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Objective evaluation of therapy in transitory cerebral ischemia
American
Journal September, 1964, Volume 68, Number 3
Editorial
Objective evaluation therapy in transitory
of cerebral
ischemia
Joseph F. Fazekas, M.D.* Washington, D. C. Ralph W. Alman, M.D. Cambridge, Mass.
I
n any dynamic area of scientific endeavor, it becomes necessary occasionally to assess critically the bases for current concepts. Such an attitude is particularly justifiable in regard to the present-day management of recurrent episodes of cerebral ischemia in patients with cerebral vascular disease, since there is so little universal agreement concerning the “natural history” of this disorder. Past experience indicates that untreated patients with transitory attacks of ischemia not infrequently may experience such episodes repeatedly over a prolonged interval without incurring demonstrable damage to cerebral tissue. nlany such patients seem to recover completely ultimately, although, even in these cases, the long-term prognosis is unknown. In other patients, minor neurological residua may eventually appear, and in still others, frank and massive cerebral infarction may occur. A number of patients may exhibit inexorable, diffuse cerebral deterioration, the progression of which appears to be independent of the frequency of the transitory episodes of ischemia. From
In spite of the difficulties that a spontaneously variable course introduces in the evaluation of treatment of any disorder, in recent years several physiologically unrelated therapeutic modalities (anticoagulants, vasodilator agents, endarterectomy) have been advocated for the management of transitory episodes of cerebral ischemia. Examination of reported successes, however, reveals a peculiar statistical similarity which raises the suspicion that certain uncredited salutary factors may influence these results. Indeed, only three conclusions can be drawn from this phenomenon: (1) that any of the available therapeutic modalities, however different, may equally well arrest. or compensate for, or otherwise improve, the course of the same disease; (2) that all active therapeutic efforts are completely ineffective and that reported clinical’successes have been incidental and spontaneous; and (3) that each of the suggested methods of management owes its proportion of successes to the existence of certain patients particularly responsive to that modality. Although this last possibility
the Department of iXeurology and Neurological Surgery, Washington. D. C. Received for publication March 18. 1964. *Address: 2025 Eye Street, N. W.. Washington, D. C., 20006.
291
George
Washington
I’niversity
School
of Medirine.
202
I’uzrkas und Almun
carries with it the implication of an even distribution of responsive patients, in spite of the need to assume this coincidence, it would seem to provide the best hope of therapeutic selection of the specific modality best suited for the individual patient. Such an approach, however, requires a standardized method of evaluation of the anatomic and physiologic abnormalities responsible for transitory attacks of cerebral ischemia. At the present time, in spite of the wide interest in the investigation and management of cerebral vascular disease, there is surprisingly little uniformit> in the assemblage of basic information so necessary for the interpretation of results. Although various facets of cerebral circulatory dynamics are well within the reach of present investigative techniques, it is disappointing that, too often, the latter are not employed. Although it is obvious that the surgical approach (endarterectomy) to the treatment of transitory attacks of cerebral ischemia requires angiographic study of the aortocranial vessels, it is less widely appreciated that cerebral panangiography may be of value in the selection and evaluation of medical modalities. It must be admitted that the shortcomings of radiographic studies of the cerebral vascular tree are manifold. The physiologic significance of demonstrable lesions may be most difficult to assess, since the). may be compensated by homeostatic mechanisms to a degree not subject to estimation bl s-ray examination. Moreover, even an impressive stenotic or occlusive lesion of aortocranial vessels may be unrelated to the cerebral ischemic disorder, which may actually depend upon the presence of an apparently minor or even undemonstrated intracranial vascular lesion. I II man? cases, angiography yields no reliable information in regarcl to the distribution of the intracranial blood flow, nor does it provide quantitative data in regard to the hemodynamic effectiveness of the circle of Willis or whatever collateral sources of blood supply may or may not be demonstrated. This and similar unresolved problems may eventual]Jr prove that the deficiencies of cerebral angiography, particularly as applicable to evaluation of the medical management of cere-
