceedingly rare, and almost always involving et al provide an overvieww!& w!'), they differ greatly severe disability”!%; and although cases of late recovery in their ability to detect consciousness because of the have been reported,w!$-w!" a precise estimate of the likeli- number of domains (such as arousal and vision) assessed hood of further recovery remains difficult to formulate. and the thoroughness of the assessment. Indeed, a recent This is mainly because these cases are often difficult to study of '# patients compared on three assessment tech- verify, and when a set of %# cases claiming late recovery niques reported that the Glasgow coma scalew!) classified were reassessed by the Multi-Society Task Force on PVS, as vegetative several patients who showed signs of con- evidence of conscious awareness could be detected in sciousness according to other behavioural scales.!& The half of them well before the boundary for a diagnosis of Full Outline of UnResponsiveness (FOUR)w!* reclassified permanent vegetative state.!% !" !%% of the supposedly vegetative patients as minimally conscious, and the coma recovery scale-revised (CRS- How is the vegetative state diagnosed? R)w!, reclassified an additional $*% of the patients as No tool exists for quantifying the extent of conscious- minimally conscious. The main discrepancy between ness. Differentiating between awareness and non- scales seems to relate to their different focus on oculomo- awareness ultimately relies on a pragmatic principle tor behaviour, with the FOUR and CRS-R protocols testing that someone is conscious if they can indicate so. Cur- a greater variety of visual behaviours. For example, in all the patients reclassified by the CRS-R protocol, visual Table 2 | Differential diagnosis in severe brain injury survivors fixation was the key behaviour indicating awareness. Condition Definition Main clinical characteristics Coma Unarousable state of Absence of eye opening (even after intense stimulation) Does misdiagnosis of the vegetative state occur? unresponsiveness No evidence of awareness of the self or environment According to accumulating evidence from retrospec- Condition protracted for more than one hour tive clinical audits$ !' and comparisons of alternative Vegetative state Wakefulness accompanied Presence of eye opening and closing be havioural assessment techniques,!) !* misdiagnosis by the absence of any sign of Absence of any reproducible purposeful behaviour awareness including (a) no evidence of non-response to sensory of minimally conscious patients as being in a vegetative stimulation; (b) no evidence of awareness of the state is not uncommon. In particular, although some self or the environment; (c) no evidence of language studies have reported relatively low rates of misdiagnosis comprehension or expression w$# Minimally conscious Wakefulness accompanied by Presence of eye opening and closing (!*% ), most studies seem to converge, across time and state inconsistent but reproducible Presence of inconsistent but reproducible purposeful geographical location, on an approximate rate in excess !' !* $ !, signs of awareness behaviour including (any of) (a) non-reflexive response of "#% (%)%, "!%, "%%, "&% ). Errors in diagnosis to sensory stimulation; (b) awareness of the self or may result from lack of skill or training in the assessment the environment; (c) language comprehension or expression of patients with catastrophic brain injury, limited knowl- Lack of functional communication or object use edge of this relatively rare condition, and confusion in !' $# Locked-in syndrome Impairment in the production of Presence of eye-coded communication terminology. voluntary motor behaviour Preserved awareness Two main problems seem to underlie misdiagnosis. Complete or partial inability to produce motor Firstly, behavioural assessments of awareness present behaviour many complexities. For example, patients with physical

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(that is, they show no signs of awareness) but incorrect (in fact, they are aware).$! $$

Is there a place for brain imaging as a diagnostic tool? In recent years, techniques such as positron emission tomography, functional magnetic resonance imaging, and electroencephalography have been used to try to assess residual brain function and consciousness in vegetative patients without relying on motor behaviour. Neuroimag- ing studies in patients in a vegetative state have shown a consistent reduction in brain metabolism of as much as &#%w$$ and reduced basal resting state activity.$& In addition, unexpected levels of residual cognitive func- tion (such as processing of linguistic and self referential stimuli) are present in both minimally conscious patients and patients in a vegetative state.$' $) In some of these cases, high level functions (such as learning and actively maintaining information through time) are present,$*-%# as are awareness$% $" $* and the ability to communicate solely by modulation of brain activity.$% The Multi-Society Task Force on PVS states, however,

