Jasvinder Chawla, MD, MBA Chief , Hines Veterans Affairs Hospital, Professor of Neurology, Loyola University Medical Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic , American Society, American Medical Association.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjuct Assistant Professor, University of Nebraska Medical Center College of , Editor-in-Chief, Medscape Drug Reference

Howard S Kirshner, MD Professor of Neurology, and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine, Director, Vanderbilt Stroke Center, Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital, Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center.

Chief Editor

Helmi L Letsep, MD Professor and Vice Chair, Department of Neurology, Oregon Health and Science University School of Medicine, Associate Director, OHSU Stoke Center

Additional Contributors

Pitchaiah Mandava, MD, PhD Assistant Professor, Department of Neurology, Baylor College of Medicine, Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center.

Richard M Zweifler, MD Chief of Neurosciences, Sentara Healthcare, Professor and Chair of Neurology, Eastern Virginia .

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Thomas A Kent, MD Professor and Director of Stroke Research and Education, Department of Neurology, Baylor College of Medicine, Chief of Neurology, Michael E DeBakey Veterans Affairs Medical Center.

Course Content Definitions Practice Essentials of Hyperglycemia in Stroke Mellitus Proposed mechanisms for Hyperglycemia and worsened outcomes Possible protective effects of Hyperglycemia in lacunar stroke subtype in stroke like occurrences Signs and symptoms of Hypoglycemia Evaluation of Glycemic level and stroke Hypoglycemic symptoms and manifestations Central nervous system Laboratory studies Imaging studies Management Hyperglycemia Hypoglycemia Diagnosis Routine tests CT scanning of head in Hyperglycemia Consultations Acute Hyperglycemic therapy Intensive therapy Sulfonylurea agents Complications Therapy in Hypoglycemia

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Definitions

Hyperglycemia (also spelled hyperglycaemia or hyperglycæmia), is a condition in which an excessive amount of circulates in the blood plasma. This is generally a blood level higher than 11.1 mmol/l (200 mg/dl), but symptoms may not start to become noticeable until even higher values such as 13.9–16.7 mmol/l (~250–300 mg/dl). A subject with a consistent range between ~5.6 and ~7 mmol/l (100–126 mg/dl) (American Diabetes Association guidelines) is considered slightly hyperglycemic, and above 7 mmol/l (126 mg/dl) is generally held to have diabetes. For diabetics, glucose levels that are too hyperglycemic can vary from person to person, mainly due to the person's renal threshold of glucose and overall glucose tolerance. On average, however, chronic levels above 10–12 mmol/L (180–216 mg/dl) can produce noticeable organ damage over time.

White hexagons in the image represent glucose molecules, which are increased in the lower image. Hypoglycemia, also known as low blood sugar, is a fall in blood sugar to levels below normal. This may result in a variety of symptoms including clumsiness, trouble talking, confusion, loss of consciousness, seizures or death. A feeling of hunger, sweating, shakiness and weakness may also be present. Symptoms typically come on quickly. The most common cause of hypoglycemia is medications used to treat diabetes mellitus such as insulin and sulfonylureas. Risk is greater in diabetics who have eaten less than usual, exercised more than usual or drunk alcohol. Other causes of hypoglycemia include kidney failure, certain tumours (such as ), liver disease, , starvation, inborn error of metabolism, severe infections, reactive hypoglycemia and a number of drugs including alcohol. Low blood sugar may occur in otherwise healthy babies who have not eaten for a few hours.

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The glucose level that defines hypoglycemia is variable. In people with diabetes, levels below 3.9 mmol/L (70 mg/dL) are diagnostic. In adults without diabetes, symptoms related to low blood sugar, low blood sugar at the time of symptoms and improvement when blood sugar is restored to normal confirm the diagnosis. Otherwise, a level below 2.8 mmol/L (50 mg/dL) after not eating or following exercise may be used. In new-borns, a level below 2.2 mmol/L (40 mg/dL), or less than 3.3 mmol/L (60 mg/dL) if symptoms are present, indicates hypoglycemia. Other tests that may be useful in determining the cause include insulin and C peptide levels in the blood.

