Epidemiological studies on patients persistent stateSUMMARY Persistent vegetative state after severe brain damage was studied epidemiologi-cally in 110 cases from 1973 to 1976. The

Journal ofNeurology, Neurosurgery, andPsychiatry, 1977, 40, 876-885

Epidemiological studies on patients with a persistentvegetative stateK. HIGASHI, Y.S. KATAYAMA,M. ZENKE, AND

SAKATA, M. HATANO, S. ABIKO, K. IHARA,Y. WAKUTA, T. OKAMURA, H. UEDA,H. AOKI

From the Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Japan

SUMMARY Persistent vegetative state after severe brain damage was studied epidemiologi-cally in 110 cases from 1973 to 1976. The causes of brain damage were varied. More thanone-third of the cases were due to trauma, and about one-fifth were the result of vascularaccidents. Three year observation revealed that 65% of the patients died during this period.Mean survival time for dead patients was 38 months. Reactivity, clinical signs, EEG findings,methods of management, and results of various trials of treatment were investigated inconnection with the patient's prognosis.

Recent progress in treatment and intense carefor patients with severe brain damage has led to anincrease in the number of patients surviving for along period without recognisable mental function.Virtually hopeless, these patients, who never re-gain their functions as social human beings despiteevery effort, survive for months and even yearsin suitable medical conditions. Living at the ex-pense of their families, not only mentally buteconomically, such patients pose a serious prob-lem to their families and physicians.There is no standardised terminology for such

a state resulting from severe brain damage, al-though various names have been applied, such asprolonged coma (Nakamura et al., 1965a,b;Crompton et al., 1966), coma vigile (Gerstenbrand,1967), parasomnia (Jefferson, 1944), akineticmutism (Cairns et al., 1941), and apallic syndrome(Kretschmer, 1940). Recently, Jennett and Plum(1972) proposed that this syndrome should bedescribed as a persistent vegetative state.Although a definition of the vegetative state has

not yet been established, Jennett and Plum (1972)described such patients as those who recover fromsleep-like coma in that they have periods of wake-fulness when their eyes open and move, whoseresponsiveness is limited to primitive postural and

Address for reprint requests: Dr K. Higashi, Department of Neuro-surgery, Yamaguchi University School of Medicine, Ube, Yamaguchi-ken. 755 Japan.Accepted 24 March 1977

reflex movement of the limbs, and who neverspeak.We arbitrarily designed the following criteria in

order to study such patients: (1) defect of verbaland behavioural communication; (2) loss of ex-pression of intention; (3) absence, or at least re-duction of emotional expression; (4) urinary andfaecal incontinence; (5) complete loss of self-supportability; (6) continuation of above con-ditions for more than three months, regardless ofcausative disease.

Patients and methods

In response to simple inquiries to 269 hospitals in16 prefectures of western Japan on 1 June 1973,193 potentially suitable cases were reported from189 hospitals; we then visited each hospital andexamined each patient. Based on the abovecriteria, 110 patients were included in our study.Although we were unable to assess the incidence

of vegetative patients for all districts respondingto our inquiry our survey did cover all hospitalswithin Yamaguchi prefecture, a population ofapproximately 1.5 million. We found 37 vegetativepatients, an incidence of 0.0025%.We examined the behaviour, response to various

stimuli, and neurological signs of the 110 patientsin our sample. Analyses were also made of theresults of ancillary examinations, methods of man-agement of the patients, and effectiveness of treat-ment given. In order to assess the level of

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Epidemiological studies on patients with a persistent vegetative state

consciousness and vital reactivity of the patients,the following items were checked: (1) blinking,(2) response to painful stimuli, (3) sleep-wakeperiodicity, (4) spontaneous eye movement, (5)yawning, (6) response to sound stimuli, (7) swal-lowing movement, (8) chewing movement, (9) eye-following movement for moving object, (10)emotional expression.The patients were evenly distributed through all

age groups. The youngest patient was 2 years oldand the oldest was 81 years. There were 75 malesand 35 females (Table 1).

