Diabetes Melitus

Diabetes is the leading known* cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of morbidity and mortality in diabetes patients. It is estimated that the prevalence of neuropathy in diabetes patients is approximately 20%. Diabetic neuropathy is implicated in 50-75% of nontraumatic amputations. The main risk factor for diabetic neuropathy is hyperglycemia.It is important to note that people with diabetes are more likely to develop symptoms relating to peripheral neuropathy as the excess glucose in the blood results in a condition known as Glucojasinogen. This condition is affiliated with erectile dysfunction and epigastric tenderness which in turn results in lack of blood flow to the peripheral intrapectine nerves which govern the movement of the arms and legs. In the DCCT (Diabetes Control and Complications Trial, 1995) study, the annual incidence of neuropathy was 2% per year, but dropped to 0.56% with intensive treatment of Type 1 diabetics. The progression of neuropathy is dependent on the degree of glycemic control in both Type 1 and Type 2 diabetes. Duration of diabetes, age, cigarette smoking, hypertension, height and hyperlipidemia are also risk factors for diabetic neuropathy.

The largest group of neuropathy patients are of unknown cause, referred to as idiopathic in origin. Of the roughly 100 known causes, diabetes is by far the largest. Other known causes include genetic factors, damaging chemical agents such as chemotherapy drugs, and HIV.

There are four factors thought to be involved in the development of diabetic neuropathy:
1. 2. 3. 4. Microvascular disease, Advanced Glycation Endproduct, Protein kinase C, and the Polyol pathway.

Microvascular disease
Vascular and neural diseases are closely related and intertwined. Blood vessels depend on normal nerve function, and nerves depend on adequate blood flow. The first pathological change in the microvasculature is vasoconstriction. As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Vasodilator agents (e.g., ACE inhibitors, 1-antagonists) can lead to substantial improvements in neuronal blood flow, with corresponding improvements in nerve conduction velocities. Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy.

Advanced glycated end products

Elevated intracellular levels of glucose cause a non-enzymatic covalent bonding with proteins, which alters their structure and destroys their function. Some of these glycosylated proteins have been implicated in the pathology of diabetic neuropathy and other long term complications of diabetes.

Protein kinase C (PKC)

PKC is implicated in the pathology of diabetic neuropathy. Increased levels of glucose cause an increase in intracellular diacylglycerol, which activates PKC. PKC inhibitors in animal models will increase nerve conduction velocity by increasing neuronal blood flow.

Polyol pathway
Also called the Sorbitol/Aldose Reductase Pathway, the Polyol Pathway may be implicated in diabetic complications that result in microvascular damage to nervous tissue, and also to the retina and kidney which also have lots of microvasculature themselves. Glucose is a highly reactive compound, and it must be metabolized or it will find tissues in the body to react with. Increased glucose levels, like those seen in Diabetes, activates this alternative biochemical pathway, which in turn causes a decrease in glutathione and an increase in reactive oxygen radicals. The pathway is dependent on the enzyme aldose reductase. Inhibitors of this enzyme have demonstrated efficacy in animal models in preventing the development of neuropathy. While most body cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney and nervous tissues are insulin-independent. Therefore there is a free interchange of glucose from inside to outside of the cell, regardless of the action of insulin, in the eye, kidney and neurons. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway and be converted into sorbitol. Under normal blood glucose levels, this interchange will cause no problems, as aldose reductase has a low affinity for glucose at normal concentrations. However, in a hyperglycemic state (Diabetes), the affinity of aldose reductase for glucose rises, meaning much higher levels of sorbitol and much lower levels of NADPH, a compound used up when this pathway is activated. The sorbitol can not cross cell membranes, and when it accumulates, it produces osmotic stresses on cells by drawing water into the cell. Fructose does essentially the same thing, and it is created even further on in the chemical pathway. The NADPH, used up when the pathway is activated, acts to promote nitric oxide and glutathione production, and its conversion during the pathway leads to reactive oxygen molecules. Glutathione deficiencies can lead to hemolysis caused by oxidative stress, and we already know that nitric oxide is one of the important vasodilators in blood vessels. NAD+, which is also used up, is necessary to keep reactive oxygen species from forming and damaging cells.

