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Diabetic neuropathy.

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NEUROLOGICAL PROGRESS
Diabetic Neuropathy
Mark J. Brown, MD, and Arthur K. Asbury, M D
Peripheral nerve disorders are important late complications of diabetes mellitus. Polyneuropathy, which may involve
varying proportions of sensory, motor, and autonomic fibers, is considered the consequence of metabolic derangements
that result from chronic hyperglycemia. Symmetrical proximal motor neuropathy (“diabetic amyotrophy”) also may
have a metabolic basis. Mononeuropathies in diabetes may have an ischemic or compressive cause. Advances have been
made in understanding the biochemical basis for diabetic polyneuropathy. The treatment of symptomatic diabetic
neuropathy should be directed toward long-term normalization of blood glucose until more specific therapies become
available.
Brown MJ, Asbury AK: Diabetic neuropathy. Ann Neurol 15:2-12, 1984
The prevalence of diabetic neuropathy is not accurately
known, but a conservative estimate would be that half
the insulin-receiving diabetics, more than one million
individuals in the United States, have symptomatic
neuropathy. Three major neuropathic syndromes occur in diabetes (Table 1 ) . Most common is a distal
symmetrical polyneuropathy. Less frequent are proximal motor neuropathies and focal neuropathies, conditions more likely to attract the attention of the neurologist. None of rhese syndromes is unique to diabetic
individuals [ G ] , and two or more forms of neuropathy
may be encountered in the same diabetic patient.
Diabetes Melli.tus
Diabetes mellitus includes a group of disorders expressed by abnormal glucose metabolism. The two
forms of primary diabetes, previously called “juvenile
onset” and “adult onset,” are now referred to as insulin
dependent, ketosis prone (type I ) and non-insulin dependent, ketosis resistant (type II), since either may
occur at any age. Circulating insulin levels are low or
unmeasurable in type I diabetes. This syndrome can be
associated with or follow viral infection [28}, including
Coxsackie B4 [143]. Immunological factors may be
important, and antibodies to islet cell surface membrane and cytoplasm are present in serum from patients with type l diabetes [31, log}. Genetic factors
may have a causal role 111. I n type I1 diabetes the
timing of insulin release is abnormal, although circulating insulin levels rise in response to a glucose stimulus
[30, 1041. End-organ resistance to insulin has been
demonstrated in type I1 diabetes, along with diminished binding to cellular receptors 130, 1041. Studies of
From the Department of Neurology, University of Pennsylvania
School of Medicine, Philadelphia, PA I9 104.
Received May 9, 1983, and in revised form July 14. Accepted for
publication July 15. 1983.
2
type II diabetes have implicated obesity and genetic
predisposition in its pathogenesis [47].
Impaired glucose tolerance also may result from a
number of pancreatic, hormonal, chemical, and genetic
disorders E47, 941. The incidence of diabetes is increased in certain neurological diseases, including
myotonic dystrophy, ataxia tclangiectasia, Huntington’s
chorea, Friedreich‘s ataxia, and progeria [94].
Criteria for the diagnosis of diabetes have been accepted [47,74],but the diagnosis may be difficult in an
asymptomatic patient. When doubt exists, the diagnosis “impaired glucose tolerance test” is preferable to
“latent diabetes,” “borderline diabetes,” or “prediabetes.” The general medical treatment of diabetes is directed toward restoring blood glucose levels and toward preventing acute metabolic derangements [ 14 1]
as well as late chronic retinal, renal, and neuropathic
complications. The merits of tight blood glucose control have been debated, but present evidence from
studies of both humans arid experimental animals suggests that good control prevents or reduces the severity
of late diabetic complications.
Poly neuropathy
Estimates of the prevalence of polyneuropathy in diabetic populations range from zero to 9 3 9 C17, 1281.
This wide variation results from patient selection factors, investigators’ criteria for diagnosis of neuropathy,
and the sensitivity of detection methods. T h e lowest
prevalence rates are obtained when screening is done
on the basis of the history alone, because affected individuals may have few or no neuropathic symptoms { 5 2 ,
881. Neurological examination with careful sensory
Address reprint requests to Dr Brown, Ikpartmcnt of Neurology,
Hospital of the University of Pennsylvania, 3400 Sprure St, Philadelphis' PA 19104.
Table I. ClaJ.tzj5cationof Diabetic Neuropathies by Topography
testing will detect additional abnormal individuals, especially if supplemented with quantitative psychophysiological cutaneous sensation measurements [2?, 341.
Electrophysiological testing, a more sensitive way of
evaluating large fiber function, often shows abnormalities in asymptomatic diabetics 178, 1281. A balanced view of prevalence comes from the studies of
Pirart 11001, who found evidence of neuropathy by
clinical examination in about 89? of diabetics at the
time of diagnosis, increasing to 50% after 25 years of
disease.
In most cases diabetic polyneuropathy involves a
combination of sensory, motor, and autonomic nerve
fiber abnormalities. Cutaneous sensibility is reduced in
a length-dependent stocking-and-glove distribution, often with associated decreased vibratory and proprioceptive perception in the limbs, reduced or absent
ankle jerks, mild distal muscle weakness, and autonomic dysfunction. These features may be indistinguishable from those in a number of other metabolic,
toxic, and nutritional axonal neuropathies.
neuropathy does not appear to be a secondary response
to axonal atrophy 11251, and its occurrence suggests a
selective Schwann cell abnormality that is independent
of axonal loss. Although segmental demyelination is
prominent in some cases of diabetic polyneuropathy, it
is a minor neuropathological feature in others [8, 141.
Traditional silver staining techniques have demonstrated a decreased number of unmyelinated fibers in
somatic and autonomic nerves [SS}, and unmyelinated
fiber loss has been confirmed by electron microscopy
C9, 132). In a morphometric study of two cases involving painful neuropathy, findings of increased numbers
of small unmyelinated axons (0.1 to 0.2 km in tiiameter) suggested axonal regeneration with sprouting in
concert with reduction of unmyelinated fibers of normal caliber (0.2 to 2.0 k m in diameter) [ 1 4 ] . The
change probably reflects concurrent fiber degeneration
and regeneration, a pattern that also occurs in other
axonal polyneuropathies.
Endoneurial capillaries in peripheral nerves of diabetics are thickened [8, 1311, and perineurial basement
membranes are widened [731. Such abnormalities and
neuropathy may occur independently as a consequence
of long-standing diabetes, and their association need
not indicate cause and effect. A permeability disorder
at the blood-nerve o r blood-perineurial barrier in diabetics could lead to endoneurial metabolic derangements, however, possibly resulting in neuropathy.
Small vessel occlusive changes have been found in
nerves from human diabetics [ I 30, 1391. Focal areas of
myelinated fiber loss were found in proximal nerves of
two patients with distal polyneuropathy examined postmortem [126], a pattern similar to that seen in experimental nerve infarcts C98). These findings suggest that
proximal occlusive microvascular disease can lead to
multiple small proximal nerve infarctions and provide
the neuropathological basis for diffuse disral nerve fiber
loss.
Pathological Considerations
Neurophysiological Considerations
Diabetic polyneuropathy is best classified as an axonal
neuropathy, in that the predominant neuropathic feature is nerve fiber loss [S, 13, 23, 531. A proximaldistal gradient of myelinated fiber abnormalities has
been found postmortem [22) and in a biopsy study of
intramuscular twig nerves in asymptomatic diabetic patients IlOS]. Denervation changes are evident in histological sections of distal muscles, reflecting the lengthdependent nerve fiber loss. Ultrastructural studies of
nerves from diabetic patients have not demonstrated
distinctive features in affected axons [9, 14, 1321.
