Brain (2000), 123, 1327–1338

The neuropathology of the vegetative state after anacute brain insultJ. Hume Adams,1 D. I. Graham1 and Bryan Jennett2

University Departments of 1Neuropathology and Correspondence to: J. Hume Adams, University2Neurosurgery, Institute of Neurological Sciences, South Department of Neuropathology, Institute of NeurologicalGlasgow University Hospitals NHS Trust, Glasgow, UK Sciences, Southern General Hospital, South Glasgow

University Hospitals NHS Trust, 1345 Govan Road,Glasgow G51 4TF, UK

SummaryThe vegetative state is often described clinically as loss offunction of the cortex while the function of the brainstem ispreserved. In an attempt to define the structural basisof the vegetative state we have undertaken a detailedneuropathological study of the brains of 49 patients whoremained vegetative until death, 1 month to 8 years afteran acute brain insult. Of these, 35 had sustained a blunthead injury and 14 some type of acute non-traumaticbrain damage. In the traumatic cases the commoneststructural abnormalities identified were grades 2 and 3diffuse axonal injury (25 cases, 71%). The thalamus wasabnormal in 28 cases (80%), and in 96% of the cases whosurvived for more than 3 months. Other abnormalitiesincluded ischaemic damage in the neocortex (13 cases,

Keywords: vegetative state; head injury; cerebral hypoxia

Abbreviations: DAI � diffuse axonal injury; TCI � total contusion index

IntroductionIn the quarter of a century since Jennett and Plum describedand named the persistent vegetative state (Jennett and Plum,1972), there has been continued and increasing interest inthe medical, ethical and legal aspects of the condition(McLean, 1999). Its essential clinical features are loss ofany meaningful cognitive responsiveness, presumed lack ofawareness and therefore of consciousness, while there isspontaneous breathing and a range of reflex responses aswell as periods of wakefulness (eyes open). It is oftendescribed as loss of function in the cerebral cortex whilethe function of the brainstem is preserved (Jennett, 1997).Although the vegetative state may characterize the end-stageof progressive dementing conditions in children and in adults,most interest has focused on the vegetative state resultingfrom an acute brain insult. Some such patients may recoverto a degree after having been diagnosed as being vegetative.In the Multi-Society Task Force review of the world literature(Multi-Society Task Force, 1994), half of the patients who

© Oxford University Press 2000

37%) and intracranial haematoma (nine cases, 26%).In the non-traumatic cases there was diffuse ischaemicdamage in the neocortex in nine cases (64%) and focaldamage in four (29%); the thalamus was abnormal inevery case. There were cases in both groups where thecerebral cortex, the cerebellum and the brainstem wereof structurally normal appearance. In every case, however,there was profound damage to the subcortical whitematter or to the major relay nuclei of the thalamus, orboth. These lesions render any structurally intact cortexunable to function because connections between differentcortical areas via the thalamic nuclei are no longerfunctional, and there is also extensive damage to afferentand efferent cerebral connections.

were vegetative at 1 month after a head injury had regainedconsciousness after a year, as had one-third of those whowere vegetative for 3 months. The potential for recovery wasmuch less after non-traumatic insults. The Task Force, andmore recently the Royal College of Physicians of London(Royal College of Physicians Working Party, 1996) havetherefore recommended that the vegetative state should notbe declared permanent until a year after a head injury, butafter 3 months following non-traumatic insults accordingto the Task Force and after 6 months according to theLondon report.

Neuropathologists have also been intrigued by thevegetative state if only because, particularly in patients whosurvive for only a few months, the brain may appear normalor virtually so to the naked eye. Indeed, the underlyingstructural changes responsible for the vegetative state maybe rather subtle to elucidate even with microscopy.

In the present paper we describe the neuropathological

1328 J. H. Adams et al.

findings in 49 patients who had remained in the vegetativestate for more than 1 month after acute brain damage; in 35cases the cause had been a blunt head injury and in theremaining 14 some type of hypoxic event.

Material and methodsThe cases will be presented in two groups—those where thevegetative state was brought about by a head injury andthose where there was another cause. Most of the caseshave been taken from the records of the Department ofNeuropathology of this Institute while six were kindly referredto us by Dr J. B. Brierley, lately of the MRC Laboratoriesnear Carshalton. All had survived for at least 1 month afterthe acute event, as had all of the cases in the Multi-SocietyTask Force report (Multi-Society Task Force, 1994).

The clinical records available were reviewed by one of us(B.J.) in order to confirm that the patients had been vegetativeat the time of death. Some of these records were from severalyears ago before recent diagnostic criteria were established.In certain cases some judgement was involved in decidingthat the patient had been vegetative, but when there wasdoubt the case was rejected.

Group 1 (traumatic cases)This consisted of 35 patients who had sustained a blunt headinjury (Adams et al., 1999). There were 32 males and threefemales with an age range of 7–75 years (average 38 years).The cause of injury in 17 patients was a road traffic accident,in nine an assault, in six a fall and in three the precisecircumstance of the head injury was not known. Eleven casessurvived for less than 3 months, 11 for between 3 monthsand a year and 13 for more than a year. Particular attentionwas paid to whether or not the patient had talked after hisinjury (Reilly et al., 1975); if the patient had talked but hadnot been completely rational, the lucid interval was definedas being partial.

Group 2 (non-traumatic cases)Of the 14 patients in this group, 11 were male and threewere female. The age range was from 2 to 58 years (average32 years). Survival was less than 3 months in six patients,between 3 months and a year in six and greater than a yearin two. Five of the patients had experienced an intra-operativeor postoperative cardiac arrest, three an acute episode ofhypotension and two acute circulatory failure induced bydrugs. There was one case of asphyxia, one of smokeinhalation, one of severe bronchospasm and one of severeintracranial infection.

NeuropathologyAll brains were fixed in 10% formal saline for a minimumof 3 weeks prior to dissection, after which a full macroscopic

and microscopic examination was undertaken in each case(Adams et al., 1980). After transecting the rostral brainstem,the cerebral hemispheres were cut into coronal sections 1 cmthick. The cerebellar hemispheres were cut at right angles tothe folia and multiple horizontal sections were taken of thebrainstem. In all but four cases, large bilateral blocks of thefrontal, parietal, occipital and temporal lobes (three levelsincorporating the basal ganglia and the hippocampalstructures), each cerebellar hemisphere and the brainstem(three levels) were embedded in celloidin and sections stainedwith cresyl violet and by Heidenhain’s method for myelin.The remaining pieces of corpus callosum and brainstem wereembedded in paraffin wax. In the four cases where celloidinstudies were not undertaken, representative blocks were takenfrom all lobes of the cerebral hemispheres, the corpuscallosum, the basal ganglia and the hippocampal structures(at least at two levels), the cerebellum (both hemispheres)and the brainstem (at least at three levels). Paraffin sectionswere routinely stained with haematoxylin and eosin and bythe Luxol fast blue/cresyl violet technique. When consideredappropriate, sections were stained by the Palmgren techniquefor axons and other stains including immunohistochemistryfor astrocytes (GFAP, 1 : 3000; Dako, Ely, Cambs., UK) andmacrophages (CD68, 1 : 200; Dako), which were developedwith PAP or Vectastain ABC kit, respectively, and visualizedwith diaminobenzidine.

