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PROGNOSIS OF CEREBRAL EMBOLISM
514
which can be lost into closed fractures either of the limbs or of the trunk has been recognised for some time (Clarke et al. 1955), but it can still surprise those inexperienced in dealing with trauma. Clarke et al. (1961) said that the average loss in a closed chest injury was 2-5 litres, and that much was lost into the chest wall and would not be obvious as a hasmothorax on chest X-ray. They cited a similar figure for fractured pelvis, and added that this was one of the few single injuries which could give rise to sudden, unexpected collapse. On average they found that about 50% of the internal blood-loss in various sites occurred within two to five hours of injury.
High spinal injury causes hypotension by sympathectomy. There was only 1 patient in the present series in whom such an injury was suspected as a contributing factor (case 5). The evidence for this mechanism cannot ,be regarded as conclusive even in this case, because there was also serious scalp bleeding. Since the series was closed a patient was admitted who illustrates strikingly the importance of recognising spinal injury associated with head injury. A girl, aged 12 years, was admitted to hospital unconscious after a road accident. There were many facial abrasions, the limbs were flaccid, and the systolic blood-pressure was 60 mm. Hg. She was regarded as having suffered a serious head injury, but the following day she regained consciousness and it was evident that she had a quadriparesis. X-rays of the cervical spine revealed an atlanto-axial dislocation; skull traction was applied and she is making a good recovery. There were no other injuries, and clearly the head injury was relatively mild. Conclusion
This study reinforces the impression that hypotension after head injury is rarely due to the intracranial lesion, even when there is severe brain damage. In 11 of 14 cases the cause of shock was blood-loss, and in 8 of these the site of the loss was an associated injury.
develops after a head injury it should be regarded oligxmic and treated by blood-volume expanders. Unless there is a large scalp laceration the source of the blood-loss should be sought elsewhere, particularly in the chest, abdomen, or pelvis. When shock as
Summary In 14 of 470 cases of head injury admitted to hospital the blood-pressure was less than 90 mm. Hg within six hours of injury.
Blood-loss was the cause of the hypotension in 11 of the 14 cases; the scalp was the source of only 3. Associated injuries were a major factor contributing to shock in 10 cases.
Shock after head
fusion, and the there is
severe
injuries should be treated by transsought elsewhere in the body unless scalp bleeding. cause
The consultant surgeons in the Western Infirmary and the Royal Infirmary, Glasgow, and in the West of Scotland Neurosurgical Unit, Killearn Hospital, under whose care these patients were admitted, kindly allowed us access to their records. REFERENCES
Clarke, R., Topley, E., Flear, C. T. G. (1955) Lancet, i, 629. — Fisher, M. R., Topley, E., Davies, J. W. L. (1961) ibid. ii, 381. Dalgaard, J. B. (1960) Archs Path. 69, 359, Daniel, P. M., Prichard, M. M. L., Treip, C. S. (1959) Lancet, ii, 927. Lewin, W. (1954) Proc. R. Soc. Med. 10, 865. MacIver I. N., Smith, B. J., Tomlinson, B. E., Whitby, J. D. (1956) Br. J. Surg. 181, 505. Youmans, J. R. (1964) J. Trauma, 4, 204.
PROGNOSIS OF CEREBRAL EMBOLISM A. BARHAM CARTER Cantab., F.R.C.P., D.P.M.
M.D.
CONSULTING PHYSICIAN, ASHFORD HOSPITAL, MIDDLESEX; NEUROLOGIST, QUEEN ALEXANDRA HOSPITAL, MILLBANK, LONDON, S.W.1
THE frequency of cerebral embolism of cardiac origin appears to be lessening; the decline is probably due to
advances in the treatment of the underlying heart-disease, in particular the surgical treatment of disease of the mitral valve, and earlier recognition and better management of patients with thyrotoxicosis. A third fairly recent adjunct to medical treatment is the use of anticoagulant drugs. Patients In the twelve years 1952-63, 130 patients with cerebral embolism were admitted under my care to Ashford Hospital, Middlesex. There were 176 episodes of embolism in these patients; the diagnostic criteria have been discussed elsewhere (Carter 1957, 1960, 1963). Briefly, there should be adequate cardiac cause for the embolism, evidence of embolism elsewhere in the body, a sudden onset of neurological deficit, and improvement, if it is early, should be almost equally sudden (tablesand n). Most of the patients with mitral stenosis were fibrillating, and those in sinus rhythm probably had paroxysmal attacks of fibrillation. When cerebral embolism followed cardiac infarction, just under half of the patients showed evidence of some dysrhythmia, again usually of atrial fibrillation. The patients have been divided into three groups: in 1952 and 1953 no specific treatment was used; from 1954 to the end of 1957 all patients were given a single four-week course of anticoagulants, except those whose embolism was associated with subacute bacterial endocarditis; and from 1958 to 1963 a different regimen was followed on account of reports from other workers of cerebral haemorrhage in patients treated with anticoagulants immediately after their cerebral embolism. In the present series no major catastrophe had followed, but 2 patients had developed headache and stiffness of the neck twelve hours after heparin had been given. In 1 of these patients the red blood-cells in the cerebrospinal fluid (C.S.F.) had increased from 2 to 350 per mm., in the other from 7 to 600 per mm. Wells (1959) found an increased number of red cells in the c.s.F. of some patients treated with anticoagulants within forty-eight hours of their cerebral embolism and noted that in these the results were bad. Similar reports of serious bleeding after anticoagulation came from de Morsier and Tissot (1957) and Ushiro and Schaller (1957); it seemed likely that, if a major infarction of the brain had occurred after the embolic episode, it was probably of the hsemorrhagic type, and unlikely to be helped by anticoagulation.
Anticoagulants were therefore reserved for patients whose neurological deficit was incomplete from the first or whose lesion was apparently recovering, on the ground that there had probably been no major hsemorrhagic infarction. Anticoagulants might prevent either further embolisation or thrombotic extension of the original embolus in patients with ischasmic lesions, and so protect them from major cerebral infarction. In all such patients, treatment was continued for a year from the time of embolism; in patients whose embolism was associated with mitral stenosis this period was extended, often indefinitely, on account of the continuing danger of systemic embolism in this type of patient (Wells 1961). Natural
History
In this series, only 34 patients received no treatment, but all except 3 have been followed up for ten to twelve years. Survival Of the 34 patients first seen in 1952 and 1953, 10 did
515 TABLE I-CEREBRAL EMBOLISM 1952-63
5
recurrences
in patients with subacute bacterial endocarditis have been omitted.
