Diabetes Treatments

Diabetes is the most common cause of neuropathy in the Western world. Neuropathy may occur in both type I and type II diabetes. …

Diabetic Neuropathy

Zachary Simmons, MD1 and Eva L Feldman, MD, PhD2

1Associate Professor of Medicine Neurology and of Orthopaedics and
Rehabilitation, The Pennsylvania State University College of Medicine,
Hershey, PA 17033

2 Professor of Neurology, The University of Michigan, Ann Arbor, MI 48109

Acknowledgments: This work was supported by NIH NS36778, NIH NS38849, and
grants from the Juvenile Diabetes Foundation and American Diabetes
Association ELF

Prevalence of Diabetic Neuropathy

Diabetes is the most common cause of neuropathy in the Western world
Neuropathy may occur in both type I and type II diabetes A large cross-
sectional study of 6487 diabetic patients in the UK found the prevalence of
diabetic neuropathy to be 285 Young et al 1993 However, the
prevalence varies greatly among various series, from a low of less than 5
to a high of 100 Thomas and Tomlinson 1993 Differences in prevalence
arise partially from differences in age, but primarily from differences in
the definition of diabetic neuropathy, and whether this is based on
symptoms only, signs and symptoms, nerve conduction abnormalities,
or
composite definitions Using a definition based on symptoms, signs, nerve
conduction studies, quantitative sensory testing, and autonomic testing
Dyck et al 1992, neuropathy was present in 66 of all diabetic patients
in one series Dyck et al 1993 The most common neuropathy was
polyneuropathy, with a prevalence of 54 in patients with type I diabetes,
and 45 in patients with type II diabetes The neuropathy was subclinical
in most of these Neuropathy appears to be less common in children, with a
prevalence of 2 or less Thomas and Tomlinson 1993 The prevalence of
diabetic neuropathy increases with the known duration of diabetes, as
illustrated in Table 1

Classification of Diabetic Neuropathy

Diabetic neuropathy is very heterogeneous Thomas and Tomlinson 1993
One classification scheme is presented in Table 2