MARTIN MONTI, MRC COGNITION & BRAIN SCIENCES UNIT SCIENCES BRAIN & COGNITION MRC MONTI, MARTIN that “neurodiagnostic” tests, although recognised as The ability of novel brain imaging technologies, such as functional magnetic resonance imaging, “providing useful information when used in conjunc- to covertly detect signs of consciousness and residual cognition can contribute to correctly diagnosing the vegetative state tion with clinical evaluation” are believed to be unable, alone, to “either confirm the diagnosis of vegetative state disability may not be able to respond to stimulation— . . . or predict the potential for recovery of awareness.”" something that was true in all misdiagnosed cases in a Although we agree that functional neuroimaging cannot large retrospective study of ,) patients with profound confirm a diagnosis of vegetative state, it is increasingly brain damage.$ Sensory impairments (particularly in clear that functional neuroimaging can be used to rule the visual domain) can also mask the presence of aware- out a diagnosis of vegetative state and may even yield ness,!' $# a factor that has been reported as underlying information about prognosis. Indeed, limited data on as many as '&% of misdiagnoses.$ Other acquired condi- prognosis show that quantitative measurements of brain tions, such as hydrocephaly,% w$! can also mask the pres- activity—in particular, activations beyond primary sen- ence of awareness. In addition, patients in a minimally sory cortices—are positively correlated with recovery from conscious state may display inconsistent behaviour, mak- the vegetative state.$' $* w$% ing it difficult to interpret their responses, and they may be not aware for protracted intervals, making it difficult Conclusion to interpret failure to respond.% Disorders of consciousness remain challenging to man- Secondly, there is a conceptual problem in the logic of age because of our superficial understanding of the phe- establishing “lack of awareness”$! $$: absence of evidence nomenon of consciousness and its neural mechanisms. (of awareness) is taken as evidence of absence (of aware- Two main strategies seem promising for reducing the ness). Consequently, on the basis of the current clinical consistently high misdiagnosis rate. Firstly, behavioural standards, patients who are aware but non-responsive assessments need to be conducted more thoroughly and cannot be distinguished from non-aware (vegetative) by trained staff (a neurologist or another healthcare pro- patients.$% $" Clinically, this flaw in logic introduces a fessional who has been trained to use the formalised category of aware but non-responsive patients for whom assessments mentioned previously).$ !' !* $# Secondly, a diagnosis of vegetative state is technically appropriate we believe that the inclusion of recommendations for the use of functional neuroimaging techniques in revised QUESTIONS FOR FUTURE RESEARCH guidelines will increase the detection of covert signs of What proportion of patients with supposed vegetative awareness in the very circumstances susceptible to mis- state can show a state of consciousness by using diagnosis. In addition, these techniques can be used to functional neuroimaging methods? explore the degree of mental life possible after severe What proportion of behaviourally non-responsive patients brain injury,w$" thus tackling the medically and ethically can convey yes/no answers by wilful modulation of brain important question “what is it like to be in a vegetative activity? state?” In a minority of cases, these techniques may even Do patients with disorders of consciousness have a allow the patients to interact with their environment and “stream of thoughts”? Do they suffer? Do they understand to some extent let their voice be heard.$% their circumstance? What is their quality of life? Contributors: MMM researched the paper; all three authors contributed to Can more sophisticated brain computer interfaces be used the writing and are guarantors. to allow these patients to interact with their environment and regain some level of communication and autonomy? Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request

