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July2007 Vol.44 Issue:      2 Table of Contents
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Early Predictors of Malignant Course of Middle Cerebral Artery Infarction: Clinical, Laboratory and Radiological Study

Hanan Abdel-Azim1, Ali M. Soliman1, Amr Kamel1,Sawsan Abdel Aziz1, Sherein El-Tarhony2

Departments of Neurology1, Clinical Pathology2, Zagazig University


Background and objectives: Early predictors of deterioration may improve therapeutic decision in patients with acute cerebral ischemia. This study investigated whether measurement of serum protein S100B, beside other clinical and radiological determinants can predict a malignant course of infarction in acute middle cerebral artery (MCA) occlusion. Subjects and Methods: The study included 24 stroke patients admitted within 24 hours after the symptoms onset. In all patients, the stroke was caused by middle cerebral artery infarction as proved by transcranial Doppler (TCD) or computed tomography (CT). Patients of this study were divided into two groups: group I: included 17 patients with non malignant middle cerebral artery infarction (MCAI). Group II: included 7 patients with malignant MCAI (mMCAI). All patients were subjected to complete history taking and thorough neuroglical examination using National Institutes of Health Stroke Scale (NIHSS), brain imaging by computed tomography, transcranial Doppler examination and routine laboratory studies. S100B  serum levels were determined in all patients (on admission and 24 hours later) and in 15 age and sex matched control subjects. The functional state of patients was evaluated on discharge by Barthel index (BI) and after 2 months by modified Ranken Scale (MRS). Results: Patients with mMCAI had significantly higher S100 serum level after 24 hours, and higher NIHSS after 48 hours. These patients had higher incidence of poor outcome both early on discharge (lower BI) and after 2 months (MRS > 3). On CT examination patients with mMCAI had significantly higher frequency of early hypodensity, large sized infarction, with more severe mass effect. Regarding S100B protein: it could not be detected in any one of the control group. While no significant difference could be found between the two patients’ groups on admission, its levels were significantly higher in patients with mMCAI after 24 hours. At that time, levels of S100 were significantly correlated to NIHSS at 48 hours, the infarct volume and the severity of mass effect. Again S100B protein could be correlated to functional outcome of the patients both on discharge and after 2 months. In this study predictors of stroke poor outcome were increased mean age of the patients, presence of diabetes, hypertensions, rapid deterioration in the first 48 hours, and significantly higher S100B  after 24 hours from admission. Beside those clinical and laboratory data, neuroradiologic features such as the presence of early hypodenisty, large sized infarction (more than one lobe) and marked mass effect were good predictors of poor functional outcome. Conclusion: Serum S100B  concentration 24 to 48 hours after the onset can predict a malignant course of infarction after MCA occlusion and may provide a valuable information for both neurological status and functional impairment on discharge and on long term outcome. Other predictors of the malignant course are early clinical deterioration of the patients, early hypodensity on CT with large sized infarction and severe mass effect. All of these factors beside old age and diabetes can also predict poor outcome after MCAI. (Egypt J. Neurol. Psychiat. Neurosurg., 2007, 44(2): 437-447)



Large infarction of the middle cerebral artery (MCA) territory still represents a challenge of neurointensive care. Some patients may develop a space occupying brain edema leading to raised intracranial pressure, midline shift and in the worst case, herniation with subsequent death1. In these cases, clinical deterioration with decreasing levels of consciousness and evolvement of brain stem signs usually occurs within 2 to 5 days following symptom onset2. The prognosis of such cases is poor, in a prospective case series, 80% died from herniation despite maximum conservative treatment3. This mortality rate is 3 to 4 times higher than in general ischemic supratentorial stroke population4. 

In consideration of these characteristics, the term malignant middle cerebral artery territory infarction (mMCAI) was coined4. In order to prevent or reverse edema formation, to lower intracranial pressure, to improve cerebral perfusion and to attenuate deleterious ischemic processes, more drastic rescue therapies such as craniotomy or therapeutic hypothermia have been applied5, with more better results with earlier application1.