survive the immediate embolism; 8 more were dead the end of six months-1 died from cardiac infarction, 1 from the effects of subacute bacterial endocarditis, 1 from congestive cardiac failure, 2 from pulmonary infarction, and 3 from recurrence of cerebral embolism. After this the survival-rate began to flatten (fig. 1); at the end of a year 2 more had died-1 with a recurrence, and 1 from " pneumonia " unspecified. After five years, 4 more had died-1 from cardiac infarction, 1 from cardiac failure, and 2 from recurrent cerebral embolism. After ten years a further 2 patients were dead-1 from cardiac infarction and 1 from recurrence of cerebral embolism (tables ill and iv). 3 patients were untraced; the final figure, therefore, is 5 known survivors, of whom 1 is severely disabled, 2 have recovered naturally with a mild disability (1 with thyrotoxic atrial fibrillation, and the other in sinus rhythm with mitral stenosis and regurgitation). The remaining 2 patients are well, with no disability after successful mitral valvotomy for stenosis. Other workers have had similar results, although most of them mention only their immediate prognoses (table v). not at
1940-58. These were accepted as embolic cerebral infarcts on stringent diagnostic criteria; all the patients had rheumatic heart-disease or changing cardiac rhythms and evidence of embolism elsewhere. 53 of these patients (63 episodes of embolism) were treated conservatively. Wells found that 16 of these died within two months, as a direct result of the embolus or of its immediate complications; 20 had persisting severe neurological disabilities; and 17 (25 episodes) recovered. Wells gave no figures for a later follow-up, and no survival-rates. He found that the right hemisphere was affected in 32 patients, the left hemisphere in 18, and the brain-stem in 5. He believed that age influenced the prognosis, since the results in patients
and Lecomte (1957) concluded that none of their patients with cerebral embolism had recovered 8 died, in 1 the result was bad, and 9 made completely:
Hugues
series of 18
incomplete recoveries. Keen and Leveaux (1958) reported a series of 34 patients of 172 with rheumatic heart-disease who developed cerebral embolism. A fifth of these patients died; two-thirds made " a good recovery "; and the rest were disabled. This report is unusual in its good immediate prognosis. out
Harris and Levine (1941) reported an immediate mortality of a third and a late mortality of two-thirds in patients with mitral stenosis who had sustained cerebral embolism. Wells (1959) reported the immediate results of 82 patients with cerebral embolism admitted to the New York Hospital in TABLE II-SOURCE OF CEREBRAL EMBOLI
Fig. 1-Survival-rate (percentage) over
fifty
in cerebral embolism.
years of age were bad in 83%, and in patients under years of age the results were bad in 53%. Rheumatic
fifty
carditis was less fatal in its outcome than either hypertensive or ischxmic heart-disease when complicated by cerebral embolism, and convulsions, coma, and periodic respiration were bad prognostic signs. The future disability of Wells’s patients could not be assessed from the extent of the original deficit, but a persisting complete deficit lasting more than two days was rarely followed by recovery.
Finally, Adams and Merrett (1961), in a survey of the late results in hemiplegia from all causes, noted that out of 34 patients with cerebral embolism due to rheumatic heart-disease only 1 survived after twelve years in a long-stay unit. a
In the present series of untreated cerebral embolism, third of the patients died from the immediate effects of
the embolism; more than half were dead within a year, two-thirds within five years, and four-fifths within ten years (table iv). Relating survival to the cause of cerebral embolism in this series, nearly half the patients with mitral stenosis and atrial fibrillation, most of the patients with cardiac ischsemia or infarction, and all the patients with subacute bacterial endocarditis were dead within six months of the original cerebral embolism, but both patients with thyrotoxicosis had survived.
516 TABLE III-RESULTS OF UNTREATED CEREBRAL EMBOLISM
recovery. This is in line with the experience of (1957), who reported that out of 18 survivors from cerebral embolism only 3 were severely disabled.
DISABILITY
factory
The immediate degree of disability is most conveniently measured at six weeks after the embolism, since physiotherapy and arrangements for discharge of a patient can begin about this time. Of the original 34 patients with 45 episodes of cerebral embolism, 12 were men and 22 women with an average age of fifty-one years (range, nineteen to sixty-nine). Of these, 10 had died within six weeks. Of the 24 survivors 8 had recovered; 3 were improved sufficiently to look after themselves; and 13 were disabled. Within a year a further 10 patients had died. Of the 14 survivors at the end of a year, 10 had recovered sufficiently to return to their previous occupation. Of the other 4, 1 was bedridden; 2 required considerable help and a chair to get around; and 1 could look after herself with only a little help. By 1964, another 6 patients had died, leaving 1 severely disabled, 2 mildly disabled, 2 at work, and 3 untraced.
Rankin
TABLE IV-CAUSES OF DEATH IN UNTREATED CEREBRAL EMBOLISM
RECURRENCE
The immediate survivors in the first six years form a suitable group for assessing the natural history of TABLE VI-FOLLOW-UP IN
1963
OF LATE RESULTS IN UNTREATED AND
SHORT-TERM TREATED PATIENTS
in cerebral embolism. Though this includes patients who had a short course of anticoagulants for their original embolism, it should make no difference to the
recurrence
of later recurrence. There were 54 of these survivors ; 19 with no recurrence, 30 with one recurrence, and 5 with two recurrences; hence out of the 54 patients, 35 had forty recurrences, giving a patient-recurrence rate of 65% and an embolic recurrence-rate of 75 % in a follow-up of from six to twelve years. A third of the recurrences (fourteen) were within six months of the original embolism and another quarter (eleven) within a year. After five years a further quarter (ten) had been under observation, and the remaining five had been under observation for ten years. This of course does not represent a true percentage recurrence all through the ten-year period, since the number of survivors diminished with time, but it’accords with the general experience that the first year after a cerebral embolism is the most likely time for recurrence (fig. 2). Of the 30 patients who had a single recurrence, 12 died
rate
TABLE V-IMMEDIATE RESULTS IN UNTREATED PATIENTS
To this group must be added the patients seen from 1954 to 1957 who received only a short course of anticoagulants. There were 43 of these, including 3 with subacute bacterial endocarditis who were not given anticoagulants; of these, 9 died from the original embolism, and 9 showed no improvement. Of these latter 9, a further 8 were dead by 1963, together with 7 of the recovered and 4 of the improved groups. Thus, 28 out of 43 had died, and, of the 15 survivors, 2 were untraced; 5 were well and at work; 6 were mildly disabled; and 2 were severely disabled. Combining the two groups, we find 77 patients, 54 deaths, 7 recovered, 8 with mild disability, 3 disabled, and 5 untraced (table vi). In this series, severely disabled patients did not survive for many years; in the long term the untreated patients together with those who received only four weeks’ treatment with anticoagulants will either die or make a satis-
Fig. 2-Recurrence in 54 untreated survivors of cerebral embolism.
517 consequence, and, of the 5 patients with two recurrences, 4 died after their third embolism. The follow-up has been up to the time of the patient’s death or until 1965; the 54 survivors were followed for a total period of 294 patient-years, giving a recurrence-rate as
a
TABLE
VII-CONDITION
OF
PATIENTS
SIX
WEEKS
AFTER
CEREBRAL
EMBOLISM
of
10% per patient-year. In the 54 survivors there were twenty-five recurrences within a year, giving a rate of 46%o per first patient-year. After two years the figure had risen to thirty-one recurrences-57% of the original survivors. Other workers have had similar experiences in the natural history of recurrence. Daley et al. (1951) had a recurrence-rate of 60% of systemic embolism in rheumatic heart-disease; the first six months after embolism was the most vulnerable time. Belcher and Somerville (1955) noted that embolism took place shortly after atrial fibrillation had become established, that embolism recurred in more than a third of their patients, and that mitral valvotomy did not completely protect patients from further attacks. Rowe et al. (1960) noted that in nearly half their patients embolism recurred within a year. Szekely (1964) reported a series of 72 patients with systemic embolism from rheumatic heart-disease with 89 embolic episodes of which 63 were cerebral. 14 of these patients had seventeen recurrences, and two-thirds of these recurrences were within a year of the original embolism. Wells (1959) in a series of 82 patients with cerebral embolism had a recurrence-rate of 30%, but did not say how soon the embolism recurred. Results of Treatment
The immediate outcome six weeks after the original embolism in regard to survival and disability should be compared with the natural history before late recurrence is likely. Six weeks is a convenient time, since it covers early treatment and the beginnings of rehabilitation when a reasonable assessment of the patient can be made. It is also about the usual time of discharge from hospital and just a little too early for the second wave of recurrence, the first wave being usually within ten days of onset. The effect of anticoagulants on this first wave could not loe assessed statistically, because treatment varied according to the severity of the embolism, but some of the improvement in mortality must be associated with diminution of very early recurrence. The patients in this group comprise those admitted from 1954 to 1957 inclusive (all of whom received a single four-week course of anticoagulants immediately after their embolism) and patients admitted from 1958 to 1963 inclusive, when only patients with incomplete lesions were treated with anti-
coagulants. IMMEDIATE RESULTS
43 patients were admitted in the years 1954-57. At the end of six weeks 9 of these had died, 8 had made little recovery, 7 had improved, and 19 had recovered. At the end of six weeks, of the untreated group of 34 patients, 10 had died, 13 had made little recovery, 3 had improved, and 8 had recovered (table vil).