The severity of ischaemic brain damage was graded inboth groups. In the traumatic cases it occurred mainly in theneocortex and was classified as severe when the lesions werediffuse or multifocal, or took the form of infarcts withinspecific arterial territories, and moderate when ischaemicdamage was limited to arterial boundary zones, singly or incombination with subtotal infarction in the distribution ofarterial territories (Graham et al., 1989). In the non-traumaticcases the ischaemic damage was always severe; it was gradedeither as diffuse when there was widespread neuronal lossthroughout the affected structure, or focal when there werelines of demarcation between normal and abnormal tissue as,for example, with ischaemic damage in arterial boundaryzones. The criterion of pressure necrosis in one or bothparahippocampal gyri was used as evidence that theintracranial pressure had been high during life as a result ofa supratentorial expanding lesion (Adams and Graham, 1976).

In the traumatic cases surface contusions were assessedsemi-quantitatively using the total contusion index (TCI).This takes into account the depth and extent of the contusionsin various parts of the brain: 0 means that there were nocontusions, a contusion index of less than 9 is indicative ofminimal contusions, while one of more than 37 is indicativeof severe contusions (Adams et al., 1985b). Diffuse axonalinjury (DAI) was graded and in this series most exampleswere of the more severe grades 2 and 3. In grade 3 there arefocal lesions in the corpus callosum and in the dorsolateralsegment(s) of the rostral brainstem and in grade 2 there is afocal lesion only in the corpus callosum. In grade 1, there isagain axonal damage diffusely throughout the white matter,

Vegetative state 1329

but there are no focal lesions in the corpus callosum or inthe brainstem (Adams et al., 1985a, 1989).

Only traumatic haematomas thought to be sufficiently largeto act as significant intracranial expanding lesions (more than35 ml) were recorded. The great majority of the haematomasso recorded had been evacuated surgically before death.

ResultsGroup 1 (traumatic cases)The principal features are given in Table 1. Three of thepatients had experienced a lucid interval—two total and onepartial. All of the patients with lucid intervals had developedintracranial haematomas, one of whom had also sustained apostoperative cardiac arrest.

The commonest structural abnormalities identified in thebrains were grades 2 and 3 DAI (25 cases, 71%). Unlike theacute haemorrhagic lesions (Fig. 1) that are the characteristicfocal features of DAI in patients who survive for only ashort time after their injury, the lesions were shrunken,granular and sometimes cystic (Fig. 2). They often retainedan orange-yellow colour because of the persistence ofhaemosiderin. They were not all visible macroscopically—in 15 of the 25 cases, one or both of the focal lesions wereidentifiable only microscopically (Table 1). With increasingsurvival the bulk of the white matter became reduced andthere was enlargement of the ventricular system (Fig. 2A).Of the 10 patients without grades 2 or 3 DAI, seven haddeveloped intracranial haematomas and nine had sustainedmoderate or severe ischaemic brain damage. There were alsothree cases of grade 1 DAI: in two of these there was, inaddition, ischaemic damage in the cerebral cortex, and inone of these diffuse ischaemic damage in the thalamus also.In the third there was focal ischaemic damage in the thalamus.

Moderate or severe ischaemic brain damage was presentin 15 (43%) of the traumatic cases. In six it was centred onarterial boundary zones in the cerebral hemispheres (Fig. 3),in four the ischaemic brain damage was diffuse, in two itaffected specific arterial territories (Fig. 2A) and in one itwas multifocal. In two there was diffuse neuronal loss in thethalamus without there being any neocortical damage. Theintracranial pressure had been high in all but two of thepatients who sustained ischaemic brain damage. In six of the15 cases with ischaemic damage there was major extracranialinjuries that might have contributed to an inadequate cerebralblood flow.

Intracranial haematomas had developed in nine (26%) ofthe cases—six subdural haematomas, one extraduralhaematoma and two cases with bilateral intracerebralhaematomas. In all but one patient the intracranial pressurehad been high and all the subdural and extradural haematomashad been evacuated during life.

The intracranial pressure had been high in 25 (71%)of the patients. Only eight of these had an intracranialhaematoma.

In five cases (14%) there were abnormalities in thebrainstem other than the focal lesions that are a feature ofDAI. The intracranial pressure had been high in all of them.The lesions were in the midline in four cases and lateral (ina cerebral peduncle) in one. In all of these cases the lesionswere small and non-haemorrhagic.

The TCI ranged from 0 to 21 (median 3.9), i.e. in not onecase could contusions be classified as severe and in eightthey were absent. If surface contusions are excluded, theneocortex was abnormal in only 13 of the cases and thistook the form of ischaemic damage; this was diffuse in onlyfour cases. There were no identifiable abnormalities in thecerebral cortex resulting from DAI.

The subcortical white matter was abnormally pale andgranular in texture in 29 cases (83%), this being diffuse inall 28 patients with DAI. Focal damage to subcortical whitematter was seen in two patients who had sustained ischaemicbrain damage (Figs 2A and 3).

The thalamus was abnormal in 28 cases (80%), in 25 ofwhich the damage was diffuse. This took the form oftransneuronal change or ischaemic damage. In two of thecases with ischaemic damage there was no cortical ischaemicdamage. In the other three cases there was focal infarctionas a consequence of raised intracranial pressure and acompromised circulation through the posterior cerebralarteries or as part of the pattern of focal ischaemic braindamage. In DAI, retrograde thalamic degeneration occurs asa result of widespread axonal damage and takes some 3months to develop. On the other hand, thalamic damageassociated with ischaemia is apparent shortly after the hypoxicevent. In DAI there is atrophy due to shrinkage of nervecells and an astrocytosis in the lateral and ventral nuclei withrelative sparing of the anterior and dorsomedial nuclei, thepulvinar, the centromedian nuclei and lateral geniculatebodies. In contrast, in cases in which the thalamic damageis attributable to ischaemia, there is neuronal loss andastrocytosis in the anterior and dorsomedial nuclei withrelative sparing of the lateral and ventral nuclei. These twomain patterns correspond to those described in cases ofdiffuse degeneration of the cerebral white matter in severedementia after head injury (Strich, 1956) and in long survivalafter cardiac arrest (Brierley et al., 1971; Cole and Cowie,1987).

There was a low incidence of fracture of the skull (12cases, 34%). With the passage of time there was a trend forthe brain weight to fall and for the ventricles to enlarge.