Therefore, reliable data predicting mMACI are required as early as possible in the course of stroke to make a decision on which patients may develop malignant brain edema and thus benefit from more aggressive therapeutic measures1. In most centers, computed tomography (CT) is often the first and the only imaging for evaluation of patients with stroke6. So CT is likely to remain the cornerstone of rapid stroke investigation7.

The S100 is an acidic calcium binding protein (molecular weight 21000) consisting a major component of the cytosol, predominantly in astroglial cells8. The protein consists of two subunits (a and b) three isoforms are known. S100a (ab) is found in glial cells and melanocytes and S100b (bb) is present in high concentrations in glial cells and schwann cells of the central and peripheral nervous system as well as Langerhans cells and cells of the anterior pituitary.

S100 ao (aa), which represents 5% of the S100B protein in the brain, is found outside the nervous system in striated muscles, heart and kidney9. Both intracellular and extracellular mechanisms of action have been proposed for S100, although its biological functions are not yet understood in details8.

In recent years, it has been reported that serum concentration of S100B protein has a close relationship to primary brain damage and could be used to predict outcome quantitatively10.

So our study is aimed (1) to investigate whether measurements of serum protein S100B can predict malignant course of infarction in acute middle cerebral artery occlusion and to relate its level to both clinical and C.T finding (2) to determine the predictors of poor outcome in our stroke patients.




This study was conducted on 24 patients with acute stroke due to occlusion of MCA. The patients were selected from the Neurology Intensive Care Unite Zagazig University Hospital. Criteria for inclusion in the study were (1) exactly defined time of onset of stroke (2) complete clinical, CT, transcranial Doppler (TCD) and laboratory investigation available within 24 hours after the onset of stroke. (4) completed stroke with visible infarction on initial or repeat CT. (5) MAC occlusion on admission documented by CT or TCD studies.

We excluded patients with history of previous stroke or subarachnoid hemorrhage, neurosurgical procedures or serious concomitant disease. Patients with absent temporal window were also excluded.


1.             Assessment of clinical findings:

Systematic routine procedures at admission included, clinical examination during which vital signs and blood pressure are registered. Electrocardiogram was performed. The patients and their relatives were interviewed about the medical history of the patients, for detecting any risk factor for stroke such as hypertension, diabetes, atrial fibrillation and cigarette smoking. Quantitative assessment of the neurological deficit was performed for all patients at admission and 48 hours after, by using National Institutes of Health Stroke Scale (NIHSS)11 and on discharge, patients were assessed by the used of Barthel index (BI)12.

Diagnosis of malignant MCAI was based on clinical course of the patients and follow-up imaging (CT) according to the criteria used by Thomalla et al.(13: (1) secondary neurological deterioration including at least decline of consciousness as defined by 1 or more points of the level of consciousness item of the NIHSS and (2) large space- occupying MCA infarction on follow-up CT (covering more than two thirds of the MCA territory with compression of ventricles or midline shift).  

All patients were evaluated after 2 months by modified Ranken Scale (MRS) for assessment of the prognosis, considering £ 3 as good prognosis and > 3 as bad prognosis. For statistical purposes we included death of the patients (grade 6) in the group of bad prognosis.


2.             Laboratory investigation:

Immediately after admission, venous blood samples were obtained from all patients and centrifuged; serum was separated and stored at 25°C for measurement of the S100B serum concentrations. We used a commercially available monoclonal two site immunoluminometric assay and fully automatic LIA-mat system (Byk – Sangetec Diagnostica, Diatzenbach, Germany). This test measures the b-subunit of protein S100 as defined by 3 monoclonal antibodies. The detection limit of this test was 0.02 mg/L.

Another blood samples were collected after 24 hours from admission for further assessment of S100B protein.

Beside S100B protein detection on admission, patients were investigated by routine laboratory tests such as; fasting and 2 hour postprandial blood sugar levels, complete blood picture, liver function tests, lipid profile and serum creatinine.

For comparison the serum concentrations of S100B protein were also determined in age and sex matched group of 15 control subjects (patients from the department of orthopedics, in whom clinical assessment showed no signs of neurological or sever general diseases.