Follow-up examinations were carried out oncea year for three years after the first investigation.For the dead the cause of death and necropsyfindings were recorded. Complete bedside exam-inations on surviving patients were performed atthe first (June 1974) and the third (June 1976)follow-up studies. Examination of the changes ofclinical state of the patients was made on thebasis of judgement of both the attending physicianand one of the authors.

Results

CAUSE OF BRAIN DAMAGEThe causes of brain damage were varied (Table 1).More than one-third of the cases were due totrauma. Eighteen patients with head injury(47.4%) had had intracranial haematoma(epidural 6, subdural 7, intracerebral 2, combinedintra- and extracerebral 3). Two patients had hadopen depressed skull fractures. All of these 20cases had undergone surgery.

In approximately one-fifth of the total cases,

causative diseases were cerebrovascular lesion(seven cases of intracerebral haemorrhage, threeof ruptured intracranial aneurysm, three of cere-

bral thrombosis or embolism, two of cerebralarteriosclerosis, one subarachnoid haemorrhage of

unknown origin, and five where the cause was un-known). Of these 21 cases, five had undergone anoperation.The group of developmental disorders con-

sisted of nine cerebral palsies, two congenitalhydrocephalus, two microcephalus, and oneLennox syndrome. Cerebral anoxia from cardiacarrest occurred in four cases, asphyxia neona-torum in four, drowning in one, and other causesin three. Brain tumours were supratentorial in sixcases (two meningiomas and one each of astrocy-toma, glioblastoma, craniopharyngioma, andmetastatic tumour), and infratentorial in four(two pontine tumours, one acoustic neurinoma andone fourth ventricle ependymoma). All thesetumour cases except one were postoperative.Inflammatory diseases were two cases of

meningitis, two brain abscesses, and one each ofencephalitis japonica, subacute sclerosing pan-encephalitis, and Creutzfelt-Jacob syndrome. Re-gressive degenerative diseases were two of Pick'sdisease, one familial primary amyloidosis, and onediffuse encephalopathy of unknown origin. Intoxi-cations were due to carbon monoxide in threecases, and agricultural chemicals in one.

Patients with cerebrovascular and regressive-degenerative diseases tended to be in the oldergroup, while those with developmental disordersand cerebral anoxia were younger (Table 1).

DURATION OF VEGETATIVE STATEDuration of the vegetative state at the time of thefirst survey (June 1973) was classified in six groups(Table 1). Approximately half of the patientscontinued to live in this state for less than a yearfrom the onset of the state. On the other hand, itis worth noting that over a quarter of the patientscontinued their vegetative existence for more thanthree years; four patients had lived more than 10years. The survival period after head injury, cere-

Table 1 Some characteristics of the patient population in relation to the cause of brain damage

Cause ofbrain damage Number Age distribution (yr) Sex Duration of vegetative stateofcases (at time offirst examination)

0- 21- 41- 61+ M F20 40 60 3- 6- 1- 3- 5- 1Oyr+

6 mo 12 mo 3 yr 5 yr 10 yr

Head injury 38 6 13 10 9 34 4 14 8 10 4 2 0Cerebrovascular lesion 21 0 0 8 13 10 11 11 3 4 3 0 0Developmental disorder 14 12 2 0 0 9 5 0 2 0 2 7 3Cerebral anoxia 12 8 2 1 1 9 3 5 0 4 3 0 0Brain tumour 10 2 3 3 2 5 5 0 5 5 0 0 0Inflammatory disease 7 1 3 2 1 4 3 3 2 1 0 0 1Regressive-degenerativedisease 4 0 2 0 2 1 3 1 0 2 1 0 0Intoxication 4 0 2 1 1 3 1 2 0 0 0 2 0Total 110 29 27 25 29 75 35 36 20 26 13 11 4

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brovascular disease and tumour was relativelyshort, while that of patients with developmentaldisorder was relatively long.

TREATMENT DURING ACUTE STAGECardiac massage and artificial respiration had beencarried out in 12 (10.9%) and 15 (13.6%) casesrespectively. Except for patients whose braindamage resulted from cardiac arrest, relativelyfew cases had received artificial respiration, sug-gesting relative integrity of the medullary vitalcentres, regardless of the cause of brain damage.Tracheostomy, performed in the acute stage for 51cases (46.4%), was still in use at the time of thefirst survey for 33 cases (30.0%).

