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(Stroke. 1997;28:1835-1839.)
© 1997 American Heart Association, Inc.

Articles

Some Clinical Aspects of Acute Stroke

Excellence in Clinical Stroke Award Lecture

J.P. Mohr

From the Neurological Institute, Columbia-Presbyterian Medical Center, New York, NY.

Correspondence to J.P. Mohr, MD, Stroke Unit Neurological Institute, Columbia-Presbyterian Medical Center, 710 W 168th St, New York, NY 10032-2603. E-mail jpm10{at}columbia.edu

	Introduction

Top Introduction TIA and Stroke Time From Known Occlusion... Factors Affecting Outcome Implications for Trials References

 
None of us in current neurology regret the passage of the "diagnose and adios" era humorously criticized years ago by Dr Labe Scheinberg in a grand rounds talk. Rapid innovations in imaging, the rush to ever more clinical trials, and the shortening time frame for action are turning many of us into happy interventionists, rivaling colleagues in cardiology and emergency medicine.

The very pace of events is quickly rendering obsolete the more leisurely approach to the analysis of the meaning of symptoms and signs. The practical needs dictated by hyperacute therapy threaten to change our field so thoroughly as to eclipse the once intensely debated clinical issues of how the brain responds to injury, for which stroke has always been the leading model. Proposals for four areas referable to clinical stroke research are offered, including those for clinical trials.

	TIA and Stroke

Top Introduction TIA and Stroke Time From Known Occlusion... Factors Affecting Outcome Implications for Trials References

 
The first proposal is that we adopt a "1-hour rule" for diagnosing stroke. Approaching the end of the 20th century, clinical trialists are still hobbled by the now-outmoded 24-hour rule. This, a working definition, not one handed down by the Great Neurologist, was created in the trials in the 1950s by default: beyond 24 hours, there was general agreement that the syndrome was a stroke; less than that, it was uncertain.¹ Proposals for a 1-hour definition were made soon after but with little success, lacking modern imaging.² Transient ischemic attacks (TIAs) in a setting of high-grade carotid stenosis typically last minutes,³ which argues for a dichotomy between TIA and stroke for time frames far less than 24 hours. Changes in brain structure by CT and MR can be present within a few hours,^{4 5} and some can be seen within minutes with diffusion-weighted MR (DWI).⁶

Few studies have actually attempted prospectively to relate the initial clinical status to that at 24 hours or later. Most of them have been from small data sets for patients within a week,⁷ 24 hours,⁸ and 12 hours after syndrome onset,⁹ among them two efforts in which the author was a participant. Raw data from the nimodipine study of acute stroke¹⁰ showed 25 patients of the total cohort of 1064 treated within 6 hours of syndrome onset. By day 4 (the time of uniform repeat standard examination dictated by the protocol), only 2 patients had returned to an essentially normal score (Toronto <5 and Mathew >95). Even lower rates of normal scores were seen for those entering the study 6 to 12 hours or more after syndrome onset. In the MR versus CT comparison study sponsored by the National Institute of Neurological Disorders and Stroke,⁴ 68 of 75 case patients without hemorrhage were enrolled within 4 hours. No clear correlation was found between the initial NIH or Motor Strength Scale score and positive CT or MR scan. Of the patients without hemorrhage, 26 returned to normal by 24 hours (NIH score <1). The initial CT scan had been positive in 5, and the MR scan had been positive in 10 patients, indicating that a "reversible ischemic neurological deficit" can be associated with a positive scan and diagnosed as a stroke. At 24 hours, differences in frequency of positive and negative 24-hour scan findings by Stroke Scale outcome were significant for both CT (²=10.01, P<.01) and MR (²=8.47, P<.01): the worse the clinical scale score, the more likely a positive image. The NIH tissue plasminogen activator study enrolled subjects within 3 hours of symptom onset as well. The 24-hour outcome for the placebo group was not detailed for readers in such a way as to enable them to assess the percentage of the cohort in whom neurological findings on enrollment could have been considered transient.¹¹

Drastic revision downward for the 24-hour definition for TIA thus seems well justified. Exceptions occur, but there is a need for timely intervention, and for the small percentage of patients whose symptoms resolve and who appear normal after being seen within the first hour after symptom onset, the proof that a stroke has occurred can be settled afterward. A 1-hour dividing line is proposed: syndromes lasting more than 1 hour can be considered a stroke, those lasting shorter periods can be diagnosed as a TIA.