Distal Sensory and Sensorimotor Polyneuropathy

Symptoms and Signs A distal sensory neuropathy with an insidious
onset is the most common neuropathy in patients with diabetes Thomas and
Tomlinson 1993 This is a length-dependent process, with the most distal
portions of the longest nerves affected earliest Thus, the earliest
symptoms typically involve
the toes, and then ascend Upper extremity
involvement is later, less severe, and less common, also proceeding
distally to proximally A stocking-glove pattern of sensory loss
results If severe, the midline abdomen may be involved The most common
symptoms are numbness, tingling, and pain The pain is particularly
troubling to most patients, and it is common for such patients to present
primarily because of pain in the feet This neuropathic pain may be
described as sharp, stabbing, burning, or aching It is often worst at
night, disturbing sleep, and the patient may have to sleep with his or her
feet out from under the covers Despite the pain, there is numbness Gait
ataxia may be reported Weakness is typically minor and occurs later
Examination generally demonstrates distal sensory loss, with reduced or
absent ankle jerks Distal weakness is less common and typically mild
Diagnostic Studies Electrodiagnostically, this neuropathy is usually
classified as having features of both axon loss and demyelination Donofrio
and Albers 1990 On nerve conduction studies, the lower extremity nerves
are affected first and most severely The earliest and most sensitive
findings are
changes in sensory nerve conduction studies, which demonstrate
a reduction in conduction velocity and a decrease in amplitude With more
severe neuropathy, the sensory responses may disappear Motor nerve
studies demonstrate some slowing even when patients have no symptoms or
signs of neuropathy, with a greater slowing in symptomatic patients A
decrease in motor amplitudes may be seen in more advanced cases Needle
electromyography may be normal in mild or neurologically asymptomatic
subjects, but demonstrates denervation in more severe cases, most prominent
distally Thomas and Tomlinson 1993, Dumitru 1995 On sural nerve biopsy,
there is loss of both myelinated and unmyelinated axons Demyelination is
also seen on teased fiber studies There is thickening of the walls of
small neural blood vessels, particularly endoneurial capillaries, due to
reduplication of the basal lamina Thomas and Tomlinson 1993
Pathogenesis Both metabolic and vascular factors appear to be
involved in the pathogenesis of diabetic polyneuropathy It now appears
that hyperglycemia results in increased activity of the enzyme aldose
reductase, with changes in the polyol pathway This eventually leads
to
oxidative stress, mitochondrial dysfunction, and ischemic nerve damage
Feldman et al 1999
Treatment of the Neuropathy Treatment of diabetic polyneuropathy has
traditionally focused on control of hyperglycemia as a means of slowing
progression or delaying the appearance of neuropathy The Diabetes Control
and Complications Trial found that intensive therapy of type I diabetes
reduced the frequency of appearance of neuropathy by 60 over a 5 year
period in patients who did not have neuropathy at the onset of the study
DCCT Research Group 1993 Pancreatic transplantation appears to halt the
progression of diabetic neuropathy, but does not clearly reverse existing
neuropathy Kennedy et al 1990, Navarro et al 1997
Aldose reductase inhibitors ARIs have been studied as a means to
prevent or improve diabetic polyneuropathy They act by reducing the flux
of glucose through the polyol pathway There have been many human clinical
trials of ARIs since 1981, with mixed results see Pfeifer et al 1997 A
recent meta-analysis of 13 randomized, controlled trials of ARIs found that
the effects on motor nerve conduction velocity were inconsistent on
different nerves within studies and
also were inconsistent between studies,
leading the authors to state that no clear conclusion can be drawn
regarding the benefits of ARIs in the treatment of diabetic neuropathy
Nicolucci et al 1996 An analysis of 32 trials of ARIs on patients with
distal symmetrical diabetic polyneuropathy found that ARIs showed promise
for possibly slowing the progression of diabetic neuropathy, but that many
of these trials were flawed, being of insufficient duration and size
Pfeifer et al 1997 A recent double-blind, placebo-controlled trial of
the ARI zenarestat demonstrated that doses producing 80 suppression of
nerve sorbitol content were required to demonstrate efficacy, so that even
low residual levels of aldose reductase activity might be neurotoxic Green
et al 1999 Thus, the issue of whether ARIs are effective in the
treatment of diabetic polyneuropathy has not yet been settled
Nerve growth factor NGF may be useful Recombinant human NGF was
found to be well tolerated in an open-label, phase I clinical trial Petty
et al 1994 A randomized, double-blind, placebo-controlled phase II study
of NGF in the treatment of diabetic polyneuropathy was recently completed
Apfel et al 1998
Improvement was noted compared to placebo on the
sensory component of the neurological exam, on quantitative sensory
testing, and in the impression of the subjects The results of two phase
III trials are not yet available
Diabetic Foot Care Twenty-five percent of patients with diabetes
develop foot complications at some point Most and Sinnock 1983, and
patients with diabetes account for approximately half of all nontraumatic
lower extremity amputations performed in the United States each year Bild
et al 1989 Plantar ulceration often precedes amputation Pecoraro et al