CLINICAL FINDINGSBehaviour and reactivity At the initial examina-tion, primitive responses of wakefulness such asblinking, response to painful stimuli, sleep-wakeperiodicity, and spontaneous eye movement wereseen in a majority of the patients. Patients whosevegetative state results from head trauma or cere-brovascular accident usually wake from sleep-likecoma and begin to open their eyes, at first only inresponse to painful stimuli, but later spontane-ously. In our series sleep-wake periodicity becamemanifest within one to 12 weeks (average of fiveweeks) after onset. A few patients never openedtheir eyes and were still in sleep-like coma eventhree months after onset; such patients were in-cluded in this survey. More than half of thepatients had yawning, some response to auditorystimuli, and some swallowing movements, nearlyhalf had chewing and eye-following movements.Less than one-third of the cases showed anyemotional expression, not necessarily indicatingemotion; many such patients had meaninglesslaughter or weeping, a kind of emotional incon-tinence (Table 2). When assessments were madeagain on the survivors one and three years afterthe initial examination there was a slight increase

Table 2 Reactivity and behavioural responses ofvegetative patients (%). (Numbers in parenthesesrepresent number of cases examined)

June 1973 June 1974 June 1976(110) (63) (38)

Blinking 90.7 88.3 100.0Sleep-wake rhythm 86.0 93.5 94.7Response to painful stimuli 84.4 90.2 81.6Spontaneous eye movement 75.0 83.1 81.6Yawning 73.8 82.0 76.3Response to auditory stimuli 57.5 60.7 52.6Swallowing 50.5 57.4 81.6Chewing 46.2 57.4 63.2Eye-following movement 42.7 32.7 31.4Emotional expression 30.9 41.0 47.4

in the rate of appearance of almost all responsestested, except for eye-following movement, whicldecreased progressively (Table 2).

Function and posture of extremities At theinitial examination, 43% of the patients hadquadriplegia. Hemiplegia was seen in 17%. Con-tracture of one or more joints was common.Quadriplegia was seen more frequently in thosewith a longstanding vegetative state, while hemi-plegia and paraplegia were more frequent in thepatients with shorter duration of the vegetativestate. This suggests that quadriplegia may developin relation to longstanding immobility. Spasticityand rigidity were observed in 32% and 46%respectively, representing pyramidal or extra-pyramidal lesions. The decerebrate rigidity whichhad occurred in approximately one-third of thepatients during the acute stage cleared in somecases as the vegetative state became manifest.Convulsions occurred in half the cases.Follow-up studies revealed an increased fre-

quency of contracture, while decerebrate rigiditybecame less frequent at the time of the secondand third examinations (Table 3).

Table 3 Functions and posture of extremities (%).(Numbers in parentheses represent number of casesexamined)

June 1973 June 1974 June 1976(110) (64) (38)

Quadriplegia 43.1 43.8 55.3Triplegia 2.8 14.1 5.3Paraplegia 5.5 9.4 7.9Hemiplegia 17.4 12.5 18.4Diplegia 0.9 0 2.6Monoplegia 0.9 1.6 2.6Contracture of joints 64.8 79.7 89.5Spasticity 32.4 21.9 23.7Rigidity 46.3 50.0 47.4Decerebrate rigidity 31.2 9.4 10.5

Neurological signs At the initial examination,conjugate deviation of the eyes and nystagmuswere infrequently seen (12.6% and 3.7% respec-tively). Anisocoria was observed in one-fifth of thecases. Diminished or sluggish pupillary light re-flex was seen in a quarter of the patients andoptic nerve atrophy in 39%.A ciliary reflex was remarkably common

(91.6%) in the vegetative patients whereasabdominal reflexes were absent in 90%. Exag-gerated deep tendon reflexes were almost as com-mon in upper as in lower extremities, whilediminished deep tendon reflexes were morefrequently observed in the lower extremities thanin the upper. Pyramidal tract signs were elicited

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in 60% of cases. Of the primitive reflexes, thesnout reflex was most frequently demonstrated,then the grasping reflex, and the tonic neck reflexwas least frequently elicited.