	Time From Known Occlusion to Syndrome

Top Introduction TIA and Stroke Time From Known Occlusion... Factors Affecting Outcome Implications for Trials References

 
We badly need better information on the evolution of infarction in humans: its timetable, expected topography by given vascular territory, and what explains any exceptions. Lacking imaging data, early neurologists had no way to know how the time of clinical stroke onset related to that of the occlusion. Embolism is considered the classic model of simultaneity of occlusion and stroke syndrome onset. Yet even in this setting, some cases have a nonsudden onset.¹² Admittedly rare, instances are reported of occlusion occurring during an angiogram with no immediate onset of a stroke syndrome, such onset being delayed by minutes or hours (1.8% of 1002 cases in one report).¹³ One of our patients years ago had balloon occlusion of the length of the middle cerebral artery stem for more than 100 minutes during a complicated Silastic pellet embolization procedure before becoming symptomatic, promptly remitting on balloon deflation.¹⁴

How to predict the outcome of an occlusion is of no small concern to interventionists. Many of the variables involved are well known, such as the patency and size of collaterals via the circle of Willis and the hemisphere border zones. Less well understood is some variability in the syndrome triggered by a given infarct and vice versa (see below).

Opportunities are arising for more definitive study. Quantitative behavioral techniques have proved to be sensitive heralds for those destined to develop focal signs.¹⁵ The behavioral change provides at least a safe and reversible marker of the first effects of ischemia. Some attempt can be made to gather time-to-effect data for individual branches of the major cerebral arteries in humans. It can be hoped that a correlation eventually can be made with the more satisfying quantitation of the course of ischemia in the animal model,¹⁶ as is already indicated for the ischemic penumbra in studies of humans.¹⁷ If the time-to-stroke effects are patient specific and idiosyncratic, methods will have to be developed to account for the range of expected findings as they apply to clinical trials.

	Factors Affecting Outcome

Top Introduction TIA and Stroke Time From Known Occlusion... Factors Affecting Outcome Implications for Trials References

 
Even if we succeed in establishing the time course and topographic spread of the infarct process, factors influencing the clinical outcome need to be defined better, not least among them variations in the clinical effect of the lesion on the stroke syndrome.

As indicated in the Table, some variables influencing outcome are already well known. The effect of injury size seems obvious. For the syndromes of aphasia, size appears to be a governing factor, with the smaller lesions being followed by rapid devolution of the syndrome and the larger ones being far more persistent and subject to less change,^{18 19 20} suggesting that whatever "compensatory" mechanisms are present lie in adjacent regions (see below). At the other extreme, location far exceeds size as a factor: one example is in anterior choroidal artery territory infarction in which a small, deep infarct damages much of the motor pathway, compacted into a very small space.²¹ Exclusion of these cases from clinical trials is worth considering because the motor deficit is far more severe than that expected from volumetric studies,²² skewing calculations of tissue-saving effects. Another example is the striking disturbances in cerebral blood flow—and gross derangement of behavior—from small, deep infarcts in the genu of the capsule, which interrupt thalamocortical projections, causing so-called strategic infarct dementia²³ or aphasia and neglect.²⁴ How many and how wide is the range of effects of lesions in the neurotransmitter pathways is yet unknown, but these cases also play havoc with estimates of correlations of lesion volume with syndrome severity.

View this table: [in this window] [in a new window]   Table 1. Factors Affecting Outcome

These and other observations should shake the confidence of clinicians in an easy correlation between syndrome severity and lesion volume save in the most gross sense. Some studies (but with small sample size) have shown no correlation at all.²⁵ If the range of variation is wide enough, it could explain some of the frustration in efforts to infer that neuroprotective therapy prevented an infarct from reaching its predestined size. It is a further concern that minor reductions in infarct volume from neuroprotective therapy (sufficient to be demonstrated in modern imaging techniques) could easily escape detection as measured by current clinical scales (see below). Worse, the imaging data could be considered irrelevant if crude scales fail to show a major "functional" effect.

So-called progressing stroke remains something of an enigma.²⁶ Sharply focused epidemiological studies have identified high initial blood sugar, early positive CT scan, and angiographic evidence of carotid siphon stenosis among the risk factors for early worsening.²⁷ Clinicians have accepted edema and metabolic factors as major causes of stroke worsening but have documented them only on occasion.²⁸ Inferred perilesional edema may account for intensification of an initial syndrome, especially in pure motor stroke attributable to small, deep infarction.²⁹ The timetable of worsening parallels that classically settled for edema, and improvement toward or to baseline occurs over a period of days as edema subsides. Worsening motor syndromes from convexity infarction show far less frequent improvement. Although edema subsidence is a relief to physicians, it is a source of concern that so many of these patients appear in neuroprotective clinical trials. Admittedly, they are alert and can give consent and have deficits that are unusually easy to characterize. However, their natural course toward improvement could dilute any treatment effect sought in a trial. It may also be prudent for pure motor stroke to be an exclusion, not an inclusion, for neuroprotective trials.