1991 Patients with diabetic neuropathy develop foot problems for several
reasons Mayfield et al 1998, Cavanagh et al 1996, Stevens et al 1992,
Boulton 1990: 1 They have a loss of protective sensation on their feet,
which may result in painless injuries 2 Atrophy of the intrinsic foot
muscles can lead to foot deformities and an abnormal distribution of weight
when walking, producing increased plantar pressures 3 There is often
autonomic neuropathy, causing dry skin which can crack and also causing
arteriovenous shunting leading to altered skin and bone perfusion These
factors may lead to foot deformities a
Charcot foot with disruption of
the normal bony architecture and with plantar ulcers
Good preventative foot care has been emphasized, including such
practical measures as careful inspection, proper trimming of nails, and
proper footwear The evidence base for such preventative care in patients
with diabetes recently has been reviewed Mayfield et al 1998 There have
not been randomized, controlled trials of treatment of the Charcot foot
However, in patients with diabetic neuropathy and plantar ulcers, a total
contact cast often leads to healing of the ulcers Caputo et al 1997,
Caputo et al 1998
Control of Pain In managing diabetic neuropathy, a major goal of
most patients and their physicians is control of pain A large number of
agents have been studied in both uncontrolled and controlled clinical
trials
A placebo-controlled, single-blind, crossover study demonstrated both
ibuprofen 600 mg qid and sulindac 200 mg bid to be more effective than
placebo in relieving the pain of diabetic neuropathy The response to
sulindac was significantly better than the response to ibuprofen Cohen and
Harris 1987 Caution must be exercised when using nonsteroidal
anti-
inflammatory medications in patients with diabetes, due to the risk of
nephrotoxicity, although none was noted in the study above
Tricyclic antidepressants have been studied extensively They act by
blocking neuronal re-uptake of norepinephrine and serotonin, thereby
potentiating the inhibitory effect of these neurotransmitters in
nociceptive pathways Joss 1999 Amitriptyline, imipramine, and
desipramine were all found to relieve pain in patients with diabetic
neuropathy better than placebo in double-blind, placebo-controlled trials
These compounds were effective in both depressed and non-depressed
patients, and the efficacy appeared to be independent of any antidepressant
effect Kvinesdal et al 1984, Max et al 1987, Sindrup et al 1989, Max et al
1991, Max et al 1992 Additional support for the efficacy of tricyclic
antidepressants was provided by a meta-analysis of 21 different clinical
trials McQuay et al 1996 Although nortriptyline as monotherapy would
also be expected to be effective in treatment of painful diabetic
neuropathy, and is often used in this manner, ,there is no study to support
this When used in combination with fluphenazine, it has been shown to
be
more effective than placebo and as effective as carbamazepine in double-
blind, crossover studies Gomez-Perez et al 1985, Gomez-Perez et al 1996
The use of neuroleptics may produce extrapyramidal symptoms, and therefore
we do not recommended their use in the routine treatment of diabetic
neuropathy pain
All of the tricyclic antidepressants may produce sedation, confusion,
and anticholinergic side effects such as constipation, dry mouth, blurred
vision, urinary hesitancy, and orthostatic dizziness These agents are
contraindicated in patients with a variety of heart diseases, and must be
used with great caution in patients orthostatic hypotension or angle-
closure glaucoma Arranged in order from most to least potent
anticholinergic effects, the most commonly used agents are amitriptyline,
imipramine, nortriptyline, and desipramine Richelson 1994 Thus, for
patients who do not tolerate amitriptyline, other tricyclic
antidepressants, particularly despiramine, may represent useful
alternatives The usual dosage schedule is 10-25 mg at bedtime initially,
increasing as tolerated up to 100 or 150 mg as a single bedtime dose
Serotonin reuptake inhibitors are another
category of antidepressants
which may have some efficacy, but the evidence for this is less convincing
than that for tricyclic antidepressants In a randomized, double-blind,
crossover study, paroxetine 40 mg per day reduced symptoms significantly
more than placebo, although it was somewhat less effective than imipramine
Sindrup et al 1990 Fluoxetine at a mean daily dose of 40 mg was shown
to be no more effective than placebo except in patients who were depressed
in a double-blind, placebo-controlled study Max et al 1992 Open-label
sertraline up to 150 mg/day was shown to lead to a reduction in pain from
diabetic neuropathy in a small study of 8 patients, but a placebo-
controlled study has not yet been carried out Goodnick et al 1997
Trazodone is often used empirically Open-label use raises the possibility
that it may have some efficacy in treating painful diabetic neuropathy, but
there are no controlled studies Khurana 1983
Another group of medications with utility in pain control is the
anticonvulsants Gabapentin has been shown to be more effective than
placebo when used in doses ranging from 900 to 3600 mg per day Backonja et
al 1998 The lower end of this dosage
range may be relatively ineffective;
another placebo-controlled study did not demonstrate efficacy at a dose of
900 mg per day Gorson et al 1999 The main side effects of gabapentin
are dizziness, somnolence, headache, diarrhea, confusion, and nausea The
dose is typically started at 300 mg per day or less, and increased very