After one and three years, neurological findingsin the survivors were essentially similar, exceptfor progressively increased occurrence of the ab-dominal reflex and the snout reflex (Table 4).

Table 4 Neurological findings (% of positive signs).(Numbers in parentheses represent number of casesexamined)

June 1973 June 1974 June 1976(110) (64) (38)

Anisocoria 21.2 22.4 14.7Light reflex 73.7 64.4 78.4Ciliospinal reflex 37.7 25.0 47.2Optic nerve atrophy 39.0 34.7 54.8Ciliary reflex 91.6 96.7 97.3Abdominal reflex 10.0 28.2 45.5Deep tendon reflexesUpper extremities

diminished or weakened 23.0 15.3 27.0exaggerated 31.0 39.0 48.6

Lower extremitiesdiminished or weakened 51.5 59.3 36.1exaggerated 30.7 23.7 38.9

Pyramidal tract signs 60.0 55.7 58.3Primitive reflexesSnout reflex 34.7 48.3 69.4Grasping reflex 19.4 19.7 22.9Tonic neck reflex 6.5 5.4 3.1

CLASSIFICATION OF VEGETATIVE PATIENTS

We tried to classify the vegetative state into threegrades according to the severity based on re-

activity of the patients (Table 5). More than halfof the cases fell into grade II and the proportionin each group for surviving patients did notchange during the three year follow-up period.The condition of patients in grade III appeared

to be more serious than average. Most would opentheir eyes spontaneously or in response to pain,but usually after a short period they would resumethe appearance of sleep, so that no recognisablecycle or rhythm between sleeping and waking wasobserved. Others never opened their eyes andwere immobile unless stimulated.

Analysis based on our classification revealedthat there was a correlation between severity of avegetative state and reactivity or incidence ofabnormal behavioural and neurological findings.Blinking, spontaneous eye movement, response tosound stimuli, swallowing and chewing move-ments were seen more frequently when the gradeof severity was low, while quadriplegia anddecerebrate rigidity were often encountered inthe higher grade of severity.The relationship between the classification of

vegetative state and outcome of the patients isshown in Table 5. We found that the mortalityrate did not correlate strictly with the severity ofthe vegetative state except for patients in gradeIII in whom mortality was higher than averageduring the first and third year, though none diedduring the second year.

FATE OF THE PATIENTSAfter one year 45 patients had died (mortalityrate 40.9%). Among the 65 survivors, nine hadrecovered from the vegetative state. Two wereable to comprehend their surroundings and tocommunicate; they spoke and moved their limbsvoluntarily. The remaining seven patients re-sponded to calling; some were able to followsimple commands and some spoke short words,though they showed no interest in their surround-ings nor initiated activity. One of these sevenpatients died and three became vegetative againbefore the last examination. Of the remaining 56survivors, two (3.6%) improved remarkably(moved to a better grade by two steps in com-parison with the initial evaluation), 12 (21.4%)improved slightly (one step up), 31 (55.4%) wereunchanged, 11 (19.6%) deteriorated slightly (onestep down), and none deteriorated remarkably(two steps down).Fourteen patients died during the second year

and during the third year 12 more patients died.In total, 71 patients died during three years; theoverall mortality for three years was 64.5%.At the last examination eight patients were

assessed as no longer vegetative. Among them,three became comprehending and communica-tive; one conversed freely and was able to walkwithout assistance; the second patient compre-hended well, spoke spontaneously, and was ableto move around in a wheelchair if he was helpedto sit in it; the last one comprehended well andspoke a little but was confined to his bed. Theremaining five patients recovered only to the statethat they obeyed simple commands and/or spokemonosyllabic words. Excluding these eight cases,among 39 survivors, one (3.2%) improved re-markably, five (16.1%) improved slightly, sixteen(51.6%) were unchanged, and nine (29.0%)deteriorated slightly in comparison with the stateat the second examination.The fate of the patients according to the cause

of brain damage showed that mortality was higherin those with cerebrovascular lesion and braintumour, and lower than average in those withhead injury, inflammatory, and regressive-degenerative diseases (Table 6). Mean survivaltime in dead patients was extremely long in the

