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(Stroke. 1995;26:484-487.)
© 1995 American Heart Association, Inc.

Articles

Hyperglycemia and Hemorrhagic Transformation of Cerebral Infarcts

Joseph P. Broderick, MD; Timothy Hagen, DO; Thomas Brott, MD Thomas Tomsick, MD

From the Departments of Neurology and Neuroradiology (T.T.), University of Cincinnati Medical Center (Ohio).

	Abstract

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Background Identification of factors that predispose to bleeding into ischemic brain could lead to safer use of thrombolytic agents in the setting of ischemic stroke. Recently de Courten-Meyers and colleagues reported that occluding the middle cerebral artery of markedly hyperglycemic cats was associated with 5-fold more frequent and 25-fold more extensive hemorrhage into infarcts than in normoglycemic animals. Hemorrhage associated with hyperglycemia in cats was much more pronounced with reperfusion than with permanent middle cerebral artery occlusion.

Case Descriptions We describe two patients with a unique presentation of diffuse hemorrhagic infarction of the caudate and lentiform nuclei associated with initially marked hyperglycemia and the subsequent development of hemichorea.

Conclusions We hypothesize that the marked hyperglycemia due to poor control of diabetes contributed to the hemorrhagic change of the caudate and lenticular nuclei. Because the hemorrhage in hyperglycemic cats was more pronounced in the setting of reperfusion, hemorrhagic risk associated with hyperglycemia should be investigated, particularly in ongoing thrombolytic treatment trials for acute ischemic stroke. We encourage other acute stroke investigators to prospectively look at the risk of brain hemorrhage in stroke patients with marked hyperglycemia.

Key Words: cerebral hemorrhage • cerebral infarction • diabetes mellitus • hyperglycemia • reperfusion

	Introduction

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Bleeding into cerebral infarcts is the major safety issue in acute treatment studies of thrombolytic therapy for acute cerebral infarction. Factors that have been associated with an increased risk of bleeding in stroke patients treated with thrombolytic agents include the dose of thrombolytic agent per kilogram of body weight, delay in treatment with thrombolytic therapy, an initial diastolic blood pressure of 100 mm Hg or greater, and very low levels of residual cerebral blood flow in the region of ischemia.^{1 2 3 4} Identification of other factors that predispose to bleeding into ischemic brain could lead to safer use of thrombolytic agents in the setting of ischemic stroke.

Recently de Courten-Myers and colleagues⁵ reported that occluding the middle cerebral artery of markedly hyperglycemic cats was associated with 5-fold more frequent and 25-fold more extensive hemorrhage into infarcts than in normoglycemic animals. We now describe two patients with a unique presentation of diffuse hemorrhagic infarction of the caudate and lentiform nuclei associated with initially marked hyperglycemia and the subsequent development of hemichorea.

	Case Reports

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Case 1
A 69-year-old right-handed man presented with acute onset of hemichorea of the left arm and leg 2 days before admission. The patient had chronic hypertension and poorly controlled diabetes as well as a remote history of schizophrenia that had been treated with thioridazine 15 years before admission. The admission general physical and neurological examination was significant only for choreiform movements of the left arm and leg. An admission noncontrast computed tomographic (CT) scan of the head showed increased attenuation of the right caudate nucleus (Fig 1). A magnetic resonance (MR) scan of the brain performed 4 days after onset of symptoms showed increased signal intensity of the caudate nucleus on T₁-weighted images and decreased signal intensity of the same region on T₂-weighted images (Fig 2). These findings were consistent with intracellular methemoglobin due to diffuse petechial hemorrhage of the caudate and lenticular nuclei. Carotid noninvasive studies showed bilateral 50% to 79% stenosis of the internal carotid arteries. Echocardiography demonstrated a slightly stenotic aortic valve. Prothrombin time, partial thromboplastin time, platelet count, and toxicology screen were normal. Initial serum glucose was 33 mmol/L (597 mg/dL).

View larger version (92K): [in this window] [in a new window]   Figure 1. Admission computed tomographic scan of patient 1 performed 2 days after onset of symptoms.

View larger version (133K): [in this window] [in a new window]   Figure 2. Magnetic resonance images of patient 1 performed 4 days after onset of symptoms.

The patient's chorea resolved completely with haloperidol. The haloperidol was discontinued after 2 weeks, and the patient's hemichorea returned. Brain MR imaging done 3 weeks after onset of the initial movements showed continued high-intensity signal changes in the caudate and lenticular nuclei on T₁-weighted images (Fig 3). The patient's hemichorea was not as responsive to a second trial of haloperidol. He was switched to pimozide (4 mg twice a day) without good control. Addition of sodium valproate (250 mg twice a day) improved his hemichorea significantly.

View larger version (137K): [in this window] [in a new window]   Figure 3. Magnetic resonance images of patient 1 performed 3 weeks after onset of symptoms.

Case 2
A 71-year-old right-handed woman presented to an outlying hospital with confusion and decreased responsiveness. Medical history was significant for poorly controlled insulin-dependent diabetes, hypertension, past coronary arterial bypass operation, and prior occipital stroke. Brain CT on admission to the emergency department of an outlying hospital showed increased attenuation of the left caudate nucleus (CT not shown). Her serum blood sugar was 37.6 mmol/L (678 mg/dL), and her serum sodium was 123 mEq/mL. She was transferred to the University of Cincinnati Medical Center for evaluation. Admission vital signs at the University of Cincinnati Medical Center included blood pressure of 118/68 mm Hg, pulse of 80 beats per minute, respiratory rate of 18/min, and temperature of 37.0°C. The neurological examination demonstrated generalized confusion; disorientation to time, place, and date; poor attention; and poor short-term recall. The examination was limited because of the patient's complaint of severe right-sided flank and chest pain. However, no focal weakness, sensory loss, or reflex changes could be demonstrated. A brain MR scan done 2 days after onset of original symptoms showed hyperintensity on T₁-weighted images of the left caudate and lentiform nuclei (Fig 4). Hypointensity on T₂-weighted images was seen in these same regions as well as in the right lentiform nucleus. These signal changes were consistent with diffuse petechial hemorrhage of the deep gray matter structures.