In summary, excessive activation of the Polyol pathway leads to increased levels of sorbitol and reactive oxygen molecules and decreased levels of nitric oxide and glutathione, as well as increased osmotic stresses on the cell membrane. Any one of these elements alone can promote cell damage, but here we have several acting together. Experimental evidence has yet to confirm that the polyol pathway actually is responsible for microvasculature damage in the retina, kidney and/or neurons of the body. However, physiologists are fairly certain that it plays some role in neuropathy.
CLINICAL MANIFESTATIONS

Diabetic neuropathy affects all peripheral nerves: pain fibers, motor neurons, autonomic nerves. It therefore necessarily can affect all organs and systems since all are innervated. There are several distinct syndromes based on the organ systems and members affected, but these are by no means exclusive. A patient can have sensorimotor and autonomic neuropathy or any other combination. Symptoms vary depending on the nerve(s) affected and may include symptoms other than those listed. Symptoms usually develop gradually over years. Usual symptoms may be:

Numbness and tingling of extremities Dysesthesia (decreased or loss of sensation to a body part) Diarrhea ,Erectile dysfunction ,Urinary incontinence (loss of bladder control) Impotence Facial, mouth and eyelid drooping Vision changes Dizziness Muscle weakness Dysphagia (swallowing difficulty) Speech impairment Fasciculation (muscle contractions) Anorgasmia Burning (especially in evenings) Electric Stabbing Pains

Sensorimotor polyneuropathy
Longer nerve fibers are affected to a greater degree than shorter ones, because nerve conduction velocity is slowed in proportion to a nerve's length. In this syndrome, decreased sensation and loss of reflexes occurs first in the toes bilaterally, then extends upward. It is usually described as glove-stocking distribution of numbness, sensory loss, dysesthesia and night time pain. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception, the sense of where a limb is in space, is affected early. These patients cannot feel when they are stepping on a foreign body, like a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk for developing ulcers and infections on the feet and legs, which can lead to amputation. Similarly, these patients can get multiple fractures of the knee, ankle or foot, and develop a Charcot joint. Loss of motor function results in dorsiflexion, contractures of the toes, loss of the interosseous muscle function and leads to contraction of the digits, so called hammer toes. These contractures occur not only in the foot but also in the hand where the loss of the musculature makes the hand appear gaunt and skeletal. The loss of muscular function is progressive.

Autonomic neuropathy
The autonomic nervous system is composed of nerves serving the heart, gastrointestinal system and Genitourinary system. Autonomic neuropathy can affect any of these organ systems. The most commonly recognized autonomic dysfunction in diabetics is orthostatic hypotension, or the uncomfortable sensation of fainting when a patient stands up. In the case of diabetic autonomic neuropathy, it is due to the failure of the heart and arteries to appropriately adjust heart rate and vascular tone to keep blood continually and fully flowing to the brain[failure of the sensitivity of the baroreceptors]. This symptom is usually accompanied by a loss of sinus respiratory variation, that is, the usual change in heart rate seen with normal breathing. When these 2 findings are present, cardiac autonomic neuropathy is present. GI tract manifestations include delayed gastric emptying, gastroparesis, nausea, bloating, and diarrhea. Because many diabetics take oral medication for their diabetes, absorption of these medicines is greatly affected by the delayed gastric emptying. This can lead to hypoglycemia when an oral diabetic agent is taken before a meal and does not get absorbed until hours, or sometimes days later, when there is normal or low blood sugar already. Sluggish movement of the small instestine can cause bacterial overgrowth, made worse by the presence of hyperglycemia. This leads to bloating, gas and diarrhea. Urinary symptoms include urinary frequency, urgency, incontinence and retention. Again, because of the retention of urine, urinary tract infections are frequent. Urinary retention can lead to bladder diverticula, stones, reflux nephropathy.

Cranial neuropathy
When cranial nerves are affected, oculomotor (3rd) neuropathies are most common. The oculomotor nerve controls all of the muscles that move the eye with the exception of the lateral rectus and superior oblique muscles. It also serves to constrict the pupil and open the eyelid. The onset of a diabetic third nerve palsy is usually abrupt, beginning with frontal or periorbital pain and then diplopia. All of the oculomotor muscles innervated by the third nerve may be affected, except for those that control pupil size. This is because pupillary function within CNIII is found on the periphery of the nerve (in terms of a cross sectional view), which makes it less susceptible to ischemic damage (as it is closer to the vascular supply). The sixth nerve, the abducens nerve, which innervates the lateral rectus muscle of the eye (moves the eye laterally), is also commonly affected but fourth nerve, the trochlear nerve, (innervates the superior oblique muscle, which moves the eye downward) involvement is unusual. Mononeuropathies of the thoracic or lumbar spinal nerves can occur and lead to painful syndromes that mimic myocardial infarction, cholecystitis or appendicitis. Diabetics have a higher incidence of entrapment neuropathies, such as carpal tunnel syndrome.
TREATMENT

Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited by side effects and lack of efficacy. Thus, with the exception of tight glucose control,

treatments are for reducing underlying problems.

pain and other symptoms and do not address the

Agents for pain control include tricyclic antidepressants (TCAs), serotonin reuptake inhibitors (SSRIs) and antiepileptic drugs (AEDs). A systematic review concluded that "tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants."[1]

Tight glucose control

Treatment of early manifestations of sensorimotor polyneuropathy involves improving glycemic control.[2] Tight control of blood glucose can reverse the changes of diabetic neuropathy, but only if the neuropathy and diabetes is recent in onset. Conversely, painful symptoms of neuropathy in uncontrolled diabetics tend to subside as the disease and numbness progress. Of course, these uncontrolled patients are at great risk for diabetic foot ulcers and amputation because of neuropathy.

Tricyclic antidepressants
TCAs include imipramine, amitriptyline, desipramine and nortriptyline. These drugs are effective at decreasing painful symptoms but suffer from multiple side effects that are dosage dependent. One notable side effect is cardiac toxicity, which can lead to fatal arrhythmias. At low dosages used for neuropathy, toxicity is rare, but if symptoms warrant higher doses, complications are more common. Among the TCAs, amitriptyline is most widely used for this condition, but desipramine and nortriptyline have fewer side effects.

Serotonin reuptake inhibitor

SSRIs include fluoxetine, paroxetine, sertraline and citalopram. They are less effective than TCAs in relieving pain but are better tolerated. Side effects are rarely serious, and do not cause any permanent disabilities. They cause sedation and weight gain, which can worsen a diabetic's glycemic control. They can be used at dosages that also relieve the symptoms of depression, a common concommitent of diabetic neuropathy. The SSNRI duloxetine (Cymbalta) is approved for diabetic neuropathy. By targeting both serotonin and norepinephrine, it targets the painful symptoms of diabetic neuropathy, and also treats depression if it exists. Typical dosages are between 60 mg and 120 mg.

Antiepileptic drugs
AEDs, especially gabapentin and the related pregabalin, are emerging as first line treatment for painful neuropathy. Gabapentin compares favorably with amitriptyline in terms of efficacy, and is clearly safer. Its main side effect is sedation, which does not diminish over time and may in fact worsen. It needs to be taken three times a day, and it sometimes causes weight gain, which can worsen glycemic control in diabetics. Carbamazepine (Tegretol) is effective but not necessarily safe for diabetic neuropathy. Its first metabolite, oxcarbazepine, is both safe and effective in other

neuropathic disorders, but has not been studied in diabetic neuropathy. Topiramate has not been studied in diabetic neuropathy, but has the beneficial side effect of causing mild anorexia and weight loss, and is anecdotally beneficial.

Other treatments
-lipoic acid, an anti-oxidant that is a non-prescription dietary supplement has shown benefit in a randomized controlled trial that compared once-daily oral doses of 600 mg to 1800 mg compared to placebo, although nausea occurred in the higher doses.[3] In addition to pharmacological treatment there are several other modalities that help some cases. While lacking double blind trials, these have shown to reduce pain and improve patient quality of life particularly for chronic neuropathic pain: Interferential Stimulation; Acupuncture; Meditation; Cognitive Therapy; and prescribed exercise. In more recent years, Photo Energy Therapy devices are becoming more widely used to treat neuropathic symptoms. Photo Energy Therapy devices emit near infrared light typically at a wavelength of 890 nm. This wavelength is believed to stimulate the release of Nitric Oxide, an Endothelium-derived relaxing factor into the bloodstream, thus vasodilating the capilaries and venuoles in the microcirculatory system. This increase in circulation has been shown effective in various clinical studies to decrease pain and improve sensation in diabetic and non-diabetic patients. Photo Energy Therapy devices seem to address the underlying problem of neuropathies, poor microcirculation, which leads to pain and numbness in the extremities4, 5. While it is quite true that recognized treatment modalities backed up by double blind trials do not address the underlying causality of diabetic neuropathy, two other programs have had substantial although still anecdotal results. The first involves a program of nutritional supplements put forth in an Internet article researched and published by diabetic neuropathy patients themselves (although heavily referencing peer-reviewed research articles). This article is entitled "A Multidisciplinary Approach to Diabetic Neuropathy Treatment" and its treatment regimen has been instrumental in substantial reversal in individuals throughout the world.[4] The second method involves a combination of a vegan diet combined with moderate walking exercise. It has been used over several decades to affect both Type II diabetes as well as diabetic peripheral neuropathy.[citation needed] Though not yet commercially available, C-peptide has shown promising results in treatment of diabetic complications, including neuropathies. Once thought to be a useless bi-product of insulin production, it helps to ameliorate and reverse the major symptoms of diabetes[5]. Epalrestat: Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.[citation needed]