Group 2 (non-traumatic cases)The structural abnormalities in these cases, given in Table 2,cover the spectrum of brain damage brought about by anacute hypoxic episode (Auer and Benveniste, 1997). Themost common abnormality was diffuse damage in theneocortex (nine cases, 64%). This took the form of laminarnecrosis, more severe in the depths of sulci than on theircrests, and increasing in intensity from the frontal to the

1330 J. H. Adams et al.T

able

1Tr

aum

atic

case

s.T

hepr

inci

pal

clin

ical

and

neur

opat

holo

gica

lfe

atur

esin

35pa

tien

tsw

hosu

rviv

edin

ave

geta

tive

stat

efo

r1

mon

thor

mor

eaf

ter

ahe

adin

jury

Cas

eA

geSe

xC

ause

Surv

ival

Luc

idSk

ull

Bra

inIn

trac

rani

alIC

P�T

CI

DA

IIB

DA

bnor

mal

ities

Hyd

roce

phal

usno

.(y

ears

)fr

actu

rew

eigh

tha

emat

oma

(g)

Neo

cort

exSC

WM

Tha

lam

usB

rain

stem

157

MR

TA5

wN

oY

es14

50IC

HY

es19

No

�C

No

DN

o–

236

MR

TA6

wN

oY

es15

40N

oN

o4

3M

mN

oC

DN

oN

o–

39

MR

TA7

wN

oN

o14

30N

oY

es0

3m

No

No

DN

oN

o�

418

MR

TA7

wN

oY

es14

90N

oY

es3

3M

mN

oC

DN

oN

o–

532

MR

TA7

wN

oN

o15

00N

oN

o3

3M

mN

oC

DN

oN

o�

�6

38M

Fall

8w

PN

o12

50SD

He

Yes

71

No

CD

FM

–7

59M

Ass

ault

8w

No

No

1370

No

No

43

MN

oC

DT

No

–8

47M

Ass

ault

8w

No

No

1390

No

No

63

MN

oC

DN

oN

o�

943

MFa

ll10

wN

oY

es13

50N

oY

es14

No

�C

,B

ZN

oF

No

�10

24M

RTA

10w

No

Yes

1520

SDH

eY

es16

1�

�C

,B

ZD

DN

o�

�11

29M

Fall

12w

No

No

1650

No

No

03

MN

oN

oD

No

No

–12

15F

Fall

3m

NK

No

1160

No

No

43

MN

oC

DT

No

–13

65M

RTA

3m

NK

Yes

1440

No

Yes

151

�C

,B

ZD

DM

��

�14

18M

RTA

3m

No

Yes

1160

No

Yes

193

m�

C,

FD

TN

o�

1527

MR

TA4

mN

oY

es14

30SD

He

No

62

m�

�C

DD

No

–16

31M

RTA

6m

No

No

1300

No

Yes

63

Mm

No

CD

TN

o�

�17

42M

Ass

ault

9m

No

No

1270

No

Yes

03

Mm

No

No

DT

No

��

1858

MR

TA9

mN

oN

o15

50N

oY

es0

3m

No

No

DT

No

��

1956

MR

TA9

mN

oN

o11

90N

oY

es4

3M

No

CD

TN

o�

�20

75F

Ass

ault

11m

No

No

1260

No

No

02

MN

oN

oD

TN

o�

�21

50M

Ass

ault

1y

No

No

1260

SDH

eY

es4

No

�C

,B

ZF

DM

��

2249

MA

ssau

lt1

yT

No

1070

SDH

eY

es9

No

��

C,

AT

FF

L�

�23

34F

RTA

1y

6m

No

No

1070

No

Yes

213

Mm

�C

,D

DD

No

��

2464

MA

ssau

lt1

y6

mN

oY

es11

50N

oY

es3

2M

No

CD

TN

o�

�25

27M

NK

1y

6m

No

No

1130

No

No

03

Mm

No

No

DN

oN

o�

�26

18M

Ass

ault

2y

No

No

1200

No

Yes

63

Mm

No

CD

TN

o�

�27

44M

NK

2y

2m

No

Yes

1300

No

Yes

63

Mm

No

CD

TN

o�

�28

61M

NK

2y

3m

No

No

1350

ICH

Yes

6N

o�

�C

,D

No

DN

o�

�29

52M

RTA

2y

4m

No

No

NK

No

Yes

03

Mm

�A

TD

,F

DN

o�

�30

7M

RTA

2y

5m

No

Yes

NK

No

Yes

33

MN

oC

DT

M�

�31

56M

Ass

ault

3y

No

No

1260

No

No

03

MN

oN

oD

TN

o�

�32

15M

RTA

3y

No

No

1140

No

Yes

20N

o�

�C

,D

No

DN

o�

��

338

MFa

ll4

yT

Yes

670

ED

He

Yes

4N

o�

�C

,D

No

DN

o�

��

3420

MR

TA6

yN

oN

o10

20N

oY

es3

3M

m�

C,

BZ

DD

No

��

3542

MFa

ll8

y6

mN

oN

o12

20SD

He

Yes

143

M�

C,

BZ

DD

No

��

�

Cau

se:

RTA

�ro

adtr

affic

acci

dent

.Su

rviv

al:

w�

wee

k(s)

;m

�m

onth

(s);

y�

year

(s).

Luc

id:

T�

tota

llylu

cid

imm

edia

tely

afte

rin

jury

;P

�pa

rtia

llylu

cid;

NK

�no

tkn

own.

Bra

inw

eigh

t:N

K�

not

know

n.In

trac

rani

alha

emat

oma:

SDH

�su

bdur

alha

emat

oma;

ED

H�

extr

adur

alha

emat

oma;

ICH

�in

trac

ereb

ral

haem

atom

a;e

�ev

acua

ted.

ICP�

�ra

ised

intr

acra

nial

pres

sure

.T

CI

�to

tal

cont

usio

nin

dex.

DA

I�

diff

use

axon

alin

jury

:1,

2,3

indi

cate

grad

e;m

�fo

cal

lesi

ons

seen

only

mic

rosc

opic

ally

;M

�fo

cal

lesi

ons

seen

mac

rosc

opic

ally

;M

m�

one

lesi

onse

enm

acro

scop

ical

ly,

the

othe

ron

lym

icro

scop

ical

ly.

IBD

�is

chae

mic

brai

nda

mag

ein

cere

bral

cort

ex:

��

mod

erat

e;�

��

seve

re.

Neo

cort

ex:

BZ

�is

chae

mic

brai

nda

mag

ein

arte

rial

boun

dary

zone

s;A

T�

isch

aem

icbr

ain

dam

age

inar

teri

alte

rrito

ries

;D

�di

ffus

eda

mag

e;F

�fo

cal

dam

age;

C�

cont

usio

ns(f

orse

veri

tyse

eT

CI)

.SC

WM

�su

bcor

tical

whi

tem

atte

r:D

�di

ffus

eda

mag

e;F

�fo

cal

dam

age

inre

latio

nto

isch

aem

icda

mag

e.T

hala

mus

:F

�fo

cal

dam

age;

T�

tran

sneu

rona

lda

mag

e;D

�di

ffus

eis

chae

mic

dam

age.

Bra

inst

em:

M�

foca

lda

mag

ein

mid

line;

L�

late

ral

dam

age.