Thus, in the treated group, 60% showed a good result (either recovered or improved) as against 34% in the untreated group. Though these results were satisfactory and justified the of
in the immediate treatment of cerebral to be considered that most of the benefit might have occurred in patients with ischsemic rather than infarcted brain. The results were therefore analysed to detect any possible difference between the outcome in patients with incomplete lesions and with complete lesions. Table VII shows that in the untreated patients 20% of the complete lesions and 40% of the incomplete lesions were in the combined " recovered and improved " groups, thus confirming that the incomplete lesion had the better prognosis. In the treated patients (table vii) the improvement in the results of complete use
anticoagulants
embolism, the possibility had
slight but not signiiicant, but much greater and in the results of-the incomplete lesions, with 84% of these in the combinedrecovered and improved " group. lesions
was
significant
These results suggest that anticoagulants were useful in the immediate treatment of patients whose neurological deficit was not severe, but made very little difference when the lesion remained persistently complete for the first week of observation. This trend was confirmed during the second six years of treatment (1958-63) in which 53 patients were admitted. Of these, 3 with subacute bacterial endocarditis were not treated with anticoagulants, nor were 20 whose lesion was persistently complete. The results in this group differ very little from those in the previous group (table vil). LATE RESULTS
The late results in
patients who did not receive longanticoagulant therapy have already been described. Excluding 4 patients with subacute bacterial endocarditis, of the other 73 patients, 52 were dead, 7 had recovered, 7 had improved, 2 were disabled, and 5 were untraced by 1965. There had been thirty-five recurrences in 30 patients, and thirteen of these were fatal. In the years 1958-63 inclusive, 53 patients were admitted term
with cerebral embolism of whom 3 with subacute bacterial endocarditis were excluded from anticoagulant therapy. Of the 50 remaining patients, 12 died within six weeks, leaving 38 for long-term follow-up studies extending from two to seven years. Of the original 50 patients, 18 had mitral stenosis with atrial fibrillation 2 had ischaemic atrial fibrillation, 23 had recent cardiac infarction, 4 had thyrotoxic fibrillation, and 3 had mitral stenosis with sinus rhythm. For purposes of comparison the late survival-rate is taken at the end of two years, because this is the longest observation period for all the patients. In the untreated group, only 40% of the immediate survivors were alive after this time, as against 73% of the treated group. Thus, the survival-rate has nearly doubled. Analysis of the causes of death shows that the greatest improvement has been a decrease in fatal recurrent cerebral embolism and in pulmonary infarction. The cause of death in the treated group was cardiac infarction (5), recurrent cerebral infarction (2), and cardiac failure (3), compared with the untreated group (table iv), recurrent cerebral infarction (7), cardiac infarction (3), pulmonary infarction (2), cardiac failure (2), and unknown (2). RECURRENCE
The 38
embolism
were alive six weeks after cerebral followed from two to seven years. All the
patients who were
518
patients were traced after two years, and as the natural history of recurrences has shown that thirty-one out of forty (78%) fell within this time, this period is obviously a useful yardstick for assessment of the effects of treatment. In the treated group of 38 survivors, there were six recurrences in 5 patients, of which five were in the first one in the second. Three of these were in with one with cardiac infarction, mitral patients stenosis, and one with coronary insufficiency; and all the patients were fibrillating. The recurrence-rate after two years treatment was 16%, two of the six recurrences being fatal.
TABLE IX-SUBGROUP OF PATIENTS WITH MITRAL STENOSIS AND ATRIAL FIBRILLATION
year and
Discussion
In this series, treatment with anticoagulants has significantly improved the prognosis of cerebral embolism
in relation
immediate outcome, late survival, and The degree of eventual disability could not properly be compared, since the disabled survivors in the control group were so few. To a large extent even late survival was dependent on factors outside the cerebral embolism itself as well as on recurrence, so that any pronounced improvement in this respect may be equated with prevention of recurrence. The anticoagulant drugs used were heparin and phenindione. In view of the many of this no further details of this descriptions technique need be given. to
recurrence.
IMMEDIATE RESULTS
the immediate results, although patients treated anticoagulants fared significantly better than the controls-60% good result in the treated against 34% in the controls as described above (table vil)—further analysis showed that most of this improvement had been in the outcome of patients with incomplete or varying neurological deficits. If these were not treated, 8 out of 15 did badly compared with 3 out of 19 in the treated group, whereas in the untreated completely disabled group 15 out of 19 did badly compared with 14 out of 24 of the treated group. The difference between the results of treating or not treating complete lesions with anticoagulants, therefore, is only marginal, suggesting that it is inadvisable to use them when the lesion is complete. Patients in this group do not benefit greatly and the potential dangers are well established. Previous conclusions (Carter 1957) must therefore be reconsidered; and the immediate treatment of cerebral embolism with anticoagulants should be restricted to patients with an incomplete neurological deficit, where presumably the lesion is cerebral ischxmia rather than infarction and where the results of treatment are significantly better than in a similar untreated group.
As with
to
RECURRENCE
There seems little doubt that long-term anticoagulants have significantly reduced the recurrence-rate of cerebral embolism. Out of 54 untreated survivors, 28 had thirty-one recurrences within two years, giving a recurrence-rate of
*
28
patients (6
men, 22
women),
average age 48 years.
t 15 patients (3 men, 12 women), average age 50 years.
57 %. In the treated group there were six recurrences affecting 5 patients out of a total of 38 survivors, giving a recurrence-rate of 16% (table vm), which is significantly less (p <0-01). The mortality-rate of the recurrences was the same in each group-namely, 1 in 3. There are two other possible factors besides anticoagulant treatment that may have influenced the outcome: difference in matching between the groups; and the effect of treatment other than the use of these drugs. With regard to matching, the mean age in the control group 53 years, with a sex-distribution of 5 men to 8 women, and in the treated group the age was 51 years, and there were 3 men and 5 women. There was little difference in the relative numbers with atrial fibrillation-74% in the controls and 70% in the treated-but the most suspect group for comparison was the one comprising fibrillating mitral lesions, since there were 28 of these in the controls and only 15 in the treated. The influence of previous treatment, other than anticoagulants, arises particularly in patients with atrial fibrillation due to mitral stenosis-the same subgroup in which there is a striking numerical difference. Two other forms of treatmentnamely, restoration of sinus rhythm, and valvotomy, were used. Table ix shows that previous treatment in the two subgroups had been fairly uniform, although a higher proportion of the treated group had undergone valvotomy before embolism. This would invalidate the comparison if the operation could be shown to have reduced the recurrence-rate in the control series. 7 of these patients had had valvotomy before embolism, and embolism recurred in 4 of these within five years. In the whole " fibrillating mitral stenotic " group of 28 patients, embolism recurred in 19 over this period; so that, although the surgically treated patients were a little less liable to recurrence, the difference is not significant. As to the effectiveness of previous medical treatment, unfortunately the number of patients with mitral stenosis who can be converted permanently to sinus rhythm is small, and repeatedly changing rhythms are obviously undesirable. Greenwood et al. (1963) were successful in reducing the number of recurrences of cerebral embolism by means of mitral valvotomy, and preferred it to anticoagulant therapy; other workers, however, have had disappointing results (Szekely 1964, Wang et al. 1960) and have pointed out that embolism may make its first appearance after valvotomy. For this reason many thoracic surgeons give anticoagulants after this operation. Moreover, as patients for conversion to sinus rhythm or for valvotomy are a specially selected group, it is difficult to draw any general conclusions about the effects of these treatments on the overall recurrence-rate of cerebral embolism. In my experience, many patients admitted with
was
TABLE VIII-PATIENTS ADMITTED TO ASHFORD HOSPITAL WITH DIAGNOSIS OF CEREBRAL EMBOLISM
(1952-63)
519 cerebral embolism have already been assessed by cardiologists; consequently, the choice between restoration to sinus rhythm and valvotomy has been considered very carefully in all patients, attempted in many, and abandoned in a fair proportion, leaving very little room for further choice between these two forms of
INTESTINAL BIOPSY IN KWASHIORKOR M.D.