CT technique:

All patients were subjected to CT scan of the brain using GE high speed (Tomo scan 350). All CT were evaluated for the presence of early signs indicating mMCAI such as hyperdense middle cerebral artery sign, focal brain swelling and midline shift14.

The size of the infarct was quantified as follows: (1) small involvement with less than one half of a lobe or consistently normal CT scans. (2) medium involvement with one half of a lobe to one lobe, and (3) large lesion involvement with more than one lobe15. Mass effect was defined as follows: (1) slight when only a sulcal effacement or compression of ventricles without dislocation was present, (2) moderate and (3) severe when we observed respectively, a partial or total ventricular shift across the midline16.


Transcranial Doppler scanning (TCD):

Bilateral TCD monitoring was performed at admission using pulsed wave range gated directional 2 MHZ Doppler instrument (promelec s.a. France), pluri Dop program with acoustical focusing and real-time spectrum analysis.


Statistical analysis:

The data were statistically processed using Epi-Info soft ware state backage17. The significance of difference between the mean values of the study variables were evaluated by upaired student t-test. The significance of difference between the qualitative variables were evaluated by X2 or fisher exact test. The correlation coefficient (r) was used to test the association between two continuous variables.




This study included 24 patients. 17 had non malignant MCAI and the others were proved to have malignant MCAI.

Table (1) shows the overall comparison of the demographic data baseline and vascular risk factors, clinical characteristics and laboratory characteristics in mMCAI patients and non malignant MACI patients.

No statistically significant differences could be detected between the two groups regarding age, sex, history of A.F., cigarette smoking diastolic hypertension, diabetes or side of hemiplegia. On admission, higher NIHSS was found in mMCAI patients than non malignant patients but the difference was statistically insignificant, 48 hours later, NIHSS became significantly higher in mMCAI group (P = 0.007).

Patients in mMCAI group were proved to have significantly lower Barthel index on discharge (P > 0.07) with more patients’ deaths (P = 0.002) and more patients with bad progressive on long term follow up (47.1% vs 100%, P = 0.022).

At the first CT scan (Table 2). There was a significantly higher frequency of early hypodensity among patients with mMCAI (P = 0.029). At repeated CT scan mass effect was detected in 2 patients only in non malignant MCAI group, whereas in mMCAI group it was detected in all patients (100%).

The mass effect was significantly different in degree between patients of the two groups. While no one of the non malignant group had severe mass effect, it was found in 6 patients (85.7%) of the mMCAI group (P = 0.001).

Regarding the size of infarction, non malignant group patients has mainly small and medium sized lesions, while large sized infarcts significantly prevailed among patients in the malignant group (P = 0.003).

In the control group S100B protein serum concentration was less than 0.02 mg/L in all cases. The mean S100 value was significantly lower in the control group than in the patients group (P < 0.001). In between the two patients’ group, levels of S100B were insignificantly higher in patients with mMCAI (1.26±1.04 mg/L) than non malignant MCAI (0.98±0.91 mg/L) patients on admission with a cut off value of 1.50 mg/L. Data are shown in Table (1). 

After 24 hours S100B level raised significantly in mMCAI group patients (P = 0.007). It did not show any correlation to NIHSS of the patients on admission (r=0.12, P > 0.05), but it showed positive correlation to both functional state of the patients after 48 hours (r = 0.53, P < 0.001).

Regarding CT findings S100B was significantly correlated with the extent of the infarction on CT (r = 0.75, P < 0.001) and mass effect (r = 0.49, P < 0.01).

Again after 24 h S100B plasma levels were significantly correlated with worse clinical outcome both at discharge (measured by Barthel index (r = 0.46, P < 0.01) and long term outcome, (MRS > 3) two months after the stroke (r = 0.48, P < 0.01).