Thomas and Lascelles 11291 and others 18,9, 351
described an increased incidence of segmental demyelination in the nerves of some diabetics. In several cases
extensive remyelinative changes led to frank onion
bulb formations { 7 , 1311. Demyelination in diabetic
Nerve conduction abnormalities in diabetes were described in some of the early clinical neurophysiological
studies of peripheral neuropathy [ 4 8 , 92). In patients
with established diabetes of short duration, motor conduction often is normal 1401, but most patients with
symptomatic neuropathy show a mild to moderate
slowing of motor conduction velocities [?6, 921, a
finding consistent with loss of larger diameter motor
axons and sparing of smaller, slower-conducting motor
fibers. Lower extremity nerves are slowed first t403,
and distal conduction is slowed more than proximal
[76}. Electromyography is more sensitive to early
neuropathic changes than are conduction velocity measurements 178,921 and has detected denervation abnormalities in diabetics before slowing of the fastest
motor velocities [68].
I. Distal symmetrical polyneuropathy
A. Mixed sensory-motor-autonomicneuropathy
B. Predominantly sensory neuropathy
1. Predominantly large fiber
2. Mixed large and small fiber
3 . Predominantly small fiber
C. Predominantly motor neuropathy
D. Predominantly autonomic neuropathy
11. Proximal symmetrical motor neuropathy (“diabetic
amyotrophy”)
111. Focal and multifocal neuropathies
A. Asymmetrical proximal motor neuropathy
B. Cranial neuropathy
C. lntercostal and other mononeuropathies
D. Entrapment neuropathy
Neurological Progress: Brown and Asbury: Diabetic Neuropathy
3
Since the introduction of signal averagers, sensory
nerve studies have become a standard part of the assessment of diabetic neuropathy. Reduction in sensory
potential amplitudes 178, 953 and slowing of spinal
somatosensory conduction [651 are early electrophysiological signs of diabetic polyneuropathy. In general,
sensory potential amplitudes decline in the nerves of
the foot sooner than in the hand, and distal portions of
sensory nerves are affected before proximal ones 1951.
The pattern reflects early loss of distal myelinated sensory axons. In advanced diabetic neuropathy, as fiber
loss progresses sensory potentials may be impossible
to detect in the legs and difficult to obtain in the
arms.
At times nerve conduction velocities are lowered to
a greater degree than would be expected on the basis of
axonal loss alone, and often these decreased velocities
are accompanied by dispersed evoked responses. This
additional slowing is probably a consequence of segmental demyelination [S]. There may be a very small
degree of further slowing that has not been explained
on a structural basis [S]. This poorly understood “metabolic” phenomenon may underlie the small improvement in motor conduction velocity that has been
reported following short-term insulin therapy [lo, 5 1,
62, 1351 o r other treatment 1741 in early diabetes.
Because these rapidly reversible changes may have a
pathogenesis different from that of axonal degeneration o r segmental demyelination, such improvement
cannot be taken as synonymous with reversal of neuropathy.
Diabetic patients with or without symptomatic neuropathy are unusually resistant to the loss of vibration
perception and the motor and sensory nerve conduction failure that follow limb ischemia [6l, 701. The
basis for this resistance is unknown, but resistance to
ischemia may be lessened following treatment of hyperglycemia [62, 701. Nerves of patients with other
metabolic o r neurological disorders are occasionally
more resistant t o ischemia than those of normal subjects, suggesting that the persistence of conduction in
diabetics results from factors other than elevated blood
glucose alone.
Nerve conduction studies can be reliable tools for
following myelinated fiber function in diabetes if
proper attention i s paid to skin temperature and electrode placement. Routine electrophysiological methods do not measure unmyelinated fiber conduction
[ 5 ] , but functional tests of modalities served by these
fibers, both somatic and autonomic, are being developed for clinical use. These include quantitative
psychophysiological testing of the threshold for appreciating sensory stimuli { 341,quantification of resting
heart rate and cardiac responses to the Valsalva maneuver (21, and cutaneous sweat gland density measurements [ 7 5 ] .
4 Annals of Neurology
Vol 15
No 1 January 1784
Table 2.Symmetnral Diabetic Polyneuropathq:
Estimated Prevalence of Subtypa
Subtype
Mixed sensory-motor-autonomic neuropathy
Predominantly sensory neuropathy
Predominantly large fiber
Mixed large and small fiber
Predominantly small fiber
Predominantly motor neuropathy
Predominantly autonomic neuropathy
‘% of
All Cases
70
30
5
15
8-10
<1
<1
Clinical Features
The clinical manifestations of diabetic polyneuropathy
vary considerably [ 5 2 , 85, 88, 1281. Onset may be
abrupt o r insidious, progression rapid o r slow. The
course may appear static, o r there can be partial recovery. The neuropathy may be asymptomatic or lead to
severe disability, and the pattern of nerve fiber involvement itself may vary (see Table 1).
We examined these patterns by evaluating the clinical and electrophysiological features of 38 consecutive
male outpatients in a diabetes clinic (M. J. Brown, A. J.
Sumner, A. K. Asbury, unpublished observations,
1974). Seven (mean duration of diabetes, 4.7 years)
had no evidence of neuropathy; the remaining 31
(mean duration of diabetes, 12.1 years) had either clinical o r subclinical (electrophysiological) findings of a
neuropathic disorder. Several types and subtypes of
polyneuropathy were identified among the affected.
Whereas 22 had mixed sensory and motor fiber involvement, 9 had a predominantly sensory neuropathy ,
of whom 3 had disproportionate small fiber abnormalities 1141. Motor nerve dysfunction was a dominant
feature in 4 of the mixed group, although none had a
“pure” motor or autonomic neuropathy. We have estimated the frequency of the types and subtypes of
diabetic polyneuropathy that the clinician may expect
to see, based on our experience and a review of published clinical studies (Table 2).
MIXED SENSORY-MOTOR-AUTONOMIC POLYNEUROPAT-.
This is the most common clinical subtype of
diabetic neuropathy. The symptoms and signs of sensory, motor, and autonomic fiber involvement, which
we will consider, are present in varying degrees. In
symptomatic patients sensory disturbances are common. Weakness and atrophy may not be striking,
but motor nerve conduction and electromyographic
findings are nevertheless abnormal. Autonomic nervous system abnormalities range from clinically inapparent to severe.
Both large
and small fiber modalities may be involved in this rela-
SELECTIVE SENSORY POLYNEUROPATHY.
tively common subtype. Sensory abnormalities range
from mild toe numbness to profound anesthesia with
neuropathic ulcers and arthropathy. Corneal sensation
and hearing may be affected [43, 1131. Sensory deficits
occur in a symmetrical stocking-and-glove pattern, a
feature that is easily overlooked if the level of hypoesthesia reaches areas more proximal than the groin and
shoulders. At that point anterior chest hypoesthesia is
demonstrable [ 1103, a reflection of the fiber lengthdependent nature of this neuropathy.
Some patients with sensory polyneuropathy show a
disproportionate loss of large fiber functions, manifested in impaired balance, decreased perception of
distal vibration and position stimuli, and loss of ankle
jerks. In its most severe form, position sense loss may
result in sensory ataxia, the “pseudotabetic” form of
diabetic neuropathy. Further confusion with syphilitic
tabes dorsalis may arise if the pupils are small and sluggishly reactive to light because of autonomic fiber involvement { 12 1]. In other patients small fiber modalities are most affected. Pain and temperature sensibility
are disturbed, with relative preservation of position and
vibration perception, and reflexes are normal or nearly
so { 141. Disabling spontaneous pains, dysesthesias, and
paresthesias are common. Orthostatic hypotension and
sexual dysfunction seem to be especially common in
this group, reflecting the associated autonomic nervous
system involvement.
Several kinds of pains may occur with diabetic sensory neuropathy. Most patients will have typical neuropathic distal paresthesias (spontaneously occurring
uncomfortable sensations) or dysesthesias (contact sensory discomfort). Occasional individuals with otherwise
mild neuropathy report excessive skin hypersensitivity to slight touch, reminiscent of reflex sympathetic
dystrophy (causalgia). Shooting or stabbing pains can
be multifocal, and arresting in their impact. Some
individuals complain of superficial cutaneous burning
pain. Most troublesome is a sense of bone-deep, aching, burning pain, lasting throughout the day with varying intensity. Cramps in the small muscles of the feet,
later ascending to calves or thighs, are similar to those
that occur in muscle denervated from other disorders.