Hyd

roce

phal

us:

��

slig

hten

larg

emen

tof

the

vent

ricu

lar

syst

em;

��

�m

oder

ate;

��

��

seve

re.

Vegetative state 1331

Fig. 1 Acute DAI. There are focal haemorrhagic lesions in (A)the corpus callosum and in (B) the dorsolateral part of the rostralbrainstem. Reproduced, with permission, from Adams et al. (1977).

occipital poles often with selective sparing of the calcarinecortex. With the passage of time the affected cortex becamerather granular and shrunken, there was a reduction in thebulk of the white matter and there was ventricular enlargement(Fig. 4). In three cases the ischaemic damage was restrictedto arterial boundary zones of the type known to be associatedwith an acute episode of hypotension (Adams et al., 1966).In the one case with ischaemic damage in more than onearterial territory, there had been an intracranial expandinglesion in the form of an abscess in the left frontal lobebrought about by a localized penetrating head injury that hadinitially not caused a disturbance of consciousness. As canbe seen from Table 2, there were variable abnormalities inthe caudate nucleus, the putamen, the globus pallidus andthe cerebellum, but in every case there was profound diffuseneuronal loss in each thalamus and hippocampus. In eightcases there were variable minor abnormalities in thebrainstem, the most common being focal changes in thesubstantia nigra or in some of the major motor nuclei. Innone of the cases was there histological evidence to suggestthat the intracranial pressure had been high (Adams andGraham, 1976).

Fig. 2 DAI. (A) Table 1, case 29: survival 2 years 4 months aftera head injury. The corpus callosum is narrowed because of an oldfocal lesion. There is also an old shrunken infarct in the leftmiddle cerebral arterial territory. There is enlargement of theventricular system. (B) Table 1, case 19: survival 9 months after ahead injury. There is a shrunken cystic lesion in the dorsolateralpart of the rostral brainstem. B is reproduced, with permission,from Adams et al. (1977).

There was only one case in which the neocortex wasstructurally of normal appearance (case 12). This patienthad been accidentally incarcerated in a hermetically sealedmotorized vehicle and there was a possibility that there hadbeen carbon monoxide in the atmosphere. The most dramaticabnormality was extensive damage to the subcortical whitematter associated with widespread destruction of axons andloss of myelin, and reactive changes in astrocytes andmicroglia. In this patient there were also diffuse abnormalitiesin the thalamus and in the hippocampi.

As with the patients in group 1, there was a trend for thebrain weight to decrease and for the ventricles to enlarge assurvival increased.

1332 J. H. Adams et al.

Fig. 3 Table 1, case 21: survival 1 year after a head injury. Thereis an old infarct in the boundary zone between the anterior andmiddle cerebral arterial territories.

DiscussionThere have in the past been many reports of disorders ofconsciousness after acute brain insults, usually of hypoxiccausation (French, 1952; Adams et al., 1966; Brierley et al.,1971; Ingvar et al., 1978; Dougherty et al., 1981; Cole andCowie, 1987; Relkin et al., 1990). Very few publications,however, have specifically addressed the underlying basis ofthe persistent vegetative state. An exception is the review ofthe literature by Kinney and Samuels of cases of the vegetativestate of traumatic and non-traumatic causation (Kinney andSamuels, 1994). Precise clinical details and duration ofsurvival were not defined in this review and not all of thecases would be accepted as being vegetative using currentcriteria. They concluded, however, that the vegetative stateresults from widespread and bilateral damage to (i) thecerebral cortex itself; (ii) the thalamus; or (iii) many of theintra- and subcortical connections (via axonal injury and/ordemyelination of the cerebral hemispheric white matter).They present three diagrams: one with diffuse destruction ofthe cerebral cortex only, one with diffuse damage to thesubcortical white matter only and one with diffuse damageto each thalamus only. We have never seen a case in whichthere was diffuse hypoxic damage to the cerebral cortexwithout there being correspondingly severe damage in eachthalamus. Kinney and colleagues reported a single case ofthe vegetative state in a young woman who survived for 10years after cardiopulmonary arrest (Kinney et al., 1994). Inthis patient the damage to the cerebral cortex was in theparasagittal regions, i.e. in arterial boundary zones, and muchof the neocortex was spared. There was, however, severebilateral thalamic damage and they suggested that this maysometimes be more important than cortical damage in theproduction of the vegetative state. A similar case has beenreported by Jellinger (Jellinger, 1994).

The concept that axons may be damaged directly at the

time of a head injury has a long and chequered history. Strichwas the first to suggest that it could be an important factorwhen she described the neuropathological findings in a seriesof cases with ‘severe post-traumatic dementia’ in which therewas widespread Wallerian-type degeneration in subcorticalwhite matter and in descending tracts in the brainstem andspinal cord (Strich, 1956). She was of the opinion that therehad been disruption of axons at the time of injury broughtabout by shearing strains. In support of this view was thework of Holbourn (Holbourn, 1943, 1945) and of Pudenzand Shelden (Pudenz and Shelden, 1946) on shearing injuryand the fact that in patients with this type of brain damagethere are gross and permanent neurological abnormalitiesfrom the moment of injury. The observations of Strich andher opinion as to the pathogenesis of axonal damage werealso supported by Peerless and Rewcastle (Peerless andRewcastle, 1967) and by Zimmerman and colleagues(Zimmerman et al., 1978), both groups describing examplesof shearing injury, and by ourselves (Adams et al., 1977) inan account of 19 patients found post-mortem to have ‘diffusedamage to white matter of immediate impact type’. Others,however, were of the opinion that the damage to axons wassecondary to factors such as hypoxia and ischaemia, brainswelling, or damage to the brainstem secondary to a highintracranial pressure brought about by an intracranialexpanding lesion (Jellinger and Seitelberger, 1970; Jellinger,1977; Peters and Rothemund, 1977).

The final proof that axons could be damaged at the timeof a head injury came about as a result of experimentalstudies in non-human primates when it was shown that axonaldamage identical to the type already known to occur in mancould be produced by non-impact angular acceleration of thehead (Adams et al., 1982; Gennarelli et al., 1982). At thattime we introduced the term ‘diffuse axonal injury’, now theinternationally accepted term (Gennarelli et al., 1998) todescribe this type of brain damage resulting from a headinjury. On the basis of this controlled experimental model,three grades of severity of DAI were defined and wereapplied to man (Adams et al., 1989). In the most severe form(grade 3) there are, in addition to microscopical evidence ofwidespread damage to axons in all parts of the brain, focallesions in the corpus callosum and in the dorsolateral sector(s)of the rostral brainstem. In grade 2 there is a focal lesiononly in the corpus callosum, while in grade 1 there are nofocal lesions (Adams et al., 1989). There were three caseswith grade 1 DAI in the present series and in all three therewas also ischaemic brain damage; this grade of DAI may bea cause of persistent disability after a head injury (B. Jennett,personal communication), but, on its own, does not appearto be a cause of the vegetative state.

