AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

This article primarily addresses effects of hyperglycemia and hypoglycemia in the setting of acute stroke. Preexisting hyperglycemia is found commonly in patients presenting with acute stroke, and hypoglycemia may present with focal symptoms mimicking acute stroke. The reader is referred to more definitive discourses about the general management of diabetes and other manifestations of hyperglycemia and hypoglycemia in the general neurologic and endocrinologic literature.

Hyperglycemia: Although confounded by other factors, such as severity of the infarct, hyperglycemia in the face of acute stroke worsens clinical outcome. Nondiabetic hyperglycemic ischemic stroke patients have a 3-fold higher 30-day mortality and diabetic patients have a 2-fold 30-day mortality (Capes, 2001). In several trials involving thrombolytic and anticoagulation therapy in patients with stroke, hyperglycemia appears to be an independent risk factor for worsened outcome. Hyperglycemia has been suggested as an independent risk factor in hemorrhagic conversion of the stroke after administration of thrombolytic therapy.

Hypoglycemia: Several case reports describe hypoglycemia mimicking acute stroke or symptoms of transient ischemic attack (TIA). Misdiagnosis and improper treatment could worsen the outcomes. Therefore, evaluation of glucose levels is recommended in patients presenting with symptoms suggestive of acute stroke, particularly prior to administration of recombinant tissue-type plasminogen activator (rtPA). Symptoms caused by hypoglycemia can occur suddenly and fluctuate, suggesting a vascular etiology.

Pathophysiology

Hyperglycemia

Diabetes mellitus is an independent risk factor for stroke and may be one of the factors causing strokes at younger ages in groups such as Hispanic Americans that have a relatively high incidence of diabetes. The mechanism is believed to be accelerated atherosclerosis, which can affect vessels in many distributions, including small and large vessels. Cardiac involvement may predispose to embolic strokes as well. In addition, patients with diabetes may have any of several lipid abnormalities. Elevated levels of triglycerides, low-density lipoproteins (LDL), and very low-density lipoproteins (VLDL), along with lower than normal levels of high-density lipoprotein (HDL), are common findings in the lipid profiles of patients with diabetes. The combined effect of these factors results in promotion of atherosclerosis and thrombosis.

The specific mechanism(s) by which hyperglycemia leads to poorer clinical outcome in patients receiving anticoagulants or thrombolytics is not known, although several have been proposed, including the following:

• In some vascular beds, hyperglycemia causes glycosylation and thereby interferes with protein and enzyme function, including those functions that regulate production of substances that cause vasodilation and cellular adhesion within the vasculature.
• Hyperglycemia results in the formation of advanced glycation end products that are toxic to endothelial cells, and production of free radicals from various sources may result in further vascular injury.

Hyperglycemia worsens outcome and increases rate of mortality from stroke. Two mechanisms have been postulated to explain the negative influence of hyperglycemia on outcome following stroke:

• Poorer reperfusion due to vascular injury
• Increased acidosis, perhaps from lactic acid, leading to further tissue injury

Both mechanisms have been supported by experimental data. Parsons et al (2002) used MRI and MR spectroscopy in patients with hyperglycemic stroke and report that the detrimental effect of hyperglycemia may be due to metabolic acidosis in the infracted brain parenchyma. However, earlier animal studies suggested that hyperglycemia has a detrimental effect on cerebral vascular tree (Kawai, 1997; Quast, 1997).

In some studies, hyperglycemia appears to be associated with a reduced incidence of primary intracerebral hemorrhage. However, risk of hemorrhagic conversion of strokes appears to increase after rtPA administration in patients with diabetes. This risk may be present even at moderate elevations of serum glucose level. Notably, moderate hyperglycemia is presently not an exclusion criterion for administration of rtPA in patients with acute stroke; the range of blood glucose for which rtPA treatment of patients with acute stroke is acceptable is 50-400 mg/dL.

