POSTGRAD. MED. J. (1961), 37, 412 THE DIAGNOSIS AND TREATMENT OF CEREBROVASCULAR DISEASE D. A. SHAW, M.B., M.R.C.P.(Edin.) Lecturer in Clinical Neurology, Institute of Neurology, National Hospital for Nervous Diseases, Queen Square, London, w.C.I1 THE considerable investment of thought and endeavour in the field of cerebrovascular disease in recent years, has not yet yielded substantial dividend. Measured purely in terms of direct benefit to the individual afflicted by this disease in its wide variety of forms, advances have not been outstanding. Nevertheless it is justifiable to hope that we are reaching a stage, identifiable in all medical progress, when increasing knowledge can be translated into terms of practical achievement in diagnosis and treatment. Before describing in detail such clinical advances as have been made, it is perhaps worth while considering some of the past and present impedi- ments to progress and the fields of study designed to overcome them. With growing interest in mor- bidity and mortality statistics it has become increasingly apparent that this group of diseases, formerly regarded as an inevitable part of the ageing process if not, indeed, its very definition, takes its toll in the younger age-groups also. While it is undoubtedly in the later decades that cerebrovascular accidents have their maximum incidence, scrutiny of the age distributions in nearly all published clinical studies reveals the extent to which the younger groups are affected. The wider recognition of this fact has in itself provided a stimulus to research. For the purposes of this discussion we are not concerned with conditions such as spontaneous or traumatic extracerebral hkmorrhage, intracranial aneurysm or angioma, but with, the various mani- festations of occlusive vascular disease and intra- cerebral hbmorrhage. In other words with conditions which result from atherosclerotic and hypertensive vascular disease, and it has too often been assumed that any real advance in the treat- ment of cerebrovascular disease must await solution of these fundamental problems. The vast amount of work in a wide range of disciplines that is being directed towards this end is, of course, relevant to cerebrovascular disease; no attempt will be made here to review it but one recent piece of work may be of particular relevance because it postulates a relationship between cere- brovascular disease and the 'causation' of hyper- tension. That hypertension is an important factor in atherogenesis is not disputed but Dickinson and Thomson (I959, I960) have recently produced evidence that narrowing of the arteries to the brain may be a cause as well as a result of hyper- tension. In this they have revived a suggestion made by Starling (1925) that interference with the blood supply to the vasomotor centre in the medulla oblongata due to vascular'narrowing may result in an elevation of blood pressure in order to maintain the needs of the centre. Fortunately, progress is not entirely dependent on the solution of these major problems. Adams (1958), discussing cerebrovascular diseases, rightly stated that 'their ultimate solution will be accom- plished by whosoever learns the secret of athero- matosis and elevated blood pressure', but he went on to consider many of the factors which determine their impact on cerebral function and ways in which these might be modified. Martin, Whisnant and Sayre (I960) have demonstrated in a precise post-mortem study of the extracranial cerebral circulation the remarkable extent to which these vessels are frequently affected by occlusive disease even in absence of any evidence of cerebral ischmmia and the question arises-why does one individual with cerebrovascular disease develop overt neurological manifestations while another, with comparable or more extensive disease, fails to do so? There must be conditioning mechanisms, some of which Adams (I958) has called 'ischimia- modifying factors', which determine the effects of arterial disease on brain function and which may themselves be amenable to modification by medical treatment. Clearly the anastomotic systems of the cerebral vessels are relevant to this concept. Willis himself perceived not only the anatomical arrangement of the circle of vessels which bears his name but appreciated its physiological signi- ficance. He encountered the condition of carotid obstruction and recognised that the circle provided a mechanism whereby one carotid artery might assume the functional role of both. While the circle of Willis must undoubtedly copyright. on July 7, 2020 by guest. Protected by http://pmj.bmj.com/ Postgrad Med J: first published as 10.1136/pgmj.37.429.412 on 1 July 1961. Downloaded from
Transcript
POSTGRAD. MED. J. (1961), 37, 412
THE DIAGNOSIS AND TREATMENT OFCEREBROVASCULAR DISEASE
D. A. SHAW, M.B., M.R.C.P.(Edin.)Lecturer in Clinical Neurology, Institute of Neurology, National Hospital for Nervous Diseases, Queen Square, London,
w.C.I1
THE considerable investment of thought andendeavour in the field of cerebrovascular diseasein recent years, has not yet yielded substantialdividend. Measured purely in terms of directbenefit to the individual afflicted by this disease inits wide variety of forms, advances have not beenoutstanding. Nevertheless it is justifiable to hopethat we are reaching a stage, identifiable in allmedical progress, when increasing knowledge canbe translated into terms of practical achievementin diagnosis and treatment.
Before describing in detail such clinical advancesas have been made, it is perhaps worth whileconsidering some of the past and present impedi-ments to progress and the fields of study designedto overcome them. With growing interest in mor-bidity and mortality statistics it has becomeincreasingly apparent that this group of diseases,formerly regarded as an inevitable part of theageing process if not, indeed, its very definition,takes its toll in the younger age-groups also.While it is undoubtedly in the later decades thatcerebrovascular accidents have their maximumincidence, scrutiny of the age distributions innearly all published clinical studies reveals theextent to which the younger groups are affected.The wider recognition of this fact has in itselfprovided a stimulus to research.
For the purposes of this discussion we are notconcerned with conditions such as spontaneous ortraumatic extracerebral hkmorrhage, intracranialaneurysm or angioma, but with, the various mani-festations of occlusive vascular disease and intra-cerebral hbmorrhage. In other words withconditions which result from atherosclerotic andhypertensive vascular disease, and it has too oftenbeen assumed that any real advance in the treat-ment of cerebrovascular disease must awaitsolution of these fundamental problems. Thevast amount of work in a wide range of disciplinesthat is being directed towards this end is, ofcourse, relevant to cerebrovascular disease; noattempt will be made here to review it but onerecent piece of work may be of particular relevancebecause it postulates a relationship between cere-
brovascular disease and the 'causation' of hyper-tension. That hypertension is an important factorin atherogenesis is not disputed but Dickinson andThomson (I959, I960) have recently producedevidence that narrowing of the arteries to thebrain may be a cause as well as a result of hyper-tension. In this they have revived a suggestionmade by Starling (1925) that interference with theblood supply to the vasomotor centre in themedulla oblongata due to vascular'narrowing mayresult in an elevation of blood pressure in orderto maintain the needs of the centre.