The focal lesions of DAI can often be seen macroscopically,but sometimes only on microscopic examination. In earlierstudies the identification of axonal injury was dependent onsilver staining techniques to identify axonal swellings (the‘retraction’ balls of Cajal), but more recently immuno-histochemical methodology using an antibody to the precursor

Vegetative state 1333

Tab

le2

Non

-tra

umat

icca

ses.

The

prin

cipa

lcl

inic

alan

dne

urop

atho

logi

cal

feat

ures

in14

pati

ents

who

surv

ived

ina

vege

tati

vest

ate

for

mor

eth

an4

wee

ksaf

ter

anac

ute

non-

trau

mat

icce

rebr

alin

sult

Cas

eA

geSe

xC

ause

Surv

ival

Bra

inIC

P�H

ydro

ceph

alus

Abn

orm

aliti

esno

.(y

ears

)w

eigh

t(g

)

Neo

cort

exSC

WM

Cau

date

Puta

men

Glo

bus

Tha

lam

usH

ippo

cam

pus

Cer

ebel

lum

Bra

inst

emnu

cleu

spa

llidu

s

142

MPo

st-o

p.C

A4

w13

75N

o�

DN

oD

DD

DD

Dm

22.

5M

Intr

a-op

.C

A4

w12

50N

o�

�D

No

DD

DD

DD

m3

30M

Intr

acra

nial

8w

1420

No

��

BZ

FN

oD

DD

DD

No

infe

ctio

n:co

nvul

sion

:hy

pot.

446

FPo

st-o

p.C

A8

w12

00N

oN

oB

ZN

oN

oD

DD

DF

No

544

MD

rugs

/alc

ohol

:10

w13

00N

o�

�D

No

DD

No

DD

Dm

hypo

t.6

22F

Car

diom

yopa

thy

11w

1320

No

�B

ZN

oN

oN

oN

oD

DD

No

(pre

gnan

cy):

hypo

t.7

24M

Cer

ebra

lab

sces

s/4

m14

20N

o�

�A

TF

DN

oF

DD

Dm

men

ingi

tis8

48M

Bro

msu

lpht

hale

in5

m12

50N

o�

��

DA

DD

DD

DD

mC

A9

58M

Bro

ncho

spas

m5

m11

00N

o�

�D

AD

DD

DD

Dm

CA

1048

MSm

oke

inha

latio

n7

m11

10N

o�

�D

AD

DD

DD

Dm

1117

MPo

st-o

p.C

A9

mN

KN

o�

��

DA

DD

DD

DD

m12

21M

Asp

hyxi

a–

seal

ed10

m14

60N

oN

oN

oD

LM

No

No

DD

DB

ZN

ove

hicl

e(?

CO

)13

38M

Stab

wou

nd:

1y

9m

1050

No

��

DA

DD

DD

DD

No

hypo

t.,co

nvul

sion

s14

2F

Post

-op.

CA

4y

515

No

��

�D

AD

DD

DD

DN

o

Cau

se:

CA

�ca

rdia

car

rest

;hy

pot.

�an

acut

eep

isod

eof

hypo

tens

ion;

CO

�po

ssib

lepr

esen

ceof

carb

onm

onox

ide.

Surv

ival

:w

�w

eek(

s);

m�

mon

th(s

);y

�ye

ar(s

).B

rain

wei

ght:

NK

�no

tkn

own.

ICP�

�ra

ised

intr

acra

nial

pres

sure

.H

ydro

ceph

alus

:�

�sl

ight

enla

rgem

ent

ofth

eve

ntri

cula

rsy

stem

;�

��

mod

erat

e;�

��

�se

vere

.N

eoco

rtex

:D

�di

ffus

ehy

poxi

cda

mag

e;B

Z�

hypo

xic

dam

age

inar

teri

albo

unda

ryzo

nes;

AT

�hy

poxi

cda

mag

ein

arte

rial

terr

itori

es.

SCW

M�

subc

ortic

alw

hite

mat

ter:

F�

foca

lda

mag

ein

rela

tion

toda

mag

eto

the

neoc

orte

x;A

�as

troc

ytos

is;

DL

M�

diff

use

loss

ofm

yelin

.In

all

othe

rco

lum

ns:

D�

diff

use

hypo

xic

dam

age;

F�

foca

lda

mag

e;B

Z�

dam

age

inar

teri

albo

unda

ryzo

nes;

m�

min

imal

abno

rmal

ities

iden

tified

only

mic

rosc

opic

ally

.

1334 J. H. Adams et al.

Fig. 4 Table 2, case 8: survival 5 months after an episode ofcardiac arrest. The cerebral cortex is thin and granular. Thethalamus is small and there is enlargement of the ventricularsystem. Reproduced with permission from Graham (1992).

protein of β-amyloid has rendered the identification of axonalinjury much more reliable (Gentleman et al., 1993; Sherriffet al., 1994). Indeed, it would now appear that grade 1 DAIis of frequent occurrence in head injuries (Gentleman et al.,1995). There is now, as a result of these more recent studies,a structural basis to account for persisting minimal clinicalsequelae after what appeared to have been only a minorhead injury (Oppenheimer, 1968; Clark, 1974; Blumbergset al., 1994).

Whether or not there is total disruption of axons at themoment of injury, as had originally been suggested byStrich (Strich, 1956) and subsequently supported by otherinvestigators, has been controversial. In ultrastructural studiesof the brains of non-human primates subjected to shear-strains identical to those known to produce DAI in the brain,disruption immediately after injury has been seen (Maxwellet al., 1993). Such primary axotomy, however, is uncommonand there is increasing recognition of damaged axonsundergoing a process of secondary axotomy (Maxwell et al.,1997). The axons undergo a sequence of events: initiallythere is focal swelling of axons (Maxwell et al., 1995; Pettusand Povlishock, 1996) and thereafter swelling of axonalmitochondria (Pettus et al., 1994; Maxwell et al., 1995;Pettus and Povlishock, 1996), the development of nodal blebs(Maxwell et al., 1991) and/or a focal decrease in theinternodal axonal diameter. This is followed by loss of axonalmicrotubules (Maxwell, 1995, 1996; Pettus and Povlishock,1996; Jafari et al., 1997; Povlishock et al., 1997) andalterations of the intra-axonal relationships of neurofilaments(Pettus and Povlishock, 1996; Jafari et al., 1997). Next, thereis involution of the internodal axolemma (Povlishock, 1992;Pettus et al., 1994; Maxwell et al., 1995) followed byseparation of the axolemma from the internal aspect of themyelin sheath (Maxwell et al., 1995), the development ofaxonal swellings (Maxwell et al., 1991, 1995; Povlishock,1992), the development of myelin intrusions (Povlishock

et al., 1983; Maxwell et al., 1995) and finally axonalseparation (Povlishock, 1992; Jafari et al., 1997) to formaxonal (‘retraction’) bulbs. Subsequently, more severemorphological changes take place including axonal ruptureand Wallerian-type degeneration (Strich, 1956). This has ledto the concept of secondary axotomy in the pathogenesis ofDAI. In a review of the literature, Maxwell and colleaguesconcluded that, whereas primary axotomy could be identifiedwithin 60 min of injury, secondary axotomy required aminimum of 4 h to develop (Maxwell et al., 1997).