Practice Essentials

Pre-existing hyperglycemia worsens the clinical outcome of acute stroke. Nondiabetic ischemic stroke patients with hyperglycemia have a 3-fold higher 30-day mortality rate than do patients without hyperglycemia. In diabetic patients with ischemic stroke, the 30-day mortality rate is 2-fold higher.

With regard to hypoglycemia, the condition can mimic acute stroke or symptoms of transient ischemic attack (TIA).

Signs and symptoms in Hyperglycemia The degree of hyperglycemia can change over time depending on the metabolic cause, for example, impaired glucose tolerance or fasting glucose, and it can depend on treatment. Temporary hyperglycemia is often benign and asymptomatic. Blood glucose levels can rise well above normal and cause pathological and functional changes for significant periods without producing any permanent effects or symptoms. During this asymptomatic period, an abnormality in metabolism can occur which can be tested by measuring plasma glucose. Chronic hyperglycemia at above normal levels can produce a very wide variety of serious complications over a period of years, including kidney damage, neurological damage, cardiovascular damage, damage to the retina or damage to feet and legs. may be a result of long-term hyperglycemia. Impairment of growth and susceptibility to certain infection can occur as a result of chronic hyperglycemia. Acute hyperglycemia involving glucose levels that are extremely high is a medical emergency and can rapidly produce serious complications (such as fluid loss through osmotic diuresis). It is most often seen in persons who have uncontrolled insulin-dependent diabetes. The following symptoms may be associated with acute or chronic hyperglycemia, with the first three composing the classic hyperglycemic triad:

• – frequent hunger, especially pronounced hunger • Polydipsia – frequent thirst, especially excessive thirst • Polyuria – increased volume of urination (not an increased frequency, although it is a common consequence) • • • Restlessness • Weight loss • Poor wound healing (cuts, scrapes, etc.) • Dry mouth • Dry or itchy skin • Tingling in feet or heels • Erectile dysfunction • Recurrent infections, external ear infections (swimmer's ear) • Cardiac arrhythmia

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• Stupor • Coma • Seizures Frequent hunger without other symptoms can also indicate that blood sugar levels are too low. This may occur when people who have diabetes take too much oral hypoglycemic medication or insulin for the amount of food they eat. The resulting drop in to below the normal range prompts a hunger response. Polydipsia and polyuria occur when blood glucose levels rise high enough to result in excretion of excess glucose via the kidneys, which leads to the presence of glucose in the urine. This produces an osmotic diuresis. Signs and symptoms of may include:

• Ketoacidosis • Kussmaul hyperventilation (deep, rapid breathing) • Confusion or a decreased level of consciousness • Dehydration due to glycosuria and osmotic diuresis • Increased thirst • 'Fruity' smelling breath odour • and • Impairment of cognitive function, along with increased sadness and • Weight loss Hyperglycemia causes a decrease in cognitive performance, specifically in processing speed, executive function, and performance. Decreased cognitive performance may cause forgetfulness and concentration loss. Hyperglycemia in stroke

Pre-existing hyperglycemia is found commonly in patients presenting with acute stroke and is reported to be present in 20 to 50% of patients. In many trials of thrombolytic agents, hyperglycemia occurred in about 20-30% of subjects.

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. In several trials involving thrombolytic and anticoagulation therapy in patients with stroke, hyperglycemia appears to be an independent risk factor for worsened outcome. In addition, hyperglycemia has been suggested as an independent risk factor in hemorrhagic conversion of the stroke after administration of thrombolytic therapy.

Several case reports describe hypoglycemia mimicking acute stroke or symptoms of transient ischemic attack (TIA). Berkovic et al reported that hypoglycemia was the cause of symptoms mimicking acute stroke in 3 of 1460 patients admitted to their stroke unit over a 5-year period.

Diabetes mellitus 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.

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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. Proposed mechanisms for hyperglycemia and worsened outcomes 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. In some vascular beds, hyperglycemia causes glycosylation and thereby interferes with 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: (1) poorer reperfusion due to vascular injury and a loss of vascular tone through oxidation of nitric oxide dependent mechanisms; and (2) increased acidosis, perhaps from lactic acid/acid sensing channels, leading to further tissue injury. Both mechanisms have been supported by experimental data.