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Table 6 Mortality and mean survival time for dead patients related to the cause of brain damage

Cause of brain damage After I yr (June 1974) After 2 yr (June 1975) After 3 yr (June 1976) Mean survivaltime for dead

Alive Dead Mortality (%) Alive Dead Mortality (°'O) Alive Dead Mortality (%) patients(Months)(Mean + SD)

Head injury 28 10 26.3 22 16 42.1 17 21 55.3 33.0±25.8Cerebrovascular lesion 9 12 57.1 6 15 71.4 5 16 76.2 21.3±16.3Developmental disorder 8 6 42.9 5 9 64.3 4 10 71.4 89.2±55.0Cerebral anoxia 7 5 41.7 6 6 50.0 4 8 66.7 34.6±28.5Brain tumour 4 6 60.0 4 6 60.0 2 8 80.0 30.0± 19.0Inflammatory disease 4 3 42.9 3 4 57.1 3 4 57.1 13.3± 6.9Regressive-degenerativedisease 3 1 25.0 3 1 25.0 2 2 50.0 39.5Intoxication 2 2 50.0 2 2 50.0 2 2 50.0 73.0Total 65 45 40.9 51 59 53.6 39 71 64.5 38.4 37.6

group of developmental disorders. In the group ofintoxications, survival time was also long, becauseit included one patient who had lived for morethan 10 years. Mean survival time for deadpaSients was 38 months.The causes of death are shown in Table 7. More

than half died from pulmonary complications.

Table 7 Causes of death

Cause ofdeath No. of cases

Pulmonary infection 39 54.9General emaciation or cardiac insufficiency 14 19.7Recurrence of intracranial haemorrhage orthrombosis 4 5.6Asphyxia or respiratory paralysis 3 4.2Recurrence of brain tumour 1 1.4Meningitis 1 1.4Unknown 7 9.9

Total 71 99.9

ANCILLARY EXAMINATIONS

By the time of our initial examination, cerebralangiography had been performed in 38 cases(34.5%); 66.7% of them were found to be normal,abnormal courses of the cerebral vessels weredemonstrated in 14.3%, while occlusion of thecerebral arteries was found in 9.5%. Pneumoence-phalography or pneumoventriculography had beenperformed in 18 cases (16.4%); various grades ofventricular dilatation were demonstrated in 62.5%.Isotope cisternography revealed a disturbance ofthe flow of CSF in seven of nine cases. Electro-encephalography (EEG) had been carried out in59 cases (53.6%). The first EEG findings after thevegetative state had become manifest are sum-

marised in Table 8. Diffuse slow activity in whichtheta and delta waves were dominant was seen in63.8%, while in 25.5% alpha waves were domi-nant. Some of the latter cases showed essentiallynormal EEG records but an isoelectric recordwas observed in three cases.

Table 8 EEG findings in the first examination afteronset of vegetative state

EEGfindings No. of cases %

Dominant frequency,l] 2 4.3a 12 25.50 20 42.5a 10 21.3

Flat EEG 3 6.4Total 47 100.0

Focal or hemispheric slow waves 11 23.4Spikes 8 17.0

During the second year of this survey, ancillaryexaminations other than EEG were seldom per-formed, but EEG was examined in 23 cases. Table9 shows the relationship between EEG findingsand clinical findings in 17 cases in which theEEGs were performed more than twice over theperiod of two or more years. Some cases showeddeterioration of EEG findings despite clinicalimprovement, while others demonstrated improvedEEG although the clinical state was unchangedor had deteriorated.

MANAGEMENT AND COMPLICATIONSMore than half of the patients were fed by anasogastric tube, while 26% of the cases couldbe fed orally. Gastrostomy for feeding had beenperformed in 15% at the time of the first survey.