View larger version (128K): [in this window] [in a new window]   Figure 4. Magnetic resonance images of patient 2 performed 2 days after onset of symptoms.

The patient's altered mental status improved over several days with correction of her hyperglycemia and hyponatremia. However, on hospital day 5 she awoke with chorea of both arms and legs; the right-sided movements were most prominent. Carotid noninvasive testing showed bilateral 16% to 49% stenosis of the internal carotid arteries near the bifurcation. The echocardiogram showed a mildly dilated left ventricle with normal systolic function and no valvular abnormalities. Clotting studies including protein C, protein S, and antithrombin III were normal.

Rib films, electrocardiograms, cardiac enzymes, and lung ventilation and perfusion scan revealed no clear clause of the patient's chest pain. The chest pain resolved with nonsteroidal anti-inflammatory medication. The choreiform movements diminished with haloperidol but persisted at discharge.

	Discussion

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Hemorrhagic transformation of cerebral infarcts in both patients was limited to the caudate and lenticular nuclei. In this type of mild to moderate hemorrhagic change, hemorrhage is thought to result from diapedesis of red blood cells through ischemic capillary endothelium, usually without vessel rupture.⁶ If this is true, then the capillary endothelium of the deep gray matter structures in our two patients was preferentially affected by ischemia and by subsequent red blood cell leakage compared with capillaries of the white matter. We hypothesize that the marked hyperglycemia due to poor control of diabetes in both patients contributed to the hemorrhagic change of the caudate and the lenticular nuclei.

In a cat model of temporary and permanent middle cerebral artery occlusion, de Courten-Meyers and colleagues⁵ reported a 5-fold increase in hemorrhagic infarcts in cats who were hyperglycemic (approximately four times the normal glucose level) at onset of ischemia compared with normoglycemic animals. In addition, the areas of hemorrhage in the hyperglycemic cats were 25-fold larger than the areas of hemorrhage in normoglycemic cats. Removal of the clip on the middle cerebral artery in hyperglycemic cats at 4 and 8 hours substantially increased the volume of infarction and edema as well as areas of hemorrhage. Areas of hemorrhagic infarction correlated with regions of near-total depletion of high-energy phosphates and high levels of lactate (>30 mmol/L per kilogram).

Hyperglycemia at the onset of focal brain ischemia in cats, rats, and gerbils increases the volume of cerebral infarction by enhancing intracellular or extracellular acidosis.^{7 8 9 10 11 12} However, Siesjö and colleagues⁹ report that exaggeration of ischemic damage by hyperglycemia-enhanced lactic acidoses occurs only at high tissue lactate values (15 to 20 mmol/L per kilogram). Lower levels of hyperglycemia with a similar degree of focal brain ischemia would be expected to result in lower levels of lactic acid and less tissue damage. We hypothesize that the combination of very high levels of serum glucose coupled with the higher metabolic rate of the deep gray matter nuclei led to high levels of lactate in the caudate and lenticular nuclei. These very high lactate levels and associated acidosis may have then exacerbated endothelial damage in these structures with subsequent extravasation of red blood cells through the leaky vessels.

What support is there for the role of hyperglycemia in the precipitation of hemorrhage into areas of infarction? In a case-control study of 41 patients with a hemorrhagic infarct, Beghi and colleagues¹³ reported that 31% of diabetics had hemorrhagic conversion of their infarct compared with 18% of stroke patients without a history of diabetes (odds ratio, 1.85; 95% confidence interval, 0.65 to 5.26). Although this small study is suggestive of a relationship between hemorrhage and hyperglycemia, the hemorrhagic risk associated with hyperglycemia and diabetes was not statistically significant. In addition, serum glucose can increase from physiological stress,^{14 15} and hemorrhagic infarction occurs more commonly with larger infarcts.⁶ Thus, a causal connection between hyperglycemia at stroke onset and subsequent hemorrhagic transformation in humans may be difficult to prove.

Because the hemorrhagic risk associated with hyperglycemia in cats was much more pronounced in the setting of reperfusion, the question of hemorrhagic risk in association with hyperglycemia needs to be examined, particularly in the setting of thrombolytic treatment trials for acute ischemic stroke. At least one of these trials, the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial,¹⁶ excludes patients with a glucose of 22.2 mmol/L (400 mg/dL) or more. However, in their analysis of factors that predispose to symptomatic brain hemorrhage, these large trials should be able to investigate the relationship between hyperglycemia and brain hemorrhage and to adjust for the severity of the initial stroke as a potentially confounding variable. We encourage other acute stroke investigators to prospectively look at the risk of brain hemorrhage in stroke patients with marked hyperglycemia.

	Acknowledgments

 
We wish to thank Joan Mohlman for her assistance in the preparation of this manuscript.

	Footnotes

 
Reprint requests to Joseph P. Broderick, MD, University of Cincinnati Medical Center, Department of Neurology, 231 Bethesda Ave, Room 4010, Cincinnati, OH 45267-0525.

Received October 24, 1994; revision received December 2, 1994; accepted December 2, 1994.

	References

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