gradually, up to a maximum of 2400-3600 mg per day if tolerated and as
needed for control of pain Carbamazepine 200 mg tid was more effective
than placebo in a double-blind crossover trial Rull et al 1969 An open-
label trial Chakrabarti and Samantaray 1976 also appeared to demonstrate
efficacy Side effects are somnolence, dizziness, unsteadiness, nausea,
vomiting We suggest beginning at 100 mg bid or tid, increasing gradually
to 200 qid as tolerated and if needed for pain control Because aplastic
anemia and agranulocytosis may occur on rare occasions, patients should
undergo hematologic monitoring at baseline and regularly while being
treated Double-blind studies have not demonstrated efficacy of phenytoin
in patients with diabetic neuropathy Ellenberg 1968, Saudek et al 1977
Randomized, double-blind, placebo-controlled trials of the
anti-
arrhythmic agent mexiletine have demonstrated efficacy in the treatment of
painful diabetic neuropathy Dejgard et al 1988, Stracke et al 1992,
Oskarsson et al 1997, although one small, double-blind study did not
demonstrate efficacy Wright et al 1997 The side effects most commonly
are gastrointestinal distress nausea, vomiting, heartburn,
dizziness/lightheadedness, tremor, nervousness, and incoordination We
recommend an initial dose of 150 mg per day, increasing gradually until
there is relief of pain, up to a maximum dose of 600- 800 mg per day in 3-4
divided doses Obtain a baseline ECG to make sure there are no cardiac
contraindications, and consult a cardiologist if there are any concerns
The response to oral mexiletine can be predicted by an infusion of
intravenous lidocaine Galer et al 1996
Several other oral agents have been used Tramadol acts via low-
affinity binding to micro-opioid receptors and weak inhibition of
norepinephrine and serotonin reuptake Raffa et al 1998 It was recently
found to be effective in treatment of pain in diabetic neuropathy in a
double-blind, placebo-controlled, randomized trial Harati et al 1998 It
is often good treatment for
breakthrough or refractory pain, and can be
given as 50-100 mg every 4 to 6 hours, up to 400 mg per day Levodopa at a
dosage of 100 mg three times a day was used in conjunction with a dopa
decarboxylase inhibitor in a 4-week placebo-controlled trial, and was found
to be more effective than placebo from weeks 2 to 4 Ertas et al 1998
The proof of efficacy of clonidine is questionable Two double-blind,
placebo-controlled trials have not shown a significant effect Ziegler et
al 1992, Cohen et al 1990 However, one trial in which the positive
responders to clonidine were entered into a second double-blind, placebo-
controlled phase demonstrated some benefit, suggesting that perhaps
clonidine is effective in a subset of patients Byas-Smith et al 1995
Some rather unconventional systemic agents have been tried Based on
the impaired conversion of linoleic acid to gamma-linolenic acid in
patients with diabetes, gamma-linolenic acid 360 mg per day was found to be
superior to placebo for control of pain in a small, 6-month, randomized,
placebo-controlled double-blind trial Jamal and Carmichael 1990
Intravenous infusion of alpha-lipoic acid, an antioxidant, was shown to
reduce pain in
a large multicenter randomized, double-blind, placebo-
controlled trial Ziegler et al 1995 Dextromethorphan was superior to
placebo in a randomized, double-blind crossover trial of pain control in
diabetic neuropathy The initial dose of 30 mg qid was increased gradually
to 240 mg qid Side effects were sedation, dizziness, lightheadedness,
ataxia, and confusion Nelson et al 1997
Not all agents for pain control must be administered systemically
Topical capsaicin cream stimulates the release and subsequent depletion of
substance P from sensory fibers A placebo-controlled study Capsaicin
Study Group 1991, Capsaicin Study Group 1992 demonstrated the superiority
of capsaicin cream 0075 to placebo in control of pain and improvement of
daily activities, while another double-blind study found it to be overall
as effective as amitriptyline Biesbroek et al 1995 In contrast, a
double-blind, placebo-controlled study of capsaicin cream in patients with
chronic distal painful neuropathy of various causes demonstrated no benefit
over placebo Low et al 1995 Overall, capsaicin cream appears to be
effective A meta-analysis of 4 randomized, double-blind, placebo-
controlled trials of
capsaicin in diabetic neuropathy found capsaicin
overall to be more effective than placebo Zhang and Po 1994 Poor
compliance is common, due to the need for frequent applications, an initial
exacerbation of symptoms, and frequent burning and redness at application
site Other non-systemic treatments which have been studied include
transcutaneous electrical nerve stimulation TENS units and acupuncture
In a controlled study, TENS was more effective than sham treatment in
reducing pain in patients with diabetic neuropathy Kumar and Marshall
1997 Uncontrolled studies of TENS and of acupuncture have been reported
to decreased pain in over 75 of patients with diabetic neuropathy Julka
et al 1998, Abuaisha et al 1998 However, the powerful effect of placebo
treatment in diabetic neuropathy, documented in multiple studies, raises
questions about the reliability of such uncontrolled trials
Narcotic analgesics are often used for severe, refractory pain, but
are controversial for treatment of this chronic condition, due to the
habituation which typically occurs Some experts use it at night for
sleep, but patients must be cautioned not to escalate the dose
A summary of treatments
used for painful diabetic polyneuropathy is
provided in Table 3