The paradoxical coexistence of spontaneous pain
and insensitivity t o painful stimuli has not been explained fully. The “gate” theory of Melzack and Wall
suggested that the selective loss of large-diameter
pain-suppressing fibers would result in painful neuropathy, but pain is not a feature of some large-fiber
neuropathies 1931. I t seems more likely that pain results from increased activity of injured small-diameter
fibers 114, 331. Regenerating nerve fibers in experimental neuromas fire rapidly and at abnormally low
thresholds [ 1341, and depolarization of damaged or regenerating fibers in humans with neuropathy could
contribute to the pain in these patients. The loss or
dysfunction of small-diameter fibers would account for
the associated cutaneous hypoesthesia.
SELECTIVE
MOTOR
POLYNEUROPATHY. Chronic
motor polyneuropathy is unusual in diabetes and
should prompt a search for another cause. In many
apparent cases sensory abnormalities can be found on
careful examination. We and others El271 have followed several young diabetic individuals who developed acute, reversible motor neuropathy after a period
of ketoacidosis. The clinical findings included quadriparesis, slowed nerve conduction, and elevated spinal
fluid protein concentration, all more consistent with
inflammatory demyelinative polyneuropathy than a disorder unique to diabetics.
Motor neuropathy or anterior horn cell loss may
occur in psychiatric patients who have been treated
with exogenous insulin-induced coma, and patients
with hypoglycemia from an insulinoma can develop a
motor neuronopathy that clinically and electrophysiologically is indistinguishable from a predominantly
motor polyneuropathy [91). Strength and the mild sensory symptoms may improve if hyperinsulinism is relieved [72). Experimentally, acute hypoglycemia in
otherwise normal rats may cause neuronopathy and axonal loss 1117). Insulin excess should be considered in
a diabetic patient with motor neuropathy and a history
consistent with hypoglycemic episodes.
Only a small
number of diabetic patients have preferential autonomic nervous system involvement. There seems to be
a disproportionate number of young patients with type
I diabetes in this group. Abnormalities include gastroparesis, diarrhea, resting tachycardia, orthostatic hypotension, sweating disorders, incomplete bladder
emptying, and impotence. Diabetic autonomic neuropathy has been the subject of recent reviews {24, 691.
The morphological basis of diabetic autonomic neuropathy appears to be both axonal loss and segmental demyelination 141, 831, but this condition has not been
studied as extensively as somatic neuropathy. Electrophysiological findings almost always indicate associated
sensory and motor nerve involvement. Conversely, autonomic dysfunction is often present in diabetic individuals without autonomic symptoms [97]. Diabetics
with autonomic neuropathy reportedly have an increased incidence of cardiac arrest and sudden death
124,971.
SELECTIVE AUTONOMIC NEUROPATHY.
Relationship Between Hyperglycemia
and Polyneuropathy
Most investigators now believe that neuropathy and
other long-term complications of diabetes result from
the interaction of multiple metabolic, genetic, and
other factors, of which the most important is chronic
Neurological Progress: Brown and Asburp: Diabetic Neuropathy
5
hyperglycemia. The presence and extent of polyneuropathy generally parallels the duration and severity of diabetes, even when diabetes is secondary to
acquired pancreatic disease 132, 961. There is no evidence that the neuropathic complications of type I and
type I1 diabetes differ. Although neuropathic signs
have been elicited within months of onset in type I
diabetes 1791, clinical neuropathy usually does not appear in diabetics until after 5 or 10 years of hyperglycemia. Neuropathic symptoms may develop suddenly
after an interval of poor control [44};rarely does neuropathy become evident following the institution of
good control C373.
Convincing evidence of the importance of chronic
hyperglycemia in the production of diabetic neuropathy is the finding that treatment that maintains relative
euglycemia may reverse clinical neurological abnormalities. Neuropathic pains may subside within a few
weeks after institution of insulin therapy (101, and sensory signs and symptoms may diminish over several
months 144, 52, 5 5 , 881. Some of the reported instances in which diabetic neuropathy has failed to improve with therapy C44, 52) may reflect the inability of
some patients to achieve good control.
Support for the role of duration and severity of
hyperglycemia in the pathogenesis of diabetic polyneuropathy comes from the 25-year prospective clinical studies of Pirart {loo}. H e reported that
neuropathy, retinopathy, and nephropathy all were
correlated directly with duration of diabetes but were
less severe in patients with “good” control than in those
with “poor” control. Investigators have had difficulty
carrying out randomized clinical trials of the effect of
treatment on diabetic neuropathy. Many months may
be required before improvement can be documented
[ S S ) , and ethical considerations limit the possibility of
including a population whose diabetes is poorly controlled [ 1 141. In one carefully designed study of newly
diagnosed diabetics, the authors could not demonstrate
a significant benefit of conventional over rigorous therapy {114). There were only small differences in the
degree of control in the two treatment groups, however. Results of certain tests of peripheral nerve function indicated improvement in both groups, suggesting
that treatment of diabetes in a closely monitored study
may lessen the ex tent of peripheral neuropathy.
PathogeneJ i r
Human diabetic polyneuropathy is best thought of as a
distal axonal neuropathy with variable manifestations.
The symptoms and signs reflect the pattern of nerve
fiber involvement and are related to fiber length. This
distribution would result if diabetic polyneuropathy
were a dying-back neuropathy or distal axonopathy
{ 1231. Alternately, a neurophysiological mechanism
has been proposed that would explain distal symptoms
6 Annals o f Neurology
Vol 15
No 1 January 1984
and signs if diabetes caused randomly distributed abnormalities of axonal function 11371.
Biochemical studies of human diabetic neuropathy
have been limited by restricted access to nerve tissue.
Myelin lipids can be reduced in nerves of human
diabetics [66], but this reduction appears to be a
nonspecific consequence of loss of myelinated fibers
{ 131. There may be a disproportionate early loss of the
myelin lipid fraction that includes phosphatidyl inositol
1131. Myo-inositol deficiency may have a place in the
pathogenesis of diabetic polyneuropathy (to be discussed), and nerve myo-inositol levels were found to be
depressed in one postmortem study {87]. In a biopsy
series of less severely ill patients, however, nerve m y inositol levels were elevated [35}.
Investigators have examined nerve metabolism in
animal models of diabetes since Eliasson { 361 reported
slowed nerve conduction in alloxan-induced diabetes.
The genetically determined disorders occurring in
small laboratory animals can be divided into those that
resemble type I, insulin-dependent diabetes (in the BB
rat), and those that resemble type I1 diabetes (in the
Chinese hamster, ob/ob mouse, and db/db mouse) { 16,
901. Among these, the BB-Wistar rat holds the greatest interest for current peripheral nerve research [ I 181.
Streptozotocin is the drug most widely used to produce experimental diabetes. Injected animals develop
hyperglycemia and weight loss, and motor nerve conduction velocity falls within a few days [56). Myelinated fiber caliber is reduced within 4 weeks of
streptozotocin diabetes 115, 711, but this minor
morphological change does not account for the marked
electrophysiological abnormality; slowing may reflect a
metabolic rather than an anatomical lesion { 1151. Conduction does not slow if hyperglycemia is rigorously
corrected with twice-daily insulin injections based on
frequent plasma glucose monitoring {56). After I or
more months of streptozotocin diabetes, distal fibcr
breakdown and segmental demyelination ensue [ 15,
101, 142). Only then does the nerve fiber structure
resemble that in human diabetics.
Fast, slow, and retrograde transport are reported to
be altered in experimental diabetes {I 1, 112, 1161.
Peripheral nerve myelin protein metabolism is irnpaired { 1241, and protein glycosylation is increased
{ 1331. The functional and structural significance of
these observations is not known.