Rapid improvement in what seemed initially to be a clearly established syndrome gave rise to the hopeful term "reversible ischemic neurological deficit" (RIND).³⁰ Whether it was the syndrome that was reversible or the process of ischemia-infarction has long been a matter of semantics. In some cases, the embolus, in place long enough to precipitate a syndrome, migrates distally, leaving a smaller zone of infarction.^{31 32} Yet it has long been recognized that some patients undergo a striking and rapid improvement toward or to normal despite subsequently proven infarction affecting clinically important structures.³³ How? The mechanisms are unclear; diaschisis, once a popular explanation for initial impairment followed by improvement, has lost ground.³⁴ Whether due to ipsilateral perilesional function of surviving brain or contralateral homologous cerebrum^{35 36} or some other possible mechanisms that may be at work, the existence of these cases could be characterized as compensation³⁷ or functional reorganization.³⁸ It is too early to call it restitution, since it is unknown whether the functions that emerge are those restored from the original, a weaker version of the original, or a new means of accomplishing some of the original function. If some of these changes are mediated by neurotransmitter pathways, therapies might be possible using the model for parkinsonism.

	Implications for Trials

Top Introduction TIA and Stroke Time From Known Occlusion... Factors Affecting Outcome Implications for Trials References

 
The scope of the clinical scales developed for trials needs to be expanded as was done for diagnosis. Like the six blind men feeling the elephant, the varied specialists have brought different points of view to the classification of ischemic stroke. The simplest and earliest dichotomy, that of thrombosis versus embolism, is still valid. However, dissatisfaction with an algorithm that assigned to thrombosis all patients save those with mitral valve disease and atrial fibrillation gave rise to further subdivisions: those more interested in the source of the inferred embolism than in its frequency compared with thrombosis pushed into etiologic issues such as aortic arch atheroma, patent foramen ovale, mitral annulus calcification, and the like; others emphasized the clinical effects of the site and locus of infarction, stressing a dichotomy between small, deep infarcts (lacunes) and those affecting the surface. What we have currently is a multisided matrix of issues that contribute to the currently accepted subtypes of ischemic stroke, to which has been added the extra issue of certain, probable, and possible stroke, which is needed for clinical trials.³⁹ So why not then have a similar multifaceted approach to attempts at quantitative assessment of the clinical syndrome caused by stroke? Never mind that the scores created remain frustratingly nonlinear; some attempt to estimate the effects of stroke is here to stay.

Clinical trials needed some kind of quantitation of the syndrome, given the awareness that death, that easily scored variable, was not a frequent outcome of stroke. Most of the current scales grew out of the traditional neurological examination and have been subjected to numerous comparison studies.^{40 41} Whether or not the specific elements (eg, sensory impairment in the face, arm, and leg) had a lesion-volume, clinicoanatomic correlation was not settled, and some elements were included because of completeness of the traditional neurological exam. Increasing reliance on imaging, a wish to avoid time-consuming and tiresome delays imposed by detailed traditional examination, and a plan to rely on non-neurologists in many centers in acute evaluation are among factors that forced and fully justified the fact that many of the scales were sharply condensed in scope. Thanks in part to these economies, satisfactory reliability testing⁴² has caused them to become more entrenched as time passes. It can only be hoped these efforts are rewarded by acceptance of the applicability of data from trial by bodies such as the Food and Drug Administration.

Reliability and practical success with scales aside, the contents of the scales are worth review from a different angle: what insights they give into pathophysiology. Most clinical trials (at least for neuroprotective agents) focus on patients with middle cerebral artery territory infarction. (The course of basilar disease has proved frustrating to characterize⁴³ ; the anterior and posterior cerebral territories are not frequently the sites of infarction, and their syndromes have fairly circumscribed clinical features.) Emphasis on motor function in middle cerebral artery territory infarction makes clinical sense since it bears on disability and functional outcome, which allows the trialist to focus on these readily measured variables in a manner similar to rating scales popularized for heart disease and cancer. Yet raw motor power tested by strength scales seems to reflect function of only a narrow band of the rolandic region. The long-assumed homuncular correlation of weakness profiles with exact site and extent of convexity rolandic infarction appears to have been an overestimate⁴⁴ ; likewise, the classic homuncular pattern in the internal capsule.²² Arm weakness is the main sign of cerebral infarction.^{45 46} Heavy reliance on the motor weakness profile could be an unsafe guide to neuroprotective effects from a given therapy if the scale is intended to infer tissue sparing from the drug. Disorders of sensation have been notoriously difficult to map reliably to a specific locus, change little in the hyperacute period, and probably need not be represented in a scale. Forced eye deviation is usually a sign of a large lesion, often deep, not superficial.