Small-Fiber Polyneuropathy

Some patients have a selective small-fiber polyneuropathy, or small-
fiber sensory neuropathy SFSN Brown et al 1976, Said et al 1983, Kennedy
and Wendelschafer-Crabb 1996, Kennedy et al 1996, Holland et al 1998,
Hermann et al 1999 The patient with SFSN typically presents with pain as
a chief complaint, most commonly in the distal limb, which he or she
describes in a variety of terms, including tingling, prickling, burning,
coldness, deep aching, jabbing, or shooting Autonomic dysfunction is
frequently present The examination demonstrates distal sensory loss
affecting pain and temperature, with relative preservation of large fiber-
mediated modalities vibration and proprioception Reflexes are generally
preserved although ankle jerks may be decreased or absent, and strength
is normal Nerve conduction studies are normal or minimally abnormal,
since such tests assess primarily the largest, fastest-conducting fibers
Quantitative sensory testing QST is abnormal in 60 100 of patients
tested Autonomic testing may be abnormal Biopsies of sural nerve show
predominantly small fiber loss,
but may rarely be normal Skin biopsies
demonstrate abnormalities of intra-epidermal nerves Treatment is directed
toward control of pain, using the agents discussed above

Autonomic Neuropathy

Visceral autonomic neuropathy was present in 7 of patients with type
I diabetes and 5 of those with type II diabetes in one series Dyck et al
1993 The clinical features of diabetic autonomic neuropathy are varied
Thomas and Tomlinson 1993, and are presented are presented in Table 4
Treatment of some of the major clinical manifestations is discussed here
Treatment of Orthostatic Hypotension: This involves the use of non-
pharmacological as well as pharmacological measures Many of the non-
pharmacological treatments are based on commonly-accepted clinical
practices, rather than controlled studies Onrot et al 1986, Thomas and
Tomlinson 1993, Hilsted and Low 1997, Mathias and Kimber 1998, Vinik 1999a,
Vinik 1999b Such measures include the following: 1 Avoidance of sudden
changes in body posture to the head-up position, particularly in warm
weather, and after taking a warm bath, both of which produce cutaneous
vasodilation 2 Avoiding medications that aggravate hypotension, such
as
tricyclic antidepressants and phenothiazines 3 Taking small, frequent
meals to avoid the postprandial hypotension which may occur after a large
carbohydrate-containing meal 4 Avoiding activities that involve
straining, since increased intra-abdominal and intra-thoracic pressure
decrease venous return In contrast, the efficacy of some non-
pharmacological treatments has been demonstrated in case reports or small
uncontrolled studies 1 Elevation of the head of the bed 18 inches at
night improved symptoms in a small series of patients with orthostatic
hypotension from various causes MacLean and Allen 1940 2 The
efficacy of a compressive garment over the legs and abdomen has been
demonstrated in multiple case reports Schatz et al 1963, Levin et al 1964,
Lewis and Dunn 1967, Sheps 1976 3 An inflatable abdominal band was
shown to be effective in a small study of 6 patients with orthostatic
hypotension Tanaka et al 1997 4 A low portable chair used by patients
as needed for symptoms was found to be effective in one study Smit et al
1997
Some pharmacological means are part of commonly-accepted clinical
practice, but without studies to document efficacy Plasma expansion
by
increased salt intake or by the use of prostaglandin inhibitors such as
ibuprofen or indomethacin are commonly recommended Onrot et al 1986 One
of the first effective pharmacological treatments which was studied was
plasma expansion with 9-alpha-fluorohydrocortisone, a compound that has
potent mineralocorticoid activity The earliest report described a single
patient Hickler et al 1959 Other case reports followed Bannister et al
1969 A small, open-label study of 14 patients demonstrated symptomatic
as well as objective improvement Campbell et al 1976 The effects are
not immediate, but occur over a 1-2 week period Supine hypertension,
hypokalemia, and hypomagnesemia may occur Caution must be used,
particularly in patients with congestive heart failure, to avoid fluid
overload Chobanian et al 1979, Robertson and Davis 1995 We recommend
beginning at 50 g at bedtime, and titrating upward gradually to a maximum
of 200 g daily The dose can ultimately be titrated up to 400 g, but at
these higher doses there is more of a tendency to develop hypokalemia and
excessive fluid retention with resulting hypertension and congestive heart
failure
Sympathomimetic drugs can be
helpful Ephedrine is often used
empirically at a dosage of 15-45 mg three times a day It is best given
upon awakening, at lunch, and at dinner Side effects which may limit its
use are tremulousness, irritability, insomnia, hypertension, tachycardia,
reduction in appetite, and in males urinary retention Mathias 1998 An
alternative is midodrine, an alpha agonist which activates alpha-1
receptors on arterioles and veins to increase total peripheral resistance
Zachariah et al 1986, McTavish and Goa 1989 Because it does not cross
the blood-brain barrier, it has fewer central side effects than ephedrine
Several double-blind, placebo-controlled studies have documented its
efficacy in the treatment of orthostatic hypotension Low et al 1997,
Kaufman et al 1988, Wright et al 1998 The main adverse effects are
piloerection, pruritis, paresthesias, urinary retention, and supine
hypertension Of course, all sympathomimetic drugs must be used with
caution in patients with ischemic heart disease, cardiac arrhythmias, and
peripheral vascular disease The usual dose of midodrine is 25 to 10 mg
three times a day
Dihydroergotamine in combination with caffeine, indomethacin, and the
alpha-2
adrenergic antagonist yohimbine has been used in refractory
patients Vinik 1999a, Vinik 1999b In an experimental animal model of
orthostatic hypotension, yohimbine has been found to delay the fall in BP
elicited by head-up tilting, but not to modify its magnitude Verwaerde et
al 1997
Beta blockers have shown efficacy in some open-label studies of
patients with orthostatic hypotension due to varying etiologies Chobanian
et al 1977, Brevetti et al 1981, Man int Veld and Schalekamp 1981, but a
double-blind, placebo-controlled crossover study of 8 patients with
diabetic autonomic neuropathy and orthostatic hypotension failed to
demonstrate efficacy Dejgaard and Hilsted 1988
Treatment of Diabetic Gastroparesis Some treatments are based simply
on commonly-accepted clinical practices These include the use of multiple
small feedings and changes in diet such as a decrease in dietary fat and
fiber Hilsted and Low 1997, Verne and Sninsky 1998, Vinik 1999a, Vinik
1999b The principal pharmacological means of treatment has been the use
of a prokinetic agent such as metoclopramide, cisapride, or domperidone
Metoclopramide has antiemetic properties, stimulates
acetylcholine
release in the myenteric plexus, and is a dopamine antagonist Verne and
Sninsky 1998 There have been 1 open trial, 2 single-blind trials, and 5
double-blind trials The single-blind and double-blind trials demonstrated
improvement in gastric emptying, while the open trial demonstrated no