Outcomes of our patients were assessed at 2 months using MRS and rated as good if the MRS was 0 to 3 and as bad if the MRS was 4 or 5, or the patient was dead (grade 6). These two groups were compared in terms of their clinical background, risk factors, vital signs, laboratory data, cranial CT and S100B level after 24 hours from admission (Table 4). There were 9 patients with good prognosis and 15 patients with bad prognosis. In univariate analysis, patients with poor functional outcome were older, with more prevalence of diabetes, hypertension and higher S100B serum level with rapid deterioration through first 48 hours as detected by significantly higher NIHSS. On CT examination patients with poor prognosis had more frequently early focal hypodensity, large sized infarction with more severe mass effect.

Table 1. Clinical characteristics of patients. 


Clinical characteristics
No (%)

Non malignant MCAI
N = 17

N = 7


Mean age Y ( ±SD)










- Male






- Female




















































Hemispheric lesion






- Right






- Left









     At admission




     After 48 h.




S100B (mg/L):( ±SD)




At admission




After 24 h




BI: ( ±SD)










MRS > 3






* = significance


Table 2. CT characteristics of benign and malignant MCAI patients.



Non malignant n=17 No (%)

Malignant n = 7

No (%)


Early hypodensity

4 (23.5)

5 (71.4)


HMCA sign

1 (5.9)

3 (42.8)


Size of infarction





3 (17.6)

6 (85.7)


     Medium sized

6 (35.3)

1 (14.3)



8 (47.1)

0 (0.0)


Mass effect





0 (0.0)

0 (0.0)



2 (11.7)

1 (14.3)



0 (0.0)

6 (85.7)


* = significance.

Table (3): Correlation between serum S100 and patients characteristics.





NIHSS at admission



             at 48 hours



Infarct volume



Mass effect



Barthel index


< 0.01*




* = significance.


Table 4. Univariate statistical analysis of 2 months good functional outcome versus month's poor functional outcome among stroke patients.


Clinical characteristics No (%)

Good functional  outcome n=9

Poor functional outcome n=15


Demographic data:




Age ( ±SD)




Sex female






10 (66.7)



3 (33.3%)

12 (80.0)


Side of hemiplegia






6 (40.0)



7 (77.8)







     On admission




     After 24h




Barthel index: ( ±SD)




Neuroradiological data:




early hypodensity

4 (44.4)



HMCA sig

0 (0.0)

4 (26.6)


Large size infarction

2 22.2)

7 (46.6)


Severe mass effect


6 (40.0)


S100B protein24h (mg/L) ( ±SD) 




* = significance





Stroke remains a common and costly problem world wide, but substantial advances have been made in recent decades in understanding stroke mechanisms, risk factors and therapies18.

In the preset study on stroke patients caused by MCA territory infarction, no significant difference could be detected regarding the mean age between the non malignant group and the malignant group. In the literature, the study of age difference between mMCAI and non malignant MCAI patients revealed contradictory results. While Levey et al.9, found that the mean age of their patients with mMCAI was 74.5±14.2 years, Kriger et al.20, and Oppenheim et al.21, demonstrated that their patients with mMACI were significantly younger than the non malignant patients. Kucinski, et al.22, explained the occurrence of mMCAI in the younger age as in old age there is a certain degree of age related cerebral atrophy which protects the brain from space occupying swelling.

In our patients, among the clinical data obtained at hospital entry hypertension was more prevalent among mMCAI patients. This is in agreement with Thomas and Bogousslarsky23, who found that more than two thirds of their mMCAI patients were hypertensive. Toni et al.16, found that high systolic blood pressure and elevated blood sugar concentration at admission were independently related to the deterioration occurring during the first 48 hours. In our patients no significant difference in the prevalence of diabetes between malignant and non malignant group. This result was in accordance to Serena et al.24, who found no difference in blood glucose levels between their malignant and non malignant MCAI patients. On the other hand it was proposed that increased serum glucose levels favored the progressing course by enhancing brain edema which has been reported to be one of the determinants of stroke progression25.

In this study assessment of the clinical state by NIHSS demonstrated no significant difference between non malignant MCAI group and mMCAI group at the time of admission while after 48 hours, patients with mMACI had significantly higher NIHSS score. This is in agreement with Qureshi et al.26, who concluded that neurological deterioration related to cerebral edema after massive middle cerebral artery infarction occur in most patients within 48 hours of symptom onset.