Martini and Kent suggest that, even if an occluded vessel causing stroke is recanalized, effective reperfusion may not be established in patients with hyperglycemia. By setting up a “pro-constrictive, pro-thrombotic and pro-inflammatory” state, hyperglycemia may be harmful to the endothelial cells and the vascular tree.

Parsons et al. used magnetic resonance imaging (MRI) and magnetic resonance spectroscopy in patients with hyperglycemic stroke and reported 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 the cerebral vascular tree. Possible protective effects of hyperglycemia in lacunar stroke subtype Although hyperglycemia worsens clinical outcome in ischemic strokes, this does not appear to be the case in lacunar strokes. In reporting data from the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) database, Bruno et al found that, despite higher baseline glucose levels being associated with worse functional outcomes in nonlacunar stroke patients, there was a complex relationship between baseline glucose values and excellent functional outcomes in lacunar strokes.

In another study, Uyttenboogaart et al reported that, in lacunar stroke subjects, moderate hyperglycemia, defined as glucose levels between 8 and 12 mmol/L, was associated with better clinical outcome (modified Rankin Score of 0-2) compared with normoglycemic patients. However, clinical outcome was worsened for subjects with baseline glucose values greater than 12 mmol/L.

The mechanism by which hyperglycemia may be protective in lacunar stroke is not known, although it could involve particular sensitivity of white matter to glucose levels in the face of ischemia.

• Patients may come to the attention of clinicians because of pre-existing diabetes mellitus

• Diabetes may also be seen with other risk factors for stroke, such as hypertension and hypercholesterolemia

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• High glycemic levels may also be seen in the setting of an acute stroke without a , presumably due to a sympathetic response to the infarct

• Retinopathy, neuropathy, and peripheral vascular disease may be found in patients with long- standing diabetes

Hypoglycemia in stroke-like occurrences

In the literature, signs of an acute stroke, such as hemiplegia, aphasia, and cortical blindness, have been reported with hypoglycemia.

In individuals presenting with low glycemic levels and stroke-like symptoms, diabetes mellitus may have been previously diagnosed, and recent changes in the doses of hypoglycemic agents and insulin may have been instituted. In particular, aggressively tight glucose control, either patient driven, or clinician directed, may give rise to chronic or recurrent episodes of hypoglycemia. However, if factitious hypoglycemia is suspected, such behaviour may have manifested earlier as similar episodes or other factitious behaviours.

Symptoms caused by hypoglycemia can occur suddenly and fluctuate, suggesting a vascular etiology.

Signs and Symptoms in Hypoglycemia

Hypoglycemic symptoms and manifestations can be divided into those produced by the counterregulatory hormones (epinephrine/ and ) triggered by the falling glucose, and the neuroglycopenic effects produced by the reduced brain sugar. Low levels of glucose can result from overuse of oral hypoglycemic agents or insulin, overproduction of endogenous insulin (which may be a result of an insulinoma), or medical illnesses such as sepsis, renal failure, and hepatic failure.

Two different mechanisms have been suggested as the causes of hypoglycemia-related stroke-like episodes. First, 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. Second, Gold and Marshall suggest that coagulation defects may be the cause of stroke-like episodes. Shukla et al. described the role of hypoglycemia in neuroinflammation and cerebral ischemic damage in diabetics.

Evaluation of Glycemic Levels and Stroke

Presentation of patients with hyperglycemia and acute stroke Patients may come to the attention of clinicians because of pre-existing diabetes mellitus. Diabetes may also be seen with other risk factors for stroke such as hypertension and hypercholesterolemia. However, high glycemic levels may also be seen in the setting of an acute stroke without a history of diabetes, presumably due to a sympathetic response to the infarct.

Retinopathy, neuropathy, and peripheral vascular disease may be found in patients with long-standing diabetes. Presentation of patients with hypoglycemia and stroke-like symptoms In the literature, signs of an acute stroke, such as hemiplegia, aphasia, and cortical blindness, have been reported with hypoglycemia.