improvement Sturm et al 1999 Extrapyramidal symptoms such as acute
dystonic reactions, drug-induced parkinsonism, akathisia, and tardive
dyskinesia may be side effects Galactorrhea, amenorrhea, gynecomastia,
and hyperprolactinemia are potential side effects as well The usual dose
is 10 mg given 30 minutes before meals and at bedtime
Cisapride increases gut motility by increasing the release of
acetylcholine from postganglionic myenteric neurons Verne and Sninsky
1998 There have been 10 open trials and 7 double-blind trials which
demonstrated improvement in gastric emptying Sturm et al 1999 It
appears to maintain efficacy in long-term use Kendall et al 1997 It
does not have the dopaminergic activity of metoclopramide, and so avoids
the extrapyramidal and other side effects noted above It is contra-
indicated in some patients with heart disease or
abnormal
electrocardiograms The usual dose is 10-20 mg given 15-30 minutes before
meals and at bedtime
Erythromycin is effective in accelerating gastric emptying It is
believed to act by stimulating motilin receptors in the gut Peeters et al
1989 It may be used orally or intravenously Richards et al 1993,
DiBaise and Quigley 1999 There have been 5 open trials involving 71
patients, with a mean improvement in gastric emptying of over 40 Sturm et
al 1999 One single-blind trial also demonstrated an improvement in
gastric emptying of 50 Sturm et al 1999
Domperidone has also demonstrated efficacy, although only small
numbers of patients have been studied There have been 2 open trials
involving 18 patients and 2 double-blind trials involving 28 patients, all
of which demonstrated improvement in gastric emptying Sturm et al 1999
A double-blind, randomized trial has demonstrated that domperidone and
metoclopramide are equally effective Patterson et al 1999
An analysis of 36 studies of prokinetic agents found all 4 of these
agents appear to have efficacy in improving gastric emptying times and
symptoms Sturm et al 1999 When compared with one another, improvement
in
gastric emptying time was greatest with erythromycin, followed by
domperidone, cisapride, then metoclopramide Improvement in symptoms was
greatest with erythromycin, then domperidone, then metoclopramide, then
cisapride The choice of an agent will usually be determined by
availability, cost, and side effects
Persistent vomiting may require a surgical approach: Placement of a
feeding jejunostomy to bypass an atonic stomach has been advocated, based
on clinical practice Verne and Sninsky 1998 Radical surgery, consisting
of resection of a large portion of the stomach, with performance of a Roux-
en-Y loop, has been reported to be successful in a small series of patients
Ejskjaer et al 1999 A recent, novel approach is gastric pacing In one
series of 9 patients with gastroparesis, 5 of whom had diabetes, gastric
pacing accelerated gastric emptying and improved symptoms McCallum et al
1998
Treatment of Diabetic Diarrhea: Diarrhea in diabetics is often due to
bacterial overgrowth, which can be diagnosed via a hydrogen breath test
An early double-blind study involving a single patient demonstrated that
the diarrhea subsided when the patient was treated with an oral
antibiotic
preparation a combination of tetracycline, amphotericin B, and potassium
metaphosphate, then recurred when placebo was substituted Green et al
1968 Broad-spectrum antibiotics are commonly used to treat diabetic
diarrhea, either when the breath test is positive, or as an empiric trial
Several different regimens have been advocated: 1 Ampicillin or
tetracycline 250 mg every 8 hours Vinik 1999a, Vinik 1999b 2
Amoxicillin 875mg and clavulanate potassium twice daily for 14 days Verne
and Sninsky 1998 3 Metronidazole 500 mg every 6 hours or 750 mg every 8
hours for 3 weeks Vinik 1999a, Vinik 1999b; caution must be used since
long-term use of metronidazole can lead to neuropathy
Other treatments have been based largely on accepted clinical practice
patterns Vinik 1999a, Vinik 1999b Cholestyramine can be used in an
attempt to chelate bile salts if the hydrogen breath test is normal, or if
patients fail an empiric trial of broad-spectrum antibiotics
Diphenoxylate with atropine or loperamide can also be used
Octreotide a somatostatin analog 50-75 ug subcutaneously twice a day
was effective in a case report of a single patient with diabetic diarrhea
Tsai et al 1986
A recent study demonstrated that octreotide was
effective in accelerating gastric emptying, inhibiting small bowel transit,
reducing ileocolonic bolus transfers, inhibiting post-prandial colonic
tonic response, and increasing colonic phasic pressure activity in healthy
volunteers, and thus should be of value in the treatment of diarrheal
states Von der Ohe et al 1995
Treatment of the Neurogenic Bladder Dysfunction of the lower urinary
tract occurs in 26 to 87 of patients with diabetes Frimodt-Moller 1980
These patients experience a decrease in the ability to sense a distended
bladder, due to loss of afferent autonomic innervation As a result, they
urinate less frequently, and develop a hypocontractile bladder and urinary
retention Buck et al 1976, Frimodt-Moller 1980, Menendez et al 1996
This leads to recurrent urinary tract infections, overflow incontinence,
dribbling, and poor stream Recommendations from a number of sources are
similar, and based largely on commonly-accepted clinical practices Hilsted
and Low 1997, Vinik 1999a, Vinik 1999b The patient with should be
scheduled for an evaluation by a urologist with a cystometrogram If
abnormal, scheduled voiding is
recommended, often coupled with Credes
maneuver: manual squeezing of the bladder to initiate urination
Bethanechol, a parasympathomimetic agent, 10-30 mg three times a day may be
helpful Some patients may require intermittent catheterization
Transurethral surgery of the bladder neck may be needed in selected cases,
and occasional patients may require an indwelling catheter Based on an
animal model, some patients may benefit from surgery to reduce bladder size
Watanabe and Miyagawa 1999
Treatment of Impotence The prevalence of erectile dysfunction in men
with diabetes is high, varying from 35 to 75 Rundles 1945, Rubin and
Babbott 1958, McCulloch et al 1980, Zemel 1988 The treatment of choice
is now sildenafil which was shown to be significantly more effective than
placebo in a randomized, double-blind, placebo-controlled study of 268 men
with diabetes and erectile dysfunction Rendell et al 1999 The main side
effects were headache, dyspepsia, and respiratory tract disorder The dose
is 25 to 100 mg taken 1 hour before sexual activity
Traditionally, a number of other treatments have been used, based on
clinicians experience and case reports, including vacuum devices,
rigid
penile implants, and inflatable prostheses Saulie and Campbell 1997,
Spollett 1999 Direct injections into the corpus cavernosum of either
papaverine or alprostadil represent another option The success rate of
intra-cavernosal injections is high, with nearly 90 of patients achieving
erection Virag et al 1984, Spollett 1999 Yohimbine, an alpha-2
adrenergic antagonist, is occasionally used A meta-analysis of 7
randomized clinical trials found it to be more effective than placebo
Ernst and Pitter 1998