Fortunately, progress is not entirely dependenton the solution of these major problems. Adams(1958), discussing cerebrovascular diseases, rightlystated that 'their ultimate solution will be accom-plished by whosoever learns the secret of athero-matosis and elevated blood pressure', but hewent on to consider many of the factors whichdetermine their impact on cerebral function andways in which these might be modified. Martin,Whisnant and Sayre (I960) have demonstratedin a precise post-mortem study of the extracranialcerebral circulation the remarkable extent to whichthese vessels are frequently affected by occlusivedisease even in absence of any evidence of cerebralischmmia and the question arises-why does oneindividual with cerebrovascular disease developovert neurological manifestations while another,with comparable or more extensive disease, failsto do so? There must be conditioning mechanisms,some of which Adams (I958) has called 'ischimia-modifying factors', which determine the effects ofarterial disease on brain function and which maythemselves be amenable to modification by medicaltreatment. Clearly the anastomotic systems of thecerebral vessels are relevant to this concept.Willis himself perceived not only the anatomicalarrangement of the circle of vessels which bearshis name but appreciated its physiological signi-ficance. He encountered the condition of carotidobstruction and recognised that the circle provideda mechanism whereby one carotid artery mightassume the functional role of both.While the circle of Willis must undoubtedly
July I96I SHAW: The Diagnosis and Treatmnent of Cerebrovascular Disease 4r3
mitigate the adverse effects of proximal occlusivedisease in many cases, its reliability is not invari-able as emphasized by Alpers, Berry and Paddison(I959). In a series of 350 autopsies they foundthat the circle of Willis conformed to what isregarded as the normal anatomical pattern inonly 52.3% and there were multiple anomalies inI3.4%. A large number of individuals must havea vascular arrangement which is below optimalefficiency in maintaining blood flow under patho-logical conditions.The existence of anastomotic pathways other
than the circle of Willis has also been established.Vander Eecken and Adams (1953) in a series ofpost-mortem injection studies demonstrated theextensive leptomeningeal communications andtheir capacity for connecting adjacent vascularterritories when required to do so. There are alsothe capillary anastomoses but apart from thesethere are no communications between neigh-bouring arteries once they have entered thesubstance of the brain.
It was probably faith in the capacity andintegrity of the anastomotic arrangement of thecircle of Willis combined with an unwarrantedconviction that all its distal branches were end-arteries which delayed the full realisation of theimportance of the four great proximal vessels inthe causation of strokes. Whereas formerly themajority of fore-brain infarcts were attributed to'middle cerebral thrombosis', in spite of thecomparative rarity of this finding at post-mortem(Moossy, I959; Blackwood, I96I), it is now gener-ally accepted that in many instances the occlusivelesions are to be found in the extracranial arteriesand that no post-mortem examination is completeunless it includes these vessels. Fisher (195I,1954), on the basis of an extensive autopsy study,demonstrated the high incidence of occlusivedisease in the internal carotid arteries and in thiscountry Hutchinson and Yates (I956, 1957) havestressed the importance of atherosclerosis in thevertebral arteries and have shown that in a highproportion of cases of cerebrovascular diseaseboth the carotid and vertebral arteries are affected.In 40 instances where significant stenosis orocclusion of one or more of the major neck vesselswas found at post-mortem, disease was confinedto the carotid arteries in io, and to the vertebralarteries in 7, whereas in 23 both systems wereinvolved. Studies such as these emphasize ourdependence on the anastomotic pathways for themaintenance of blood supply to the brain underpathological conditions and they have obviousbearing on the problems of reconstructive surgery.They help us to understand some of the apparentanomalies encountered in clinical practice as whenocclusion of a major vessel results in infarction in
a part of the brain beyond its normal territory ofsupply.Most of the studies discussed so far have been
based on anatomical and pathological observation.The physiological and pharmacological approacheshave, on the whole, shed less light on problems incerebrovascular disease principally because noconvenient method is available for measuringregional cerebral blood flow in man. The polaro-graphic technique employed by Meyer andHunter (I957) has only very limited application inman. The nitrous oxide method for determinationof total cerebral blood flow described by Ketyand Schmidt (1945, I948) has been of great valuein the study of metabolic diseases of the brain andof physicochemical factors which affect overallcerebral circulation. However, the clinical mani-festations of cerebrovascular disease are seldomrelated to disturbances of flow to the cerebrum as awhole: rather are they reflections of focal disordersof blood flow beyond the scope of the method, andwe have no experimental evidence that proceduressuch as stellate ganglionectomy or drugs whichcause vasodilatation increase the blood flow toisch2emic zones of the brain. The total flowmethods may prove of value in connection with theuse of hypothermia as a therapeutic measurefollowing cerebrovascular accidents, an approachthat has been tried by Howell and his associates(Howell, Stratford and Posnikoff, 1956), butthat has not yet been fully explored. Otherwise,however, these methods are of little practicalvalue in the problems we are concerned with.
Perhaps the greatest contribution to our under-standing of the dynamic factors involved in theproduction of symptoms of cerebrovascular diseasederives from the studies of Denny-Brown, Meyerand their co-workers. Their extensive series ofexperiments has recently been reviewed byDenny-Brown (i96o). Their starting point wasthe observation that the recurrent episodes oftransient hemiplegia in patients with carotidocclusion could in many instances be related tosituations that lowered the systolic blood pressureor the cardiac output. Transient attacks precipi-tated by blood loss, syncope or the use of peri-pheral vasodilator drugs had been encounteredand catastrophic hemiplegia determined by myo-cardial infarction was cited. Denny-Brownelaborated the concept of carotid insufficiency inwhich the vascular territory of a stenosed oroccluded carotid artery becomes dependent oncollateral supply and therefore susceptible toinfluences which impair that supply. He recog-nized a similar situation in relation to the basilarartery accounting for insufficiency of blood supplyto the brain stem and posterior cerebral territoryof that artery. Carotid or basilar insufficiency
was defined as 'a physiological, potential hmmo-dynamic state, in which reversible hmmodynamiccrises could be elicited by any factor that impairedthe collateral circulation. The liemodynamiccrisis resulted in symptoms that were transient,and completely or partially reversible, dependingon whether the crisis was so prolonged or sosevere as to produce anatomical damage in thevulnerable area'.
Inasmuch as this concept of insufficiencyinvolves a failure of collateral blood flow it ledDenny-Brown and his associates to further studyof the physiological factors governing it. Theycarried out a beautiful series of experiments onmonkeys in which they recorded inter alia changesunder varying conditions in the oxygen saturationof cerebral cortical tissue, the blood flow incortical vessels and latterly also the stereomicro-scopic appearance of the arterioles and capillaries.By occluding a major vessel and lowering thesystemic blood pressure they were able to repro-duce experimentally the conditions in which theinsufficiency syndromes occur in man and to studyprecisely the physiology of collateral blood flow.