bral vascular disease, are due to inadequate correlation of radiographic findings with clinical observations, and their resolution nia?; well require tnore widespread use oi the technique. For example, the inability. to predict, with satisfactory confidence, the relative effectiveness of any medical therapeutic modality may be remedied in some degree by studies comparing the responses of patients who have multiple aortocranial lesions with those of patients who have single lesions and,‘or intracranial lesions. Such vital information can be obtained only through panangiography. 1111fortunately, none of the data so far submitted concerning the alleged efficac>- of anticoagulants and vasodilator agents in cerebral vascular disease has been a~companied by sufficient panangiographic visualization to permit study of any possible relationship between type of vascular abnormality and therapeutic success or failure. Furthermore, there is virtual11 no information available in regard to angiographic follow-up studies in such medically managed cases. Inasmuch as transitory episodes of cerebral ischemia are attributed to localized reduction of cerebral blood supply, it should not be surprising that over-all quantitative measurements commonly are found to show no significant reduction from normal values. 111fact, it has been our observation that, where such a reduction is demonstrated, diffuse cerebral dysfunction is usually present, and the transitor;. episodes of ischemia represent a tomplication rather than the major problem. Moreover, the value of estimatiotl of total cerebral blood flow alone ma\’ further be called into question by the observation that cerebral blood flow can often be markedly reduced, as by controlled hypotension, in patients subject to transitory episodes of cerebral ischemia, without provoking such attacks. It is probable that in many of these itlstances, compensation is accomplished by vasodilatation which occurs regionally or in collaterals which supply the marginally o~ygenated area, thereby protecting it from further ischemia in spite of the relatively brief experimental reduction in blood pressure. It would appear, therefore, that information concerning the reactivity of
Evaluation
of therapy in transitory
the cerebral vascular tree is often more pertinent in the evaluation of presently utilized therapeutic modalities than is quantitative estimation of total cerebral blood flow. It has been observed that the cerebral vasodilator response to inhalation of 5 to 7 per cent carbon dioside is not so predictably uniform in patients with cerebral vascular disease as it is in the normal population. Although some of the former patients show the same range of increase in cerebral blood flow as do normal subjects, others show a less than normal response, and in a significant number the inhalation of carbon dioxide is apparently without effect. Since even the latter patients demonstrate an increase in cerebral vascular resistance with hyperventilation, it may be concluded that the refractoriness to cerebral vasodilatation on inhalation of carbon dioxide is better attributable to pre-existing maximal dilatation of these vessels than to their pathologic rigidity. Carbon-dioxide challenge to the reactivity of the cerebral vessels is a relatively simple and safe procedure and may permit an important correlation between the responsiveness of these vessels and the results of any therapeutic approach, medical or surgical. For example, studies have indicated that patients with multiple degenerative lesions of the aortocranial vessels may, nevertheless, be capable of significantly increasing cerebral oxygen delivery during the inhalation of carbon dioxide, and one may question the need for or value of the surgical approach in these cases. Such doubts cannot be resolved, however, until the clinical results have been compared with those in similarly managed patients who appear to have exhausted the dilating capacity ‘of their cerebral vessels, Inasmuch as, in our experience, the acute administration of “general” vasodilators has been singularly ineffective in increasing cerebral blood flow (because of the concomitant reduction in blood pressure), it might be suggested that these agents may even be detrimental in patients whose cerebral vessels are already maximally dilated. Nevertheless, it would seem important to determine objectively whether there may be a difference in the
cerebral ischemia
293
clinical or quantitative effectiveness of “general” vasodilators between patients who do not respond to the inhalation of carbon dioxide and those whose cerebral vessels have retained significant reactivity. It is not unreasonable to suppose that those patients who show no response to the inhalation of carbon dioxide may be more vulnerable than others to frequently repeated attacks of cerebral ischemia and even infarction (although this point, too, is worthy of investigation). If such is indeed the case, this propensity may facilitate more definitive evaluation than is presently available concerning the role of anticoagulants in the management of the disorder. No doubt, other modalities for collection of standardized data concerning the status of the cerebral circulation may be included in a format for evaluation of therapy in recurrent attacks of cerebral ischemia. One may mention ophthalmodynamometry, carotid compression tolerance, hypoxic, hypoglycemic, or hypotensive challenge of cerebral circulatory sufficiency, and techniques such as rheoencephalography, thermography, and isotope studies, which may provide information concerning regional changes in cerebral blood flow. Unfortunately, these are not yet so well understood that interpretation of the results is likely to add materially to evaluation of treatment at the