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In individuals presenting with low glycemic levels and stroke-like symptoms, diabetes mellitus may have been diagnosed earlier, and recent changes in the doses of hypoglycemic agents and insulin may have been instituted. In particular, aggressively tight control, either patient driven, or clinician directed, may give rise to chronic hypoglycemia or recurrent episodes of hypoglycemia. However, if factitious hypoglycemia is suspected, such behaviour may have manifested earlier by similar episodes or other factitious behaviours.

Misdiagnosis and improper treatment of hypoglycemia could worsen the outcomes. Thus, evaluation of glucose levels is recommended in patients presenting with symptoms suggestive of acute stroke, particularly before administration of recombinant tissue-type plasminogen activator (rtPA). Symptoms caused by hypoglycemia can occur suddenly and fluctuate, suggesting a vascular etiology.

Rundel et al. suggest that measuring using the model assessment index may help improve estimation of future risk of stroke in nondiabetic individuals.

Hypoglycemic symptoms and manifestations

• Shakiness, anxiety, nervousness • , • Sweating, feeling of warmth (sympathetic muscarinic rather than adrenergic) • , coldness, clamminess • Dilated pupils (mydriasis) • Hunger, borborygmus • Nausea, vomiting, abdominal discomfort •

Central nervous system

• Abnormal thinking, impaired judgment • Nonspecific dysphoria, moodiness, , crying, exaggerated concerns • Feeling of numbness, pins and needles () • Negativism, irritability, belligerence, combativeness, rage • Personality change, emotional lability • Fatigue, weakness, apathy, lethargy, daydreaming, sleep • Confusion, memory loss, light-headedness or , delirium • Staring, glassy look, blurred vision, double vision • Flashes of light in the field of vision • Automatic behaviour, also known as automatism • Difficulty speaking, slurred speech • Ataxia, incoordination, sometimes mistaken for drunkenness • Focal or general motor deficit, paralysis, hemiparesis • Headache • Stupor, coma, abnormal breathing • Generalized or focal seizures

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Not all the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms, if symptoms even occur. Specific manifestations may also vary by age, by severity of the hypoglycemia and the speed of the decline. In young children, vomiting can sometimes accompany morning hypoglycemia with ketosis. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise. The symptoms of a single person may be similar from episode to episode but are not necessarily so and may be influenced by the speed at which glucose levels are dropping, as well as previous incidents. In new-borns, hypoglycemia can produce irritability, jitters, myoclonic jerks, cyanosis, respiratory distress, apneic episodes, sweating, hypothermia, somnolence, hypotonia, refusal to feed, and seizures or "spells." Hypoglycemia can resemble asphyxia, hypocalcemia, sepsis, or failure. In both young and old people with hypoglycemia, the brain may habituate to low glucose levels, with a reduction of noticeable symptoms despite neuroglycopenic impairment. In insulin-dependent diabetic people this phenomenon is termed hypoglycemia unawareness and is a significant clinical problem when improved glycemic control is attempted. Another aspect of this phenomenon occurs in type I glycogenosis, when chronic hypoglycemia before diagnosis may be better tolerated than acute hypoglycemia after treatment is underway. Hypoglycemic symptoms can also occur when one is sleeping. Examples of symptoms during sleep can include damp bed sheets or clothes from . Having nightmares or the act of crying out can be a sign of hypoglycemia. Once the individual is awake, they may feel tired, irritable, or confused and these may be signs of hypoglycemia as well. In nearly all cases, hypoglycemia that is severe enough to cause seizures or can be reversed without obvious harm to the brain. Cases of death or permanent neurological damage occurring with a single episode have usually involved prolonged, untreated unconsciousness, interference with breathing, severe concurrent disease, or some other type of vulnerability. Nevertheless, brain damage or death has occasionally resulted from severe hypoglycemia. Research in healthy adults shows that mental efficiency declines slightly but measurably as blood glucose falls below 3.6 mM (65 mg/dL). Hormonal defence mechanisms (adrenaline and glucagon) are normally activated as it drops below a threshold level (about 55 mg/dL (3.0 mM) for most people), producing the typical hypoglycemic symptoms of shakiness and dysphoria. Obvious impairment may not occur until the glucose falls below 40 mg/dL (2.2 mM), and many healthy people may occasionally have glucose levels below 65 in the morning without apparent effects. Since the brain effects of hypoglycemia, termed , determine whether a given low glucose is a "problem" for that person, most doctors use the term hypoglycemia only when a moderately low glucose level is accompanied by symptoms or brain effects. Determining the presence of both parts of this definition is not always straightforward, as hypoglycemic symptoms and effects are vague and can be produced by other conditions; people with recurrently low glucose levels can lose their threshold symptoms so that severe neuroglycopenic impairment can occur without much warning, and many measurement methods (especially glucose meters) are imprecise at low levels. It may take longer to recover from severe hypoglycemia with unconsciousness or seizure even after restoration of normal blood glucose. When a person has not been unconscious, failure of carbohydrate to reverse the symptoms in 10–15 minutes increases the likelihood that hypoglycemia was not the cause of the symptoms. When severe hypoglycemia has persisted in a hospitalized person, the amount of glucose required to maintain satisfactory blood glucose levels becomes an important clue to the underlying cause.