This concept of insufficiency was offered as analternative to the vexed question of vasospasmwhich has so often been invoked, faute de mieux, asa cause of transient and recoverable neurologicaldeficits of one sort and another. In fact, thesituations in which cerebrovascular spasm doesoccur were examined: these include mechanicaltraction on vessels, perhaps comparable to the'effect produced by localised haemorrhages fromaneurysms in the region of the circle of Willis,and sudden rises in intraluminal pressure whichmay explain the marked narrowing of vessels notinfrequently-encountered in cerebral angiography.A third situation was demonstrated experimentallyin hypertensive monkeys where spasm of corticalvessels was encountered similar to that observedby Byrom (1954) in rats. However, the conclusionwas reached that spasm was not a mechanismwhich usually operated in insufficiency states. Itwas emphasized that the latter was a physiologicaland not a pathological entity and a plea was madefor restriction in the use of the term to the precisesituation which it was intended originally torepresent.Denny-Brown also turned his attention to the
problem of embolism and observed, and in oneexperiment actually photographed (Denny-Brownand Meyer, 1957), a fibrin-platelet embolus froma partially damaged middle cerebral artery in amonkey, lodged in a small peripheral branch oftthat artery. They were able to observe its effectson the territory of the artery in question andpostulate that such a mechanism may be respon-sible for the production of symptoms of transient
ischbmia in patients whose clinical attacks cannotbe related to circumstances associated with fall inblood pressure and in whom neither an attack nora change in the EEG can be induced by loweringthe pressure. Of interest in connection with thishypothesis is the report by Fisher (I959) of apatient subject to repeated attacks of visual failurein whom a retinal embolus of similar type wasobserved. Denny-Brown suggests that it may bein patients whose transient ischemic attacks aredetermined in this way that anticoagulant therapymay be effective rather than in those sufferingfrom the true insufficiency syndromes as hedefined them. He also draws attention to thepossibility of repeated trauma to the vertebralarteries from spondylitic disease or congenitalanomaly of the cervical spine resulting in the pro-duction of platelet emboli. The clinical associa-tion between cervical spondylosis and vertebralartery syndromes has recently been emphasizedby Williams (I96I).Thus far we have been concerned principally
with the physiological and pathological features ofthe blood vessels themselves and their contribu-tion to the development of neurological disturb-ances. There are undoubtedly situations, how-ever, where disturbances in the transportation ofoxygen to the nerve cells must be determined bychanges in the nature of the blood which flowsthrough the cerebral vessels with or withoutcoincidental disease of those vessels. The pre-disposition to major cerebrovascular accidents ofpatients with polycythmmia has long been recog-nized, but recently Millikan, Siekert and Whisnant(I960) have drawn attention to the association ofthis condition with intermittent carotid andvertebro-basilar ischlemic attacks. The sameauthors (Siekert et al., I960) have described fivepatients in whom they suggested that an anmmiamight be related to focal, as opposed to general,cerebral ischmmic attacks. The administration ofhigh-fat meals to experimental animals has beenshown by Meyer and Waltz (I959) to increase theaggregation of erythrocytes within the pial vesselsproducing a tendency to clumping and slowingof blood flow. Other features of the circulatingblood of possible significance in this context havebeen described by Swank (I959), who has reportedthe viscosity of the blood to be relatively high inpatients with cerebrovascular disease, and byElliott and Buckell (I96I) who have demonstratedchanges in blood fibrinogen level in relation tocerebrovascular accidents.These then are some of the recent concepts
which have been formulated and lines of investiga-tion which have been followed. Many of themand others have been more fully discussed byWells (I960) in his excellent review, but it is hoped
July I96I SHAW: The Diagnosis and Treatment of Cerebrovascular Disease 415
that they serve to show that progress in the studyof cerebrovascular disease has been made whichcannot be measured purely in terms of advancesin diagnosis and treatment. They represent muchnew thought and provide a foundation on whichfurther researches will be based. Some of themhave already been assimilated into the clinicalprecepts that we are about to consider, wherebypatients are managed, and it is reasonable to hopethat others will mature into practical instrumentsof therapy.
Diagnosis of Cerebrovascular DiseaseClinical Considerations
Let us turn now to some of the advances whichhave been incorporated in the everyday manage-ment of patients suffering from cerebrovasculardisease. It is probably in the field of clinicaldiagnosis that the most marked changes have beenwitnessed in recent years: many new distinctionshave been made and new terms introduced.Whereas formerly ' stroke ' and ' hemiplegia'were frequently accepted as clinical diagnoses,and pathological interest was largely confined todistinguishing between hiemorrhage, thrombosisand embolism, attempts are generally made nowa-days at more precise definition of the clinicalsyndrome. In the case of brain stem disease it istrue that posterior inferior cerebellar artery throm-bosis, pontine heemorrhage and one or two othershave long been taught as specific vascular syn-dromes, but it is only during the past few yearsthat clinicians generally have become aware of thevariety of presentations of patients with occlusivedisease of the vertebro-basilar system. So too withfore-brain infarcts which were usually designatedmiddle cerebral thrombosis or embolism, whilenow the frequency of internal carotid occlusion iswidely recognized. A major advance has been thedevelopment of the concept of the insufficiencysyndromes, whose underlying mechanisms havebeen discussed, and which are already acceptedas familiar clinical entities.
It is unnecessary to describe in detail the variouspatterns of neurological disturbance which resultfrom these vascular syndromes. Many series ofpatients have been studied and described, themost valuable being those in which clinical featuresare correlated with angiographic and pathologicalfindings. The papers of Symonds (I957) andSilverstein (I959) embody most of our knowledgeabout occlusive disease of the carotid arteries andMeyer, Sheehan and Bauer (I960) have recentlyreviewed the clinical features of vertebro-basilardisease in light of a carefully studied series of theirown. In his Lumleian lectures, Elkington (1958)surveyed the whole problem of the diagnosis of
insufficiency and occlusion of the internal carotidand basilar arteries.
Other advances in diagnosis have resulted fromthe wider usage of cerebral angiography whichhas demonstrated the importance of vascular mal-formations in the causation of cerebral bimorrhageand has permitted a more accurate estimate of thefrequency of aneurysms. The realization of thesignificance of systemic diseases and of inflam-matory diseases of arteries in the production ofcerebrovascular symptoms has added further tothe complexity of the problems of diagnosis, whilethe introduction of new forms of treatment hasdemanded an increased degree of accuracy. Theseand other developments have raised problems inclassification and terminology which have been tosome extent clarified by an ad hoc committeeappointed by the Advisory Council for the NationalInstitute of Neurological Diseases and Blindness,Bethesda. Its report (1958) deals with the defini-tion, classification and general clinicopathologicalaspects of cerebrovascular disease.
In spite of our more precise approach to diag-nosis in cerebrovascular disease and the delineationof new clinical syndromes, there is still one out-standing defect, namely our inability to distinguishwith complete confidence between infarction andhimorrhage. Aring and Merritt (1935) attemptedto define the diagnostic features of each bycorrelating the symptoms and signs in life withthe autopsy findings in a series of 245 cerebro-vascular accidents. Application of their diagnosticcriteria is not however infallible, and, of course, itis not justifiable to extrapolate their findings infatal cases for non-fatal ones. Dalsgaard-Nielsen(1956) found that the diagnosis of cerebralhmemorrhage made clinically in 239 patients wasconfirmed at autopsy in only I55 (65%). Theclinical diagnosis of cerebral arterial thrombo-embolic occlusion in I39 patients proved correctin only 8I (58%). Lumbar puncture was notperformed in all these cases and this investiga-tion undoubtedly raises considerably diagnosticaccuracy. It is not an infallible test, however.Intracerebral hemorrhages very seldom rupturethrough the surface of the brain, nor do theynecessarily reach the ventricular system; thuscontamination of the cerebrospinal fluid pathwayis not invariable. Nor is the presence of red cellsin the spinal fluid incompatible with the diagnosisof cerebral infarction. This inability to make soimportant a pathological distinction with com-plete certainty is unfortunate and introduces anelement of uncertainty and hazard in the planningof therapy.
