Coexisting Causes of Ischemic Stroke

Background  Coexistence of multiple potential causes of cerebral infarct (MPCI) has been poorly studied.

Objective  To determine the risk factors, clinical findings, and topographical patterns of patients with at least 2 potential causes of cerebral infarct.

Design  Data analysis from a prospective acute stroke registry (the Lausanne Stroke Registry, Lausanne, Switzerland) in a community-based primary care center.

Results  Among 3525 patients with first-ever ischemic stroke consecutively admitted to a primary care stroke center, 250 patients (7%) had at least 2 MPCIs, with the following subgroups: large artery disease and a cardiac source of embolism (LAD + CSE) (43%), small artery disease and CSE (SAD + CSE) (34%), LAD + SAD (18%), and LAD + SAD + CSE (5%). Hypertension, cardiac ischemia, and a history of atrial fibrillation predominated in the LAD + SAD + CSE subgroup (P<.001), while cigarette smoking was more prevalent in the LAD + SAD subgroup (P<.05). A decreased level of conciousness and speech disorders were more common in the LAD + CSE subgroup (P<.001). Lacunar syndromes predominated in the LAD + SAD subgroup. Pure motor stroke was the most frequent lacunar syndrome in all subgroups, but sensory motor stroke predominated in the LAD + CSE subgroup (P<.05). The outcome at 1 month was worse in the LAD + CSE and SAD + CSE subgroups (P<.001). Other stroke characteristics and clinical features did not differ significantly between the 4 subgroups of patients with MPCI.

Conclusions  Our findings suggest that MPCIs are uncommon. The most frequent association is LAD + CSE. Topographical patterns of stroke and clinical characteristics in patients with MPCI only rarely allow emphasis of a preeminent cause.

CEREBRAL infarction, the leading stroke subtype in more than 80% of patients, is a heterogeneous disorder encompassing several pathophysiological mechanisms.^1,2 Acute- and long-term management and the prediction of outcome in each case depend on its origin.^1,3,4 This may involve extensive diagnostic investigation and depends, in turn, on the criteria used.^5,6

The most common single causes of cerebral infarcts (CIs) have been overemphasized in stroke registries,^1,5 while the coexistence of multiple potential causes of CI (MPCI) has rarely been mentioned.^7,8 Coexistence of 2 or more MPCIs may not be common, but, to our knowlege, this matter has not been systematically studied.We studied the risk factors, clinical findings, and topographical patterns of all patients with MPCI who were included into the prospective Lausanne Stroke Registry, Lausanne, Switzerland.

The study sample was obtained from patients with a first-ever ischemic stroke who where admitted to our population-based primary care center—The Lausanne Stroke Registry⁹—between January 1, 1979, and December 31, 1997, and studied those with at least 2 potential causes of cerebral infarction. All patients were studied according to the Lausanne Stroke Registry protocol, which included the patient's having at least 1 brain computed tomographic or magnetic resonance imaging scan, extracranial Doppler ultrasonography with frequency spectral analysis, and B-mode echo tomography of the carotid and vertebral arteries, continuous 3-lead electrocardiographic monitoring for at least 24 hours after admission to our hospital, 12-lead electrocardiogram, and standard urine and blood tests. Conventional cerebral angiography or 3-dimensional magnetic resonance angiography, transcranial Doppler ultrasonography, and 2-dimensional or transesophageal echocardiography were performed electively.

