Peripheral
diabetic neuropathy
(Portuguese
PDF version)
Antonio
R.T. Gagliardi*
*PhD,
University of Kentucky, Lexington - KY, USA. Assistant Physician,
Clinical Unit of Lipids, Incor-HC-FMUSP. Assistant Professor, Department
of Physiology, School of Medicine of Santos, Fundação
Lusíada. Endocrinologist, Institute of Cardiovascular Diseases
of Santos, Angiocorpore.
Correspondence:
Dr. Antonio R. T. Gagliardi
Rua Mário Amaral, 459
CEP: 04002-021 - São Paulo - SP
Tel.: +55 11 3559 8099
J
Vasc Br 2003;2(1):67-74
INTRODUCTION
Chronic
peripheral neuropathy (PN) associated with diabetes mellitus is an insidious
and progressive pathological process in which severity is not directly
represented by signs and symptoms developed by patients.1
PN is the causal agent, that is, the mechanism that triggers off the
pathophysiological process and leads to ulceration and amputation. On
top of that, PN alone may cause painful paresthesia, sensory ataxia
and Charcot deformity.2 The early detection
and identification of the neuropathic process provides the patient with
a crucial opportunity for controlling blood sugar levels and taking
proper care of his/her feet before morbidity becomes relevant. The Diabetes
Control and Complications Trial (DCCT) showed that intense insulin therapy
in type 1 diabetes reduced the risk of clinical and electrophysiological
complications of diabetic neuropathy (DN) by 61%.3
On the other hand, several electrophysiological studies have shown a
direct relationship between the levels of glycated hemoglobin and the
severity of PN.
DN, in a broader sense, comprehends a wide range of disorders that affect
the components of the peripheral and autonomic nervous system. Neurological
disorders occur both in type 1 and type 2 diabetes, as well as in acquired
diabetes. DN is not a simple entity, but a group of syndromes with various
clinical and subclinical disorders.
For simplicity, we may classify DN into somatic (autonomic), focal (mononeuritis
and compression syndromes) and diffuse (proximal neuropathies, distal
symmetric polyneuropathies, involvement of large-diameter and small-diameter
fibers.
MECHANISMS
INVOLVED IN THE PATHOGENESIS OF NEUROPATHY
Several
mechanisms are responsible for the development of DN, such as metabolic,
vascular, and autoimmune mechanisms, in addition to neurohormonal deficiencies
and growth factors. However, persistent hypoglycemia seems to be the
most important primary etiological factor based on the metabolic theory.
Persistent hyperglycemia causes accumulation of polyol pathway (e.g.:
sorbitol and fructose) in the nerves, producing lesions by means of
a mechanism that is still unclear.
The reduction in myoinositol uptake and the inhibition of the Na/K/ATPase
pump results in sodium retention, edema of the myelin sheath, axoglial
disjunction and nerve degeneration. The deficiency of linoleic acid
and n-acetyl-l-carnitine seems to be involved as well. In a subpopulation
of patients, especially those with proximal neuropathy and who present
with an important motor component, there seems to be an autoimmune mechanism
involved, with the presence of antineuronal antibodies against components
of sensory and motor structures detected in patients' serum.
Another mechanism that might be involved is microvascular insufficiency,
due to absolute or relative ischemia of endoneural and epineural vessels.
Histopathological studies confirm findings of microvascular disorders
and thickening of the basement membrane, while functional studies reveal
reduction in blood perfusion, increase in peripheral resistance and
alterations to vascular permeability.4
Aside from metabolic, immunological and vascular factors, some data
suggest that the relative or absolute lack of growth factors play an
essential role in the development of neuropathy, observed when growth
factors are depleted by axotomy or use of specific antibodies. Neuronal
growth factors may warrant the survival and regeneration of neurons
submitted to the harmful effects of diabetes, in such a way that the
capacity of diabetic patients to maintain the structure and function
of nerves depends on the expression and efficiency of these neuronal
growth factors. For instance, sympathetic neurons and those ones at
the dorsal root ganglion rely on the neural growth factor (NGF) during
the developmental stage. Populations of these adult neurons, which are
most affected by DN, depend on NGF for maintaining their functions and
survival.