J. P. STANFIELD Lpool, M.R.C.P., D.C.H.
SENIOR LECTURER IN PÆDIATRICS
M. S. R. HUTT
treatment.
Despite a less than perfectly matched control group, therefore, the results are probably a reliable indication of the effect of anticoagulant therapy. In the control series, the of cerebral embolism is three and a half times more frequent than in the treated group (57% as against 16%), and the results of other workers support this. Szekely (1964) has shown that in rheumatic heart-disease the incidence and recurrence of systemic embolism was two and a half times more frequent in patients not on long-term anticoagulants; Wright (1949) and McDevitt (1961) reduced the recurrence-rate of cerebral embolism in rheumatic heart-disease from 70 to 21 % with this treatment.
M.D. Lond., M.R.C.P., M.C.Path. PROFESSOR OF PATHOLOGY
R. TUNNICLIFFE
recurrence
The length of treatment required seems to depend on the underlying heart condition. In recent cardiac infarction, all danger of systemic embolism seems to have disappeared by the end of a year. In thyrotoxic fibrillation, embolism is uncommon but recurrence is early in about half the patients, unless a return to permanent sinus rhythm is brought about. This is now often possible, unless ischxmic heart-disease has supervened; hence anticoagulants are not usually needed for longer than a year.
F.I.M.L.T. CHIEF TECHNICIAN
MAKERERE UNIVERSITY
COLLEGE, KAMPALA, UGANDA
DISTURBANCE of structure and function of the gastrointestinal tract in severe malnutrition has only recently come under study. In severe kwashiorkor the intestinal wall and mucosa are abnormally thin (Trowell et al. 1954); none the less there does not seem to be any gross failure of function as judged by clinical response to protein feeding and crude absorption tests. Diarrhoea, however, is a rather common feature of more severe cases of kwashiorkor, and usually pathogenic agents cannot be isolated. We have studied some aspects of the structure and function of the upper intestinal mucosa in children admitted, with moderate to severe kwashiorkor, to the Mulago Hospital or to the Infant Malnutrition Unit in
Kampala.
Clinical Material and Methods clinical stenosis, if embolism follows 21 children (aged one to three years) with kwashiorkor of paroxysmal fibrillation it usually happens within a year of varying severity have been studied. The first 10 children were this (Wood 1956) and anticoagulant prophylaxis is accepted admitted to the Mulago Hospital, Kampala, and 4 of these by most physicians as essential when conversion to sinus were readmitted after one month for a repeat biopsy. The rhythm is attempted. If conversion is unsuccessful, the remaining 11 children were studied at the Medical Research most vulnerable period is the first two years after Council’s Infant Malnutrition Unit. 7 of these were included embolism; on the results of this series anticoagulants in a prolonged follow-up study, and 9 were included in a small should be used for two years. Some patients seem to be study on the correlation of mucosal-enzyme assay and mucosal vulnerable for a longer period: they are characterised by appearance. Routine clinical examination and weight measurements persisting atrial fibrillation resistant to conversion, a were made on all the children. Blood was taken for estimation of recurrent rheumatic infection, a large left history of total serum-protein. In addition, the aminoacid-ratio test atrium, and frequent clinical systemic peripheral embolisa(Whitehead and Dean 1964) was done on a few of the later tion. These patients may well require lifelong anticases. Small-intestinal-biopsy specimens were taken with a coagulation, but presumably this is better decided by the Crosby capsule (either the 9-5 mm. adult type or the 8 mm. cardiologist than by the neurologist. type) using the technique described by Burman (1963); there were no serious complications. All the biopsy specimens were Summary taken between 30 and 45 cm. from the mouth, and represented 130 patients with 176 episodes of cerebral embolism mucosal sampling from the terminal part of the duodenum
In mitral
were
followed up for twelve years
on
to
or
determine whether
anticoagulant therapy had influenced the natural history of this condition. The results show no significant gain from the immediate use of anticoagulants in patients whose neurological lesion is persistently complete. If anticoagulants are used to prevent recurrence in these patients an interval of three weeks should elapse before commencing
and the first 4
of the
jejunum.
The
specimens
were
were
out on
oriented and embedded in
treatment.
The survival-rate improved significantly in patients with incomplete or fluctuating lesions (in whom ischaemia is likelier than infarction) when anticoagulants were used in the early stages. In all patients the recurrence-rate was high immediately after the initial cerebral embolism. The rate remained high for six months after embolism associated with cardiac infarction, and for two years in patients with mitral stenosis and atrial fibrillation, and then, except in a few special cases, fell away. The recurrence-rate and the mortality-rate of cerebral embolism was significantly lowered in this series by the use of long-term anticoagulant therapy for two years after embolism.
cm.
cards, mucosal surface uppermost, and fixed in Bouin’s fixative. They were then examined under the dissecting microscope, and usually photographs were taken (Holmes et al. 1961a and b). Specimens, taken for microscopical examination,
pinned
paraffin wax, and sections
were
DR. BARHAM CARTER: REFERENCES
F., Merrett, J. D. (1961) Br. med. J. i, 309. Belcher, J. R., Somerville, W. (1955) ibid. ii, 1000. A. Barham Carter, (1957) Q. Jl Med. 26, 335. — (1960) Lancet, i, 345. (1963) Proc. R. Soc. Med. 56, 483. Daley, R., Mattingley, T. W., Holt, L., Bland, E. F., White, P. (1951) Am. Heart J. 42, 566. de Morsier, G., Tissot, R. (1957) Rapp. Congr. fr. Méd. i, 110. Greenwood, W. F., Aldridge, H. E., McKelvey, A. D. (1963) Am. J. Cardiol. 2, 348. Harris, A. W., Levine, S. A. (1941) Ann. intern. Med. 15, 637. Hugues, J., Lecomte, J. (1957) Acta clin. belg. 12, 270. Keen, G., Leveaux, V. M. (1958) Br. med. J. ii, 91. McDevitt, E. (1961) Cerebral Vascular Disease; p. 90. New York. Rankin, J. (1957) Scott. med. J. 2, 200. Rowe, J. C., Bland, E. F., Sprague, H. B., White, P. D. (1960) Ann. intern. Med. 52, 741. Szekely, P. (1964) Br. med. J. i, 1209. Ushiro, C. S., Schaller, W. R. (1957) Neurology, 7, 253. Wang, Y., Bland, E. F., Scannel, J. G. (1960) Circulation, 22, 829. Wells, C. E. (1959) Archs Neurol. Psychiat., Chicago, 81, 667. — (1961) Archs Neurol. 5, 490. Wood, P. (1956) Diseases of the Heart and Circulation; p. 525. London. Wright, I. S. (1949) Ann. intern. Med. 30, 80. Adams,
—
G.
which can be lost into closed fractures either of the limbs or of the trunk has been recognised for some time (Clarke et al. 1955), but it can still surprise those inexperienced in dealing with trauma. Clarke et al. (1961) said that the average loss in a closed chest injury was 2-5 litres, and that much was lost into the chest wall and would not be obvious as a hasmothorax on chest X-ray. They cited a similar figure for fractured pelvis, and added that this was one of the few single injuries which could give rise to sudden, unexpected collapse. On average they found that about 50% of the internal blood-loss in various sites occurred within two to five hours of injury.