Radiological DiagnosisThe radiological investigation of patients with
cerebrovascular disease was reviewed by Bull(1958); he pointed out that plain radiographs and,in a limited number of cases, pneumoencephalo-grams could be of value, but it is, of course, on theuse of opaque media that we mainly depend. Thedevelopment of percutaneous cerebral angiographyhas brought enormous advance in the study ofcerebrovascular disease, apart altogether from itsuse in cases of cerebral tumour, and there is nosingle technique of comparable diagnostic value.Its greatest application in this field is probablystill in regard to aneurysms and vascular mal-formations, but it is also as a result of angiographicinvestigation that we are now aware of the highincidence of internal carotid occlusion in thecausation of cerebrovascular symptoms. In othervascular occlusions and in the demonstration ofintracerebral h;rmatomas its precise use and limita-tions are less clearly defined; the extent to whichit should be employed in patients suffering acutestrokes is a matter of controversy. Bull, Marshalland Shaw (I960) studied angiographically 8opatients admitted to hospital with strokes andfound the angiogram to be of positive diagnostichelp in 33 cases (41%); in I7 of these the lesiondemonstrated was other than that suspectedclinically. They encountered I4 cases of internalcarotid artery occlusion: I0 were complete andfour partial. Only the vessel appropriate to theanatomical site of the lesion as judged clinicallywas examined and complete angiography, bilateralcarotid and vertebral, might have yielded a highernumber of positive findings. Dobrak, Beck,Murphy and Zoll (I960) found definite angio-graphic abnormality in 39% of a series of 38patients who had had cerebrovascular accidents;they made complete examinations in some butnot all of their patients.While the diagnostic value of cerebral angio-
graphy in many situations is beyond dispute, theinvestigation in its present form has its limitations.It is a relatively crude procedure in that only thelarger vessels can be clearly outlined and identified,and this may be the reason why quite extensivebrain damage can exist on the basis of vasculardisease without there necessarily being any ab-normality, which we are capable of recognizing,in the angiographic pattern. Nor is it entirelywithout hazard. The exact complication rate isdifficult to assess and varies in different series,depending on such factors as the contrast mediumused and the clinical condition of the patientssubmitted to examination. Furthermore, in acutelyill patients it is not always possible to decidewhether deterioration is attributable to the in-vestigative procedure or to the natural course ofthe disease. Kuhn (I959) referred to the completeabsence of morbidity and mortality associated with
angiography in over I00 patients with strokes,but Bull et al. (I960) observed transient deteriora-tion with no fatalities in I I% of patients examinedin their series. Of the i6 deaths in the series ofDobrak et al. (I960) four were considered in partat least attributable to angiography. Segelov (1956)had no complications in a series of 66o angio-grams, but he reviewed nine reported series com-prising a total of 3,788 angiograms and listed 2zdeaths and 8i other complications. It wouldseem therefore that we must accept that some riskattaches to the procedure, but whether or not thatrisk is increased in the presence of cerebrovasculardisease is not definitely established; Riishede(I957), on the basis of a very wide experience,has expressed the view that the risk is not greaterthan in neurosurgical patients generally, but thereare many who would disagree with this opinion;vertebral angiography in particular is widelythought to carry increased hazard in patients withdiseased arteries.
Reference has already been made to the factthat in a high proportion of patients there isdisease of main vessels other than or in additionto the one apparently implicated by the clinicalsymptoms. Ideally, therefore, it is desirable tomake a complete examination which necessitatesbilateral carotid and vertebral angiography-afairly formidable procedure. Furthermore, thestandard method of examination does not demon-strate the origins of the vertebral arteries, theimportance of which has been stressed by Hutchin-son and Yates (I957). There is also the objectionthat the standard procedures involve puncturingdiseased arteries which many regard as dangerous.For these reasons methods are now being soughtwhich will obviate the necessity of making multipleinjections, which will show the origins of the greatvessels and at the same time avoid puncturingdiseased arteries. It is beyond the scope of thisreview to describe them in detail, but recentlySchramel, Creech, Llewellyn and Corales (I96I)have advocated a modified technique of cardio-angiography for demonstrating the extracranialcerebral vessels. A catheter is introduced via thesaphenous vein into the inferior vena cava andgo% sodium diatrizoate (Hypaque Sodium) isinjected' by hand. Serial exposures allow demon-stration of both the aortic arch and its branchesand also of the intracranial cerebral vessels.Alternatively the opaque medium can be deliveredby catheterization of the right atrium as advocatedby Zerbi-Ortiz and Weldon (I96I) who prefer amechanical injector. These methods probablygive better opacification than do the intravenoustechniques described by Viallet, Sendra, Chevrot,Combe, Descuns and Aubry (1956) and by Stein-berg, Finby and Evans (I959) which require
July I96I SHAW: The Diagnosis and Treatment of Cerebrovascular Disease 417
injection of large quantities of contrast material.All these methods obviously involve the passageof the bolus of contrast medium through thepulmonary vascular bed, and to avoid this, tech-niques have been developed whereby it is deliveredintra-arterially but proximal to the orthodox sitesof vertebral and carotid puncture. In this waydirect puncture of affected vessels is avoided andseveral vessels can be outlined simultaneously.Gensini and Ecker (I960) have achieved very goodresults by passing a catheter into the arch of theaorta via the femoral artery, although difficulty isQccasionally encountered in presence of markedtortuosity or plaque formation in the iliac artery.The main objection to direct subclavian puncturehas always been the risk of inducing pneumo-thorax, but Baker (I960) has described an approachwhich has given very good filling of vessels with-out the occurrence of this complication in a seriesof over 6o consecutive cases.
It will be seen that considerable strides havebeen taken towards achieving our aim which mustbe a standardized, safe and reasonably simplemethod of pan-angiography, capable of demon-strating both extracranial and intracranial cerebralvessels. In concentrating on the former, the lattermust not be neglected because occasional caseswill always be encountered where an apparentlyvascular clinical presentation results from an intra-cranial tumour distinguishable only by a patho-logical circulation or displacement of intracranialvessels.
Ancillary Diagnostic InvestigationsLumbar PunctureThe importance of examination of the cerebro-
spinal fluid in the diagnosis of the acute cerebro-vascular accident has already been mentioned. Itis not an infallible method of distinguishing be-tween infarction and hamorrhage, but it shouldnot be omitted. The presence of blood doesusually indicate that a hlmorrhage has occurredand from time to time the unexpected positiveWassermann reaction or grossly elevated proteinlevel will indicate that the underlying pathologyis contrary to expectation.
Pulsations and BruitsWhilst angiography remains much the most
reliable investigation in the diagnosis of internalcarotid occlusion, various ancillary aids have beenadvocated; these can undoubtedly be helpfulalthough none is entirely reliable. Thus absenceof a palpable arterial pulsation in the neck mayindicate an occlusion, but Rosegay (I956) hasfound this sign to be of inconstant value. Palpationof the vessel in the pharynx as described byDunning (1953) is not practised by many and
methods involving compression of the carotidartery may be dangerous to the patient. Thedetection and localisation of audible bruits isgenerally a more useful indication of occlusivedisease and the importance of auscultation in thiscontext has been emphasized by Peart and Rob(I960). Crevasse (I96I) has studied in detail theinterpretation of carotid artery murmurs.
OphthalmodynamometryA more objective assessment of flow in the
internal carotid artery depends on the measurablefall in pressure in its ophthalmic branch when theinternal carotid is occluded. This is the basis ofophthalmodynamometry by means of which theophthalmic artery pressures are compared on thetwo sides. It is performed by applying pressureon the sclera with a dynamometer and observingthe effects upon the pulsations of the centralretinal artery. Wood and Toole (I957), Hurwitz,Groch, Wright and McDowell (959), Smith(I960) and others have found this technique tobe reliable in the diagnosis of internal carotidocclusion, although in long-standing cases theestablishment of collateral flow via the externalcarotid artery may reduce the differential. It isundoubtedly a technique which requires consider-able experience before consistent results areobtainable.