As yet the postulated pathogenetic link between
blood sugar elevation and neuropathy has not been
identified. Both normal peripheral nerves and those of
diabetics are relatively insensitive to insulin {GO], and it
is unlikely that insulin deficiency alone is responsible
for diabetic neuropathy. Concentrations of nerve sorbitol and fructose are elevated in experimental diabetes, a consequence of increased conversion of glucose
to sorbitol by aldose reiluctase (251. Gabbay C45l pro-
posed that increased osmotic pressure from the accumulation of polyol glucose metabolites damages
Schwann cells and produces neuropathy, but this hypothesis has not been supported by morphological evidence of intracellular swelling in either human or experimental diabetic neuropathy.
Myo-inositol appears to play a pivotal role in the
pathogenesis of experimental diabetic neuropathy. It is
rapidly incorporated into myelin [so) and, as a constituent of phosphatidylinositol, is important in the
maintenance and biophysical functioning of axonal
membranes. Unlike most other polyols, nerve myoinositol is reduced in concentration in experimental
diabetes [ 2 51. Dietary supplementation of myo-inositol
prevents or corrects conduction slowing in streptozotocin-diabetic rats, although hyperglycemia and weight
loss persist {56, 591. The fall in nerve myo-inositol
levels in diabetic animals may be a consequence of
increased polyol pathway activity [86], and in this way
the polyol pathway may affect nerve conduction
through a myo-inositol-related mechanism.
Altered nerve myo-inositol metabolism may lead to
impaired nerve sodium-potassium adenosine triphosphatase ( ATPase) function. A defect in sodium-potassium ATPase function has been identified in diabetic
rat [ 5 8 ] and rabbit [29] peripheral nerve. The rat nerve
sodium-potassium ATPase defect is preventable by
oral myo-inositol administration and appears to be
the consequence of deranged myo-inositol metabolism
[ 58). Sodium-potassium ATPase, as a membranebound enzyme, is affected by its surrounding lipid
milieu [ 1071. Membrane phosphatidylinositol is the
endogenous activator of sodium-potassium ATPase activity, at least in rabbit kidney E84). Because watersoluble myo-inositol levels influence nerve inositol
phospholipid metabolism [ 1191, deranged mjwinositol
metabolism may impair sodium-potassium ATPase
activity by altering phosphatidylinositol. A self-reinforcing cyclic abnormality involving both sodiumpotassium ATPase function and myo-inositol uptake is
present in diabetic peripheral nerve [54, 57).
The sodium-potassium ATPase defect may have
functional implications. Slowed nerve conduction in
the BB-Wistar rat has been attributed to an increased
resting intracellular sodium content possibly stemming
from reduced sodium-potassium ATPase function
[12). Abnormal axonal transport is reported to be a
consequence of altered myo-inositol metabolism {86),
perhaps via a sodium-potassium ATPase mechanism.
Sodium-potassium ATPase generates the gradient necessary to maintain the concentration of various metabolic substrates in nerve, including amino acids [ 1381,
and the metabolism of many water-soluble nutrients
may be affected by a sodium-potassium ATPase defect. Thus, one can speculate that chronic myo-inositol-related impairment of sodium-potassium ATPase
could lead to widespread biophysical, biochemical, and
structural abnormalities in diabetic peripheral nerve.
Therapy
The diagnosis of diabetic polyneuropathy may be
difficult to establish with certainty, because both diabetes mellitus and axonal polyneuropathies are common
disorders. Most cases of Symptomatic neuropathy appear after many years of diabetes, so another cause
must be sought if the diagnosis of diabetes is not firmly
established or if blood glucose has been elevated for
only a short time. Abnormal glucose tolerance test results may not fulfill the diagnostic criteria for diabetes
mellitus. Nerve conduction studies are useful in documenting the nature and extent of the neuropathy and in
identifying superimposed compression neuropathies
that occur with increased frequency in diabetics. Spinal
fluid protein levels may be elevated in diabetes, but the
information is seldom of diagnostic value. Sensory
nerve biopsy is rarely useful except for research purposes.
Because the severity of diabetic neuropathy appears
to be correlated with the magnitude and duration of
hyperglycemia, one should try to obtain a high degree
of blood glucose control. The method must be individualized. Obese patients with type I1 disease may become euglycemic by losing weight, and exercise and
sulfonylureas may be effective for other patients with
type I1 diabetes who are not candidates for insulin therapy [30]. Most individuals with symptomatic type I or
type I1 diabetes and neuropathy will require insulin
replacement. Perfect control remains elusive; none of
the presently available methods of insulin administration provides the subtle degree of autoregulation that
occurs throughout the day in normal individuals. There
is presently no evidence, however, that rigorous control is superior to good conventional treatment [ 1141.
The most widely advocated conventional means of
obtaining “good” control is by monitoring finger-stick
blood sugar levels at home, using glucose oxidase strips
and a portable colorimeter and adjusting insulin dosage
accordingly. Urine glucose test results often poorly
reflect blood sugar levels. Hemoglobin is glycosylated
at a faster rate during times of hyperglycemia [l81, and
glycohemoglobin levels can serve as a cumulative
record of prior blood glucose elevation for long-term
monitoring. Mechanical devices that administer a predetermined program of insulin release throughout the
day (open loop) [lo, 891, or that vary the dose in response to signals from an on-line blood glucose sensor
(closed loop), may provide the means for improved
control [ 106). Ultimately, islet cell transplantation may
become a therapy for diabetes. In animal experiments
both allograft and xenograft islet cells have survived
and ameliorated hyperglycemia in previously diabetic
hosts [77].
Neurological Progress: Brown and Asbury: Diabetic Neuropathy
7
Clinical trials of myo-inositol [26, 55, 64) and aldose
reductase inhibitors 1741 have been carried out, so far
with inconclusive results. Neither myo-inositol nor aldose reductase inhibitors are presently indicated for
routine clinical use. Vitamin supplementation has no
demonstrable value in the treatment of diabetic neuropath y.
The results of treatment of pain in diabetic neuropathy are often disappointing. The most important step in
reducing pain may be to improve blood glucose control. Occasional patients have a transient increase in
pain intensity after restoration of blood glucose levels
toward normal, but there is no evidence that this represents a worsening of the neuropathy. We and others
have observed that pain often subsides after a number
of months [8S), even in poorly controlled patients, although not all agree on this point [10]. If deep burning
pain is worse on standing, elastic stockings may reduce
its severity. Simple analgesics should be tried, but their
success with neuropathic pain is limited. About half of
patients with shooting, stabbing pains will respond to
either phenytoin or carbamazepine given in doses
sufficient to achieve therapeutic anticonvulsant levels.
In contrast, these anticonvulsants do not seem to be of
value for deep, constant, aching pain. Amitriptyline, 25
to 150 mg orally at bedtime, sometimes brings relief.
One should begin with small doses and increase the
dosage slowly, because the therapeutic window for
amitriptyline may be small. Analgesia may appear in
only a few days, preceding the expected time of antidepressant effect. The full dosage should be reached
slowly, to avoid lethargy as well as anticholinergic side
effects, such as urinary retention and impotence, that
are especially likely to occur in a patient with coexisting
autonomic neuropathy. The addition of fluphenazine is
inadvisable because of the risk of inducing tardive
d yskinesias.
Skin care is of great importance for diabetics and
other patients with cutaneous sensory loss. Evidence
from studies of leprosy indicates that neuropathic lesions can heal quickly, and that “trophic” ulcers result
from repeated painless trauma and undetected infection, rather than from loss of any measurable direct
effect of nerve o n skin [lo$)]. Patients with loss o f
distal pain sensitivity should twice daily check their feet
and hands for injuries, and assiduously protect any
break in the skin. Wound healing can be difficult in
diabetics with neuropathy if they have accompanying
large- or small-vessel disease.
