Acta Neurol Scand., 1985:71:396-400

Key words: Blood leukocytosis; cerebral infarction: CT scan; clinical outcome

Peripheral white blood cell count in cerebral ischemic infarction

C. Pouilli, G. L. Lenzi, C. Argentino, L. Bouao, M. Rasura, F. Giubilei and C. Fieschi.

Department of Neurological Science, University of Rome, Rome, Italy

ABSTRACT- Peripheral white blood cell (WBC) count was determined in 95 patients with ischemic cerebral infarction 3 days after the onset of the stroke. At this time, higher WBC counts were found in patients with more severe neurological impairment and larger infarct size. A relationship between increase of WBC count and poor clinical outcome was also demonstrated. The elevation of peripheral WBC count observed soon after cerebral infarction reflects the degree of the inflammatory response in the acute hase and seems to have a direct relationship with the extent of the local cerebral damage.

Accepted for publication November 6, 1984

The development of a local inflammatory reaction following cerebral infarction is a well-recognized phenomenon from histopathological studies on human material and experimental infarction in animals (1,2,3). In man, this inflammatory re- sponse has recently been shown in vivo by means of radiolabelled leukocytes (4).

A transitory increase of polymorphonuclear neutrophilic leukocytes in the cerebrospinal fluid, presumably reflecting the cellular reaction to in- farction, has been demonstrated three or four days after the stroke (5 ) . Normal or slight in- creases of the peripheral venous white blood cell (WBC) count are usually found following cerebral ischemic infarction, whereas a leukocytosis of 12-20 x 103/mm3 is not uncommon in patients with cerebral hemorrhagic events (6,7). When present, the increase of peripheral WBC count following ischemic infarction is considered a nonspecific in- dicator of complicating infection rather than a primary event due to brain damage (7). By con-

trast, a correlation between an increase of pe- ripheral WBC count and poor clinical outcome has been reported for myocardial infarction and for subarachnoid hemorrhage (8,9,10).

In order to investigate whether increased WBC count could be related to the brain damage, we examined the relationship between peripheral WBC count, measured three days after a cerebral ischemic infarction, and also: i) the patient’s clini- cal status; ii) the extent of tissue damage; and iii) the patient’s final clinical outcome, when the symptomatology had finally stabilized.

Patients and methods We reviewed retrospectively the records of 109 consecutive patients with completed ischemic cer- ebral infarction who were admitted to the Stroke Unit of the 111 Neurological Clinic, University of Rome, between September 1982 and February 1984. Criteria of eligibility were the lack of

CEREBRAL ISCHEMIC INFARCTION 397

CT-scan signs of hemorrhage and admission to the Unit less than 72 h after the onset of stroke.

Fourteen patients were excluded from the study: a) seven patients, because they had re- ceived corticosteroids before blood samples were drawn for the examination of peripheral WBC count. Steroid administration is a potent cause of peripheral neutrophil leukocytosis (11); b) three patients, because they were found to have an addi- tional myocardial infarction at the time of admis- sion to the Unit; c) two patients, because chest X-ray performed shortly after admission showed a broncopneumonia; d) two patients, because they recovered completely during the first 24 h showing persistent negative CT-scan findings.

A population of 95 patients with completed is- chemic cerebral infarction (66 men of mean age 64 f 9.2 years; 29 women of mean age 67 f 11.1 years), therefore, comprised the case material of the study.

All patients had a clinical assessment of the level of consciousness and a full neurological ex- amination three days after the onset of stroke. On this basis, the patients were placed into one of three groups: 1) alert with mild neurological weakness (hemiparesis); 2) alert with severe neu- rological weakness (hemiplegia); 3) impaired con- sciousness (stupor and coma).

The patients remained at the Unit until they were able to go home or were transferred to a long-stay ward. The average length of stay in the Unit was 20.4 f 10 days. All deaths included in this study occurred in the Stroke Unit, within ten days of the stroke (6.4 k 2.2 days).

The patient’s outcome was defined in terms of functional status on discharge from the Unit as measured by ability to perform activities of daily living (ADL) and ability to walk (12). From this assessment, the patients were classified into those with a Good Outcome (GO) (independent or mildly disabled in ADL and able to walk without aids) and those with a Poor Outcome (PO) (mod- erately to severely disabled in ADL und unable to walk safely without aids).