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from the corresponding author) and declare: MMM had support from the !' The Multi-Society Task Force on PVS. Medical aspects of the persistent Medical Research Council (U.1055.01.002.00001.01) and the European vegetative state ("). N Engl J Med !%%(;''#:!$)"-%. Commission (Deployment of Brain-Computer Interfaces for the Detection of !( Jennett B. The vegetative state. J Neurol Neurosurg Psychiatry Consciousness in Non-Responsive Patients) for the submitted work. AMO "##";)':'$$-). had support from the Medical Research Council (U.1055.01.002.00007.01 !$ Schnakers C, Giacino J, Kalmar K, Piret S, Lopez E, Boly M, et al. Does and U.1055.01.002.00001.01), the James S McDonnell Foundation and the the FOUR score correctly diagnose the vegetative and minimally conscious states? Ann Neurol "##&;&#:)((-$; author reply )($. European Commission (Deployment of Brain-Computer Interfaces for the !& Childs NL, Mercer WN, Childs HW. Accuracy of diagnosis of persistent Detection of Consciousness in Non-Responsive Patients) for the submitted vegetative state. Neurology !%%';(':!(&$-). work. SL had support from the James S McDonnell Foundation, the European !) Gill-Thwaites H. The sensory modality assessment rehabilitation Commission (Deployment of Brain-Computer Interfaces for the Detection technique—a tool for assessment and treatment of patients with severe of Consciousness in Non-Responsive Patients, Disorders and Coherence brain injury in a vegetative state. Brain Injury !%%);!!:)"'-'(. of the Embodied Self, Mindbridge, and Consciousness: A Transdisciplinary, !* Schnakers C, Vanhaudenhuyse A, Giacino J, Ventura M, Boly M, Majerus Integrated Approach), Fonds de la Recherche Scientifique, the Mind Science S, et al. Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral Foundation, the Reine Elisabeth Medical Foundation, the Belgian French- assessment. BMC Neurology "##%;%:'$. Speaking Community Concerted Research Action, University Hospital !% Gill-Thwaites H, Munday R. The sensory modality assessment and of Liege, the University of Liege, and the National Institute for Health rehabilitation technique (SMART): a valid and reliable assessment for Research Biomedical research Centre (Neuroscience Theme); no financial vegetative state and minimally conscious state patients. Brain Injury relationships with any organisations that might have an interest in the "##(;!*:!"$$-&%. submitted work in the previous 3 years; no other relationships or activities "# Gill-Thwaites H. Lotteries, loopholes and luck: misdiagnosis in the that could appear to have influenced the submitted work. vegetative state patient. Brain Injury "##&;"#:!'"!-*. "! Monti MM, Coleman MR, Owen AM. Neuroimaging and the vegetative Provenance and peer review: Commissioned; externally peer reviewed. state: resolving the behavioural assessment dilemma? Disorders ! Laureys S. The neural correlate of (un)awareness: lessons from the of Consciousness: Annals of the New York Academy of Sciences vegetative state. Trends in Cognitive Sciences "##$;%:$$&-%. "##%;!!$):*!-%. " Andrews K, Murphy L, Munday R, Littlewood C. Misdiagnosis of the "" Owen AM, Coleman MR. Functional neuroimaging of the vegetative vegetative state: retrospective study in a rehabilitation unit. BMJ state. Nat Rev Neurosci "##*;%:"'$-('. !%%&;'!':!'-&. "' Monti MM, Vanhaudenhuyse A, Coleman MR, Boly M, Pickard JD, ' Royal College of Physicians. The permanent vegetative state: Tshibanda L, et al. Willful modulation of brain activity in disorders of guidance on diagnosis and management. Report of a working party. consciousness. N Engl J Med "#!#;'&":$)%-*%. RCP, "##'. http://bookshop.rcplondon.ac.uk/contents/()a"&"a)- "( Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. '$#a-(%#a-b**d-&f$*bbf#)&a'.pdf Detecting awareness in the vegetative state. Science "##&;'!':!(#". ( The Multi-Society Task Force on PVS. Medical aspects of the "$ Boly M, Tshibanda L, Vanhaudenhuyse A, Noirhomme Q, Schnakers C, persistent vegetative state (!). N Engl J Med !%%(;''#:!(%%-$#*. Ledoux D, et al. Functional connectivity in the default network during $ Andrews K. International Working Party on the Management of the resting state is preserved in a vegetative but not in a brain dead patient. Vegetative State: summary report. Brain Injury !%%&;!#:)%)-*#&. Hum Brain Mapp "##%;'#:"'%'-(##. & Laureys S, Boly M. The changing spectrum of coma. Nat Clin Pract "& Coleman MR, Davis MH, Rodd JM, Robson T, Ali A, Owen AM, et al. Neurol "##*;(:$((-&. Towards the routine use of brain imaging to aid the clinical diagnosis of ) Posner JB, Saper CB, Schiff ND, Plum F. The diagnosis of stupor and coma. (th ed. Oxford University Press, "##). disorders of consciousness. Brain "##%;!'"(part %):"$(!-$". * Laureys S. Science and society: death, unconsciousness and the brain. ") Qin P, Di H, Liu Y, Yu S, Gong Q, Duncan N, et al. Anterior cingulate Nat Rev Neurosci "##$;&:*%%-%#%. activity and the self in disorders of consciousness. Human Brain % Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, et al. The Mapping [forthcoming]. minimally conscious state: definition and diagnostic criteria. Neurology "* Bekinschtein TA, Shalom DE, Forcato C, Herrera M, Coleman MR, "##";$*:'(%-$'. Manes FF, et al. Classical conditioning in the vegetative and minimally !# Kinney HC, Samuels MA. Neuropathology of the persistent vegetative conscious state. Nat Neurosci "##%;!":!'('-%. state. A review. J Neuropathol Exp Neurol !%%(;$':$(*-$*. "% Monti MM, Coleman MR, Owen AM. Executive functions in the absence !! Adams JH, Graham DI, Jennett B. The neuropathology of the vegetative of behavior: functional imaging of the minimally conscious state. Prog state after an acute brain insult. Brain "###;!"'(part )):!'")-'*. Brain Res "##%;!)):"(%-&#. !" Braakman R, Jennett WB, Minderhoud JM. Prognosis of the '# Schnakers C, Perrin F, Schabus M, Majerus S, Ledoux D, Damas P, et al. posttraumatic vegetative state. Acta Neurochirurgica (Wien) Voluntary brain processing in disorders of consciousness. Neurology !%**;%$(!-"):(%-$". "##*;)!:!&!(-"#.