High spinal injury causes hypotension by sympathectomy. There was only 1 patient in the present series in whom such an injury was suspected as a contributing factor (case 5). The evidence for this mechanism cannot ,be regarded as conclusive even in this case, because there was also serious scalp bleeding. Since the series was closed a patient was admitted who illustrates strikingly the importance of recognising spinal injury associated with head injury. A girl, aged 12 years, was admitted to hospital unconscious after a road accident. There were many facial abrasions, the limbs were flaccid, and the systolic blood-pressure was 60 mm. Hg. She was regarded as having suffered a serious head injury, but the following day she regained consciousness and it was evident that she had a quadriparesis. X-rays of the cervical spine revealed an atlanto-axial dislocation; skull traction was applied and she is making a good recovery. There were no other injuries, and clearly the head injury was relatively mild. Conclusion
This study reinforces the impression that hypotension after head injury is rarely due to the intracranial lesion, even when there is severe brain damage. In 11 of 14 cases the cause of shock was blood-loss, and in 8 of these the site of the loss was an associated injury.
develops after a head injury it should be regarded oligxmic and treated by blood-volume expanders. Unless there is a large scalp laceration the source of the blood-loss should be sought elsewhere, particularly in the chest, abdomen, or pelvis. When shock as
Summary In 14 of 470 cases of head injury admitted to hospital the blood-pressure was less than 90 mm. Hg within six hours of injury.
Blood-loss was the cause of the hypotension in 11 of the 14 cases; the scalp was the source of only 3. Associated injuries were a major factor contributing to shock in 10 cases.
Shock after head
fusion, and the there is
severe
injuries should be treated by transsought elsewhere in the body unless scalp bleeding. cause
The consultant surgeons in the Western Infirmary and the Royal Infirmary, Glasgow, and in the West of Scotland Neurosurgical Unit, Killearn Hospital, under whose care these patients were admitted, kindly allowed us access to their records. REFERENCES
Clarke, R., Topley, E., Flear, C. T. G. (1955) Lancet, i, 629. — Fisher, M. R., Topley, E., Davies, J. W. L. (1961) ibid. ii, 381. Dalgaard, J. B. (1960) Archs Path. 69, 359, Daniel, P. M., Prichard, M. M. L., Treip, C. S. (1959) Lancet, ii, 927. Lewin, W. (1954) Proc. R. Soc. Med. 10, 865. MacIver I. N., Smith, B. J., Tomlinson, B. E., Whitby, J. D. (1956) Br. J. Surg. 181, 505. Youmans, J. R. (1964) J. Trauma, 4, 204.
PROGNOSIS OF CEREBRAL EMBOLISM A. BARHAM CARTER Cantab., F.R.C.P., D.P.M.
M.D.
CONSULTING PHYSICIAN, ASHFORD HOSPITAL, MIDDLESEX; NEUROLOGIST, QUEEN ALEXANDRA HOSPITAL, MILLBANK, LONDON, S.W.1
THE frequency of cerebral embolism of cardiac origin appears to be lessening; the decline is probably due to
advances in the treatment of the underlying heart-disease, in particular the surgical treatment of disease of the mitral valve, and earlier recognition and better management of patients with thyrotoxicosis. A third fairly recent adjunct to medical treatment is the use of anticoagulant drugs. Patients In the twelve years 1952-63, 130 patients with cerebral embolism were admitted under my care to Ashford Hospital, Middlesex. There were 176 episodes of embolism in these patients; the diagnostic criteria have been discussed elsewhere (Carter 1957, 1960, 1963). Briefly, there should be adequate cardiac cause for the embolism, evidence of embolism elsewhere in the body, a sudden onset of neurological deficit, and improvement, if it is early, should be almost equally sudden (tablesand n). Most of the patients with mitral stenosis were fibrillating, and those in sinus rhythm probably had paroxysmal attacks of fibrillation. When cerebral embolism followed cardiac infarction, just under half of the patients showed evidence of some dysrhythmia, again usually of atrial fibrillation. The patients have been divided into three groups: in 1952 and 1953 no specific treatment was used; from 1954 to the end of 1957 all patients were given a single four-week course of anticoagulants, except those whose embolism was associated with subacute bacterial endocarditis; and from 1958 to 1963 a different regimen was followed on account of reports from other workers of cerebral haemorrhage in patients treated with anticoagulants immediately after their cerebral embolism. In the present series no major catastrophe had followed, but 2 patients had developed headache and stiffness of the neck twelve hours after heparin had been given. In 1 of these patients the red blood-cells in the cerebrospinal fluid (C.S.F.) had increased from 2 to 350 per mm., in the other from 7 to 600 per mm. Wells (1959) found an increased number of red cells in the c.s.F. of some patients treated with anticoagulants within forty-eight hours of their cerebral embolism and noted that in these the results were bad. Similar reports of serious bleeding after anticoagulation came from de Morsier and Tissot (1957) and Ushiro and Schaller (1957); it seemed likely that, if a major infarction of the brain had occurred after the embolic episode, it was probably of the hsemorrhagic type, and unlikely to be helped by anticoagulation.
Anticoagulants were therefore reserved for patients whose neurological deficit was incomplete from the first or whose lesion was apparently recovering, on the ground that there had probably been no major hsemorrhagic infarction. Anticoagulants might prevent either further embolisation or thrombotic extension of the original embolus in patients with ischasmic lesions, and so protect them from major cerebral infarction. In all such patients, treatment was continued for a year from the time of embolism; in patients whose embolism was associated with mitral stenosis this period was extended, often indefinitely, on account of the continuing danger of systemic embolism in this type of patient (Wells 1961). Natural
History
In this series, only 34 patients received no treatment, but all except 3 have been followed up for ten to twelve years. Survival Of the 34 patients first seen in 1952 and 1953, 10 did
515 TABLE I-CEREBRAL EMBOLISM 1952-63
5
recurrences
in patients with subacute bacterial endocarditis have been omitted.