Table 9 Relation belwee,s chlanges in EEG andclinical status

EEG Iniprored Unchanged Deteriorated Totalfindings

Clinlica{l\finldings\

I mproved 3 3 7Unchaniged 4 4 1 9Deteriorated 1 0 0 ITotal 6 7 4 17

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Table 10 Nutritional state in relation to method of feeding

Method offeeding June 1973 June 1974 June 1976

No. of Nutritional state No. o Nutritional state No. of Nutritional statecases cases cases

Good Fair Poor Good Fair Poor Good Fair Poor

Oral 28 10 12 6 22 11 9 2 18 8 5 5Nasal tube 66 9 25 32 36 8 20 8 17 7 4 6Gastrostomy 16 2 11 3 7 1 4 2 4 0 4 0Total 110 21 48 41 65 20 33 12 39 15 13 1 1

The relationship between method of feeding andnutritional status is summarised in Table 10. Dif-ference in effectiveness between nasal feedingand gastrostomy was equivocal.

Respiratory and urinary tract infections oc-curred in 43.6% and 41.8% respectively, and54.5% of the patients had decubiti. Gastro-intestinal bleeding had occurred at some time in2.7% of the patients.

In spite of a variety of therapeutic efforts(Table 11), only three patients responded to treat-ment: one to ventriculo-peritoneal shunt and twoto administration of levodopa.

Table 11 Various trials of treatment and theireffectiveness

Methods No. ofcases No. ofeffectiv ecases

Decompressive procedures includingventricular drainage and shunt operation 19 1Intracarotid injection with autogenous blood 6 0Systemic administration of levodopa 5 2Resection or block of cervicalsympathetic ganglia 3 0Intrathecal administration of CDP-choline 3 0Intracarotid administration of CDP-choline 2 0Fever therapy with mixed typhoid andparatyphoid vaccine 1 0Total 44 3

Discussion

In recent years the term 'vegetative state' hasoften been used to describe the condition of a

patient who is living a useless life without highlydifferentiated adaptability to external circum-stances, due to severe brain damage. In general,this term has been used in a wide range of cir-cumstances, from the patient who can communi-cate to some extent to the state of brain death.However, the latter should be distinguished froma vegetative state because the patient in this statehas lost even vegetative functions such as respira-tion, and must die within about a week (Mohandasand Chou, 1971).

The term 'prolonged coma' is also used as asynonym of a persistent vegetative state, but thisstate cannot be called 'coma' as ordinarily defined(Jennett and Plum, 1972). The terms 'akineticmutism' (Cairns et al., 1941) and 'apallic syn-drome' (Kretschmer, 1940) are defined preciselyby the original authors but are clinically indis-tinguishable.We interpret the term vegetative state according

to its original meaning as 'a state in which animalfunctions are lost, preserving only vegetativefunctions such as respiration, nutrition, andexcretion'. We, therefore, included patients in astate of sleep-like coma if this had continued formore than three months, although they deviatedfrom Jennett and Plum's definition, because dur-ing the first three months after brain damage thereis a possibility of full recovery.The behaviour and reactivity which we tested

are a good indication of the severity of thevegetative state. More reactive patients have moreof these signs, while the patients belonging to highgrades of severity show only primitive reactions.However, more reactive patients do not necessarilyhave a good prognosis. Outcome analysis indicatedthat there was no definite correlation betweenseverity of the reactive state and mortality, pos-sibly because complications, particularly pul-monary infections, were substantially responsiblefor their deaths, while progression of the braindamage itself appeared to be less fatal in suchchronic stages. Therefore, reactivity is not animportant factor in prognosis. Nakamura et al.(1965a,b) also had difficulty in estimating theprognosis of patients with prolonged coma due totrauma on the basis of reactivity.Abnormal posturing and disturbed function of

extremities were usually related to both theseverity and duration of the state. Some patientsshowed unusual posture of the lower extremitiesdue to a combination of decerebration and con-tracture. Immobile legs were often combined withpes equinus.