Twenty patients died, 29 were included in the PO group and 46 were classified as having a GO. In all patients, a peripheral WBC count was

available on the third day after the onset of stroke.

/

0-48 48-72 HOURS AFTER STROKE

Fig. 1. Changes in peripheral WBC count between the first (< 48 h) and second (48-72 h) measurements after a stroke. The increase in WBC count is significant ( P < 0.001). *Student’s f-test, paired samples.

Other hematological tests including erythrocyte sedimentation rate (ESR) and the serum enzyme creatine phosphokinase (CPK) were also per- formed at the same time. In 33 out of the 95 patients studied, an addi-

tional earlier peripheral WBC count was available within the first 48 h from the onset of stroke. Computerized Tomography was performed with a Siretom 2000 Scanner (scan time one min; 256x256 matrix system, each section ten mm in thickness) within the first four days and then re- peated before the discharge of the patients from the Unit.

When the CT scan was normal in the early phase after stroke, tardive scan only was considered in order to evaluate any extension of tissue damage. Early scans only were available for analysis in patients who died shortly after their stroke.

The infarct size was considered “small” when the largest diameter of the low attenuation area measured up to 2.5 cm, “medium” when it mea- sured from 2.5-5 cm and “large” when it exceeded five cm.

398 C. POZZILLI ET AL.

Results The mean value of WBC count measured three days after cerebral ischemic infarction was 11.4 (x103/mm3) * 0.55 (k SEM), rz = 95. The change in WBC count between the first (< 48 h) and the second (third day) count after stroke in 33 patients is shown in Fig. 1. There was an increase in WBC count, with a mean of 9.6 k 0.5 (k SEM) for the first study and 13.0 * 0.8 (+ SEM) for the second, and this difference was statistically significant (P < 0.001, Student’s t-test, paired samples).

There was a clear elevation of peripheral WBC count with worsening of clinical features. Table 1 shows the relationship between mean WBC count and clinical state of the patients, as evaluated three days after the stroke. The different values of

WBC counts between the groups were statistically significant ( P < 0.01, analysis of variance).

In table 2, the mean values of WBC in patients with different size of CT hypodense areas are sum- marized. Larger hypodense areas were correlated with an increase of mean WBC count (P < 0.001, analysis of variance).

Table 3 shows the relationship between mean WBC count and clinical outcome. Peripheral WBC count was higher in patients with a poor outcome than in those with a good outcome. Mor- tality was associated with the highest WBC count values. The difference between the groups was statistically significant (P < 0.01, analysis of vari- ance).

A positive relationship between WBC count and increasing serum CPK value measured on the

Table 1 Relationship between WBC count and clinical status of the patients evaluated three days after stroke

Clinical status No patients WBC (xirm11~113) WBC range

Impaired consciousness Hemiplegia Hemiparesis

28 21 46

14.8 f 1.2 11.7 f 0.9 9.6 f 0.5

(9.6-24.3) (7.8-20.2) (5.0-13.2)

Values are means f SEM. The difference among the groups is statistically significant (P ? 0.01, anaysis of variance).

Table 2 Relationship between WBC count and size of hypodense area as shown on CT scan

Hypodense area No patients WBC (~103/11~4 WBC range

Large size 26 16.6 f 1.0 (10.8-24.3) Medium size 34 10.9 f. 0.6 (6.2-14.7) Small size 35 8.0 k 0.4 (5.0-12.0)

~

Values are means ? SEM. The difference among the groups is statistically significant (P < 0.001, analysis of variance).

Table 3 Relationship between WBC count, measured three days after a stroke, and clinical outcome of the patients

Clinical outcome No patients WBC (~1w-3) WBC range

Death Poor outcome (PO) Good outcome (GO)

20 29 46

16.4 f 1.1 12.2 f 0.8 8.7 f 0.4

(11.2-24.3) (8.1-20.2) (5.0-14.4)

Values are means f SEM. The difference among the groups is statistically significant (P < 0.01, analysis of variance).