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Glucose requirements above 10 mg/kg/minute in infants, or 6 mg/kg/minute in children and adults are strong evidence for hyperinsulinism. In this context this is referred to as the glucose infusion rate (GIR). Finally, the blood glucose response to glucagon given when the glucose is low can also help distinguish among various types of hypoglycemia. A rise of blood glucose by more than 30 mg/dL (1.70 mmol/l) suggests insulin excess as the probable cause of the hypoglycemia. Laboratory studies

In the setting of acute stroke, obtaining the following is routine practice:

• Serum glucose levels

• Complete blood count (CBC)

• Electrolyte values

• Prothrombin time (PT)

• Activated partial thromboplastin time (aPTT)

Imaging studies

Because hyperglycemia may accelerate the ischemic process in stroke, it is possible that characteristic features of acute stroke will appear on computed tomography (CT) or magnetic resonance imaging (MRI) scans sooner than they would in patients without hyperglycemia.

CT scan of the brain showing a prior right-sided ischemic stroke from blockage of an artery. Changes on a CT may not be visible early on.

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If stroke-like symptoms are a result of hypoglycemia, a CT scan of the head may initially be normal. Later, in patients with severe hypoglycemia that is prolonged and complicated by anoxic brain injury and coma, CT scanning of the brain may show cortical atrophy (reflecting laminar necrosis). If the hypoglycemia is transitory and the clinical status of the patient returns to normal, follow-up CT-scan findings may again be normal.

Management

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 the following:

• Reduction of low-density lipoprotein (LDL) - To below 100 mg/dL in diabetic patients

• Increase of high-density lipoprotein (HDL) - With fibrates if tolerated, an effect that is especially beneficial in patients with insulin resistance

• Tight glucose control

• Hypertensive management

Patients with acute stroke and hyperglycemia are often kept NPO (nothing by mouth), because of the complicating effects of feeding on the blood glucose level.

Typically, hyperglycemia in the setting of acute stroke is treated with subcutaneous insulin on a sliding scale. Refractory hyperglycemia may require the use of intravenous (IV) insulin; however, IV insulin increases the risk of hypoglycemia. The safety and efficacy of IV insulin in the treatment of hyperglycemia in patients with acute stroke are being determined by ongoing/planned clinical trials. Researchers have revealed that the rates of hemorrhagic transformation incidence have been associated with increased blood glucose levels. They recommend optimizing insulin therapy for the prevention of hemorrhagic transformation during the treatment of acute ischemic stroke.

Bellolio et al. analysed the results of 7 trials involving 1296 participants (639 in the intervention group and 657 in the control group) and concluded that the administration of intravenous insulin to maintain serum glucose levels in the first hours after an acute ischemic stroke did not provide any benefit in terms of function, death, or improvement in final outcome.

Ntaios et al. designed an intravenous insulin protocol that controls acute poststroke hyperglycemia but frequently leads to hypokalemia. Further study is therefore required.