Arthropathy can complicate insensitivity of extremities, producing subluxation, degeneration of joint
surfaces, bony resorption, and Charcot joints [SO,
1201. Unlike the Charcot joints seen in syphilis, diabetic neurogenic arthropathy tends to involve the articular surfaces of small joints in the feet. Unusual foot
deformities or the appearance of calluses in new areas
8 Annals of Neurology
Vol 15 No 1 January 1084
should suggest this disorder and indicate the need for
foot roentgenograms or appropriate referral.
Most patients with symmetrical diabetic polyneuropathy have normal strength. Profound generalized weakness suggests long-standing uncontrolled
diabetes, repeated hypoglycemia, or the presence of
another disorder. Simple ankle braces and other
mechanical measures should be considered, as with any
neuromuscular disorder. If weakness is asymmetrical
or lies in the distribution of a major nerve trunk, one
should search for superimposed compression neuropathy (to be discussed).
Autonomic dysfunction is especially difficult to treat.
Disorders of gastrointestinal motility may respond to
metoclopramide or other drugs 142, 122). Orthostatic
hypotension may be relieved by physical measures,
such as use of elastic garments, or by pharmacological
therapy, including administration of fludrocortisone
and vasoactive compounds [ 11I]. Sexual dysfunction is
a common feature of diabetic autonomic neuropathy in
males. It may include erectile incompetence and disorders of ejaculation. Semirigid or inflatable penile prostheses may help in some patients. Many are reassured
to learn that their symptoms are not psychogenic. Sex
therapists are familiar with the problem of neurogenic
impotence and often can provide useful counseling.
Chronic diabetes has not been shown to cause sexual
dysfunction in females [39f.
Symmetrical Proximal Motor Neuropathy
(“Diabetic Amyotrophy”)
Diabetic symmetrical proximal motor neuropathy produces progressive weakness of hip and thigh muscles,
sometimes associated with aching thigh pain. Many patients are middle-aged or older diabetics with type I1
disease who give a history of profound weight loss. The
length of the progressive phase may be weeks or
months, a figure that is difficult to obtain because published reports include early recovery phases as part of
the duration of disability. Proximal sensory loss is unusual, although most affected patients have evidence of
an associated distal sensory-motor polyneuropathy {21,
52, 95, 140). Careful muscle testing may demonstrate
minor asymmetries in the degree of iliopsoas, quadriceps, and other muscle involvement, and anterior
compartment leg muscles may be involved. The pattern may suggest a myopathic disorder, especially when
shoulder girdle muscles are affected [81]. Electromyography and biopsy of affected muscles, however, yield
evidence of denervation and subsequent reinnervation
[48, 67, 1401, and there is no direct evidence of a
primary myopathic disorder.
The nature of diabetic proximal motor neuropathy
remains obscure [31. Clinical and electromyographic
findings could reflect dysfunction of anterior horn cells,
motor roots, the lumbosacral plexus, or intramuscular
nerve twigs C21). Garland’s original view 1461, that the
lesion is in the anterior spinal cord, has not been supported by pathological findings. The overlap with polyneuropathy has led some to suggest that the two disorders are in fact one {631, but this view is not widely
accepted. Both diffuse metabolic and vascular abnormalities have been implicated as the cause. Metabolic
factors do seem to play a role, as indicated by the antecedent weight loss and a frequent history of poor
diabetic control {67). Most affected patients recover to
some degree within 6 to 12 months of improvement in
blood glucose control [20, 46, 67).
Focal and Multifocal Neuropathies
Asymmetrical Pvoximal Motor Neuropatby
Acute mononeuropathy or mononeuropathy multiplex
affecting the femoral nerve or lumbar plexus appears in
long-standing diabetics, often during periods of poor
control C19, 49, 102). The progressive phase is short,
lasting but a few hours or days. Clinically, anterior
thigh and knee pain is prominent, and weakness is most
apparent in the iliopsoas and quadriceps muscles, with
loss of the ipsilateral knee jerk. Detailed examination
may show that obturator-innervated and other muscles
are affected, and the disorder may coexist with distal
sensory-motor polyneuropathy { 191. If the progressive
phase is longer and the contralateral leg is affected, the
syndrome may be indistinguishable clinically from symmetrical proximal motor neuropathy. Neuroradiological studies often are required to exclude a lumbosacral
radiculopathy or plexopathy.
Most patients with asymmetrical proximal mononeuropathy have an initial weeks-long period of rapid
recovery followed by a later, slower period of improvement, lasting many months. This biphasic course
suggests that weakness may result from two components-conduction
block (“neuropraxia”) and axonal
destruction. In one case of asymmetrical proximal
motor neuropathy examined in detail postmortem,
there were multifocal infarctive lesions in the distribution of the lumbar plexus and proximal obturator and
femoral nerve trunks Cl031, supporting an ischemic
basis for this acute disorder.
and possibly facial nerve palsies are thought to occur
with increased frequency in diabetes, and they presumably have the same acute ischemic basis. The prognosis
is good. If the neuropathy does not improve within 3 to
6 months, or if more than one nerve is affected, another cause should be sought.
Intercostal and Other Mononeuroputbies
Ellenberg C38) called attention to the occurrence of
acute thoracic sensory mononeuropathies or radiculopathies in individuals with diabetic polyneuropathy. This disorder can mimic the pain of acute cardiac or intraabdominal medical emergencies [82). The
unilateral nature, acute onset, and good resolution
suggest a vascular basis and distinguishes this entity
from the symmetrical anterior chest sensory loss that
occurs with advanced polyneuropathy C 1361. Other
rare isolated mononeuropathies occur in diabetic individuals, but their incidence may not be higher than in
nondiabetics.
Entrapment Neuropatby
Single and multiple entrapment mononeuropathies,
either clinically evident or demonstrable only electrophysiologically, are frequently associated with diabetic
polyneuropathy C48, 921. In our own series of 38
patients, we found clinical or electrophysiological
evidence of entrapment neuropathy in 15. Diabetic
mononeuropathies occur at the common sites of nerve
compression, including the wrist and palm (median
nerve), the elbow (ulnar nerve), and the fibular head
(peroneal nerve). When of short duration, these entrapment neuropathies appear to respond to accepted
treatment in a manner similar to that found in patients
without polyneuropathy.
Supported in part by grants from the Muscular Dystrophy Association and The Kroc Foundation, and Grant NS-08075 from the National Institutes of Health.
The authors thank Douglas A. Greene, MD, for his helpful suggestions, and Kathy McDevitt for typing the manuscript.