We recorded the following risk factors: arterial hypertension (blood pressure >160/90 mm Hg at least twice before CI or those already receiving antihypertensive treatment); diabetes mellitus (≥2 fasting blood glucose samples with levels >6 mmol/L [>108 mg/dL], and glucosuria before stroke); hypercholesterolemia (cholesterol level >6.5 mmol/L [>251 mg/dL]); venous hematocrit; cardiac ischemia or arrhythmia; regular cigarette smoking (at least 5 cigarettes daily); previous transient ischemic attacks; current or past oral contraceptive use; and a family history of stroke or ischemic heart disease. The anatomical location of lesions was assessed following lesion mapping templates developed in our center and elsewhere.¹⁰

Cerebral infarcts were classified in the following potential causes: (1) atheroesclerosis with large artery disease (LAD) was presumed in patients with risk factors (at least 1 of the following: age >50 years, arterial hypertension, diabetes mellitus, cigarette smoking, and hypercholesterolemia) who had stenosis of at least 50% of the lumen diameter in the appropriate large artery demonstrated by Doppler ultrasonography, 3-dimensional magnetic resonance angiography, or conventional angiography; (2) small artery disease (SAD) was presumed in patients with long-standing arterial hypertension or diabetes mellitus and a CI less than 15 mm in diameter limited to the territory of deep perforators (in absence of potential cardiac or arterial source of embolism); (3) cardiac embolism alone was presumed when a potential source of embolism was present, eg, endocarditis, mitral stenosis, atrial fibrillation (AF), sick sinus syndrome, intracardiac thrombus or tumor, prosthetic aortic or mitral valves, left ventricular aneurysm or akinesia after myocardial infarct, and global cardiac hypokinesia or dyskinesia; (4) combined causes if there coexist at least 2 potential causes of CI (LAD, SAD, or cardiac embolism); and (5) other and undetermined lacunar syndrome causes.

All patients with combined causes of CI were selected. According to the different patterns of combination, we established the following subgroups: (1) LAD and a cardiac source of embolism (LAD + CSE), (2) SAD + CSE, (3) LAD + SAD, and (4) LAD + SAD + CSE. We studied the risk factors, clinical findings, and topographical patterns of stroke in these patients with MPCI.

For statistical analysis, the 2-tailed Fisher exact test was used to evaluate 2 × 2 tables, with the χ² test to evaluate tables with more than 1 df. For comparison of age distribution between subgroups, the Kruskal-Wallis test was used.

Of the 3525 patients with first-ever ischemic stroke, 250 patients (7%) had at least 2 potential causes of CI. These subgroups are shown in Figure 1.

The mean (SD) age of the 250 patients with MPCI was 69.9 (8.8) years (age range, 33-90 years). The patients in both the LAD + SAD and LAD + SAD + CSE subgroups were younger than those in the other subgroups (P>.05).

Men predominated in all subgroups except the LAD + SAD + CSE subgroup, where there was an equal number of men and women. The distribution of age and sex in the various subgroups of patients with MPCI is given in Table 1.

The risk factor profile for patients with MPCI is summarized in Table 1. Patients in the LAD + SAD + CSE subgroup had more risk factors: hypertension (12/12; 100%), diabetes mellitus (5/12; 42%), hypercholesterolemia (4/12; 33%), cardiac ischemia (8/12; 67%), previous AF (6/12; 50%), and vascular claudication (2/12; 17%) predominated, but only hypertension (P<.001), cardiac ischemia (P<.001), and a history of AF (P<.001) were statistically significant.

Cigarette smoking was more frequent in the LAD + SAD subgroup (18/45; 40%) (P<.05). Previous transient ischemic attacks were not significantly predominated in the LAD + CSE subgroup (40/108; 37%).

Compared with the LAD + CSE subgroup (29/108; 27%) and the LAD + SAD + CSE subgroup (3/12; 25%), a higher proportion in the SAD + CSE subgroup had AF on an electrocardiogram (40/85; 47%) P<.05 (Table 2).

Echocardiography was performed in approximately half of the patients with a suspected CSE. A potential cardiac source of embolism (PCSE) was found in echocardiography in at least 60% of the patients with cardiac embolism and other coexisting cause(s). The most common abnormality was a myocardial akinetic segment without thrombus. Twenty-five (57%) of the 44 patients with LAD + CSE had an akinetic segment; a substantial increase was observed in 22 (88%) of the 25 patients with SAD + CSE; and all 5 patients (100%) with LAD + SAD + CSE had this finding. The frequency of this PCSE in comparison with other PCSEs was statistically significant (P<.05) (Table 2).