Brain imaging is an integral component of the assessment of patients with acute stroke. The appearance of the brain on imaging like computed tomography (CT) may influence treatment decisions in ischemic stroke so it is important to extract as much diagnostic and prognostic information as possible from imaging7. In this work, many CT findings could be coupled to a malignant course of middle cerebral artery infarction, these include the presence of early focal hypodensity, large sized infarction on the initial or on the repeated CT and severe mass effect. The sensitivity and prognostic value of early CT in MCA occlusion have been extensively investigated. Many authors reported that the presence of early CT findings of parenchymal hypodensity and sulcal effacement was associated with severe stroke and unfavorable functional outcome20,27,7. The hyperdense middle cerebral artery sign (HMCAS) on plain axial CT scans indicates large clot burden in the intracerebral vasculature20. In our study there was no statistically significant difference between malignant and non malignant patients regarding the presence of HMCAS. In the literature there is controversy regarding the importance of this sign. While Krieger et al.20, showed no difference in the frequency of this finding between patients with and without fatal brain swelling, Somford et al.28, found that HMCAS was present more frequently in patients with mMCAI.

Regarding the size of infarction and mass effect Harding et al.4, demonstrated mass effect in about 80% of their mMCAI patients. Moreover, they added that CT scanning within 18 hours of stroke onset may help to early identify patients who may develop mMCAI by the presence of extended MCA hypodensity, hemispheric brain swelling, midline shift and HMCAS4.

In the present study poor functional outcome at 2 months follow up (MRS > 3) was strongly correlated to age of the patients beside many of the afro-mentioned clinical and CT findings presented in patients who developed mMCAI. This is in accordance with a previous study of Barber et al.29, who stated that early neurological deterioration after ischemic stroke is associated with poor outcome or death.

Comparison of baseline characteristics of our patients revealed that those who developed fatal or poor outcome were significantly older, more frequently had diabetes systolic hypertension, with higher NIHSS after 48 hours and had lower BI on discharge. Tei et al.30, found in univariant analysis, their patients with good prognosis were younger, had lower scores in NIHSS and had fewer rates of deterioration within 7 days than patients with bad prognosis.

In many previous studies old age was significantly associated with fatal outcome of ischemic stroke patients31,32.

The significant role of hyperglycemia on the outcome of stroke is in agreement with Matz et al.33; Martini et al.34, and Nakamura et al.35, who reported that hyperglycemia independently predicts poor outcome after acute stroke. Several mechanisms has been reported for explanation of poor outcome among diabetic stroke patients. An alteration of post ischemic cerebral blood flow related to an impaired autoregulation of cerebral blood flow related to acceleration of the cerebral atherosclerosis36. Moreover Martini and Kent37, stated that both human and animal studies have showed that hyperglycemia is particularly detrimental in ischemia reperfusion, as hyperglycemia produces biochemical and molecular changes that result in a pro-vasocostrictive pro-thrombotic and pro-inflammatory phenotype that renders the vasculature vulnerable to reperfusion injury.

Systolic blood pressure is another determinant factor for poor outcome. Adeoye and Jauch38; Nakamura et al.35, and Spriqq et al.39, reported the same result. Furthermore, Adeoye and Jauch38, stated that extremes of blood pressure are associated with poor outcomes in all stroke subtypes.

The relationship between admission stroke severity and outcome of patients with first-ever ischemic stroke is assessed by Kwan & Hand40, and Tseng & Chang41. They found that the NIHSS score at admission (within 48 hours of stroke onset) was strongly associated with outcomes of acute hospitalization after multivariate adjustment. Toni et al.25, stated that early deterioration (change in Canadian Neurological Scale score by (1) predicted a 30-day bad outcome (death and poor functional outcome) in 88% of their patients. 

Regarding CT scanning three significant associations could be detected for poor outcome; early focal hypodensity, large sized infarction and severe mass effect. Early focal hypodensity and large sized infarction were found more commonly in patients with poor prognosis than patients with good prognosis. It was demonstrated that the presence of a visible infarction significantly and independently increase the risk of early death and poor long term outcome, after all other major predictors of poor outcome have accounted for (7). Krieger et al.20, reported that the early CT hypodensity findings were not statistically significantly associated with herniation, but when combined with > 50% hypodensity, this was shown to be a strong predictor. Similarly Toni et al.16, stated that absence of early hypodensity of first CT is independent predictor of early improvement with lower thirty day case fatality rate and disability.