survive the immediate embolism; 8 more were dead the end of six months-1 died from cardiac infarction, 1 from the effects of subacute bacterial endocarditis, 1 from congestive cardiac failure, 2 from pulmonary infarction, and 3 from recurrence of cerebral embolism. After this the survival-rate began to flatten (fig. 1); at the end of a year 2 more had died-1 with a recurrence, and 1 from " pneumonia " unspecified. After five years, 4 more had died-1 from cardiac infarction, 1 from cardiac failure, and 2 from recurrent cerebral embolism. After ten years a further 2 patients were dead-1 from cardiac infarction and 1 from recurrence of cerebral embolism (tables ill and iv). 3 patients were untraced; the final figure, therefore, is 5 known survivors, of whom 1 is severely disabled, 2 have recovered naturally with a mild disability (1 with thyrotoxic atrial fibrillation, and the other in sinus rhythm with mitral stenosis and regurgitation). The remaining 2 patients are well, with no disability after successful mitral valvotomy for stenosis. Other workers have had similar results, although most of them mention only their immediate prognoses (table v). not at
1940-58. These were accepted as embolic cerebral infarcts on stringent diagnostic criteria; all the patients had rheumatic heart-disease or changing cardiac rhythms and evidence of embolism elsewhere. 53 of these patients (63 episodes of embolism) were treated conservatively. Wells found that 16 of these died within two months, as a direct result of the embolus or of its immediate complications; 20 had persisting severe neurological disabilities; and 17 (25 episodes) recovered. Wells gave no figures for a later follow-up, and no survival-rates. He found that the right hemisphere was affected in 32 patients, the left hemisphere in 18, and the brain-stem in 5. He believed that age influenced the prognosis, since the results in patients
and Lecomte (1957) concluded that none of their patients with cerebral embolism had recovered 8 died, in 1 the result was bad, and 9 made completely:
Hugues
series of 18
incomplete recoveries. Keen and Leveaux (1958) reported a series of 34 patients of 172 with rheumatic heart-disease who developed cerebral embolism. A fifth of these patients died; two-thirds made " a good recovery "; and the rest were disabled. This report is unusual in its good immediate prognosis. out
Harris and Levine (1941) reported an immediate mortality of a third and a late mortality of two-thirds in patients with mitral stenosis who had sustained cerebral embolism. Wells (1959) reported the immediate results of 82 patients with cerebral embolism admitted to the New York Hospital in TABLE II-SOURCE OF CEREBRAL EMBOLI
Fig. 1-Survival-rate (percentage) over
fifty
in cerebral embolism.
years of age were bad in 83%, and in patients under years of age the results were bad in 53%. Rheumatic
fifty
carditis was less fatal in its outcome than either hypertensive or ischxmic heart-disease when complicated by cerebral embolism, and convulsions, coma, and periodic respiration were bad prognostic signs. The future disability of Wells’s patients could not be assessed from the extent of the original deficit, but a persisting complete deficit lasting more than two days was rarely followed by recovery.
Finally, Adams and Merrett (1961), in a survey of the late results in hemiplegia from all causes, noted that out of 34 patients with cerebral embolism due to rheumatic heart-disease only 1 survived after twelve years in a long-stay unit. a
In the present series of untreated cerebral embolism, third of the patients died from the immediate effects of
the embolism; more than half were dead within a year, two-thirds within five years, and four-fifths within ten years (table iv). Relating survival to the cause of cerebral embolism in this series, nearly half the patients with mitral stenosis and atrial fibrillation, most of the patients with cardiac ischsemia or infarction, and all the patients with subacute bacterial endocarditis were dead within six months of the original cerebral embolism, but both patients with thyrotoxicosis had survived.
516 TABLE III-RESULTS OF UNTREATED CEREBRAL EMBOLISM
recovery. This is in line with the experience of (1957), who reported that out of 18 survivors from cerebral embolism only 3 were severely disabled.
DISABILITY
factory
The immediate degree of disability is most conveniently measured at six weeks after the embolism, since physiotherapy and arrangements for discharge of a patient can begin about this time. Of the original 34 patients with 45 episodes of cerebral embolism, 12 were men and 22 women with an average age of fifty-one years (range, nineteen to sixty-nine). Of these, 10 had died within six weeks. Of the 24 survivors 8 had recovered; 3 were improved sufficiently to look after themselves; and 13 were disabled. Within a year a further 10 patients had died. Of the 14 survivors at the end of a year, 10 had recovered sufficiently to return to their previous occupation. Of the other 4, 1 was bedridden; 2 required considerable help and a chair to get around; and 1 could look after herself with only a little help. By 1964, another 6 patients had died, leaving 1 severely disabled, 2 mildly disabled, 2 at work, and 3 untraced.
Rankin
TABLE IV-CAUSES OF DEATH IN UNTREATED CEREBRAL EMBOLISM
RECURRENCE
The immediate survivors in the first six years form a suitable group for assessing the natural history of TABLE VI-FOLLOW-UP IN
1963
OF LATE RESULTS IN UNTREATED AND
SHORT-TERM TREATED PATIENTS
in cerebral embolism. Though this includes patients who had a short course of anticoagulants for their original embolism, it should make no difference to the
recurrence
of later recurrence. There were 54 of these survivors ; 19 with no recurrence, 30 with one recurrence, and 5 with two recurrences; hence out of the 54 patients, 35 had forty recurrences, giving a patient-recurrence rate of 65% and an embolic recurrence-rate of 75 % in a follow-up of from six to twelve years. A third of the recurrences (fourteen) were within six months of the original embolism and another quarter (eleven) within a year. After five years a further quarter (ten) had been under observation, and the remaining five had been under observation for ten years. This of course does not represent a true percentage recurrence all through the ten-year period, since the number of survivors diminished with time, but it’accords with the general experience that the first year after a cerebral embolism is the most likely time for recurrence (fig. 2). Of the 30 patients who had a single recurrence, 12 died
rate
TABLE V-IMMEDIATE RESULTS IN UNTREATED PATIENTS
To this group must be added the patients seen from 1954 to 1957 who received only a short course of anticoagulants. There were 43 of these, including 3 with subacute bacterial endocarditis who were not given anticoagulants; of these, 9 died from the original embolism, and 9 showed no improvement. Of these latter 9, a further 8 were dead by 1963, together with 7 of the recovered and 4 of the improved groups. Thus, 28 out of 43 had died, and, of the 15 survivors, 2 were untraced; 5 were well and at work; 6 were mildly disabled; and 2 were severely disabled. Combining the two groups, we find 77 patients, 54 deaths, 7 recovered, 8 with mild disability, 3 disabled, and 5 untraced (table vi). In this series, severely disabled patients did not survive for many years; in the long term the untreated patients together with those who received only four weeks’ treatment with anticoagulants will either die or make a satis-
Fig. 2-Recurrence in 54 untreated survivors of cerebral embolism.
517 consequence, and, of the 5 patients with two recurrences, 4 died after their third embolism. The follow-up has been up to the time of the patient’s death or until 1965; the 54 survivors were followed for a total period of 294 patient-years, giving a recurrence-rate as
a
TABLE
VII-CONDITION
OF
PATIENTS
SIX
WEEKS
AFTER
CEREBRAL
EMBOLISM
of
10% per patient-year. In the 54 survivors there were twenty-five recurrences within a year, giving a rate of 46%o per first patient-year. After two years the figure had risen to thirty-one recurrences-57% of the original survivors. Other workers have had similar experiences in the natural history of recurrence. Daley et al. (1951) had a recurrence-rate of 60% of systemic embolism in rheumatic heart-disease; the first six months after embolism was the most vulnerable time. Belcher and Somerville (1955) noted that embolism took place shortly after atrial fibrillation had become established, that embolism recurred in more than a third of their patients, and that mitral valvotomy did not completely protect patients from further attacks. Rowe et al. (1960) noted that in nearly half their patients embolism recurred within a year. Szekely (1964) reported a series of 72 patients with systemic embolism from rheumatic heart-disease with 89 embolic episodes of which 63 were cerebral. 14 of these patients had seventeen recurrences, and two-thirds of these recurrences were within a year of the original embolism. Wells (1959) in a series of 82 patients with cerebral embolism had a recurrence-rate of 30%, but did not say how soon the embolism recurred. Results of Treatment
The immediate outcome six weeks after the original embolism in regard to survival and disability should be compared with the natural history before late recurrence is likely. Six weeks is a convenient time, since it covers early treatment and the beginnings of rehabilitation when a reasonable assessment of the patient can be made. It is also about the usual time of discharge from hospital and just a little too early for the second wave of recurrence, the first wave being usually within ten days of onset. The effect of anticoagulants on this first wave could not loe assessed statistically, because treatment varied according to the severity of the embolism, but some of the improvement in mortality must be associated with diminution of very early recurrence. The patients in this group comprise those admitted from 1954 to 1957 inclusive (all of whom received a single four-week course of anticoagulants immediately after their embolism) and patients admitted from 1958 to 1963 inclusive, when only patients with incomplete lesions were treated with anti-
coagulants. IMMEDIATE RESULTS
43 patients were admitted in the years 1954-57. At the end of six weeks 9 of these had died, 8 had made little recovery, 7 had improved, and 19 had recovered. At the end of six weeks, of the untreated group of 34 patients, 10 had died, 13 had made little recovery, 3 had improved, and 8 had recovered (table vil).