Whether or not axons are disrupted at the moment ofinjury in patients who sustain DAI, they are clearly renderedimmediately dysfunctional and temporary changes ofconduction in damaged axons now seem the most likelycause of transient disturbances of consciousness after a headinjury (concussion). Further clinicopathological studies haveestablished that there are many differences between patientswith the more severe grades of DAI compared with othertypes of head injury. For example, the former never experiencea lucid interval; they have a low incidence of fracture ofthe skull, traumatic intracranial haematomas and increasedintracranial pressure; and surface contusions are seldomsevere—all features of the present series (Table 1).

The occurrence of structural changes in the thalamus inassociation with DAI is dependent on the length of survivalof the patient because it is transneuronal in origin and takesabout 3 months to appear. Thus, in the present series thethalamus appeared normal on microscopical examination insix of the seven patients with DAI who survived for 12weeks or less after their injuries, notwithstanding the presenceof widespread damage to subcortical white matter (Table 1).There is no rational explanation for the fact that there wasno transneuronal change in the thalamus of traumatic case25 who survived in a vegetative state for 18 months as aresult of DAI despite there being diffuse degeneration in thesubcortical white matter. This was the only patient in thetraumatic group who survived for 3 months or more in whomthere were no identifiable abnormalities in the thalamus. Inthe traumatic group the thalamus was abnormal in 28 (80%)of all cases and in 96% of those who survived for more than3 months.

The importance of grades 2 and 3 DAI as a cause of thevegetative state after head injury is evident from Table 1,these being a feature of 71% of the cases in the present series.

Moderate to severe ischaemic brain damage, particularlyin the patients with intracranial haematomas or extracranialinjuries, was also common (43%). It has long been knownthat ischaemic damage is not uncommon in patients withfatal head injuries (Graham et al., 1978), particularly if theintracranial pressure has been high (Graham et al., 1987,1989). In the series of 151 unselected non-missile headinjuries published by Graham and colleagues, moderate tosevere ischaemic brain damage was observed in 96 cases(64%) (Graham et al., 1978). Its pathogenesis, namely aregional or global failure of cerebral blood flow, is likely to

Vegetative state 1335

be similar to the cause of the brain damage in some of thenon-traumatic cases to be discussed in the next section.

A striking feature in the traumatic cases of the vegetativestate is the low incidence of damage to the brainstem (14%);in all five cases with this type of brain damage it was slightand never haemorrhagic. This confirms the view we haveheld for a long time that patients who develop classicsecondary haemorrhage and infarction in the brainstem as aresult of an acute intracranial expanding lesion survive foronly a short time. Thus, a post-traumatic vegetative statemay occur in patients in whom both the cerebral cortex andbrainstem are intact.

The causes and patterns of hypoxic brain damage inpatients who have sustained an acute circulatory catastrophehave long been an interest of neuropathologists and clinicians(Adams et al., 1966; Dougherty et al., 1981; Cole and Cowie,1987; Kinney and Samuels, 1994). The classic example isthe brain damage brought about by a period of true cardiacarrest. This takes the form of diffuse neuronal necrosis inthe regions of selective vulnerability. In the neocortex thereis laminar necrosis, more severe in the depths of sulci thanon their crests, and tending to increase in severity from thefrontal to the occipital poles, but often with some sparing ofthe medial occipital cortex. There is also diffuse neuronalnecrosis in the hippocampal and amygdaloid structures, inthe major relay nuclei of the thalamus, in the Purkinje cellsof the cerebellum and, variably, in other structures in thedeep grey matter. Essentially similar patterns of brain damagemay occur as a result of other types of hypoxic insultsuch as status epilepticus, carbon monoxide poisoning andasphyxia (Auer and Benveniste, 1997), and hypoglycaemia(Auer et al., 1989). This diffuse pattern of ischaemic damagewas found in nine of the cases of the non-traumatic vegetativestate (Table 2). The second pattern of brain damage is focal.Here the classic example is brain damage brought about bya short episode of profound hypotension (Adams et al., 1966;Torvik and Jorgensen, 1969; Auer and Benveniste, 1997)when ischaemic damage is confined to the arterial boundaryzones in the cerebral and cerebellar hemispheres. The affectedzones tend to be wedge-shaped with their base on the surfaceand their apex deep within the brain, e.g. adjacent to the angleof a lateral ventricle. There is almost always involvementof the thalamus and there is variable involvement of thehippocampal structures and the deep grey matter. This patternof brain damage was present in three of the non-traumaticcases (Table 2). Another type of focal ischaemic brain damageis, because of local factors compromising the blood flowthrough individual arteries, restricted to specific arterialterritories. There was one case of this type in the presentseries; there were also variable ischaemic lesions in otherstructures, but damage to the thalamus was diffuse (Table 2).

In one case (case 12 in Table 2) there were no abnormalitiesin the cerebral cortex, the principal abnormality being severedestruction of the subcortical white matter of the typeassociated with carbon monoxide poisoning (Lapresle andFardeau, 1966; Vuia, 1967; Auer and Benveniste, 1997), and

Fig. 5 Carbon monoxide poisoning: survival 21 days. Thecerebral cortex is intact but there is extensive destruction of thesubcortical white matter. (A) Heidenhain’s stain for myelin, (B)cresyl violet. Bar � 1 cm.

1336 J. H. Adams et al.

there was the unconfirmed possibility that there could havebeen some carbon monoxide in the vehicle in which he hadbecome accidentally sealed. An almost identical case ofconfirmed carbon monoxide poisoning (Fig. 5) that we havereported (Hart et al., 1988) would have been included in thispaper had the patient survived in a vegetative state for theadditional few days required to fulfil the criterion of amonth’s survival. In both cases, there was diffuse neuronalloss in the thalamus. It is of some interest that we have neverseen or encountered a case of the vegetative state caused byhypoglycaemia. It would appear, therefore, that most suchcases either die less than a month after the episode or makevarying degrees of recovery. However, one of us (B.J.) hasseen a clinical case of a teenager who survived for severalyears in a vegetative state after hypoglycaemia. Somecertainly remain severely disabled (Kalimo and Olsson, 1980;Auer et al., 1989).

In patients who sustain severe brain damage as a result ofsome catastrophic circulatory event, there is characteristicallyminimal or no damage in the brainstem, as was the case inthe present series.

Thus, as in the traumatic group of cases, there are patientsin the non-traumatic group where the vegetative state waspresent without there being diffuse damage to the cerebralcortex or severe damage in the brainstem. Diffuse neuronalloss in the thalamus was, however, a common factor in all.