Approximately 80% of patients in all subgroups had nonprogressive onset of ischemic stroke. Clinical findings are listed in Table 3.

On admission to the hospital, a decreased level of consciousness (27/108; 25%), speech disorders (59/108; 55%), agnosia (34/108; 31%), and apraxia (31/108; 29%) predominated significantly in the LAD + CSE subgroup than in other subgroups (P<.001). A sensory motor deficit was more common in the LAD + SAD + CSE subgroup (5/12; 42%), whereas the highest frequency of pure motor involvement was found in the LAD + SAD subgroup (32/45; 71%) (Table 3).

One hundred forty-five patients (58%) with MPCI had a CI smaller than 15 mm in diameter. Pure motor stroke was the most common lacunar syndrome in all patients with MPCI (75/145; 52%) and one third of the patients had a sensory motor stroke (42/145; 29%). Ataxic hemiparesis was found in 20 (13%) of the 145 patients; whereas both dysarthria–clumsy hand syndrome and pure sensory stroke were found in one (3%) patient in each of these categories. Patients who had CIs smaller than 15 mm in diameter and coexisting LAD + SAD had more classic lacunar syndromes(42/45; 93%) in comparison with the other 3 subgroups (P>.05) Figure 2.

Pure motor stroke predominated in the LAD + SAD subgroup (30/42; 71%), whereas sensory motor stroke was found in half of the LAD + CSE subgroup. Ataxic hemiparesis and pure motor stroke occurred each in one third of the LAD + SAD + CSE subgroup (Table 4).

Cerebral infarcts in the LAD + CSE subgroup most commonly involved the pial middle cerebral artery territory (49/108; 45%). In all subgroups, CIs smaller than 15 mm in diameter were more common in deep perforator territory than in the medullary perforators of the middle cerebral artery. We also found in all subgroups that CIs in the deep perforator territory of carotid circulation more commonly involved the anterior choroidal artery territory than that of lenticulostriate arteries. This trend was more pronounced in the SAD + CSE subgroup (32/37; 86%) and in patients with coexisting LAD + SAD (17/20; 85%) (Table 5).

Cerebral infarcts in posterior circulation occurred more frequently in the SAD + CSE subgroup (31/85; 36%) (P>.05). Cerebral infarcts smaller than 15 mm in diameter were more common in the pons in all subgroups.

The outcome at 1 month was best in the LAD + SAD + CSE and the LAD + SAD subgroups, since all of these patients had a good outcome (ie, no disability or slight functional disability). The LAD + CSE and SAD + CSE subgroups, however, had a worse prognosis; major functional disability resulted in 41 (38%) of the 108 cases and 28 (33%) of the 85 cases, respectively (P<.001).

A low 30-day case-fatality rate occurred in all subgroups, with a frequency of 4% (2 of 45 patients) in the SAD + CSE subgroup and 5% (5 of 108 patients) in the LAD + CSE subgroup. No deaths occurred in the other 2 subgroups.

Our rate of MPCI is higher than in the Besançon Stroke Registry⁷ and the Ege Stroke Registry,⁸ which have reported rates of 4.7% and 3.4%, respectively (however, only in the latter patients with a PCSE and either large or small vessel disease were included). However, it does seem possible that MPCI has been underestimated, since several stroke registries have shown a tendency to choose only one presumed cause of CI to improve diagnostic accuracy. Moreover, in other studies, patients with MPCI are included in the "undetermined cause" stroke subgroup, which comprises patients with 2 potential causes of CI and those with no definite origin despite diagnostic investigations.^1,5,11 Therefore, as far as we know, this study, to the best our knowledge, provides the first detailed information regarding patients with at least 2 MPCI.