Transition from acute therapy to the initiation of chronic therapy in hyperglycemia depends on the condition’s persistence or whether evidence of diabetes exists.

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Hypoglycemia

When hypoglycemia is discovered, the glucose level must be brought expeditiously to a normal level. IV fluids, such as dextrose 25% in water (D25W) or dextrose 50% in water (D50W), may be necessary. Treatment of hypoglycemia beyond the initial therapy depends on the condition’s underlying cause.

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.

Diagnosis

Hyperglycemic hyperosmolar state (HHS) can cause focal symptoms including visual loss, focal seizures, and movement disorders. Stroke can precipitate the hyperglycemic state and must be distinguished from primary HHS. In addition, hyperglycemia has been associated with onset of focal neurologic symptoms in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome. Infection may also be associated with both acute stroke and hyperglycemia.

Hypoglycemia is a stroke mimic, and its underlying cause needs to be investigated.

Routine Tests

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.

CT Scanning of the Head

Obtain a computed tomography (CT) scan of the head when stroke is suspected. More recently, magnetic resonance imaging (MRI) with diffusion/perfusion sequences has been used for assessment of acute stroke.

The mechanism by which CT scanning and MRI 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 scans, may be seen earlier than in patients without hyperglycemia.

If stroke-like 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 scanning of the brain may show cortical atrophy reflecting laminar necrosis. The regions that are most prone to injury are cortical grey 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.

Bevers et al. revealed that interventions designed to target hyperglycemia in acute ischemic stroke, a concomitant effect on the evolution of apparent diffusion coefficient may provide insight into whether hyperglycemia leads to or reflects worse cytotoxic injury.

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Therapy in 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 low-density lipoprotein (LDL) (to below 100 mg/dL in diabetic patients), increase of high-density lipoprotein (HDL) (with fibrates if tolerated, an effect especially beneficial in patients with insulin resistance) tight glucose control, and hypertensive management.

Studies indicate that treatment of hypertension in patients with diabetes reduces stroke risk by more than 40%. Guidelines published by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommend lower, more strict hypertension targets of 130/80 mm Hg in persons with diabetes.

Patients with acute stroke and hyperglycemia are often kept NPO because of complicating effects of feeding on blood sugar level. Transition from acute therapy to initiation of chronic therapy depends on persistence of hyperglycemia or evidence that the patient has diabetes. 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. Acute hyperglycemic therapy Typically, hyperglycemia in the setting of acute stroke is treated with subcutaneous insulin on a sliding scale. Refractory hyperglycemia may require the use of intravenous (IV) insulin; however, IV insulin increases the risk of hypoglycemia. The safety and efficacy of IV insulin in treatment of hyperglycemia in patients with acute stroke are being determined by ongoing/planned clinical trials.

Vigilance is recommended regarding blood glucose levels, as sliding scale insulin may be ineffective for those patients who had diabetes and were hyperglycemic in the acute stroke setting. Those patients who were hyperglycemic but did not have a history of diabetes (eg, "stress hyperglycemia") did respond well to a sliding scale.

Transition from acute therapy to initiation of chronic therapy depends on persistence of hyperglycemia or evidence that the patient has diabetes.

Intensive insulin therapy The Diabetes Control and Complications Trial (DCCT) reported that intensive insulin therapy delays the onset and slows the progression of , nephropathy, and neuropathy in patients with insulin-dependent diabetes. However, the investigators also 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. A study by Lawson et al also found that intensive insulin therapy decreases the extent of early macrovascular disease in young individuals with , but there were no effects on the numbers of affected patients or on macrovascular mortality.

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Van den Berghe et al studied intensive insulin therapy for hyperglycemia in the surgical intensive care unit setting and demonstrated a reduction in the incidence of critical care neuropathy. The investigators performed a subgroup analysis of patients with traumatic brain injury that suggested long-term clinical outcome was better in the group that was treated with intensive insulin, but patients with stroke were not widely represented in this study. Although morbidity was reduced in patients treated with intensive insulin who were admitted to the medical intensive care unit (ICU), overall mortality was unchanged. However, in the subset of patients who had ICU stays of at least 3 days, mortality was reduced.