NGF belongs to a group of growth factors known as neurotrophins and
has a wide range of functions, such as vasodilation, intestinal motility
and nociception. The decreased NGF synthesis in diabetes seems to be
involved in the pathogenesis of the degeneration of small-diameter fibers,
which have a crucial role in pain and thermal sensation. Another member
of the group of neurotrophins seems to be important for the survival
and functioning of large-diameter nerve fibers, responsible for vibratory,
position and possibly motor sensation. Insulin growth factors (IGF)
I and II are implicated in the growth and differentiation of nerve fibers,
and the presence of IGF receptors was observed in neurons, Schwann cells
and ganglia. IGFs and IGF binding proteins, essential for normal biological
activity, are regulated by insulin and by blood sugar level. Therefore,
one of the consequences of insulin reduction is the decrease of IGF
I levels. In brief, DN is a heterogeneous disease that suggests pathogenetic
differences as to the distinct mechanisms of clinical syndromes.5
CLINICAL
PRESENTATION AND DIAGNOSIS
Focal
neuropathy: mononeuritis and compression syndromes
Mononeuropathies are caused by vasculitis and subsequent ischemia or
infarction of the nerves. There is spontaneous regeneration in a period
of approximately six to eight weeks. Usually, ulnar, median, radial,
femoral, and the lateral cutaneous nerves of the thigh are affected.
Quite often, mononeuropathies involve cranial pairs 3, 4, 6 and 7 and
the peroneal, sural, sciatic, femoral, ulnar and peripheral median nerves.
The onset is acute and painful, and spontaneous resolution occurs within
the same time period. It should be distinguished from compression syndrome
with insidious and progressive onset, which persists if no therapeutic
intervention occurs.
The most frequent compression syndromes affect the median and medial
and lateral plantar nerves. The carpal tunnel syndrome is twice as frequent
in diabetics. Notably, the clinical presentation of this syndrome in
diabetics may vary and the symptoms may be present all over the hand
and even on the forearm, thus masking the local compressive factor,
since the affected site is much larger. Compression syndromes are very
frequent in diabetics and their diagnosis must be well established,
since the treatment might involve surgery. The comparison of clinical
characteristics between mononeuropathies and compression syndromes is
shown in Table 1.
 Table
1 - Comparative
clinical characteristics
 |
| Characteristic |
Mononeuropathy |
Compression
syndrome |
|
| Onset |
abrupt |
gradual |
| Pain |
acute |
chronic |
| Multiple |
occurs |
rare |
| Outcome |
resolves |
persists |
| Treatment |
Physical
therapy |
rest/support/surgery |
|
Polyneuropathies
Proximal motor neuropathy often affects elderly patients. The initial
symptoms are pain, followed by muscle weakness (either unilateral or
bilateral). It coexists with distal peripheral polyneuropathy and includes
patients with chronic inflammatory demyelinating polyneuropathy, monoclonal
gammopathies, and inflammatory vasculitis. This type of neuropathy has
an important immune component, which can be resolved by immunotherapy.
Distal symmetric polyneuropathy: in general (but not always),
diabetes initially affects small-diameter nerve fibers, manifesting
itself clinically on the lower limbs through pain sensation and hyperalgesia,
followed by loss of thermal and pain sensitivity and reduction of superficial
tactile sensation. The involvement of large-diameter fibers may affect
sensory or motor nerves and is characterized by reduced vibratory and
position sensation, reduction in deep reflexes, ataxia, shortened Achilles
tendon and increased blood flow to the foot (warm foot sensation). Most
patients with distal symmetric polyneuropathy present involvement of
both types of nerve fibers, resulting in the classic "gloves and
socks syndrome." At the initial stage of the neuropathic process,
multifocal sensory loss may be observed. It should be underscored that
other causes may be present and should be considered for the differential
diagnosis; among these we have B12 and folate deficiency, syphilis,
monoclonal gammopathy, paraneoplastic disorders (myelomas, lymphomas
and carcinomas), uremia, hypothyroidism, porphyria, alcoholism, sarcoidosis
and HIV.
Symptoms
of distal sensory polyneuropathy:
a) Sensory
symptoms: insensitivity or loss of foot function (dead feet), tingling
pain in feet (paresthesia), stabbing pain, burning pain or deep painful
sensation, snug bandlike sensation around the feet, sensation of walking
on a cotton blanket or on hot sand, contact hypersensitivity (allodynia),
gait instability.
b) Motor symptoms: difficulty in walking or climbing stairs, lifting
objects, and holding small objects.