Decerebrate rigidity or decerebrate posture wasoriginally described in animals by physiologists

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after brain stem transection (Sherrington, 1898).According to Plum and Posner (1972), decerebraterigidity is encountered clinically in the followingcases: (1) involvement of the midbrain by ex-tension of diencephalic damage during the courseof rostro-caudal deterioration due to cerebralherniation, (2) destruction of expansive posteriorfossa lesions damaging the midbrain and upperpons, (3) severe metabolic disturbances which sup-press the upper brain stem functions, such ashepatic coma, hypoglycaemia, anoxia, andintoxication.

In cases with severe brain damage from variouscauses resulting in a vegetative state, the midbrainand upper pons may be involved partly throughany one of the above three mechanisms, thuscausing decerebrate rigidity. In some cases, therigidity abates later, suggesting that lesions occur-ring in the upper brain stem might be reversible.However, Okada et al. (1972), in a clinicopatholo-gical study of 13 cases of prolonged coma due totrauma, reported that it was difficult to correlatean identifiable brain stem lesion with decerebraterigidity.

In the present series of 110 cases, 34 had de-cerebrate rigidity which occurred spontaneouslyor was elicited by stimulation at the time of thefirst examination. Five had had such posture orresponse during the acute phase but did not haveit by the time of the examination. Precise analysiswas made of these 39 cases. The rate of appear-ance of decerebrate rigidity in each group of thecausative diseases is shown in Table 12. A remark-ably frequent occurrence is seen in the group withbrain tumour. Although it is easy to see that in-fratentorial brain tumours may readily causedecerebrate rigidity by direct compression of theupper brain stem structures, even supratentorialtumours may initiate the rostro-caudal deteriora-tion which is responsible for a vegetative stateand decerebration due to involvement of

Table 12 Numbers and percentages of patients wit/hdecerebrate rigidity grouped according to causativelesions

Cauise of brain dam^1age No. of cases ivithdecerebrate rigidit-y/total cases

Head injury 17/38 44.7Cerebrovascular lesion 1/21 4.8Developmental disorder 2/14 14.3Cerebral anoxia 7/12 58.3Brain tumour 8/10 80.0Inflammatory disease 2/7 28.6Regressive-degenerative disease 1/4 25.0Intoxication 1/4 25.0

Total 39/110 35.5

mesencephalic or upper pontine tissues. In thegroup with cerebral anoxia and head injury, thefrequency of decerebrate rigidity was also highsuggesting that the critical areas in the upper brainstem may be involved.The contrast between retention of ciliary re-

flexes and abolition of abdominal reflexes hasbeen referred to above. Even in the face of braindamage so devastating as to bring about a vegeta-tive state, the simplest reflex, such as blinking,remained. On the other hand, the abdominalreflex is said to involve an elaborate reflex arc inwhich there are several neurones connecting tothe motor cortex (Haymaker, 1956) which mightaccount for its loss with severe cortical or sub-cortical dysfunction. Primitive reflexes, parti-cularly the snout reflex, were elicitable morefrequently in the patients with longstandingvegetative state, and tended to be less common inthe patients without sleep-wake rhythm (gradeIII).Necropsy reports have been published on 43

patients who had prolonged unconsciousnesssimilar to our cases (French, 1952; Jacobson, 1956;Strich, 1956; Denst et al., 1958; Nystrbm, 1960;Strich and Oxon, 1961; Jellinger et al., 1963;Utsumi et al., 1963; Nakamura et al., 1965b;Crompton et al., 1966; Arai and Ueki, 1971;Okada et al., 1972). The clinical condition in thesecases before death had been in keeping with ourcriteria for a vegetative state. Thirty-five of the43 (81.4%) had extensive demyelinative degenera-tion of the cerebral white matter as a principalpathological change, while destruction of thebrain stem reticular formation was found only infour (9.3%) cases (Higashi et al., 1974).On the basis of these observations, it is sug-

gested that the brain stem structures are relativelyuninjured in vegetative patients, in spite of ex-tensive destruction of the tissues above the brainstem. The relatively few cases rendered apnoeic inthe acute stage in the present series may supportthe observation that there exists considerableintegrity of the lower brain stem, including themedulla, because complete destruction of thebrain stem is incompatible with survival. Manypatients, however, had signs of damage to themidbrain or upper pons such as decerebraterigidity and pupillary changes. Although thenature and site of the lesion within the brainvaried because of the variety of causes of braindamage, lesions in the brain may be consideredto exist in any areas, disrupting the connectionbetween the cephalic brain stem and the entirecortex.The cephalic brain stem, including the central

