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(Stroke. 2005;36:902.)
© 2005 American Heart Association, Inc.
Progress Reviews |
Editorial Comment— Time to Burn the TOAST
Department of Neurology, Washington University School of Medicine, Saint Louis, Mo
There will be a rediscovery of the worth of the now-almost-abandoned autopsy and clinical pathological conference and the realization that MRI, computed tomography, and ultrasonography cannot substitute for direct postmortem examination of the brain and blood vessels.1— James F. Toole
The observations of many 20th century stroke studies led their authors to question whether there were any significant special risk factors, like hypertension, for little strokes. By assuming the onerous and painstaking task of systematically reviewing all of the pertinent literature, Jackson and Sudlow have accomplished a unique task, the proof of a negative!2 There are no specific etiological diagnostic risk factors for small-vessel occlusion (lacune), the most common variety of stroke in the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) tabulation.3 TOAST was the standard classification system for clinical definition of ischemic strokes.
Even BT (before TOAST), the common knowledge of most experienced clinicians was that family history, age, smoking, hypertension, cardiac or systemic atherosclerosis, previous stroke, diabetes, obesity, and cachexia of any cause are pertinent to general health and probably to the incidence of stroke. And they knew that big strokes are worse than little strokes, especially for debilitated older patients. In 1993, the TOAST stroke investigators recognizing "the etiology of ischemic stroke affects prognosis, outcome, and management," proposed a "classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial."3 Their premise was "determining the cause of stroke does influence choices for management."
Their Table 1 illustrates the range of their causal conclusions, 5 major categories, segregated with modest hedging. For large-artery atherosclerosis, there is an (embolus/thrombosis) choice, and for cardioembolism, a choice of (high-risk/medium-risk). These, along with small-vessel occlusion (lacune) and stroke of other determined etiology, are adorned with an asterisk whose footnote indicates the premise that "investigators are allowed to express their certainty by classifying the likelihood of diagnosis as probable or possible.... because most etiological diagnoses in stroke are not based on pathological confirmation and are thus presumptive." The reliability test of the system was that "two physicians agreed in their final diagnosis of subtype of ischemic stroke in 19 of 20 [independently assessed] patients."
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In 1998, the authors of the TOAST system reported their therapeutic trial of danaparoid. "Subtypes of acute ischemic stroke were also a pre-specified end point.... The effects of the severity of stroke on admission or the cause [italics ours] of stroke on outcomes at 3 months are listed in Table 3" (Table 2).4 The diffident asterisks and graded choices have been replaced by unqualified "cause." "Subtypes are determined by the Clinical Coordination Center." Their terminal extension of this democratic method was, "A panel of three physicians who are not aware of the treatment allocation ascertained the most likely cause of death" (82 deaths, 0 autopsies). (Recall the story of the kindergarten teacher who explained to her class that she could not ascertain by inspection the sex of their new pet gerbil. The bright girl in the first row solved the conundrum; "Let’s vote!") This article established the unfortunate precedent of verbal slippage from possible to probable, then often via risk factor or mechanism to cause, a noun that should carry the rigorous onus of homology to Koch’s postulate.5,6 The same slippage is evident in the recent classification of posterior circulation strokes.7
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Review of the projected TOAST criteria for the choice of cause is pertinent.3
Large-artery atherosclerosis requires big symptoms, multiple or severe, forebrain or hindbrain, big lesion, and imaging evidence of stenosis >50% of an appropriate artery, intracranial or extracranial. It is well known that such vasculopathy is commonplace in the absence of stroke, a fact underlined by the secondary need to "exclude potential sources of cardiogenic embolism." Conversely, it is certain that such strokes do occur in the absence of conspicuous arteriographic pathology.