Cranial Neuropathies

Cranial neuropathies affecting extraocular movements occur more
frequently in diabetic than nondiabetic patients Patients are usually
greater than 50 years of age The onset us typically abrupt, and may be
painless or associated with a headache A lesion of oculomotor nerve CN
III is the most common single cranial neuropathy in diabetes, often
sparing the pupil Dysfunction of the trochlear nerve CN IV is less
common The abducens nerve CN VI is rarely involved alone, but may be
involved with other cranial nerves While facial palsy CN VII and other
cranial neuropathies occur in patients with diabetes, their relationship to
the diabetes is
uncertain Asbury 1987, Thomas and Tomlinson 1993 There
is no specific treatment, although gradual recovery typically occurs

Limb Mononeuropathies

Compression and entrapment neuropathies are common in patients both
without and with diabetes, and it is uncertain if these are causally
related to diabetes The most commonly involved nerve is the median nerve
at the wrist carpal tunnel syndrome Symptomatic carpal tunnel syndrome
occurs in 11 of patients with type I diabetes, and 6 of patients with
type II diabetes Asymptomatic carpal tunnel syndrome is much more common
Dyck 1993 Ulnar neuropathy at the elbow occurs commonly as well
Typically such neuropathies are slowly developing lesions characterized by
variable amounts of pain and weakness Treatment has been empiric, and may
be conservative or surgical The presence of a superimposed generalized
polyneuropathy does not preclude surgical intervention in such patients,
but the degree of polyneuropathy which is contributing to the patients
symptoms must be taken into account when making decisions regarding surgery
al-Quattan et al 1994
Dysfunction of some nerves may be abrupt and painful, likely secondary
to nerve
infarctions Common examples include the radial nerve wrist
drop, peroneal nerve foot drop, femoral nerve quadriceps weakness, and
lateral femoral cutaneous nerve meralgia paresthetica
Electrodiagnostic tests reveal axon loss Recovery typically occurs over
months or years, and depends on the extent of axon loss and the site
proximal vs distal of the lesion Distal muscle strength is often
recovered incompletely If multiple nerve are affected in this way, a
mononeuropathy multiplex will result There is no specific treatment for
these abrupt limb neuropathies, though some have advocated immunomodulating
therapy when there is multi-nerve involvement, similar to that used by some
for treatment of diabetic amyotrophy see below

Diabetic Truncal Mononeuropathy

This is typically characterized by pain around the abdomen or lower
chest Cutaneous hyperesthesia may occur, as may abdominal wall weakness
Some cases appear to be a restricted form of diabetic radiculopathy, and
demonstrate paraspinal muscle denervation on EMG Thomas and Tomlinson
1993 Once structural abnormalities have been ruled out, treatment
consists of pain management Gradual improvement generally
occurs