ElectroencephalographyThe value of electroencephalography in the
diagnosis of cerebrovascular diseases was recentlycommented upon by Wells (I96I). With regardto structural damage resulting from vascularlesions he conceded that it might aid in preciselocalization, that a normal pattern might implicatethe brain stem rather than hemisphere and that aresolving pattern favoured a vascular lesion ratherthan a tumour; however, he concluded that theresults of electroencephalography were disappoint-ing in the routine diagnosis of patients. So tooin the case of functional vascular disturbancewithout structural damage it is as yet an investiga-tion of limited practical application.
Treatment of Cerebrovascular DiseaseIt is probably fair to say that most recent
innovations in treatment have stimulated ratherthan derived from the various advances in know-ledge that have so far been considered. When atherapeutic technique is applied in a new field itimmediately demands greater precision in diag-nosis, greater understanding of xtiological mecha-nisms and greater knowledge of the natural historyof the disease in the absence of treatment. Defi-ciencies in these three respects have made appraisalof the new forms of treatment in cerebrovasckilar
disease extremely difficult. Patterns of the diseaseare so variable and unpredictable that unless a newtherapeutic approach is conspicuously successful,its value is very hard to measure. Spontaneousrecovery may bestow on a treatment a reputationthat it never deserved. This has undoubtedlybeen the case with some of the measures advo-cated in the past in cerebrovascular disease andnowadays there is increasing awareness of thenecessity for controlled experiment in the trial ofnew forms of treatment.
Before considering any specialized medical orsurgical methods of treatment it is worth recallingthe extent to which the general supportive manage-ment can modify the mortality and morbidity inpatients with cerebrovascular disease. This appliesboth to the acute and chronic phases. In theformer, the standard of nursing care and physio-therapy, for both lungs and limbs, probably hasgreater influence on the outcome than any of themore sophisticated forms of treatment. In thechronic stage, too, the quality of the life achievedis in many cases proportional to the amount oftime and effort devoted to the patient's rehabilita-tion. Adams (I960) has outlined the principles ofmanagement of patients with acute strokes andthe practical measures which are so important inthe rehabilitation of those that survive.
Drug TreatmentDiscussion here will be limited to the possible
applications of hypotensive, anticoagulant andfibrinolytic agents; of the many others which havebeen tried, all have been found wanting and it isnot proposed to consider them further. The mosteffective cerebral vasodilator substance is un-doubtedly carbon dioxide and it is surely alreadypresent in abundance at the site of an acutecerebral infarct.
Hypotensive DrugsThe position regarding the use of hypotensive
drugs is far from clear. There is no evidencethat they reduce the mortality in acute strokes,infarctions or hbemorrhages, in severely hyper-tensive patients unless there are coexisting featuressuch as left ventricular failure or Grade IV retino-pathy which, in their own right, demand theirapplication. In hypertensive patients with chroniccerebrovascular disease there is usually reluctanceto use hypotensive agents because of the antici-pated .risk of inducing further infarcts or in-sufficiency attacks. Beyond doubt this risk mustexist, but on the other hand, untreated hyper-tensive patients with cerebrovascular disease havea much shorter average survival than do thosewith relatively normal blood pressures (Marshalland Kaeser, I96I), and it might be that the
advantages of hypotensive therapy would out-weigh the hazards.
Anticoagulant TherapyThe apparent benefits of anticoagulant drugs in
coronary artery disease inspired the hope that theymight prove of value in the treatment of occlusivecerebrovascular disease. Over the past few yearsmany reports have been published of series ofpatients with various types of cerebrovasculardisease treated with anticoagulants, but becauseof the variable pattern of the disease, its un-predictable natural history and its limited suscepti-bility to precision in diagnosis, their evaluationhas been difficult. The necessity for strictly con-trolled trial has not always been appreciated; thefactors mentioned make such control hard toachieve but mandatory for valid clinical assess-ment. Without it, not only do we lack a yard-stick whereby we can measure the beneficial effectsof the treatment but, and of equal importance, theprecise magnitude and the implications of theadverse effects are easily overlooked. Barron andFergusson (1959) have drawn attention to the largenumber of fatal cerebral hbmorrhages among theextensive reports on anticoagulant therapy incerebrovascular disease.On the whole, enthusiasm for anticoagulant
therapy has waned with the passage of time andit has become clear that it does not have wideapplication in cerebrovascular disease. However,its restricted use in a few particular situations isgenerally accepted to be of benefit and the indica-tions have become fairly clearly defined. Wrightand his co-workers (McDevitt, Carter, Gatje,Foley and Wright, 1958), on the basis of a veryextensive experience, have clearly established theplace of long-term anticoagulants in the prophy-laxis of cerebral embolism in patients known to beat risk because of conditions such as rheumaticheart disease. So too in the immediate treatmentof established cerebral embolism, Carter (I957)and Wells (I959) found that anticoagulants reducedthe mortality rate. In the case of non-emboliccerebral infarction, however, such benefit has notbeen shown (Marshall and Shaw, I960). Thereare several possible explanations for this discrep-ancy between the results of therapy in the twotypes of infarction which runs contrary to whatmight be expected on pathological grounds. Themain reason is probably that there is less likeli-hood of diagnostic error qua intracerebral haema-toma in the embolic group in virtue of the existenceof a demonstrable predisposing cause such as afibrillating left atrium. Also there is often nointrinsic disease of the cerebral vasculature inpatients who sustain embolic infarction and theyare usually in a younger age-group and less likely
July 196I SHAW: The Diagnosis and Treatment of Cerebrovascular Disease 419
to be hypertensive than are those who have non-embolic infarcts. It may be that these factorsmodify the response to anticoagulant therapy.Although Carter (I959) also found that patientswith non-embolic cerebral infarction resulting insudden hemiplegia were not benefited by anti-coagulants, he has reported that these drugs im-prove the outlook for patients whose infarctionis of gradual onset (Carter, I960). Fisher (1958)also reported that the downhill course of the pro-gressively evolving stroke due to cerebral throm-bosis might be arrested and reversed. With regardto immediate treatment with anticoagulants in theacute phase of the illness, Millikan, Siekert andWhisnant (1958) have recommended their use inactively advancing occlusion of the carotid systemand thrombosis with infarction in the vertebro-basilar system.
Apart from their use in the prophylaxis ofcerebral embolism the only real indication forlong-term therapy in cerebrovascular disease is inpatients suffering from frequently recurring tran-sient ischlimic attacks where Fisher (1958) andMillikan and his co-workers (1958) have shownstriking benefit. Such cases, however, are numeri-cally few in proportion to the total number of casesof cerebrovascular disease and reference to hospitalat the stage of transient ischlemia, without estab-lished neural damage, is relatively uncommon.In the broad spectrum of stroke cases commonlyencountered in general medical practice Hill,Marshall and Shaw (I960) found that anticoagu-lants neither increased the expectation of life nordecreased the incidence of further non-fatalcerebrovascular accidents. They emphasized thehazard of inducing cerebral hmemorrhage withanticoagulant treatment as did Fisher (I96I) inhis interim report on the national co-operativestudy of anticoagulant therepy in cerebral throm-bosis and cerebral embolism under his chair-manship.