Perhaps such limitations have made so welcome the likes of the justifiably popular Barthel Index,⁴⁷ on which many trials hinge. This 20-point scale includes feeding, bathing, grooming, dressing, bowel and bladder function separately assessed, capacity to use a toilet, and motor skills (transfer, ambulation, and stairs). These are all worthy points of assessment, surely, but lack any detailed assessment of higher cerebral function, are not well correlated with specific brain lesions, and (assessed as independent, needs help, or dependent) carry little insight into higher cerebral function (including praxis under this term).

That quantitation of disorders of higher cerebral function is said to be difficult and time consuming may explain their underrepresentation in most scales. This deemphasis seems unfortunate. Few would argue that communication skills are unimportant; in many respects, the functions assessed by the Barthel Index and other indices are shared with spinal cord cases, while impairment of higher cerebral function from stroke has a far greater impact on independence and employability of the victim. The classic clinicoanatomic correlations on which they are based are now understood to be less firm than previously thought. How some initial aphasia syndromes resolve quickly while others persist is a fruitful area to explore possible brain plasticity.^{18 19 20} Current investigations with selective local anesthesia testing with microcatheterization of individual middle cerebral artery branches before and after occlusions suggest the nature of the syndrome can change.⁴⁸

Whether higher cerebral functions deserve more emphasis in scales proved an interesting question to test using data from the American nimodipine study of 10 years ago.¹⁰ This study, enrolling 1064 patients from 53 centers, was one of the first of the acute trials. Its 48-hour "window" of recruitment is now unfashionably long. However, this cohort had some useful features, including the separate assessment of each patient by three clinical scales (Toronto, Mathew, and the NIH Stroke Data Bank–based motor scales, which assess, some in similar fashion and others in special ways, functions of the face, shoulder, wrist, hip, and ankle separately). The protocol required a standard examination, which included scales, for each patient at enrollment and at day 4, day 10, and day 21. From these data, it proved possible to select elements to reconstruct a common data source for meta-analysis.⁴⁹ This same source allowed the reconstruction of many of the other scales in popular use, including the Canadian, Frithz-Werner, NIH, Orgogozo, and Scandinavian scales (including the specific features of the motor examination for each scale) and was used to create the data collection system currently in use in the Warfarin-Aspirin Recurrent Stroke Study. The last-value-carried-forward covariant analysis done on the data from the trial had shown a positive result for one dose of nimodipine compared with placebo that satisfied the Bonferroni corrections for multiple testing. Reanalysis of these data,⁵⁰ focusing in turn on one subset after another, showed no differences at all for sensory function over time; too small a range of changes for eye movements to allow this variable to be analyzed alone; changes favoring drug effect in the motor examination over time; and huge changes, sufficient to carry most of the drug effect, when the elements reflecting "higher cerebral function" were combined as a subset. Reviewing the other scales, the drug effect observed proved detectable largely as a function of the degree to which the "higher cerebral functions" were represented in the scoring system: in those scales having virtually no inclusion of this variable, the drug effect was insignificant or small; in those in which it was well represented (the Toronto scale in particular), the impact was high.

These observations are not intended to support interest in nimodipine, only to suggest that higher cerebral function, an important aspect of the neurological examination and an activity many of us believe occupies much of the hemisphere volume, may be a sensitive marker to neuroprotective effects of drugs and deserves a greater place in modern clinical stroke scales.

The data from the nimodipine study suggest we may already have therapies that actually improve some of the outcomes, such as higher cerebral functions, if not sensory function and motor function, only slightly. Further studies would necessitate a change in the content of the scales, bringing back a more detailed assessment of higher cerebral function. The compact, one-page data collection method the current author has long preferred may well go by the board in favor of longer forms. Some useful scales for higher cerebral function already exist.⁵¹ If such reinvestigations show effects on higher cerebral function, the effect might well prove to be a sign of a reduction in total infarct size that may soon be easily imaged by use of DWI or its successors. Apart from drug effects that limit infarct size, we may actually be able to see drug effects that awaken or augment the compensatory processes about which we know too little.

All told, it is too early to consider the clinical scoring systems to be a sufficient stand-alone basis for judging the effects of therapy. Improvements in our understanding of the all-important variations in clinicoanatomic correlation are sorely needed to sharpen the focus of the scoring systems used in clinical trials. Until this is forthcoming, it is suggested that brain-imaging evidence of tissue sparing be given at least equal weight to that of clinical outcome scores.

Clearly, there has never been a better time to be a clinical neurologist.

	Footnotes

 
Presented at the 21st International Joint Conference on Stroke and Cerebral Circulation, January 25-27, 1996, San Antonio, Tex.

© 1997 American Heart Association, Inc.

	References

Top Introduction TIA and Stroke Time From Known Occlusion... Factors Affecting Outcome Implications for Trials References

 
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