Asymmetric Lower Limb Motor Neuropathy Diabetic Amyotrophy

There are many names for this syndrome, including proximal diabetic
neuropathy, diabetic polyradiculopathy, diabetic femoral neuropathy,
diabetic lumbar plexopathy, and diabetic lumbosacral plexus neuropathy
Affected individuals have type II diabetes mellitus, and are usually males
greater than 50 years of age The initial symptom is pain in most
patients, usually in the territory of the lower thoracic and upper lumbar
nerve roots The pain typically is worst at onset, and gradually subsides
Paresthesia and hyperesthesia are common Weakness, generally in the
upper legs, commonly follows the pain Weight loss is common On
examination, weakness is most common in the L2-L4 distribution Thus, the
weakness primarily affects the iliopsoas, quadriceps, and adductor muscles,
usually sparing hip extensors and hamstrings The weakness may be
unilateral or bilateral, and when bilateral it is frequently asymmetric
Sensory loss is mild and mainly distal in most patients, consistent with a
coexisting distal sensory or sensorimotor polyneuropathy Knee and/or
ankle jerks are lost in most patients Bastron and Thomas
1981
Progression of symptoms and signs occurs over a very variable period
of time; as short as 1-2 weeks, and as long as a year or more Most
patients experience improvement or resolution of pain or dysesthesia
Recovery of motor function is often incomplete and usually slower,
proceeding for up to 18 months Nerve conduction studies often reveal
evidence of a sensory or sensorimotor polyneuropathy The needle
examination typically reveals fibrillations and positive sharp waves in
lower extremity muscles and in thoracic and/or lumbar paraspinal muscles
Most commonly affected are the L2-L4 levels, although low thoracic and L5-
S1 levels are abnormal in some patients The etiology appears to be
microscopic vasculitis producing nerve ischemia, with multifocal
involvement of lumbosacral roots, plexus, and peripheral nerves This has
led to the recent use of the term diabetic lumbosacral radiculoplexus
neuropathy to characterize this type of neuropathy Llewelyn et al 1998,
Dyck et al 1999
Typically, no treatment is given other than controlling the diabetes
However, the inflammatory changes on biopsy have raised the issue of
whether immunomodulating agents might be useful for
treatment of this type
of diabetic neuropathy In patients with particularly severe cases,
prednisone, intravenous immunoglobulin IVIg, and plasmapheresis have
shown some promise in open-label, uncontrolled studies Patients appeared
to stop worsening and to begin to improve after beginning these treatments
However, since untreated patients also gradually improve, the efficacy of
these treatments is unproven at this time Krendel et al 1995, Krendel et
al 1997, Pascoe et al 1997, Jaradeh et al 1999

Table 1 Change in The Prevalence of Diabetic Neuropathy Over Time

|Reference |Initial |Time of |Later |Time of Later|
| |Prevalence |Initial |Prevalence |Prevalence |
| | |Prevalence | | |
| | | | | |
|Pirart 1978 |75 |At diagnosis |50 |25 years |
| | | | |after |
| | | | |diagnosis |
|Palumbo et al|4 |Within 5 |15 |20 years |
|1978 | |years of |
|after |
| | |diagnosis | |diagnosis |
|Young et al |208 |Less than 5 |368 |Greater than |
|1993 | |years | |10 years |
| | |duration | |duration |
|Partanen et |83 |At diagnosis |419 |10 years |
|al 1995 | | | |after |
| | | | |diagnosis |

Table 2 Classification of Diabetic Neuropathies

Symmetric polyneuropathies
2 Sensory or sensorimotor polyneuropathy
3 Selective small-fiber polyneuropathy
4 Autonomic neuropathy
Focal and multifocal neuropathies
6 Cranial neuropathy
7 Limb mononeuropathy
8 Compression and entrapment neuropathies
9 Nerve infarction
10 Trunk mononeuropathy
11 Mononeuropathy multiplex
12 Asymmetric lower limb motor neuropathy amyotrophy
Mixed forms

Table 3 Summary of Treatments for Painful Diabetic Polyneuropathy

|Treatment |Double-bl|Open-lab|Other |
| |ind, |el |see |
|
|controlle| |text |
| |d | | |
|Non-steroidal | | | |
|anti-inflammatory agents | | | |
|Ibuprofen | | |X |
|Sulindac | | |X |
| | | | |
|Tricyclic Antidepressants | | | |
|Amitriptyline |X | | |
|Imipramine |X | | |
|Desipramine |X | | |
|Nortriptyline | | |X |
| | | | |
|Serotonin Reuptake | | | |
|Inhibitors | | | |
|Paroxetine |X | | |
|Sertraline | |X | |
| | | | |
|Anticonvulsants | | | |
|Gabapentin |X | | |
|Carbamazepine |X |X | |
|
| | | |
|Antiarrhythmics | | | |
|Mexiletine |X | | |
| | | | |
|Other Oral Agents | | | |
|Tramadol |X | | |
|Levodopa |X | | |
|Clonidine | | |X |
|Gamma-linolenic acid |X | | |
|Dextromethorphan |X | | |
|Phenothiazines | | |X |
|Narcotics | | |X |
| | | | |
|Intravenous agent | | | |
|Alpha-lipoic acid |X | | |
| | | | |
|Non-systemic treatment | | | |
|Capsaicin cream |X | | |
| | | | |
|Non-pharmacological | | | |
|treatments | | | |
|TENS unit |
|X |X |
|Acupuncture | |X | |

Table 4 Clinical Features of Diabetic Autonomic Neuropathy

Pupillary dysfunction
Cardiovascular disturbances
16 Abnormalities of heart rate
17 Orthostatic hypotension
Gastrointestinal disturbances
19 Esophageal, gastric, duodenal and colonic atony
20 Diarrhea
21 Gallbladder atony
22 Anal sphincter weakness
Genitourinary disturbances
24 Bladder dysfunction
25 Retrograde ejaculation
26 Impotence
27 Female sexual dysfunction
Unawareness of hypoglycemia
Abnormalities of sweating

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