Thus, in the treated group, 60% showed a good result (either recovered or improved) as against 34% in the untreated group. Though these results were satisfactory and justified the of
in the immediate treatment of cerebral to be considered that most of the benefit might have occurred in patients with ischsemic rather than infarcted brain. The results were therefore analysed to detect any possible difference between the outcome in patients with incomplete lesions and with complete lesions. Table VII shows that in the untreated patients 20% of the complete lesions and 40% of the incomplete lesions were in the combined " recovered and improved " groups, thus confirming that the incomplete lesion had the better prognosis. In the treated patients (table vii) the improvement in the results of complete use
anticoagulants
embolism, the possibility had
slight but not signiiicant, but much greater and in the results of-the incomplete lesions, with 84% of these in the combinedrecovered and improved " group. lesions
was
significant
These results suggest that anticoagulants were useful in the immediate treatment of patients whose neurological deficit was not severe, but made very little difference when the lesion remained persistently complete for the first week of observation. This trend was confirmed during the second six years of treatment (1958-63) in which 53 patients were admitted. Of these, 3 with subacute bacterial endocarditis were not treated with anticoagulants, nor were 20 whose lesion was persistently complete. The results in this group differ very little from those in the previous group (table vil). LATE RESULTS
The late results in
patients who did not receive longanticoagulant therapy have already been described. Excluding 4 patients with subacute bacterial endocarditis, of the other 73 patients, 52 were dead, 7 had recovered, 7 had improved, 2 were disabled, and 5 were untraced by 1965. There had been thirty-five recurrences in 30 patients, and thirteen of these were fatal. In the years 1958-63 inclusive, 53 patients were admitted term
with cerebral embolism of whom 3 with subacute bacterial endocarditis were excluded from anticoagulant therapy. Of the 50 remaining patients, 12 died within six weeks, leaving 38 for long-term follow-up studies extending from two to seven years. Of the original 50 patients, 18 had mitral stenosis with atrial fibrillation 2 had ischaemic atrial fibrillation, 23 had recent cardiac infarction, 4 had thyrotoxic fibrillation, and 3 had mitral stenosis with sinus rhythm. For purposes of comparison the late survival-rate is taken at the end of two years, because this is the longest observation period for all the patients. In the untreated group, only 40% of the immediate survivors were alive after this time, as against 73% of the treated group. Thus, the survival-rate has nearly doubled. Analysis of the causes of death shows that the greatest improvement has been a decrease in fatal recurrent cerebral embolism and in pulmonary infarction. The cause of death in the treated group was cardiac infarction (5), recurrent cerebral infarction (2), and cardiac failure (3), compared with the untreated group (table iv), recurrent cerebral infarction (7), cardiac infarction (3), pulmonary infarction (2), cardiac failure (2), and unknown (2). RECURRENCE
The 38
embolism
were alive six weeks after cerebral followed from two to seven years. All the
patients who were
518
patients were traced after two years, and as the natural history of recurrences has shown that thirty-one out of forty (78%) fell within this time, this period is obviously a useful yardstick for assessment of the effects of treatment. In the treated group of 38 survivors, there were six recurrences in 5 patients, of which five were in the first one in the second. Three of these were in with one with cardiac infarction, mitral patients stenosis, and one with coronary insufficiency; and all the patients were fibrillating. The recurrence-rate after two years treatment was 16%, two of the six recurrences being fatal.
TABLE IX-SUBGROUP OF PATIENTS WITH MITRAL STENOSIS AND ATRIAL FIBRILLATION
year and
Discussion
In this series, treatment with anticoagulants has significantly improved the prognosis of cerebral embolism
in relation
immediate outcome, late survival, and The degree of eventual disability could not properly be compared, since the disabled survivors in the control group were so few. To a large extent even late survival was dependent on factors outside the cerebral embolism itself as well as on recurrence, so that any pronounced improvement in this respect may be equated with prevention of recurrence. The anticoagulant drugs used were heparin and phenindione. In view of the many of this no further details of this descriptions technique need be given. to
recurrence.
IMMEDIATE RESULTS
the immediate results, although patients treated anticoagulants fared significantly better than the controls-60% good result in the treated against 34% in the controls as described above (table vil)—further analysis showed that most of this improvement had been in the outcome of patients with incomplete or varying neurological deficits. If these were not treated, 8 out of 15 did badly compared with 3 out of 19 in the treated group, whereas in the untreated completely disabled group 15 out of 19 did badly compared with 14 out of 24 of the treated group. The difference between the results of treating or not treating complete lesions with anticoagulants, therefore, is only marginal, suggesting that it is inadvisable to use them when the lesion is complete. Patients in this group do not benefit greatly and the potential dangers are well established. Previous conclusions (Carter 1957) must therefore be reconsidered; and the immediate treatment of cerebral embolism with anticoagulants should be restricted to patients with an incomplete neurological deficit, where presumably the lesion is cerebral ischxmia rather than infarction and where the results of treatment are significantly better than in a similar untreated group.
As with
to
RECURRENCE
There seems little doubt that long-term anticoagulants have significantly reduced the recurrence-rate of cerebral embolism. Out of 54 untreated survivors, 28 had thirty-one recurrences within two years, giving a recurrence-rate of
*
28
patients (6
men, 22
women),
average age 48 years.
t 15 patients (3 men, 12 women), average age 50 years.
57 %. In the treated group there were six recurrences affecting 5 patients out of a total of 38 survivors, giving a recurrence-rate of 16% (table vm), which is significantly less (p <0-01). The mortality-rate of the recurrences was the same in each group-namely, 1 in 3. There are two other possible factors besides anticoagulant treatment that may have influenced the outcome: difference in matching between the groups; and the effect of treatment other than the use of these drugs. With regard to matching, the mean age in the control group 53 years, with a sex-distribution of 5 men to 8 women, and in the treated group the age was 51 years, and there were 3 men and 5 women. There was little difference in the relative numbers with atrial fibrillation-74% in the controls and 70% in the treated-but the most suspect group for comparison was the one comprising fibrillating mitral lesions, since there were 28 of these in the controls and only 15 in the treated. The influence of previous treatment, other than anticoagulants, arises particularly in patients with atrial fibrillation due to mitral stenosis-the same subgroup in which there is a striking numerical difference. Two other forms of treatmentnamely, restoration of sinus rhythm, and valvotomy, were used. Table ix shows that previous treatment in the two subgroups had been fairly uniform, although a higher proportion of the treated group had undergone valvotomy before embolism. This would invalidate the comparison if the operation could be shown to have reduced the recurrence-rate in the control series. 7 of these patients had had valvotomy before embolism, and embolism recurred in 4 of these within five years. In the whole " fibrillating mitral stenotic " group of 28 patients, embolism recurred in 19 over this period; so that, although the surgically treated patients were a little less liable to recurrence, the difference is not significant. As to the effectiveness of previous medical treatment, unfortunately the number of patients with mitral stenosis who can be converted permanently to sinus rhythm is small, and repeatedly changing rhythms are obviously undesirable. Greenwood et al. (1963) were successful in reducing the number of recurrences of cerebral embolism by means of mitral valvotomy, and preferred it to anticoagulant therapy; other workers, however, have had disappointing results (Szekely 1964, Wang et al. 1960) and have pointed out that embolism may make its first appearance after valvotomy. For this reason many thoracic surgeons give anticoagulants after this operation. Moreover, as patients for conversion to sinus rhythm or for valvotomy are a specially selected group, it is difficult to draw any general conclusions about the effects of these treatments on the overall recurrence-rate of cerebral embolism. In my experience, many patients admitted with
was
TABLE VIII-PATIENTS ADMITTED TO ASHFORD HOSPITAL WITH DIAGNOSIS OF CEREBRAL EMBOLISM
(1952-63)
519 cerebral embolism have already been assessed by cardiologists; consequently, the choice between restoration to sinus rhythm and valvotomy has been considered very carefully in all patients, attempted in many, and abandoned in a fair proportion, leaving very little room for further choice between these two forms of
INTESTINAL BIOPSY IN KWASHIORKOR M.D.