present time. Indeed, the broad view of the problem of evaluation of therapeutic modalities revolves upon uncertainty as to the value of investigative techniques in cerebral vascular insufficiency. Currently, we are faced with this impasse : There is reluctance to employ investigative techniques, the results of which are of uncertain significance, and the significance of such results cannot be determined until the techniques are more widely used and until there is better correlation with anatomic, physiologic, and clinical observations. Obviously, the SOlution of this paradox lies in the continued undertaking of comprehensive studies, rather than enthusiasm based upon narrow investigative approaches. In summary, the similarity of successful results reported by advocates of unrelated therapeutic modalities in the management
294
Fazekas and Alman
of transitory episodes of cerebral ischemia warrants reservations in regard to these claims. There is a pressing need for a standardized method of evaluating the anatomic and physiologic abnormalities in cerebral vascular disease, so that the results of treatment can be interpreted against the background of spontaneous variability and compared on a truly objective basis. Cerebral panangiography, with all its shortcomings, is a necessary preliminary to assessment of the efficacy of agents advocated for medical management of cerebral vascular insufficiency, as well as of surgical treatment, and should be repeated for follow-up evaluation. Quantitative estimation of total cerebral blood flow yields results of dubious significance, unless abnormally low; knowledge of the reactivity of the cerebral vasculature is probably more important in the case of transitory episodes of cerebral ischemia. This can best be studied by measuring the response of the cerebral vascular resistance
Am Heart 1. Sc~tcmbcv. 1964
to the inhalation of 5 to 7 per cent carboll dioxide. At the present time, the most reasonable explanation for refractoriness to this agent is pre-existing masimal dilatation of the cerebral vessels. Patients whose cerebral hemodynamics are distinguished by this characteristic may well possess a peculiar vulnerability to frequent transitory episodes of ischemia or even cerebral infarction and may respond to a different degree or even in a different manner to therapeutic modalities than do patients who have a normal cerebral vascular reaction to carbon dioxide. In the list of standardized data needed for evaluation of therapy of cerebral vascular insufficiency there is room also for other types of challenge of cerebral hemodynamics and for methods of measuring regional cerebral blood flow. The relative importance of contribution of those investigative modalities now available remains to be determined, but must be determined for rational evaluation of management.
Journal September, 1964, Volume 68, Number 3
Editorial
Objective evaluation therapy in transitory
of cerebral
ischemia
Joseph F. Fazekas, M.D.* Washington, D. C. Ralph W. Alman, M.D. Cambridge, Mass.
I
n any dynamic area of scientific endeavor, it becomes necessary occasionally to assess critically the bases for current concepts. Such an attitude is particularly justifiable in regard to the present-day management of recurrent episodes of cerebral ischemia in patients with cerebral vascular disease, since there is so little universal agreement concerning the “natural history” of this disorder. Past experience indicates that untreated patients with transitory attacks of ischemia not infrequently may experience such episodes repeatedly over a prolonged interval without incurring demonstrable damage to cerebral tissue. nlany such patients seem to recover completely ultimately, although, even in these cases, the long-term prognosis is unknown. In other patients, minor neurological residua may eventually appear, and in still others, frank and massive cerebral infarction may occur. A number of patients may exhibit inexorable, diffuse cerebral deterioration, the progression of which appears to be independent of the frequency of the transitory episodes of ischemia. From
In spite of the difficulties that a spontaneously variable course introduces in the evaluation of treatment of any disorder, in recent years several physiologically unrelated therapeutic modalities (anticoagulants, vasodilator agents, endarterectomy) have been advocated for the management of transitory episodes of cerebral ischemia. Examination of reported successes, however, reveals a peculiar statistical similarity which raises the suspicion that certain uncredited salutary factors may influence these results. Indeed, only three conclusions can be drawn from this phenomenon: (1) that any of the available therapeutic modalities, however different, may equally well arrest. or compensate for, or otherwise improve, the course of the same disease; (2) that all active therapeutic efforts are completely ineffective and that reported clinical’successes have been incidental and spontaneous; and (3) that each of the suggested methods of management owes its proportion of successes to the existence of certain patients particularly responsive to that modality. Although this last possibility
the Department of iXeurology and Neurological Surgery, Washington. D. C. Received for publication March 18. 1964. *Address: 2025 Eye Street, N. W.. Washington, D. C., 20006.