Signs of distal sensory polyneuropathy at inspection: normal
foot; dry skin, dilated veins, edema; toenail deformities, hallux valgus,
Charcot joint; muscle atrophy; callus formation; plantar ulceration;
ataxia; physical examination; dry and lukewarm foot; restricted pedal
pulses; loss or reduction of tendinous reflexes of the knee and ankle;
loss of ankle dorsiflexion (the patient cannot walk on his/her heels).
RISK
FACTORS FOR DN
Risk factors
may not be determinant, but include, in this case, glycemia and insulinemia,
age and duration of diabetes, alcoholism, smoking and albuminuria.6,7
Glycemia
and insulinemia
The Seattle Prospective Foot Study was conducted to assess the incidence
and the determinants of foot disorders among diabetic patients in the
United States. The study showed that relative hyperglycemia preceded
the manifestation of peripheral sensory neuropathy (PSN), defined as
insensitivity to monofilament of 10 g tested at several sites and on
either of the feet. The increase in risk was estimated at 15% for every
1% increase in glycated hemoglobin. In the Diabetes Control and Complications
Trial, the aggressive control of glycemia in type 1 diabetes reduced
the risk of PSN. In the United Kingdom Prospective Diabetes Study, the
intensive control of glycemia was associated with the reduction of PSN,
especially in patients that were followed up for a long period (in this
study, the necessity for strict and long-term control is underscored).
On the other hand, an association between the use of insulin and the
increase in the risk of PSN has been described, which formulates the
hypothesis that this increase in risk could be related to hyperinsulinemia.
However, we should consider that, in fact, the probability of insulin
use is higher in cases in which the duration of the disease is longer
or in critically ill patients, that is, the correlation would be with
barely treatable hyperglycemia, which requires the use of insulin.
Age
and duration of diabetes
The duration of diabetes was associated with the increase of the prevalence
of PSN in over 4,000 diabetic patients followed by Pirart.4
In addition, there have been some data suggesting that elderly patients
are at a higher risk for PSN. There appears to be no difference as far
as gender is concerned.
Alcoholism
and smoking
In type 1 and 2 diabetes, there is independent association between smoking
and the incidence of PSN. In the Seattle study, the patients who reported
increased use of alcohol had a sevenfold risk for PSN than those who
consumed alcoholic beverages more moderately.
Albuminuria
In type 1 diabetes patients, the increase in the urinary excretion of
albumin was associated with the development of PSN. In general, arterial
hypertension preceded PSN.
MANAGEMENT
OF NEUROPATHIES THAT AFFECT LARGE-DIAMETER FIBERS
Patients
with neuropathies that affect large-diameter fibers often have ataxia
and incoordination.8,9 Consequently,
they are 17 times more prone to falls than non-neuropathic controls.
Elderly patients have more neuropathy of large-diameter fibers than
younger ones.
Improving
muscle strength and balance is one of the treatment priorities. Recently,
it has been shown that resistive muscle exercises such as leg press,
knee extension, and extension of the dorsal and abdominal muscles, increase
the strength of several muscles, and significantly improve motor coordination
and balance. Low-impact activities, such as tai chi chuan, are also
recommended.
MANAGEMENT
OF NEUROPATHIES THAT AFFECT SMALL-DIAMETER FIBERS
Demyelinated
small-diameter C fibers are responsible for thermal sensation, pain
sensitivity and autonomic function. At the initial stage of fiber injury,
the patient feels burning pain with hyperalgesia and allodynia. This
pain differs from the one observed in large-diameter fibers, where there
is deep stabbing pain. Since sympathetic involvement may occur, the
regulation of sweat glands and of arteriovenous shunts on the feet is
altered, predisposing to the growth and penetration of bacteria secondary
to skin dryness, which causes small fissures that, in their turn, serve
as a point of entry for microorganisms. All this is associated with
reduced blood perfusion and, consequently, malfunction of the defense
mechanisms. The total disappearance of pain sensation should be carefully
analyzed, since it may mean definitive loss of local nerve terminations,
instead of pronounced improvement. The following are simple measures
to protect a foot depleted of C fibers in order to prevent the development
of ulcers and progression into gangrene and amputation:
- Foot protection is highly important. Wearing smooth and thick socks,
avoiding synthetic and seamless ones, at the toe level, can prevent
severe lesions.