Prognosis

The mechanisms of diabetic neuropathy are poorly understood. At present, treatment alleviates pain and can control some associated symptoms, but the process is generally progressive. As a complication, there is an increased risk of injury to the feet because of loss of sensation (see diabetic foot). Small infections can progress to ulceration (skin and soft tissue breakdown) and this may require amputation. In addition, motor nerve damage can lead to psychotic breakdown and imbalance.

Metabolic Disease & Stroke: Hyperglycemic

Author and Editor Disclosure Synonyms and related keywords: hyperglycemia, hypoglycemia, acute stroke, diabetes, diabetes mellitus, thrombolytic therapy, anticoagulation therapy, transient ischemic attack, TIA, recombinant tissue-type plasminogen activator, rtPA, metabolic disease and stroke

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 30day 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 5year period.

CLINICAL
History

Hyperglycemia and acute stroke

Patients may come to the attention of physicians because of preexisting diabetes mellitus. o Diabetes may be seen with other risk factors for stroke such as hypertension and hypercholesterolemia. o 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 o Diabetes mellitus may have been diagnosed earlier, and recent changes in the doses of hypoglycemic agents and insulin may have been instituted. o Aggressively tight control, either patient driven or physician directed, may give rise to chronic hypoglycemia or recurrent episodes of hypoglycemia. o If factitious hypoglycemia is suspected, such behavior may have manifested earlier by similar episodes or other factitious behaviors.
o

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.

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.
o

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.
o o

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
Medical Care

Hyperglycemia
o

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
o

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 glucosecontaining 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
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. Insulin (Humulin, Novolin, Lente) Stimulates proper utilization of glucose by cells and Description reduces blood sugar levels. Use sliding scale. Sliding scales for insulin vary widely and must be tailored to individual needs of patient; an example using regular insulin is given below but local practices may mandate a tighter glucose control: Adult Dose Blood glucose 150-200 mg/dL: 2 units SC Blood glucose 201-250 mg/dL: 4 units SC Blood glucose 251-300 mg/dL: 6 units SC Blood glucose 301-350 mg/dL: 8 units SC Blood glucose 351-400 mg/dL: 10 units SC Pediatric Dose Administer as in adults Contraindications Documented hypersensitivity; hypoglycemia Acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine, isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid hormone, estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine Interactions sulfate, and niacin may decrease hypoglycemia effects Calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone may increase hypoglycemic effects Pregnancy B - Usually safe but benefits must outweigh the risks. Closely monitor blood glucose levels when using sliding scale insulin in order to avoid hypoglycemia, especially when used in combination with oral hypoglycemic agents, Precautions because they may not reach maximum efficacy until several hours after administration and may have prolonged duration of action Drug Name

Drug Category: Vitamins These are essential for normal DNA synthesis.

Thiamine; vitamin B-1 (Thiamilate) For thiamine deficiency including Description Wernicke encephalopathy syndrome. Initial: 100 mg IV/IM qd; can be given PO, but for initial treatment parenteral routes preferable owing to poor oral Adult Dose absorption; occasionally, higher doses (eg, 300 mg) have been given as initial treatment Pediatric Dose Not established Contraindications Documented hypersensitivity Interactions None reported Pregnancy A - Safe in pregnancy Sensitivity reactions can occur (intradermal test-dose recommended in suspected sensitivity); deaths have resulted from IV use; sudden onset or worsening of Wernicke Precautions encephalopathy, following glucose, may occur in thiamine-deficient patients; administer before or together with dextrose-containing fluids in suspected thiamine deficiency

Drug Name

Patient Education

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

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.