291
George
Washington
I’niversity
School
of Medirine.
202
I’uzrkas und Almun
carries with it the implication of an even distribution of responsive patients, in spite of the need to assume this coincidence, it would seem to provide the best hope of therapeutic selection of the specific modality best suited for the individual patient. Such an approach, however, requires a standardized method of evaluation of the anatomic and physiologic abnormalities responsible for transitory attacks of cerebral ischemia. At the present time, in spite of the wide interest in the investigation and management of cerebral vascular disease, there is surprisingly little uniformit> in the assemblage of basic information so necessary for the interpretation of results. Although various facets of cerebral circulatory dynamics are well within the reach of present investigative techniques, it is disappointing that, too often, the latter are not employed. Although it is obvious that the surgical approach (endarterectomy) to the treatment of transitory attacks of cerebral ischemia requires angiographic study of the aortocranial vessels, it is less widely appreciated that cerebral panangiography may be of value in the selection and evaluation of medical modalities. It must be admitted that the shortcomings of radiographic studies of the cerebral vascular tree are manifold. The physiologic significance of demonstrable lesions may be most difficult to assess, since the). may be compensated by homeostatic mechanisms to a degree not subject to estimation bl s-ray examination. Moreover, even an impressive stenotic or occlusive lesion of aortocranial vessels may be unrelated to the cerebral ischemic disorder, which may actually depend upon the presence of an apparently minor or even undemonstrated intracranial vascular lesion. I II man? cases, angiography yields no reliable information in regarcl to the distribution of the intracranial blood flow, nor does it provide quantitative data in regard to the hemodynamic effectiveness of the circle of Willis or whatever collateral sources of blood supply may or may not be demonstrated. This and similar unresolved problems may eventual]Jr prove that the deficiencies of cerebral angiography, particularly as applicable to evaluation of the medical management of cere-
bral vascular disease, are due to inadequate correlation of radiographic findings with clinical observations, and their resolution nia?; well require tnore widespread use oi the technique. For example, the inability. to predict, with satisfactory confidence, the relative effectiveness of any medical therapeutic modality may be remedied in some degree by studies comparing the responses of patients who have multiple aortocranial lesions with those of patients who have single lesions and,‘or intracranial lesions. Such vital information can be obtained only through panangiography. 1111fortunately, none of the data so far submitted concerning the alleged efficac>- of anticoagulants and vasodilator agents in cerebral vascular disease has been a~companied by sufficient panangiographic visualization to permit study of any possible relationship between type of vascular abnormality and therapeutic success or failure. Furthermore, there is virtual11 no information available in regard to angiographic follow-up studies in such medically managed cases. Inasmuch as transitory episodes of cerebral ischemia are attributed to localized reduction of cerebral blood supply, it should not be surprising that over-all quantitative measurements commonly are found to show no significant reduction from normal values. 111fact, it has been our observation that, where such a reduction is demonstrated, diffuse cerebral dysfunction is usually present, and the transitor;. episodes of ischemia represent a tomplication rather than the major problem. Moreover, the value of estimatiotl of total cerebral blood flow alone ma\’ further be called into question by the observation that cerebral blood flow can often be markedly reduced, as by controlled hypotension, in patients subject to transitory episodes of cerebral ischemia, without provoking such attacks. It is probable that in many of these itlstances, compensation is accomplished by vasodilatation which occurs regionally or in collaterals which supply the marginally o~ygenated area, thereby protecting it from further ischemia in spite of the relatively brief experimental reduction in blood pressure. It would appear, therefore, that information concerning the reactivity of
Evaluation
of therapy in transitory
the cerebral vascular tree is often more pertinent in the evaluation of presently utilized therapeutic modalities than is quantitative estimation of total cerebral blood flow. It has been observed that the cerebral vasodilator response to inhalation of 5 to 7 per cent carbon dioside is not so predictably uniform in patients with cerebral vascular disease as it is in the normal population. Although some of the former patients show the same range of increase in cerebral blood flow as do normal subjects, others show a less than normal response, and in a significant number the inhalation of carbon dioxide is apparently without effect. Since even the latter patients demonstrate an increase in cerebral vascular resistance with hyperventilation, it may be concluded that the refractoriness to cerebral vasodilatation on inhalation of carbon dioxide is better attributable to pre-existing maximal dilatation of