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. Microvascular disease,
2. Advanced Glycation Endproduct,
3. Protein kinase C, and the
4. 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 pain and other symptoms and do not address the
underlying problems.

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 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
History

Hyperglycemia and acute stroke

 o 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.

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.
o 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 Initially, results on CT scan of the head may be normal.
o 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.
o 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.
o 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).
o 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.
o 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).
o 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.
o 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.
o 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
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 Name 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 Category: Vitamins

These are essential for normal DNA synthesis.

 Drug Name 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

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.