- Appropriate footwear with proper support.
- Regular examination of the feet: patients should use a small mirror
to examine the plantar region of the foot every day.
- Extreme care with heat exposure: water temperature should always be
checked with a body part with preserved sensation.
- Use of moisturizing creams to avoid skin dryness and fissures.
THERAPEUTIC
POSSIBILITIES
Pirart's
classic study,4 which followed
up 4,400 diabetic patients over 25 years, found 12% of clinically detectable
neuropathy at the beginning of the study and 50% at the end of 25 years
of follow up, historically establishing the relationship between chronically
decompensated diabetes mellitus and the prevalence of DN. During the
last years of the study, considerable progress was attained regarding
new therapeutic options, especially those related to the symptomatology
of painful DN. Nevertheless, metabolic control undoubtedly continues
to be the best option for the prevention and treatment of painful DN.
Management
the pathogenetic process
Aldose
reductase inhibitors
Aldose reductase inhibitors10 reduce glucose
flow by polyol pathways, inhibiting the buildup of sorbitol and fructose
in the tissue and avoiding oxidative processes that are detrimental
to nerve function. Alrestatin, sorbinil and tolrestatin are aldose reductase
inhibitors clinically used in several countries. Although a subjective
initial improvement has been described in some studies, such as vibratory
sensation and some autonomic cardiovascular reflexes, there is a great
concern with important side effects, such as lymphadenopathy, fever,
and pancytopenia.
Gangliosides
Gangliosides11 are sialoglycolipids, essential
components of the nerve cell membrane. Several studies have suggested
some subjective improvement, but with no evident change to the velocity
of nerve cell conduction. Therefore, the results were not encouraging.
Gamma linolenic acid
Gamma linolenic acid12 is an essential
fatty acid metabolized into dihomo-gamma linolenic acid, which is an
important phospholipid element of the neuronal membrane. It also has
substrate for the formation of prostaglandin, which is in charge of
maintaining the blood perfusion of the nerve. In diabetic patients,
the initial conversion reaction is inhibited and, consequently, the
production of metabolites is reduced, which may contribute to the pathogenesis
of DN. Some preliminary clinical studies show satisfactory results after
one year of treatment.
Aminoguanidine
Aminoguanidine inhibits the formation of advanced glycosylation end
products, showing good therapeutic effect on DN in experimental diabetes
in rats. Clinical evidence has not been clearly established yet.
N-acetyl-l-carnitine
The excellent results obtained with experimental animals were not repeated
in multicenter studies with diabetic patients.
Myoinositol
DN animal models show myoinositol deficiency. Some clinical studies
suggest that nutritional supplementation with myoinositol may have a
beneficial effect after prolonged use (six months).
ACE
inhibitors
Recently, some studies have suggested that lisinopril, an angiotensin-converting
enzyme inhibitor, may have a positive effect on the evolution of painful
DN. Although results seem to be encouraging, comprehensive clinical
studies are necessary in order to validate this new therapeutic option.13
Intravenous
human immunoglobulin
It is indicated to patients who have DN associated with antineuronal
autoimmunity. The neuropathic syndrome observed in these patients predominantly
includes distal symmetric motor polyneuropathy, distal diabetic neuropathy
with severe motor component and distal symmetric polyneuropathy with
predominant dysfunction of large-diameter fibers. It has been shown
that the use of intravenous immunoglobulin produces significant and
rapid improvement of neurological and non-neurological diseases with
autoimmunity component. Treatment with immunoglobulin is safe and well
tolerated. However, some precautions have to be taken due to the possibility
of anaphylactic shock.
Neurotrophic
growth factors
The use of neurotrophic growth factors14
is still at the experimental stage, and there are some specific therapeutic
projects, such as the use of NGF for the treatment of neuropathy with
predominant involvement of small-diameter fibers, the use of neurotrophin
3 for large-diameter fibers and of IGF-1 and IGF-2 in case of motor
fibers. Few clinical results with NGF proved to be encouraging; however,
the availability and access to this kind of treatment is not yet used
on a regular basis.