References
Crun ial Neu ropatb.y
Extraocular mononeuropathies are sufficiently common in diabetes mellitus for their occurrence in isolation to suggest diabetes. Oculomotor neuropathy is
most frequent, manifested in painful ophthalmoplegia
of sudden onset with pupillary sparing in a setting of
established or previously unrecognized diabetes. The
basis (of this mononeuropathy appears to be centrofascicular ischemia of the oculomotor nerve 141. The preservation of circumferentially located parasympathetic
fibers explains the pupillary sparing that is usually
found in this syndrome. Acute trochlear, abducens,
1. Albin J , & k i n H : Etiologies of diabetes mellitus. Med Clin
North Am 661209-1226, 1982
2. Appenzeller 0: The Autonomic Nervous System: An Inrroduction to Basic and Clinical Concepts. Amsterdam, Elsevier
Biomedical Press, 1982
3. Asbury A K Proximal diabetic neuropathy. Ann Neurol
2:179-180, 1977
4. Asbury AK, Aldredge H, Hershberg R, Fisher CM:
Oculomotor palsy in diabetes mellitus: a clinico-patholo~gical
study. Brain 93:555-566, 1970
5. Asbury AK, Brown MJ: Clinical and pathological studies of
diabetic neuropathies. In Goto Y ,Horiuchi A, Kogure K (eds):
Diabetic Neuropathy. Amsterdam, Excerpta Medica, 1982, pp
50-57
Neurological Progress: Brown and Asbury: Diabetic Neuropathy
9
6. Asbury AK, Johnson PC: Pathology of Peripheral Nerve. Philadelphia, Saunders, 1978
7. Ballin RHM, Thomas PK: Hypertrophic changes in diabetic
neuropathy. Acta Neuroparhol 1 193-102, I968
8. Behse F, Buchthal F, Carlsen F: Nerve biopsy and conduction
studies in diabetic neuropathy. J Neurol Neurosurg Psychiatry
40:1072-1082, I977
9. Bishoff A: Ultrastructural pathology of peripheral nervous system in early diabetes. In Camerini-Davalos RA, Cole HS (eds):
Vascular and Neurologic Changes in Early Diabetes. New
York, Academic, 1973, pp 441-449
10. Boulton AJM, Drury J, Clarke B, Ward JD: Continuous subcutaneous insulin infusion in the management of painful diabetic neuropathy. Diabetes Care 5386-300, 1982
11. Brimijoin WS: Abnormalities of axonal transport: are they a
cause of peripheral nerve disease! Mayo Clin Proc 57:707714, 1382
12. Brismar T, Sima AAF: Changes in nodal function in nerve
fibers of the spontaneously diabetic BB-Wisrar rat: potential
clamp analysis. Acta Physiol Scand 113:499-506, 1981
13. Brown MJ, Iwamori M, Kishimoto Y , et al: Nerve lipid abnormalities in human diabetic neuropathy: a correlative study. Ann
Neurol 5:245-252, 1979
14. Brown MJ, Martin JR, Asbury AK: Painful diabetic neuropathy: a morphometric study. Arch Neurol 33:164-171, 1976
15. Brown MJ, Sumner AJ, Greene DA, er al: Distal neuropathy
in experimental diabetes mellitus. Ann Neurol 8:168-1 7 8 ,
1980
16. Brown MR, Dyck PJ, McClearn GE, er al: Central and peripheral nervous system complications. Diabetes [Suppi) 3 1 6 %
70, 1982
17. Bruyn GW, Garland H: Neuropathies of endocrine origin. In
Vinken PJ, Bruyn G W (eds): Handbook of Clinical Neurology, Vol 8. Amsterdam, North-Holland, 1970, pp 29-7 1
18. Bunn HF: Evaluation o f glycosylated hemoglobin in diabetic
patients. Diabetes 30:613-617, 1981
19. Calverley JR, Mulder DW: Femoral neuropathy. Neurology
(Minneap) 10963-967, 1960
20. Casey EG, Harrison MJG: Diabetic- amyotrophy: a follow-up
study. Br Med J 1:656-659, 1'972
21. Chokroverty S, Reyes MG, Rubino FA, Tonaki H: The syndrome o f diabetic amyotrophy. Ann Neurol2:181-194, 1977
22. Chopra JS, Fannin T: Pathology o f diabetic neuropathy. J
Pathol 104:175-184, 197 I
23. Chopra JS, Hurwitz LJ: Surd nerve myelinated fiber density
and size in diabetics. J Neurol Neurosurg Psychiatry 32: 149154, 1969
24. Clarke BF, Ewing DJ, Campbell IW: Diabetic autonomic neuropdthy. Diabetologia 17: 195-2 12, 1979
25. Clements RS Jr: Diabetic neuropathy: new concepts of its etiology. Diabetes 28:604-61 I , 1979
26. Clements RS Jr. Vourganti B, Kuba T, et al: Dietary myoinosirol intake and peripheral nerve function in diabetic nerve.
Metabolism 28:477-483, 1970
27. Conomy JP, Barnes KL, Conomy JM: Cutaneous sensory function in diabetes mellitus. J Neurol Neurosurg Psychiatry 42:
656-661, 1979
28. Craighead JE: Viral diabetes in man and experimental animals.
Am J Med 70:127-134, 1981
29. Das PK, Bray GM, Aguayo AJ, Rasminsky M: Diminished
ouabain-sensitive, sodium-potassium ATPase activity in sciatic
nerves of rats with streptozotocin-induced diabetes. Exp
Neurol 53:285-288, 1976
30. DeFronzo RA, Ferrannini E: The parhogenesis of non-insulindependent diabetes: an update. Medicine 61: 125-140, 1982
31. Dobersen MJ, Scharff JE, Ginsberg-Fellner F, Notkins A F
Cytotoxic auroancibodies to beta cells in the serum of patients
10 A n n a l s of N e u r o l o g y
Vol 13 No 1 January 1984
with insulin-dependent diabetes mellirus. N Engl J Med
26:1493-1498, 1980
32. Duncan LJP, MacFarlane A, Robson JS: Diabetic retinopathy
and nephropathy in pancreatic diabetes. Lancer 1:822-826,
1958
33. Dyck PJ, Lambert EH, OBrien PC: Pain in peripheral neuropachy related to rate and kind of fiber degeneration. Neurology
(Minneap) 26:446-47 1, 1976
34. Dyck PJ, OBrien PC, Bushek W, et al: Clinical vs. quantitative
evaluation of cutaneous sensation. Arch Neurol 3365 1-65>,
1976
35. Dyck PJ, Sherman WR, Hallcher LM, et al: Human diabetic
endoneurial sorbitol, fructose, and myo-inositol related to surd
nerve morphomerry. Ann Neurol 8:590-596, 1980
36. Eliasson SG: Nerve conduction changes in experimental diabetes. J Clin Invest 4312353-2358, 1064
37. Ellenberg M: Diabetic neuroparhy precipitated by diabetic control with tolburamide. JAMA 169:1755-1757, I959
38. Ellenberg M: Diabetic truncal mononeuropdthy: a new clinical
syndrome. Diabetes Care 1:10-13, 1978
39. Ellenberg M: Sexual function in diabetic patients, Ann Intern
Med 92331-333, 1980
40. Eng G D , Hung N , August GP: Nerve conduction velocity
determination in juvenile diabetes. Mod Probl Paediatr 12:
213-219, 1975
41. Faerman I, Glocer L, Celener D, et al: Autonomic nervous
system and diabetes: histological and histochemical study of the
autonomic nerve fibers of the urinary bladder i n diabetic patients. Diabetes 22:225-237, 1973
42. Feldman M, Schiller LR: Disorders of gastrointestinal motility
associated with diabetes mellitus. Ann Intern Med 98:378384, 1983
43. Friedman SA, Schulinan RH, Weiss S: Hearing and diabetic
neuropathy. Arch Intern Med 135.573-576, 1975
44. Fry IK, Hardwick C, Scott GW: Diabetic neuropathy: a survey
and follow-up of 66 cases. Guy's Hosp Rep 1 1 1. I 1 3-129,
1962
45. Gabbay KH: The sorbitol pathway and the complications of
diabetes. N Engl J Med 288:831-836, 1973
46. Garland HT: Diabetic amyotrophy. Br Med J 2:1287-1290,
1955
47. Genuth S: Classification and diagnoses of diabetes mellitus.
Med Clin North Am 66:l l9ILl2O7, 1982
48. Gilliatt RW, Willison RG: Peripheral nerve conduction in diabetic neuropathy. J Neurol Neurosurg Psychiatry 25: l l - 18,
1962
49. Goodman JI: Femoral neuropathy in relation to diabetes mellitus: report of 17 cases. Diabetes 3:266-273, 1954
50. Gould RM: Inositol lipid synthesis localized in axons unmyelinared fibers of peripheral nerve. Brain Res 1 17: 169- 174,
1976
51. Graf RJ, Halter JB, Pfeifer MA, et al: Glycemic control and
nerve conduction abnormalities in non-insulin-dependent ciiabetic subjects. Ann Intern Med 94:307-31 I , 1981
52. Greenbaum D: Observations on the homogeneous nature and
parhogenesis of diabetic neuroparhy. Brain 87:2 15-232, I064
53. Greenbaum D , Richardson PC, Salmon MV, Urich H. Pathological observations on six cases of diabetic neuropathy. Brain
87:201-214, 1964
54. Greene DA: Metabolic abnormalities in diabetic peripheral
nerve: relation to impaired function. Metabolism 32(suppl 1)
118-123, 1983
5 5 . Greene DA, Brown MJ, Braunstein SN, et al: Comparison of
clinical course and sequential electrophysiological tests in diabetics with symptomatic polyneuropathy and its implications
for clinical trials. Diabetes 30: 139- 147, 1981
56. Greene DA, DeJesus PV, Winegrad At: Effects of insulin and
dietary myoinositol on impaired peripheral motor nerve conduction velocity in adult streptozotocin diabetes. J Clin Invest
55:1326-1336, 1975
57. Greene DA, h t i m e r SA: Sodium- and energy-dependent uptake of myo-inositol by rabbit peripheral nerve: competitive
inhibition by glucose and lack of an insulin effect. J Clin Invest
70: 1009- 1018, I982
58. Green? DA, Lattimer SA: N d K ATPase defect in diabetic rat
peripheral nerve: correction by myo-inositol administration. J
Clin Invest 72:1058-1063, 1983
59. Greene DA, Lewis RA, Lattimer SA, Brown MJ: Selective
effects of myoinositol administration on sciatic and tibia1 motor
nerve conduction parameters in the streptozotocin-diabetic rat.