Hypoglycemia

Low levels of glucose can result from the following:

• Overuse of oral hypoglycemic agents or insulin
• Overproduction of endogenous insulin, which may be a result of an insulinoma
• Medical illnesses such as sepsis, renal failure, and hepatic failure

Two different mechanisms have been suggested as the causes of hypoglycemia-related strokelike episodes, as follows:

• The brain uses glucose predominantly for oxidative metabolism. Different brain regions have different metabolic demands. The need for glucose is highest in the cerebral cortex and basal ganglia. The cerebellum and the subcortical white matter have less demand for this substrate. Focal deficits may be a result of asymmetric distribution of glucose transporters.
• Gold and Marshall suggest that coagulation defects may be the cause of strokelike episodes.

Frequency

International

Hyperglycemia: Hyperglycemia is reported to be present in 20-50% of patients incurring acute stroke. In many trials of thrombolytic agents, hyperglycemia occurred in about 20-30% of subjects.

Hypoglycemia: The Diabetes Control and Complications Trial (DCCT) found a 3-fold higher rate of severe hypoglycemia in the group that received intensive treatment for diabetes than in those who received conventional therapy. Patients in the group receiving intensive therapy required medical attention for hypoglycemia at an incidence of 62 episodes per 100 patient-years. Berkovic et al reported that hypoglycemia was the cause of symptoms mimicking acute stroke in 3 of a total of 1460 patients admitted to their stroke unit over a 5-year period.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• Hyperglycemia and acute stroke
• • Patients may come to the attention of physicians because of preexisting diabetes mellitus.
  • Diabetes may be seen with other risk factors for stroke such as hypertension and hypercholesterolemia.
  • Hyperglycemia also may be seen in the setting of an acute stroke without a history of diabetes, presumably due to a sympathetic response to the infarct.
• Hypoglycemia and strokelike symptoms
• • Diabetes mellitus may have been diagnosed earlier, and recent changes in the doses of hypoglycemic agents and insulin may have been instituted.
  • Aggressively tight control, either patient driven or physician directed, may give rise to chronic hypoglycemia or recurrent episodes of hypoglycemia.
  • If factitious hypoglycemia is suspected, such behavior may have manifested earlier by similar episodes or other factitious behaviors.

Physical

• Signs and symptoms of acute stroke are covered in other articles (Stroke, Hemorrhagic; Stroke, Ischemic).
• Retinopathy, neuropathy, and peripheral vascular disease may be found in patients with long-standing diabetes.
• In the literature, signs of an acute stroke, such as hemiplegia, aphasia, and cortical blindness, have been reported with hypoglycemia.

WORKUP

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• In the setting of acute stroke, obtaining serum glucose levels along with a broader panel of complete blood count, electrolyte values, prothrombin time (PT), and activated partial thromboplastin time (aPTT) is routine practice.

Imaging Studies

• Obtain CT scan of the head when stroke is suspected. More recently, MRI with diffusion/perfusion sequences has been used for assessment of acute stroke.
• • The mechanism by which these tests specifically affect the diagnosis or treatment of patients with stroke and hyperglycemia is not clear.
  • However, that hyperglycemia may accelerate the ischemic process has been postulated, so that features characteristic of acute stroke, such as hypodensity on CT scan, may be seen earlier than in patients without hyperglycemia.
• If strokelike symptoms are a result of hypoglycemia, abnormal findings on imaging studies are dependent on the degree and duration of insult to the brain.
• • Initially, results on CT scan of the head may be normal.
  • Later, in patients with severe hypoglycemia that is prolonged and complicated by anoxic brain injury and coma, CT scan of the brain may show cortical atrophy reflecting laminar necrosis. The regions that are most prone to injury are cortical gray matter, followed by basal ganglia and cerebellar cortex.
  • If hypoglycemia is transitory and the clinical status of the patient returns to normal, follow-up CT scan findings also may be normal.