Marked mass effect is another common sign in patients with poor outcome. This is ingoing with previous studies3,42, who found severe mass effect associated with big sized infarction to be significantly associated with high mortality rate.

Many markers of ischemic brain damage have been investigated in CSF and serum after acute ischemic stroke both experimentally and in patients. These include lactate, various brain specific proteins like myeline basic proteins, enolase and S100B protein.

In the current work, study of S100B level showed high values in stroke patients than controls. Many previous studies proved that serum S100 level increases significantly in ischemic stroke reaching their maximal levels within 2.5 days from the onset43,44.

While no significant difference could be detected in S100B level between patients with malignant and non malignant infraction at the time of admission (0.98±0.91 mg/L vs 1.26±1.04 mg/L), significant higher values were detected in the malignant group 24 hours later (1.06±0.93 mg/L vs 2.48±1.53 mg/L) with a cut off 1.50 mg/L. This release pattern of S100B protein confirms the results of previous clinical studies45,44. Foerch et al.44, found that the temporal profile of serum S100B concentration after cerebral infarction is similar to that of metabolic changes of the infracted tissue as demonstrated by positron emission tomography (PET) and microdialysis in a study done by Dehem et al.46. They added that this delayed peak level of S100B protein concentration may reflect later responses in the pathophysiological cascade and microglial reaction to ischemia. Both necrotic cell damage in the penumbral zone of focal infarctions and a breakdown of membrane integrity due to cytotoxic and vasogenic edema may provide leakage of S100B protein from cytosol to the extracellular space47,44. Again, Foerch et al.44, stated that patients with a non malignant course of infarction may have better collateral blood supply, resulting in smaller infarcts with a flattened S100B kinetic.

In accordance with our results, previous studies have demonstrated significant correlation between serum concentrations of S100B level and infarct volume in patients with acute ischemic stroke8,43,48,10. This result could be explained by the work of Foerch et al.49, who found that early recanalization (< 6 hours after symptom onset is associated with a significantly lower mean S100B level compared with patients with no recanalisation. They hyposthesized that early and sufficient clot lysis in proximal middle cerebral artery occlusion may result in smaller lesion volumes that are directly mirrored in the S100 kinetic.

In the current study S100B protein level after 24 hours was significantly correlated with neurological state of the patients at 48 hours after admission as assessed by NIHSS (r = 0.53) and with the functional status of the patient both on discharge (BI)  (r = 0.46) and after 2 months assessed by MRS (r = 0.48). Missler et al.8; Wunderlich et al.45, and Foerch et al.49, showed similar significant associated between S100 concentration and functional status at discharge from the hospital. Buttner and Coworkers43, reported a significant correlation between S100B protein and neurological status at admission, but they failed to calculate significant correlations between S100B values and the functional outcome 4 weeks after stroke onset. These different results may be due to the use of different techniques as well as different commercial kits45. In this study we used the newly developed immuno-luminometric assay with a lower detection threshed (0.02 mg/L).

Recently Foerch et al.10, stated that single S100B values obtained 48 and 72 hours after stroke onset provide the highest predictive values with respect to the functional outcome and infarct volume in nonlacunar middle cerebral artery infarction.

Conclusion: one of the main results of the current study in that single measurement of S100B serum concentration obtained from 24 to 48 hours after symptoms onset can predict a malignant course of infarction in patients with MCA occlusion. This study confirms the significant associated between S100B level and both the size of the infarct volume and the presence of mass effect. Again, S100B was found to be one of the best indicators for both early outcome (on discharge) and later outcome (after two months).

Patients with mMCAI had higher NIHSS after 48 hours, with early hypodensity on CT with large sized infarction and marked brain edema.

In this study old age and diabetic were predictors of poor outcome but not of mMCAI.




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