these vessels than to their pathologic rigidity. Carbon-dioxide challenge to the reactivity of the cerebral vessels is a relatively simple and safe procedure and may permit an important correlation between the responsiveness of these vessels and the results of any therapeutic approach, medical or surgical. For example, studies have indicated that patients with multiple degenerative lesions of the aortocranial vessels may, nevertheless, be capable of significantly increasing cerebral oxygen delivery during the inhalation of carbon dioxide, and one may question the need for or value of the surgical approach in these cases. Such doubts cannot be resolved, however, until the clinical results have been compared with those in similarly managed patients who appear to have exhausted the dilating capacity ‘of their cerebral vessels, Inasmuch as, in our experience, the acute administration of “general” vasodilators has been singularly ineffective in increasing cerebral blood flow (because of the concomitant reduction in blood pressure), it might be suggested that these agents may even be detrimental in patients whose cerebral vessels are already maximally dilated. Nevertheless, it would seem important to determine objectively whether there may be a difference in the
cerebral ischemia
293
clinical or quantitative effectiveness of “general” vasodilators between patients who do not respond to the inhalation of carbon dioxide and those whose cerebral vessels have retained significant reactivity. It is not unreasonable to suppose that those patients who show no response to the inhalation of carbon dioxide may be more vulnerable than others to frequently repeated attacks of cerebral ischemia and even infarction (although this point, too, is worthy of investigation). If such is indeed the case, this propensity may facilitate more definitive evaluation than is presently available concerning the role of anticoagulants in the management of the disorder. No doubt, other modalities for collection of standardized data concerning the status of the cerebral circulation may be included in a format for evaluation of therapy in recurrent attacks of cerebral ischemia. One may mention ophthalmodynamometry, carotid compression tolerance, hypoxic, hypoglycemic, or hypotensive challenge of cerebral circulatory sufficiency, and techniques such as rheoencephalography, thermography, and isotope studies, which may provide information concerning regional changes in cerebral blood flow. Unfortunately, these are not yet so well understood that interpretation of the results is likely to add materially to evaluation of treatment at the present time. Indeed, the broad view of the problem of evaluation of therapeutic modalities revolves upon uncertainty as to the value of investigative techniques in cerebral vascular insufficiency. Currently, we are faced with this impasse : There is reluctance to employ investigative techniques, the results of which are of uncertain significance, and the significance of such results cannot be determined until the techniques are more widely used and until there is better correlation with anatomic, physiologic, and clinical observations. Obviously, the SOlution of this paradox lies in the continued undertaking of comprehensive studies, rather than enthusiasm based upon narrow investigative approaches. In summary, the similarity of successful results reported by advocates of unrelated therapeutic modalities in the management
294
Fazekas and Alman
of transitory episodes of cerebral ischemia warrants reservations in regard to these claims. There is a pressing need for a standardized method of evaluating the anatomic and physiologic abnormalities in cerebral vascular disease, so that the results of treatment can be interpreted against the background of spontaneous variability and compared on a truly objective basis. Cerebral panangiography, with all its shortcomings, is a necessary preliminary to assessment of the efficacy of agents advocated for medical management of cerebral vascular insufficiency, as well as of surgical treatment, and should be repeated for follow-up evaluation. Quantitative estimation of total cerebral blood flow yields results of dubious significance, unless abnormally low; knowledge of the reactivity of the cerebral vasculature is probably more important in the case of transitory episodes of cerebral ischemia. This can best be studied by measuring the response of the cerebral vascular resistance
Am Heart 1. Sc~tcmbcv. 1964
to the inhalation of 5 to 7 per cent carboll dioxide. At the present time, the most reasonable explanation for refractoriness to this agent is pre-existing masimal dilatation of the cerebral vessels. Patients whose cerebral hemodynamics are distinguished by this characteristic may well possess a peculiar vulnerability to frequent transitory episodes of ischemia or even cerebral infarction and may respond to a different degree or even in a different manner to therapeutic modalities than do patients who have a normal cerebral vascular reaction to carbon dioxide. In the list of standardized data needed for evaluation of therapy of cerebral vascular insufficiency there is room also for other types of challenge of cerebral hemodynamics and for methods of measuring regional cerebral blood flow. The relative importance of contribution of those investigative modalities now available remains to be determined, but must be determined for rational evaluation of management.