TREATMENT

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

• Hyperglycemia
• • In terms of primary prevention, treatment of diabetes appears to reduce the incidence of atherosclerotic complications. Intensive approaches to multiple risk factors in stroke have been suggested, including reduction of LDL (to below 100 mg/dL in diabetics), increase of HDL (with fibrates if tolerated, an effect especially beneficial in patients with insulin resistance [Robins, 2001]), tight glucose control, and hypertensive management.
  • Intensive insulin treatment for hyperglycemia has been studied in the surgical intensive care unit setting and has been proven to reduce incidence of critical care neuropathy (Van den Berghe, 2001). A subgroup analysis of patients with traumatic brain injury suggested that long-term clinical outcome was better in the group that was treated with intensive insulin (Van den Berghe, 2005).
  • Morbidity was reduced in patients treated with intensive insulin who were admitted to the medical intensive care unit, but overall mortality was unchanged (Van den Berghe, 2006). Mortality was reduced in the subset of patients who had ICU stays of at least 3 days.
  • Studies indicate that treatment of hypertension in diabetic patients reduces stroke risk by over 40%. Guidelines published by Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommend lower, more strict hypertension targets in diabetics of 130/80 (Chobanian, 2003).
  • The benefit of treatment of hyperglycemia with insulin in the setting of acute stroke has not been confirmed in randomized controlled clinical trials, and there is not yet sufficient evidence to recommend changing current recommendations to maintain glucose levels below 180 mg/dL. The risk of inducing hypoglycemia as part of an aggressive correction of serum glucose is as yet unknown in the acute stroke setting.
• Hypoglycemia
• • Frequent monitoring of glucose levels may be necessary to prevent hypoglycemia, especially when changes in doses of medications have been made. Other metabolic abnormalities, such as hepatic or renal failure, also may carry a risk of hypoglycemia.
  • When hypoglycemia is discovered, the glucose level must be brought expeditiously to a normal level. Intravenous fluids, such as dextrose 25% in water (D25W) or dextrose 50% in water (D50W), may be necessary. Note that dextrose 5% in water (D5W) is not an appropriate fluid because excess of free water may exacerbate cerebral edema, and because hyperglycemia may be induced, with harmful effects as above. Also, serum glucose levels should be monitored at frequent intervals.
  • Neurologists typically do not treat patients with glucose-containing fluids without coadministration of thiamine in order to avoid the possibility of precipitating acute Wernicke encephalopathy or chronic Korsakoff psychosis. A patient who is hypoglycemic because of systemic illness or malnutrition may be particularly vulnerable to vitamin deficiency.

Consultations

• Diabetes is managed in a primary care setting. However, certain patients whose diabetes is difficult to control or patients who may be experiencing the myriad of complications of diabetes may benefit from consultation with an endocrinologist.

Diet

Advise patients with new-onset diabetes to consult a dietitian for dietary advice.

MEDICATION

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Regarding the general management of diabetes, refer to appropriate sections of articles that deal with treatment of diabetes (Diabetes Mellitus, Type 1 - A Review; Diabetes Mellitus, Type 2 - A Review; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2).

Typically, hyperglycemia in the setting of acute stroke is treated with subcutaneous insulin in a sliding scale. Refractory hyperglycemia may require the use of intravenous (IV) insulin; however, IV insulin increases the risk of hypoglycemia.

Safety and efficacy of IV insulin in treatment of hyperglycemia in patients with acute stroke are being determined by ongoing/planned clinical trials.

Drug Category: Antihyperglycemic agents

These agents increase glucose metabolism.

Drug Category: Vitamins

These are essential for normal DNA synthesis.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Patient Education

• For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• The usual medicolegal risks of delayed diagnosis or misdiagnosis of stroke as well as medication adverse effects are pertinent to this chapter.
• Hypoglycemia also is associated with complications, especially in the setting of stroke and possible ongoing cerebral ischemia. These complications were defined earlier in this article.