Initial hopes that anticoagulant therapy mightrepresent a major advance in the treatment ofcerebrovascular disease have thus not been ful-filled and, to summarize, in the present stage ofknowledge their use should be limited to: (i) theprophylaxis and immediate treatment of cerebralembolism; (2) the prophylaxis of transient ischaemicattacks in carotid and vertebro-basilar insufficiencysyndromes; (3) infarcts in either of these terri-tories characterized by gradually increasing neuro-logical deficit, although even this clinical presenta-tion can result from hmemorrhage so that treatmentwill not be without risk.
Thrombolytic TherapyInterest has recently turned to the development
of methods of dissolving intravascular thrombus.
Fibrin, which is the principal insoluble constituentof the clot, is susc~eptile to enzymatic lysis sothat such methods' would appear to be rationaland to raise exciting therapeutic possibilities inocclusive cerebrovascular disease. Already smallseries of patients treated with fibrinolysin havebeen reported (Sussman and Fitch, 1959; Hern-don, Meyer, Johnson and Landers, I960; Clarkeand Cliffton, I960) but results are inconclusive.It would seem probable that commercial prepara-tion and standardization of thrombolytic agents ofthe types used in these studies, and also themethods of therapeutic control are as yet at a stagewhen clinical evaluation is premature. Moreover,it is unlikely on theoretical grounds that prepara-tions purporting to contain therapeutic doses offibrinolysin (plasmin) will prove effective. Methodsinvolving their use are based on the assumptionthat because plasmin is the physiologically occur-ring fibrinolytic enzyme, an infusion of this sub-stance will be effective in resolving pathologicalthrombus. This concept disregards the dynamicsof the thrombolytic mechanism which Alkjaersig,Fletcher and Sherry (I959) have shown to dependon the diffusion of a plasminogen activator intothe thrombus, with activation of the intrinsicthrombus plasminogen and consequent production,of plasmin, rather than on the direct action ofcirculating plasmin. Furthermore, it overlooksthe fact that infused plasmin will readily be in-activated by plasma inhibitors. Were doses ofplasmin infused which were adequate to resistcomplete inhibition, then a state of excessiveplasma proteolysis would ensue with resultantrevere coagulation defects. Sherry and Fletcher(I960) have expressed the view that the thera-peutic use of the enzyme plasmin is unlikely toprove effective in man. Other proteolytic enzymessuch as trypsin are likewise rendered biochemicallyinactive by plasma inhibitors unless administeredin such excess that a himorrhagic state is liableto result.The alternative approach, and the one which
holds much more therapeutic promise, dependson the control of the plasminogen activator levelof the plasma. Although not ideal, because of itsantigenic properties, streptokinase is the onlyactivator at present available which is capable ofraising the thrombolytic activity of the plasma andwhich can be produced in a sufficiently pure andnon-pyrogenic form to be used in man. Dependingupon previous streptococcal infections, humanplasma contains variable concentrations of specificstreptokinase antibody which renders strepto-kinase inert. Thus individual dosage requirementsmust obviously vary and it becomes necessarybefore starting treatment to assay the patient'splasma for streptokinase antibody. The dosage
schedule necessary to sustain the required degreeof thrombolytic activity can then be calculated toinclude a priming dose sufficient to neutralize allcirculating antibody. A course of treatment willresult in further immunization which may compli-cate subsequent therapy should such be required.There is thus a need for a non-antigenic plas-minogen activator, and it is hoped that it mayprove possible to develop a preparation of uro-kinase sufficiently pure for therapeutic use.
It is too early to assess the potential value ofthrombolytic therapy in cerebrovascular disease,but it undoubtedly warrants exploration and mayhold promise for the future. Should it prove tobe effective, the same problem of differentiatingbetween infarction and hiemorrhage encounteredin anticoagulant therapy will arise, and its use willprobably be limited to cases in which vascular occlu-sions have been demonstrated angiographically.
Surgical TreatmentReference was made in an earlier section to
studies which showed that cerebral blood flowwas not increased by methods designed to inter-fere with its very limited neurogenic regulation.There is thus no rational basis for surgical pro-cedures such as stellate ganglion block or cervicalsympathectomy in the treatment of cerebrovas-cular disease. Surgical treatment along other lineshas, however, established its place, although pre-cise indications and limitations have yet to bedefined. Apart from its contribution to themanagement of aneurysms and arteriovenous mal-formations, which are beyond our present scopethere are two main situations in which surgerymay be indicated.The first is in internal carotid artery occlusion
where the scope of surgical treatment has beenconsiderably expanded by advances in operativetechnique and the introduction of hypothermia.Edwards, Gordon and Rob (I960) have reviewedtheir experience of the surgical treatment of in-ternal carotid artery occlusion in light of follow-upover periods extending from one month to threeand a half years. Forty patients were included inthe study of whom thirty-two had operations. Ineighteen of these it was found possible to removethe obstruction, whereas in the remaining fourteenpatients blood flow could not be re-established.Nearly all of those in whom the operation wastechnically successful had partial as opposed tocomplete occlusions, and the latter are consideredto be operable only if the occlusion is very recentand as yet unorganized clot can be removed bygentle suction. This report has the great meritof discussing operative detail and the authorsprovisionally express the view that in carotidsurgery the best results follow a direct end-to-end
anastomosis, although this operation is seldomtechnically possible. Otherwise they have prefer-ence for thromboendarterectomy, finding thisprocedure generally more satisfactory than arterialtransplant or venous graft.
This study thus sheds considerable light uponthe surgical aspects of restoring blood flow in thecarotid arteries and on the selection of patientsin whom surgical treatment is most likely to betechnically successful. However, what has yet tobe established is the precise influence of suchsuccessful operative treatment on the course ofthe disease. The subsequent follow-up of thetotal series of forty patients, after a maximuminterval of three and a half years, showed thatnine had died, the condition of twenty had notsignificantly altered and that of the remainingeleven was thought to have improved. Unfortu-nately we do not possess sufficient knowledge ofthe natural history of the disease to judge fromthese figures what has been the exact influence ofthe surgical treatment. The authors expressed theview that the patients most likely to benefit fromsurgery were those in whom partial obstructionof the artery was manifest by ' stuttering ' onsetof symptoms, i.e. patients with transient ischaemicattacks before the development of severe andpermanent neurological disability. They felt thatthe operation should be regarded as primarilyprophylactic to prevent transient symptoms frombecoming permanent and already permanentsymptoms from becoming worse.An aggressive surgical approach to extracranial
arterial occlusive lesions is recommended byCrawford, De Bakey, Fields, Cooley, and Morris(1959). They report highly successful results ofreconstructive surgery not only in internal carotidartery disease but also in occlusions of vertebralarteries and great vessels arising from the aorticarch. Although the selection of their patients hasbeen different Riishede, Ottosen and S0ndergaard(I960) are much more cautious in the interpreta-tion of their results of surgical treatment ininternal carotid occlusion.The other situation in which surgery may be
indicated is in the treatment of patients withprimary intracerebral hemorrhage. McKissock,Richardson and Walsh (I959) have reported theresults of surgical treatment in a consecutive seriesof 244 such patients. Hmematoma was evacuatedby burr-hole aspiration or by craniotomy and insome patients both procedures were undertaken.The operative mortality was 5i% and the overallmortality, after an average follow-up period of twoyears, was 74%. It was found that the mortalitywas influenced by the site rather than the size ofthe lesion, capsular hlemorrhages carrying the
July I961 SHAW: The Diagnosis and Treatment of Cerebrovascular Disease 421
worst prognosis. The existence of hypertensionadversely affected the prognosis and the greaterthe impairment of consciousness at the time ofoperation, the higher was the mortality. Againwe have no satisfactory data on untreated patientsagainst which these results can be measured and,as the authors emphasize, a controlled trial willbe necessary before a proper assessment of the
value of this form of therapy can be made.These then are some of the advances in diag-
nosis and treatment that have been made in recentyears. Their contribution to the alleviation ofsuffering occasioned by cerebrovascular disease issmall, but they do reflect a very considerablegrowth in knowledge from which it can be hopedthat greater benefits will derive.