J. P. STANFIELD Lpool, M.R.C.P., D.C.H.
SENIOR LECTURER IN PÆDIATRICS
M. S. R. HUTT
treatment.
Despite a less than perfectly matched control group, therefore, the results are probably a reliable indication of the effect of anticoagulant therapy. In the control series, the of cerebral embolism is three and a half times more frequent than in the treated group (57% as against 16%), and the results of other workers support this. Szekely (1964) has shown that in rheumatic heart-disease the incidence and recurrence of systemic embolism was two and a half times more frequent in patients not on long-term anticoagulants; Wright (1949) and McDevitt (1961) reduced the recurrence-rate of cerebral embolism in rheumatic heart-disease from 70 to 21 % with this treatment.
M.D. Lond., M.R.C.P., M.C.Path. PROFESSOR OF PATHOLOGY
R. TUNNICLIFFE
recurrence
The length of treatment required seems to depend on the underlying heart condition. In recent cardiac infarction, all danger of systemic embolism seems to have disappeared by the end of a year. In thyrotoxic fibrillation, embolism is uncommon but recurrence is early in about half the patients, unless a return to permanent sinus rhythm is brought about. This is now often possible, unless ischxmic heart-disease has supervened; hence anticoagulants are not usually needed for longer than a year.
F.I.M.L.T. CHIEF TECHNICIAN
MAKERERE UNIVERSITY
COLLEGE, KAMPALA, UGANDA
DISTURBANCE of structure and function of the gastrointestinal tract in severe malnutrition has only recently come under study. In severe kwashiorkor the intestinal wall and mucosa are abnormally thin (Trowell et al. 1954); none the less there does not seem to be any gross failure of function as judged by clinical response to protein feeding and crude absorption tests. Diarrhoea, however, is a rather common feature of more severe cases of kwashiorkor, and usually pathogenic agents cannot be isolated. We have studied some aspects of the structure and function of the upper intestinal mucosa in children admitted, with moderate to severe kwashiorkor, to the Mulago Hospital or to the Infant Malnutrition Unit in
Kampala.
Clinical Material and Methods clinical stenosis, if embolism follows 21 children (aged one to three years) with kwashiorkor of paroxysmal fibrillation it usually happens within a year of varying severity have been studied. The first 10 children were this (Wood 1956) and anticoagulant prophylaxis is accepted admitted to the Mulago Hospital, Kampala, and 4 of these by most physicians as essential when conversion to sinus were readmitted after one month for a repeat biopsy. The rhythm is attempted. If conversion is unsuccessful, the remaining 11 children were studied at the Medical Research most vulnerable period is the first two years after Council’s Infant Malnutrition Unit. 7 of these were included embolism; on the results of this series anticoagulants in a prolonged follow-up study, and 9 were included in a small should be used for two years. Some patients seem to be study on the correlation of mucosal-enzyme assay and mucosal vulnerable for a longer period: they are characterised by appearance. Routine clinical examination and weight measurements persisting atrial fibrillation resistant to conversion, a were made on all the children. Blood was taken for estimation of recurrent rheumatic infection, a large left history of total serum-protein. In addition, the aminoacid-ratio test atrium, and frequent clinical systemic peripheral embolisa(Whitehead and Dean 1964) was done on a few of the later tion. These patients may well require lifelong anticases. Small-intestinal-biopsy specimens were taken with a coagulation, but presumably this is better decided by the Crosby capsule (either the 9-5 mm. adult type or the 8 mm. cardiologist than by the neurologist. type) using the technique described by Burman (1963); there were no serious complications. All the biopsy specimens were Summary taken between 30 and 45 cm. from the mouth, and represented 130 patients with 176 episodes of cerebral embolism mucosal sampling from the terminal part of the duodenum
In mitral
were
followed up for twelve years
on
to
or
determine whether
anticoagulant therapy had influenced the natural history of this condition. The results show no significant gain from the immediate use of anticoagulants in patients whose neurological lesion is persistently complete. If anticoagulants are used to prevent recurrence in these patients an interval of three weeks should elapse before commencing
and the first 4
of the
jejunum.
The
specimens
were
were
out on
oriented and embedded in
treatment.
The survival-rate improved significantly in patients with incomplete or fluctuating lesions (in whom ischaemia is likelier than infarction) when anticoagulants were used in the early stages. In all patients the recurrence-rate was high immediately after the initial cerebral embolism. The rate remained high for six months after embolism associated with cardiac infarction, and for two years in patients with mitral stenosis and atrial fibrillation, and then, except in a few special cases, fell away. The recurrence-rate and the mortality-rate of cerebral embolism was significantly lowered in this series by the use of long-term anticoagulant therapy for two years after embolism.
cm.
cards, mucosal surface uppermost, and fixed in Bouin’s fixative. They were then examined under the dissecting microscope, and usually photographs were taken (Holmes et al. 1961a and b). Specimens, taken for microscopical examination,
pinned
paraffin wax, and sections
were
DR. BARHAM CARTER: REFERENCES
F., Merrett, J. D. (1961) Br. med. J. i, 309. Belcher, J. R., Somerville, W. (1955) ibid. ii, 1000. A. Barham Carter, (1957) Q. Jl Med. 26, 335. — (1960) Lancet, i, 345. (1963) Proc. R. Soc. Med. 56, 483. Daley, R., Mattingley, T. W., Holt, L., Bland, E. F., White, P. (1951) Am. Heart J. 42, 566. de Morsier, G., Tissot, R. (1957) Rapp. Congr. fr. Méd. i, 110. Greenwood, W. F., Aldridge, H. E., McKelvey, A. D. (1963) Am. J. Cardiol. 2, 348. Harris, A. W., Levine, S. A. (1941) Ann. intern. Med. 15, 637. Hugues, J., Lecomte, J. (1957) Acta clin. belg. 12, 270. Keen, G., Leveaux, V. M. (1958) Br. med. J. ii, 91. McDevitt, E. (1961) Cerebral Vascular Disease; p. 90. New York. Rankin, J. (1957) Scott. med. J. 2, 200. Rowe, J. C., Bland, E. F., Sprague, H. B., White, P. D. (1960) Ann. intern. Med. 52, 741. Szekely, P. (1964) Br. med. J. i, 1209. Ushiro, C. S., Schaller, W. R. (1957) Neurology, 7, 253. Wang, Y., Bland, E. F., Scannel, J. G. (1960) Circulation, 22, 829. Wells, C. E. (1959) Archs Neurol. Psychiat., Chicago, 81, 667. — (1961) Archs Neurol. 5, 490. Wood, P. (1956) Diseases of the Heart and Circulation; p. 525. London. Wright, I. S. (1949) Ann. intern. Med. 30, 80. Adams,
—
G.