Management
of sensory disorders
Management
of pain is one of the hardest tasks in the treatment of DN. The assessment
of pain severity is hindered by the presence of depression, which should
not be overlooked and should be seen as an essential part of the treatment.
Different types of neuropathy have been described, and the painful syndrome
may result from pathological processes at several levels of the neural
axis, including peripheral nerve or muscle, pathological activation
of the sympathetic nervous system, abnormal excitatory or inhibitory
activity of spinal synapses, which mediate the sensation of pain or
abnormalities at the supraspinal level of the brain. Therefore, specific
treatment may be targeted at different levels.
In general, the patients are mainly grouped according to the involvement
of A delta or C fibers.
Management
of patients with preferential involvement of c fibers
Initial
treatment may include capsaicin or clonidine.15
Capsaicin
Intense hyperesthesia with burning pain, sometimes stabbing and characteristic
of C fiber involvement, usually responds to the topic use of capsaicin
three or four times a day. Capsaicin is extracted from cayenne pepper,
and a simple homemade recipe consists in adding three tablespoons of
cayenne pepper powder in a jar of vaseline, and applying the mixture
on the affected sites. Special precautions should be taken with the
eyes and genital organs. As the medication is compound and volatile,
the affected site must be wrapped in thin plastic for a while. After
initial applications, the symptoms are exacerbated and, after two weeks,
a good therapeutic response is observed.
Clonidine
There may be a component of sympathetic mediation of pain by C fiber,
which could improve with the use of clonidine. Clonidine should be used
topically during one week. After this time, the therapeutic response
may be assessed properly.
Isosorbide
nitrate
Recent studies suggest that the local use of isosorbide nitrate spray
has a beneficial effect on painful DN. However, a larger number of cases
should still be treated so that this new therapeutic option can be properly
evaluated.
Management
of patients with involvement of a fibers
This is
a type of deep pain that is refractory to previously mentioned treatment
options.
An alternative in these cases is to use continuous intravenous infusion
of insulin for 48 hours in the dose of approximately 1.0 U/hour. There
is usually good response and the treatment is then discontinued. The
mechanism of the therapeutic effect is still unknown.
Peripheral block of the nerve should be performed in cases of untreatable
pain, with infusion of 5 mg/kg of lidocaine for 30 minutes, which alleviates
the symptoms during five to fifteen days. This option should only be
used in cases of self-limited neuropathy.
If peripheral drugs are not efficient, the treatment may be implemented
at the medullary level with the use of tramadol or dextromethorphan
in the dose of 30 to 150 mg.
Carbamazepine16 has been classically used
and proved to be clinically efficient for the management of pain in
DN. The usual dose is 400 mg up to 800 mg a day. Special attention should
be given to the adverse effects and drug interactions that this drug
may bring about.
Phenylhydantoin has already been used to treat painful DN, but there
are no consistent data that show good results. Currently, it is no longer
used. Babapentin17 is an anticonvulsant
agent whose mechanism of action is not yet clearly known, but which
has proved to be efficient for the treatment of painful DN.
Transcutaneous nerve stimulation nay produce good results in some cases
and certainly represents the most benign treatment against painful DN.
Painkillers are not often recommended since they do not have a good
clinical response, except in the case of painful paralysis of the third
cranial pair, in which pain lasts for a short time.
Rheological agents, such as pentoxifylline, a drug that increases erythrocyte
deformability and blood perfusion, improving oxygenation in the tissues,
have not shown therapeutic effect on painful DN in recent studies.
The use of salmon calcitonin spray showed a positive response in 38%
of patients treated during two weeks after its daily use (100 IU a day).
The initial description was occasional and controlled studies were carried
out later on, confirming its effect.
As far as antidepressants18 are concerned,
recent studies have demonstrated that interruption of pain with the
use of antidepressants that inhibit the recapture of norepinephrine
and serotonin relieves the symptoms of painful DN. In fact, this central
action enhances the effects of these neurotransmitters as endogenous
activators of circuits that inhibit the transmission of pain sensation
to the brain, which, in their turn, modulate the transmission of pain
to spinal neurons. Several studies have shown that tricyclic antidepressants
combined with phenothiazines are quite efficient in managing neuropathic
pain, regardless of their antidepressive effect. Tricyclics alone are
also efficacious, preventing the development of late dyskinesia occasionally
observed in patients treated with phenothiazines.
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