Cardioembolism "presumably due to an embolus arising in the heart." This presumption automatically magnifies the incidence of cardioembolism by arbitrarily purging the possibility of any other cause for stroke while lumping together with atrial fibrillation 23 listed less common sources of cardioembolism. It has been proved only that the incidence of stroke is reduced by coumadin in patients with atrial fibrillation.8
Small-vessel occlusion (lacune). Walter Alvarez first called special attention to the clinical phenomenology of "little strokes."9,10 Two score years ago, before computed tomography, Miller Fisher first sponsored the term "lacune" and the impression that lacunes are caused by a specific lesion called lipohyalinosis, conditioned by vascular hypertension.11–14 He further came to believe, "These data support the proposition that small penetrating branch artery disease tends to occur where it gives rise to symptoms rather than being distributed by chance." In his 1991 review, he claimed to have defined 70, although only 65 specific syndromes are listed, and several of these are multiple-lesion or redundant.15 Here he also opined "MRI has made dependence on clinical detail more or less obsolete." General use of computed tomography and magnetic resonance imaging has made certain that little lesions are not always associated with acute symptoms, and that the syndromes do not always meet rigidly prescribed clinical patterns.14,16
Miller Fisher’s careful pathological observations in 22 new "lacunar infarcts" included only 4 with lipohyalinosis.15 Four empty-vessel cases were presumed to represent lysed emboli, rather than spasm or other mechanism. The other 14 cases included "stenosing atheroma with super-imposed thrombus, 5; stenosing atheroma, 5; mural atheroma of the basilar artery, 2; microaneurysm, 1; and inconclusive, 1." Evidently there is no longer a specific vascular occlusive pathology of little strokes. Jackson and Sudlow now show that there are no specific clinical risk factors.2
It follows that smallness of lesion by clinical estimate or imaging is the only criterion for lacunes. The best common sense hypothesis for the prevalence of small strokes is that simply because they are very narrow, the tiny lumina of myriad small terminal arteries/arterioles are most readily brought to complete occlusion by any partial obstruction: atheroma, or clot, or circulating detritus. TOAST provides no rationale for arbitrarily limiting the lacune label to cross-sectional diameters less than 1.5 cm.
Stroke of other determined etiology solicits a vote for long-shot risk-factor diseases involving blood vessels or coagulation that require exclusion of the more common conditions. Unproven, such cases may offer excuse for therapeutic failure or complication. Nevertheless, there are too few to complicate most large-scale clinical studies anyway.
Stroke of undetermined etiology is the uncontroversial democratic vote of maximal insecurity, either too poor or too rich; incomplete or absent basis for exculpation of a cause, or conversely, 2 or more adequate but mutually exclusive causes. It would not be fair to vote for one or the other. (Cf. kindergarten simile.)
We accept the hope that therapeutic efficacy may differ among various sorts of pathology. Different strokes may need different pokes. But the fact is that every clinician’s best operational diagnosis is based on integration of hard data, some measurable with real numbers: chronological history of symptom details, clinical examination, and laboratory and imaging data. The specious character of TOAST is the translation of a majority guess into an autonomous causal power, a factoid, "an invented fact believed to be true because of its appearance in print."17 Even a 0.05 correlation coefficient between phenomenon X and some aspect of stroke does not become a scientifically proven cause by endowing the association with the pejorative title of risk factor. "Impression" is not the singular form of the noun "data." Consistently reliable guessing provides no proof of validity. After a decade of the routine TOAST classification system, we question whether it has contributed to the efficacy of stroke treatment or prevention.
Instead of including the intervening variable of each clinician’s analogical estimate, we submit that it is valid, and essentially more reliable, to record for each case the original data points, a computerized census of the bases of each operational diagnosis. Without prejudice regarding mechanism, it is now possible to measure the volume and vascular location of every stroke, including dynamic magnetic resonance imaging variant techniques.18–22 Correlations can be sought only after the facts are recorded. Retrievable details of interest beyond age and sex might include duration of onset, stepwise or continuous, multiple lesions in brain or other organs, specific nature of cardiac abnormalities, stroke adjacent to or away from previous infarction, severity details of systemic disease like hypertension and diabetes, ad infinitum and ad libitum. Cholesterol can be spared.23,24
As Toole points out, stroke investigators have neglected modern opportunities for neuropathological auditing of disease process and therapeutic endeavors. For example, several studies have indicated that microhemorrhage may be associated with ischemic infarction.25–29 Is there anything different about the brains of patients who have gross hemorrhage from tissue plasminogen activator treatment?30 To our knowledge, no one has looked.
In the last decade or so, our colleagues in neurology who are concerned with dementia, movement disorders, and multiple sclerosis have accomplished powerful conceptual and practical new information by aggressive recruitment of autopsy material. The unfortunate fact is that many stroke patients do not survive long.31–33 Whether they die in acute hospital, nursing facility, or home, early or late, how does their neuropathological status relate to their intensive clinical evaluation and therapeutic effort? Patients and families are certain to cooperate if solicited with sincerity and grace. The predominant know-it-all separation of clinical stroke specialists from the fine tissue neuropathology of stroke seems to us to be improvident, if not unforgivable. We welcome Dr Toole’s hopeful prediction.
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References |
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