CEREBRAL ISCHEMIC INFARCTION 399

The significant positive correlation found be- tween WBC count and the extent of hypodense area shown by X-ray CT scan, suggests that the raised cell count reflects a direct inflammatory response related to the degree of tissue damage. This is substantiated further by the positive cor- relation between WBC count and serum CPK el- evation. Among the serum enzymes, CPK has been shown to correlate with the amount of struc- tural cerebral damage in stroke patients (13). We postulate that the increase of peripheral WBC count may not be merely a passive reflection of the amount of cerebral infarction. Elevated WBC count in a biennal examination period has been shown to be a significant predictor of cerebral

39

I infarction in the Hiroshima and Nagasaki popula- tions (14). This association was not explained on the basis of corresponding age, sex or blood pres-

were analyzed, a significant role for the neutrophil count emerged in that study. Cerebral infarction

0-50 50-150 150+ CPKtrn U/m I )

Fig. 2. Relationship between wBc count and Serum sure levels, When differential leukocyte counts CPK both measured three days after a stroke. Number of patients is indicated. Values are means f SEM.

same day, is shown in Fig. 2. The correlation co- efficient for n = 95 is 0.43 (P < 0.001).

Finally, no significant correlation was found be- tween WBC count and ESR values.

Discussion The results of this study demonstrate that the early increase of total WBC count after cerebral ische- mic infarction correlates with the severity of ill- ness and is a good predictor of poor outcome and stroke-associated mortality.

The use of WBC count as a clinical indicator in cerebral infarction can be meaningful only if the patient is free from infections and from drug treat- ment that may alter the WBC count. Thus, in this study, the WBC count was obtained three days after the stroke: at this time, the patients included in the study were free from any clinically detec- table infection and were not receiving therapy with anti-inflammatory drugs. In the 33 patients in whom WBC count was performed within 48 h after stroke, the mean value was already high in comparison to normal expected values which sup- ports the contention that infarction and raised white count were causally related.

attributable to leukocytosis and increased blood viscosity is common and intense in myeloid leuke- mia (15).

A specific increase of circulating neutrophils is presumed to account for the early blood leuko- cytosis seen after a cerebral infarction; a common finding after any inflammatory process following tissue injury. Thus, increased WBC count may be at the same time a predictor of brain infarction and an indicator of prognosis and outcome.

Brain ischemia due to a critical reduction of cerebral blood flow is a well-recognized and com- mon cause of irreversible brain damage. However, delayed post-ischemic neuronal damage (as seen after a period of ischemia in animals) may contribute to further late tissue damage. This late phenomenon has been at- tributed to several biochemical processes such as a disruption of ion homeostasis, the breakdown of membrane phospholipids, the synthesis of vasoac- tive prostaglandins, the formation of active oxy- gen species, the release of cellular lysosomes, cel- lular acidosis and the breakdown of the blood- brain barrier (16,17).

It is not known whether delayed post-ischemic neuronal damage has a human counterpart. Clini- cal deterioration, attributable to ischemic necrotic edema, is usually observed between 36 and 72 h

400 C. POZZILLI ET AL.

(17,18) and corresponds with the time of the fre- quent deterioration of stroke patients after admis- sion to hospital (19).

The early rise in WBC count and its further significant increase after three days from the onset of stroke may have a more direct role in the deter- mination of the extent of final cellular damage. Recent studies on the inflammatory process have stressed that accumulation of stimulated neu- trophik at the site of tissue injury may augment tissue necrosis and further inflammatory reaction by the release of histolytic enzymes, toxic oxygen radicals and substances generated from degener- ating membranes (20,21). Furthermore, it has been experimentally demonstrated that a crude membrane fraction of granulocytes induces cytotoxic brain edema, increases intracellular so- dium with loss of intracellular K+, increases glucose utilization, lactate production and a re- duction in energy charge potential without hypo- xia (22). In addition, a reduction of the extent of ischemic myocardial injury by neutrophil deple- tion in dogs has been demonstrated, suggesting that neutrophil infiltration into infarcted myocar- dium may exacerbate the ischemic insult (23). This latter hypothesis may also have relevance for ischemic brain disease and deserves further val- idation.

Acknowledgements The authors wish to thank Dr. R.S.J. Frackowiak, Dr. G. Lucig- nani and Dr. F. Orzi for their valuable discussions; and Mrs. F. di Giacomo and C. Mattei for editorial assistance.