ANSWERS TO ENDGAMES, p 307. For long answers go to the Education channel on bmj.com

ANATOMY QUIZ CASE REPORT T2 weighted axial magnetic resonance image Recurrent vomiting and lethargy in an infant— of the brain just another viral illness? A Right medial rectus muscle 1 The differential diagnoses are metabolic disorder, neglect, coeliac B Right side of the pons disease, viral gastroenteritis, hypothyroidism, and HIV infection. C Left lateral rectus muscle 2 Hyperammonaemia is responsible for this patient’s clinical D Basilar artery picture. E 4th ventricle 3 The raised plasma concentration of ammonia and respiratory alkalosis suggest a urea cycle defect caused by inherited defects STATISTICAL QUESTION of enzymes responsible for the metabolism of waste nitrogen. Relative risks and confidence intervals Further tests showed raised urinary orotate and plasma glutamine Answers a, b, and d, are true, whereas c is false. and low plasma citrulline, consistent with a diagnosis of ornithine transcarbamylase (OTC) deficiency. ON EXAMINATION QUIZ ICD-10 classification 4 Hyperammonaemia should be managed with nil by mouth; False. infusion of 10% dextrose and sodium benzoate; arginine More questions on this topic are available from supplementation; and regular monitoring of plasma ammonia, www.onexamination.com/endgames until midnight on Wednesday. glucose, urea, and electrolytes in addition to blood gases.

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