REFERENCESADAMS, G. F. (I960): Progress in the Management of Cerebral Vascular Disorders, Brit. J. clin. Pract., 14, 36I.ADAMS, R. D. (1958): Recent Developments in Cerebrovascular Diseases, Brit. med. J7., i, 785.ADVISORY COUNCIL FOR THE NATIONAL INSTITUTE OF NEUROLOGICAL DISEASES AND BLINDNESS, PUBLIC HEALTH SERVICE:
Report by ad hoc Committee (1958) : A Classification and Outline of Cerebrovascular Diseases, Neurology (Min-neap.), 8, No. 5.
ALKJAERSIG, N., FLETCHER, A. P., and SHERRY, S. (1959): The Mechanism of Clot Dissolution by Plasmin, J. clin.Invest., 38, io86.
ALPERS, B. J., BERRY, R. G., and PADDISON, R. M. (959) : Anatomical Studies of the Circle of Willis in Normal Brain,A.M.A. Arch. Neurol., Psychiat., 8I, 409.
ARING, C. D., and MERRITT, H. H. (1935) : Differential Diagnosis between Cerebral Hiemorrhage and CerebralThrombosis, Arch. intern. Med., 56, 435.
BAKER, H. L. (I96o): A New Approach to Percutaneous Subclavian Angiography, Proc. Mayo Clin., 35, I69.BARRON, K. D., and FERGUSSON, G. (1959) : Intracranial Hemorrhage as a Complication of Anticoagulant Therapy,
Neurology (Minneap.), 9, 447.BLACKWOOD, W. (I96I) : Observations on Occlusive Vascular Disease of the Brain. Proceedings of the Fourth Inter-
national Congress of Neuropathology, Munich. To be published.BULL, J. W. D. (1958): Radiological Investigation in Cases of Cerebrovascular Disease, Brit. med. J7., i, 795.
, MARSHALL, J., and SHAW, D. A. (I96o) : Cerebral Angiography in the Diagnosis of the Acute Stroke, Lancet, i,56z.
BYROM, F. B. (I954): The Pathogenesis of Hypertensive Encephalopathy and its Relation to the Malignant Phase ofHypertension: Experimental Evidence from the Hypertensive Rat, Lancet, ii, 20I.
CARTER, A. B. (1957): The Immediate Treatment of Cerebral Embolism, Quart. J. Med., 26, 335.(I959): The Immediate Treatment of Non-embolic Hemiplegic Cerebral Infarction, Ibid., 28, I25.(I96o): Ingravescent Cerebral Infarction, Ibid., 29, 6II.
CLARKE, R. L., and CLIFFTON, E. E. (I960) : The Treatment of Cerebrovascular Thromboses and Embolism withFibrinolytic Agents, Amer. J. Cardiol., 6, 546.
CRAWFORD, E. S., DE BAKEY, M. E., FIELDS, W. S., COOLEY, D. A., and MORRIS, G. C. (1959) : Surgical Treatment ofAtherosclerotic Occlusive Lesions in Patients with Cerebral Arterial Insufficiency, Circulation, 20, I68.
CREVASSE, L. (I 96 I): Carotid Artery Murmurs: Clinical and Pathophysiologic Correlation, Neurology (Minneap.), II, IOo.DALSGAARD-NIELSEN, T. (I956) : Some Clinical Experience in the Treatment of Cerebral Apoplexy (I,ooo Cases),
Acta psychiat. scand. Suppl. Io8, IOI.DENNY-BROWN, D., and MEYER, J. S. (1957): The Cerebral Collateral Circulation: II. Production of Cerebral Infarction
by Ischemic Anoxia and its Reversibility in Early Stages, Neurology (Minneap.), 7, 567.(I960): Recurrent Cerebrovascular Episodes, A.M.A. Arch. Neurol., 2, 194.
DICKINSON, C. J., and THOMSON, A. D. (1959): Vertebral and Internal Carotid Arteries in Relation to Hypertensionand Cerebrovascular Disease, Lancet, ii, 46.
(I960): A Post-mortem Study of the Main Cerebral Arteries with Special Reference to their Possible Rolein Blood Pressure Regulation, Clin. Sci., 19, 513.
DOBRAK, A. H., BECK, A. L., MURPHY, T. J., and ZOLL, J. G. (I96o): Cerebral Angiography in Patients Over Fifty,A.M.A. Arch. Neurol., 3, 582.
DUNNING, H. S. (1953) : Detection of Occlusion of the Internal Carotid Artery by Pharyngeal Palpation, _'. Amer.med. Ass., 152, 321.
EDWARDS, C. H., GORDON, N. S., and ROB, C. (I960)::The Surgical Treatment of Internal Carotid Artery Occlusion,Quart. 5'. Med., 29, 67.
ELKINGTON, J. ST. C. (1958) : Cerebral Vascular Disease in the Light of Modern Techniques, Lancet, ii, 275 and 327.ELLIOTT, F. A., and BUCKELL, M. (I96I) : Fibrinogen Changes in Relation to Cerebrovascular Accidents, Neurology
(Minneap.), II, 120.FISHER, C. M. (1951): Occlusion of the Internal Carotid Artery, A.M.A. Arch. Neurol., Psychiat., 6s, 346.
(1954): Occlusion of the Internal Carotid Arteries: Further Experiences, Ibid., 72, I87.(I958): The Use of Anticoagulants in Cerebral Thrombosis, Neurology, 8, 311.(1959): Observations on the Fundus Oculi in Transient Monocular Blindness, Ibid., 9, 333.(I96I): Anticoagulant Therapy in Cerebral Thrombosis and Cerebral Embolism, Ibid., II, 11 9.
GENSINI, G. G., and ECKER, A. (I960): Percutaneous Aortocerebral Angiography, Radiology, 75, 885.HERNDON, R. M., MEYER, J. S.; JOHNSON, J. F., and LANDERS, J. (I960): Treatment of Cerebrovascular Thrombosis
with Fibrinolysin. Preliminary Report, Amer. 5'. Cardiol., 6, 540.HILL, A. B., MARSHALL, J., and SHAw, D. A. (I960): A Controlled Clinical Trial of Long-term Anticoagulant Therapy
in Cerebrovascular Disease, Quart. 5'. Med., 29, 597.HOWELL, D. A., STRATFORD, J. G., and POSNIKOFF, J. (1956): Prolonged Hypothermia in Treatment of Massive Cere-
HuRwITZ, L. J., GROCH, S. N., WRIGHT, I. S., and McDOWELL, F. H. (1959): Carotid Artery Occlusive Syndrome,A.M.A. Arch. Neurol., I, 491.