As has been pointed out, 10% to 30% of the patients with PCSE may also have a significant large vessel atheromatosis in the appropriate territory^12-14 and 10% to 30% of cases of lacunar infarct presumed to be of microatheroma or lipohyalinosis origin may also involve PCSE or ipsilateral large vessel disease.^13-17 In view of this fact, it is difficult to define the mechanism involved solely on the basis of clinical criteria. It is possible that the coexistence of other potential mechanisms may be a mere coincidence, but it may also play a role in the pathogenesis of CI. In our study, the 2 most common MPCIs were LAD + CSE and LAD + SAD, the former accounting for 43% of all cases and the latter for one third.

In general, the prevalence of risk factors in our patients with MPCI was similar to that found in other studies, both with respect to cases with mixed⁸ or single^1,8,11,18-20 mechanisms. However, our patients with a CI smaller than 15 mm in diameter exhibited higher frequencies of hypertension than what has been reported in patients with classical pathophysiological mechanism of lacunar infarct.^1,8,19,20 This finding may be explained by the rigorous criteria used in patients with small deep infarcts in our study.

As in other studies of CI from a CSE, nonvalvular AF and akinetic wall segment were the most common findings in patients with a coexisting PCSE associated either with SAD alone or with both LAD + SAD.^14,17,20 Also, our findings were consistent with the clinical characteristics of the mixed cause subgroup in the Ege Stroke Registry for the frequencies of onset of stroke, speech disorders, and type of sensory motor deficit.⁸ However, some clinical findings, such as altered level of consciousness, cognitive dysfunction, and sensory motor deficit predominated in patients with coexisting LAD + CSE, although this subgroup included patients with large cortical and subcortical CIs.

Pure motor stroke, sensory motor stroke, pure sensory stroke, ataxic hemiparesis, and dysarthria–clumsy hand are the main lacunar syndromes.^15,18,21-23 In our study, like in most reports including patients with CIs having a single suspected cause and those with combined causes,^8,15,18,22 pure motor stroke was the most common lacunar syndrome, but in patients with coexisting LAD + CSE sensory motor stroke predominated.

The topographical distribution of CIs in the LAD + CSE subgroup, which included large cortical and subcortical CIs as well as small deep infarcts, did not differ much from those in patients with a single mechanism.²⁴ The topographical distribution of CI was different in another series of patients, especially with regard to CIs involving cortical branches of middle cerebral artery, border zone CIs, and CIs involving multiple locations.⁸

Cerebral infarcts smaller than 15 mm in diameter in the centrum ovale have been mainly associated with local small vessel disease. Other causes are less common.^21,25-27 In our study, at least one fifth of small deep infarcts were located in the centrum ovale.

As in other small CIs, in situ small vessel disease is the leading cause in CIs involving the anterior choroidal artery territory.^11,28,29 Nevertheless, a coexistent arterial source has been found in 13% to 25% of these patients and a concomitant CSE has been reported in 15% to 30%.^11,28,29 Simultaneous arterial and cardiac sources along with classic risk factors linked to in situ small vessel disease were found in no more than 6% of the cases.¹¹

Usually, in situ occlusion of the perforating artery is the main cause in CIs involving the inferolateral thalamus.^30,31 Our findings are consistent with another study, which reported a similar percentage of coexisting CSE and SAD in a series of 14 patients with CIs involving this arterial territory.³² Our findings in patients with small deep infarcts involving the basis of the pons, argue against views that CIs in this location are not associated with MPCI.³³

Multiple potential causes of cerebral infarct seem rather uncommon, although the subject has not been systematically investigated. When present, the most frequent association is the coexistence of LAD + CSE. In our study no major differences were noted in topographical patterns of stroke and clinical characteristics between patients with MPCI and those with only 1 suspected mechanism of CI, or within the MPCI subgroups. Topographical patterns of stroke and clinical characteristics in MPCI only rarely allow emphasis of a preeminent cause.

Accepted for publication February 12, 2000.

Corresponding author: Julien Bogousslavsky, MD, Department of Neurology, Centre Hospitalier Universitaire Vaudois, CH 10-11 Lausanne, Switzerland (e-mail: Julien.Bogousslavsky@chuv.hospvd.ch).