Diabetes 31:573-578, 1982
60. Greene DA, Winegrad AI: Effects of acute experimental diabetes on composite energy metabolism in peripheral nerve axons and Schwann cells. Diabetes 30967-974, 198 1
61. Gregerson G: A study of the peripheral nerves in diabetic
subjects during ischemia. J Neurol Neurosurg Psychiatry
31:175-181, 1968
62. Gregerson G: Variations in motor conduction velocity produced by acute changes of the metabolic state in diabetic patients. Diabetologia 4:273-277, 1968
63. Gregerson G: Diabetic amyotrophy: a well defined syndrome?
Acta Med Scand 185:103-310, 1969
64.Gregerson G: Oral supplementation of myoinositol effects on
peripheral nerve function in human diabetics and on the concentration in plasma, erythrocytes, urine and muscle tissue in
human diabetics and normals. Acra Neurol Scand 67:164-172,
1983
65. Gupta PR, Dorfman LJ: Spinal somatosensory conduction in
diabetes. Neurology ( N Y ) 312341-845, 1981
66. Gupta PR, Puri VK, Sircar AR, Tandon N N : Serum spinal
fluid and neural total lipids, phospholipids and cholesterol in
diabetes mellitus and non-diabetic neuropathy. J Assoc Physicians India 20:361-365, 1972
67. Hamilton CR, Dobson HL, Marshall J: Diabetic amyotrophy:
clinical and electronmicroscopic studies of six patients. Am J
Mecl Sci 256:81-90, 1968
68. Hansen S, Ballantyne JP: Axonal dysfunction in the neuroparhy of diabetes mellitus: a quantitative electrophysiologicd
study. J Neurol Neurosurg Psychiatry 403555-564, 1977
69.Hilsted J: Pathophysiology in diabetic autonomic neuropathy:
cardiovascular, hormonal, and metabolic studies. Diabetes
31:730-’37, 1982
70. Horowitz SH, Ginsberg-Fellner F: Ischemia and sensory nerve
conduction in diabetes mellitus. Neurology ( N Y ) 29:695-704,
1979
71. Jakobsen J: Axonal dwindling in early experimental diabetes. I.
A study ofcross sectioned nerves. Diabetologia 12:539-546,1976
7 2 . Jaspan JB, Wollman RL, Bernstein L, Rubenstein AH: Hypoglycemic peripheral neuropathy in association with insulinoma:
implication of glucopenia rather than hyperinsulinism. M e d cine 61:33-44,1982
73. Johnson PC, Brendel K, Meezan E: Human diabetic perineurial cell basement membrane thickening. Lab Invest 44:265270, 1981
74. Judzewitsch RG, Jaspan JB, Polonsky KS, et al: Aldose reduccase inhibition improves nerve conduction velocity in diabetic
patients. N Engl J Med 308:l 19-125, 1983
75. Kennedy WR, Sakuta M: Swrat gland dysfunction in diabetic
neuropathy (abstract). Ann Neurol 12:106, 1982
76. Kimura J, Yamada T, Stevland NP: Distal slowing of motor
nerve conduction velocity in diabetic polyneuropathy. J Neurol
Sci 42:291-302, 197‘9
77. Lacy PE, Davie JM, Finke EH: Transplantation of insulinproducing tissue. Medicine 70:589-594, 1981
78. Lamonragne A, Buchthal F: Electrophysiological studies in diabetic neuropathy. J Neurol Neurosurg Psychiatry 33:442-452,
1970
79. Lawrence DG, Locke S: Neuropathy in children with diabetes
mellitus. Br Med J 1:784-786, 1963
80. Lippmann HI, Perotto A, Farrar R: The neuropathic foot of the
diabetic. Bull N Y Acad Med 52:1150-1178, 1976
81. Locke S, Lawrence DG, Legg MA: Diabetic ,amyotrophy. Am J
Med 34:775-785, 1963
82. Longstreth GF, Newcomer AD: Abdominal pain caused by
diabetic radicdopathy. Ann Intern Med 86:166-168, 1977
83. Low PA, Walsh JC, Huang CY, McLeod JG: The sympathetic
nervous system in diabetic neuropathy: a clinical and pathological study. Brain 98:341-356, 1975
84. Mandersloot JG, Roelofsen B, DeGrier J: Phosphatidyliiiositol
as the endogenous activator of the (Na’ + K )-ATPase in
microsomes of rabbit kidney. Biochim Biophys Acra 508:478485, 1978
85. Martin MM: Diabetic neuropathy: a clinical study of 150 cases.
Brain 76594-624, 1953
86. Mayer J H , Tomlinson DR: The influence of aldose reductase
inhibition and nerve myo-inositol on axonal transport and nerve
conduction velocity in rats with experimental diabetes. J Physiol (Lond) 340:25p-Z6p, 1983
87. Mayhew JA, Gillon KRW, Hawthorne J N : Free and lipid
inositol, sorbitol and sugars in sciatic nerve obtained postmortem from diabetic patients and control subjects. Diabetologia 24: 13-1 5 , 1983
88. Mayne N : The short-term prognosis in diabetic neuropathy.
Diabetes 17:270-273, 1068
89. Mecklenburg RS, Benson JW Jr, Becker NM, et al: Clinical use
of the insulin infusion pump in 100 patients with type I diabetes. N Engl J Med 307:513-518, 1982
90. Mordes JP, Rossini AA: Animal models of diabetes. Am J
Med 70:353-360, I981
91. Mulder DW, Bastron JA, Lamberr EH: Hyperinsulin neuropathy. Neurology (Minneap) 6:627-635, 1036
92. Mulder DW, Lamberr EH, Bastron JA, Sprague RG: The
neuropathies associated with diabetes: a clinical and electromyographic study of 103 unselected diabetic patients. Neurology (Minneap) 11:275-284, 1961
93. Nathan PW: The gate-control theory of pain: a critical review.
Brain 50123-158, 1976
94. National Diabetes Data Group: Classification and diagnosis of
diabetes mellitus and other categories of glucose intolerance.
Diabetes 28: 1039- 1057, 1979
95. Noel P: Sensory nerve conduction in the upper limbs at various
stages of diabetic neuropathy. J Neurol Neurosurg Psychiatry
36.786-796, 1973
96. Osuntokun BO: The neurology of non-alcoholic pancreatic diabetes mellitus in Nigerians. J Neurol Sci 11:17-43, 1970
97. Page M McB, Watkins PJ: Cardiorespiratory arrest and diabetic
autonomic neuropathy. Lancet 1:14-16, 1978
98. Parry GJ, Brown MJ: Selective fiber vulnerability in acute ischemic neuropathy. Ann Neurol 11:147-154, 1982
99. Pfeifer MA, Cook D. Urodsky J, et a]: Quantitative evaluarion
of cardiac parasympathetic activity in normal and diabetic man.