Results of a large single-blinded multi-centre randomized study disagreed with the findings of the Van den Berghe reports. Mortality was increased in the group of patients with glucose targets of 81-108 mg/dL compared with the group with glucose target less than 180 mg/dL. Severe hypoglycemia that was defined as glucose less than 40 mg/dL was also increased in the group receiving intensive therapy.

In addition, 2 small randomized studies failed to show clear clinical efficacy of intensive glucose control. In both trials, the intensive treatment groups had an increased incidence of hypoglycemia. In addition, mortality was increased in the groups receiving intensive treatment, but the values did not reach statistical significance in either study.

Larger trials are planned to determine definitive safety and efficacy of intensive glucose control. For the time being, it appears reasonable to use a sliding scale in order to maintain reasonable levels of blood glucose (e.g. 140 mg/dL), as more aggressive targets may worsen outcome. Sulfonylurea agents Animal studies and retrospective analyses suggest that the sulfonylurea agent glibenclamide improves outcome after large artery stroke. The mechanism does not appear to involve reduction in blood glucose as the benefit was seen in rats even if blood glucose was maintained at higher levels, and the dose is lower than needed for glucose reduction. Whether these findings will be confirmed in prospective human trials remains to be seen. Complications 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 recombinant tissue-type plasminogen activator 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.

Therapy in 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, may also 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.

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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.

Treatment of hypoglycemia beyond the initial therapy depends on the underlying cause. Treatment of some forms of hypoglycemia, such as in diabetes, involves immediately raising the blood sugar to normal through the eating of such as , determining the cause, and taking measures to hopefully prevent future episodes. However, this treatment is not optimal in other forms such as reactive hypoglycemia, where rapid carbohydrate ingestion may lead to a further hypoglycemic episode. Blood glucose can be raised to normal within minutes by taking (or receiving) 10–20 grams of carbohydrate. It can be taken as food or drink if the person is conscious and able to swallow. This amount of carbohydrate is contained in about 3–4 ounces (100–120 ml) of orange, apple, or grape although fruit contain a higher proportion of fructose which is more slowly metabolized than pure dextrose. Alternatively, about 4–5 ounces (120–150 ml) of regular (non-diet) soda may also work, as will about one slice of bread, about 4 crackers, or about 1 serving of most starchy foods. Starch is quickly digested to glucose (unless the person is taking acarbose) but adding fat or protein retards digestion. Symptoms should begin to improve within 5 minutes, though full recovery may take 10–20 minutes. Overfeeding does not speed recovery and if the person has diabetes will simply produce hyperglycemia afterwards. A mnemonic used by the American Diabetes Association and others is the "rule of 15" – consuming 15 grams of carbohydrate followed by a 15-minute wait, repeated if glucose remains low (variable by individual, sometimes 70 mg/dL). If a person has such severe effects of hypoglycemia that they cannot (due to combativeness) or should not (due to seizures or unconsciousness) be given anything by mouth, medical personnel such as paramedics, or in-hospital personnel can establish IV access and give intravenous dextrose, concentrations varying depending on age (infants are given 2 ml/kg dextrose 10%, children are given dextrose 25%, and adults are given dextrose 50%). Care must be taken in giving these solutions because they can cause skin necrosis if the IV is infiltrated, sclerosis of veins, and many other fluid and electrolyte disturbances if administered incorrectly. If IV access cannot be established, the person can be given 1 to 2 milligrams of glucagon in an intramuscular injection. More treatment information can be found in the article diabetic hypoglycemia. If a person has less severe effects, and is conscious with the ability to swallow, medical personal may administer gelatinous oral glucose. The soft drink Lucozade has been used for hypoglycemia in the United Kingdom, however it has recently replaced much of its glucose with the artificial sugars, which do not treat hypoglycemia. One situation where starch may be less effective than glucose or sucrose is when a person is taking acarbose. Since acarbose and other alpha-glucosidase inhibitors prevents starch and other sugars from being broken down into monosaccharides that can be absorbed by the body, people taking these medications should consume monosaccharide-containing foods such as glucose tablets, honey, or juice to reverse hypoglycemia.

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