References 1. Yates P. 0. Vascular disease of the central nervous system

(chap. 3) In: Blackwood W, Corsellis J A N, eds. Gren- field‘s Neuropathology. London: Edward Arnold Ltd,

2. Alcalh H, Gado M, Torack R M. The effect of size, histo- logic elements and water content on the visualization of cerebral infarcts. Arch Neurol 1978:35:1-7.

3. Garcia J H, Kamijyo Y. Cerebral infarction: Evolution of histopathological changes after occlusion of a middle cere- bral artery in primates. J Neuropathol Exp Neurol

4. Pozzilli C, Lenzi G L, Argentino C, et al. Imaging of leuko- cytic infiltration in human cerebral infarcts. Stroke 1984 1985:16:2.

5. Somas R, Osterlund H, Muller R. Cerebrospinal fluid cytol- ogy after stroke. Arch Neurol 1972:26:489-501.

1976:lOl-6.

1974:33:409-421.

6. Merrit H H. Vascular lesion (chap. 2). In: H.H. Memt, ed. A textbook of neurology. Philadelphia: Lea & Febiger.

7. Van Buskirk C. Intracerebral vascular disease (vol2, chap. 10). In Baker A B, eds. Clinical neurology New York: Harper & Brother, 1962564-615.

8. Hughes W L, Kalbfleisch J M, Brandt E N, Costiloe J P. Myorcardial infarction prognoses by discriminant analysis. Arch Intern Med 1963:111:338-345.

9. Neil-Dwyer G, Cruickshank J . The blood leucocyte count and its prognostic significance in subarachnoid hemorrhage. Brain 1974:97:79-86.

10. Parkinson D, Stephensen S . Leucocytosis and subarachnoid hemorrhage. Surg Neurol 1984:21:132-134.

11. Shoenfeld Y, Gurewich Y, Gallant A, Pinkhas J. Pred- nisone-induced leukocytosis. Am J Med 1981:71:773-8.

12. Feigenson J S , McDowel F H, Meese P, MCarthy M L, Greenberg S D. Factors influencing outcome and length of stay in a stroke rehabilitation unit. Stroke 1977:8:651-6.

13. WolintzAH, Jacobs LD, Christoff N, SolomonM, Chernik N. Serum and cerebrospinal fluid enzymes in cerebrovascu- lar disease. Creatin phosphokinase, aldolase and lactic de- hydrogenase. Arch Neurol 1969: 20: 54-61.

14. Prentice R L, Szatrowski T P, Kato H, Mason M W. Leuko- cyte counts and cerebrovascular disease. J Chron Dis

15. D’Eramo N, Levi M. Neurological symptoms in leukemia (chap. 6). In: Neurological symptoms in blood diseases. Baltimore: University Park Press, 1972:100-142.

16. Raichle M E. The pathophysiology of brain ischemia. Ann Neurol 1983:13:2-10.

17. Plum F. What causes infarction in ischemic brain? The Robert Wartenberg lecture. Neurology: 33.222-33.

18. Plum F. Brain swelling and edema in cerebral vascular dis- ease. In: W k a n C H, ed. Cerebrovascular disease. Res Pub1 Assoc Res New Ment Dis 1966:41:318-348.

19. Roden A, Brotton M. Progression of stroke after arrival at hospital. Acta Neurol Scand 1982:suppl91:24.

20. Del Maestro R F. An approach to free radicals in medicine and biology. Acta Physiol Scand 198O:suppl492:153-168.

21. Weissmann G, Smolen J E, Korchak H M. Release of inflammatory mediators from stimulated neutrophils. N Engl J Med 1981:303:27-34.

22. Fishman R A, Sligar K, Hake R B. Effect of leukocytes on brain metabolism in granulocytic brain edema. Ann Neurol

23. Romson J L, Hook B G, Kunkel S L, Abrams G D, Schork M A, Lucchesi B R. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Cir- culation 1983:67:1016-23.

1967: 174-193.

1982:35:703-714.

19773:89-94.

Address Dr. Carlo Pozzilli Department of Neurological Science University of Rome Viale dell’Universit3 30 00185 Rome, Italy