The Multi-Society Task Force recognized that the potentialfor recovery from the vegetative state was greater aftertraumatic than non-traumatic insults (Multi-Society TaskForce, 1994). This may be related to the differing types ofdamage sustained by neurons in the thalamus. In acutehypoxic episodes the neurons that are lost have undergoneischaemic necrosis and will therefore never function again.In contrast, in DAI there is no actual loss of neurons, onlytransneuronal degeneration. If there is any delayed restorationof function in the axons damaged at the time of the originalinjury, the substrate of thalamic neurons is still there and,conceivably, may be able to function again. Anotherdifference between the traumatic and non-traumatic caseswas the frequency of diffuse ischaemic damage in theneocortex: this occurred in 64% of the non-traumatic casesbut in only 11% of the traumatic cases. The respective figuresfor any type of ischaemic damage in the neocortex were 93and 37%.

We also have considerable experience of the neuro-pathological abnormalities in patients who remained severelydisabled but not vegetative as a result of an acute braininsult. In some of these brains there were lesions similar tothose found in some of the vegetative patients, particularlyin the traumatic group, in that some severely disabled patientshad grades 2 or 3 DAI including damage to the thalamus.The severity of the damage may have been more severe inthe vegetative patients but, as yet, we have been unable todevise a quantitative method to measure damage to axons.

It is clear from the present account of 49 clinicallyconfirmed patients who were in a vegetative state for 1 month

or more, that this condition can occur in patients in whomthere are no identifiable structural abnormalities in thecerebral cortex, the cerebellum or the brainstem. The featurescommon to all are widespread destruction of the white matterof the cerebral hemispheres and/or the thalamus. With oneexception (case 25)—and we cannot account for this—all ofthe patients with DAI in whom no abnormalities could beidentified in the thalamus had not survived long enough fortransneuronal degeneration to have occurred. Diffuse damageto subcortical white matter was, however, common to allpatients. In all of the patients in whom the vegetative statehad been produced by some hypoxic episode, there wasdiffuse and severe damage to each thalamus. It must thereforebe concluded that the fundamental structural abnormality inpatients with the vegetative state is subcortical and is relatedto damage to the white matter of the cerebral hemispheresand/or the thalamus. These lesions do, however, renderany structurally intact cortex unable to function becauseconnections between different cortical areas via the thalamicnuclei are no longer viable, and there is also extensivedamage to afferent and efferent cerebral connections.

ReferencesAdams JH, Graham DI. The relationship between ventricular fluidpressure and the neuropathology of raised intracranial pressure.Neuropathol Appl Neurobiol 1976; 2: 323–32.

Adams JH, Brierley JB, Connor RC, Treip CS. The effects ofsystemic hypotension upon the human brain. Clinical andneuropathological observations in 11 cases. Brain 1966; 89: 235–68.

Adams JH, Mitchell DE, Graham DI, Doyle D. Diffuse braindamage of immediate impact type. Brain 1977; 100: 489–502.

Adams JH, Graham DI, Scott G, Parker LS, Doyle D. Brain damagein fatal non-missile head injury. J Clin Pathol 1980; 33: 1132–45.

Adams JH, Graham DI, Murray LS, Scott G. Diffuse axonal injurydue to nonmissile head injury in humans: an analysis of 45 cases.Ann Neurol 1982; 12: 557–63.

Adams JH, Doyle D, Graham DI, Lawrence AE, McLellan DR.Microscopic diffuse axonal injury in cases of head injury. Med SciLaw 1985a; 25: 265–9.

Adams JH, Doyle D, Graham DI, Lawrence AE, McLellan DR,Gennarelli TA, et al. The contusion index: a reappraisal in human andexperimental non-missile head injury. Neuropathol Appl Neurobiol1985b; 11: 299–308.

Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellanDR. Diffuse axonal injury in head injury: definition, diagnosis andgrading. Histopathology 1989; 15: 49–59.

Adams JH, Jennett B, McLellan DR, Murray LS, Graham DI. Theneuropathology of the vegetative state after head injury. J ClinPathol 1999; 52: 804–6.

Auer RN, Benveniste H. Hypoxia and related conditions. In: GrahamDI, Lantos PL, editors. Greenfield’s neuropathology, Vol. 1, 6th ed.London: Arnold; 1997. p. 263–314.

Vegetative state 1337

Auer RN, Hugh J, Cosgrove E, Curry B. Neuropathologic findingsin three cases of profound hypoglycemia. Clin Neuropathol 1989;8: 63–8.

Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA,McLean AJ. Staining of amyloid precursor protein to study axonaldamage in mild head injury. Lancet 1994; 344: 1055–56.

Brierley JB, Graham DI, Adams JH, Simpson JA. Neocortical deathafter cardiac arrest: a clinical, neurophysiological, and neuro-pathological report of two cases. Lancet 1971; 2: 560–5.

Clark JM. Distribution of microglial clusters in the brain after headinjury. J Neurol Neurosurg Psychiatry 1974; 37: 463–74.

Cole G, Cowie VA. Long survival after cardiac arrest: case reportand neuropathological findings. Clin Neuropathol 1987; 6: 104–9.

Dougherty JH Jr, Rawlinson DG, Levy DE, Plum F. Hypoxic-ischemic brain injury and the vegetative state: clinical andneuropathologic correlation. Neurology 1981; 31: 991–7.

French JD. Brain lesions associated with prolonged unconsciousness.Arch Neurol Psychiat 1952; 68: 727–40.

Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ,Marcincin RP. Diffuse axonal injury and traumatic coma in theprimate. Ann Neurol 1982; 12: 564–74.

Gennarelli TA, Thibault LE, Graham DI. Diffuse axonal injury: animportant form of traumatic brain damage. Neuroscientist 1998; 4:202–15.

Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW.β-amyloid precursor protein (βAPP) as a marker for axonal injuryafter head injury. Neurosci Lett 1993; 160: 139–44.

Gentleman SM, Roberts GW, Gennarelli TA, Maxwell WL, AdamsJH, Kerr S, et al. Axonal injury: a universal consequence of fatalclosed head injury? Acta Neuropathol (Berl) 1995; 89: 537–43.

Graham DI. Hypoxia and vascular disorders. In: Adams JH, DuchenLW, editors. Greenfield’s neuropathology. 5th ed. London: EdwardArnold; 1992. p. 153–268.

Graham DI, Adams JH, Doyle D. Ischaemic brain damage in fatalnon-missile head injuries. J Neurol Sci 1978; 39: 213–34.

Graham DI, Lawrence AE, Adams JH, Doyle D, McLellan DR. Braindamage in non-missile head injury secondary to high intracranialpressure. Neuropathol Appl Neurobiol 1987; 13: 209–17.

Graham DI, Ford I, Adams JH, Doyle D, Teasdale GM, LawrenceAE, et al. Ischaemic brain damage is still common in fatal non-missile head injury. J Neurol Neurosurg Psychiatry 1989; 52: 346–50.

Hart IK, Kennedy PG, Adams JH, Cunningham NE. Neurologicalmanifestation of carbon monoxide poisoning. Postgrad Med J 1988;64: 213–6.