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portion of the midbrain tegmentum, the sub-thalamus and hypothalamus as well as the medialthalamus, is believed to be a centre of wakefulness(Magoun, 1952). Although extensive damage tothese crucial structures or their cortical reflectionswould lead to sleep-like coma, their partial or in-complete destruction could be compatible withcrude awakening and sleeping, as French (1952)stated. If damage to the cephalic brain stem isreversible the patient may awake from the sleep-like coma, and sleep-wake rhythm may appear.If there occurs an interruption from the cephalicbrain stem to the cortex, the patient may neverregain conscious awareness. The extensive de-generation of white matter which is frequentlyfound in the brains of vegetative patients accountswell for the clinical behaviour observed.

Severe metabolic dysfunction accompaniesstructural changes in the brain. Cerebral bloodflow studies have revealed a decrease of flow rateby a half to a quarter of normal (Shinmura et al.,1972; Ingvar, 1973; Kanaya et al., 1975). Suchsevere disturbance in cerebral circulation may beresponsible for degeneration of cortical nervecells and contribute to the characteristic mani-festation in this syndrome or they may result frombrain damage.The opinions of previous authors have tended to

be that EEG results do not reliably represent thedegree of damage to the brain (Utsumi et al.,1963; Nakamura et al., 1965a; Handa and Mori-take, 1971). In our hands the EEG findings didnot correspond to the severity of damage; manyEEG records disclosed diffuse slow activity butsome demonstrated normal EEG activity. We alsofound that changes in EEG findings did not cor-relate well with the changes in clinical conditionduring the follow-up period.

Vegetative patients have a consistently poorprognosis. During the three year follow-up period,more than 60% of the patients died, despiteattentive medical care. On the other hand, somepatients regained awareness and were able to speaka little but were unable to resume activity as asocial human being. Persistent recovery of com-municability has been attained in three cases outof 110 during the period of three years. Amongthem, however, only one patient regained nearlynormal brain function.

In spite of painstaking efforts to maintain vege-tative patients, the results have been poor. Kyoiet al. (1975) reported a favourable result from anoperation to shunt the CSF. If, as emphasised,secondary normal-pressure hydrocephalus plays animportant role in the clinical manifestation ofvegetative patients, and if functional disturbance

of the brain is reversible, such procedures mightbe effective. In our series, however, ventriculo-peritoneal shunting was effective in only one outof 19 cases. This patient showed excellent tem-porary improvement after the procedure, but wasagain vegetative several months later, despitepatency of the shunt. Sasabe et al. (1970) reporteda favourable effect of forceful intracarotid orintravertebral injection of blood in patients withtraumatic prolonged coma, a treatment performedin several cases in this series but in vain.Treatment with levodopa had a more favour-

able effect. At least two patients recovered fromthe vegetative state in our series after systemicadministration of levodopa. As reported elsewhere(Higashi et al., 1977), those who responded tolevodopa therapy were young adults who had goodcortical function as demonstrated by the initialEEG. Although the mode of action of levodopa onthe disturbance of consciousness is unknown, itsawakening effect has been reported in animals(Blaschko and Chrusciel, 1960; Kadzielawa andWidy-Tyszkiewicz, 1970) as well as in clinicalpractice (Parkes et al., 1970; Fukushima et al.,1972).On the basis of our survey patients with per-

sistent vegetative state have a poor prognosis, butthe possibility of complete recovery exists for atleast two months after onset.

We gratefully acknowledge the cooperation ofthe doctors in each institution who kindly per-mitted us to examine the patients in their charge.

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Documents

Epidemiological studies on patients persistent stateSUMMARY Persistent vegetative state after severe brain damage was studied epidemiologi-cally in 110 cases from 1973 to 1976. The