ACKNOWLEDGMENTS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Sharyl Martini, MD to the development and writing of this article.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

• Aslan Y, Dinc H. MR findings of neonatal hypoglycemia [letter; comment]. AJNR Am J Neuroradiol. May 1997;18(5):994-6. [Medline].
• Bath PM. Optimising homeostasis. Br Med Bull. 2000;56(2):422-35. [Medline].
• Berkovic SF, Bladin PF, Darby DG. Metabolic disorders presenting as stroke. Med J Aust. Mar 31 1984;140(7):421-4. [Medline].
• Browning RG, Olson DW, Stueven HA. 50% dextrose: antidote or toxin?. Ann Emerg Med. Jun 1990;19(6):683-7. [Medline].
• Bruno A, Biller J, Adams HP Jr. Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology. Jan 15 1999;52(2):280-4. [Medline].
• Calles-Escandon J, Garcia-Rubi E, Mirza S. Type 2 diabetes: one disease, multiple cardiovascular risk factors. Coron Artery Dis. 1999;10(1):23-30. [Medline].
• Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. Oct 2001;32(10):2426-32. [Medline].
• Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. May 21 2003;289(19):2560-72. [Medline].
• DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. Sep 30 1993;329(14):977-86. [Medline].
• Demchuk AM, Morgenstern LB, Krieger DW. Serum glucose level and diabetes predict tissue plasminogen activator- related intracerebral hemorrhage in acute ischemic stroke. Stroke. Jan 1999;30(1):34-9. [Medline].
• Garg R, Chaudhuri A, Munschauer F, Dandona P. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke. Jan 2006;37(1):267-73. [Medline].
• Gold AE, Marshall SM. Cortical blindness and cerebral infarction associated with severe hypoglycemia. Diabetes Care. Sep 1996;19(9):1001-3. [Medline].
• Gorelick PB, Sacco RL, Smith DB. Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA. Mar 24-31 1999;281(12):1112-20. [Medline].
• Kawai N, Keep RF, Betz AL. Hyperglycemia and the vascular effects of cerebral ischemia. Stroke. Jan 1997;28(1):149-54. [Medline].
• Lawson ML, Gerstein HC, Tsui E. Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes. A systematic review and meta-analysis. Diabetes Care. Mar 1999;22 Suppl 2:B35-9. [Medline].
• Lukovits TG, Mazzone TM, Gorelick TM. Diabetes mellitus and cerebrovascular disease. Neuroepidemiology. 1999;18(1):1-14. [Medline].
• Parsons MW, Barber PA, Desmond PM, et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol. Jul 2002;52(1):20-8. [Medline].
• Quast MJ, Wei J, Huang NC, et al. Perfusion deficit parallels exacerbation of cerebral ischemia/reperfusion injury in hyperglycemic rats. J Cereb Blood Flow Metab. May 1997;17(5):553-9. [Medline].
• Richardson ML, Kinard RE, Gray MB. CT of generalized gray matter infarction due to hypoglycemia. AJNR Am J Neuroradiol. Jul-Aug 1981;2(4):366-7. [Medline].
• Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA. Mar 28 2001;285(12):1585-91. [Medline].
• Shotliff K, Prasad A, Millard P. Hypoglycaemia masquerading as a stroke [letter]. Postgrad Med J. Oct 1992;68(804):843. [Medline].
• The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. Dec 14 1995;333(24):1581-7. [Medline].
• The NINDS t-PA stroke study group. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. Nov 1997;28(11):2119-25. [Medline].
• Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology. Apr 26 2005;64(8):1348-53. [Medline].
• Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. Feb 2 2006;354(5):449-61. [Medline].
• van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. Nov 8 2001;345(19):1359-67. [Medline].
• Wallis WE, Donaldson I, Scott RS. Hypoglycemia masquerading as cerebrovascular disease (hypoglycemic hemiplegia). Ann Neurol. Oct 1985;18(4):510-2. [Medline].
• Young GB, Roper AH, Bolton CF. Metabolic encephalopathies. Coma and impaired consciousness: a clinical perspective. 1998;Chapter 13:333-8.
• Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96:380-5. [Medline].

Article Last Updated: Apr 4, 2006