Holbourn AHS. Mechanics of head injuries. Lancet 1943; 2: 438–41.

Holbourn AHS. The mechanics of brain injuries. Br Med Bull 1945;3: 147–9.

Ingvar DH, Brun A, Johansson L, Samuelsson SM. Survival aftersevere cerebral anoxia with destruction of the cerebral cortex: theapallic syndrome. Ann NY Acad Sci 1978; 315: 184–214.

Jafari SS, Maxwell WL, Neilson M, Graham DI. Axonal cytoskeletal

changes after non-disruptive axonal injury. J Neurocytol 1997; 26:207–21.

Jellinger K. Pathology and pathogenesis of apallic syndromesfollowing closed head injuries. In: Dalle Ore G, Gerstenbrand F,Lucking CH, Peters F, Peters UH, editors. The Apallic syndrome .Berlin: Springer-Verlag; 1977. p. 88–103.

Jellinger KA. The brain of Karen Ann Quinlan [letter]. N Engl JMed 1994; 331: 1378–9.

Jellinger K, Seitelberger F. Protracted post-traumatic encephalo-pathy: pathology, pathogenesis and clinical implications. J NeurolSci 1970; 10: 51–94.

Jennett B. A quarter century of the vegetative state: an internationalperspective. J Head Trauma Rehabil 1997; 12: 1–12.

Jennett B, Plum F. Persistent vegetative state after brain damage.A syndrome in search of a name. Lancet 1972; 1: 734–7.

Kalimo H, Olsson Y. Effects of severe hypoglycemia on the humanbrain. Neuropathological case reports. Acta Neurol Scand 1980; 62:345–56.

Kinney HC, Samuels MA. Neuropathology of the persistentvegetative state. A review. [Review]. J Neuropathol Exp Neurol1994; 53: 548–58.

Kinney HC, Korein J, Panigrahy A, Dikkes P, Goode R.Neuropathological findings in the brain of Karen Ann Quinlan. Therole of the thalamus in the persistent vegetative state. N Engl JMed 1994; 330: 1469–75.

Lapresle J, Fardeau M. The leukoencephalopathies caused by carbonmonoxide poisoning. Study of sixteen anatomo-clinical observations.[French]. Acta Neuropathol (Berl) 1966; 6: 327–48.

McLean SA. Legal and ethical aspects of the vegetative state. J ClinPathol 1999; 52: 490–3.

Maxwell WL. Microtubular changes in axons after stretch injury[abstract]. J Neurotrauma 1995; 12: 363.

Maxwell WL. Histopathological changes at central nodes of Ranvierafter stretch-injury. Microsc Res Tech 1996; 34: 522–35.

Maxwell WL, Irvine A, Graham DI, Adams JH, Gennarelli TA,Tipperman R, et al. Focal axonal injury: the early axonal responseto stretch. J Neurocytol 1991; 20: 157–64.

Maxwell WL, Watt C, Graham DI, Gennarelli TA. Ultrastructuralevidence of axonal shearing as a result of lateral acceleration of thehead in non-human primates. Acta Neuropathol (Berl) 1993; 86:136–44.

Maxwell WL, McCreath BJ, Graham DI, Gennarelli TA.Cytochemical evidence for redistribution of membrane pumpcalcium-ATPase and ecto-Ca-ATPase activity, and calcium influxin myelinated nerve fibres of the optic nerve after stretch injury.J Neurocytol 1995; 24: 925–42.

Maxwell WL, Povlishock JT, Graham DI. A mechanistic analysisof nondisruptive axonal injury: a review. [Review]. J Neurotrauma1997; 14: 419–40.

Multi-Society Task Force on PVS. Medical aspects of the persistentvegetative state. [Review]. N Engl J Med 1994; 330: 1572–9.

1338 J. H. Adams et al.

Oppenheimer DR. Microscopic lesions in the brain following headinjury. J Neurol Neurosurg Psychiatry 1968; 31: 299–306.

Peerless SJ, Rewcastle NB. Shear injuries of the brain. Can MedAssoc J 1967; 96: 577–82.

Peters G, Rothemund E. Neuropathology of the traumatic apallicsyndrome. In: Dalle Ore G, Gerstenbrand F, Lucking CH, Peters F,Peters UH, editors. The Apallic syndrome. Berlin: Springer-Verlag;1977. p. 78–87.

Pettus EH, Povlishock JT. Characterization of a distinct set of intra-axonal ultrastructural changes associated with traumatically inducedalteration in axolemmal permeability. Brain Res 1996; 25: 722: 1–11.

Pettus EH, Christman CW, Giebel ML, Povlishock JT. Traumaticallyinduced altered membrane permeability: its relationship totraumatically induced reactive axonal change. J Neurotrauma 1994;11: 507–22.

Povlishock JT. Traumatically induced axonal injury: pathogenesisand pathobiological implications. [Review]. Brain Pathol 1992; 2:1–12.

Povlishock JT, Becker DP, Cheng CL, Vaughan GW. Axonal changein minor head injury. J Neuropathol Exp Neurol 1983; 42: 225–42.

Povlishock JT, Marmarou A, McIntosh T, Trojanowski JQ, Moroi J.Impact acceleration injury in the rat: evidence for focal axolemmalchange and related neurofilament sidearm alteration. J NeuropatholExp Neurol 1997; 56: 347–59.

Pudenz RH, Shelden CH. The lucite calvarium – a method for

direct observation of the brain: II. Cranial trauma and brainmovement. J Neurosurg 1946; 3: 487–505.

Reilly PL, Graham DI, Adams JH, Jennett B. Patients with headinjury who talk and die. Lancet 1975; 2: 375–7.

Relkin NR, Petito CK, Plum F. Coma and the vegetative stateassociated with thalamic injury after cardiac arrest [abstract]. AnnNeurol 1990; 28: 221–2.

Royal College of Physicians Working Party. The permanentvegetative state. J R Coll Physicians Lond 1996; 30: 119–21.

Sherriff FE, Bridges LR, Sivaloganathan S. Early detection ofaxonal injury after human head trauma using immunocytochemistryfor β-amyloid precursor protein. Acta Neuropathol (Berl) 1994; 87:55–62.

Strich SJ. Diffuse degeneration of the cerebral white matter in severedementia following head injury. J Neurol Neurosurg Psychiatry 1956;19: 163–85.

Torvik A, Jorgensen L. Ischaemic cerebrovascular diseases in anautopsy series. 2. Prevalence, location, pathogenesis, and clinicalcourse of cerebral infarcts. J Neurol Sci 1969; 9: 285–320.

Vuia O. Subcortical leukoencephalopathy caused by CO poisoning.[French]. Acta Neuropathol (Berl) 1967; 7: 305–14.

Zimmerman RA, Bilaniuk LT, Genneralli T. Computed tomographyof shearing injuries of the cerebral white matter. Radiology 1978;127: 393–6.

Received September 14, 1999. Revised November 29, 1999.Accepted December 10, 1999