Diabetes 31:339-345, 1982
100. Pirart J: Diabetes mellitus and its degenerative complications. a
prospective study of 4,400parients observed benveen 194’
and 1973. Diabetes Care 1:168-188, 252-263, 1978
101. Powell H , Knox D, Lee S, et al: Alloxan diabetic neuropathy
electron microscopic studies. Neurology (Minneap)27:60-66,
1977
102. Raff MC, Asbury AK: Ischemic mononeuropathy and mononeuropathy multiplex in diabetes mellitus. N Engl J Med
279:17-22, 1968
+
Neurological Progress: Brown and Asbury: Diabetic Neuropathy
11
103. Raff MC, Sangalang V, Asbury A K
Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch
Neurol 18:487-499, 1968
104. Reaven GM: Insulin-independent diabetes mellitus: metabolic
characteristics. Metabolism 29445-454, 1980
105. Reske-Nielsen E. Harmsen A, Vorre P Ultrastructure o f muscle biopsies in recent, short-term and long-term juvenile diabetes. Acta Neurol Scand 55:345-162, 1977
106. Rizza RA, Gerich JE, Haymond MW, et al: Control of blood
sugar in insulin-dependent diabetes: comparison of an artificial
endocrine pancreas, continuous subcutaneous insulin infusion,
and intensified conventional insulin therapy. N Engl J MeJ
303:1313-1318, 1980
107. Roelofsen B: The cnon)specihcity in the lipid-requirement
of the calcium- and (sodium plus potassium)-transporting
adenosine triphosphatase. Life Sci 292235-2247, 1981
108. Rossini AA: linmunotherapy for insulin-dependent diabetics?
N Engl J Med 308:333-335, 1983
109. Sabin TD: Lessons from leprosy. Am J Occup Ther 33:473478, I903
110. Sabin TD, Geschwind N , Waxman SG: Patterns of clinical
deficits in peripheral nerve disease. In Waxman SG (ed): Physiology and Pathobiology of Axons. New York, Raven, 1978, pp
431-438
11 1. Schatz IJ: Current management concepts in orthostatic hypotension. Arch Intern Med 140:1152-1154, 1980
112. Schmidt RE, Matschinsky FM, Godfrey DA, et al: Fast and
slow axoplasmic flow in sciatic nerve of diabetic rats. Diabetes
24: 1081-1085, 1?75
113. Schwartz DE: Corneal sensitivity in diabetics. Arch Ophthalmol 91:1?4-1-78, 1974
114. Service FJ, Daube JR, O'Brien PC, et al: Effect of blood glucose control on peripheral nerve function in diabetic patients.
Mayo Clin Proc 58:283-298, 1?83
115. Sharma AK, Thomas PK, DeMolina AF: Peripheral nerve fiber
size in experimental diabetes. Diabetes 26689-692, 1977
116. Sidenius P: The axonopathy of diabetic neuropathy. Diabetes
31:156-363, 1982
117. Sidenius P, Jakobsen J: Peripheral neuropathy in rats induced
by insulin treatment. Diabetes 22:383-386, 1983
118. Sima AAF: Peripheral neuropathy in the spontaneously diabetic BB-Wistar rat: an ultrastructura~study. Acta Neuropathol
5 1.223-227, 1980
119. Simmons DA, Winegrad AI, Martin DB: Significance of tissue
myo-inositol concentrations in metabolic regulation in nerve.
Science 217:848-851, 1982
120. Sinha S, Munichoodappa CS, Kozack GP: Neuroarthropathy
(Charcot joints) in diabetes mellitus: clinical study o f 101 CdSCS.
Medicine 51:191-210, 1972
121. Smith SE, Smith SA, Brown PM, et al: Pupillary signs in diabetic autonomic neuropathy. Br Med J 2:924-927, 1978
122. Snape WJ, Battle WM, Schwarrz SS, et al: Metoclopramide to
treat gastroparesis due to diabetes mellitus: a double-blind,
controlled trial. Ann Intern Med 96:444-446, I982
123. Spencer PS, Schaumburg HH: Central-peripheral distal axonopathy: the pathology of dying-back polyneuropathies. Prog
Neuropathol 3953-295, 1976
124. Spritz N, Singh 14, Marinan B: Metabolism of peripheral nerve
12 Annals of Neurology
Vol 15 No 1 January 1984
myelin in experimental diabetes. J Clin Invest 55: 1049- 1056,
1975
125. Sugimura K, Dyck PJ: Sural nerve myelin thickness and axis
cylinder caliber in human diabetes. Neurology ( N Y ) 3 1-1087-1091, 1981
126. Sugimura K, Dyck PJ: Multifocal fiber loss in proximal sciatic
nerve in symmetrical distal diabetic neuropathy. J Neurol Sci
5 3:50 1-509, 1982
127. Thomas PK: Diabetic neuropathy. I n Keen H, Jarrett J (eds):
Complications of Diabetes. London, Edward Arnold, 1982, pp
109-136
128. Thomas PK, Eliilsson SG: Diabetic neuropathy. In Dyck PJ,
Thomas PK, Lambert E H (eds): Peripheral Neuropathy. Philadelphia, Saunders, 1075, pp 956-981
129. Thomas PK, Lascelles RG: The pathology of diabetic neuropathy. Q J Med 35:489-509, lY66
130. Timperley WR, Ward JD, Preston FE, et al: Clinical and histological studies in diahetic neuropathy: a reassessment of vascular factors in relation to intravascular coagulation. Diabetologia
12:237-243, 1976
131. Vital C, Vallat JM: Ultrastructural Study of the Human Diseased Peripheral Nerve. New York, Masson, 1980, pp 76-80
132. Vital CI, Vallat JM. LeBlanc M, et al. Les neuropdthies
peripheriques du diabete sucre: etude ultrastructurale de 12cas biopsies. J Neurol Sci 18:381-3?8, lO73
133. Vlassara H , Brownlee M, Cerami A: Nonenzymatic glyrosylation of peripheral nerve protein in diabetes mellitus. Proc Natl
Acad Sci USA 78:5190-5192, 1981
134. Wall PD, Gutnick M: Properties o f afferent nerve impulses
originating from a neuroma. Nature 248:740-743, 1974
135. Ward JD, Barnes CG, Fisher DJ, et al: Improvement in nerve
conduction following treatment i n newly diagnosed diabetes.
Lancet 1:428-430, 1971
136. Waxman SG: Diabetic radiculoneuropathy: clinical patterns of
sensory loss and distal paresthesias. Actd Diabetol Lat 10: 109207, 1982
137. Waxman SG, Brill MH, Geschwind N , et al: Probability of
conduction deficit as related to fiber length in ran~loindistribution models of peripheral ncuroparhies. J NeuroL Sci
2?:39-53, 1976
138. Wheeler DD: Amino acid transport in peripheral nerve:
specificity of uptake. J Neurochem 2497-104, 1975
139. Williams E, Timperley WR, Ward J D , Duckworth T: Electron
microscopical studies of vessels in diabetic peripheral neuropathy. J Clin Pathol 31:462-470, 1980
140. Williams IR, Mayer RF: Subacute proximal diabetic neuropathy. Neurology (Minneap) 26: 108-1 16, 1976
141. Winegrad AI, Morrison AD: Diabetic ketoacidosis, nonketotic
hyperosmolar coma and Lactic acidosis. In IXGrout LJ, Cahill
G F Jr. Martini L, et al (eds): Endocrinology, Vol2. New York,
Grune & Stratton, 1979, pp 1025-1040
142. Yagihashi S, Kudo K, Nishihira M: Peripheral nerve structures
of experimental diabetes rats and the effcct of insulin treatment. Tohoku J Exp Med 127:35-44, lY79
143. Yoon J-W, Austin M, Onodera T. Notkins AL. Virus-induced
diabetes mellitus: isolation of a virus from the pancreas of a
child with diabetic ketoacidosis. N Engl .J Med 300: I 1731179, 1979
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