HUTCHINSON, E. C., and YATEs, P. 0. (1956): The Cervical Portion of the Vertebral Artery: A Clinico-PathologicalStudy, Brain, 79, 3I9.
(I957): Carotico-Vertebral Stenosis, Lancet, i, 2.KETY, S. S., and SCHMIDT, C. F. (1945): The Determination of Cerebral Blood Flow in Man by the Use of Nitrous
Oxide in Low Concentrations, Amer. _'. Physiol., 143, 53.--- (1948): The Nitrous Oxide Method for the Quantitative Determination of Cerebral Blood Flow in Man:
Theory, Procedure and Normal Values, JX. clin. Invest., 27, 476.KUHN, R. A. (I959): Importance of Accurate Diagnosis by Cerebral Angiography in Cases of Stroke, J'. Amer. med.
Ass., 169, I 867.MCDEvITT, -E., CARTER, S. A., GATJE, B. W., FOLEY, W. T., and WRIGHT, I. S. (I958): Use of Anticoagulants in Treat-
ment of Cerebral Vascular Disease-io-year Experience in Treatment of Thrombo-embolism, Ibid., i66, 592.McKISSOCK, W., RICHARDSON, A., and WALSH, L. (I959): Primary Intracerebral Haemorrhage: Results of Surgical
Treatment in 244 Consecutive Cases, Lancet, ii, 683.MARSHALL, J., and SHAW, D. A. (I960): Anticoagulant Therapy in Acute Cerebrovascular Accidents. A Controlled
Trial, Lancet, i, 995.-,and KAESER, A. C. (I96I): Survival after Non-hlemorrhagic Cerebrovascular Accidents. A Prospective Study,Brit. med. 5'. (in the press).
MARTIN, M. J., WHISNANT, J. P., and SAYRE, G. P. (I960): Occlusive Vascular Disease in the Extracranial CerebralCirculation, A.M.A. Arch. Neurol., 3, 530.
MEYER, J. S., and HUNTER, J. (1957): Polarographic Study of Cortical Blood Flow in Man, Y. Neurosurg., 14, 382.--, and WALTZ, A. G. (1959): Effects of Changes in Composition of Plasma on Pial Blood Flow: I-Lipids and
Lipid Fractions, Neurology (Minneap.), 9, 728., SHEEHAN, S., and BAUER, R. B. (I960): An Arteriographic Study of Cerebrovascular Disease in Man. I-Stenosisand Occlusion of the Vertebral-Basilar Arterial System, A.M.A. Arch. Neurol., 2, 27.
MILLIKAN, C. H., SIEKERT, R. G., and WHISNANT, J. P. (1958): Anticoagulant Therapy in Cerebral Vascular Disease-Current Status, Y'. Amer. med. Ass., I66, 587.
I
- (1960)-: Intermittent Carotid and Vertebral-Basilar Insufficiency Associated with Polycythemia,Neurology (Minneap.), IO, i88.
MOOSSY, J. (1959): Development of Cerebral Atherosclerosis in Various Age Groups, Ibid., 9, 569.PEART, W. S., and ROB, C. (I960): Arterial Auscultation, Lancet, ii, 2I9.RIISHEDE, J. (1957): Cerebral Apoplexy: An Arteriographical and Clinical Study of IOO Cases, Acta psychiat. scand.,
32, Suppl. I I8.OTTosEN, P., and S0NDERGAARD, T. (I960): Cerebral Apoplexy: Surgical Treatment of Internal Carotid Occlu-
sion, Dan. med. Bull., 7, I85.ROSEGAY, H. (I956): Limited Value of Carotid Pulse in Diagnosis of Internal Carotid Artery Thrombosis, Neurology
(Minneap.), 6, 143.SCHRAMEL, R., CREECH, 0., LLEWELLYN, R., and CORALES, R. (I96I): Visualization of the Extracranial Cerebral Cir-I culation by Cardio-Angiography, Y. Amer. med. Ass., 175, 804.SEGELOV, J. N. (1956): Safe Angiography, Y. Neurosurg., I3, 567.SHERRY, S., and FLETCHER, A. P. (I96o): Proteolytic Enzymes: A Therapeutic Evaluation, Clin. Pharmacol. Therap.,
I, 202.SIEKERT, R. G., WHISNANT, J. P., and MILLIKAN, C. H. (I96o): Aniemia and Intermittent Focal Cerebral Arterial
Insufficiency, A.M.A. Arch. Neurol., 3, 386.SILVERSTEIN, A. (I959): Occlusive Disease of the Carotid Arteries, Circulation, 20, 4.SMITH, V. H. (I960): Carotid Insufficiency, Trans. ophthal. Soc. U.K., 8o, 253.STARLING, E. H. (I925): The Physiological Factors in Hyperpiesia, Brit. med. Y'., ii, I I63.STEINBERG, I., FINBY, N., and EvANS, J. A. (1959): A Safe and Practical Intravenous Method for Abdominal Aorto-
graphy, Peripheral Arteriography and Cerebral Angiography, Amer. 5'. Roentgenol., 82, 758.SUSSMAN, B. J., and FITCH, T. S. P. (1959): Thrombolysis with Fibrinolysin in Cerebral Arterial Occlusion; The Role
of Angiography, Angiology, 1O, No. 4, part 2, 268.SWANK, R. L. (I959): Blood Viscosity in Cerebrovascular Disease. Effects of Low Fat Diet and Heparin, Neurology
(Minneap.), 9, 553.SYMONDS, C. P. (1957): Occlusion of the Internal Carotid Arteries in 'Modern Trends in Neurology', ed. D. Williams.
London: Butterworth.VANDER EECKEN, H. M., and ADAMS, R. D. (1953): The Anatomy and Functional Significance of the Meningeal Arterial
Anastomoses of the Human Brain, 5'. Neuropath. exp. Neurol., 12, 132.VI,ALLET, P., SENDRA, L., CHEVROT, L., COMBE, P., DESCUNS, P., and AUBRY, P. (1956): Nouvelle m6thode d'angio-
graphie cer6brale simultanee totale par injection intraveineuse rapide, Acta Radiol. (Stockh.), 46, 273.WELLS, C. E. (I959): Cerebral Embolism, A.M.A. Arch. Neurol., Psychiat., 8i, 667.
(I960): The Cerebral Circulation. The Clinical Significance of Current Concepts, A.M.A. Arch. Neurol., 3, 3I9.(I96I): Discussion of 'The Electroencephalogram in Cerebrovascular Diseases', Neurology (Minneap.), II, I 12.
WILLIAMS, D. (I96 I): The Syndromes of Basilar Insufficiency in 'Scientific Aspects of Neurology', ed. H. Garland.Edinburgh and London: E. and S. Livingstone.
WOOD, F. A., and TOOLE, J. F. (1957): Carotid Artery Occlusion and its Diagnosis by Ophthalmodynamometry,5. Amer. med. Ass., I65, 1264.
ZERBI-ORTIZ, A., and WELDON, W. V. (I96I): Aortography by Catheterization of the Right Atrium. A Safe and ReliableMethod, New Engl. 5'. Med., 264, 19.
